Silicon-containing ionizable cationic lipids

Abstract

The present invention relates to a novel family of silicon-containing ionizable cationic lipids, which belong to the first generation of lipids under the trademark LipexSil TM to date, and are effective as ionizable cationic lipids in the formulation of empty or loaded lipid nanoparticles (LNP). The novel linker according to the present invention was designed through a borane catalyst [WO2022 / 129966]. The present invention describes the synthesis of lipids of formula (I), the formation and characterization of nanoparticles and biological experiments show that lipid nanoparticles prepared with these novel lipids are able to efficiently deliver their cargo (e.g. RNA, DNA, mRNA, siRNA, pDNA, circular DNA, biologically active small molecules) into cells.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine and drug delivery.

[0002] This invention relates to a novel family of silicon-containing ionizable cationic lipids, which belongs to the trademark LipexSil. TM The first-generation lipids contain at least one of their two side chains containing a silyl acetal linker. Lipids containing silyl acetal linkers are unprecedented in the art to date and are effective as ionizable cationic lipids in formulations of empty or loaded lipid nanoparticles (LNPs). The novel linker according to the invention is designed using a borane catalyst [WO2022 / 129966]. This invention describes the synthesis of lipids of formula (I), the formation and characterization of nanoparticles, and biological experiments demonstrating that lipid nanoparticles prepared from these novel lipids can efficiently deliver their cargo (e.g., RNA, DNA, mRNA, siRNA, pDNA, circular DNA, bioactive small molecules) into cells. Background Technology

[0003] In biological systems, numerous challenges exist related to transfecting nucleic acid reagents (e.g., messenger RNA, antisense oligonucleotides, ribozymes, plasmids) and small molecules to elicit desired responses. There is a need to design and synthesize novel second-generation lipids (biodegradable, ionizable amine lipids) to improve the delivery of bioactive agents (e.g., DNA, RNA, mRNA, and various small molecules) into cells. In the medical field, these therapies are most effective, selectively and directly targeting affected cells or tissues with appropriate active agents. Given this, therapeutic efficiency should be improved, and undesirable toxic side effects should be avoided or reduced. Lipid-loaded nanoparticles (LNPs) containing lipid components have proven to be effective carrier systems, capable of being functionalized to protect and deliver the payload to the target site. It is worth emphasizing that LNPs formed from ionizable cationic lipids have also demonstrated excellent lipid carriers in gene therapy.

[0004] LNPs also contain synthetic lipids that can be toxic to human cells, and the cytotoxicity of synthetic lipids depends on certain motifs (e.g., headgroups, linker types) in the lipids that are associated with their biodegradability and metabolic pathways in the human body.

[0005] LNPs possess several key parameters that play a crucial role in successful drug delivery applications, such as particle size, polydispersity index (PDI), zeta potential, and apparent pKa. According to literature data, the average particle size of LNPs typically ranges from 100 to 400 nm, accompanied by a narrow particle size distribution, <0.2 PDI (Advanced NanoBiomed Research, 2022, 2, 2100109). The optimal apparent pKa for LNPs is between 6 and 7 (Trends in Pharmacological Sciences, 2021, 42: 6, 448-460).

[0006] In this field, few examples have been found demonstrating that silicon atoms in lipids are also suitable components of LNPs [WO2011134675, WO 2021055835], which are effective in delivering DNA, RNA, siRNA, and nucleotides. Silicon is a carbon-electron isostere in drug research, and the introduction of silicon atoms can provide innovative solutions to medicinal chemistry problems. Silicon atoms in lipids can enhance lipophilicity, thereby improving membrane permeability. However, as gene therapy becomes part of routine treatments in the next decade, the need for efficient, biodegradable, and less toxic delivery platforms continues to grow. Detailed Implementation

[0007] This invention provides a series of novel silicon-containing lipids having the structure of formula (I), details of the synthesis method, details of the formation and characterization of LNPs, and toxicity and transfection experiments of loaded LNPs.

[0008] In one embodiment, the present invention provides an ionizable cationic lipid of formula (I) or a salt or stereoisomer thereof.

[0009]

[0010] in:

[0011] G 1 It is an unsubstituted C2-C9 alkylene group.

[0012] -(CH2) x -CH = CH-(CH2) y -, where x is an integer selected from 1 to 6, y is an integer selected from 1 to 6, and the sum of x + y is an integer selected from 2 to 7, or

[0013] -(CH2) w -X-(CH2) z-, where w is an integer selected from 1 to 7, z is an integer selected from 2 to 7, and the sum of w+z is an integer selected from 3 to 8, where -(CH2) z - Attached to N, and X is selected from O, S, SO and SO2;

[0014] T 1 for

[0015]

[0016] in

[0017] b 1 For G 1 The key,

[0018] X1 and X2 can be the same or different, and each can independently represent O or S.

[0019] R1 is a linear C1-C 17 Alkyl, nonlinear C3-C 17 Alkyl group, optionally containing one of S, SO, SO2, O or Si(R) in both cases. a )2, where R a A C1-C6 alkyl group located at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; or a C3-C6 alkyl group containing a double bond. 17 Alkenyl group, provided that at least one -CH2- group exists between the double bond and X2; or polyunsaturated C8-C 20 Alkenyl, provided that at least one -CH2- group exists between the first double bond and X2, or

[0020] R1 is

[0021]

[0022] Among them, R 17 R 18 and R 19 They can be the same or different, and each can independently be H, OH, -C1-C6 alkoxy or fluorine;

[0023] R2 is

[0024] Linear C1-C 17 Alkyl, nonlinear C3-C 17 Alkyl group, in both cases optionally containing one of S, SO, SO2, O or Si(R) b )2, where R b A C1-C6 alkyl group located at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; or a C3-C6 alkyl group containing a double bond. 17Alkenyl group, provided that there is at least one -CH2- group between the double bond and the carbons connecting X1 and X2; or polyunsaturated C8-C 20 Alkenyl, provided that at least one -CH2- group exists between the first double bond and the carbons connecting X1 and X2, or

[0025] R2 is

[0026] Among them, R 20 R 21 and R 22 They can be the same or different, and each can independently be H, OH, -C1-C6 alkoxy, or fluorine.

[0027] The condition is that R1 and R2 cannot exist at the same time;

[0028]

[0029] R1 is attached to R3 via an alkylene or monounsaturated alkenyl group, forming a C5-C group. 30 -Meta-ring, or

[0030] R2 is attached to R3 via an alkylene or monounsaturated alkenyl group to form a C5-C group. 30 A ring in which the carbon atom at the first or second position of R2 can optionally be replaced by an O or S heteroatom, the first or second position being numbered starting from the carbon atom attached to the carbon atom connecting X1 and X2, or

[0031] R2 is attached to R1 via an alkylene or monounsaturated alkenyl group, forming a C5-C... 30 A ring in which the carbon atom at a first or second position of R2 can optionally be replaced by an O or S heteroatom, the first or second position being derived from the carbon atom attached to the linking carbon atoms X1 and X2.

[0032] Carbon atoms begin to be numbered;

[0033] R3 is

[0034]

[0035] R5-b 1 for

[0036]

[0037] in

[0038] b 2 For the link (chain) to X1,

[0039] Y1 is -O-, -CH2-, or -O-CH2-CH2-, where -CH2- is attached to Si.

[0040] Each X3 is independently selected from the group consisting of C1-C4 alkyl or C1-C4 alkoxy groups.

[0041] R4 is a linear C2-C 17 Alkyl or nonlinear C3-C 17 Alkyl group, optionally containing one of S, SO, SO2, O or Si(R) in both cases. c )2, where R c A C1-C6 alkyl group located at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; or a C3-C6 alkyl group containing a double bond. 20 Alkenyl group, provided that at least one -CH2- group exists between the double bond and Y1; or polyunsaturated C8-C 20 Alkenyl, provided that at least one -CH2- group exists between the first double bond and Y1, or,

[0042] R4 is

[0043]

[0044] Where b 3 It is the key to Y1.

[0045] R6, R7, and R8 may be the same or different, and each can independently be H, OH, -C1-C6 alkoxy or fluorine;

[0046] D 1 Choose from the following groups

[0047] as well as

[0048] in

[0049] b 4 For nitrogen,

[0050] R9 can be C1-C6 alkyl, cyclopentyl, cyclohexyl, hydroxy, hydroxymethyl, hydroxyethyl, phenyl, benzyl, 4-hydroxybenzyl,

[0051]

[0052] R 10 and R 11 Independently selected from H and C1-C6 alkyl groups,

[0053] m is an integer selected from 1 to 6.

[0054] n is an integer selected from 0 to 6.

[0055] o is an integer selected from 0 to 6.

[0056] p is an integer selected from 2 to 6.

[0057] q is an integer selected from 0 to 6.

[0058] j is an integer selected from 1 to 4.

[0059] Cy1 is a C3-C6 cycloalkyl group optionally substituted with one or more -OH groups, or

[0060] Cy1 is a pyranose or furanose ring that can be linked by any of its OH groups, wherein the pyranose or furanose ring is optionally substituted with a -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine, a monosaccharide, or an oligosaccharide, or substituted with a 4-, 5-, 6-, or 7-membered heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S; or

[0061] Cy1 is a 4-, 5-, 6-, or 7-membered heterocycle containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, wherein the heterocycle is optionally separated by R. 12 replace,

[0062] in

[0063] R 12 The term represents a C1-C6 alkyl group, a peptide-containing arginine ring, a pyranose or furanose ring, wherein the pyranose or furanose ring is attached to a 4-, 5-, 6-, or 7-membered heterocycle via any one of its ring carbon atoms, wherein the pyranose or furanose ring is optionally substituted with an -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine, or a monosaccharide or oligosaccharide.

[0064] R 12 It can be a group selected from (d), (e) or (f), wherein b 4 For heterocyclic bonds, m, n, o, p, R9, R 10 and R 11 As defined above, or

[0065] R 12 Able to provide A group, wherein r is an integer selected from 1 to 4, and Cy2 is a 4-, 5-, 6-, or 7-membered heterocycle containing 1, 2, 3, or 4 heteroatoms selected from O, N, and S, the heterocycle optionally being substituted with a C1-C6 alkyl group;

[0066] P is selected from

[0067] (i)G 2 -T 2

[0068] in

[0069] G 2 As mentioned above, G 1 Define, where G 1 and G 2 They can be the same or different;

[0070] T 2 As mentioned above, T 1 Definition, b 1 For G 2 The key, and where T 1 and T 2 They can be the same or different; or

[0071] (ii)G 2 -T 3

[0072] in

[0073] G 2 As defined above;

[0074] T 3 for

[0075] in

[0076] b 5 For G 2 The key,

[0077] X4 and X5 can be the same or different, and each can be O, S, or NR independently. d , where R d It is H, C1-C6 alkyl, -OH or C1-C6 alkoxy.

[0078] R 13 For linear C2-C 17 Alkyl, nonlinear C3-C 17 Alkyl groups, both optionally containing S, SO, SO2, O, Si(R) e One of )2, where R e A C1-C6 alkyl group located at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; or a C3-C6 alkyl group containing a double bond. 20 Alkenyl, provided that at least one -CH2- group exists between the double bond and X5; or polyunsaturated C8-C20 alkenyl, provided that at least one -CH2- group exists between the first double bond and X5, or

[0079] R 13 for

[0080] Among them, R 23 R24 R 25 They can be the same or different and each can independently be H, OH, -C1-C6 alkoxy, or fluorine.

[0081] R 14 For linear C2-C 17 Alkyl, nonlinear C3-C 17 Alkyl groups, both optionally containing S, SO, SO2, O, Si(R) f One of )2, where R f A C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; or a C3-C6 alkyl group containing a double bond. 20 Alkenyl group, provided that at least one -CH2- group exists between the double bond and the carbons connecting X4 and X5; or polyunsaturated C8-C 20 Alkenyl, provided that at least one -CH2- exists between the first double bond and the carbons connecting X4 and X5, or

[0082] R 14 for

[0083] Among them, R 26 R 27 R 28 They can be the same or different and each independently can be H, OH, -C1-C6 alkoxy or fluorine, and (iii)T 4 ,in

[0084] T 4 for

[0085]

[0086] Among them, b 6 For the bond to the nitrogen atom, R 29 R 30 R 31 They can be the same or different, and each can independently be H, OH, -C1-C6 alkoxy or fluorine;

[0087] C4-C containing a double bond 20 Alkenyl group, provided that at least one -CH2- exists between the double bond and N, or

[0088] Polyunsaturated C8-C 20 Alkenyl group, provided that at least one -CH2- exists between the first double bond and N.

[0089] Unsubstituted C2-C9 alkylene compounds refer to ethylene (-(CH2)2-), propylene (-(CH2)3-), butene (-(CH2)4-), pentene (-(CH2)5-), hexene (-(CH2)6-), heptenene (-(CH2)7-), octene (-(CH2)8-), or nonene (-(CH2)9-).

[0090] Linear C1-C 17 Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, or heptadecyl.

[0091] Nonlinear C3-C 17 Alkyl refers to a saturated branched alkyl group containing 3 to 17 carbon atoms, such as isopropyl, isobutyl, 3-methylpentyl, 2-propylpentyl, 2-methylhexyl, 2-ethylhexyl, 2-ethyldecyl, 2-propyldecyl, 2-butyldecyl, 2-pentyldecyl, 2-hexyldecyl, or 2-heptyldecyl.

[0092] C1-C6 alkyl groups refer to linear or nonlinear alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, tert-butyl, neopentyl, isopentyl, neohexyl or isohexyl, preferably methyl or ethyl.

[0093] C1-C4 alkyl groups refer to linear or nonlinear alkyl groups containing 1 to 4 carbon atoms, preferably methyl.

[0094] Linear C1-C 17 Alkyl or nonlinear C3-C 17 Both alkyl groups contain an S, SO, SO2, O, or Si(R)2, where R is at any position in the carbon chain as defined above for C1-C6 alkyl groups, provided that the heteroatom is not at the α or Ω position in the carbon chain, and the alkyl group is linear C1-C6. 17 Alkyl or nonlinear C3-C 17 Alkyl is as defined above, wherein a -CH2- at the terminal position of the alkyl chain, not on either side of the chain, is replaced by one of the following groups: -O-, -S-, -SO-, SO2-, -Si(R)2-.

[0095] C3-C containing a double bond 17 Alkenyl or C3-C containing a double bond 20Alkenyl means a linear or nonlinear alkyl group as defined above, comprising 3 to 17 or 3 to 20 carbon atoms, and containing a double bond in the chain, for example, hex-3-en-1-yl, oct-3-en-1-yl, dec-3-en-1-yl, dec-2-en-1-yl, undec-3-en-2-yl, preferably hex-3-en-1-yl or oct-3-en-1-yl.

[0096] C1-C6 alkoxy means -O-C1-C6 alkyl group, where C1-C6 alkyl group is as defined above.

[0097] C1-C4 alkoxy means -O-C1-C4 alkyl group, wherein the C1-C4 alkyl group is as defined above, such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, sec-butoxy or tert-butoxy.

[0098] C5-C is formed by attaching an alkylene or monounsaturated alkenyl group to R3. 30 R1 in a metacycle means, for example:

[0099]

[0100] C5-C is formed by attaching an alkylene or monounsaturated alkenyl group to R3. 30 R2 of the ring, wherein the carbon atom at the first or second position of R2 can optionally be replaced by an O or S heteroatom, the first or second position being numbered starting from the carbon atom attached to the carbon atom connecting X1 and X2, R2 signifying, for example:

[0101]

[0102] C5-C is formed by attaching an alkylene or monounsaturated alkenyl group to R1. 30 R2 of the ring, wherein the carbon atom at the first or second position of R2 can optionally be replaced by an O or S heteroatom, the first or second position being numbered starting from the carbon atom attached to the carbon atom connecting X1 and X2, R2 signifying, for example:

[0103]

[0104] Polyunsaturated C8-C 20 Alkenyl refers to a linear alkyl chain containing 8 to 20 carbon atoms, wherein the chain contains more than one isolated double bond, preferably a group derived from Ω-3 and Ω-6 fatty acids, such as T. 4 R1 or R 13 One of the following groups:

[0105]

[0106] and R2 or R 14One of the following groups:

[0107]

[0108] The group is linked via b.

[0109] C3-C6 cycloalkyl means, for example, cyclopropyl, cyclopentyl, or cyclohexyl.

[0110] A 4-, 5-, 6-, or 7-membered heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S refers to an aromatic ring or an unsaturated, partially saturated, or fully saturated heterocycle, such as aziridine, aziridine, pyrrolidine, oxazolidine, piperidine, piperazine, morpholine, pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazolium, pyridine, pyrimidine, pyridazine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetraazine, oxazole, isoxazole, thiazole, isothiazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, aziridine, heptane. Alkane, azepine, 1,2-diazacycloheptane, 1,3-diazacycloheptane, 1,4-diazacycloheptane, 1,2-diazacycloheptane, 1,3-diazacycloheptane, 1,4-diazacycloheptane, 1,2-oxazazepine, 1,3-oxazazepine, 1,4-oxazazepine, 1,2-oxazazepine, 1,3-oxazazepine, 1,4-oxazazepine, 1,2-thioazazepine, 1,3-thioazazepine, 1,4-thioazazepine, 1,2-thioazazepine, 1,3-thioazazepine or 1,4-thioazazepine ring, preferably pyrrolidine, imidazole, 1,2,3-triazole, piperidine, piperazine or morpholine.

[0111] Furanoses refer to all stereoisomers of furanose, deoxyfuranose, xylfuranose, fructose, glucose, galactose, mannose, allofuranose, arabinose, or altrofuranose, which can also be protected by groups such as acetyl, benzyl, benzoyl, isopropylidene, or benzenemethyl. For example, 2,3,5,6-tetra-O-acetyl-galactose.

[0112] Pyranoses refer to all stereoisomers of pyranose glucose, galactopyranose, mannopyranose, argenopyranose, fructopyranose, arabinopyranose, or argenopyranose, which can also be protected by groups such as acetyl, benzyl, benzoyl, isopropylidene, or benzenemethyl. For example, 2,3,4,6-tetra-O-acetyl-glucose pyranose.

[0113] Monosaccharides and oligosaccharides refer to monosaccharides as defined above, and also to oligosaccharides, such as sucrose, lactose, maltose, isomaltose, cellobiose, and trehalose.

[0114] A peptide containing arginine refers to a peptide of 6 amino acids or fewer that includes at least one arginine residue. Peptides are linked by their C-terminus or N-terminus.

[0115] Salts of formula (I) refer to salts of formula (I) with inorganic or organic acids. Preferred salts are salts of pharmaceutically acceptable acids. These salts are, for example, chlorides, sulfates, phosphates, formates, acetates, fumarates, maleates, oxalates, citrates, or tartrates. Salts formed during purification or separation are also the subject of this invention.

[0116] Stereoisomers refer to optical and geometric isomers. Compounds of formula (I) may contain one or more asymmetric carbon atoms, and therefore can exist as optical isomers, enantiomers, or diastereomers. Compounds of formula (I) may contain double bonds, and the groups attached to the double bonds may have different (cis or trans) structures, such as cis or trans fatty acid moieties.

[0117] The specific group of compounds of formula (I) is where

[0118] G 1 It is an unsubstituted C2-C9 alkylene group.

[0119] -(CH2) x -CH = CH-(CH2) y -, where x is an integer selected from 1 to 6, y is an integer selected from 1 to 6, and the sum of x + y is an integer selected from 2 to 7, or

[0120] -(CH2) w -X-(CH2) z -, where w is an integer selected from 1 to 7, z is an integer selected from 2 to 7, and the sum of w+z is an integer selected from 3 to 8, where -(CH2) z - Attached to N, and X is selected from O, S, SO and SO2;

[0121] T 1 for

[0122] b 1 For G 1 The key,

[0123] X1 and X2 can be the same or different, and each can independently represent O or S.

[0124] R1 is a linear C2-C 17 Alkyl, nonlinear C3-C17 Alkyl groups, in both cases optionally containing an S, SO, SO2, O, or Si(R) moiety. a )2, where Ra is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not at the α or Ω position of the carbon chain; C3-C containing a double bond 17 Alkenyl groups are defined as having at least one -CH2- group between the double bond and X2; or polyunsaturated C8-C... 20 Alkenyl group, provided that at least one -CH2- group exists between the first double bond and X2.

[0125] R² is linear C²-C² 17 Alkyl, nonlinear C3-C 17 Alkyl group, in both cases optionally containing one of S, SO, SO2, O or Si(R) b )2, where R b A C1-C6 alkyl group located at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; or a C3-C group containing a double bond. 17 Alkenyl group, provided that at least one -CH2- group exists between the double bond and the carbons connecting X1 and X2; or a polyunsaturated C8-C group. 20 Alkenyl, provided that at least one -CH2- group exists between the first double bond and the carbons connecting X1 and X2.

[0126] R3 is

[0127] R5-b 1 for in

[0128] b 2 For the link to X1,

[0129] Y1 is -O-, -CH2-, or -O-CH2-CH2-, where -CH2- is attached to Si.

[0130] Each X3 is independently selected from the group consisting of C1-C4 alkyl or C1-C4 alkoxy groups.

[0131] R4 is a linear C2-C 17 Alkyl, or nonlinear C3-C 17 Alkyl group, optionally containing one of S, SO, SO2, O or Si(R) in both cases. c )2, where R c A C1-C6 alkyl group located at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; or a C3-C6 alkyl group containing a double bond. 20 Alkenyl group, provided that at least one -CH2- group exists between the double bond and Y1; or polyunsaturated C8-C20 Alkenyl, provided that at least one -CH2- group exists between the first double bond and Y1, or,

[0132] R4 is

[0133] Where b 3 For the bond to Y1, R6, R7, and R8 can be the same or different, and each can independently be H, OH, -C1-C6 alkoxy, or fluorine;

[0134] D 1 Choose from the following groups

[0135] as well as in

[0136] b 4 For nitrogen,

[0137] R9 can be a C1-C6 alkyl, hydroxy, or hydroxymethyl group.

[0138] m is an integer selected from 1 to 6.

[0139] n is an integer selected from 0 to 6.

[0140] o is an integer selected from 0 to 6.

[0141] p is an integer selected from 2 to 6.

[0142] R 10 and R 11 Independently selected from H and C1-C6 alkyl groups,

[0143] q is an integer selected from 0 to 6.

[0144] Cy1 is a C3-C6 cycloalkyl group optionally substituted with one or more -OH groups, or

[0145] Cy1 is a pyranose or furanose ring that can be linked by any of its OH groups, wherein the pyranose or furanose ring is optionally substituted with a -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine, a monosaccharide, or an oligosaccharide, or substituted with a 4-, 5-, 6-, or 7-membered heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S; or

[0146] Cy1 is a 4-, 5-, 6-, or 7-membered heterocycle containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, wherein the heterocycle is optionally separated by R. 12 replace,

[0147] in

[0148] R 12This indicates a C1-C6 alkyl group, a peptide-containing arginine ring, a pyranose or furanose ring, wherein the pyranose or furanose ring is attached to a 4-, 5-, 6-, or 7-membered heterocycle via any one of its ring carbon atoms, wherein the pyranose or furanose ring is optionally substituted with a -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine, or a monosaccharide or oligosaccharide.

[0149] R 12 It can be a group selected from (d), (e), or (f), wherein b4 is a bond to a heterocyclic ring, and m, n, o, p, R9, R 10 and R 11 As defined above, or

[0150] R 12 Able to provide A group, wherein r is an integer selected from 1 to 4, and Cy2 is a 4-, 5-, 6-, or 7-membered heterocycle containing 1, 2, 3, or 4 heteroatoms selected from O, N, and S, the heterocycle optionally being substituted with a C1-C6 alkyl group;

[0151] P is selected from

[0152] (i)G 2 -T 2 ,in

[0153] G 2 As mentioned above, G 1 As defined, where G 1 and G 2 They can be the same or different;

[0154] T 2 As mentioned above, T 1 As defined, b 1 For G 2 The key, and where T 1 and T 2 They can be the same or different; or

[0155] (ii)G 2 -T 3 ,in

[0156] G 2 As defined above;

[0157] T 3 for

[0158] in

[0159] b 5 For G 2 The key,

[0160] X4 and X5 can be the same or different, and each can be O, S, or NR independently. d , where R d H, C1-C6 alkyl,

[0161] -OH or C1-C6 alkoxy group,

[0162] R 13 For linear C2-C 17 Alkyl, nonlinear C3-C 17 Alkyl groups, both optionally containing S, SO, SO2, O, Si(R) e One of )2, where R e It is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain;

[0163] C3-C containing a double bond 20 Alkenyl group, provided that at least one -CH2- group exists between the double bond and X5; or polyunsaturated C8-C 20 Alkenyl group, provided that at least one -CH2- exists between the first double bond and X5;

[0164] R 14 For linear C2-C 17 Alkyl, nonlinear C3-C 17 Alkyl groups, both optionally containing S, SO, SO2, O, Si(R) f One of )2, where R f It is a C1-C6 alkyl group at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain;

[0165] C3-C containing a double bond 20 Alkenyl, provided that at least one -CH2- group exists between the double bond and the carbons connecting X4 and X5;

[0166] or polyunsaturated C8-C 20 Alkenyl group, provided that at least one -CH2- exists between the first double bond and the carbons connecting X4 and X5; and

[0167] (iii)T 4 ,in

[0168] T 4 for

[0169]

[0170] Among them, b 6 For the bond to the nitrogen atom, R 29 R 30 R 31They can be the same or different, and each can independently be H, OH, -C1-C6 alkoxy, or fluorine; or

[0171] C4-C containing a double bond 20 Alkenyl group, conditional double bond with at least one -CH2- present between N, or

[0172] Polyunsaturated C8-C 20 Alkenyl group, provided that at least one -CH2- exists between the first double bond and N.

[0173] The narrower group of compounds of formula (I) is, where G 1 and G 2 (If present) are the same or different, and each is independently linear C4-C9 alkylene, preferably C5-C9 alkylene, or alternatively, each is independently linear C5, C6, C7 or C9 alkylene.

[0174] Another set of compounds of formula (I) is, where R1 is a linear combination of C1, C2, C4, C6, C7, C8, C9, C 10 Or C 12 Alkyl group, or R1 is a linear C9 alkenyl group, and / or R2 is a linear C1, C3, C5, C6, C7, C8, C9 or C 11 Alkyl groups, preferably R1 being linear C2, C8, C6. 10 Alkyl, or R1 is a linear C9 alkenyl and / or R2 is a linear C1, C3, C7 or C9 alkyl.

[0175] The specific implementation plan of this group is as follows, where T 1 For (c) and R1 is linear, C2, C4, C6, C7, C8, C9, C 10 Or C 12 Alkyl group, or R1 is a linear C9 alkenyl group, and R2 is a linear C1, C3, C5, C6, C7, C8, C9 or C 11 Alkyl groups, preferably R1 being linear C2, C8, C6. 10 Alkyl, or R1 is a linear C9 alkenyl, and R2 is a linear C1, C3, C7 or C9 alkyl.

[0176] Another group of compounds of formula (I) is, wherein R4 is a linear C5, C7, or C8 alkyl group, or R4 is a nonlinear C5, C7, or C8 alkyl group. 16 alkyl.

[0177] The specific implementation plan of this group is as follows: T 1 (b)

[0178] Another group of compounds of formula (I) is, where P is G 2 -T 2 .

[0179] In a specific implementation of this group, G 1 -T 1 and G 2 -T 2 They are the same.

[0180] Another group of compounds of formula (I) is, where P is G 2 -T 3 .

[0181] In a specific implementation of this group, T 1 -G 1 It has one of the following structures

[0182]

[0183] The narrower group of compounds of formula (I) is, where T 3 It has one of the following structures

[0184]

[0185] Among them, b 5 For G 2 The key.

[0186] Another group of compounds of formula (I) is where P is T 4 .

[0187] In a specific implementation of this group, T 4 for

[0188]

[0189] Among them, b 6 For the bond to the nitrogen atom, R 29 R 30 R 31 They can be the same or different, and each can independently be H, OH, -C1-C6 alkoxy or fluorine;

[0190] or

[0191] Polyunsaturated C8-C 20 Alkenyl group, provided that at least one -CH2- exists between the first double bond and N.

[0192] In other specific implementations of this group, T 4 It has the following structure

[0193]

[0194] Among them, b 6 The bond is to the nitrogen atom.

[0195] The other compound of formula (I) is D. 1 It has one of the following structures:

[0196]

[0197] Another set of compounds of formula (I) is where D 1 It has one of the following structures:

[0198]

[0199] Where q is an integer selected from 1 to 4, and b4 is a bond to nitrogen.

[0200] In some implementation schemes, D 1 It has one of the following structures:

[0201]

[0202] The present invention also provides lipid nanoparticles (LNPs) comprising compounds of formula (I) as defined above and therapeutic agents (e.g., RNA, DNA, mRNA, siRNA, pDNA, circular DNA or small bioactive molecules).

[0203] In a particular embodiment, the present invention provides lipid nanoparticles comprising compound (I) and mRNA (e.g., luciferase or green fluorescent protein (GFP)).

[0204] The present invention also provides a method for delivering mRNA into cells.

[0205] This invention opens up a new chemical space via a silicon-containing linker, thereby producing novel biodegradable lipids of formula (I). The aforementioned linkers are difficult to synthesize using the conventional chemical toolbox, but recently published borane catalysts [WO2022 / 129966] have made their synthesis possible. The hybrid acetal building blocks of this invention are prepared by a method similar to that described in WO2022 / 129966. These novel hybrid acetals differ structurally from those disclosed in WO2022 / 129966, and are further distinguished in that the hybrid acetal moiety is retained and incorporated into the lipids according to the invention.

[0206] Another important feature of this invention is its modularity. Due to the properties of the designed silicon-based junctions, a large number of compounds and various lipid libraries can be designed and synthesized from simple and readily available starting materials.

[0207] Furthermore, the chemical stability (e.g., sensitivity to hydrolysis) of silicon-containing ionizable lipids can be fine-tuned by the chemical properties of the substituents and the number of O and Si atoms on the mixed silyl acetal groups (connectors), which is reflected in the biodegradability of the lipids.

[0208] Another aspect of the present invention is the preparation of compounds of formula (I) and intermediates and structural units used therein.

[0209] The compound of formula (I) can be prepared according to the following reaction scheme.

[0210] General Reaction Scheme 1 - Synthesis of Symmetrical Lipids

[0211]

[0212] General reaction scheme 1 illustrates a method for preparing the symmetrical lipids of the present invention having the structure of formula (I), wherein T 1 -G 1 P is the same, X6 is a halogen or pseudohalogen, G 1 X1, X2, R1, R2, R3, D 1 As described above, compounds with structures A-1, A-1', A-1”, A-2, A-2', A-3, A-3', A-3” and A-4, A-4' and A-6 can be purchased or prepared according to methods known in the art. The reaction of carboxylic acid derivative A-1 or A-1' or A-1” with alcohol derivative A-2 or A-2' under suitable esterification conditions (e.g., oxaloyl chloride, Et3N) yields ester A-3 or A-3' or A-3”, which can be converted into mixed silyl acetals A-5 or A-5' or A-5” by suitable silane derivative A-4 or A-4' and borane catalyst [borane catalyst disclosed in WO2022 / 129966]. The mixed silyl acetals A-5 or A-5' or A-5” corresponding to formula (II) containing halogen or pseudohalogen atoms react with amine derivative A-6 under suitable alkylation conditions (e.g., KI, BrF(F3s)2 in CPME / MeCN) to yield compounds A-7 or A-7' or A-7”, respectively.

[0213] General Reaction Scheme 2 - Synthesis of Asymmetric Lipids

[0214] Route A

[0215]

[0216] Route A of general reaction scheme 2 illustrates a method for preparing the asymmetric lipids of the present invention having the structure of formula (I), wherein T 1 -G 1 P is different from G, and P is G 2 -T3 or T 4 X6 is a halogen or pseudohalogen, G 1 X1, X2, R1, R2, R3, D 1 As defined above. Compounds of structures A-8, A-8', and A-6 can be purchased or prepared according to methods known in the art. The reaction of carboxylic acid derivatives A-8 or A-8' with methanol or ethanol (HO-X7) under suitable esterification conditions (e.g., oxaloyl chloride, Et3N) yields ester A-9 or A-9', which can be converted to mixed silyl acetals A-10 or A-10' using triethylsilane and a suitable borane catalyst [borane catalysts are disclosed in WO2022 / 129966]. The resulting mixed silyl acetals A-10 or A-10' are converted to aldehydes (pre- or in situ), which are then reacted with a suitable amine derivative A-6 under reductive amination conditions (e.g., NaHB(OAc)3, AcOH) to produce compound A-11 or A-11' as an intermediate. Intermediate A-11 or A-11' reacts with mixed silyl acetals A-5 or A-5' or A-5" (compounds of formula II) under appropriate alkylation conditions (e.g., KI, BrF(F3s)2 in CPME / MeCN) to produce compounds A-12 or A-12' or A-12".

[0217] Route B

[0218]

[0219] Route B of general reaction route 2 illustrates a method for preparing the asymmetric lipids of the present invention having the structure of formula (I), wherein T 1 -G 1 P is different from G, and P is G 2 -T 2 G 2 -T 3 or T 4 X6 is a halogen or pseudohalogen, G 1 X1, X2, R1, R2, R3, D 1As defined above. A silyl acetal A-5 or A-5' or A-5" of formula (II) containing a halogen or pseudohalogen reacts with an amine derivative A-6 under suitable alkylation conditions (e.g., KI, BrF(F3s)2 in CPME / MeCN) to generate A-13 or A-13' or A-13" as an intermediate having the structure of formula (Ia). The generated intermediate A-13 or A-13' or A-13" reacts with A-10 or A-10' (A-10 or A-10' converted to an aldehyde (pre- or in situ)) under suitable reductive amination conditions to generate A-14 or A-14' or A-14"; or in other cases, A-13 or A-13' or A-13" reacts with a silyl acetal containing a halogen or pseudohalogen to generate A-14 or A-14' or A-14".

[0220] General reaction scheme 3 - Synthesis of first-component modified lipids via click chemistry

[0221]

[0222] General reaction scheme 3 illustrates a method for manufacturing first-group modified lipids having the structure of formula (I) via click chemistry of the present invention, wherein T 1 -G 1 P can be the same as or different from X6, X6 can be halogen or pseudohalogen, W can be N3 or ethynyl, depending on the meaning of Z1, and G 1 X1, X2, R1, R2, R3, D 1 Z1 is defined as above. Only one case is shown in Scheme 3, but other cases can be similarly derived based on general reaction schemes 1 and 2. Compounds of structures A-1, A-2, A-3, A-4, A-15, and A-19 can be purchased or prepared according to methods known in the art. The reaction of carboxylic acid derivative A-1 with alcohol derivative A-2 under suitable esterification conditions (e.g., oxalyl chloride, Et3N) yields ester A-3, which can be converted to mixed silyl acetal A-5 in the presence of a suitable silane derivative A-4 and a borane catalyst [the borane catalyst is disclosed in WO2022 / 129966]. The resulting mixed silyl acetal A-5 containing halogens or pseudohalogens reacts with amine derivative A-15 under suitable alkylation conditions (e.g., KI, BrF(F3s)2 in CPME / MeCN) to yield compound A-16 (a compound of formula (Ib)).

[0223] From the obtained intermediate A-16, compound A-17 (formula (Ic)) can be synthesized via further alkylation reaction as described above, or compound A-18 (formula (Ic)) can be synthesized under suitable reductive amination conditions (e.g., NaHB(OAc)3, AcOH). The reaction of A-17 or A-18 with A-19 under suitable click chemistry conditions (e.g., azide in DMF, CuBr, PMDT) yields compounds A-7 or A-12, wherein D… 1 (g), and Cy1 is an optionally substituted 1,2,3-triazole ring. Attached Figure Description

[0224] Figure 1 Example 139: Transfection rate and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Based on Method B experiments)

[0225] Figure 2 Example 153: Transfection rate and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Based on Method B experiments)

[0226] Figure 3 Example 154: Transfection rate and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Based on Method B experiments)

[0227] Figure 4 Example 155: Transfection rate and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Based on Method B experiments)

[0228] Figure 5 Example 206: Transfection rate and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Based on Method B experiments)

[0229] Figure 6 Example 209: Transfection rate and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Based on Method B experiments)

[0230] Figure 7 Example 211: Transfection rate and toxicity at different doses of GFP mRNA (3.3-800 ng mRNA / well): (Based on Method B experiments)

[0231] Example

[0232] The present invention is illustrated by the following embodiments. These embodiments illustrate the invention but do not limit it. For all embodiments, standard processing and purification methods known to those skilled in the art can be used.

[0233] synthesis

[0234] Ester synthesis (general procedure AD)

[0235]

[0236] General Procedure A

[0237] A three-necked round-bottom flask equipped with a titration funnel, a drying tube (containing CaCl2), and a thermometer contained 1 equivalent of acid and diethyl ether (concentration: 1.0 mmol of acid in 0.8 mL of diethyl ether). The solution in the flask was cooled to 0°C, and 1.10 equivalents of oxaloyl chloride were added dropwise. The reaction mixture was heated to room temperature and stirred overnight. After this period, the mixture was concentrated under reduced pressure to obtain an oil, which did not require further purification for subsequent use.

[0238] A three-necked round-bottom flask equipped with a titration funnel, a drying tube (with CaCl2), and a thermometer contained 1.0 equivalent of alcohol, 1.0 equivalent of triethylamine, and dichloromethane (concentration: 1.0 mmol alcohol in 4.0 mL dichloromethane). The mixture in the flask was cooled to 0 °C, and a solution of 1.0 equivalent of acyl chloride in dichloromethane (concentration: 1.0 mmol acyl chloride in 1.0 mL dichloromethane) was added dropwise. The reaction mixture was heated to room temperature and stirred overnight. The reaction was monitored by TLC (hexane / ethyl acetate 4 / 1, PMA visualization). After overnight incubation, volatiles were removed under reduced pressure, and triethylamine hydrochloride was filtered off. The filtrate was evaporated onto silica gel under reduced pressure and purified by rapid column chromatography.

[0239] General Procedure B

[0240] A three-necked round-bottom flask equipped with a titration funnel, a drying tube (containing CaCl2), and a thermometer contained 1.0 equivalent of acid and diethyl ether (concentration: 1.0 mmol of acid in 0.8 mL of diethyl ether). The solution in the flask was cooled to 0°C, and 1.1 equivalents of oxaloyl chloride were added dropwise. The reaction mixture was heated to room temperature and stirred overnight. After this period, the mixture was concentrated under reduced pressure to obtain an oil, which did not require further purification for subsequent use.

[0241] A three-necked round-bottom flask equipped with a titration funnel, a drying tube (with CaCl2), and a thermometer contained 1.0 equivalent of alcohol, 1.0 equivalent of triethylamine, and dichloromethane (concentration: 1.0 mmol alcohol in 4 ml dichloromethane). The mixture in the flask was cooled to 0°C, and a solution of 1.0 equivalent of acyl chloride in dichloromethane (concentration: 1.0 mmol acyl chloride in 1.0 ml dichloromethane) was added dropwise. The reaction mixture was heated to room temperature and stirred overnight. The reaction was monitored by TLC (hexane / ethyl acetate 4 / 1, PMA visualization). After overnight, the mixture was concentrated to half its original volume, and the precipitated triethylamine hydrochloride was filtered off. The salt was washed with 20 ml dichloromethane and 50 ml hexane. The filtrate was evaporated. The residue was dissolved in 150 ml hexane, and 30 g silica gel was added, stirred for 10 minutes, and filtered. The silica gel was washed with 2 × 100 ml n-hexane. The filtrate was concentrated under reduced pressure to give the product as an oil.

[0242] General procedure C

[0243] A three-necked round-bottom flask was equipped with a titration funnel, a drying tube (containing CaCl2), and a thermometer, and contained 1.25 equivalents of oxaloyl chloride and anhydrous dichloromethane (concentration: 1.0 mmol oxaloyl chloride in 0.41 mL anhydrous dichloromethane). The solution in the flask was cooled to 0 °C and 1.0 equivalent of acid was added dropwise. The reaction mixture was heated to room temperature and stirred overnight. After this period, the mixture was concentrated under reduced pressure to obtain an oil, which requires no further purification for use in ester synthesis.

[0244] A three-necked round-bottom flask equipped with a titration funnel, a drying tube (with CaCl2), and a thermometer contained 1.0 equivalent of alcohol, 1.0 equivalent of triethylamine, and dichloromethane (concentration: 1.0 mmol alcohol in 4 mL dichloromethane). The mixture in the flask was cooled to 0 °C, and a solution of 1.0 equivalent of acyl chloride in dichloromethane (concentration: 1.0 mmol acyl chloride in 1.0 mL dichloromethane) was added dropwise. The reaction mixture was heated to room temperature and stirred overnight. The reaction was monitored by TLC (hexane / ethyl acetate 9 / 1). After overnight incubation, volatiles were removed under reduced pressure, and the triethylamine hydrochloride was filtered off. The filtrate was evaporated onto silica gel under reduced pressure and purified by rapid column chromatography.

[0245] General Procedure D

[0246] A three-necked round-bottom flask was equipped with a titration funnel, a drying tube (containing CaCl2), and a thermometer, and contained carboxylic acid (1.0 equivalent), alcohol (1.0 equivalent), DMAP (0.5 equivalent), and anhydrous dichloromethane (concentration: 1.0 mmol carboxylic acid in 8.5 mL anhydrous dichloromethane). The solution in the flask was cooled to 0 °C, and 2.5 equivalents of DCC solution in dichloromethane (concentration: 1.0 mmol DCC in 0.45 mL anhydrous dichloromethane) was added dropwise. The reaction mixture was then stirred at 0 °C for 1 h, followed by stirring overnight at room temperature. The reaction mixture was diluted with petroleum ether and filtered through a diatomaceous earth pad. The diatomaceous earth was washed with petroleum ether, and the filtrates were combined and concentrated under reduced pressure. The starting material was purified by rapid column chromatography (0–15% petroleum ether in dichloromethane).

[0247] Ester Synthesis Examples

[0248] Example 1

[0249] Synthesis of octyl 6-bromohexanoate

[0250] Octyl 6-bromohexanoate was prepared from 6-bromohexanoic acid and 1-octanol according to general procedure A, and purified using the following method: 250 g silica gel column, eluent: hexane / ethyl acetate 4 / 1. The product was a pale yellow oil: 27.7 g, 90.15 mmol, yield 87%.

[0251] 1H NMR (500MHz, CDCl3) δ4.08(t,2H), δ3.42(t,2H), δ2.33(t,2H), δ1.89(p,2H) ,δ1.70-1.60(m,4H),δ1.55-1.49(m,2H),δ1.45-1.21(m,10H),δ0.90(t,3H)

[0252] Example 2

[0253] Synthesis of decyl 6-bromohexanoate

[0254] Decyl 6-bromohexanoate was prepared from 6-bromohexanoic acid and 1-decyl alcohol according to general procedure A, and purified using the following method: 750 g silica gel column, eluent: ethyl acetate in 0-20% hexane. The product was a pale yellow oil: 35.0 g, 104.37 mmol, yield 89%.

[0255] 1H NMR (500MHz, benzene-d6) δ4.03(t,2H), δ2.86(t,2H), δ2.02(t,2H), δ1.48(p,2 H), δ1.41-1.34(m,4H), δ1.32-1.14(m,14H), δ1.09(m,2H), δ0.90(t,3H)

[0256] Example 3

[0257] Synthesis of octyl 10-bromodecanoate

[0258] Octyl 10-bromodecanoate was prepared from 10-bromodecanoic acid and 1-octanol according to general procedure A, and purified using the following method: 250 g silica gel column, eluent: ethyl acetate in 0-20% hexane. The product was a pale yellow oil: 20.23 g, 55.67 mmol, yield 70%.

[0259] 1H NMR (500MHz, benzene-d6) δ4.06(t,2H), δ2.95(t,2H), δ2.19(t,2H), δ1.59(p,2H), δ1.53-1.43(m,4H), δ1.31-0.94(m,20H), δ0.88(t,3H)

[0260] Example 4

[0261] Synthesis of hexyl 6-bromooctanoate

[0262] 6-Bromooctylhexanoate was prepared from octanoic acid and 6-bromo-1-hexanol according to general procedure B. The product was a pale yellow oil: 46.0 g, 149.70 mmol, yield 90%.

[0263] 1H NMR (500MHz, benzene-d6) δ3.95(t,2H), δ2.89(t,2H), δ2.17(t,2H), δ1.59(p,2H), δ1.40(p,2H), δ1.32(p,2H), δ1.27-1.10(m,8H), δ1.01(m,4H), δ0.85(t,3H)

[0264] Example 5

[0265] Synthesis of hexyl 6-bromodecanoate

[0266] Hexyl 6-bromodecanoate was prepared from decanoic acid and 6-bromo-1-hexanol according to general procedure B, yielding a pale yellow oil: 26.4 g, 78.73 mmol, yield 75%.

[0267] 1H NMR (500MHz, benzene-d6) δ3.95(t,2H), δ2.89(t,2H), δ2.18(t,2H), δ1.61(p,2H), δ1.40(p,2H), δ1.32(p,2H), δ1.29-1.12(m,12H), δ1.01(m,4H), δ0.89(t,3H)

[0268] Example 6

[0269] Synthesis of nonyl 9-bromooctanoate

[0270] Nonyl 9-bromooctanoate was prepared from octanoic acid and 9-bromo-1-nonanol according to general procedure B, yielding a pale yellow oil: 51.42 g, 147.18 mmol, yield 89%.

[0271] 1H NMR (500MHz, benzene-d6) δ4.05(t,2H), δ2.96(t,2H), δ2.18(t,2H), δ1.60(p,2H), δ1.48(m,4H), δ1.29-0.92(m,18H), δ0.85(t,3H)

[0272] Example 7

[0273] Synthesis of octyl octanoate

[0274] Octyl octanoate was prepared from octanoic acid and 1-octanol according to general procedure B. The product was a pale yellow oil: 37.40 g, 145.85 mmol, yield 89%.

[0275] 1H NMR (500MHz, benzene-d6) δ4.05(t,2H), δ2.17(t,2H), δ1.59(m,2H), δ1.48(m,2H), δ1.33-1.07(m,18H), δ0.86(m,6H)

[0276] Example 8

[0277] Synthesis of heptyl octanoate

[0278] Heptyl octanoate was prepared from octanoic acid and 1-heptanol according to general procedure A. The product was a pale yellow oil: 2.18 g, 8.99 mmol, yield 77%.

[0279] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.57-1.49(m,4H), δ1.35-1.10(m,16H), δ0.83-0.79(m,6H)

[0280] Example 9

[0281] Synthesis of nonyl octanoate

[0282] Nonyl octanoate was prepared from octanoic acid and 1-nonanol according to general procedure A, yielding a pale yellow oil: 2.03 g, 7.05 mmol, yield 61%.

[0283] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.57-1.50(m,4H), δ1.29-1.10(m,20H), δ0.83-0.79(m,6H)

[0284] Example 10

[0285] Synthesis of octyl heptaate

[0286] Octyl heptanate was prepared from heptanic acid and 1-octanol according to general procedure A. The product was a pale yellow oil: 2.49 g, 10.27 mmol, yield 86%.

[0287] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.57-1.50(m,4H), δ1.27-1.10(m,16H), δ0.83-0.79(m,6H)

[0288] Example 11

[0289] Synthesis of octyl nonanoate

[0290] Octyl nonanoate was prepared from nonanoic acid and 1-octanol according to general procedure A. The product was a pale yellow oil: 2.62 g, 9.69 mmol, yield 78%.

[0291] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.57-1.50(m,4H), δ1.34-1.10(m,20H), δ0.83-0.79(m,6H)

[0292] Example 12

[0293] Synthesis of hexyl decanoate

[0294] Hexyl decanoate was prepared from decanoic acid and 1-hexanol according to general procedure A. The product was a pale yellow oil: 2.63 g, 10.26 mmol, yield 88%.

[0295] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.57-1.48(m,4H), δ1.24-1.12(m,18H), δ0.84-0.79(m,6H)

[0296] Example 13

[0297] Synthesis of decyl hexanoate

[0298] Decyl hexanoate was prepared from hexanoic acid and 1-decyl alcohol according to general procedure A. The product was a pale yellow oil: 2.77 g, 10.8 mmol, yield 90%.

[0299] 1H NMR (500MHz, benzene-d6) δ3.99(t,2H), δ2.22(t,2H), δ1.60-1.49(m,4H), δ1.29-1.12(m,18H), δ0.85-0.79(m,6H)

[0300] Example 14

[0301] Synthesis of Octyl octanethioate

[0302] Octyl thiooctanoate was prepared from octanoic acid and 1-octylthiol according to general procedure C. The product was a pale yellow oil: 3.38 g, 13.08 mmol, yield 90%.

[0303] 1H NMR (500MHz, benzene-d6) δ2.79(t,2H), δ2.46(t,2H), δ1.63-1.53(m,2H), δ1.51-1.44(m,2H), δ1.35-1.10(m,18H), δ0.83-0.78(m,6H)

[0304] Example 15

[0305] Synthesis of decyl butyrate

[0306] Decyl butyrate was prepared from butyryl chloride and 1-decyl alcohol according to general procedure A, and the product was a pale yellow oil: 3.05 g, 13.36 mmol, yield 93%.

[0307] 1H NMR (500MHz, benzene-d6) δ4.05(t,2H), δ2.27(t,2H), δ1.72-1.57(m,4H), δ1.38-1.20(br.m,14H), δ0.94(t,3H), δ0.87(t,3H)

[0308] Example 16

[0309] Synthesis of (Z)-non-6-en-1-yl octanoate

[0310] (Z)-Non-6-en-1-yl octanoate was prepared from octanoic acid and (Z)-non-6-en-1-ol according to general procedure C. The product was a pale yellow oil: 2.10 g, 7.82 mmol, yield 85%.

[0311] 1H NMR (500MHz, benzene-d6) δ5.46-5.30(m,2H), δ4.03(t,2H), δ2.17(t,2H), δ2.03-1.91(m,4H), δ1.62-1.55(m,2H), δ1.50-1.42(m,2H) δ1.30-1.12(m,12H), δ0.93(t,3H), δ0.85(t,3H)

[0312] Example 17

[0313] Synthesis of (Z)-non-3-ene-1-yl octanoate

[0314] (Z)-Non-3-en-1-yl octanoate was prepared from octanoic acid and (Z)-non-3-en-1-ol according to general procedure C. The product was a pale yellow oil: 2.17 g, 8.07 mmol, yield 88%.

[0315] 1H NMR (500MHz, benzene-d6) δ5.44-5.35(m,2H), δ5.27-5.18(m,2H), δ3.95(t,2H), δ2.31-2.13( m,4H),δ1.98-1.87(m,2H),δ1.58-1.44(m,2H)δ1.32-1.08(m,12H),δ0.82-0.73(m,6H)

[0316] Example 18

[0317] Synthesis of heptadecanyl-9-yl-8-bromooctanoate

[0318] Heptadecan-9-yl 8-bromooctanoate was prepared from 8-bromooctanoic acid and heptadecan-9-ol according to general procedure C. The product was a pale yellow oil: 3.20 g, 6.93 mmol, yield 13%.

[0319] 1H NMR (500MHz, CDCl3) δ4.92-4.84(m,1H), δ3.41(t,2H), δ2.30(t,2H), δ1.90-1.84(m,2H), δ1.70-1.20(br.m,36H), δ0.89(m,6H)

[0320] Example 19

[0321] Synthesis of 6-ethoxy-6-oxohexyl-2-hexyldecanoate

[0322] Step a) In a 500 mL two-necked flask equipped with a stir bar and a reflux condenser, 2-hexyldecanoic acid (44.6 g, 51.0 mL, 1 equivalent 174 mmol) was dissolved in anhydrous toluene (150 mL) under inert conditions (nitrogen). Then, with stirring, 5 drops of DMF and thioyl chloride (51.7 g, 31.7 mL, 2.5 equivalent 435 mmol) were added. The reaction mixture was stirred at room temperature until gas escape slowed down (about 2 hours). The mixture was then heated to 80–90 °C and stirred for another 2 hours until gas escape stopped. The reaction was monitored by TLC.

[0323] Step b) Next, the solvent and residual thioyl chloride were removed under vacuum, and the resulting crude product was used in the next reaction step without further purification. Ethyl 6-hydroxyhexanoate (26.4 g, 26.8 mL, 1 equivalent 165 mmol) was dissolved in 100 mL of anhydrous toluene under inert conditions (nitrogen) in a two-necked 500 mL flask equipped with a stir bar, condenser, and feeding funnel. Next, triethylamine (25.0 g, 34.5 mL, 1.5 equivalent 248 mmol) was added, followed dropwise by the addition of 2-hexyldecanoyl chloride (47.8 g, 1.05 equivalent 174 mmol) dissolved in 60 mL of anhydrous toluene. Immediately, TEA-HCl precipitation began. The reaction was monitored by TLC and stirred overnight at room temperature (16 h). The reaction mixture was then filtered through diatomaceous earth and washed with additional toluene. The resulting clear solution was washed with 1M hydrochloric acid aqueous solution, followed by washing with saturated NaHCO3(aq) and saturated NaCl(aq). The extracted organic phase was dried over MgSO4, filtered, and concentrated under vacuum to give 73.2 g of crude product. The ester was purified by silica gel column chromatography using hexane and ethyl acetate as eluents to give 6-ethoxy-6-oxohexyl-2-hexyldecanoate (58.50 g, 147 mmol, cumulative yield of 89% for both reaction steps).

[0324] 1H NMR(500MHz, CDCl3)δ4.16-4.12(q,2H),δ4.08(t,2H),δ2.33-2.30(m,2H),δ 1.71-1.54(m,6H),δ1.48-1.37(m,4H),δ1.34-1.20(br.m,24H),δ0.89(t,6H)

[0325] Example 20

[0326] Synthesis of 6-methoxy-6-oxohexyl-2-(decylthio)hexanoate

[0327]

[0328] Step a) A flame-dried 500 mL three-necked round-bottom flask was purged with argon gas. The flask was equipped with a titration funnel, thermometer, and argon balloon, and contained 2-bromohexanoic acid (10.00 g, 51.27 mmol) and 300 mL anhydrous tetrahydrofuran. The reaction mixture was cooled to 0 °C. KOtBu (16.51 g, 69.21 mmol) was added portionwise to maintain the internal temperature at 0 °C. After stirring at 0 °C for one hour, 1-decylthiol (12.06 g, 69.21 mmol) was added dropwise to maintain the internal temperature at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC (hexane / ethyl acetate 4:1, PMA visualization), and almost complete conversion was detected after stirring overnight. 250 mL of 1N-HCl solution was added to the reaction mixture, and the mixture was extracted with 3 × 250 mL of hexane. The combined organic phases were washed with 3 × 100 mL of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography with gradient elution (0-20% EtOAc in n-hexane) to give 2-(decylthio)hexanoic acid (12.46 g, 43.19 mmol, 84% yield) as a pale yellow oil.

[0329] 1H NMR (500MHz, DMSO-d6) δ3.15(t,1H), δ2.56(m,2H), δ1.78-1.67(m,1H), δ1.58-1.45(m,3H), δ1.39-1.17(m,18H), δ0.86(t,6H)

[0330] Step b) Following general procedure C, 6-methoxy-6-oxohexyl-2-(decylthio)hexanoate was prepared from 2-(decylthio)hexanoic acid and methyl 6-hydroxyhexanoate, and purified using a 250 g silica gel column as eluent: ethyl acetate in 0-10% hexane. The resulting product was a brown oil: 10.77 g, 25.85 mmol, yield 79%.

[0331] 1H NMR (500MHz, benzene-d6) δ4.00(m,2H), δ3.33(s,3H), δ3.27(t,1H), δ2.74-2.65(m,1H), δ2.64-2.55( m,1H),δ2.02(t,3H),δ1.75(m,1H),δ1.58(m,2H),δ1.5-1.1(m,24H),δ0.90(t,3H),δ0.80(t,3H)

[0332] Example 21

[0333] Synthesis of 6-methoxy-6-oxohexyl-2-(pentathio)decanoate

[0334]

[0335] Step a) A flame-dried 250 mL three-necked round-bottom flask was purged with an argon stream. The flask was equipped with a titration funnel, thermometer, and argon balloon, and contained 2-bromodecanoic acid (6.80 g, 27.07 mmol), 1-pentanethiol (3.81 g, 36.55 mmol), and 60 mL of anhydrous tetrahydrofuran. The reaction mixture was cooled to 0 °C. 80 mL of anhydrous THF in KOtBu (8.72 g, 77.7 mmol) was added dropwise while maintaining the internal temperature at 0 °C. The reaction mixture was further stirred overnight at room temperature. The reaction was monitored by TLC (hexane / ethyl acetate 4:1, PMA visualization), and almost complete conversion was detected after overnight incubation. 150 mL of 1N-HCl solution was added to the reaction mixture, and the mixture was extracted with 3 × 150 mL of hexane. The combined organic phases were washed with 2 × 150 mL of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography with gradient elution (0-20% EtOAc in n-hexane) to give a pale yellow oil, 2-(pentathio)decanoic acid (6.20 g, 22.59 mmol, yield 83%).

[0336] 1H NMR (500MHz, DMSO-d6) δ3.16(t,1H), δ2.56(m,2H), δ1.77-1.66(m,1H), δ1.58-1.44(m,3H), δ1.41-1.14(m,16H), δ0.85(t,6H)

[0337] Step b) Following general procedure C, 6-methoxy-6-oxohexyl-2-(pentathio)decanoate was prepared from 2-(pentathio)decanoic acid and methyl 6-hydroxyhexanoate, and purified using a 250 g silica gel column as eluent: ethyl acetate in 0-10% hexane. The resulting product was a brown oil: 9.37 g, 23.27 mmol, yield 75%.

[0338] 1H NMR (500MHz, benzene-d6) δ4.00(m,2H), δ3.33(s,3H), δ3.30(t,1H), δ2.71-2.64(m,1H), δ2.61-2.53(m,1H), δ2.0 2(t,3H),δ1.78(m,1H),δ1.55(m,2H),δ1.48-1.32(m,6H),δ1.32-1.07(m,16H),δ0.88(t,3H),δ0.81(t,3H)

[0339] Example 22

[0340] Synthesis of methyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)valerate

[0341] Lithochoic acid (5.00 g, 13.30 mmol), 240 mL of anhydrous acetonitrile, cesium carbonate (9.53 g, 29.26 mmol), and methyl iodine (8.30 g, 58.52 mmol) were placed in a 1000 mL pressure flask under an argon atmosphere. The flask was sealed, and the reaction mixture was heated to 110 °C for 24 hours. The reaction mixture was then cooled, and 20 mL of sodium sulfite (10 w / w%) solution and 200 mL of water were added. The mixture was extracted with 3 × 200 mL of ethyl acetate. The combined organic phases were washed with 1 × 100 mL of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography with gradient elution (5-20% ethyl acetate in hexane) to obtain a white solid methyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)valerate (1.30 g, 3.21 mmol, 24% yield).

[0342] 1H NMR (500MHz, benzene-d6) δ3.40(s,3H), δ3.38(t,3H), δ2.32-2.23(m,1H), δ2.20-2.10(m,1H), δ1.95-1.83(m,2 H), δ1.83-1.70(m,3H), δ1.67-1.54(m,3H), δ1.53-086(m,19H), δ0.84(d,3H), δ0.74(s,3H), δ0.52(s,3H)

[0343] Example 23

[0344] Synthesis of undecyl 6-bromohexanoate

[0345] Undecyl 6-bromohexanoate was prepared from 6-bromooctanoic acid and 1-undecaneol according to general procedure C. The product was a pale yellow oil: 27.95 g, 80 mmol, yield 78%.

[0346] 1H NMR (500MHz, DMSO-d6) δ4.01(t,2H), δ3.52(t,2H), δ3.52(t,2H), δ2.30(t,2H), δ1.85-1. 78(m,2H),δ1.58-1.52(m,4H),δ1.42-1.38(m,2H),δ1.33-1.20(br.m,14H),δ0.87(t,3H)

[0347] Example 24

[0348] Synthesis of 4-chlorobutyl(9Z,12Z)-octadeca-9,12-dienoate

[0349] 4-Chlorobutyl(9Z,12Z)-octadec-9,12-dienoic acid was prepared from (9Z,12Z)-octadec-9,12-dienoic acid and 4-chlorobutane-1-ol according to general procedure D. The product was a pale yellow oil: 1.20 g, 3.23 mmol, yield 45%.

[0350] 1H NMR (500MHz, benzene-d6) δ5.41-5.27(m,4H), δ4.1(t,2H), δ3.58(t,2H), δ2.27(t,2H), δ2.29(t,2H), δ2.08-2.00(m,4H), δ1.86-1.78(m,4H), δ1.64-1.59(m,2H), δ1.37-1.25(m,14H), δ0.88(t,3H)

[0351] Example 25

[0352] Synthesis of 4-chlorobutyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)valerate

[0353] 4-Chlorobutyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)valerate was prepared from (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)valerate by 4-chlorobutane-1-ol. The product was a colorless oil: 2.75 g, 5.72 mmol, yield 81%.

[0354] 1H NMR(500MHz, CDCl3)δ4.12-4.07(m,2H),δ3.56(t,2H),δ3.34(s,3H)δ3.21-3.11(m,1H),δ2.40-2.29(m,1H ), δ2.26-2.14(m,1H), δ1.92-1.51(br.m,14H), δ1.49-0.99(br.m,16H), δ0.91-0.89(m,6H), δ0.63(s,3H)

[0355] Examples of silane synthesis

[0356] Example 26

[0357] Synthesis of dimethyl(octyl)silane

[0358]

[0359] A flame-dried 250 mL three-necked round-bottom flask was purged with argon gas. The flask was equipped with a diaphragm, thermometer, and argon balloon, and contained chloro(dimethyl)octylsilane (20.00 g, 96.70 mmol) and 100 mL anhydrous diethyl ether. The reaction mixture was cooled to 0 °C, and lithium aluminum hydride (3.38 g, 88.96 mmol) was added in portions over 6 hours, maintaining the internal temperature between 0 and 5 °C. The reaction was stirred overnight at room temperature. The reaction mixture was then cooled again to 0 °C and quenched with a mixture of 30 mL water and 50 mL 5 w / w% NaOH solution to maintain the internal temperature below 5 °C. Another portion of water (30 mL) was then added, and the mixture was heated to room temperature. The phases were separated, and the organic phase was washed with 25 mL of water and dried with MgSO4. After filtration of MgSO4, the volatiles were evaporated under reduced pressure, and the resulting product was a colorless oil, dimethyl (octyl)silane (14.40 g, 83.53 mmol, yield 86%).

[0360] 1H NMR (500MHz, CDCl3) δ3.85 (m, 1H), δ1.25 (m, 12H), δ0.90 (t, 3H), δ0.59 (m, 2H), δ0.08 (d, 6H)

[0361] Example 27

[0362] Synthesis of dimethyl(hexyl)silane

[0363]

[0364] A flame-dried 250 mL three-necked round-bottom flask was purged with argon gas. The flask was equipped with a thermometer, condenser, argon balloon, and contained dimethylchlorosilane (10.00 g, 105.69 mmol), 1-hexene (8.09 g, 96.17 mmol), Karstedt catalyst (0.111 mL 2% Pt in xylene solution), and 100 mL anhydrous tetrahydrofuran. The reaction mixture was refluxed for 5 hours. The reaction was monitored by GC, and complete conversion was detected after 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give colorless oil dimethylchlorochloro(hexyl)dimethylsilane (15.60 g, 87.26 mmol, 83% yield).

[0365] A flame-dried 250 mL three-necked round-bottom flask was purged with argon gas. The flask was equipped with a diaphragm, thermometer, and argon balloon, and contained 15.60 g (87.26 mmol) of dichloro(dimethyl)hexylsilane and 90 mL of anhydrous diethyl ether. The reaction mixture was cooled to 0 °C, and lithium aluminum hydride (3.05 g, 80.28 mmol) was added in portions over 5 hours, maintaining the internal temperature between 0 and 5 °C. The reaction was stirred for an additional hour at room temperature. The reaction mixture was then cooled again to 0 °C and quenched with a mixture of 30 mL of water and 50 mL of 5 w / w% NaOH solution, maintaining the internal temperature below 5 °C. Another portion of water (30 mL) was then added, and the mixture was heated to room temperature. The phases were separated, and the organic phase was washed with 25 mL of water and dried with MgSO4. After filtration through MgSO4, the volatiles were evaporated under reduced pressure. The residue was purified by constant pressure distillation to give colorless oil dimethyl(hexyl)silane (10.30 g, 71.36 mmol, yield 82%).

[0366] 1H NMR (500MHz, benzene-d6) δ4.12(m,1H), δ1.31(m,8H), δ0.89(t,3H), δ0.53(m,2H), δ0.04(d,6H)

[0367] Example 28

[0368] Synthesis of 1,1,3,3-tetramethyl-1-octyldisiloxane

[0369]

[0370] A flame-dried 500 ml three-necked round-bottom flask was purged with argon gas. The flask was equipped with a titration funnel, thermometer, condenser, argon balloon, and contained 1,1,3,3-tetramethyldisiloxane (119.70 g, 891 mmol), Wilkinson catalyst (5 mg, 0.0054 mmol), and 48.50 ml anhydrous toluene. The reaction mixture was heated to 40 °C, and 1-octene (20.00 g, 178.22 mmol) was added dropwise. After the addition of 1-octene, the resulting mixture was stirred at 50 °C for an additional 5 hours. After the reaction time was completed, the mixture was... 1 Complete conversion was detected by ¹H NMR. The reaction mixture was concentrated under reduced pressure to obtain a colorless oil, 1,1,3,3-tetramethyl-1-octyldisiloxane (46.00 g, 186.58 mmol, 98% yield).

[0371] 1H NMR (500MHz, CDCl3) δ4.69 (m, 1H), δ1.28 (m, 12H), δ0.90 (t, 3H), δ0.55 (m, 2H), δ0.18 (d, 6H), δ0.07 (s, 6H)

[0372] Example 29

[0373] Synthesis of dimethyl(octoxy)silane

[0374]

[0375] A 250 mL three-necked round-bottom flask was purged with a helium stream. The flask was equipped with a titration funnel, thermometer, argon balloon, and contained 1-octanol (5.20 g, 40.00 mmol), triethylamine (6.07 g, 60.00 mmol), and 40.0 mL of anhydrous toluene. The reaction mixture was cooled to 0 °C, and dimethylchlorosilane (4.54 g, 48.00 mmol) was added dropwise while maintaining the internal temperature between 0 °C and 5 °C. After the addition of silane, the reaction mixture was stirred overnight at room temperature. The reaction mixture was then filtered through a diatomaceous earth mat and washed with 2 × 15 mL pentane, and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated under reduced pressure. The crude product was purified by vacuum distillation at 0.02–0.05 mbar (46 °C–51 °C) to obtain a colorless oil, dimethyl(octyloxy)silane (4.86 g, 25.80 mmol, 64% yield).

[0376] 1H NMR (500MHz, benzene-d6) δ4.88(m,1H), δ3.57(t,2H), δ1.54(p,2H), δ1.32(m,2H), δ1.23(m,8H), δ0.88(t,3H), δ0.15(d,6H)

[0377] Example 30

[0378] Synthesis of ((2-hexyldecyl)oxy)dimethylsilane

[0379]

[0380] A 250 mL three-necked round-bottom flask was purged with a helium stream. The flask was equipped with a titration funnel, thermometer, argon balloon, and contained 2-hexyldecane-1-ol (6.23 g, 22.87 mmol), triethylamine (3.47 g, 34.31 mmol), and 44.2 mL of anhydrous toluene. The reaction mixture was cooled to 0 °C, and dimethylchlorosilane (2.60 g, 27.45 mmol) was added dropwise, maintaining the internal temperature between 0 °C and 5 °C. After the addition of silane, the reaction mixture was stirred overnight at room temperature. The reaction mixture was then filtered through a diatomaceous earth mat and washed with 2 × 15 mL of pentane to remove the precipitated triethylamine hydrochloride. The filtrate was concentrated under reduced pressure. The crude product was purified by vacuum distillation to obtain colorless oil ((2-hexyldecyl)oxy)dimethylsilane (2.61 g, 8.68 mmol, 34% yield).

[0381] 1H NMR (500MHz, benzene-d6) δ4.90(p,1H), δ3.57(d,2H), δ1.56(m,1H), δ1.47(m,2H), δ1.28(m,22H), δ0.90(m,6H), δ0.17(d,6H)

[0382] Example 31

[0383] Synthesis of 1,1,3,3-tetramethyl-1-(octoxy)disiloxane

[0384]

[0385] A flame-dried 500 mL three-necked round-bottom flask was purged with argon gas. The flask was equipped with a titration funnel, thermometer, argon balloon, and contained 1.41 mL of BrF(F3s)2-borane catalyst solution (202 mg dissolved in 4.00 mL anhydrous toluene) [borane catalyst disclosed in WO2022 / 129966] and 1,1,3,3-tetramethyldisiloxane (128.42 g, 965 mmol). A toluene solution of 1-octanol (4.15 g, 31.87 mmol, in 16 mL anhydrous toluene) was added dropwise to the reaction mixture, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by vacuum distillation using a Vigreux column at 0.02–0.05 mbar (52–60 °C) to obtain a colorless oil, 1,1,3,3-tetramethyl-1-(octoxy)disiloxane (8.36 g, 21.86 mmol, yield 69%).

[0386] 1H NMR (500MHz, benzene-d6) δ5.04(m,1H), δ3.70(t,2H), δ1.60(p,2H), δ1.38(m,2H), δ1.27(m,8H), δ0.89(t,3H), δ0.21(d,6H), δ0.17(s,6H)

[0387] Example 32

[0388] Synthesis of (6-bromohexyl)dimethylsilane

[0389]

[0390] A flame-dried 250 mL three-necked round-bottom flask was purged with argon gas. The flask was equipped with a thermometer, condenser, argon balloon, and contained dimethylchlorosilane (6.38 g, 67.40 mmol), 6-bromo-1-hexene (10.00 g, 61.33 mmol), Karstedt catalyst (69.6 μl 2% Pt in xylene solution), and 60 mL of anhydrous tetrahydrofuran. The reaction was monitored by GC, and complete conversion was detected overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a yellow oil (6-bromohexyl)dimethylchlorosilane (16.65 g, 64.61 mmol, 96% yield).

[0391] A flame-dried 250 mL three-necked round-bottom flask was purged with argon gas. The flask was equipped with a titration funnel, thermometer, argon balloon, and contained a ground NaBH4 suspension (4.89 g, 129.23 mmol) and 11 mL of anhydrous tetrahydrofuran. A mixture of (6-bromohexyl)chlorodimethylsilane (16.65 g, 64.61 mmol) and 50 mL of anhydrous tetrahydrofuran was added dropwise to the suspension, and the mixture was stirred overnight at room temperature. Volatiles were removed under reduced pressure, and 50 mL of hexane was added to the residue. The suspension was passed through a small piece of silica gel. The filtrate was concentrated under reduced pressure. The residue was further purified by vacuum distillation at 0.02–0.05 mbar (38–39 °C) to give a colorless oil and (6-bromohexyl)dimethylsilane (9.70 g, 43.45 mmol, 67% yield).

[0392] 1H NMR (500MHz, benzene-d6)δ4.09(m,1H),δ2.95(t,2H),δ1.48(p,2H),δ1.20-1.04(m,6H),δ0.48-0.4(m,2H)δ0.02(d,6H)

[0393] Example 33

[0394] Synthesis of ((6-bromohexyl)oxy)dimethylsilane

[0395]

[0396] A 250 mL three-necked round-bottom flask was purged with a helium stream. The flask was equipped with a titration funnel, thermometer, and argon balloon, and contained 8.00 g (44.20 mmol) of 6-bromo-1-hexanol, 6.70 g (66.30 mmol) of triethylamine, and 44.2 mL of anhydrous toluene. The reaction mixture was cooled to 0 °C, and dichlorosilane (5.02 g, 53.04 mmol) was added dropwise, maintaining the reaction temperature between 0 °C and 5 °C. After the addition of silane, the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through a diatomaceous earth filter and washed with 2 × 15 mL of pentane to remove the precipitated triethylamine hydrochloride. The filtrate was concentrated under reduced pressure. The crude product was purified by vacuum distillation at 0.02-0.05 mbar (63℃-64℃) to give colorless oil ((6-bromohexyl)oxy)dimethylsilane (7.27 g, 30.39 mmol, yield 63%).

[0397] 1H NMR (500MHz, benzene-d6)δ4.85(m,1H),δ3.47(t,2H),δ2.90(t,2H),δ1.45(m,2H),δ1.37(m,2H),δ1.11(m,4H)δ0.14(d,6H)

[0398] Example 34

[0399] Synthesis of ((5-bromopentyl)oxy)dimethylsilane

[0400]

[0401] Triethylamine (8.39 g, 82.94 mmol, 1.50 equivalent) was added to a stirred mixture of 5-bromopentan-1-ol (9.24 g, 55.29 mmol, 1.00 equivalent) and 50 mL of dry toluene under an Ar atmosphere. Dimethylchlorosilane (6.28 g, 66.35 mmol, 1.20 equivalent) was added, and the mixture became a white slurry. The mixture was shaken several times before stirring overnight. After 16 h, the mixture (glass fused) was filtered, and the precipitate was washed with toluene. The filtrate was evaporated. The residue was diluted with petroleum ether (~20 mL) to give a white precipitate, which was separated by centrifugation. The clear solution was concentrated. The remaining oil was purified by vacuum distillation at 1 mbar to obtain a colorless oil ((5-bromopentyl)oxy)dimethylsilane (9.23 g, 40.99 mmol, 74% yield).

[0402] 1H NMR (500MHz, benzene-d6) δ4.84(m,1H), δ3.42(t,2H), δ2.92(t,2H), δ1.50-1.43(m,2H), δ1.35-1.18(m,4H), δ0.13(d,6H)

[0403] Example 35

[0404] Synthesis of ((4-bromobutyl)oxy)dimethylsilane

[0405]

[0406] Triethylamine (7.93 g, 78.42 mmol, 1.50 equivalent) was added to a stirred mixture of 4-bromobutane-1-ol (8.00 g, 52.28 mmol, 1.00 equivalent) and 50 mL of dry toluene under an Ar atmosphere. Dimethylchlorosilane (5.93 g, 62.74 mmol, 1.20 equivalent) was added, and the mixture became a white slurry. The mixture was shaken several times before stirring overnight. After 16 h, the mixture (glass fused) was filtered, and the precipitate was washed with toluene. The filtrate was evaporated. The residue was diluted with petroleum ether (~20 mL) to give a white precipitate, which was separated by centrifugation. The clear solution was concentrated. The remaining oil was purified by vacuum distillation at 10 mbar (65–70 °C) to obtain a colorless oil ((4-bromobutyl)oxy)dimethylsilane (7.65 g, 36.22 mmol, 69% yield).

[0407] 1H NMR (500MHz, benzene-d6) δ4.78(m,1H), δ3.36(t,2H), δ2.96(t,2H), δ1.68-1.56(m,2H), δ1.46-1.34(m,2H), δ0.10(d,6H)

[0408] Example 36

[0409] Synthesis of 1-(4-bromobutoxy)-1,1,3,3-tetramethyldisiloxane

[0410]

[0411] A flame-dried 250 mL three-necked round-bottom flask was purged with argon gas. The flask was equipped with a titration funnel, thermometer, argon balloon, and contained 100 μL of a BrF(F3s)2 borane catalyst solution [borane catalyst disclosed in WO2022 / 129966] (58.42 mg dissolved in 100 μL) and 1,1,3,3-tetramethyldisiloxane (105.34 g, 784.22 mmol, 30 equivalents). A toluene solution of 4-bromo-1-butanol (4.00 g, 26.14 mmol, in 16 mL anhydrous toluene) was added dropwise to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by vacuum distillation using a Vigreux column at 5 mbar (65℃-75℃) to obtain a colorless oil 1-(4-bromobutoxy)-1,1,3,3-tetramethyldisiloxane (4.56 g, 15.98 mmol, yield 61%).

[0412] 1H NMR (500MHz, benzene-d6) δ4.99(m,1H), δ3.49(t,2H), δ3.00(t,2H), δ1.74.1.61(m,2H), δ1.54-1.40(m,2H), δ0.18(d,6H), δ0.10(s,6H)

[0413] Synthesis of mixed silyl acetals (general procedure EF)

[0414] The BrF(F3s)2 and BrF(F4)2 borane catalysts disclosed in WO2022 / 129966 were used in the synthesis, as defined in each embodiment.

[0415] General Procedure E

[0416] A flame-dried three-necked round-bottom flask was purged with argon gas. The flask was equipped with a diaphragm, thermometer, and argon balloon, and contained a mixture of anhydrous toluene (1.0 ml toluene / 1.0 mmol ester) and the ester. A portion of the catalyst solution was added to the reaction mixture, followed by dropwise addition of silane, maintaining the internal temperature between 20 and 30 °C. The reaction mixture was stirred at room temperature for several hours (described in detail in the examples). The reaction was monitored by TLC (hexane / ethyl acetate 9 / 1, PMA visualization, and described in detail in the examples if different). After the reaction was complete, 1 ml EtOAc, 0.6 ml MeCN, and silica gel were added to the reaction mixture, and the mixture was stirred for another 10 min. The silica gel was filtered off, and the mixture was washed with 2 × 25 ml n-pentane. Volatiles were removed under reduced pressure to obtain the crude product, which was then obtained by rapid column chromatography or simple filtration via a silica gel septum.

[0417] General Procedure F

[0418] A flame-dried three-necked round-bottom flask was purged with an argon stream. The flask was equipped with a diaphragm, thermometer, and argon balloon, and contained the catalyst and anhydrous toluene (4.00 ml). The mixture of ester and silane was added dropwise to the catalyst solution, maintaining the internal temperature between 20 and 30 °C. The reaction mixture was stirred for 12 hours. 1 The reaction was monitored by ¹H NMR or TLC (described in detail in the examples). After the reaction was complete, 1 ml EtOAc, 0.6 ml MeCN and silica gel were added to the reaction mixture, and the mixture was stirred for 10 min. The silica gel was filtered off, and the mixture was washed with 2 × 15 ml n-pentane. Volatiles were removed under reduced pressure to obtain the crude product, which was obtained by rapid column chromatography or by simple filtration through a silica gel septum.

[0419] Examples of the synthesis of mixed silyl acetals

[0420] Example 37

[0421] Synthesis of ((6-bromo-1-(octoxy)hexyl)oxy)dimethyl(octyl)silane

[0422]

[0423] According to general procedure E, ((6-bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane was prepared from 6-bromohexyl octanoate (4.00 g, 13.02 mmol) and dimethyl(octyl)silane (1.1 equivalent, 2.47 g, 14.32 mmol) using 616 μl BrF(F3s)2borane as catalyst (189 mg catalyst dissolved in 4.00 mL anhydrous toluene). The reaction was completed after 2 hours. The crude product was purified by rapid column chromatography with gradient elution (0-20% EtOAc in n-hexane) to give clear oil ((6-bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane (4.72 g, 9.84 mmol, 76% yield).

[0424] 1H NMR (500MHz, benzene-d6) δ4.79(dt,1H), δ3.73-3.69(dq,1H), δ3.35-3.31(dq,1H), δ2.95(t,2H) ,δ1.71-1.57(m,4H),δ1.47-1.19(m,28H),δ0.92-0.87(t,6H),δ0.71(dd,2H),δ0.2(d,6H)

[0425] Example 38

[0426] Synthesis of ((1-((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane

[0427]

[0428] According to general procedure E, (1-(((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane was prepared from octyl 6-bromohexanoate (5.00 g, 16.27 mmol) and dimethyl(octyl)silane (1.1 equivalent, 3.09 g, 17.90 mmol) using 770 μl of BrF(F3s)2borane catalyst solution (189 mg dissolved in 4.00 mL anhydrous toluene). The reaction was completed after 2 hours. The crude product was purified by rapid column chromatography with gradient elution (0-20% EtOAc in n-hexane) to give clear oil ((1-(((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane (4.26 g, 8.88 mmol, yield 55%).

[0429] 1H NMR (500MHz, benzene-d6) δ4.84(t,1H), δ3.68-3.64(dq,1H), δ3.30-3.27(dq,1H), δ2.94(t,2H), δ1.84-1.77(m,1H), δ1.75- 1.68(m,1H),δ1.54-1.44(m,8H),δ1.39(m,2H),δ1.36-1.17(m,20H),δ0.92-0.87(t,6H),δ0.71(dd,2H),δ0.22(d,6H)

[0430] Example 39

[0431] Synthesis of ((6-bromo-1-(decoxy)hexyl)oxy)(hexyl)dimethylsilane

[0432]

[0433] According to general procedure E, ((6-bromo-1-(decyloxy)hexyl)oxy)(hexyl)dimethylsilane was prepared from decyl 6-bromohexanoate (4.00 g, 11.93 mmol) and dimethyl(hexyl)silane (1.1 equivalent, 1.89 g, 13.12 mmol) using 573 μl of BrF(F3s)2borane catalyst solution (186 mg catalyst dissolved in 4.00 mL anhydrous toluene). The reaction was completed after 2 hours. The crude product was purified by rapid column chromatography with gradient elution (0-10% EtOAc in n-hexane) to give clear oil ((6-bromo-1-(decyloxy)hexyl)oxy)(hexyl)dimethylsilane (4.52 g, 9.42 mmol, 79% yield).

[0434] 1H NMR (500MHz, benzene-d6) δ4.78(t,1H), δ3.73-3.69(dq,1H), δ3.36-3.31(dq,1H), δ2.94(t,2H), δ1.71-1.56(m,4H), δ1.54-1.47(m,2H), δ1.46-1.38(m,4H), δ1.37-1.17(m,22H), δ0.93-0.88(t,6H), δ0.69(dd,2H), δ0.21(d,6H)

[0435] Example 40

[0436] Synthesis of ((10-bromo-1-(octoxy)decyl)oxy)(hexyl)dimethylsilane

[0437]

[0438] According to general procedure E, (10-bromo-1-(octoxy)decyl)oxy)(hexyl)dimethylsilane was prepared from octyl 10-bromodecanoate (5.00 g, 11.69 mmol) and dimethyl(hexyl)silane (1.1 equivalent, 1.86 g, 12.86 mmol) using 517 μl BrF(F3s)2borane catalyst (202 mg dissolved in 4.00 mL anhydrous toluene). The reaction was completed overnight. The crude product was purified by rapid column chromatography with gradient elution (0–10% EtOAc in n-hexane) to give clear oil ((10-bromo-1-(octoxy)decyl)oxy)(hexyl)dimethylsilane (3.60 g, 7.10 mmol, 61% yield). 1H NMR (500MHz, benzene-d6) δ4.87(t,1H), δ3.77-3.72(dq,1H), δ3.39-3.35(dq,1H), δ2.95(t,2H), δ1.86-1.78(m,1H), δ1.77-1.70(m,1H), δ1.67-1.61(p,2H), δ1.56-1.20(m,26H), δ1.17-1.11(p,4H), δ1.10-1.01(m,2H), δ0.94-0.86(m,6H), δ0.71(dd,2H), δ0.23(d,6H)

[0439] Example 41

[0440] Synthesis of ((1-((6-bromohexyl)oxy)decyl)oxy)(hexyl)dimethylsilane

[0441]

[0442] According to general procedure E, ((1-((6-bromohexyl)oxy)decyl)oxy)(hexyl)dimethylsilane was prepared from 6-bromohexyldecanoate (5.00 g, 14.91 mmol) and dimethyl(hexyl)silane (1.1 equivalent, 2.37 g, 16.40 mmol) using 717 μl of BrF(F3s)2borane catalyst solution (186 mg dissolved in 4.00 mL anhydrous toluene). The reaction was completed after 3 hours. The crude product was purified by rapid column chromatography with gradient elution (0-10% EtOAc in n-hexane) to give clear oil ((1-((6-bromohexyl)oxy)decyl)oxy)(hexyl)dimethylsilane (5.04 g, 10.51 mmol, yield 71%).

[0443] 1H NMR (500MHz, benzene-d6) δ4.84(t,1H), δ3.68-3.64(dq,1H), δ3.30-3.26(dq,1H), δ2.94(t,2H), δ1.85-1.77(m,1H), δ1.76-1.68(m,1H), δ1.61-1.41(m,8H), δ1.40-1.15(m,22H), δ0.92-0.88(m,6H), δ0.70(dd,2H), δ0.23(d,6H).

[0444] Example 42

[0445] Synthesis of ((1-((9-bromononyl)oxy)octyl)oxy)(hexyl)dimethylsilane

[0446]

[0447] According to general procedure E, (1-(((9-bromononyl)oxy)octyl)oxy)(hexyl)dimethylsilane was prepared from 9-bromononyl octanoate (5.00 g, 14.31 mmol) and dimethyl(hexyl)silane (1.1 equivalent, 2.27 g, 15.74 mmol) using 633 μl of BrF(F3s)2 borane catalyst solution (202 mg dissolved in 4.00 mL anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (0-10% EtOAc in n-hexane) to give clear oil ((1-(((9-bromononyl)oxy)octyl)oxy)(hexyl)dimethylsilane (6.00 g, 12.15 mmol, 85% yield).

[0448] 1H NMR (500MHz, benzene-d6) δ4.87(t,1H), δ3.77-3.72(dq,1H), δ3.39-3.35(dq,1H), δ2.95(t,2H), δ1.86-1.78(m,1H), δ1.77-1.68(m,1H) ,δ1.66-1.58(m,2H),δ1.57-1.18(m,24H),δ1.17-1.10(m,4H)δ1.09-1.01(m,2H),δ0.92-0.86(m,6H),δ0.71(dd,2H),δ0.23(d,6H)

[0449] Example 43

[0450] Synthesis of 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silicotetraane

[0451]

[0452] 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silicotetramonane was prepared from octyl 6-bromohexanoate (5.00 g, 16.27 mmol) and dimethyl(octyloxy)silane (1.1 equivalent, 3.37 g, 17.90 mmol) using 503 μl of BrF(F3s)2 borane catalyst solution (253 mg dissolved in 3.50 mL anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (0–10% EtOAc in n-hexane) to give clear oil 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silicotetramonane (3.78 g, 7.63 mmol, 47% yield).

[0453] 1H NMR(500MHz, benzene-d6)δ4.93(t,1H),δ3.85-3.83(dq,1H),δ3.76-3.73(t,2H),δ3.40-3.39(dq,1H),2.97(t,2H),δ1 .80-1.60(m,6H),δ1.60-1.50(m,2H),δ1.50-1.30(m,6H),δ1.57-1.18(m,18H),δ0.92-0.89(m,6H),δ0.23(d,6H)

[0454] Example 44

[0455] Synthesis of 1-bromo-8-hepty-10,10-dimethyl-7,9,11-trioxa-10-silane

[0456]

[0457] 1-Bromo-8-hepta-10,10-dimethyl-7,9,11-trioxa-10-silenodaeane was prepared from 6-bromohexyl octanoate (5.00 g, 16.27 mmol) and dimethyl(octoxy)silane (1.1 equivalent, 3.37 g, 17.90 mmol) with 706 μl of BrF(F3s)2 borane catalyst solution (206 mg dissolved in 4.00 mL anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (0–10% EtOAc in n-hexane) to give clear oil 1-bromo-8-hepta-10,10-dimethyl-7,9,11-trioxa-10-silenodaeane (5.00 g, 10.08 mmol, yield 62%).

[0458] 1H NMR (500MHz, benzene-d6) δ4.96(t,1H), δ3.79-3.71(dq,3H), δ3.34-3.30(dq,1H), δ2.94 (t,2H),δ1.92-1.75(m,2H),δ1.65-1.11(m,30H),δ0.90-0.87(m,6H),δ0.25(d,6H)

[0459] Example 45

[0460] Synthesis of 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane

[0461]

[0462] The reaction was carried out according to general procedure E, with octyl 6-bromohexanoate (5.0 g, 16.27 mmol) and 1,1,3,3-tetramethyl-1-octyldisiloxane (1.1 equivalent, 4.41 g, 17.90 mmol) prepared from 1,1,3,3-tetramethyl-3-octyldisiloxane using 782 μl of BrF(F3s)2 borane catalyst solution (186 mg dissolved in 4.00 mL anhydrous toluene). The reaction was completed after 3 hours. The crude product was purified by rapid column chromatography with gradient elution (0–10% EtOAc in n-hexane) to give clear oil 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (7.80 g, 14.08 mmol, 87% yield).

[0463] 1H NMR (500MHz, benzene-d6) δ4.92(dt,1H), δ3.85-3.80(dq,1H), δ3.40-3.36(dq,1H), δ2.96(t,2H), δ1.79-1.61(m,4 H), δ1.56-1.50(p,2H), δ1.48-1.20(p,26H), δ0.92-0.87(m,6H), δ0.66(m,2H), δ0.23(d,6H), δ0.19(s,6H).

[0464] Example 46

[0465] Synthesis of 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane

[0466]

[0467] According to general procedure E, 1-((1-(((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane was prepared from 6-bromohexyl octanoate (5.0 g, 16.27 mmol) and 1,1,3,3-tetramethyl-3-octyldisiloxane (1.1 eq, 4.41 g, 17.90 mmol) using 589 μl of BrF(F3s)2 borane catalyst solution (216 mg dissolved in 3.50 mL anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (0-10% EtOAc in n-hexane) to give clear oil 1-((1-(((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (6.92 g, 12.49 mmol, 77% yield).

[0468] 1H NMR (500MHz, benzene-d6) δ4.97(t,1H), δ3.79-3.75(dq,1H), δ3.35-3.30(dq,1H), δ2.94(t,2H), δ1.92 -1.75(m,2H),δ1.60-1.13(m,30H),δ0.92-0.87(m,6H),δ0.66(m,2H),δ0.22(d,6H),δ0.19(s,6H)

[0469] Example 47

[0470] Synthesis of 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octoxy)disiloxane

[0471]

[0472] According to general procedure E, 1-((6-bromo-1-(octyloxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane was prepared from octyl 6-bromohexanoate (5.0 g, 16.27 mmol) and 1,1,3,3-tetramethyl-1-(octyloxy)disiloxane (1.1 equivalent, 4.70 g, 17.90 mmol) using 144 μl of BrF(F3s)2borane catalyst solution (202 mg dissolved in 4.00 mL of anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (0-10% EtOAc in n-hexane) to give transparent oil 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octoxy)disiloxane (8.29 g, 14.55 mmol, 89% yield).

[0473] 1H NMR (500MHz, benzene-d6) δ4.95(dt,1H), δ3.86-3.82(dq,1H), δ3.76-3.72(t,2H), δ3.41-3.37(dq,1H), δ2.96(t,2H), δ1.82-1. 59(m,6H), δ1.56-1.51(p,2H), δ1.46-1.35(m,6H), δ1.34-1.18(m,18H), δ0.90-0.87(m,6H), δ0.27(d,6H), δ0.21(s,6H).

[0474] Example 48

[0475] Synthesis of 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane

[0476]

[0477] According to general procedure E, 1-((1-(((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octoxy)disiloxane was prepared from 6-bromohexyl octanoate (4.00 g, 13.01 mmol) and 1,1,3,3-tetramethyl-1-(octoxy)disiloxane (1.1 equivalent, 3.76 g, 14.32 mmol) using 565 μl of BrF(F3s)2 borane catalyst solution (206 mg dissolved in 4.00 mL anhydrous toluene). The reaction was carried out after stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (0-10% EtOAc in n-hexane) to give transparent oil 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (4.02 g, 7.05 mmol, yield 54%).

[0478] 1H NMR (500MHz, benzene-d6) δ5.00(dt,1H), δ3.82-3.71(m,3H), δ3.36-3.31(dq 1H), δ2.94(t,2H), δ1.95-1.76(m,2H), δ1.68-1.45(m,8H), δ1.45-1.11(m,22H), δ0.90-0.87(m,6H), δ0.29(d,6H), δ0.22(s,6H)

[0479] Example 49

[0480] Synthesis of (6-bromohexyl)dimethyl((1-(octoxy)octyl)oxy)silane

[0481]

[0482] According to general procedure E, (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane was prepared from octyl octanoate (5.00 g, 19.50 mmol) and (6-bromohexyl)dimethylsilane (1.1 equivalent, 4.79 g, 21.45 mmol) using 603 μl of BrF(F3s)2borane catalyst solution (248 mg dissolved in 3.43 mL of anhydrous toluene). The reaction was carried out overnight with stirring. The crude product was purified by rapid column chromatography with gradient elution (0–5% EtOAc in n-hexane) to give clear oil (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (9.11 g, 18.99 mmol, 97% yield). 1H NMR (500MHz, benzene-d6) δ4.87(dt,1H), δ3.77-3.72(dq,1H), δ3.40-3.35(dq 1H), δ2.99(t,2H), δ1.87-1.80(m,1H), δ1.77-1.70(m,1H), δ1.68-1.63(m,2H), δ1.57-1.49(p, 4H), δ1.48-1.40(p,2H), δ1.39-1.14(m,22H), δ0.92-0.88(m,6H), δ0.65(m,2H), δ0.23(d,6H).

[0483] Example 50

[0484] Synthesis of 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silane

[0485]

[0486] 1-Bromo-10-hepty-8,8-dimethyl-7,9,11-trioxa-8-silenodaeane was prepared from octyl octanoate (5.00 g, 19.50 mmol) and ((6-bromohexyl)oxy)dimethylsilane (1.1 equivalent, 5.13 g, 21.45 mmol) using 603 μl of BrF(F3s)2borane catalyst solution (253 mg dissolved in 3.50 mL of anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (0–5% EtOAc in n-hexane) to give clear oil 1-bromo-10-hepty-8,8-dimethyl-7,9,11-trioxa-8-silenodaeane (8.20 g, 10.08 mmol, 85% yield).

[0487] 1H NMR (500MHz, benzene-d6) δ4.99(dt,1H), δ3.86-3.84(dq,1H), δ3.70-3.67(t,2H), δ3.42-3.41(dq 1H), δ2.96(t,2H), δ1.87-1.81(m,1H), δ1.79-1.70(m,1H), δ1.70-1.64(m,2H ), δ1.62-1.40(m,8H), δ1.40-1.13(m,20H), δ0.91-0.89(m,6H), δ0.27(d,6H)

[0488] Example 51

[0489] Synthesis of 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silicotetraane

[0490]

[0491] According to general procedure E, 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silicotetraane was prepared from octyl 6-bromohexanoate (5.00 g, 16.27 mmol) and (2-hexyldecyl)oxy)dimethylsilane (1.1 eq, 5.38 g, 17.90 mmol) using 503 μl of BrF(F3s)2borane catalyst (253 mg catalyst dissolved in 3.50 mL anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (0-2% EtOAc in n-hexane) to give clear oil 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silicotetratriane (6.66 g, 10.96 mmol, 67% yield).

[0492] 1H NMR (500MHz, benzene-d6) δ4.93(dt,1H), δ3.86-3.82(dq,1H), δ3.72-3.71(d,2H), δ3.42-3.37(dq 1H), δ2.96(t,2H), δ1.81-1.47(m,9H), δ1.47-1.18(m,36H), δ0.91-0.88(m,9H), δ0.26(d,6H)

[0493] Example 52

[0494] Synthesis of 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silicotetraane

[0495]

[0496] 1-Bromo-8-hepty-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silicotetramonane was prepared from 6-bromohexyl octanoate (4.00 g, 13.01 mmol) and (2-hexyldecyl)oxy)dimethylsilane (1.1 equivalent, 4.30 g, 14.32 mmol) using 402 μl of BrF(F3s)2 borane catalyst solution (253 mg dissolved in 3.50 mL anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (0–2% EtOAc in n-hexane) to give clear oil 1-bromo-8-hepty-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silicotetramonane (4.03 g, 6.63 mmol, 51% yield).

[0497] 1H NMR (500MHz, benzene-d6) δ4.99(dt,1H), δ3.82-3.78(dq,1H),3.74-3.73(d,2H),3.37-3.33(dq 1H),2.96(t,2H),δ1.88-1.75(m,2H),δ1.75-1.45(m,9H),δ1.45-1.14(m,34H),δ0.92-0.89(m,9H),δ0.28(d,6H)

[0498] Example 53

[0499] Synthesis of triethyl(((9Z,12Z)-1-methoxyoctadec-9,12-dien-1-yl)oxy)silane

[0500]

[0501] According to general procedure F, triethyl(((9Z,12Z)-1-methoxyoctadecano-9,12-dien-1-yl)oxy)silane was prepared from methyl (9Z,12Z)-octadecano-9,12-dienoic acid (12.68 g, 43.07 mmol) and triethylsilane (5.16 g, 44.36 mmol) using 208 mg (0.43 mmol) BrF(F4)2borane catalyst. 1 The reaction was monitored by ¹H NMR. After purification, the product was a pale yellow oil triethyl(((9Z,12Z)-1-methoxyoctadec-9,12-dien-1-yl)oxy)silane (14.61 g, 35.56 mmol, yield 83%).

[0502] 1 H NMR (500MHz, benzene-d6) δ5.50-5.42(m,4H), δ4.74(t,1H), δ3.21(s,3H), δ2.86(t,2H), δ2.10-2.02(m,4H), δ1.77-1.68(m,1H), δ1.68-1. 58(m,1H),δ1.58-1.50(m,1H),δ1.50-1.40(m,1H),δ1.40-1.20(m,14H),δ1.03-0.99(t,9H),δ0.90-0.80(m,3H),δ0.67-0.62(q,6H)

[0503] Example 54

[0504] Synthesis of triethyl(((9Z,12Z,15Z)-1-methoxyoctadec-9,12,15-trien-1-yl)oxy)silane

[0505]

[0506] According to general procedure F, triethyl(((9Z,12Z,15Z)-1-methoxyoctadecano-9,12,15-trienyl)oxy)silane was prepared from methyl (9Z,12Z,15Z)-octadecano-9,12,15-trienyl)oxy)silane (11.55 g, 39.50 mmol) and triethylsilane (4.73 g, 40.68 mmol) using 191 mg (0.39 mmol) BrF(F4)2borane catalyst. The reaction mixture was stirred overnight at 30 °C. The reaction was monitored by TLC (hexane / ethyl acetate 9:1). After purification, the product was obtained as a pale yellow oil, triethyl(((9Z,12Z,15Z)-1-methoxyoctadecano-9,12,15-trienyl)oxy)silane (15.81 g, 38.68 mmol, 98% yield).

[0507] 1H NMR (500MHz, benzene-d6) δ5.32-5.17(m,6H), δ4.56(t,1H), δ3.02(s,3H), δ2.72-2.60(m,4H), δ1.93-1.75(m,4H), δ1.64-1.39(m,2H), δ1.36-1.22(m,2H), δ1.16-1.01(m,8H), δ0.84(t,9H), δ0.72(m,3H), δ0.50-0.42(q,6H)

[0508] Example 55

[0509] Synthesis of (((5Z,8Z,11Z,14Z,17Z)-1-ethoxyeicosico-5,8,11,14,17-penten-1-yl)oxy)triethylsilane

[0510]

[0511] According to general procedure F, (((5Z,8Z,11Z,14Z,17Z)-1-ethoxyeicosano-5,8,11,14,17-penten-1-yl)oxy)triethylsilane was prepared from (5Z,8Z,11Z,14Z,17Z)-eicosano-5,8,11,14,17-penten-1-yl)oxy)triethylsilane using 194 mg (0.40 mmol) BrF(F4)2 borane catalyst. 1 The reaction was monitored by ¹H NMR. The product was a pale yellow oil (((5Z,8Z,11Z,14Z,17Z)-1-ethoxyeicosico-5,8,11,14,17-penten-1-yl)oxy)triethylsilane (17.01 g, 38.08 mmol, 95% yield).

[0512] 1 H NMR (500MHz, benzene-d6) δ5.52-5.39(m,10H), δ4.82(t,1H), δ3.70-3.64(dp,1H), δ3.37-3.31(dp,1H), δ2.91-2.80(m,8H), δ2.16-2.07(m,2H) ,δ2.07-1.98(m,2H),δ1.83-1.74(m,1H),δ1.74-1.65(m,1H),δ1.65- 1.54(m,2H),δ1.15(t,3H),δ1.04(t,9H),δ0.92(t,3H),δ0.67(q,6H)

[0513] Example 56

[0514] Synthesis of triethyl(((4R)-1-methoxy-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)oxy)silane

[0515]

[0516] According to general procedure F, triethyl(((4R)-1-methoxy-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)valerate (1.82 g, 4.50 mmol) and triethylsilane (0.57 g, 4.95 mmol) were prepared using 21.72 mg (0.045 mmol) BrF(F4)2borane catalyst. The reaction was monitored by TLC (hexane / ethyl acetate 9:1, PMA visualization). The crude product was purified by rapid column chromatography with gradient elution (0-10% EtOAc in n-hexane) to give a white solid triethyl(((4R)-1-methoxy-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)oxy)silane (0.84 g, 1.61 mmol, 36% yield).

[0517] 1 H NMR (500MHz, benzene-d6) δ4.81-476(m,1H), δ4.76-4.68(m,1H), δ3.41(s,3H), δ3.25(d,3H), δ1.95-1. 10(m,25H),δ1.10-1.02(t,12H),δ1.00(d,3H),δ0.75(s,3H),δ0.71-0.66(dq,6H),δ0.57(s,3H)

[0518] Example 57

[0519] Synthesis of 6-methoxy-6-(triethylsilyl)oxy)hexyl-2-(decylthio)hexanoate

[0520]

[0521] According to general procedure F, 6-methoxy-6-(triethylsilyl)oxy)hexyl 2-(decylthio)hexanoate was prepared from 6-methoxy-6-oxohexyl)oxy)hexyl 2-(decylthio)hexanoate (10.1 g, 24.24 mmol) and triethylsilane (3.10 g, 26.66 mmol) using 117 mg (0.24 mmol) BrF(F4)2borane catalyst. The reaction was monitored by TLC (hexane / ethyl acetate 9:1, PMA visualization). The crude product was purified by rapid column chromatography with gradient elution (0-10% EtOAc in n-hexane) to give clear oil 6-methoxy-6-(triethylsilyl)oxy)hexyl 2-(decylthio)hexanoate (4.35 g, 8.16 mmol, 34% yield).

[0522] 1 H NMR (500MHz, benzene-d6) δ4.69(t,1H), δ4.12-4.03(m,2H), δ3.29(dt,1H), δ3.19 (s,3H)δ3.75-3.65(m,1H),δ3.65-3.57(m,1H),δ2.06-1.95(m,1H),δ1.79-1 .77(m,1H),δ1.77-1.63(m,1H),δ1.62-1.54(m,3H),δ1.53-1.46(m,2H),δ1 .43-1.14(m,22H),δ1.02(t,9H),δδ0.90(t,3H),δ0.80(t,3H),δ0.64(q,6H)

[0523] Example 58

[0524] Synthesis of 6-methoxy-6-((triethylsilyl)oxy)hexyl-2-(pentylthio)decanoate

[0525]

[0526] According to general procedure F, 6-methoxy-6-((triethylsilyl)oxy)hexyl 2-(pentylthio)decanoate was prepared from 6-methoxy-6-oxohexyl 2-(pentylthio)decanoate (9.00 g, 22.35 mmol) and triethylsilane (2.86 g, 24.59 mmol) using 108 mg (0.22 mmol) BrF(F4)2borane catalyst. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC (hexane / ethyl acetate 9 / 1, PMA visualization). The crude product was purified by rapid column chromatography with gradient elution (0-10% EtOAc in n-hexane) to give clear oil 6-methoxy-6-((triethylsilyl)oxy)hexyl 2-(pentylthio)decanoate (5.79 g, 11.16 mmol, 50% yield).

[0527] 1 H NMR (500MHz, benzene-d6) δ4.69(t,1H), δ4.14-4.03(m,2H), δ3.31(dt,1H), δ3.19 (s,3H)δ3.73-3.64(m,1H),δ3.62-3.53(m,1H),δ2.09-1.98(m,1H),δ1.84-1 .72(m,1H),δ1.70-1.62(m,1H),δ1.62-1.46(m,5H),δ1.46-1.33(m,4H),δ1 .31-1.12(m,16H),δ1.02(t,9H),δδ0.89(t,3H),δ0.81(t,3H),δ0.64(q,6H)

[0528] Example 59

[0529] Synthesis of 6-ethoxy-6-((triethylsilyl)oxy)hexyl-2-hexyldecanoate

[0530]

[0531] In a dry 100 mL flask equipped with a stir bar, rubber diaphragm, thermometer, and nitrogen inlet, 6-ethoxy-6-oxohexyl-2-hexyldecanoate (23.9 g, 60.0 mmol, 1.0 equivalent) was dissolved in anhydrous toluene (30 mL) under inert conditions (nitrogen). Next, a toluene solution of catalyst, BrF(F4)2 (14.49 mg in 600 μL of anhydrous toluene), was added. Finally, triethylsilane (7.47 g, 10.3 mL, 64.2 mmol, 1.07 equivalent) was added dropwise to maintain the reaction temperature between 24 °C and 28 °C. Occasionally, the release of hydrogen gas is observable at the start of the reaction, indicating the presence of a small amount of residual water in the system, but this does not affect the results. The reaction was further stirred overnight (approximately 20 hours) at room temperature. The reaction was monitored by TLC and NMR. After the reaction was complete, 1 ml EtOAc, 0.6 ml MeCN, and silica gel were added to the reaction mixture, and the mixture was stirred for another 10 min. The silica gel was then filtered off, and the mixture was washed with 2 × 50 ml n-pentane. Volatiles were removed under reduced pressure to obtain a product (29.00 g, 57.89 mmol, 97% yield) that could be used without further purification.

[0532] 1H NMR (500MHz, benzene-d6) δ4.79(t,1H), δ4.10(t,2H), δ3.66(m,1H), δ3.32(m,1H), δ2.50-2.39 (m,1H),δ1.86-1.20(br.m,32H),δ1.15(t,3H),δ1.04(t,9H),δ.91(q,6H),δ.67(q,6H),

[0533] Example 60

[0534] Synthesis of 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicatadecane

[0535]

[0536] 1-Bromo-10-hepta-8,8-dimethyl-7,9,11-trioxa-8-silicatadecane was prepared from hepta-octanoate (727.19 mg, 3.00 mmol, 1.0 equivalent) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 equivalent) using 100 μl of BrF(F3s)2borane catalyst solution (1.34 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out overnight with stirring. The crude product was purified by rapid column chromatography with gradient elution (20%–66% DCM in petroleum ether) to give clear oil 1-bromo-10-hepta-8,8-dimethyl-7,9,11-trioxa-8-silicatadecane (1.34 g, 2.86 mmol, 95% yield).

[0537] 1 H NMR(500MHz, benzene-d6)δ4.96(m,1H),δ3.84-3.79(m,1H),δ3.66(dt,2H),δ3.43-3.35(m,1H),δ 2.96(t,2H),δ1.87-1.77(m,2H),δ1.70-1.10(br.m,28H),δ0.91-0.86(m,6H),δ0.27(m,6H)

[0538] Example 61

[0539] Synthesis of 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicoeicosane

[0540]

[0541] 1-Bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicoeicosane was prepared from nonyl octanoate (811.35 mg, 3.00 mmol, 1.0 equivalent) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 equivalent) using 100 μl of BrF(F4)2borane catalyst solution (1.45 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out overnight with stirring (TLC: petroleum ether:chloroform 1:1, ~0.4 Rf). The crude product was purified by rapid column chromatography with gradient elution (20%-66% DCM in petroleum ether) to give transparent oil 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicoeicosane (1.32 g, 2.59 mmol, yield 86%).

[0542] 1 H NMR (500MHz, benzene-d6) δ4.99(dt,1H), δ3.89-3.80(m,1H), δ3.68(t,2H), δ3.46-3.37(m,1H), δ2.96(t,2 H), δ1.98-1.75(m,2H), δ1.73-1.39(br.m,10H), δ1.38-1.11(br.m,22H), δ0.91(m,6H), δ0.27(d,6H)

[0543] Example 62

[0544] Synthesis of 1-bromo-10-hexyl-8,8-dimethyl-7,9,11-trioxa-8-silenodecane

[0545]

[0546] 1-Bromo-10-hexyl-8,8-dimethyl-7,9,11-trioxa-8-silenodae was prepared from octyl heptaate (727.19 mg, 3.0 mmol) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 equivalence) using 100 μl of BrF(F3s)2borane catalyst solution (1.34 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out overnight with stirring (TLC petroleum ether:chloroform 1:1, ~0.4 Rf). The crude product was purified by rapid column chromatography with gradient elution (20%–66% DCM in petroleum ether) to give clear oil 1-bromo-10-hepta-8,8-dimethyl-7,9,11-trioxa-8-silenodae (1.26 g, 2.71 mmol, 90% yield).

[0547] 1H NMR(500MHz, benzene-d6)δ4.98(dd,1H),δ3.87-3.82(m,1H),δ3.68(t,2H),δ3.43-3.38(m,1H),δ 2.96(t,2H),δ1.93-1.76(m,2H),δ1.70-1.12(br.m,28H),δ0.92-0.87(m,6H),δ0.26(d,6H)

[0548] Example 63

[0549] Synthesis of 1-bromo-8,8-dimethyl-10-octyl-7,9,11-trioxa-8-silenodecane

[0550]

[0551] 1-Bromo-8,8-dimethyl-10-octyl-7,9,11-trioxa-8-silenodae was prepared from octyl nonanoate (811.35 mg, 3.0 mmol) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 eq) using 100 μl of BrF(F3s)2borane catalyst solution (1.34 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out overnight with stirring (TLC petroleum ether:chloroform 1:1, ~0.4 Rf). The crude product was purified by rapid column chromatography with gradient elution (20%–66% DCM in petroleum ether) to give clear oil 1-bromo-8,8-dimethyl-10-octyl-7,9,11-trioxa-8-silenodae (1.29 g, 2.62 mmol, 87% yield).

[0552] 1 H NMR (500MHz, benzene-d6) δ4.99(m,1H), δ3.88-3.83(m,1H), δ3.68(t,2H), δ3.44-3.39(m,1H), δ2 .96(t,2H),δ1.90-1.80(m,2H),δ1.71-1.14(br.m,32H),δ0.92-0.88(m,6H),δ0.27(d,6H)

[0553] Example 64

[0554] Synthesis of 1-bromo-8,8-dimethyl-10-nonyl-7,9,11-trioxa-8-silane-heptadecane

[0555]

[0556] 1-Bromo-8,8-dimethyl-10-nonyl-7,9,11-trioxa-8-silachadecane was prepared from hexyl decanoate (769.3 mg, 3.00 mmol, 1.0 equivalent) and ((6-bromohexyl)oxy)dimethylsilane (789.44 g, 3.30 mmol, 1.1 equivalent) using 100 μl of BrF(F4)2 borane catalyst solution (1.45 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out overnight with stirring. The crude product was purified by rapid column chromatography with gradient elution (20–65% DCM in petroleum ether) to give clear oil 1-bromo-8,8-dimethyl-10-nonyl-7,9,11-trioxa-8-silachadecane (1.20 g, 2.42 mmol, 81% yield).

[0557] 1 H NMR (500MHz, benzene-d6) δ4.98(m,1H), δ3.86-3.79(m,1H), δ3.68(t,2H), δ3.43-3.36 (m,1H),δ2.96(t,2H),δ1.95-1.23(br.m,32H),δ0.93-0.86(m,6H),δ0.26(d,6H)

[0558] Example 65

[0559] Synthesis of 1-bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silicotetraane

[0560]

[0561] 1-Bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silicotetramonane was prepared from decanoate (769.27 mg, 3.00 mmol) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 equivalence) using 100 μl of BrF(F4)2 borane catalyst solution (1.45 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out overnight with stirring. The crude product was purified by rapid column chromatography with gradient elution (20–65% DCM in petroleum ether) to give clear oil 1-bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silicotetramonane (1.04 g, 2.11 mmol, 70% yield).

[0562] 1H NMR (500MHz, benzene-d6) δ4.98(m,1H), δ3.88-3.81(m,1H), δ3.68(t,2H), δ3.45-3.37 (m,1H),δ2.96(t,2H),δ1.95-1.27(br.m,32H),δ0.95-0.84(m,6H),δ0.26(d,6H)

[0563] Example 66

[0564] Synthesis of ((6-bromohexyl)oxy)dimethyl((oxocyclohexadecane-2-yl)oxy)silane

[0565]

[0566] According to general procedure E, ((6-bromohexyl)oxy)dimethyl((oxetane-2-yl)oxy)silane was prepared from oxetane-2-one (1.00 g, 3.827 mmol) and ((6-bromohexyl)oxy)dimethylsilane (1.00 g, 4.21 mmol, 1.1 equivalents) using 100 μl of BrF(F3s)2borane catalyst solution (8.55 mg dissolved in 100 μl of anhydrous toluene). The reaction was completed after stirring overnight. The solvent was evaporated, and clear oil ((6-bromohexyl)oxy)dimethyl((oxetane-2-yl)oxy)silane (1.83 g, 3.83 mmol, 100% yield) was obtained.

[0567] 1 H NMR (500MHz, benzene-d6) δ4.80(dd,1H), δ3.85-3.78(m,1H), δ3.68(t,2H), δ3.40(t,2H ), δ3.31-3.22(m,1H), δ1.90-1.83(m,2H), δ1.75-1.18(br.m,32H), δ0.15(d,6H)

[0568] Example 67

[0569] Synthesis of 1-(4-bromobutoxy)-1,1,3,3-tetramethyl-3-((1-(octoxy)octyl)oxy)disiloxane

[0570]

[0571] According to general procedure E, 1-(4-bromobutoxy)-1,1,3,3-tetramethyl-3-((1-(octoxy)octyl)oxy)disiloxane was prepared from octyl octanoate (750 mg, 2.925 mmol) and 1-(4-bromobutoxy)-1,1,3,3-tetramethyldisiloxane (0.75 equivalents, 625.9 mg, 2.190 mmol) using 100 μl of BrF(F3s)2borane catalyst solution (6.54 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (10-90% EtOAc in petroleum ether) to give transparent oil 1-(4-bromobutoxy)-1,1,3,3-tetramethyl-3-((1-(octoxy)octyl)oxy)disiloxane (1.27 g, 2.35 mmol, 80% yield).

[0572] 1 H NMR (500MHz, benzene-d6) δ4.79 (dd, 1H), δ3.73-3.62 (m, 2H), δ3.44 (t, 1H), δ3.32-3 .26(m,1H),δ1.72-1.19(br.m,30H),δ0.89-0.86(m,6H),δ0.15-0.08(d,12H)

[0573] Example 68

[0574] Synthesis of 1-bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silicotetraane

[0575]

[0576] 1-Bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silicotetramonane was prepared from decyl acetate (400.03 mg, 1.997 mmol) and ((6-bromohexyl)oxy)dimethylsilane (477.73 mg, 1.997 mmol, 1.0 equivalent) using 100 μl of BrF(F3s)2borane catalyst solution (8.93 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out overnight with stirring. The crude product was purified by rapid column chromatography with gradient elution (0-100% DCM and 1% TEA in petroleum ether) to give clear oil 1-bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silicotetramonane (743 mg, 1.69 mmol, 85% yield).

[0577] 1H NMR (500MHz, benzene-d6) δ5.05(m,1H), δ3.82-3.74(m,1H), δ3.66-3.55(m,2H), δ3.38-3. 31(m,1H),δ3.01-2.92(m,2H),δ1.66-1.10(br.m,27H),δ0.91(t,3H),δ0.20(t,6H)

[0578] Example 69

[0579] Synthesis of 1-bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silicotetraane

[0580]

[0581] 1-Bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silicotetramonane was prepared from decyl butyrate (1.00 g, 4.028 mmol, 1.0 equivalent) and ((6-bromohexyl)oxy)dimethylsilane (1.060 g, 4.431 mmol, 1.1 equivalent) using 100 μl of BrF(F3s)2borane catalyst solution (9.0 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out overnight with stirring. The crude product was purified by rapid column chromatography with gradient elution (20–65% DCM in petroleum ether) to give clear oil 1-bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silicotetramonane (1.88 g, 4.0 mmol, 100% yield).

[0582] 1 H NMR (500MHz, benzene-d6) δ4.81(dd,1H), δ3.70-3.63(m,3H), δ3.40(t,2H), δ3.34-3.29(m ,1H),δ1.90-1.83(m,2H),δ1.69-1.21(br.m,26H),δ0.93-0.86(m,6H),δ0.16(d,6H)

[0583] Example 70

[0584] Synthesis of 1-bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silicotetraane

[0585]

[0586] 1-Bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silicotetraane was prepared from dodecyl butyrate (750 mg, 2.925 mmol, 1.0 equivalent) and ((6-bromohexyl)oxy)dimethylsilane (699.70 mg, 2.925 mmol, 1.0 equivalent) using 100 μl of BrF(F3s)2borane catalyst solution (6.54 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out overnight with stirring. The crude product was purified by rapid column chromatography with gradient elution (20–65% DCM in petroleum ether) to give clear oil 1-bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silicotetraane (1.38 g, 2.79 mmol, 96% yield).

[0587] 1 H NMR (500MHz, benzene-d6) δ4.81(dd,1H), δ3.70-3.63(m,3H), δ3.40(t,2H), δ3.34-3.29(m ,1H),δ1.90-1.83(m,2H),δ1.68-1.21(br.m,30H),δ0.93-0.86(m,6H),δ0.16(d,6H)

[0588] Example 71

[0589] Synthesis of 13-bromo-6,6-dimethyl-4-nonyl-3,5,7-trioxa-6-silyltridecane

[0590]

[0591] 13-Bromo-6,6-dimethyl-4-nonyl-3,5,7-trioxa-6-siltadecae was prepared from ethyl decanoate (400 mg, 1.997 mmol, 1.0 equivalent) and ((6-bromohexyl)oxy)dimethylsilane (525.46 mg, 2.196 mmol, 1.1 equivalent) using 100 μl of BrF(F3s)2borane catalyst solution (4.46 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was filtered through a short silica gel column to give clear oil 13-bromo-6,6-dimethyl-4-nonyl-3,5,7-trioxa-6-siltadecae (883 mg, 1.51 mmol, 75% yield). 1H NMR (500MHz, benzene-d6) δ5.04(dt,1H), δ3.89(m,1H), δ3.76(t,2H), δ3.48(m,1H), δ3.06(t,2H), δ2.01 -1.93(m,2H),δ1.70-1.52(m,6H),δ1.51-1.33(m,12H),δ1.28(m,7H),δ1.01(t,3H),δ0.33(d,6H)

[0592] Example 72

[0593] Synthesis of 13-bromo-6,6-dimethyl-4-undecyl-3,5,7-trioxa-6-silyltridecane

[0594]

[0595] 13-Bromo-6,6-dimethyl-4-undecyl-3,5,7-trioxa-6-siltadecae was prepared from ethyl dodecanoate (1500 mg, 6.568 mmol, 1.0 equivalent) and ((6-bromohexyl)oxy)dimethylsilane (1493 mg, 6.240 mmol, 0.95 equivalent) using 100 μl of BrF(F3s)2borane catalyst solution (29.36 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was filtered through a short silica gel column to give clear oil 13-bromo-6,6-dimethyl-4-undecyl-3,5,7-trioxa-6-siltadecae (3.04 g, 5.66 mmol, 86% yield).

[0596] 1 H NMR(500 MHz,Toluene-d8)δ4.92(t,1H),δ3.81-3.73(m,1H),δ3.63(t,2H),δ3.39-3.32(m,1H), δ2.95(t,2H), δ1.88-1.74(m,2H), δ1.61-1.10(br.m,29H), δ0.90(t,3H), δ0.21(d,6H)

[0597] Example 73

[0598] Synthesis of 15-bromo-8,8-dimethyl-6-nonyl-5,7,9-trioxa-8-silcaptadecane

[0599]

[0600] 15-Bromo-8,8-dimethyl-6-nonyl-5,7,9-trioxa-8-silcaptadecane was prepared from butyl decanoate (400 mg, 1.75 mmol) and ((6-bromohexyl)oxy)dimethylsilane (460.91 g, 1.93 mmol, 1.1 equivalents) using 100 μl of BrF(F3s)2borane catalyst solution (7.83 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was filtered through a short silica gel column to obtain clear oil 15-bromo-8,8-dimethyl-6-nonyl-5,7,9-trioxa-8-silcaptadecane (745 mg, 1.45 mmol, yield 83%).

[0601] 1 H NMR(500 MHz, benzene-d6)δ4.97(dt,1H),δ3.86-3.77(m,1H),δ3.67(t,2H),δ3.43-3.32(m,1H),δ2 .96(t,2H),δ1.93-1.76(m,2H),δ1.66-1.10(br.m,26H),δ0.91(t,6H),δ0.25(d,6H)

[0602] Example 74

[0603] Synthesis of 15-bromo-8,8-dimethyl-6-undecyl-5,7,9-trioxa-8-silcaptadecane

[0604]

[0605] 15-Bromo-8,8-dimethyl-6-undecyl-5,7,9-trioxa-8-siladecadecane was prepared from butyl dodecanoate (200 mg, 0.78 mmol) and ((6-bromohexyl)oxy)dimethylsilane (205.24 mg, 0.858 mmol, 1.1 equivalence) using 100 μl of BrF(F3s)2borane catalyst solution (0.70 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was filtered through a short silica gel column to give clear oil 15-bromo-8,8-dimethyl-6-undecyl-5,7,9-trioxa-8-siladecadecane (415 mg, 0.78 mmol, 100% yield). 1H NMR(500 MHz, benzene-d6) δ5.01 (dt, 1H), δ3.90-3.82 (m, 1H), δ3.72 (t, 2H), δ3.46-3.39 (m, 1H), δ3.02 (t,2H),δ2.00-1.79(m,2H),δ1.70-1.15(br.m,30H),δ0.99-0.93(m,6H),δ0.29(d,6H)

[0606] Example 75

[0607] Synthesis of 13-bromo-4,6,6-trimethyl-3,5,7-trioxa-6-silyltridecane

[0608]

[0609] 13-Bromo-4,6,6-trimethyl-3,5,7-trioxa-6-siltadecadecane was prepared from ethyl acetate (200 mg, 2.27 mmol) and ((6-bromohexyl)oxy)dimethylsilane (597.35 mg, 2.50 mmol, 1.1 equivalence) using 100 μl of BrF(F3s)2borane catalyst solution (5.07 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out overnight with stirring. The crude product was purified by rapid column chromatography with gradient elution (0-30% EtOAc and 1% TEA in petroleum ether) to give clear oil 13-bromo-4,6,6-trimethyl-3,5,7-trioxa-6-siltadecadecane (325 mg, 0.99 mmol, 44% yield).

[0610] 1H NMR (500MHz, benzene-d6) δ5.01(q,1H), δ3.80-3.66(m,1H), δ3.61(t,2H), δ3.36-3. 26(m,1H),δ2.95(t,2H),δ1.56-1.36(m,7H),δ1.20-1.10(m,7H),δ0.18(s,6H)

[0611] Example 76

[0612] Synthesis of 1-bromo-9-heptyl-7,7-dimethyl-6,8,10-trioxa-7-silicatadecane

[0613]

[0614] 1-Bromo-9-hepta-7,7-dimethyl-6,8,10-trioxa-7-silicatadecane was prepared from octyl octanoate (1.54 mg, 6.0 mmol) and ((5-bromopentyl)oxy)dimethylsilane (1.486 mg, 6.6 mmol, 1.1 equivalence) using 100 μl of BrF(F3s)2borane catalyst solution (2.9 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (0-5% EtOAc in petroleum ether) to give clear oil 1-bromo-9-hepta-7,7-dimethyl-6,8,10-trioxa-7-silicatadecane (2.63 g, 5.46 mmol, 91% yield).

[0615] 1 H NMR (500MHz, benzene-d6) δ5.08(q,1H), δ3.97-3.90(m,1H), δ3.73(t,2H), δ3.54-3.47(m,1H), δ3 .07(t,2H),δ2.05-1.84(m,2H),δ1.81-1.27(br.m,28H),δ1.05-0.95(m,6H),δ0.35(d,6H)

[0616] Example 77

[0617] Synthesis of 1-bromo-10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silicatadecane

[0618]

[0619] 1-Bromo-10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silicatadecane was prepared from octyl octylthioate (817.47 mg, 3.00 mmol) and ((6-bromohexyl)oxy)dimethylsilane (789.44 mg, 3.30 mmol, 1.1 equivalence) using 100 μl of BrF(F3s)2borane catalyst solution (1.34 mg dissolved in 100 μl of anhydrous toluene). The reaction was completed after stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (20–65% DCM in petroleum ether) to give clear oil 1-bromo-10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silicatadecane (1.40 g, 2.74 mmol, 91% yield).

[0620] 1 H NMR (500MHz, benzene-d6) δ5.09(t,1H), δ3.74-3.67(m,2H), δ3.00-2.92(m,2H), δ2.81-3.63( m,2H),δ2.09-1.85(m,2H),δ1.75-1.06(br.m,24H),δ0.92-0.81(m,10H),δ0.29(d,6H)

[0621] Example 78

[0622] Synthesis of (Z)-1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicos-17-ene

[0623]

[0624] (Z)-1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicoe ...

[0625] 1H NMR(500MHz, benzene-d6)δ5.49-5.36(m,2H),δ4.97(dd,1H),δ3.86-3.79(m,1H),δ3.67(t,2H),δ3.42-3.34(m,1H),δ 2.96(t,2H),δ2.08-1.97(m,4H),δ1.92-1.75(m,2H),δ1.69-1.08(br.m,24H),δ0.96-0.87(m,6H),δ0.25(d,6H)

[0626] Example 79

[0627] Synthesis of (Z)-1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicoeicos-14-ene

[0628]

[0629] (Z)-1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicoe ...

[0630] 1 H NMR (500MHz, benzene-d6) δ5.63-5.49(m,2H), δ4.98(dd,1H), δ3.90-3.82(m,1H), δ3.67(t,2H), δ3.48-3.40(m,1H), δ2.96(t,2H ), δ2.49-2.43(m,2H), δ2.11-2.03(m,2H), δ1.61-1.40(m,6H), δ1.38-1.10(br.m,20H), δ0.96-0.84(m,6H), δ0.25(d,6H)

[0631] Example 80

[0632] Synthesis of 10-bromo-3-((8Z,11Z)-heptadec-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-sildecane

[0633]

[0634] According to general procedure E, 10-bromo-3-((8Z,11Z)-heptadec-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-sildecane was prepared from methyl (9Z,12Z)-octadecano-9,12-dienoic acid (395.00 mg, 1.341 mmol) and ((4-bromobutyl)oxy)dimethylsilane (311.59 mg, 1.476 mmol, 1.1 equivalents) using 100 μl of BrF(F3s)2borane catalyst solution (6.00 mg dissolved in 100 μl of anhydrous toluene). The reaction was carried out with stirring overnight. The crude product was purified by rapid column chromatography with gradient elution (0-100% EtOAc in n-hexane) to give transparent oil 10-bromo-3-((8Z,11Z)-heptadec-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-sildecane (390 mg, 0.77 mmol, yield 58%).

[0635] 1 H NMR (500MHz, benzene-d6) δ5.53-5.40(m,4H), δ4.77(t,1H), δ3.52(t,2H), δ3.24(s,3H), δ3.01(t,2H), δ2.87(t ,2H),δ2.12-2.01(m,4H),δ1.85-1.61(m,2H),δ1.53-1.07(br.m,20H),δ0.94-0.79(m,3H),δ0.15(s,6H)

[0636] Chromatographic methods for the purification of lipids and intermediates

[0637] Purification method A

[0638] Elution buffer A: DCM:MeOH:aq.NH3 80:20:1, elution buffer B: DCM; full gradient A:B 0:100->100:0. Sample loading: ~200mg; column size: 25g SiO2. Before loading the sample, adjust the column with ~400mL of A and then ~400mL of B.

[0639] Purification method B

[0640] Elution buffer A: EtOAc, Elution buffer B: Petroleum ether + 1% Et3N; Full gradient A:B 0:100->100:0. Sample loading: ~200 mg; Column size: 25 g SiO2. Adjust the column with ~400 mL of B before loading the sample.

[0641] Synthetic methods (general procedures, GP) for the synthesis of intermediates and lipids.

[0642] General procedure G

[0643] The MW reaction flask contained 1.0 equivalent of a mixed ω-bromoalkylsilyl acetal and 1.0 equivalent of an amine, anhydrous acetonitrile (1.0 mmol of the mixed ω-bromoalkylsilyl acetal / 1.54 mL of anhydrous acetonitrile), and anhydrous cyclopentyl methyl ether (1.0 mmol of the mixed ω-bromoalkylsilyl acetal / 0.51 mL of anhydrous cyclopentyl methyl ether). K₂CO₃ (2.0 equivalent) and KI (0.5 equivalent) were added to the stirred reaction mixture, which was then purged with argon and sealed. The resulting mixture was stirred at 80 °C for 8 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and brine, followed by vigorous stirring for 15 minutes. The organic phases were separated, dried over Na₂SO₄, filtered, and concentrated.

[0644] General Procedure H

[0645] The MW reaction flask contained 2.5 equivalents of a mixed ω-bromoalkylsilyl acetal and 1.0 equivalent of an amine, 2.5 equivalents of diisopropylethylamine, and anhydrous ethanol (1.0 mmol of the mixed ω-bromoalkylsilyl acetal / 2.4 ml of anhydrous ethanol), and was purged and sealed with argon. The resulting mixture was stirred at 63 °C for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and brine, followed by vigorous stirring for 15 minutes. The organic phase was separated, dried over Na₂SO₄, filtered, and concentrated.

[0646] General Procedure I

[0647] The MW reaction flask contained 2.5 equivalents of a mixed ω-bromoalkylsilyl acetal and 1.0 equivalent of an amine, anhydrous acetonitrile (1.0 mmol of the mixed ω-bromoalkylsilyl acetal / 0.95 mL of anhydrous acetonitrile), and anhydrous cyclopentyl methyl ether (1.0 mmol of the mixed ω-bromoalkylsilyl acetal / 0.31 mL of anhydrous cyclopentyl methyl ether). K₂CO₃ (3.0 equivalents) and KI (0.2 equivalents) were added to the stirred reaction mixture, which was then purged with argon and sealed. The resulting mixture was stirred at 60 °C for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and brine, followed by vigorous stirring for 15 minutes. The organic phases were separated, dried over Na₂SO₄, filtered, and concentrated.

[0648] General Procedure J

[0649] The MW reaction flask contained 1.0 equivalent of acetaldehyde, 1.0 equivalent of amine, 1.0 equivalent of acetic acid, and anhydrous toluene (1.0 mmol aldehyde / 6.5 mL anhydrous toluene). After stirring for 15 minutes, 3.0 equivalents of sodium triacetoxyborohydride were added, and the resulting mixture was stirred overnight. The reaction mixture was then diluted with ethyl acetate and NaHCO3 solution, and stirred vigorously for 5 minutes to allow for phase separation. The organic phase was washed with brine, separated, dried on Na2SO4, filtered, and concentrated.

[0650] General procedure K

[0651] The MW reaction flask contained a mixture of ω-bromoalkylsilyl acetals, an amine, anhydrous acetonitrile (1.0 mmol of ω-bromoalkylsilyl acetal / 4.0 mL of anhydrous acetonitrile), and anhydrous cyclopentyl methyl ether (ω-bromoalkylsilyl acetal / 1.33 mL of anhydrous cyclopentyl methyl ether). K₂CO₃ (2.0 equivalents) and KI (0.2 equivalents) were added to the stirred reaction mixture, which was then purged with argon and sealed. The resulting mixture was stirred at 62 °C for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and brine, followed by vigorous stirring for 15 minutes. The organic phases were separated, dried over Na₂SO₄, filtered, and concentrated.

[0652] General Procedure L

[0653] The MW reaction flask contained 1.0 equivalent of a mixed ω-bromoalkylsilyl acetal, 2.0 equivalent of an amine, 2.0 equivalent of K₂CO₃, and anhydrous ethanol (1.0 mmol of the mixed ω-bromoalkylsilyl acetal / 0.32 ml of anhydrous ethanol), and was purged with argon and sealed. The resulting mixture was stirred overnight at room temperature. The reaction mixture was then partitioned between ethyl acetate and brine, and stirred vigorously for 15 minutes. The organic phase was separated and dried over Na₂SO₄, filtered, and concentrated.

[0654] General procedure M

[0655] The MW reaction flask contained 1.0 equivalence of a mixed silyl acetal, 3.0 equivalence of an amine, tetrahydrofuran (1.0 mmol of the mixed silyl acetal / 4.5 mL of tetrahydrofuran), and water (1.0 mmol of the mixed silyl acetal / 0.9 mL of water). 3.0 equivalence of trifluoroacetic acid was added to the reaction mixture, and the mixture was stirred for 6 hours. Then, 2.3 equivalences of sodium triacetoxyborohydride were added to the reaction mixture, and the mixture was stirred overnight at 60 °C. The reaction mixture was cooled to room temperature, diluted with a saturated NaHCO3 solution, and extracted with ethyl acetate. The organic phase was washed with brine, separated, dried over Na2SO4, filtered, and concentrated.

[0656] General procedure N

[0657] The MW reaction flask contained 1.0 equivalent of ω-bromoalkyl ester, amine, 0.2 equivalent of KI, 2.2 equivalents of K₂CO₃, and anhydrous DMF (1.0 mmol ω-bromoalkyl ester / 8.73 mL anhydrous DMF), and was purged with argon and sealed. The resulting mixture was stirred at 63 °C for 18 h. The reaction mixture was then cooled to room temperature, diluted with saturated NaHCO₃ solution, and extracted with ethyl acetate. The organic phase was washed with saturated NaHCO₃ solution and brine, separated, dried on Na₂SO₄, filtered, and concentrated.

[0658] General Procedure O

[0659] The MW reaction flask contained 2.5 equivalents of a mixed ω-bromoalkylsilyl acetal, 1.0 equivalent of an amine, 3.0 equivalents of K₂CO₃, 0.2 equivalents of KI, and anhydrous DMF (1.0 mmol of mixed ω-bromoalkylsilyl acetal / 2.6 mL of anhydrous DMF), and was purged and sealed with argon. The resulting mixture was stirred at 64 °C for 24 h. The reaction mixture was then concentrated to dryness under vacuum, and the residue was purified by rapid column chromatography.

[0660] General procedure P

[0661] The MW reaction flask contained 1.0 equivalent of propargylamine derivative, 1.5 equivalent of azide derivative, 0.33 equivalent of CuBr, 0.33 equivalent of 1,1,4,7,7-pentamethyldiethylenetriamine, and anhydrous DMF (0.1 mmol propargylamine derivative / 3.0 mL anhydrous DMF), and was purged with argon and sealed. The resulting mixture was stirred at 50 °C for 20 h. The reaction mixture was then concentrated to dryness under vacuum, and the residue was purified by rapid column chromatography.

[0662] Examples of intermediate synthesis

[0663] Example 81

[0664] Synthesis of 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)amino)but-1-ol

[0665]

[0666] 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)amino)but-1-ol was prepared from ((6-bromo-1-(octoxy)hexyl)oxy)dimethyl(octyl)silane (300.0 mg, 0.625 mmol, 1.0 eq) and 4-amino-1-butanol (1115.01 mg, 12.51 mmol, 20.0 eq). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 100.0 mg, 0.205 mmol, yield 33%.

[0667] 1 H NMR (500MHz, benzene-d6) δ4.89(t,1H), δ3.78-3.73(m,1H), δ3.65-3.62(m,2H), δ3.39-3.34(m,1H), δ2.31-2.27(m,4H), δ1.83-1.20(m,36H), δ0.94-0.88(m,6H), δ0.76-0.72(m,2H), δ0.26(d,6H)

[0668] Example 82

[0669] Synthesis of 13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silicoserosan-1-ol

[0670]

[0671] 13-Heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silicoseriate-1-ol was prepared from ((1-((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane (300.0 mg, 0.625 mmol, 1.0 equivalent) and 4-amino-1-butanol (1115.01 mg, 12.51 mmol, 20.0 equivalent) according to general procedure L. The crude product was purified by rapid column chromatography according to purification method A to obtain a colorless oil product, 95.0 mg, 0.195 mmol, yield 31%.

[0672] 1 H NMR (500MHz, benzene-d6) δ4.89(t,1H), δ3.77-3.71(m,1H), δ3.64-3.61(m,2H), δ3.39-3.32(m,1H), δ2.30-2.29(m,4H), δ1.87-1.18(m,36H), δ0.92-0.88(m,6H), δ0.75-0.71(m,2H), δ0.25(d,6H)

[0673] Example 83

[0674] Synthesis of 4-((6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol

[0675]

[0676] 4-((6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxane)oxy)hexyl)amino)but-1-ol was prepared from 1-((6-bromo-1-(octoxy)hexyl)oxy)1,1,3,3-tetramethyl-3-(octoxy)disiloxane (100.00 mg, 0.175 mmol, 1.0 equivalent) and 4-amino-1-butanol (312.87 mg, 3.509 mmol, 20.0 equivalent)

[0677] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ3.93-3.84(m,1H), δ3.78-3.75(t,2H), δ3.64-3.61(m,2H), δ3.49- 3.35(m,1H),δ2.36-2.25(m,4H),δ1.93-1.17(m,36H),δ0.92-0.88(m,6H),δ0.31(d,6H),δ0.25(s,6H)

[0678] Example 84

[0679] Synthesis of 15-heptyl-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetraco-1-ol

[0680]

[0681] 15-Heptyl-13,13-Dimethyl-12,14,16-Trioxa-5-aza-13-silicotetraco-1-ol was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicotetradecane (500.0 mg, 1.010 mmol, 1.0 equivalent) and 4-amino-1-butanol (1.798 g, 20.175 mmol, 20.0 equivalent) according to general procedure L. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 200.0 mg, 0.397 mmol, yield 40%.

[0682] 1 H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ3.93-3.79(m,1H), δ3.75(t,2H), δ3.61(t,1H), δ3.44 -3.40(m,2H),δ2.32-2.27(m,2H),δ1.96-1.14(m,38H),δ0.93-0.87(m,6H),δ0.28(d,6H)

[0683] Example 85

[0684] Synthesis of 4-(((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-pentaen-1-yl)amino)but-1-ol

[0685]

[0686] 4-(((5Z,8Z,11Z,14Z,17Z)-eicos ...

[0687] 1 H NMR (500MHz, CDCl3) δ5.43-5.27 (m, 10H), δ3.98 (broad s,2H),δ3.57(m,2H),δ2.88-2.76(m,8H),δ2.68-2.61(m,4H),δ2.12-2.03(m, 4H), δ1.71-1.60(m,4H), δ1.57-1.48(m,2H), δ1.43-1.35(m,2H), δ0.97(t,3H)

[0688] Example 86

[0689] Synthesis of 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate

[0690]

[0691] 6-(4-hydroxybutyl)amino)hexyl-2-hexyldecanoate was prepared from 6-ethoxy-6-((triethylsilyl)oxy)hexyl-2-hexyldecanoate (1488.4 mg, 2.891 mmol, 1.0 equivalent) and 4-amino-1-butanol (772.99 mg, 8.672 mmol, 3.0 equivalent) according to general procedure M. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 1056 mg, 2.469 mmol, yield 85%.

[0692] 1 H NMR (500MHz, CDCl3) δ4.05(t,2H), δ3.56(m,2H), δ2.65-2.58(m,4H), δ2.33-2.26(m,1H), δ1.70-1.19(m,36H), δ0.88-0.85(dt,6H)

[0693] Example 87

[0694] Synthesis of 6-((3-hydroxypropyl)amino)hexyl-2-hexyldecanoate

[0695]

[0696] 6-(3-hydroxypropyl)amino)hexyl-2-hexyldecanoate was prepared from 6-ethoxy-6-((triethylsilyl)oxy)hexyl-2-hexyldecanoate and 3-aminopropanol (656.43 mg, 8.740 mmol, 3.0 equivalence). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 1265.0 mg, 1.651 mmol, yield 57%.

[0697] 1 H NMR (500MHz, CDCl3) δ4.03(t,2H), δ3.79(t,2H), δ2.92(t,2H), δ2.35-2.25(m,1H), δ1.95-1.90(t,2H), δ1.74-1.18(m,34H), δ0.86(t,6H)

[0698] Example 88

[0699] Synthesis of 6-((2-hydroxyethyl)amino)hexyl-2-hexyldecanoate

[0700]

[0701] 6-(2-hydroxyethyl)amino)hexyl-2-hexyldecanoate was prepared according to general procedure M from 6-ethoxy-6-((triethylsilyl)oxy)hexyl-2-hexyldecanoate (1000 mg, 1.942 mmol, 1.0 equivalent) and 2-amino-1-ethanol (355.9 mg, 5.827 mmol, 3.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 590.0 mg, 1.476 mmol, yield 76%.

[0702] 1 H NMR (500MHz, CDCl3) δ4.04(t,2H), δ3.86(t,2H), δ3.08-3.05(m,2H), δ2.95(t,2H), δ2.34-2.24(m,1H), δ1.77-1.12(m,32H), δ0.86(t,6H)

[0703] Example 89

[0704] Synthesis of 6-((2-(1-methylpyrrolidone-2-yl)ethyl)amino)hexyl-2-hexyldecanoate

[0705]

[0706] 6-((2-(1-methylpyrrolidone-2-yl)ethyl)amino)hexyl-2-hexyldecanoate was prepared from 6-ethoxy-6-((triethylsilyl)oxy)2-hexyl-2-hexyldecanoate (850 mg, 1.651 mmol, 1.0 equivalent) and 2-(1-methylpyrrolidone-2-yl)ethane-1-amine (634.98 mg, 4.953 mmol, 3.0 equivalent) according to general procedure M. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 120.0 mg, 0.257 mmol, yield 16%.

[0707] 1 H NMR (500MHz, CDCl3) δ4.03(t,2H), δ3.27-3.22(m,1H), δ3.01-2.87(m,2H), δ2.82-2.75(m,1H), δ2.54(s ,3H),δ2.49-2.43(m,1H),δ2.33-2.25(m,2H),δ2.16-2.07(m,1H),δ2.04-1.17(br.m,38H),δ0.86(t,6H)

[0708] Example 90

[0709] Synthesis of 6-((4-hydroxybutyl)amino)hexyl-2-(pentathio)decanoate

[0710]

[0711] 6-(4-hydroxybutylamino)hexyl 2-(pentathio)decanoate was prepared according to general procedure M from 6-methoxy-6-(triethylsilyl)oxy)hexyl 2-(pentathio)decanoate (1500.00 mg, 2.891 mmol, 1.0 equivalent) and 4-amino-1-butanol (772.99 mg, 8.672 mmol, 3.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 1123.0 mg, 2.519 mmol, yield 87%.

[0712] 1 H NMR (500MHz, CDCl3) δ4.11(t,2H), δ3.56(t,2H), δ3.22-3.19(m,1H), δ2.65 -2.42(m,6H),δ1.89-1.80(m,1H),δ1.70-1.16(m,31H),δ0.90-0.85(dt,6H)

[0713] Example 91

[0714] Synthesis of 6-((4-hydroxybutyl)amino)hexyl-2-(decylthio)hexanoate

[0715]

[0716] 6-(4-hydroxybutylamino)hexyl 2-(decylthio)hexanoate was prepared according to general procedure M from 6-methoxy-6-((triethylsilyl)oxy)hexyl 2-(decylthio)hexanoate (400.00 mg, 0.751 mmol, 1.0 equivalent) and 4-amino-1-butanol (200.71 mg, 2.252 mmol, 3.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 211.0 mg, 0.459 mmol, yield 61%.

[0717] 1 H NMR (500MHz, CDCl3) δ4.12(t,2H), δ3.56(m,2H), δ3.22-3.19(m,1H), δ2.66 -2.51(m,6H),δ1.90-1.81(m,1H),δ1.70-1.20(m,33H),δ0.91-0.86(dt,6H)

[0718] Example 92

[0719] Synthesis of 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino)but-1-ol

[0720]

[0721] 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)oxy)silane (237.00 mg, 0.455 mmol, 1.0 equivalent) and 4-amino-1-butanol (121.67 mg, 1.365 mmol, 3.0 equivalent) were prepared from triethyl(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino)but-1-ol according to general procedure M. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 178.0 mg, 0.398 mmol, yield 87%.

[0722] 1 H NMR (500MHz, CDCl3) δ4.62(m,1H), δ3.76(s,3H), δ3.57(t,2H), δ2.66-2.63(m, 2H), δ2.61-2.49(m,2H), δ1.97-1.02(m,32H), δ0.92-0.89(m,6H), δ0.63(s,3H)

[0723] Example 93

[0724] Synthesis of 4-((4-hydroxybutyl)amino)butyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)valerate

[0725]

[0726] 4-((4-hydroxybutyl)amino)butyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)valerate was prepared from 4-chlorobutyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)valerate (237.00 mg, 0.455 mmol, 1.0 equivalent) and 4-aminobutanol (121.67 mg, 1.365 mmol, 3.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 194.0 mg, 0.364 mmol, yield 80%.

[0727] 1 H NMR (500MHz, CDCl3) δ4.05(m,2H), δ3.60(t,2H), δ3.35(s,3H), δ3.18-3.11(m,1H), δ2.90-2.85(q,2H), δ2.80-2.71(q,3H), δ2.36-2.29(m,1H), δ2.22-2.14(m,1H), δ1.93-1.50(br.m,16H), δ1.44-0.88(br.m,18H), δ0.90-0.88(m,6H), δ0.62(s,3H)

[0728] Example 94

[0729] Synthesis of undecyl 6-((2-hydroxyethyl)amino)hexanoate

[0730]

[0731] Undecyl 6-((2-hydroxyethyl)amino)hexanoate was prepared from undecyl 6-bromohexanoate (1000.00 mg, 2.862 mmol, 1.0 equivalent) and 2-amino-1-ethanol (192.33 mg, 3.148 mmol, 1.1 equivalent) according to general procedure N. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 350.0 mg, 1.062 mmol, yield 37%.

[0732] 1H NMR (500MHz, CDCl3) δ4.04(t,2H), δ3.63(m,2H), δ2.76(m,2H), δ2.61(t,2H), δ2.29(t,2H), δ2.09(broad s,2H),δ1.67-1.57(m,4H),δ1.54-1.47(m,2H),δ1.39-1.22(m,18H),δ0.87(t,3H)

[0733] Example 95

[0734] Synthesis of undecyl 6-((4-hydroxybutyl)amino)hexanoate

[0735]

[0736] Undecyl 6-((4-hydroxybutyl)amino)hexanoate was prepared from undecyl 6-bromohexanoate (1124.21 mg, 3.218 mmol, 1.0 equivalent) and 4-amino-1-butanol (5737.05 mg, 64.36 mmol, 20 equivalent) according to general procedure N. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a thick yellow oil, 969.0 mg, 2.607 mmol, yield 81%.

[0737] 1 H NMR (500MHz, CDCl3) δ4.03(t,2H), δ3.57(t,2H), δ2.71-2.63(m,4H), δ2.29(t,2H), δ1.69-1.52(m,10H), δ1.40-1.19(m,18H), δ0.86(t,3H)

[0738] Example 96

[0739] Synthesis of heptadecano-9-yl 8-((2-hydroxyethyl)amino)octanoate

[0740]

[0741] Heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate was prepared from heptadecan-9-yl 8-bromooctanoate (200.00 mg, 0.412 mmol, 1.0 equivalent) and 2-amino-1-ethanol (27.66 mg, 0.453 mmol, 1.1 equivalent) according to general procedure N. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 100.0 mg, 0.226 mmol, yield 55%.

[0742] 1H NMR (500MHz, CDCl3) δ4.89-4.83(m,1H), δ3.62(s,2H), δ2.78-2.75(m,2H), δ2.60(t,2H), δ2.27(t,2H), δ1.65-1.56(m,2H), δ1.53-1.41(m,6H), δ1.36-1.16(m,30H), δ0.87(t,6H)

[0743] Example 97

[0744] Synthesis of heptadecano-9-yl 8-((4-hydroxybutyl)amino)octanoate

[0745]

[0746] Heptadecan-9-yl 8-((4-hydroxybutyl)amino)octanoate was prepared from heptadecan-9-yl 8-bromooctanoate (950 mg, 1.841 mmol, 1.0 equivalent) and 4-amino-1-butanol (3.28 g, 36.83 mmol, 20 equivalent) according to general procedure L. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 865.0 mg, 1.28 mmol, yield 69%.

[0747] 1 H NMR (500MHz, CDCl3) δ5.19(m,1H), δ3.80-3.76(m,2H), δ3.48-3.40(m,2H), δ2.61 (t,2H),δ2.51(t,2H),δ2.28(t,2H),δ1.83-1.10(br.m,40H),δ0.98-0.91(m,6H)

[0748] Example 98

[0749] Synthesis of 6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)-N-(prop-2-yn-1-yl)hexane-1-amine

[0750]

[0751] The MW reaction flask contained ((6-bromo-1-(octoxy)hexyl)oxy)dimethyl(octyl)silane (400 mg, 0.834 mmol, 1.0 eq), propargyl hydrochloride (381.69 mg, 0.834 mmol, 1.0 eq), K₂CO₃ (806.79 mg, 5.838 mmol, 7.0 eq), KI (13.84 mg, 0.083 mmol, 0.1 equivalent), 1.5 mL of anhydrous acetonitrile, and 1.0 mL of cyclopentyl methyl ether, and was purged with argon and sealed. The resulting mixture was stirred at 62 °C for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and brine, followed by vigorous stirring for 15 minutes. The organic phases were separated, dried on Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 260 mg, 0.573 mmol, yield 69%.

[0752] 1H NMR (500MHz, benzene-d6) δ4.85(t,1H), δ3.77-3.72(q,1H), δ3.39-3.34(q,1H), δ3.16(d,2H), δ2.50( t,2H),δ1.93(t,1H),δ1.83-1.16(m,32H),δ0.94-0.88(m,6H),δ0.75-0.71(m,2H),δ0.24(d,6H)

[0753] Example 99

[0754] Synthesis of 6-((dimethyl(octyl)silyl)oxy)-N-(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)-6-(octyl)-N-(prop-2-yn-1-yl)hexane-1-amine

[0755]

[0756] The MW reaction flask contained ((6-bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane (431.22 mg, 0.899 mmol, 1.2 equivalents), 6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)-N-(prop-2-yn-1-yl)hexane-1-amine (340.00 mg, 0.749 mmol, 1.0 eq), K₂CO₃ (207.09 mg, 1.499 mmol, 2.0 equivalents), KI (12.44 mg, 0.075 mmol, 0.1 equivalents), 1.5 mL of anhydrous acetonitrile, and 0.5 mL of cyclopentyl methyl ether, and was purged with argon and sealed. The resulting mixture was stirred at 62 °C for 24 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and brine, followed by vigorous stirring for 15 minutes. The organic phase was separated, dried on Na2SO4, filtered, and concentrated. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 530 mg, 0.622 mmol, yield 83%.

[0757] 1 H NMR (500MHz, benzene-d6) δ4.87(t,2H), δ3.79-3.72(q,2H), δ3.42-3.34(q,2H), δ3.32(d,2H), δ2.51(t ,4H),δ1.92(t,1H),δ1.88-1.17(m,64H),δ0.95-0.89(m,12H),δ0.75-0.71(m,4H),δ0.25(d,12H)

[0758] Example 100

[0759] Synthesis of 6-(octoxy)-N-(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)-N-(prop-2-yn-1-yl)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexane-1-amine

[0760]

[0761] The MW reaction flask contained 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (453.74 mg, 0.819 mmol, 2.5 equivalents), propargylamine hydrochloride (30.00 mg, 0.328 mmol, 1.0 equivalents), K₂CO₃ (181.18 mg, 1.311 mmol, 4.0 equivalents), KI (10.88 mg, 0.065 mmol, 0.2 equivalents), 1.2 mL of anhydrous acetonitrile, and 0.4 mL of cyclopentyl methyl ether, and was purged with argon and sealed. The resulting mixture was stirred at 62 °C for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and brine, followed by vigorous stirring for 15 minutes. The organic phase was separated, dried over Na₂SO₄, filtered, and concentrated. Purification method B was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 83 mg, 0.083 mmol, yield 25%.

[0762] 1 ¹H NMR (500 MHz, benzene-d6) δ 5.00 (t, 2H), δ 3.90–3.83 (q, 2H), δ 3.46–3.38 (q, 2H), δ 3.33 (d, 2H), δ 2.52 (t, 4H), δ 1.92–1.17 (m, 65H), δ 0.95–0.89 (m, 12H), δ 0.71–0.66 (m, 4H), δ 0.27 (d, 12H), δ 0.22 (s, 12H), Examples of lipid synthesis

[0763] Example 101

[0764] Synthesis of 4-(bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)amino)but-1-ol

[0765]

[0766] 4-(bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)amino)but-1-ol was prepared from ((6-bromo-1-(octyl)silyl)oxy)dimethyl(octyl)silane (93.4 mg, 0.195 mmol, 1.0 equivalent) and 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)amino)but-1-ol (95 mg, 0.195 mmol, 1.0 equivalent)). The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 70 mg, 0.079 mmol, yield 40%.

[0767] 1H NMR (500MHz, benzene-d6) δ4.88(t,2H), δ3.79-3.72(m,2H), δ3.62(t,2H), δ3.41-3.36(m,2H), δ2.33(t,4 H), δ2.24(t,2H), δ1.77-1.25(m,68H), δ0.94-0.89(m,12H), δ0.76-0.72(m,4H), δ0.26(d,12H); TOF MS ES+[M+H+]:886.8069m / z

[0768] Example 102

[0769] Synthesis of 5-(6-((1-((dimethyl(octyl)silyl)oxy)octyl)oxy)hexyl)-13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silicoserosan-1-ol

[0770]

[0771] According to general procedure G, 5-(6-((1-(((dimethyl(octyl)silyl)oxy)octyl)oxy)hexyl)-13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silicotriane-1-ol) was prepared from ((1-((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane (147.47 mg, 0.307 mmol, 1.0 equivalent) and 13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silicotriane-1-ol) (150.00 mg, 0.307 mmol, 1.0 equivalent). The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 100 mg, 0.113 mmol, yield 37%.

[0772] 1 H NMR (500MHz, benzene-d6) δ4.89(t,2H), δ3.79-3.74(m,2H), δ3.63(t,2H), δ3.41-3.35(m,2H), δ2.32(m,4 H), δ2.25(t,2H), δ1.89-1.24(m,68H), δ0.95-0.89(m,12H), δ0.77-0.72(m,4H), δ0.26(d,12H); TOF MS ES+[M+H+]:886.8039m / z

[0773] Example 103

[0774] Synthesis of 4-(bis(6-(decoxy)-6-((hexyldimethylsilyl)oxy)hexyl)amino)but-1-ol

[0775]

[0776] 4-(bis(6-(decoxy)-6-((hexyldimethylsilyl)oxy)hexyl)amino)but-1-ol was prepared from ((6-bromo-1-(decoxy)hexyl)oxy)(hexyl)dimethylsilane (403.27 mg, 0.841 mmol, 2.5 equivalents) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equivalents). The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 45 mg, 0.051 mmol, yield 15%.

[0777] 1 H NMR (500MHz, benzene-d6) δ4.89(t,2H), δ3.80-3.74(m,2H), δ3.63(t,2H), δ3.43-3.36(m,2H), δ2.35-2.31(m ,4H), δ2.25(t,2H), δ1.89-1.26(m,68H), δ0.96-0.91(m,12H), δ0.76-0.71(m,4H), δ0.25(d,12H); TOF MS ES+[M+H+]:886.8082m / z

[0778] Example 104

[0779] Synthesis of 5-(6-((1-((hexyldimethylsilyl)oxy)decyl)oxy)hexyl)-15,15-dimethyl-13-nonyl-12,14-dioxa-5-aza-15-silicodecane-1-ol

[0780]

[0781] According to general procedure H, 5-(6-((1-(((hexyldimethylsilyl)oxy)decyl)oxy)hexyl)-15,15-dimethyl-13-nonyl-12,14-dioxa-5-aza-15-silicodecane-1-ol) was prepared from ((1-((6-bromohexyl)oxy)decyl)oxy)hexyl)dimethylsilane (403.27 mg, 0.841 mmol, 2.5 equivalents) and 4-amino-1-butanol (30.00 mg, 0.336 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil: 45 mg, 0.051 mmol, yield 15%; 53 mg, 0.060 mmol, yield 18%.

[0782] 1 H NMR (500MHz, benzene-d6) δ4.89(t,2H), δ3.78-3.73(m,2H), δ3.63(t,2H), δ3.41-3.35(m,2H), δ2.34-2.30(m ,4H), δ2.25(t,2H), δ1.89-1.23(m,68H), δ0.96-0.90(m,12H), δ0.75-0.70(m,4H), δ0.25(d,12H); TOF MS ES+[M+H+]:886.8081m / z

[0783] Example 105

[0784] Synthesis of 5-(6-((dimethyl(octoxy)silyl)oxy)-6-(octoxy)hexyl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicosicosano-1-ol

[0785]

[0786] According to general procedure I, 5-(6-((dimethyl(octoxy)silyl)oxy)-6-(octoxy)hexyl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicodocoane-1-ol was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silicodocoane (416.72 mg, 0.841 mmol, 2.5 equivalents) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 187 mg, 0.204 mmol, yield 61%. 1H NMR (500MHz, benzene-d6) δ5.01(dt,2H), δ3.89-3.84(m,2H), δ3.77(t,4H), δ3.62(t,2H), δ3.46-3.38(m,3H), δ2 TOF MS ES+[M+H+]:918.7984m / z

[0787] Example 106

[0788] Synthesis of 13-hepty-5-(8-hepty-10,10-dimethyl-7,9,11-trioxa-10-silenodecyl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicotetracosan-1-ol

[0789]

[0790] 13-Heptyl-5-(8-Heptyl-10,10-dimethyl-7,9,11-trioxa-10-silenodadecane)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicotetraco-1-ol was prepared from 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silenodadecane (416.72 mg, 0.840 mmol, 2.5 equivalents) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 146 mg, 0.159 mmol, yield 47%.

[0791] 1 H NMR (500MHz, benzene-d6) δ5.00(dt,2H), δ3.89-3.84(m,2H), δ3.79(t,4H), δ3.63(t,2H), δ3.45-3.38(m,2H), δ2.34 -2.30(t,4H),δ2.25(t,2H),δ1.96-1.79(m,4H),δ1.73-1.22(m,64H)δ0.94-0.89(m,12H),δ0.30(d,12H); TOF MS ES+[M+H+]:918.7991m / z

[0792] Example 107

[0793] Synthesis of 4-(bis(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)amino)but-1-ol)

[0794]

[0795] 4-(bis(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)hexyl)amino)but-1-ol was prepared from 1-((6-bromo-1-(octoxy)hexyl)oxy)1,1,3,3-tetramethyl-3-octyldisiloxane (465.62 mg, 0.841 mmol, 2.5 equivalents) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 87 mg, 0.084 mmol, yield 25%.

[0796] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,2H), δ3.91-3.84(m,2H), δ3.61(t,2H), δ3.45-3.41(m,2H), δ2.35-2.32(t,4H), δ2.25(t,2 TOF MSES + [M+H + ]:1034.8458m / z

[0797] Example 108

[0798] Synthesis of 13-heptyl-15,15,17,17-tetramethyl-5-(6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)octyl)oxy)hexyl)-12,14,16-trioxa-5-aza-15,17-disilicoserosan-1-ol

[0799]

[0800] According to general procedure I, 13-heptyl-15,15,17,17-tetramethyl-5-(6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)octyl)oxy)hexyl)-12,14,16-trioxa-5-aza-15,17-disilicoserosan-1-ol was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)hexyl)-1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)octyl)oxy)hexyl)-12,14,16-trioxa-5-aza-15,17-disilicoserosan-1-ol was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 237 mg, 0.229 mmol, yield 66%.

[0801] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,2H), δ3.88-3.83(m,2H), δ3.63(t,2H), δ3.45-3.38(m,2H), δ2.42-2.25(m ,6H), δ1.97-1.16(m,67H), δ0.97-0.84(m,13H), δ0.74-0.61(m,4H), δ0.28(d,12H), δ0.22(s,12H); TOF MSES + [M+H + ]:1034.8467m / z

[0802] Example 109

[0803] Synthesis of 4-(bis(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol)

[0804]

[0805] 4-(bis(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxane)oxy)hexyl)amino)but-1-ol was prepared from 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octoxy)disiloxane (319.90 mg, 0.561 mmol, 2.5 equivalence) and 4-amino-1-butanol (20.02 mg, 0.225 mmol, 1.0 equivalence). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 60 mg, 0.056 mmol, yield 25%.

[0806] 1H NMR (500MHz, benzene-d6) δ5.03(dt,2H), δ3.91-3.85(m,2H), δ3.76(t,4H), δ3.61(t,2H), δ3.47-3.38(m,2H), δ2.35-2.31( TOF MSES + [M+H + ]:1066.8368m / z

[0807] Example 110

[0808] Synthesis of 13-heptyl-15,15,17,17-tetramethyl-5-(6-((1-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)octyl)oxy)hexyl)-12,14,16,18-tetraoxa-5-aza-15,17-disilicosahedron-1-ol

[0809]

[0810] According to general procedure I, 13-heptyl-15,15,17,17-tetramethyl-5-(6-((1-((1,1,3,3-tetramethyl-3-(octyloxy)disiloxane)oxy)octyl)oxy)hexyl)-12,14,16,18-tetraoxa-5-aza-15,17-disilicosahedral-1-ol was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)hexyl)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane)oxy)octyl)oxy)hexyl)-1,13,3-tetramethyl-3-(octyloxy)disiloxane)oxy)octyl)oxy)hexyl)-1,14,16,18-tetraoxa-5-aza-15,17-disilicosahedral-1-ol. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 97 mg, 0.091 mmol, yield 41%.

[0811] 1H NMR (500MHz, benzene-d6) δ5.04(dt,2H), δ3.90-3.84(m,2H), δ3.76(t,4H), δ3.62(t,2H), δ3.48-3.37(m,2H), δ2.34-2.30( m,4H), δ2.25(t,2H)δ1.95-1.80(m,4H), δ1.72-1.21(m,64H), δ0.94-0.87(m,12H), δ0.31(d,12H), δ0.24(s,12H); TOF MS ES+[M+H+]:1066.8358m / z

[0812] Example 111

[0813] Synthesis of 16-hexyl-5-(6-((((2-hexyldecyl)oxy)dimethylsilyl)oxy)-6-(octoxy)hexyl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicotetraco-1-ol

[0814]

[0815] According to general procedure I, 16-hexyl-5-(6-(((((2-hexyldecyl)oxy)dimethylsilyl)oxy)-6-(octoxy)hexyl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicotetraco-1-ol was prepared from 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silicotetraco-1-ol by 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equivalent) in 0.232 mmol. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 269 mg, 0.232 mmol, yield 69%.

[0816] 1 H NMR(500MHz, benzene-d6)δ5.02(dt,2H),δ3.91-3.84(m,2H),δ3.75-3.73(d,4H),δ3.61(t,2H),3.48-3.40(m,2H),δ 2.34(t,4H),δ2.26(t,2H),δ1.97-1.76(m,4H),δ1.73-1.18(m,92H),δ0.95-0.89(m,18H),δ0.29(d,12H); TOF MSES + [M 片段 +H +]:918.7993m / z

[0817] Example 112

[0818] Synthesis of 13-heptyl-5-(8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silicotetradecyl)-18-hexyl-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicotetradecane-1-ol

[0819]

[0820] According to general procedure I, 13-hepty-5-(8-hepty-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silicotetramonoalkyl)-18-hexyl-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicotetrahexadecane-1-ol was prepared from 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silicotetramonoalkyl)-18-hexyl-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicotetrahexadecane-1-ol was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 328 mg, 0.283 mmol, yield 84%.

[0821] 1 H NMR(500MHz, benzene-d6)δ5.01(t,2H),δ3.90-3.83(m,2H),δ3.74-3.73(d,4H),δ3.62(t,2H),3.46-3.38(m,2H),δ 2.33(t,4H),δ2.25(t,2H),δ1.94-1.78(m,4H),δ1.72-1.19(m,92H),δ0.95-0.87(m,18H),δ0.29(d,12H); TOF MS ES+[M 片段 +H+]:918.7980m / z

[0822] Example 113

[0823] Synthesis of 5-(6-(dimethyl((1-(octyloxy)octyl)oxy)silyl)hexyl)-14-heptyl-12,12-dimethyl-13,15-dioxa-5-aza-12-silicoserosan-1-ol)

[0824]

[0825] According to general procedure I, 5-(6-(dimethyl((1-(octoxy)octyl)oxy)silane)-14-heptyl-12,12-dimethyl-13,15-dioxa-5-aza-12-silicotrichodo-1-ol) was prepared from (6-bromohexyl)dimethyl((1-(octoxy)octyl)oxy)silyl)hexyl)-14-heptyl-12,12-dimethyl-13,15-dioxa-5-aza-12-silicotrichodo-1-ol) by (6-bromohexyl)dimethyl((1-(octoxy)octyl)oxy)silyl)hexyl)-14-heptyl-12,12-dimethyl-13,15-dioxa-5-aza-12-silicotrichodo-1-ol) according to purification methods A and B. The crude product was purified twice by rapid column chromatography to obtain a pure product as a colorless oil, 97 mg, 0.109 mmol, yield 32%.

[0826] 1 H NMR (500MHz, benzene-d6) δ4.88(m,2H), δ3.79-3.73(m,2H), δ3.64(t,2H), δ3.42-3.35(m,2H), δ2.40-2.36(m,4 H), δ2.31-2.28(m,2H), δ1.89-1.22(m,68H), δ0.93-087(m,12H), δ0.75-0.71(m,4H), δ0.25(d,12H); TOF MSES + [M+H + ]:886.8121m / z

[0827] Example 114

[0828] Synthesis of 15-heptyl-5-(10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silenodecyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetracosan-1-ol

[0829]

[0830] 15-Heptyl-5-(10-Heptyl-8,8-dimethyl-7,9,11-trioxa-8-silenodadecane)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetraco-1-ol was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silenodadecane (416.72 mg, 0.841 mmol, 2.5 equivalents) and 4-amino-1-butanol (29.98 mg, 0.336 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 169 mg, 0.184 mmol, yield 55%.

[0831] 1H NMR (500MHz, benzene-d6) δ5.00(m,2H), δ3.91-3.82(m,2H), δ3.76(t,4H), δ3.62(t,2H), δ3.46-3.38(m,2H), δ2. 33(t,4H),δ2.26(t,2H),δ1.96-1.76(m,4H),δ1.71-1.16(m,64H),δ0.95-0.85(m,12H),δ0.28(d,12H); TOF MSES + [M+H + ]:918.7974m / z

[0832] Example 115

[0833] Synthesis of 15-heptyl-5-(10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silenodecyl)-13,13-dimethyl-12,14-dioxa-16-thia-5-aza-13-silicotetraco-1-ol

[0834]

[0835] According to general procedure I, 15-hepty-5-(10-hepty-8,8-dimethyl-7,9-dioxa-11-thia-8-silenodadecane)-13,13-dimethyl-12,14-dioxa-16-thia-5-aza-13-silicotetraco-1-ol was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silenodadecane (555.14 mg, 1.085 mmol, 2.5 equivalents) and 4-amino-1-butanol (38.68 mg, 0.4339 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 170 mg, 0.179 mmol, yield 41%.

[0836] 1 H NMR (500MHz, benzene-d6) δ5.12(m,2H), δ3.83-3.75(m,4H), δ3.64-3.61(t,2H), δ2.81-2.66(m,4H), δ2.34(t ,4H), δ2.26(t,2H), δ2.08-1.90(m,4H), δ1.70-1.16(m,64H), δ0.93-0.89(m,12H), δ0.31(d,12H); TOF MSES + [M+H + ]:950.7537m / z

[0837] Example 116

[0838] Synthesis of 6-((dimethyl(octyl)silyl)oxy)-N-(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)-N-(2-(1-methylpyrrolidone-2-yl)ethyl)-6-(octyl)hexane-1-amine

[0839]

[0840] According to general procedure O, 6-((dimethyl(octyl)silyl)oxy)-N-(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)-N-(2-(1-methylpyrrolidine-2-yl)ethyl)-6-(octyl)hexane-1-amine was prepared from ((6-bromo-1-(octyloxy)hexyl)oxy)-dimethyl(octyl)silane (233.81 mg, 0.487 mmol, 2.5 equivalents) and 2-(2-aminoethyl)-1-methylpyrrolidine (25.00 mg, 0.195 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 98 mg, 0.106 mmol, yield 54%.

[0841] 1 H NMR (500MHz, benzene-d6) δ4.89(t,2H), δ3.78-3.73(m,2H), δ3.41-3.35(m,2H), δ3.01(dt,1H), δ2.53-2.36 (m,6H),δ2.27(s,3H),δ2.12-1.19(m,72H),δ0.94-0.89(m,12H),δ0.76-0.72(4H),δ0.25(d,12H); TOF MSES + [M+H + ]:925.8552m / z

[0842] Example 117

[0843] Synthesis of 6-((dimethyl(octoxy)silyl)oxy)-N-(6-((dimethyl(octoxy)silyl)oxy)-6-(octoxy)hexyl)-N-(2-(1-methylpyrrolidone-2-yl)ethyl)-6-(octoxy)hexane-1-amine

[0844]

[0845] According to general procedure O, 6-((dimethyl(octoxy)silyl)oxy)-N-(6-((dimethyl(octoxy)silyl)oxy)-6-(octoxy)hexyl)-N-(2-(1-methylpyrrolidone-2-yl)ethyl)-6-(octoxy)hexane-1-amine was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silicodocoane (386.58 mg, 0.780 mmol, 2.5 equivalents) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 33 mg, 0.034 mmol, yield 11%.

[0846] 1 H NMR (500MHz, benzene-d6) δ5.01(t,2H), δ3.90-3.83(m,2H), δ3.77(t,4H), δ3.46-3.36(m,2H), δ3.00(dt,1 H), δ2.53-2.36(m,6H), δ2.29(s,3H), δ2.10-1.17(m,72H), δ0.93-0.88(m,12H), δ0.28(d,12H); TOF MSES + [M 片段 +H + ]:845.7217m / z

[0847] Example 118

[0848] Synthesis of N-(2-(1-methylpyrrolidone-2-yl)ethyl)-6-(octoxy)-N-(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexane-1-amine

[0849]

[0850] N-(2-(1-methylpyrrolidine-2-yl)ethyl)-6-(octoxy)-N-(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)hexane-1-amine was prepared from 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (431.93 mg, 0.780 mmol, 2.5 equivalents) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equivalents). The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 71 mg, 0.066 mmol, yield 21%.

[0851] 1 H NMR(500MHz, benzene-d6)δ5.02(t,2H),δ3.90-3.84(m,2H),δ3.46-3.30(m,2H),δ3.00(dt,1H),δ2.53-2.38(m,6H),δ 2.29(s,3H),δ2.14-1.20(m,72H),δ0.96-0.89(m,12H),δ0.74-0.66(m,4H),δ0.28(d,12H),δ0.21(s,12H); TOF MSES + [M 片段 +H + ]:518.4431m / z

[0852] Example 119

[0853] Synthesis of N-(2-(1-methylpyrrolidone-2-yl)ethyl)-6-(octoxy)-N-(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexane-1-amine

[0854]

[0855] N-(2-(1-methylpyrrolidine-2-yl)ethyl)-6-(octoxy)-N-(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxane)oxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxane)oxy)hexane-1-amine was prepared from 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octoxy)disiloxane (444.41 mg, 0.780 mmol, 2.5 equivalents) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equivalents). The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 92 mg, 0.083 mmol, yield 27%.

[0856] 1 H NMR (500MHz, benzene-d6) δ5.04(t,2H), δ3.91-3.85(m,2H), δ3.76(t,4H), δ3.47-3.36(m,2H), δ3.00(dt,1H), δ2. 53-2.38(m,6H),δ2.29(s,3H),δ2.10-1.17(m,72H),δ0.93-0.89(m,12H),δ0.32(d,12H),δ0.25(s,12H); TOF MSES + [M 片段 +H + ]:603.4640m / z

[0857] Example 120

[0858] Synthesis of 6-((1-((dimethyl(octyl)silyl)oxy)octyl)oxy)-N-(6-((1-((dimethyl(octyl)silyl)oxy)octyl)oxy)hexyl)-N-(2-(1-methylpyrrolidone-2-yl)ethyl)hexane-1-amine)

[0859]

[0860] According to general procedure O, 6-((1-((dimethyl(octyl)silyl)oxy)octyl)oxy)dimethyl(octyl)silane (374.1 mg, 0.780 mmol, 2.5 equivalents) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equivalents) were prepared from 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equivalents). The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 109 mg, 0.118 mmol, yield 38%.

[0861] 1 H NMR (500MHz, benzene-d6) δ4.88(t,2H), δ3.79-3.73(m,2H), δ3.41-3.35(m,2H), δ3.00(dt,1H), δ2.53-2. 36(m,6H),δ2.29(s,3H),δ2.12-1.19(m,72H),δ0.95-0.89(m,12H),δ0.75-0.71(4H),δ0.25(d,12H)

[0862] Example 121

[0863] Synthesis of 8-hepty-N-(8-hepty-10,10-dimethyl-7,9,11-trioxa-10-silenodecyl)-10,10-dimethyl-N-(2-(1-methylpyrrolidone-2-yl)ethyl)-7,9,11-trioxa-10-silenodecyl-1-amine

[0864]

[0865] According to general procedure O, 8-hepty-N-(8-hepty-10,10-dimethyl-7,9,11-trioxa-10-silenodadecane)-10,10-dimethyl-N-(2-(1-methylpyrrolidine-2-yl)ethyl)-7,9,11-trioxa-10-silenodadecane-1-amine was prepared from 1-bromo-8-hepty-10,10-dimethyl-7,9,11-trioxa-10-silenodadecane (386.58 mg, 0.780 mmol, 2.5 equivalents) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 60 mg, 0.063 mmol, yield 20%.

[0866] 1 H NMR (500MHz, benzene-d6) δ5.01(t,2H), δ3.90-3.84(m,2H), δ3.77(t,4H), δ3.46-3.40(m,2H), δ3.00(dt ,1H),δ2.53-2.37(m,6H),δ2.29(s,3H),δ2.10-1.17(m,72H),δ0.93-0.89(m,12H),δ0.29(d,12H)

[0867] Example 122

[0868] Synthesis of N-(2-(1-methylpyrrolidone-2-yl)ethyl)-6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)octyl)oxy)-N-(6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)octyl)oxy)hexyl)hexane-1-amine

[0869]

[0870] N-(2-(1-methylpyrrolidine-2-yl)ethyl)-6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)octyl)oxy)-N-(6-((1-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)octyl)oxy)hexyl)hexane-1-amine was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)hexyl)hexane-1-amine (431.93 mg, 0.780 mmol, 2.5 equivalents) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equivalents). Purification method B was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 200 mg, 0.186 mmol, yield 60%.

[0871] 1 H NMR (500MHz, benzene-d6) δ5.01(t,2H), δ3.91-3.83(m,2H), δ3.45-3.37(m,2H), δ2.99(dt,1H), δ2.52-2.36(m,6H) ,δ2.28(s,3H),δ2.10-1.20(m,72H),δ0.95-0.89(m,12H),δ0.69-0.65(m,4H),δ0.26(d,12H),δ0.20(s,12H)

[0872] Example 123

[0873] Synthesis of N-(2-(1-methylpyrrolidone-2-yl)ethyl)-6-((1-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)octyl)oxy)-N-(6-((1-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)octyl)oxy)hexyl)hexane-1-amine

[0874]

[0875] N-(2-(1-methylpyrrolidine-2-yl)ethyl)-6-((1-((1,1,3,3-tetramethyl-3-(octoxy)disiloxane)oxy)octyl)oxy)-N-(6-((1-((1,1,3,3-tetramethyl-3-(octoxy)disiloxane)oxy)octyl)oxy)hexyl)hexane-1-amine was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octoxy)disiloxane (444.41 mg, 0.780 mmol, 2.5 equivalents) and 2-(2-aminoethyl)-1-methylpyrrolidine (40.00 mg, 0.312 mmol, 1.0 equivalents). Purification method B was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 100 mg, 0.090 mmol, yield 29%.

[0876] 1 H NMR(500MHz, benzene-d6)δ5.03(t,2H),δ3.93-3.83(m,2H),δ3.76(t,4H),δ3.46-3.35(m,2H),δ3.00(dt,1H),δ 2.54-2.35(m,6H),δ2.28(s,3H),δ2.10-1.17(m,72H),δ0.94-0.86(m,12H),δ0.32(d,12H),δ0.27(s,12H)

[0877] Example 124

[0878] Synthesis of 2-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethanol-1-ol

[0879]

[0880] According to general procedure P, 2-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)-6-(octyl)N-(prop-2-yn-1-yl)hexane-1-amine (130.00 mg, 0.152 mmol, 1.0 equivalent) and 2-azidoethanol (39.84 mg (50%), 0.229 mmol, 1.5 equivalent) were prepared from 2-prop-2-yn-1-yl)hexane-1-ol. The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 63 mg, 0.067 mmol, yield 44%.

[0881] 1 H NMR (500MHz, CDCl3) δ4.69(t,2H), δ4.48-4.45(m,2H), δ4.04-4.02(m,2H), δ3.78(s,2H), δ3.63-3.57(m,2H), δ3.31-3.25(m ,2H), δ4.45(t,4H), δ1.62-1.42(m,12H), δ1.41-1.18(m,53H), δ0.89-0.86(m,12H), δ0.62-0.58(m,4H), δ0.12(d,12H); TOF MSES + [M+H + ]:940.554m / z

[0882] Example 125

[0883] Synthesis of (3R,4R,5S,6R)-3-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0884]

[0885] According to general procedure P, (3R,4R,5S,6R)-3-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)-6-(octyl)N-(prop-2-yn-1-yl)hexane-1-amine (130.00 mg, 0.152 mmol, 1.0 equivalent) and 2-azido-2-deoxy-D-glucose (46.93 mg, 0.229 mmol, 1.5 equivalent) were prepared from 6-((dimethyl(octyl)silyl)oxy)-N-(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol) Purification method A was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 89 mg, 0.084 mmol, yield 55%. 1 H NMR (500MHz, CDCl3) δ7.83(s,1H), δ7.63(s,1H), δ5.35(s,1H), δ5.08(d,1 H),δ4.67(t,2H),δ4.34-4.13(m,2H),δ4.01(d,1H),δ3.95-3.75(m,2H),δ3 .74-3.46(br.m,6H),δ3.30-3.25(q,2H),δ2.42-2.39(br.m,4H),δ2.23(m ,1H), δ1.64-1.11(m,64H), δ0.87(m,12H), δ0.60(m,4H), δ0.11(d,12H); LC ESIMS[M+H + ]:1057.843m / z

[0886] Example 126

[0887] Synthesis of N-((2R,3R,4R,5S,6R)-2-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide

[0888]

[0889] According to the general procedure P, 6-((dimethyl(octyl)silyl)oxy)-N-(6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)-6-(octyl)-N-(prop-2-yn-1-yl)hexane-1-amine (100.00 mg, 0.117 mmol, 1.0 equivalent) and 2-acetamido-2-deoxy-β-D-pyranosel azide (43.32 mg, 0.176 mmol, 1.5 equivalents) Preparation of N-((2R,3R,4R,5S,6R)-2-(4-((bis(6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 88 mg, 0.080 mmol, yield 68%.

[0890] 1 H NMR (500MHz, CDCl3) δ7.89(s,1H), δ6.95(s,1H), δ5.91(d,1H), δ5.30-4.87(s,2 H), δ4.71-4.68(m,2H), δ4.37-4.30(m,1H), δ3.95-3.87(m,4H), δ3.74-3.57(m,5 H), δ3.31-3.26(m,2H), δ2.47-2.40(m,4H), δ1.75(s,3H), δ1.63-1.41(m,12H), δ1.38-1.20(m,53H), δ0.89-0.86(m,12H), δ0.62-0.58(m,4H), δ0.12(d,12H); LC ESIMS[M+H + ]:1098.624m / z

[0891] Example 127

[0892] Synthesis of N-((2R,3R,4R,5S,6R)-2-(4-((bis(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide

[0893]

[0894] According to the general procedure P, 6-(octoxy)-N-(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)-N-(prop-2-yn-1-yl)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexane-1-amine (83.00 mg, 0.083 mmol, 1.0 equivalent) and 2-acetamido-2-deoxy-β-D-pyranose gluconate were used. N-((2R,3R,4R,5S,6R)-2-(4-((bis(6-(octyloxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide was prepared by glycosyl azide (30.63 mg, 0.124 mmol, 1.5 equivalence). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil (30 mg, 0.024 mmol, yield 29%).

[0895] 1 H NMR (500MHz, CDCl3) δ8.04 (s, 1H), δ7.21 (s, 1H), δ5.89 (d, 1H), δ4.77 (t, 2H), δ4.39-4.36(m,1H), δ4.14-3.83(m,6H), δ3.69-3.65(m,3H), δ3.31-3.25(m,2H ), δ2.90-2.26(m,6H), δ1.75(s,3H), δ1.65-1.45(m,12H), δ1.43-1.13(m,53H) , δ0.89-0.85(m,12H), δ0.55-0.51(m,4H), δ0.11(d,12H), δ0.09(s,12H);); LC ESIMS[M+H + ]:1247.980m / z

[0896] Example 128

[0897] Synthesis of 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(4-hydroxybutyl)amino)hexyl-2-hexyldecanoate

[0898]

[0899] According to general procedure J, 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)but-1-ol (150 mg, 0.307 mmol, 1.0 equivalent) and 6-oxohexyl-2-hexylhexanoate (109.01 mg, 0.307 mmol, 1.0 equivalent) were prepared from 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(4-hydroxybutyl)amino)hexyl-2-hexyldecanoate. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 90 mg, 0.109 mmol, yield 35%.

[0900] 1 H NMR (500MHz, benzene-d6) δ4.90(t,1H), δ4.12(t,2H), δ3.80-3.74(m,1H), δ3.62(t,2H), δ3.42-3.34(m,2H), δ2.48 (m,1H), δ2.35-2.23(m,5H), δ1.90-1.22(m,68H), δ0.95-0.88(m,12H), δ0.77-0.73(m,2H), δ0.26(d,6H); TOF MSES + [M+H + ]:826.7701m / z

[0901] Example 129

[0902] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silicopentoalkyl-2-hexyldecanoate

[0903]

[0904] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silicopentane-1-ol (150 mg, 0.307 mmol, 1.0 equivalent) and 6-oxohexyl-2-hexyldecanoate (109.01 mg, 0.307 mmol, 1.0 equivalent) were prepared according to general procedure J. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 38 mg, 0.046 mmol, yield 15%.

[0905] 1H NMR (500MHz, benzene-d6) δ4.88(t,1H), δ4.11(t,2H), δ3.78-3.73(m,1H), δ3.62(t,2H), δ3.40-3.35(m,1H), δ2.47 (m,2H), δ2.35-2.22(m,5H), δ1.87-1.12(m,68H), δ0.93-0.88(m,12H), δ0.75-0.71(m,2H), δ0.25(d,6H); TOF MSES + [M+H + ]:826.7683m / z

[0906] Example 130

[0907] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-13-(octoxy)-14,16-dioxa-7-aza-15-silicotetraalkyl-2-hexyldecanoate

[0908]

[0909] 7-(4-hydroxybutyl)-15,15-dimethyl-13-(octoxy)-14,16-dioxa-7-aza-15-silicotetraalkyl-2-hexyldecanoate was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silicotetraalkyl (191.21 mg, 0.386 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (150 mg, 0.351 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 150 mg, 0.178 mmol, yield 51%. 1 H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.12(t,2H), δ3.90-3.84(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.46-3.34(m,2H), δ2 TOF MSES + [M+H + ]:842.7618m / z

[0910] Example 131

[0911] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicosahedral 2-hexyldecanoate

[0912]

[0913] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicosaccharide decanoate was prepared from 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silicosaccharide (173.83 mg, 0.351 mmol, 1.0 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (150.00 mg, 0.351 mmol, 1.0 equivalent)

[0914] 1 H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.11(t,2H), δ3.92-3.83(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.44-3.40(m,2H) TOF MSES + [M+H + ]:842.7665m / z

[0915] Example 132

[0916] Synthesis of 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)amino)hexyl-2-hexyldecanoate

[0917]

[0918] According to general procedure K, 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)hexyl)amino)hexyl2-hexyldecanoate was prepared from 1-((6-bromo-1-(octoxy)hexyl)oxy)1,1,3,3-tetramethyl-3-octyldisiloxane (168.33 mg, 0.304 mmol, 1.0 equivalent) and 6-((4-hydroxybutyl)amino)hexyl2-hexyldecanoate. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 142 mg, 0.158 mmol, yield 52%.

[0919] 1 H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.12(t,2H), δ3.92-3.83(m,1H), δ3.62(t,2H), δ3.47-3.39(m,1H), δ2.47(m,1H) TOF MSES + [M+H + ]:900.7888m / z

[0920] Example 133

[0921] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilheptadecyl 2-hexyldecanoate

[0922]

[0923] According to general procedure K, 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilheptadecyl 2-hexyldecyl ester was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (194.22 mg, 0.351 mmol, 1.0 equivalent) and 6-((4-hydroxybutyl)amino)-2-hexyl-2-hexyldecyl ester (150 mg, 0.351 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 169 mg, 0.188 mmol, yield 54%.

[0924] 1H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.11(t,2H), δ3.93-3.85(m,1H), δ3.62(t,2H), δ3.45-3.38(m,1H), δ2.47(m,1H) TOF MSES + [M+H + ]:900.7840m / z

[0925] Example 134

[0926] Synthesis of 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)hexyl-2-hexyldecanoate

[0927]

[0928] According to general procedure J, 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol (126 mg, 0.218 mmol, 1.0 equivalent) and 6-oxohexyl-2-hexyldecanoate (77.29 mg, 0.218 mmol, 1.0 equivalent) were prepared from 4-((6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)hexyl-2-hexyldecanoate. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 53 mg, 0.058 mmol, yield 27%.

[0929] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.11(t,2H), δ3.91-3.85(m,1H), δ3.76(t,2H), δ3.61(t,2H), δ3.46-3.41(m,1 H), δ2.46(m,1H), δ2.35-2.23(m,6H), δ1.96-1.11(m,68H), δ0.93-0.87(m,12H), δ0.30(d,6H), δ0.24(s,6H); TOF MSES + [M+H + ]:916.7822m / z

[0930] Example 135

[0931] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disil-octadecyl-2-hexyldecanoate

[0932]

[0933] 15-Heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disilyladecyl-2-hexyldecyl ester was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (190.51 mg, 0.334 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecyl ester (130 mg, 0.304 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 51 mg, 0.056 mmol, yield 18%.

[0934] 1 H NMR (500MHz, benzene-d6) δ5.04(t,1H), δ4.12(t,2H), δ3.91-3.85(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.47-3.36(m,1 H), δ2.47(m,1H), δ2.34-2.22(m,6H), δ1.96-1.09(m,68H), δ0.94-0.88(m,12H), δ0.31(d,6H), δ0.24(s,6H); TOF MSES + [M+H + ]:916.7834m / z

[0935] Example 136

[0936] Synthesis of 18-hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octoxy)-14,16-dioxa-7-aza-15-silicosahedral 2-hexyldecanoate

[0937]

[0938] 18-Hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silicohexadecyl 2-hexyl decyl ester was prepared from 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silicohexadecyl ester (234.50 mg, 0.386 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyl decyl ester (150 mg, 0.351 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 179 mg, 0.188 mmol, yield 53%.

[0939] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.12(t,2H), δ3.92-3.86(m,1H), δ3.75(d,2H), δ3.62(t,2H), δ3.48-3.42 (m,1H), δ2.51-2.44(m,1H), δ2.36-2.24(m,6H), δ1.97-1.13(m,81H), δ0.96-0.87(m,15H), δ0.30(d,6H); TOF MSES + [M+H + ]:954.8895m / z

[0940] Example 137

[0941] Synthesis of 15-heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicooctadecyl-2-hexyldecanoate

[0942]

[0943] 15-Heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicocetaalkyl-2-hexyldecanoate was prepared from 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silicocetaalkyl-2-hexyldecanoate (234.50 mg, 0.386 mmol, 1.1 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (150 mg, 0.351 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 210 mg, 0.220 mmol, yield 63%.

[0944] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.12(t,2H), δ3.91-3.85(m,1H), δ3.75(d,2H), δ3.62(t,2H), δ3.46-3.40 (m,1H), δ2.50-2.43(m,1H), δ2.34-2.24(m,6H), δ1.97-1.12(m,81H), δ0.96-0.87(m,12H), δ0.30(d,6H); TOF MSES + [M+H + ]:954.8887m / z

[0945] Example 138

[0946] Synthesis of 16-heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silicopentoalkyl-2-hexyldecanoate

[0947]

[0948] 16-Heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silicopentoalkyl-2-hexyldecanoate was prepared according to general procedure K from (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (185.04 mg, 0.386 mmol, 1.1 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (150 mg, 0.351 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 197 mg, 0.238 mmol, yield 68%.

[0949] 1 H NMR (500MHz, benzene-d6) δ4.88(dt,1H), δ4.12(t,2H), δ3.79-3.73(m,1H), δ3.63(t,2H), δ3.41-3.35(m,1H), δ2.54-2 .42(m,1H), δ2.39-2.26(m,6H), δ1.88-1.13(m,68H), δ0.94-0.87(m,12H), δ0.76-0.72(m,2H), δ0.26(d,6H); TOF MSES + [M+H + ]:826.7684m / z

[0950] Example 139

[0951] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosahedral 2-hexyldecanoate

[0952]

[0953] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosaccharide 2-hexyldecanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silane-nonadecane (191.21 mg, 0.351 mmol, 1.0 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (150 mg, 0.351 mmol, 1.0 equivalent)

[0954] 1 H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.12(t,2H), δ3.89-3.84(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.45-3.37 (m,1H), δ2.50-2.43(m,1H), δ2.34-2.24(m,6H), δ1.95-1.12(m,68H), δ0.95-0.86(m,12H), δ0.28(d,6H); TOF MSES + [M+H + ]:842.7627m / z

[0955] Example 140

[0956] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicopentoalkyl-2-hexyldecanoate

[0957]

[0958] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicopentoalkyl-2-hexyldecanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicopentoyl decanoate (522.56 mg, 1.122 mmol, 1.2 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (400 mg, 0.935 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 355 mg, 0.428 mmol, yield 46%.

[0959] 1 H NMR (500MHz, benzene-d6) δ4.96(t,1H), δ4.09(t,2H), δ3.85-3.80(m,1H), δ3.74(t,2H), δ3.61(t,2H), δ3.41-3.36 (m,1H), δ2.47-2.40(m,1H), δ2.32-2.25(m,6H), δ1.91-1.15(m,66H), δ0.92-0.87(m,12H), δ0.25(d,6H); TOF MSES + [M+H + ]:828.7474m / z

[0960] Example 141

[0961] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-siliconocephaloalkyl-2-hexyldecanoate

[0962]

[0963] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silane-heptadecanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silaneicoeicosane (326.04 mg, 0.640 mmol, 1.2 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (228 mg, 0.533 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 144 mg, 0.168 mmol, yield 32%.

[0964] 1H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.12(t,2H), δ3.91-3.83(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.47-3.36( m,1H),δ2.52-2.42(m,1H),δ2.35-2.24(m,6H),δ1.98-1.10(br.m,68H),δ0.92-0.88(m,12H)δ0.29(d,6H); TOF MSES + [M+H + ]:856.7791m / z

[0965] Example 142

[0966] Synthesis of 17-hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosahedral 2-hexyldecanoate

[0967]

[0968] 17-Hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosaccharide 2-hexyldecanoate was prepared from 1-bromo-10-hexyl-8,8-dimethyl-7,9,11-trioxa-8-silicosaccharide (522.56 mg, 1.122 mmol, 1.2 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (400.0 mg, 0.935 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 385 mg, 0.465 mmol, yield 50%.

[0969] 1 H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.12(t,2H), δ3.93-3.82(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.45-3.37( m,1H),δ2.51-2.41(m,1H),δ2.35-2.24(m,6H),δ1.98-1.07(br.m,66H),δ0.95-0.86(m,12H)δ0.28(d,6H); TOF MSES + [M+H + ]:828.7489m / z

[0970] Example 143

[0971] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-17-octyl-14,16,18-trioxa-7-aza-15-silicosahedral 2-hexyldecanoate

[0972]

[0973] 7-(4-hydroxybutyl)-15,15-dimethyl-17-octyl-14,16,18-trioxa-7-aza-15-silicosaccharide decanoate was prepared from 1-bromo-8,8-dimethyl-10-octyl-7,9,11-trioxa-8-silane-nonadecane (554.04 mg, 1.122 mmol, 1.2 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (400 mg, 0.935 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 398 mg, 0.465 mmol, yield 50%.

[0974] 1 H NMR (500MHz, CDCl3) δ5.11(t,1H), δ4.22(t,2H), δ4.00-3.93(m,1H), δ3.88(t,2H), δ3.72(t,2H), δ3.56-3.45( m,1H),δ2.60-2.51(m,1H),δ2.45-2.34(m,6H),δ2.05-1.21(br.m,70H),δ1.04-0.98(m,12H)δ0.39(d,6H); TOF MSES + [M+H + ]:856.7808m / z

[0975] Example 144

[0976] Synthesis of 18-(4-hydroxybutyl)-10,10-dimethyl-8-nonyl-7,9,11-trioxa-18-aza-10-silicotetradecane-24-yl-hexyldecanoate

[0977]

[0978] 18-(4-hydroxybutyl)-10,10-dimethyl-8-nonyl-7,9,11-trioxa-8-silane-heptadecane (556.25 mg, 1.122 mmol, 1.2 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (400 mg, 0.9352 mmol, 1.0 equivalents) were prepared according to general procedure K from 1-bromo-8,8-dimethyl-10-nonyl-7,9,11-trioxa-18-aza-10-silicotetraalkyl-24-yl-2-hexyldecanoate. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 344 mg, 0.408 mmol, yield 44%. H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.12(t,2H), δ3.88-3.82(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.44-3.38( m,1H),δ2.51-2.43(m,1H),δ2.34-2.24(m,6H),δ1.95-1.15(br.m,68H),δ0.93-0.88(m,12H)δ0.28(d,6H); TOF MSES + [M+H + ]:842.7653m / z

[0979] Example 145

[0980] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-17-pentyl-14,16,18-trioxa-7-aza-15-silicooctadecyl-2-hexyldecanoate

[0981]

[0982] 7-(4-hydroxybutyl)-15,15-dimethyl-17-pentyl-14,16,18-trioxa-7-aza-15-silicocaalkyl-2-hexyldecanoate was prepared from 1-bromo-8,8-dimethyl-10-pentyl-7,9,11-trioxa-8-silicocaalkyl-2-hexyldecanoate (556.25 mg, 1.122 mmol, 1.2 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (400 mg, 0.935 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 375 mg, 0.445 mmol, yield 48%.

[0983] H NMR (500MHz, benzene-d6) δ4.97(t,1H), δ4.10(t,2H), δ3.87-3.82(m,1H), δ3.75(t,2H), δ3.61(t,2H), δ3.42-3.38( m,1H),δ2.47-2.41(m,1H),δ2.33-2.23(m,6H),δ1.91-1.10(br.m,68H),δ0.93-0.88(m,12H)δ0.26(d,6H); TOF MSES + [M+H + ]:842.7642m / z

[0984] Example 146

[0985] Synthesis of 16-heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-13,15,17-trioxa-7-aza-14-silicopentoalkyl-2-hexyldecanoate

[0986]

[0987] 16-Heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-13,15,17-trioxa-7-aza-14-silicopentoalkyl-2-hexyldecanoate was prepared from 1-bromo-9-heptyl-7,7-dimethyl-6,8,10-trioxa-7-silicopentoalkyl (270.26 mg, 0.561 mmol, 1.2 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (200 mg, 0.468 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 150 mg, 0.181 mmol, yield 39%.

[0988] H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.12(t,2H), δ3.90-3.83(m,1H), δ3.78(t,2H), δ3.62(t,2H), δ3.47-3. 39(m,1H),δ3.36(t,2H),δ2.34-2.24(m,6H),δ1.96-1.08(br.m,66H),δ0.94-0.88(m,12H)δ0.29(d,6H); LC ESIMS[M+H + ]:828.860m / z

[0989] Example 147

[0990] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16-dioxa-18-thia-7-aza-15-silicosahedral 2-hexyldecanoate

[0991]

[0992] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16-dioxa-18-thia-8-silane-nonadecane (574.28 mg, 1.122 mmol, 1.2 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (400 mg, 0.935 mmol, 1.0 equivalents) were prepared according to general procedure K from 1-bromo-10-heptyl-8,8-dimethyl-7,9-dioxa-11-thia-8-silane-hexadecyl decanoate (400 mg, 0.935 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 288 mg, 0.330 mmol, yield 35%. H NMR (500MHz, benzene-d6)δ5.11(t,1H),δ4.12(t,2H),δ3.83-3.74(m,2H),δ3.62(t,2H),δ2.80-2.65(m,2H),δ 2.50-2.41(m,1H), δ2.34-2.23(m,6H), δ2.07-1.15(br.m,68H), δ0.93-0.89(m,12H)δ0.31(d,6H); TOFMS ES+[M+H + ]:858.7407m / z

[0993] Example 148

[0994] Synthesis of 17-heptyl-7-(2-hydroxyethyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosahedral 2-hexyldecanoate

[0995]

[0996] 17-Heptyl-7-(2-hydroxyethyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosaccharide 2-hexyldecanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silane-nonadecane (654.83 mg, 1.321 mmol, 1.1 equivalent) and 6-((2-hydroxyethyl)amino)hexyl-2-hexyldecanoate (480 mg, 1.201 mmol, 1.0 equivalent)

[0997] 1 H NMR (500MHz, benzene-d6) δ5.00(dt,1H), δ4.12(t,2H), δ3.91-3.82(m,1H), δ3.77(t,2H), δ3.52(t,2H), δ3.46-3.38( m,1H), δ2.52-2.43(m,1H), δ2.38-2.24(m,6H), δ1.97-1.07(br.m,64H), δ0.95-0.88(m,12H), δ0.28(d,6H); TOF MSES + [M+H + ]:814.7322m / z

[0998] Example 149

[0999] Synthesis of 9-heptyl-20-(4-hydroxybutyl)-7,7-dimethyl-8,10-dioxa-20-aza-7-silicosahedron-26-yl-hexyldecanoate

[1000]

[1001] 9-Heptyl-20-(4-hydroxybutyl)-7,7-dimethyl-8,10-dioxa-20-aza-7-silicosahedron-26-yl-hexyldecanoate was prepared from ((1-((9-bromononyl)oxy)octyl)oxy)(hexyl)dimethylsilane (634.84 mg, 1.286 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (500 mg, 1.169 mmol, 1.0 equivalent)

[1002] 1H NMR (500MHz, benzene-d6) δ4.89(dt,1H), δ4.12(t,2H), δ3.80-3.74(m,1H), δ3.63(t,2H), δ3.42-3.36(m,1H), δ2.49-2.4 4(m,1H),δ2.36-2.25(m,6H),δ1.87-1.11(br.m,70H),δ0.95-0.88(m,12H),δ0.74-0.70(m,2H),δ0.25(d,6H); TOF MSES + [M+H + ]:840.7838m / z

[1003] Example 150

[1004] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-13,13,15,15-tetramethyl-12,14,16,18-tetraoxa-7-aza-13,15-disilicosacrylic 2-hexyldecanoate

[1005]

[1006] 17-Heptyl-7-(4-hydroxybutyl)-13,13,15,15-tetramethyl-12,14,16,18-tetraoxa-7-aza-13,15-disilhexadecyl-2-hexyldecyl ester was prepared according to general procedure K from 1-(4-bromobutoxy)-1,1,3,3-tetramethyl-3-((1-(octoxy)octyl)oxy)disiloxane (501.6 mg, 0.926 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecyl ester (360 mg, 0.842 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 194 mg, 0.218 mmol, yield 26%.

[1007] 1 H NMR(500MHz, benzene-d6)δ4.69(t,1H),δ3.95(t,2H),δ3.61-3.51(m,3H),δ3.48-3.41(m,2H),δ3.21-3.16(m,1H),δ 2.41-2.30(m,6H), δ2.23-2.16(m,1H), δ1.64-1.06(br.m,64H), δ0.77(t,12H), δ0.05(d,6H), δ0.00(s,6H); LC ESIMS[M+H + ]:888.640m / z

[1008] Example 151

[1009] Synthesis of 6-((6-((dimethyl((oxecyclohexadecyl-2-yl)oxy)silyl)oxy)hexyl)(4-hydroxybutyl)amino)hexyl-2-hexyldecanoate

[1010]

[1011] According to general procedure K, 6-((6-((dimethyl((oxecyclohexadecanyl-2-yl)oxy)silane)oxy)hexyl)(4-hydroxybutyl)amino)hexyl-2-hexyldecanoate was prepared from ((6-bromohexyl)oxy)dimethyl((oxecyclohexadecanyl-2-yl)oxy)silane (911.1 mg, 1.900 mmol, 1.25 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (650 mg, 1.520 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 366 mg, 0.443 mmol, yield 29%.

[1012] 1 H NMR (500MHz, benzene-d6) δ4.96-4.93(dd,1H), δ4.12(t,2H), δ3.98-3.90(m,1H), δ3.74(t,2H), δ3.62(t,2H), δ2.35-2. 27(m,1H), δ2.50-2.40(m,1H), δ2.34-2.24(m,6H), δ1.97-1.10(br.m,70H), δ0.93-0.88(m,6H), δ0.25(d,6H); LC ESIMS[M+H + ]:826.680m / z

[1013] Example 152

[1014] Synthesis of (Z)-17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-siliconocetane-24-en-1-yl-hexyldecanoate

[1015]

[1016] (Z)-17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicoeicosano-17-ene (1.073 g, 2.057 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (800 mg, 1.870 mmol, 1.0 equivalent) were prepared according to general procedure K from (Z)-1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-7-aza-15-silicoheptadecano-24-en-1-yl-2-hexyldecanoate. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 200 mg, 0.234 mmol, yield 12%.

[1017] 1 H NMR (500MHz, benzene-d6) δ5.48-5.38(m,2H), δ4.98(dt,1H), δ4.12(t,2H), δ3.92-3.81(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.42-3.36( LC ESIMS[M+H + ]:854.778m / z

[1018] Example 153

[1019] Synthesis of (Z)-17-hepta-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-siliconocetadecane-21-en-1-yl-hexyldecanoate

[1020]

[1021] (Z)-17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicoeicosano-21-en-1-yl-hexyldecanoate was prepared from (Z)-1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicoeicosano-14-ene (1.073 g, 2.057 mmol, 1.1 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (800 mg, 1.870 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 350 mg, 0.410 mmol, yield 22%.

[1022] 1 H NMR (500MHz, benzene-d6) δ5.63-5.49(m,2H), δ5.00(dt,1H), δ4.12(t,2H), δ3.91-3.84(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.49-3.39(m,1H), δ2 .50-2.41(m,3H),δ2.35-2.23(m,5H),δ2.10-2.03(m,2H),δ1.93-1.75 (m,4H)δ1.68-1.12(br.m,60H),δ0.95-0.85(m,12H),δ0.27(d,6H); LC ESIMS[M+H + ]:854.778m / z

[1023] Example 154

[1024] Synthesis of 7-(4-hydroxybutyl)-15,15,17-trimethyl-14,16,18-trioxa-7-aza-15-silicooctadecyl-2-hexyldecanoate

[1025]

[1026] 7-(4-hydroxybutyl)-15,15,17-trimethyl-14,16,18-trioxa-7-aza-15-silicocayl-2-hexyldecanoate was prepared from 1-bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silicocayldecanoate (700.88 mg, 1.595 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (620 mg, 1.445 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 146 mg, 0.186 mmol, yield 13%.

[1027] 1 H NMR (500MHz, benzene-d6) δ5.09(q,1H), δ4.12(t,2H), δ3.85-3.79(m,1H), δ3.73(t,2H), δ3.62(t,2H), δ3.40-3.35(m,1H), δ2 .51-2.45(m,1H), δ2.34-2.23(m,6H), δ1.85-1.76(m,2H), δ1.70-1.14(br.m,62H), δ0.93-0.87(m,9H), δ0.24(d,6H); LC ESIMS[M+H + ]:786.693m / z

[1028] Example 155

[1029] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-17-propyl-14,16,18-trioxa-7-aza-15-silicooctadecyl-2-hexyldecanoate

[1030]

[1031] 7-(4-hydroxybutyl)-15,15-dimethyl-17-propyl-14,16,18-trioxa-7-aza-15-silicocayl-2-hexyldecanoate was prepared from 1-bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silicocayldecanoate (721.56 mg, 1.543 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (600 mg, 1.403 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 248 mg, 0.305 mmol, yield 22%.

[1032] 1 H NMR (500MHz, benzene-d6) δ4.97(t,1H), δ4.11(t,2H), δ3.87-3.81(m,1H), δ3.75(t,2H), δ3.61(t,2H), δ3.42-3.37( m,1H),δ2.50-2.43(m,1H),δ2.33-2.23(m,6H),δ1.89-1.15(br.m,64H),δ0.96-0.87(m,12H)δ0.26(d,6H); TOF MSES + [M+H + ]:814.7308m / z

[1033] Example 156

[1034] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-17-propyl-14,16,18-trioxa-7-aza-15-silanetrianealkyl-2-hexyldecanoate

[1035]

[1036] 7-(4-hydroxybutyl)-15,15-dimethyl-17-propyl-14,16,18-trioxa-7-aza-15-silanetradecane 2-hexyldecanoate was prepared from 1-bromo-8,8-dimethyl-10-propyl-7,9,11-trioxa-8-silanetradecane (903.91 mg, 1.824 mmol, 1.2 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (650 mg, 1.520 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 285 mg, 0.338 mmol, yield 22%.

[1037] H NMR (500MHz, benzene-d6) δ4.97(t,1H), δ4.11(t,2H), δ3.89-3.81(m,1H), δ3.75(t,2H), δ3.62(t,2H), δ3.44-3.37( LC ESIMS[M+H + ]:842.890m / z

[1038] Example 157

[1039] Synthesis of 14-(4-hydroxybutyl)-6,6-dimethyl-4-nonyl-3,5,7-trioxa-14-aza-6-silicoeicosano-20-yl-hexyldecanoate

[1040]

[1041] 14-(4-hydroxybutyl)-6,6-dimethyl-4-nonyl-3,5,7-trioxa-6-silanetridecane (644.36 mg, 1.466 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (570 mg, 1.33 mmol, 1.0 equivalent) were prepared according to general procedure K from 13-bromo-6,6-dimethyl-4-nonyl-3,5,7-trioxa-14-aza-6-silicoeicosano-20-yl-hexyldecanoate. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 100 mg, 0.127 mmol, yield 10%.

[1042] 1 H NMR (500MHz, benzene-d6) δ4.97(dt,1H), δ4.12(t,2H), δ3.87-3.80(m,1H), δ3.75(t,2H), δ3.62(t,2H), δ3.45-3.35(m,1H), δ2 TOF MSES + [M+H + ]:786.7024m / z

[1043] Example 158

[1044] Synthesis of 14-(4-hydroxybutyl)-6,6-dimethyl-4-undecyl-3,5,7-trioxa-14-aza-6-silicoeicosano-20-yl-hexyldecanoate

[1045]

[1046] 14-(4-hydroxybutyl)-6,6-dimethyl-4-undecyl-3,5,7-trioxa-6-silanetridecane (829.38 mg, 1.543 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (600 mg, 1.403 mmol, 1.0 equivalent) were prepared according to general procedure K from 13-bromo-6,6-dimethyl-4-undecyl-3,5,7-trioxa-14-aza-6-silicoeicosano-20-yl-2-hexyldecanoate. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 190 mg, 0.233 mmol, yield 17%.

[1047] 1H NMR (500MHz, benzene-d6) δ4.97(t,1H), δ4.11(t,2H), δ3.83-3.80(m,1H), δ3.74(t,2H), δ3.62(t,2H), δ3.43-3.34(m,1H), δ2 .49-2.42(m,1H), δ2.33-2.25(m,6H), δ1.92-1.76(m,4H), δ1.65-1.14(br.m,63H), δ0.98-0.85(m,9H), δ0.25(d,6H); LC ESIMS[M+H + ]:814.747m / z

[1048] Example 159

[1049] Synthesis of 17-heptyl-15,15-dimethyl-7-(2-(1-methylpyrrolidone-2-yl)ethyl)-14,16,18-trioxa-7-aza-15-silicosahedral-2-hexyldecanoate

[1050]

[1051] 17-Heptyl-15,15-dimethyl-7-(2-(1-methylpyrrolidone-2-yl)ethyl)-14,16,18-trioxa-7-aza-15-silicosaccharide decanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicosaccharide (233.6 mg, 0.471 mmol, 1.0 equivalence) and 6-((2-(1-methylpyrrolidone-2-yl)ethyl)amino)hexyl-2-hexyldecanoate (220 mg, 0.471 mmol, 1.0 equivalence) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 72 mg, 0.082 mmol, yield 17%.

[1052] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,1H), δ4.13(t,2H), δ3.91-3.84(m,1H), δ3.78(t,2H), δ3.45-3.40(m,1H), δ3.00(t,1H) δ2.55-2.35(m,7H), δ2.29(s,3H), δ2.12-2.00(m,2H) δ1.96-1.20(br.m,72H), δ0.94-0.89(m,12H), δ0.29(d,6H); TOF MSES + [M+H + ]:881.8089m / z

[1053] Example 160

[1054] Synthesis of 16-heptyl-14,14-dimethyl-7-(2-(1-methylpyrrolidone-2-yl)ethyl)-15,17-dioxa-7-aza-14-silicopentoalkyl-2-hexyldecanoate

[1055]

[1056] 16-Heptyl-14,14-dimethyl-7-(2-(1-methylpyrrolidone-2-yl)ethyl)-15,17-dioxa-7-aza-14-silicopentoalkyl-2-hexyldecanoate was prepared according to general procedure K from (6-bromohexyl)dimethyl((1-(octoxy)octyl)oxy)silane (81.76 mg, 0.170 mmol, 1.14 equivalents) and 6-((2-(1-methylpyrrolidone-2-yl)ethyl)amino)hexyl-2-hexyldecanoate (70.00 mg, 0.15 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 40 mg, 0.046 mmol, yield 31%.

[1057] 1 H NMR(500MHz, benzene-d6)δ4.89(t,1H),δ4.13(t,2H),δ3.78-3.74(m,1H),δ3.41-3.36(m,1H),δ3.00(td,1H)δ2.54-2.38(m ,6H),δ2.29(s,3H),δ2.12-1.93(m,3H)δ1.89-1.20(br.m,70H),δ0.94-0.88(m,12H),δ0.78-0.73(m,2H)δ0.29(d,6H)

[1058] Example 161

[1059] Synthesis of 16-(4-hydroxybutyl)-8,8-dimethyl-6-nonyl-5,7,9-trioxa-16-aza-8-silicosicosano-2,2-yl-hexyldecanoate

[1060]

[1061] 16-(4-hydroxybutyl)-8,8-dimethyl-6-nonyl-5,7,9-trioxa-8-silopentadecane (661.41 mg, 1.414 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (550 mg, 1.286 mmol, 1.0 equivalent) were prepared according to general procedure K from 15-bromo-8,8-dimethyl-6-nonyl-5,7,9-trioxa-16-aza-8-silicodocoadecan-22-yl-hexyldecanoate. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 112 mg, 0.137 mmol, yield 11%.

[1062] 1 H NMR (500MHz, benzene-d6) δ4.99(dt,1H), δ4.12(t,2H), δ3.88-3.80(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.43-3.36(m,1H), δ2 .51-2.44(m,1H), δ2.35-2.23(m,6H), δ1.97-1.76(m,4H), δ1.68-1.13(br.m,60H), δ0.94-0.89(m,12H), δ0.29(d,6H); LC ESIMS[M+H + ]:814.702m / z

[1063] Example 162

[1064] Synthesis of 16-(4-hydroxybutyl)-8,8-dimethyl-6-undecyl-5,7,9-trioxa-16-aza-8-silicosicosano-22-yl-hexyldecanoate

[1065]

[1066] 16-(4-hydroxybutyl)-8,8-dimethyl-6-undecyl-5,7,9-trioxa-8-siliconpentadecane (411.21 mg, 0.772 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (300 mg, 0.702 mmol, 1.0 equivalent) were prepared according to general procedure K from 15-bromo-8,8-dimethyl-6-undecyl-5,7,9-trioxa-16-aza-8-silicodocoadecane-22-yl-hexyldecanoate. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 186 mg, 0.221 mmol, yield 32%. 1H NMR (500MHz, benzene-d6) δ4.99(dt,1H), δ4.12(t,2H), δ3.94-3.80(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.43-3.36(m,1H), δ2. TOF MSES + [M+H + ]:842.7631m / z

[1067] Example 163

[1068] Synthesis of 14-(4-hydroxybutyl)-4,6,6-trimethyl-3,5,7-trioxa-14-aza-6-silicoeicosano-20-yl-hexyldecanoate

[1069]

[1070] 14-(4-hydroxybutyl)-4,6,6-trimethyl-3,5,7-trioxa-6-silanetridecane (311.48 mg, 0.952 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-hexyldecanoate (370 mg, 0.865 mmol, 1.0 equivalent) were prepared according to general procedure K from 13-bromo-4,6,6-trimethyl-3,5,7-trioxa-14-aza-6-silicoeicosano-20-yl-hexyldecanoate. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 170 mg, 0.252 mmol, yield 29%.

[1071] 1 H NMR (500MHz, benzene-d6) δ5.04(q,1H), δ4.11(t,2H), δ3.82-3.72(m,1H), δ3.70(t,2H), δ3.62(t,2H), δ3.37-3.27(m,1H), δ2. TOF MSES + [M+H + ]:674.5767m / z

[1072] Example 164

[1073] Synthesis of 17-heptyl-7-(3-hydroxypropyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosahedral 2-hexyldecanoate

[1074]

[1075] 17-Heptyl-7-(3-hydroxypropyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosaccharide decanoate was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silane-nonadecane (498.19 mg, 1.00 mmol, 1.1 equivalent) and 6-((3-hydroxypropyl)amino)hexyl-2-hexyldecanoate (378.02 mg, 0.914 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 50 mg, 0.060 mmol, yield 6%.

[1076] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,1H), δ4.12(t,2H), δ3.91-3.82(m,1H), δ3.75(t,2H), δ3.46-3.38(m,1H), δ2.52-2.4 3(m,1H),δ2.41-2.21(m,6H),δ1.95-1.76(m,4H),δ1.69-1.10(br.m,64H),δ0.97-0.81(m,12H),δ0.29(d,6H); TOF MSES + [M+H + ]:828.7505m / z

[1077] Example 165

[1078] Synthesis of 16-hepta-7-(2-hydroxyethyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silicopentoalkyl-2-hexyldecanoate

[1079]

[1080] 16-Heptyl-7-(2-hydroxyethyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silicopentoalkyl-2-hexyldecanoate was prepared according to general procedure K from (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (263.80 mg, 0.550 mmol, 1.1 equivalents) and 6-((2-hydroxyethyl)amino)hexyl-2-hexyldecanoate (200 mg, 0.500 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 180 mg, 0.225 mmol, yield 45%.

[1081] 1 H NMR (500MHz, benzene-d6) δ4.90-4.87(m,1H), δ4.12(t,2H), δ3.79-3.74(m,1H), δ3.51(t,2H), δ3.46-3.36(m,2H), δ2.51-2 .46(m,1H), δ2.39-2.26(m,6H), δ1.88-1.73(m,4H), δ1.69-1.18(br.m,62H), δ0.94-0.87(m,12H), δ0.26(d,6H); TOF MSES + [M+H + ]:798.7377m / z

[1082] Example 166

[1083] Synthesis of 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(4-hydroxybutyl)amino)hexyl-2-(decylthio)hexanoate

[1084]

[1085] According to general procedure J, 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)but-1-ol (150.00 mg, 0.307 mmol, 1.0 equivalent) and 6-oxohexyl-2-(decylthio)hexanoate (118.87 mg, 0.307 mmol, 1.0 equivalent) were prepared from 6-oxohexyl-2-(decylthio)hexanoate (118.87 mg, 0.307 mmol, 1.0 equivalent). The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 130 mg, 0.151 mmol, yield 49%. 1H NMR (500MHz, benzene-d6) δ4.89(dt,1H), δ4.17-4.06(m,2H), δ3.79-3.73(m,1H), δ3.62(t,2H), δ3.42-3.30(m,2H), δ2.78-2.71(m,1H), δ2.67-2.60 (m,1H),δ2.35-2.23(m,6H),δ2.09-1.99(m,1H),δ1.89-1.11(m,65H),δ 0.94-0.89(m,9H), δ0.83(t,3H), δ0.77-0.72(m,2H), δ0.26(d,6H); TOF MSES + [M+H + ]:858.7409m / z

[1086] Example 167

[1087] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silicopentoalkyl-2-(decylthio)hexanoate

[1088] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silicopentane-1-ol (150.00 mg, 0.307 mmol, 1.0 equivalent) and 6-oxohexyl-2-(decylthio)hexanoate (118.87 mg, 0.307 mmol, 1.0 equivalent) were prepared according to general procedure J from 13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silicopentane-1-ol (150.00 mg, 0.307 mmol, 1.0 equivalent). The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 142 mg, 0.165 mmol, yield 54%.

[1089] 1 H NMR (500MHz, benzene-d6) δ4.88(dt,1H), δ4.16-4.07(m,2H), δ3.79-3.73(m,1H), δ3.62(t,2H), δ3.41-3.30(m,2H), δ2.77-2.70(m,1H), δ2.67-2.60 (m,1H),δ2.34-2.23(m,6H),δ2.08-1.99(m,1H),δ1.88-1.12(m,65H),δ 0.94-0.88(m,9H), δ0.83(t,3H), δ0.76-0.72(m,2H), δ0.25(d,6H); TOF MSES + [M+H+ ]:858.7404m / z

[1090] Example 168

[1091] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-13-(octoxy)-14,16-dioxa-7-aza-15-silicotetraalkyl-2-(decylthio)hexanoate

[1092]

[1093] 7-(4-hydroxybutyl)-15,15-dimethyl-13-(octoxy)-14,16-dioxa-7-aza-15-silicotetraalkyl-2-(decylthio)hexanoate was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silicotetraalkyl (177.88 mg, 0.359 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 140 mg, 0.160 mmol, yield 49%.

[1094] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,1H), δ4.16-4.06(m,2H), δ3.89-3.84(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.45-3.30(m,2H), δ2.77-2.70(m, 1H), δ2.67-2.60(m,1H), δ2.37-2.19(m,6H), δ2.08-1.99(m,1H), δ1. 95-1.09(m,65H), δ0.95-0.87(m,9H), δ0.83(t,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:874.7339m / z

[1095] Example 169

[1096] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicohexadecyl 2-(decylthio)hexanoate

[1097]

[1098] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicohexane 2-(decylthio)hexanoate was prepared according to general procedure K from 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silicohexadecane (161.71 mg, 0.326 mmol, 1.0 equivalent) and 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 123 mg, 0.141 mmol, yield 43%. 1 H NMR (500MHz, benzene-d6) δ5.01(dt,1H), δ4.16-4.07(m,2H), δ3.93-3.84(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.45-3.30(m,2H), δ3.78-3.71(m, 1H), δ2.67-2.60(m,1H), δ2.34-2.23(m,6H), δ2.09-2.00(m,1H), δ1. 95-1.11(m,65H), δ0.94-0.89(m,9H), δ0.83(t,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:874.7355m / z

[1099] Example 170

[1100] Synthesis of 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)amino)hexyl 2-(decylthio)hexanoate

[1101]

[1102] According to general procedure K, 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)hexyl)amino)hexyl 2-(decylthio)hexanoate was prepared from 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (156.59 mg, 0.2828 mmol, 1.0 equivalent) and 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate (130.00 mg, 0.2828 mmol, 1.0 equivalent)

[1103] 1 H NMR (500MHz, benzene-d6) δ5.00(dt,1H), δ4.17-4.05(m,2H), δ3.90-3.82(m,1H), δ3.61(t,2H), δ3.46-3.28(m,2H), δ3.78-3.58(m,2H), δ2.36-2. 23(m,6H),δ2.09-1.97(m,1H),δ1.93-1.09(m,65H),δ0.94-0.88(m,9 H), δ0.83(t,3H), δ0.70-0.65(m,2H), δ0.27(d,6H), δ0.21(d,6H); TOF MSES + [M+H + ]:932.7584m / z

[1104] Example 171

[1105] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilheptadecyl 2-(decylthio)hexanoate

[1106]

[1107] According to general procedure K, 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilhexadecanyl-2-(decylthio)hexanoate was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (177.88 mg, 0.321 mmol, 0.98 equivalents) and 6-((4-hydroxybutyl)amino)hexyl-2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 184 mg, 0.197 mmol, yield 60%.

[1108] 1H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.16-4.05(m,2H), δ3.89-3.84(m,1H), δ3.6 2(t,2H), δ3.45-3.39(m,1H), δ3.34-3.30(m,1H), δ3.77-3.70(m,1H), δ2.67-2. 60(m,1H),δ2.34-2.23(m,6H),δ2.08-1.99(m,1H),δ1.95-1.12(m,65H),δ0.95- 0.89(m,9H), δ0.83(t,3H), δ0.71-0.65(m,2H), δ0.27(d,6H), δ0.21(d,6H); TOF MSES + [M+H + ]:932.7599m / z

[1109] Example 172

[1110] Synthesis of 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)hexyl-2-(decylthio)hexanoate

[1111]

[1112] According to general procedure J, 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol (90 mg, 0.159 mmol, 1.0 equivalent) and 6-oxohexyl 2-(decylthio)hexanoate (61.54 mg, 0.159 mmol, 1.0 equivalent) were prepared from 4-((6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)hexyl 2-(decylthio)hexanoate. The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 40 mg, 0.042 mmol, yield 26%.

[1113] 1H NMR (500MHz, benzene-d6) δ5.04(dt,1H), δ4.16-4.06(m,2H), δ3.91-3.86(m,1H), δ3 .76(t,2H),δ3.62(t,2H),δ3.47-3.40(m,1H),δ3.34-3.30(m,1H),δ2.77-2.71 (m,1H), δ2.67-2.60(m,1H), δ2.37-2.21(m,6H), δ2.11-1.98(m,1H), δ1.95-1. 11(m,65H),δ0.94-0.89(m,9H),δ0.83(t,3H),δ0.31(d,6H),δ0.25(s,6H); TOF MS ES + [M+H + ]:948.7556m / z

[1114] Example 173

[1115] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disil-octadecyl-2-(decylthio)hexanoate

[1116]

[1117] 15-Heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disilyladecyl-2-(decylthio)hexanoate was prepared according to general procedure K from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (204.49 mg, 0.359 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 192 mg, 0.202 mmol, yield 62%.

[1118] 1H NMR (500MHz, benzene-d6) δ5.04(dt,1H), δ4.16-4.06(m,2H), δ3.90-3.85(m,1H), δ3. 76(t,2H),δ3.62(t,2H),δ3.46-3.40(m,1H),δ3.33-3.30(m,1H),δ2.77-2.70( m,1H),δ2.67-2.60(m,1H),δ2.34-2.23(m,6H),δ2.08-1.99(m,1H),δ1.96-1.1 2(m,65H),δ0.95-0.88(m,9H),δ0.83(t,3H),δ0.31(d,6H),δ0.24(s,6H);; TOF MS ES + [M+H + ]:948.7554m / z

[1119] Example 174

[1120] Synthesis of 18-hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octoxy)-14,16-dioxa-7-aza-15-silicohexadecyl 2-(decylthio)hexanoate

[1121]

[1122] According to general procedure K, 18-hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silicohexadecyl 2-(decylthio)hexanoate was prepared from 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silicohexadecyl (218.15 mg, 0.359 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 158 mg, 0.160 mmol, yield 49%.

[1123] 1H NMR (500MHz, benzene-d6) δ5.03(dt,1H), δ4.16-4.07(m,2H), δ3.92-3.86(m,1H), δ3.76(d,2H), δ3.62(t,2H), δ3.48-3.42(m,1H), δ3.34-3.30(m,1H), δ2.77 -2.70(m,1H),δ2.67-2.60(m,1H),δ2.36-2.24(m,6H),δ2.08-1.99(m,1H), δ1.97-1.12(m,78H), δ0.95-0.89(m,12H), δ0.83(t,3H), δ0.30(d,6H); TOF MSES + [M+H + ]:986.8613m / z

[1124] Example 175

[1125] Synthesis of 15-heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicooctadecyl 2-(decylthio)hexanoate

[1126]

[1127] 15-Heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicocaalkyl-2-(decyl)hexanoate was prepared from 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silicocaalkyl-2-(decyl)hexanoate (150.00 mg, 0.326 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 190 mg, 0.193 mmol, yield 59%.

[1128] 1H NMR (500MHz, benzene-d6) δ5.02(dt,1H), δ4.16-4.07(m,2H), δ3.92-3.85(m,1H) ,δ3.75(d,2H),δ3.62(t,2H),δ3.46-3.40(m,1H),δ3.34-3.30(m,1H),δ2.7 7-2.70(m,1H),δ2.67-2.60(m,1H),δ2.34-2.24(m,6H),δ2.08-1.99(m,1H) , δ1.96-1.12(m,78H), δ0.96-0.89(m,12H), δ0.83(t,3H), δ0.30(d,6H); LC ESI MS[M+H + ]:986.763m / z

[1129] Example 176

[1130] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosahedral 2-(decylthio)hexanoate

[1131]

[1132] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicohexane 2-(decylthio)hexanoate was prepared according to general procedure K from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silane-nonadecane (177.88 mg, 0.359 mmol, 1.0 equivalent) and 6-((4-hydroxybutyl)amino)hexyl 2-(decylthio)hexanoate (150.00 mg, 0.326 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 94 mg, 0.107 mmol, yield 33%. 1 H NMR (500MHz, benzene-d6) δ5.00(dt,1H), δ4.16-4.07(m,2H), δ3.89-3.84(m,1H) ,δ3.77(t,2H),δ3.62(t,2H),δ3.45-3.37(m,1H),δ3.34-3.30(m,1H),δ2.7 7-2.70(m,1H),δ2.67-2.60(m,1H),δ2.34-2.24(m,6H),δ2.08-1.99(m,1H) , δ1.95-1.12(m,65H), δ0.95-0.87(m,9H), δ0.83(t,3H), δ0.28(d,6H); TOF MSES+ [M+H + ]:874.7365m / z

[1133] Example 177

[1134] Synthesis of 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)(4-hydroxybutyl)amino)hexyl-2-(pentathio)decanoate

[1135]

[1136] According to general procedure J, 6-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)amino)but-111-ol (150.00 mg, 0.307 mmol, 1.0 equivalent) and 6-oxohexyl-2-(pentathio)decanoate (114.56 mg, 0.307 mmol, 1.0 equivalent) were prepared from 6-oxohexyl-2-(pentathio)decanoate. The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 120 mg, 0.142 mmol, yield 46%. 1 H NMR (500MHz, benzene-d6) δ4.89(t,1H), δ4.17-4.07(m,2H), δ3.82-3.74(m,1H), δ3.62(t,2H), δ3.42-3.33(m,2H), δ2.75-2.69(m,1H), δ2.65-2.58( m,1H),δ2.35-2.23(m,6H),δ2.12-2.03(m,1H),δ1.89-1.11(m,63H),δ 0.95-0.89(m,9H), δ0.84(t,3H), δ0.77-0.73(m,2H), δ0.26(d,6H); TOF MSES + [M+H + ]:844.7249m / z

[1137] Example 178

[1138] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silicopentoalkyl-2-(pentathio)decanoate

[1139]

[1140] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16-dioxa-7-aza-17-silicopentane-2-(pentanethio)decanoate was prepared from 13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silicopentane-1-ol (150.00 mg, 0.307 mmol, 1.0 equivalent) and 6-oxohexyl-2-(pentanethio)decanoate (114.56 mg, 0.307 mmol, 1.0 equivalent) according to general procedure J. The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 142 mg, 0.168 mmol, yield 55%.

[1141] 1 H NMR (500MHz, benzene-d6) δ4.88(t,1H), δ4.17-4.07(m,2H), δ3.79-3.73(m,1H), δ3.62(t,2H), δ3.40-3.31(m,2H), δ2.75-2.68(m,1H), δ2.64-2.57( m,1H),δ2.37-2.23(m,6H),δ2.11-2.00(m,1H),δ1.86-1.11(m,63H),δ 0.94-0.91(m,9H), δ0.84(t,3H), δ0.75-0.71(m,2H), δ0.25(d,6H); TOF MSES + [M+H + ]:844.7228m / z

[1142] Example 179

[1143] Synthesis of 7-(4-hydroxybutyl)-15,15-dimethyl-13-(octoxy)-14,16-dioxa-7-aza-15-silicotetraalkyl-2-(pentathio)decanoate

[1144]

[1145] 7-(4-hydroxybutyl)-15,15-dimethyl-13-(octoxy)-14,16-dioxa-7-aza-15-silicotetraalkyl-2-(pentathio)decanoate was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silicotetraalkyl (183.47 mg, 0.370 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-(pentathio)decanoate (150 mg, 0.337 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 132 mg, 0.153 mmol, yield 46%. 1 H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.17-4.07(m,2H), δ3.89-3.82(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.46-3.28(m,2H), δ2.75-2.68(m,1H), δ2.64 -2.58(m,1H),δ2.35-2.22(m,6H),δ2.11-2.02(m,1H),δ1.95-1.76(m,3H) , δ1.71-1.12(m,60H), δ0.94-0.87(m,9H), δ0.84(t,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:860.7214m / z

[1146] Example 180

[1147] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicohexadecyl 2-(pentathio)decanoate

[1148]

[1149] 15-Heptyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicosahedral 2-(pentathio)decanoate was prepared according to general procedure K from 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silicosahedral (166.79 mg, 0.336 mmol, 1.0 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-(pentathio)decanoate (150 mg, 0.336 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 100 mg, 0.116 mmol, yield 35%.1 H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.17-4.07(m,2H), δ3.89-3.83(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.44-3.32(m,2H), δ2.75-2.68(m,1H), δ2.64 -2.57(m,1H),δ2.33-2.23(m,6H),δ2.11-2.01(m,1H),δ1.95-1.76(m,3H) , δ1.71-1.13(m,60H), δ0.94-0.87(m,9H), δ0.84(t,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:860.7202m / z

[1150] Example 181

[1151] Synthesis of 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)amino)hexyl-2-(pentathio)decanoate

[1152]

[1153] According to general procedure K, 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)hexyl)amino)hexyl 2-(pentathio)decanoate was prepared from 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (186.36 mg, 0.337 mmol, 1.0 equivalent) and 6-((4-hydroxybutyl)amino)hexyl 2-(pentathio)decanoate (150 mg, 0.337 mmol, 1.0 equivalent)

[1154] 1H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.18-4.05(m,2H), δ3.90-3.82(m,1H), δ3.61(t,2H), δ3.46-3.30(m,2H), δ2.75-2.55(m,2H), δ2.36-2.23(m,6H) ,δ2.12-1.99(m,1H),δ1.94-1.73(m,3H)δ1.70-1.12(m,60H),δ0.95-0.88 (m,9H),δ0.84(t,3H),δ0.70-0.65(m,2H),δ0.27(d,6H),δ0.21(s,6H); TOF MSES + [M+H + ]:918.7435m / z

[1155] Example 182

[1156] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilheptadecyl 2-(pentathio)decanoate

[1157]

[1158] According to general procedure K, 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18-trioxa-7-aza-17,19-disilheptadecyl 2-(pentathio)decyl ester was prepared from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (161.52 mg, 0.292 mmol, 1.0 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-(pentathio)decyl ester (130 mg, 0.292 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 122 mg, 0.133 mmol, yield 45%.

[1159] 1H NMR (500MHz, benzene-d6) δ5.01(t,1H), δ4.18-4.05(m,2H), δ3.89-3.82(m,1H), δ3.62(t,2H), δ3.45-3.31(m,2H), δ2.76-2.56(m,2H), δ2.34-2. 23(m,6H),δ2.12-2.00(m,1H),δ1.96-1.12(m,63H),δ0.94-0.88(m,9 H), δ0.84(t,3H), δ0.70-0.65(m,2H), δ0.27(d,6H), δ0.21(s,6H); TOF MSES + [M+H + ]:918.7426m / z

[1160] Example 183

[1161] Synthesis of 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)hexyl-2-(pentathio)decanoate

[1162]

[1163] According to general procedure J, 6-((4-hydroxybutyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)hexyl 2-(pentathio)decanoate was prepared from 4-((6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)hexyl 2-(pentathio)decanoate (78.0 mg, 0.209 mmol, 1.0 equivalent) and 6-oxohexyl 2-(pentathio)decanoate. The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 53 mg, 0.057 mmol, yield 27%.

[1164] 1H NMR (500MHz, benzene-d6) δ5.04(t,1H), δ4.17-4.07(m,2H), δ3.91-3.86(m,1H) ,δ3.76(t,2H),δ3.62(t,2H),δ3.47-3.33(m,2H),δ2.75-2.68(m,1H),δ2 .65-2.58(m,1H),δ2.36-2.23(m,6H),δ2.12-2.02(m,1H),δ1.97-1.11(m ,63H), δ0.93-0.89(m,9H), δ0.84(t,3H), δ0.32(d,6H), δ0.25(s,6H); TOF MSES + [M+H + ]:934.7384m / z

[1165] Example 184

[1166] Synthesis of 15-heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disil-octadecyl-2-(pentathio)decanoate

[1167]

[1168] 15-Heptyl-7-(4-hydroxybutyl)-17,17,19,19-tetramethyl-14,16,18,20-tetraoxa-7-aza-17,19-disilacetaalkyl-2-(pentathio)decanoate was prepared according to general procedure K from 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (182.80 mg, 0.321 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-(pentathio)decanoate (130.00 mg, 0.292 mmol, 1.0 equivalent). The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 101 mg, 0.109 mmol, yield 37%.

[1169] 1H NMR (500MHz, benzene-d6) δ5.04(t,1H), δ4.17-4.07(m,2H), δ3.90-3.85(m,1H) ,δ3.76(t,2H),δ3.62(t,2H),δ3.46-3.32(m,2H),δ2.75-2.68(m,1H),δ2 .64-2.57(m,1H),δ2.34-2.23(m,6H),δ2.11-2.02(m,1H),δ1.96-1.10(m ,63H), δ0.92-0.89(m,9H), δ0.84(t,3H), δ0.31(d,6H), δ0.24(s,6H); TOF MSES + [M+H + ]:934.7424m / z

[1170] Example 185

[1171] Synthesis of 18-hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octoxy)-14,16-dioxa-7-aza-15-silicohexadecyl 2-(pentathio)decanoate

[1172]

[1173] According to general procedure K, 18-hexyl-7-(4-hydroxybutyl)-15,15-dimethyl-13-(octyloxy)-14,16-dioxa-7-aza-15-silicohexadecyl 2-(pentathio)decyl ester was prepared from 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silicohexadecyl (225.01 mg, 0.370 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-(pentathio)decyl ester (150.00 mg, 0.336 mmol, 1.0 equivalent). The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 130 mg, 0.134 mmol, yield 40%.

[1174] 1H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.17-4.07(m,2H), δ3.92-3.86(m,1H), δ3.76(d,2H), δ3.62(t,2H), δ3.48-3.32(m,2H), δ2.75-2.68(m,1 TOF MSES + [M+H + ]:972.8441m / z

[1175] Example 186

[1176] Synthesis of 15-heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicooctadecyl-2-(pentathio)decanoate

[1177]

[1178] 15-Heptyl-20-hexyl-7-(4-hydroxybutyl)-17,17-dimethyl-14,16,18-trioxa-7-aza-17-silicocaalkyl-2-(pentathio)decanoate was prepared according to general procedure K from 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silicocaalkyl-2-(pentathio)decanoate (150.00 mg, 0.336 mmol, 1.0 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-(pentathio)decanoate (150.00 mg, 0.336 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 161 mg, 0.165 mmol, yield 49%.

[1179] 1H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.19-4.07(m,2H), δ3.94-3.85(m,1H), δ3.76(d,2H), δ3.62(t,2H), δ3.48-3.32(m,2H), δ2.77 TOF MSES + [M+H + ]:972.8463m / z

[1180] Example 187

[1181] Synthesis of 16-heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silicopentoalkyl-2-(pentathio)decanoate

[1182]

[1183] 16-Heptyl-7-(4-hydroxybutyl)-14,14-dimethyl-15,17-dioxa-7-aza-14-silicopentoalkyl-2-(pentothio)decanoate was prepared according to general procedure K from (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (177.55 mg, 0.370 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-(pentathio)decanoate (150.00 mg, 0.336 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 178 mg, 0.211 mmol, yield 63%.

[1184] 1 H NMR (500MHz, benzene-d6) δ4.88(t,1H), δ4.17-4.07(m,2H), δ3.79-3.73(m,1H), δ3.63(t,2H), δ3.41-3.31(m,2H), δ2.75-2.68(m,1H), δ2.64-2.57( m,1H),δ2.37-2.24(m,6H),δ2.11-2.01(m,1H),δ1.88-1.13(m,63H),δ 0.92-0.89(m,9H), δ0.84(t,3H), δ0.76-0.72(m,2H), δ0.24(d,6H); TOF MSES + [M+H+ ]:844.7252m / z

[1185] Example 188

[1186] Synthesis of 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosahedral 2-(pentathio)decanoate

[1187]

[1188] 17-Heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosahedronyl-2-(pentathio)decanoate was prepared according to general procedure K from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicosahedronyl (183.47 mg, 0.370 mmol, 1.1 equivalent) and 6-((4-hydroxybutyl)amino)hexyl-2-(pentathio)decanoate (150.00 mg, 0.336 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 79 mg, 0.092 mmol, yield 27%. 1 H NMR (500MHz, benzene-d6) δ5.00(t,1H), δ4.17-4.07(m,2H), δ3.89-3.83(m,1H), δ3.77(t,2H), δ3.62(t,2H), δ3.45-3.32(m,2H), δ2.75-2.68(m, 1H), δ2.64-2.57(m,1H), δ2.34-2.24(m,6H), δ2.11-2.02(m,1H), δ1. 95-1.13(m,63H), δ0.92-0.89(m,9H), δ0.84(t,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:860.7207m / z

[1189] Example 189

[1190] Synthesis of heptadecano-9-yl 8-((6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)(2-hydroxyethyl)amino)octanoate

[1191]

[1192] Heptadecan-9-yl 8-((6-(((dimethyl(octyl)silyl)oxy)dimethyl(octyl)silane (155.28 mg, 0.324 mmol, 1.1 equivalent)) and heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate (130.00 mg, 0.294 mmol, 1.0 equivalent) were prepared according to general procedure K from ((6-bromo-1-(octyl)silyl)oxy)-6-(octyl)hexyl)(2-hydroxyethyl)amino)octanoate. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 180 mg, 0.214 mmol, yield 73%.

[1193] 1 H NMR (500MHz, benzene-d6) δ5.16(m,1H), δ4.88(t,1H), δ3.79-3.72(m,1H), δ3.50(t,2H), δ3.41-3.35(m,1H) , δ2.37-2.23(m,8H), δ1.87-1.12(m,70H), δ0.93-0.89(m,12H), δ0.76-0.71(m,2H), δ0.25(d,6H); TOF MSES + [M+H + ]:840.7825m / z

[1194] Example 190

[1195] Synthesis of heptadecano-9-yl18-(2-hydroxyethyl)-10,10-dimethyl-12-(octoxy)-9,11-dioxa-18-aza-10-silicohexadecane-26-ester

[1196]

[1197] Heptadecadecanoate-9-yl18-(2-hydroxyethyl)-10,10-dimethyl-12-(octoxy)-9,11-dioxa-18-aza-10-silicohexadecane-26-ester was prepared from 12-(5-bromopentyl)-10,10-dimethyl-9,11-dioxa-18-aza-10-silicohexadecane-26-ester according to general procedure K, using 160.45 mg, 0.324 mmol, 1.1 equivalents, and 8-((2-hydroxyethyl)amino)octanoate (130.00 mg, 0.294 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 152 mg, 0.177 mmol, yield 60%.

[1198] 1H NMR (500MHz, benzene-d6) δ5.20-5.14(m,1H), δ5.01(t,1H), δ3.90-3.84(m,1H), δ3.77(t,2H), δ3.50(t,2H) , δ3.44-3.36(m,1H), δ2.37-2.23(m,8H), δ1.94-1.13(m,70H), δ0.96-0.87(m,12H), δ0.28(d,6H); TOF MSES + [M+H + ]:856.7795m / z

[1199] Example 191

[1200] Synthesis of heptadecano-9-yl 8-((2-hydroxyethyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)amino)octanoate

[1201]

[1202] Heptadecan-9-yl 8-((2-hydroxyethyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)hexyl)amino)octanoate was prepared according to general procedure K from 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (179.28 mg, 0.324 mmol, 1.1 equivalent) and heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate (130.00 mg, 0.294 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 203 mg, 0.222 mmol, yield 75%.

[1203] 1 H NMR (500MHz, benzene-d6) δ5.19-5.12(m,1H), δ5.01(t,1H), δ3.89-3.83(m,1H), δ3.50(t,2H), δ3.45-3.38(m,1H), δ2. 37-2.24(m,8H),δ1.93-1.12(m,70H),δ0.93-0.89(m,12H),δ0.69-0.65(m,2H),δ0.27(d,6H),δ0.21(s,6H); TOF MSES + [M+H + ]:914.7997m / z

[1204] Example 192

[1205] Synthesis of heptadecano-9-yl 8-((2-hydroxyethyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)octanoate

[1206]

[1207] Heptadeca-9-yl 8-((2-hydroxyethyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxane)oxy)hexyl)amino)octanoate was prepared from 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-(octoxy)disiloxane (184.46 mg, 0.324 mmol, 1.1 equivalent) and heptadeca-9-yl 8-((2-hydroxyethyl)amino)octanoate (130.00 mg, 0.294 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 186 mg, 0.200 mmol, yield 68%.

[1208] 1 H NMR (500MHz, benzene-d6) δ5.19-5.13(m,1H), δ5.04(t,1H), δ3.91-3.85(m,1H), δ3.75(t,2H), δ3.50(t,2H), δ3. 46-3.37(m,1H),δ2.37-2.23(m,8H),δ1.95-1.12(m,70H),δ0.95-0.87(m,12H),δ0.31(d,6H),δ0.24(s,6H)

[1209] Example 193

[1210] Synthesis of heptadecano-9-yl-10-heptyl-20-(4-hydroxybutyl)-12,12-dimethyl-9,11,13-trioxa-20-aza-12-silicooctadecyl-28-ester

[1211]

[1212] Heptadecan-9-yl-10-heptyl-20-(4-hydroxybutyl)-12,12-dimethyl-9,11,13-trioxa-20-aza-12-silicocayl-28-ester was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicocayl-28-ester (649.92 mg, 1.311 mmol, 1.1 equivalent) and heptadecan-9-yl-8-((4-hydroxybutyl)amino)octanoate (560 mg, 0.1192 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 213 mg, 0.241 mmol, yield 20%. 1 H NMR (500MHz, benzene-d6) δ5.16(m,1H), δ5.00(t,1H), δ3.91-3.82(m,1H), δ3.76(t,2H), δ3.62(t,2H), δ3.46-3.38 (m,2H),δ2.36-2.24(m,7H),δ1.96-1.77(m,2H)δ1.71-1.12(m,73H),δ0.94-0.87(m,12H),δ0.28(d,6H); TOF MSES + [M+H + ]:884.8111m / z

[1213] Example 194

[1214] Synthesis of 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)((5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-pentaen-1-yl)amino)but-1-ol

[1215]

[1216] According to general procedure G, 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)((5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-penten-1-yl)amino)but-1-ol was prepared from ((6-bromo-1-(octyloxy)hexyl)oxy)dimethyl(octyl)silane (148.06 mg, 0.309 mmol, 1 equivalent) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-penten-1-yl)amino)but-1-ol (150 mg (74% purity), 0.309 mmol, 1.0 equivalent) Purification method A was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 100 mg, 0.132 mmol, yield 43%.

[1217] 1 H NMR(500MHz, benzene-d6)δ5.53-5.38(m,10H),δ4.88(dt,1H),δ3.78-3.73(m,1H),δ3.61(t,2H),δ3.41-3.35(m,1H),δ2.92-2.83(m,8H),δ TOF MSES + [M+H + ]:758.6862m / z

[1218] Example 195

[1219] Synthesis of 13-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-15,15-dimethyl-12,14-dioxa-5-aza-15-silicoserosan-1-ol

[1220]

[1221] According to general procedure G, 13-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-penten-1-yl)-15,15-dimethyl-12,14-dioxa-5-aza-15-silicoseriate-1-ol was prepared from ((1-((6-bromohexyl)oxy)octyl)oxy)dimethyl(octyl)silane (148.06 mg, 0.309 mmol, 1.0 equivalent) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-penten-1-yl)amino)but-1-ol (150 mg (74% purity), 0.309 mmol, 1.0 equivalent) Purification method A was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 234 mg, 0.207 mmol, yield 67%.

[1222] 1H NMR (500MHz, benzene-d6) δ5.60-5.39(m,10H), δ4.89-4.85(m,1H), δ3.78-3.73(m,1H), δ3.61(t,2H), δ3.40-3.31(m,1H), δ2.91-2.81(m,8 H), δ2.32(m,4H), δ2.26(t,2H), δ2.10-2.01(m,4H), δ1.88-1.19(m,40H), δ0.96-0.89(m,9H), δ0.78-0.71(m,2H), δ0.24(t,6H); TOF MSES + [M+H + ]:758.6857m / z

[1223] Example 196

[1224] Synthesis of 5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicosicosano-1-ol

[1225]

[1226] According to general procedure K, 5-((5Z,8Z,11Z,14Z,17Z)-eicos ... Purification method A was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 145 mg, 0.187 mmol, yield 45%.

[1227] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ5.00(m,1H), δ3.89-3.87(m,1H), δ3.77(t,2H), δ3.61(t,2H), δ3.45-3.35(m,1H), δ2.92- TOF MSES + [M+H + ]:774.6801m / z

[1228] Example 197

[1229] Synthesis of 13-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicosicosane-1-ol

[1230]

[1231] 13-Heptyl-5-((5Z,8Z,11Z,14Z,17Z)-Eicosena-5,8,11,14,17-penten-1-yl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicostraco-1-ol was prepared from 1-bromo-8-heptyl-10,10-dimethyl-7,9,11-trioxa-10-silicostraco-1-ol (206.76 mg, 0.417 mmol, 1.0 equivalent) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosena-5,8,11,14,17-penten-1-yl)amino)but-1-ol (150 mg, 0.417 mmol, 1.0 equivalent) according to general procedure K. Purification method B was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 155 mg, 0.200 mmol, yield 48%.

[1232] 1H NMR (500MHz, benzene-d6) δ5.50-5.39(m,10H), δ5.00(t,1H), δ3.89-3.83(m,1H), δ3.76(t,2H), δ3.61(t,2H), δ3.44-3.37(m,1H), δ2.92-2.83(m, 8H), δ2.34-2.31(m,4H), δ2.25(t,2H), δ2.10-1.99(m,4H), δ1.94-1. 78(m,2H), δ1.72-1.17(m,38H), δ0.95-0.87(m,9H), δ0.27(d,6H); TOF MSES + [M+H + ]:774.6811m / z

[1233] Example 198

[1234] Synthesis of 4-(((5Z,8Z,11Z,14Z,17Z)-eicosano-5,8,11,14,17-penten-1-yl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)amino)but-1-ol

[1235]

[1236] According to general procedure K, 4-(((5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-penten-1-yl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)hexyl)amino)but-1-ol was prepared from 1-(((6-bromo-1-(octoxy)hexyl)oxy)hexyl)amino)but-1-ol (150 mg, 0.417 mmol, 1 equivalent) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-penten-1-yl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxane)oxy)hexyl)amino)but-1-ol. Purification method B was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 187 mg, 0.225 mmol, yield 54%.

[1237] 1H NMR (500MHz, benzene-d6) δ5.52-5.38(m,10H), δ5.00(t,1H), δ3.89-3.83(m,1H) ,δ3.61(t,2H),δ3.44-3.37(m,1H),δ2.92-2.80(m,8H),δ2.36-2.29(m,4H) ,δ2.25(t,2H),δ2.09-1.99(m,4H),δ1.94-1.77(m,2H),δ1.72-1.19(m,38H ), δ0.95-0.88(m,9H), δ0.69-0.65(m,2H), δ0.26(d,6H), δ0.21(s,6H); TOF MSES + [M+H + ]:832.7034m / z

[1238] Example 199

[1239] Synthesis of 13-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-15,15,17,17-tetramethyl-12,14,16-trioxa-5-aza-15,17-disilicoserodecane-1-ol

[1240]

[1241] According to the general procedure K, 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (231.02 mg, 0.417 mmol, 1.0 equivalent) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosano-5,8,11,14,17-pentaen-1-yl)amino)butane 13-Heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-15,15,17,17-tetramethyl-12,14,16-trioxa-5-aza-15,17-disilicosicosode-1-ol was prepared from 150 mg (0.417 mmol, 1 equivalent) of 1-1-ol (150 mg, 0.216 mmol, 1 equivalent). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 180 mg, 0.216 mmol, yield 52%.

[1242] 1H NMR (500MHz, benzene-d6) δ5.55-5.40(m,10H), δ5.01(t,1H), δ3.93-3.81(m,1H), δ3.61(t,2H), δ3.45-3.37(m,1H), δ2.92-2.83(m,8H), δ2.37-2.17 (m,6H),δ2.11-1.98(m,4H),δ1.95-1.75(m,2H),δ1.73-1.18(m,38H),δ 0.96-0.88(m,9H), δ0.70-0.65(m,2H), δ0.29(d,6H), δ0.22(s,6H); TOF MSES + [M+H + ]:832.7026m / z

[1243] Example 200

[1244] Synthesis of 4-(((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol

[1245]

[1246] According to general procedure J, 4-(((5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-penten-1-yl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol was prepared from 4-((6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol (12.6 mg, 0.218 mmol, 1.0 equivalent) and (5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-penten-1-yl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol was prepared from 4-((6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol. Purification method A was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 50 mg, 0.059 mmol, yield 27%.

[1247] 1H NMR (500MHz, benzene-d6) δ5.53-5.41(m,10H), δ5.01(t,1H), δ3.93-3.85(m,1H ),δ3.76(t,2H)δ3.62(t,2H),δ3.47-3.37(m,1H),δ2.92-2.82(m,8H),δ2 .36-2.32(m,4H),δ2.26(t,2H)δ2.10-1.99(m,4H),δ1.95-1.79(m,2H),δ 1.72-1.20(m,38H), δ0.95-0.89(m,9H), δ0.31(d,6H), δ0.25(s,6H); TOF MSES + [M+H + ]:848.6975m / z

[1248] Example 201

[1249] Synthesis of 13-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-15,15,17,17-tetramethyl-12,14,16,18-tetraoxa-5-aza-15,17-disilicosahedron-1-ol

[1250]

[1251] According to the general procedure K, 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-(octyloxy)disiloxane (209.17 mg, 0.367 mmol, 1.1 equivalents) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosano-5,8,11,14,17-pentene-1-yl)amino)but- 13-Heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-15,15,17,17-tetramethyl-12,14,16,18-tetraoxa-5-aza-15,17-disilicosahedron-1-ol was prepared from 1-ol (120 mg, 0.334 mmol, 1.0 equivalent) using rapid column chromatography. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil (125 mg, 0.147 mmol, yield 44%).

[1252] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ5.04(dt,1H), δ3.90-3.84(m,1 H),δ3.76(t,2H)δ3.61(t,2H),δ3.46-3.34(m,1H),δ2.93-2.81(m,8H),δ 2.43-2.30(m,4H),δ2.25(t,2H)δ2.11-2.00(m,4H),δ1.96-1.80(m,2H), δ1.72-1.19(m,38H), δ0.95-0.87(m,9H), δ0.31(d,6H), δ0.24(s,6H); TOF MSES + [M+H + ]:848.6992m / z

[1253] Example 202

[1254] Synthesis of 16-hexyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicotetracosane-1-ol

[1255]

[1256] According to the general procedure K, 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silicosuccinate (251.03 mg, 0.413 mmol, 1.1 equivalents) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosano-5,8,11,14,17-pentaen-1-yl)amino 16-Hexyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicotetraco-1-ol was prepared from 135 mg (1.375 mmol, 1.0 equivalent) but-1-ol. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil (185 mg, 0.209 mmol, yield 56%).

[1257] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ5.02(t,1H), δ3.92-3.86(m,1H), δ3.76(d,2H), δ3.61(t,2H), δ3.48-3.38(m,1H), δ2.93-2.82(m, 8H), δ2.37-2.30(m,4H), δ2.26(t,2H), δ2.10-1.99(m,4H), δ1.96-1.7 9(m,2H), δ1.73-1.23(m,51H), δ0.96-0.89(m,12H), δ0.30(d,6H); TOF MSES + [M+H + ]:886.8077m / z

[1258] Example 203

[1259] Synthesis of 13-heptyl-18-hexyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicosahedron-1-ol

[1260]

[1261] According to the general procedure K, 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silicodecane (241.73 mg, 0.398 mmol, 1.1 equivalents) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosano-5,8,11,14,17-pentaen-1-yl)amino)butane 13-Heptyl-18-hexyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicosahedron-1-ol was prepared from 130.00 mg (0.361 mmol, 1.0 equivalent) of 1-1-ol. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 197 mg, 0.222 mmol, yield 61%.

[1262] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ5.02(t,1H), δ3.90-3.85(m,1H), δ3.75(d,2H), δ3.61(t,2H), δ3.46-3.37(m,1H), δ2.93-2.82(m, 8H), δ2.35-2.30(m,4H), δ2.25(t,2H), δ2.10-1.99(m,4H), δ1.97-1.8 0(m,2H), δ1.71-1.24(m,51H), δ0.95-0.89(m,12H), δ0.30(d,6H); TOF MSES + [M+H + ]:886.8049m / z

[1263] Example 204

[1264] Synthesis of 14-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-12,12-dimethyl-13,15-dioxa-5-aza-12-silicoserosan-1-ol

[1265]

[1266] 14-Heptyl-5-((5Z,8Z,11Z,14Z,17Z)-Eicos-5,8,11,14,17-penten-1-yl)-12,12-dimethyl-13,15-dioxa-5-aza-12-silicoseriate-1-ol was prepared from (6-bromohexyl)dimethyl((1-(octoxy)octyl)oxy)silane (198.08 mg, 0.413 mmol, 1.1 equivalent) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicos-5,8,11,14,17-penten-1-yl)amino)but-1-ol (135.00 mg, 0.375 mmol, 1.0 equivalent) according to general procedure K. Purification method A was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 159 mg, 0.210 mmol, yield 56%.

[1267] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ4.88(t,1H), δ3.79-3.73(m,1H), δ3.62(t,2H), δ3.41-3.35(m,1H), δ2.93-2.81(m,8H), δ2 TOF MSES + [M+H + ]:758.6862m / z

[1268] Example 205

[1269] Synthesis of 15-heptyl-5-((5Z,8Z,11Z,14Z,17Z)-eicosico-5,8,11,14,17-penten-1-yl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicosicosane-1-ol

[1270]

[1271] 15-Heptyl-5-((5Z,8Z,11Z,14Z,17Z)-Eicosena-5,8,11,14,17-penten-1-yl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicostraco-1-ol was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicostraco-1-ol (227.43 mg, 0.417 mmol, 1.0 equivalent) and 4-(((5Z,8Z,11Z,14Z,17Z)-eicosena-5,8,11,14,17-penten-1-yl)amino)but-1-ol (150 mg, 0.417 mmol, 1.0 equivalent) according to general procedure K. Purification method A was used to purify the crude product by rapid column chromatography to obtain a pure product as a colorless oil, 155 mg, 0.200 mmol, yield 48%.

[1272] 1H NMR (500MHz, benzene-d6) δ5.53-5.39(m,10H), δ5.00(t,1H), δ3.89-3.84(m,1H), δ3.75(t,2H), δ3.61(t,2H), δ3.45-3.35(m,1H), δ2.93-2.81(m, 8H), δ2.34-2.30(m,4H), δ2.25(t,2H), δ2.11-1.99(m,4H), δ1.95-1. 78(m,2H), δ1.71-1.20(m,38H), δ0.95-0.87(m,9H), δ0.28(d,6H); TOF MSES + [M+H + ]:774.6809m / z

[1273] Example 206

[1274] Synthesis of 15-heptyl-5-(4-hydroxybutyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetraalkyl(9Z,12Z)-octadec-9,12-dienoic acid ester

[1275]

[1276] 15-Heptyl-5-(4-hydroxybutyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetradecyl(9Z,12Z)-octadec-9,12-dienoic acid ester was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicotetradecyl(9Z,12Z)-dienoic acid ester (390.0 mg, 0.921 mmol, 1.0 equivalent) according to general procedure K. The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 72 mg, 0.086 mmol, yield 9%.

[1277] 1H NMR (500MHz, benzene-d6) δ5.54-5.43(m,4H), δ4.99(dd,1H), δ4.06(t,2H), δ3.88-3.83(m,1H), δ3.76(t,2H), δ3.58(t,2H), δ3.44-3.39(m,1H ), δ2.88(t,2H), δ2.29-2.16(m,7H), δ2.10-2.04(m,4H), δ1.94-1.77(m,2H), δ1.68-1.14(m,56H), δ0.91-0.87(m,9H), δ0.28(d,6H); TOF MSES + [M+H + ]:838.7358m / z

[1278] Example 207

[1279] Synthesis of 5-(3-((8Z,11Z)-heptadec-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-sildecane-10-yl)-15-heptyl-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetraco-1-ol

[1280]

[1281] According to the general procedure K, 10-bromo-3-((8Z,11Z)-heptadec-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-sildecane (176.6 mg, 0.349 mmol, 1.1 equivalents) and 15-heptyl-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetracosane- 5-(3-((8Z,11Z)-heptadec-8,11-dien-1-yl)-5,5-dimethyl-2,4,6-trioxa-5-sildecane-10-yl)-15-heptyl-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetraco-1-ol was prepared from 1-ol (160 mg, 0.317 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil (42 mg, 0.045 mmol, yield 14%).

[1282] 1H NMR (500MHz, benzene-d6) δ5.55-5.44(m,4H), δ5.01(dd,1H), δ4.81(dd,1H), δ3.93 -3-84(m,1H),δ3.79-3.72(m,4H),δ3.61(t,2H),δ3.45-3.38(m,1H),δ3.32(s ,3H),δ2.90(t,2H),δ2.45-2.24(m,6H),δ2.12-2.06(m,4H),δ1.96-1.75(m,4 H), δ1.71-1.20(m,58H), δ0.93-0.88(m,9H), δ0.30(d,6H), δ0.25(d,6H); TOF MSES + [M+H + ]:928.7825m / z

[1283] Example 208

[1284] Synthesis of 5-(4-hydroxybutyl)-13,13,15-trimethyl-12,14,16-trioxa-5-aza-13-silicosahedral (9Z,12Z)-octadec-9,12-dienoate

[1285]

[1286] According to general procedure K, 5-(4-hydroxybutyl)-13,13,15-trimethyl-12,14,16-trioxa-5-aza-13-silicohexadecyl(9Z,12Z)-octadecyl-9,12-dienoate was prepared from 1-bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silicohexadecyl(9Z,12Z)-dienoate (660.0 mg, 1.558 mmol, 1.0 equivalent) and 4-((4-hydroxybutyl)amino)butyl(9Z,12Z)-octadecyl-9,12-dienoate (660.0 mg, 1.558 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 50 mg, 0.064 mmol, yield 4%.

[1287] 1H NMR (500MHz, benzene-d6) δ5.55-5.45(m,4H), δ5.09(q,1H), δ4.07(t,2H), δ3.85-3.79(m,1H), δ3.73(t,2H), δ3.58(t,2H), δ3.40-3 .34(m,1H), δ2.89(t,2H), δ2.29-2.17(m,8H), δ2.11-2.05(m,4H), δ1.70-1.15(m,51H), δ0.94-0.80(m,6H), δ0.24(d,6H); LC ESIMS[M+H + ]:782.670m / z

[1288] Example 209

[1289] Synthesis of undecyl 9-heptyl-20-(2-hydroxyethyl)-7,7-dimethyl-8,10-dioxa-20-aza-7-silicohexadecane-26-ester

[1290]

[1291] Undecyl 9-heptyl-20-(2-hydroxyethyl)-7,7-dimethyl-8,10-dioxa-20-aza-7-silicosane-26-ester was prepared from ((1-((9-bromononyl)oxy)octyl)oxy)(hexyl)dimethylsilane (206.00 mg, 0.417 mmol, 1.1 equivalents) and undecyl 6-((2-hydroxyethyl)amino)hexanoate (125.00 mg, 0.379 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 201 mg, 0.2708 mmol, yield 71%.

[1292] 1 H NMR (500MHz, benzene-d6) δ4.89(dt,1H), δ4.08(t,2H), δ3.80-3.74(m,1H), δ3.49(t,2H), δ3.42-3.37(m,1H), δ2.3 4(t,2H),δ2.30-2.17(m,6H),δ1.88-1.15(m,58H),δ0.95-0.87(m,9H),δ0.74-0.70(m,2H),δ0.25(d,6H); TOF MSES + [M+H + ]:742.6735m / z

[1293] Example 210

[1294] Synthesis of undecyl 6-((10-((hexyldimethylsilyl)oxy)-10-(octoxy)decyl)(2-hydroxyethyl)amino)hexanoate

[1295]

[1296] Undecyl 6-((10-((hexyldimethylsilyl)oxy)-10-(octoxy)decyl)(2-hydroxyethyl)amino)hexanoate was prepared from ((10-bromo-1-(octoxy)decyl)oxy)(hexyl)dimethylsilane (211.85 mg, 0.417 mmol, 1.1 equivalents) and undecyl 6-((2-hydroxyethyl)amino)hexanoate (125.00 mg, 0.379 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 200 mg, 0.264 mmol, yield 70%.

[1297] 1 H NMR (500MHz, benzene-d6) δ4.89(dt,1H), δ4.08(t,2H), δ3.77-3.73(m,1H), δ3.49(t,2H), δ3.39-3.36(m,1H), δ2.3 4(t,2H), δ2.29-2.17(m,6H), δ1.90-1.15(m,60H), δ0.94-0.88(m,9H), δ0.74-0.70(m,2H), δ0.25(d,6H); TOF MSES + [M+H + ]:756.6902m / z

[1298] Example 211

[1299] Synthesis of undecyl 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicosaccharide ester

[1300]

[1301] Undecyl 17-heptyl-7-(4-hydroxybutyl)-15,15-dimethyl-14,16,18-trioxa-7-aza-15-silicohexadecyl ester was prepared from 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silicohexadecyl ester (485.15 mg, 0.979 mmol, 1.0 equivalent) and undecyl 6-((4-hydroxybutyl)amino)hexanoate (350.0 mg, 0.979 mmol, 1.0 equivalent)

[1302] 1 H NMR(500MHz, benzene-d6)δ5.11(dd,1H),δ4.18(t,2H),δ3.87(t,2H),δ3.71(t,2H),δ3.55-3.46(m,1H),δ 2.41-2.29(m,7H), δ2.06-1.88(m,2H), δ1.80-1.28(m,59H), δ1.04-0.99(m,9H), δ0.39(d,6H); TOF MSES + [M+H + ]:772.6857m / z

[1303] Example 212

[1304] Synthesis of undecyl 6-((6-((dimethyl((oxecyclohexadec-2-yl)oxy)silyl)oxy)hexyl)(4-hydroxybutyl)amino)hexanoate

[1305]

[1306] Undecyl 6-((6-((dimethyl((oxecyclohexadecanyl-2-yl)oxy)silane)oxy)hexyl)(4-hydroxybutyl)amino)hexanoate was prepared from ((6-bromohexyl)oxy)dimethyl((oxecyclohexadecanyl-2-yl)oxy)silane (1.032 g, 2.153 mmol, 1.1 equivalents) and undecyl 6-((4-hydroxybutyl)amino)hexanoate (700.0 mg, 1.958 mmol, 1.0 equivalents). The crude product was purified by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 250 mg, 0.331 mmol, yield 21%. 1H NMR (500MHz, benzene-d6) δ4.95-4.92(dd,1H), δ4.06(t,2H), δ3.95-3.90(m,1H), δ3.73(t,2H), δ3.60(t,2H), δ3.40(t,1H), δ3.29(t ,1H), δ2.30-2.17(m,7H), δ1.94-1.87(m,1H), δ1.84-1.80(m,1H), δ1.74-1.15(m,60H), δ0.93-0.90(m,3H), δ0.24(d,6H); TOF MSES + [M+H + ]:756.6555m / z

[1307] Example 213

[1308] Synthesis of undecyl 7-(4-hydroxybutyl)-15,15,17-trimethyl-14,16,18-trioxa-7-aza-15-silicooctadecyl ester

[1309]

[1310] Undecyl 7-(4-hydroxybutyl)-15,15,17-trimethyl-14,16,18-trioxa-7-aza-15-silicooctadecyl ester was prepared from 1-bromo-8,8,10-trimethyl-7,9,11-trioxa-8-silicooctadecyl ester (1250.0 mg, 2.842 mmol, 1.1 equivalent) and undecyl 6-((4-hydroxybutyl)amino)hexanoate (960.0 mg, 2.583 mmol, 1.0 equivalent)

[1311] 1 H NMR(500MHz, benzene-d6)δ5.09(q,1H),δ4.07(t,2H),δ3.85-3.76(m,1H),δ3.72(t,2H),δ3.61(t,2H),δ 3.40-3.33(m,1H), δ2.31-2.17(m,8H), δ1.70-1.15(m,55H), δ0.93-0.89(m,6H), δ0.25(d,6H); TOF MSES + [M+H + ]:716.6218m / z

[1312] Example 214

[1313] Synthesis of 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyloxy)hexyl)((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino)but-1-ol

[1314]

[1315] According to general procedure J, 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)amino)but-1-ol was prepared from 4-((6-((dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)amino)but-1-ol (150.00 mg, 0.307 mmol, 1.0 equivalent) and (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentanal (115.17 mg, 0.307 mmol, 1.0 equivalent) in 6-((6-(dimethyl(octyl)silyl)oxy)-6-(octyl)hexyl)((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentanal)amino)but-1-ol. The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 120 mg, 0.142 mmol, yield 46%.

[1316] 1 H NMR (500MHz, benzene-d6) δ4.88(dt,1H), δ4.78-4.70(m,1H), δ3.79-3.73(m,1H), δ3.64(t,2H), δ3.43(s,3H), δ3 .43-3.36(m,1H), δ2.42-2.38(m,4H), δ2.31(t,2H), δ1.97-0.70(m,78H), δ0.61(s,3H), δ0.26(d,6H); TOF MSES + [M+H + ]:846.7743m / z

[1317] Example 215

[1318] Synthesis of 13-hepta-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15-dimethyl-12,14-dioxa-5-aza-15-silicotetraane-1-ol

[1319]

[1320] According to general procedure J, 13-heptyl-15,15-dimethyl-12,14-dioxa-5-aza-15-silicoserosan-1-ol (150.00 mg, 0.307 mmol, 1.0 equivalent) and (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanyl 13-Heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15-dimethyl-12,14-dioxa-5-aza-15-silicotetrasan-1-ol was prepared from an aldehyde (115.17 mg, 0.307 mmol, 1.0 equivalent). The crude product was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 163 mg, 0.193 mmol, yield 63%. 1 HNMR (500MHz, benzene-d6) δ4.87(dt,1H), δ4.77-4.69(m,1H), δ3.77-3.72(m,1H), δ3.64(t,2H), δ3.43(s ,3H), δ3.39-3.35(m,1H), δ2.43-2.30(m,6H), δ1.96-0.70(m,78H), δ0.61(s,3H), δ0.25(d,6H); TOF MSES + [M+H + ]:846.7725m / z

[1321] Example 216

[1322] Synthesis of 5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicosicosane-1-ol

[1323]

[1324] According to the general procedure K, 12-(5-bromopentyl)-10,10-dimethyl-9,11,13-trioxa-10-silicotetramonane (113.25 mg, 0.228 mmol, 1.1 equivalents) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino 5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicosicosane-1-ol was prepared from butanol (93.00 mg, 0.208 mmol, 1.0 equivalent) using rapid column chromatography. The crude product was purified by purification method A to obtain a pure product as a colorless oil, 58 mg, 0.067 mmol, yield 32%.

[1325] 1 H NMR (500MHz, benzene-d6) δ5.00(dt,1H), δ4.78-4.70(m,1H), δ3.89-3.84(m,1H), δ3.77(t,2H), δ3.64(t, 2H), δ3.45-3.43(m,4H), δ2.32-2.29(m,6H), δ1.97-0.75(m,76H), δ0.61(s,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:862.7687m / z

[1326] Example 217

[1327] Synthesis of 13-hepta-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicotetraco-1-ol

[1328]

[1329] According to the general procedure K, 1-bromo-8-hepta-10,10-dimethyl-7,9,11-trioxa-10-silane-nonadecane (113.25 mg, 0.228 mmol, 1.1 equivalents) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino)butane 13-Heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicotetraco-1-ol was prepared from 1-ol (93.00 mg, 0.208 mmol, 1.0 equivalent) using rapid column chromatography. The crude product was purified by purification method A to obtain a pure product as a colorless oil, 39 mg, 0.045 mmol, yield 22%. 1 HNMR (500MHz, benzene-d6) δ5.00(dt,1H), δ4.78-4.68(m,1H), δ3.88-3.83(m,1H), δ3.77(t,2H), δ3.66-3.61 (m,2H), δ3.46-3.39(m,4H), δ2.45-2.25(m,6H), δ1.97-0.75(m,76H), δ0.61(s,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:862.7692m / z

[1330] Example 218

[1331] Synthesis of 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)amino)but-1-ol

[1332]

[1333] According to the general procedure K, it is composed of 1-((6-bromo-1-(octoxy)hexyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (126.53 mg, 0.228 mmol, 1.1 equivalents) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino) 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-octyldisiloxyl)oxy)hexyl)amino)but-1-ol was prepared by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 107 mg, 0.116 mmol, yield 56%.

[1334] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,1H), δ4.78-4.70(m,1H), δ3.89-3.82(m,1H), δ3.64(t,2H), δ3.48-3. 39(m,4H), δ2.45-2.29(m,6H), δ1.97-0.70(m,78H), δ0.61(s,3H), δ0.27(d,6H), δ0.22(s,6H); TOF MSES + [M+H + ]:920.7921m / z

[1335] Example 219

[1336] Synthesis of 13-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15,17,17-tetramethyl-12,14,16-trioxa-5-aza-15,17-disilicoserodecane-1-ol

[1337]

[1338] According to the general procedure K, 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (126.53 mg, 0.228 mmol, 1.1 equivalents) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino)but-1 13-Heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentaphenanthrene-17-yl)pentyl)-15,15,17,17-tetramethyl-12,14,16-trioxa-5-aza-15,17-disilicostipentane-1-ol was prepared from 13-hepta-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentaphenanthrene-17-yl)pentyl)-15,15,17,17-tetramethyl-12,14,16-trioxa-5-aza-15,17-disilicostipentane-1-ol) according to purification method A by rapid column chromatography to obtain a pure product as a colorless oil, 65 mg, 0.071 mmol, yield 34%.

[1339] 1 H NMR (500MHz, benzene-d6) δ5.01(dt,1H), δ4.78-4.70(m,1H), δ3.88-3.83(m,1H), δ3.64(t,2H), δ3.43-3. 38(m,4H), δ2.41-2.29(m,6H), δ1.97-0.70(m,78H), δ0.61(s,3H), δ0.26(d,6H), δ0.21(s,6H); TOF MSES + [M+H + ]:920.7930m / z

[1340] Example 220

[1341] Synthesis of 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol

[1342]

[1343] According to general procedure J, 4-((6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol (121.00 mg, 0.209 mmol, 1.0 equivalent) and (4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl) 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)(6-(octoxy)-6-((1,1,3,3-tetramethyl-3-(octoxy)disiloxyl)oxy)hexyl)amino)but-1-ol was prepared from pentanal (87.42 mg, 0.209 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 50 mg, 0.053 mmol, yield 25%.

[1344] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.77-4.70(m,1H), δ3.92-3.85(m,1H), δ3.76(t,2H), δ3.63(t,2H), δ3 .46-3.37(m,4H), δ2.48-2.29(m,6H), δ1.97-0.75(m,76H), δ0.61(s,3H), δ0.31(d,6H), δ0.25(s,6H); TOF MSES + [M+H + ]:936.7874m / z

[1345] Example 221

[1346] Synthesis of 13-heptayl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-15,15,17,17-tetramethyl-12,14,16,18-tetraoxa-5-aza-15,17-disilicosahedron-1-ol

[1347]

[1348] According to the general procedure K, 1-((1-((6-bromohexyl)oxy)octyl)oxy)-1,1,3,3-tetramethyl-3-octyldisiloxane (130.19 mg, 0.228 mmol, 1.1 equivalents) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino)but-1- 13-Heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)-15,15,17,17-tetramethyl-12,14,16,18-tetraoxa-5-aza-15,17-disilicosahedron-1-ol was prepared from alcohol (93.00 mg, 0.208 mmol, 1.0 equivalent). The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 69 mg, 0.074 mmol, yield 35%.

[1349] 1 H NMR (500MHz, benzene-d6) δ5.03(t,1H), δ4.78-4.70(m,1H), δ3.90-3.84(m,1H), δ3.76(t,2H), δ3.64(t,2H), δ3 .47-3.37(m,4H), δ2.43-2.29(m,6H), δ1.97-0.75(m,76H), δ0.61(s,3H), δ0.31(d,6H), δ0.24(s,6H); TOF MSES + [M+H + ]:936.7881m / z

[1350] Example 222

[1351] Synthesis of 16-hexyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicotetraco-1-ol

[1352]

[1353] According to the general procedure K, 10-(5-bromopentyl)-15-hexyl-12,12-dimethyl-9,11,13-trioxa-12-silicosuccinate (194.14 mg, 0.319 mmol, 1.19 equivalents) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino 16-Hexyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicotetraco-1-ol was prepared from butanyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecyl-1H-cyclopentanyl[a]phenanthrene-17-yl)pentyl)-13,13-dimethyl-11-(octoxy)-12,14-dioxa-5-aza-13-silicotetraco-1-ol by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 100 mg, 0.103 mmol, yield 38%.

[1354] 1 H NMR (500MHz, benzene-d6) δ5.02(t,1H), δ4.78-4.70(m,1H), δ3.91-3.86(m,1H), δ3.76(d,2H), δ3.64(t, 2H), δ3.47-3.37(m,4H), δ2.47-2.26(m,6H), δ1.97-0.74(m,92H), δ0.61(s,3H), δ0.29(d,6H); TOF MSES + [M+H + ]:974.8928m / z

[1355] Example 223

[1356] Synthesis of 13-heptyl-18-hexyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecyl-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicosahedron-1-ol

[1357]

[1358] According to the general procedure K, 1-bromo-8-heptyl-13-hexyl-10,10-dimethyl-7,9,11-trioxa-10-silicodecane (179.21 mg, 0.295 mmol, 1.10 equivalents) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino)butane 13-Heptyl-18-hexyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecane-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)-15,15-dimethyl-12,14,16-trioxa-5-aza-15-silicohexadecane-1-ol was prepared from 120.00 mg (0.268 mmol, 1.0 equivalent) of 1-1-ol. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 109 mg, 0.112 mmol, yield 42%.

[1359] 1 H NMR (500MHz, benzene-d6) δ5.02(t,1H), δ4.78-4.70(m,1H), δ3.90-3.84(m,1H), δ3.75(d,2H), δ3.64(t, 2H), δ3.46-3.38(m,4H), δ2.41-2.30(m,6H), δ1.97-0.75(m,92H), δ0.61(s,3H), δ0.30(d,6H); TOF MSES + [M+H + ]:974.8949m / z

[1360] Example 224

[1361] Synthesis of 14-hepta-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-12,12-dimethyl-1315-dioxa-5-aza-12-silicotetraane-1-ol

[1362]

[1363] According to the general procedure K, (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (176.76 mg, 0.368 mmol, 1.10 equivalents) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino)but-1-ol (150.00 mg, 0.335 mmol, 1.0 equivalent) Preparation of 14-hepta-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-12,12-dimethyl-13,15-dioxa-5-aza-12-silicotetrasan-1-ol. The crude product was purified by rapid column chromatography according to purification method A to obtain a pure product as a colorless oil, 106 mg, 0.125 mmol, yield 37%.

[1364] 1 H NMR(500MHz, benzene-d6)δ4.88(dt,1H),δ4.78-4.70(m,1H),δ3.79-3.73(m,1H),δ3.65(t,2H),δ3.43(s,3H),δ3 .41-3.36(m,1H), δ2.44-2.40(m,4H), δ2.33(t,2H), δ1.97-0.71(m,78H), δ0.61(s,3H), δ0.25(d,6H); TOF MSES + [M+H + ]:846.7731m / z

[1365] Example 225

[1366] Synthesis of 15-heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetraco-1-ol

[1367]

[1368] According to the general procedure K, 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silane-nonadecane (152.21 mg, 0.307 mmol, 1.10 equivalents) and 4-(((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)pentyl)amino)but- 15-Heptyl-5-((4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetraco-1-ol was purified twice by rapid column chromatography according to purification methods A and B to obtain a pure product as a colorless oil, 43 mg, 0.050 mmol, yield 18%.

[1369] 1 H NMR (500MHz, benzene-d6) δ5.00(td,1H), δ4.78-4.70(m,1H), δ3.89-3.84(m,1H), δ3.77(t,2H), δ3.64(t, 2H), δ3.46-3.38(m,4H), δ2.41-2.30(m,6H), δ1.97-0.75(m,76H), δ0.61(s,3H), δ0.28(d,6H); TOF MSES + [M+H + ]:862.7667m / z

[1370] Example 226

[1371] Synthesis of 15-heptyl-5-(4-hydroxybutyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetraalkyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)valerate

[1372]

[1373] According to the general procedure K, 1-bromo-10-heptyl-8,8-dimethyl-7,9,11-trioxa-8-silane-nonadecane (582.14 mg, 1.174 mmol, 1.1 equivalents) and 4-((4-hydroxybutyl)amino)butyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl) 15-Heptyl-5-(4-hydroxybutyl)-13,13-dimethyl-12,14,16-trioxa-5-aza-13-silicotetraalkyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)valerate was prepared from valerate (555.0 mg, 1.068 mmol, 1.0 equivalent) by rapid column chromatography. The crude product was purified by purification method B to obtain a pure product as a colorless oil, 84 mg, 0.089 mmol, yield 83%.

[1374] 1 H NMR (500MHz, benzene-d6) δ5.01(td,1H), δ4.10(t,2H), δ3.90-3.84(m,1H), δ3.77(t,2H), δ3.59(t,2H), δ3.45-3.40(m,1H), δ3.25 TOF MSES + [M+H + ]:948.8075m / z

[1375] Example 227

[1376] Synthesis of 14-heptyl-5-(4-hydroxybutyl)-12,12-dimethyl-13,15-dioxa-5-aza-12-silicotricaryl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)valerate

[1377]

[1378] According to the general procedure K, (6-bromohexyl)dimethyl((1-(octyloxy)octyl)oxy)silane (558.27 mg, 1.164 mmol, 1.1 equivalents) and 4-((4-hydroxybutyl)amino)butyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)valerate were used. Preparation of 14-heptyl-5-(4-hydroxybutyl)-12,12-dimethyl-13,15-dioxa-5-aza-12-silicotricaralkyl(4R)-4-((3R,10S,13R)-3-methoxy-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)valerate by rapid column chromatography according to purification method B to obtain a pure product as a colorless oil, 250 mg, 0.268 mmol, yield 25%.

[1379] 1H NMR (500MHz, benzene-d6) δ4.89(td,1H), δ4.10(t,2H), δ3.79-3.74(m,1H), δ3.60(t,2H), δ3.41-3.36(m,1H), δ3.25(s,3H), δ3.08-3.02(m,1H) TOF MS ES+[M+H+]:932.8140m / z

[1380] Preparation, characterization, transfection, and viability (viabililty) of lipid nanoparticles

[1381] The synthetic lipids were tested based on in vitro transfection efficiency and toxicity to HeLa cells. To perform the aforementioned bioassays, appropriate LNPs had to be formulated from the synthetic lipids. The formulation techniques for Method A and Method B differed. The particle size, PDI, and zeta potential of the resulting LNPs were determined using dynamic light scattering (DLS). The encapsulation efficiency (EE) of the LNPs was determined using the RiboGreen RNA assay prior to the bioassays. In Method A, luciferase-mRNA was transfected into cells, while in Method B, GFP mRNA was transfected into cells. Simultaneously with the transfection experiments, the toxicity of the LNPs under investigation was determined using the resazurin assay in Method A and the MTT assay in Method B. In certain lipid cases, the apparent pKA in LNP is determined by TNS titration according to the method described in Angew Chem Int Ed Engl. 2012, 51(34), 8529-8533, doi:10.1002 / anie.201203263.

[1382] Method A

[1383] LNP preparations and dialysis (Method A)

[1384] preparation:

[1385] 1. If necessary, prepare a stock solution by dissolving a known amount of lipid powder in a suitable solvent. Ethanol is recommended, and the recommended concentration is generally in the range of 10-50 mM. Higher concentrations are preferred to allow for flexibility in mRNA-LNP concentration.

[1386] 2. Remove the lipid stock solution from the -20°C freezer. For long-term storage, use -80°C.

[1387] 3. Inspect the vials for precipitates. DOPE (CAS#474922-05-1) (20 μm) and DSPE-PEG (CAS#474922-26-4) (5 μm) may require an incubation step at 37°C for 5–30 minutes, with intermittent vortexing to resuspend all contents. Vials with significant precipitates (from freeze-thaw cycles) may be non-recoverable. As a last resort, lipids can be heated to 50°C for resuscitation, but the time should be as short as possible to prevent oxidation or other modification or degradation processes.

[1388] 4. Mix the lipids by vortexing for 2 minutes.

[1389] 5. Cool the lipid stock solution to room temperature by incubation on a worktable, optionally in the dark. Cooling the solution prevents excessive evaporation of ethanol or similar solvents upon opening.

[1390] 6. Meanwhile, RNA samples were thawed by inserting frozen test tubes into room temperature aluminum blocks, including the latest SecNLuc control.

[1391] 7. For each LNP formulation with the same mRNA composition, prepare the RNA master mixture in clean tubes according to Table 1 below. Using the master mixture allows for more precise comparison of the interactions between lipid formulations. Aliquot the master mixture into multiple new tubes equal in number to the sample + control. Each tube contains 375 μl of mRNA at 10 mM citric acid pH 4.0.

[1392] 8. Prepare lipid master mixtures, excluding the target lipid, in new test tubes for each LNP formulation with the same lipid composition, according to Table 1 below. The use of master mixtures allows for more precise comparison of the relationships between novel ionizable lipids. Aliquot the master mixtures into multiple new test tubes, equal in number to the sample + control mixture. Each tube contains 65.5 μl of lipid master mixture.

[1393] 9. Add the target ionizable lipid to the evenly distributed master lipid mixture. Stir thoroughly by pipetting up and down. Label the test tubes according to the ionizable lipids used.

[1394] 10. Turn on the power to the 'L1 Formulation Machine' (L1 FM) and allow it to calibrate the motor position.

[1395] Table 1 Lipid formulation solutions

[1396]

[1397] *The proprietary core lipid belongs to RiboPro BV and is described as compound 101 in patent application GB2302736.0.

[1398] Rinsing and pre-wetting:

[1399] 11. Place the new microfluidic cartridge (COC plastic) into the loading slot of L1 FM.

[1400] 12. Load a 2ml Epdorf tube onto the L1 FM “receiving station”.

[1401] 13. Fill one “rinse syringe” (A) with 1 ml of RNase-free H2O and fill another “rinse syringe” (B) with 1 ml of the specified “wash” stock solution of 99% EtOH.

[1402] 14. Fix the syringes in the correct orientation. The syringe on the left is filled with H2O, and the syringe on the right is filled with EtOH.

[1403] 15. Rinse the chip by pressing "Button 2" (100μg), hold the chip in place, and check the movement of the syringe while the machine is running.

[1404] 16. Restart the machine for the next configuration.

[1405] 17. Discard the flow-through tube.

[1406] Preparation:

[1407] 18. Fill a new syringe (C) with the RNA mixture prepared in step 6 using a blunt 18G stainless steel needle. The volume should be approximately 85% of the total volume of the preparation + 25 μl (dead volume). Ensure all air bubbles are removed by tapping.

[1408] 19. Fill the new syringe (D) with the lipid master mixture through a blunt 18G stainless steel needle. The volume should be approximately 35% of the total formulation volume + 25 μl (dead volume). Again, ensure that all air bubbles are removed.

[1409] 20. Position the syringes in the correct orientation, with syringe A on the left and syringe B on the right.

[1410] 21. Load the “receiving station” into a collection container of appropriate size (2 ml Epdorf tube).

[1411] 22. Press the microfluidic chip onto the back of the machine with your thumb and hold it in place, then press "Button 1" (40 μg). The L1 FM will push the total volume of the syringe through the microfluidic mixer chip at a total flow rate (TFR) of 12 ml / ml, with a perfect 3:1 ratio (mRNA aqueous solution: lipids in EtOH).

[1412] 23. Remove the sample tube from the “receiving station” and label the tube accordingly.

[1413] 24. Reset the machine to prepare for the next preparation.

[1414] Dialysis:

[1415] 25. Transfer the single formulation to a 100 kDa MWCO SpectraPor Biotech dialysis tube and close it with the specified clamp.

[1416] 26. Immerse the dialysis bag in a beaker filled with 1x PBS buffer pH 7.4 and stir at 230 RPM at room temperature.

[1417] 27. After incubating at room temperature for 2 hours, regenerate 1x PBS buffer (pH 7.4) with stirring.

[1418] 28. Regenerate the buffer while stirring and incubate at room temperature for 2 hours.

[1419] 29. Remove the dialysis bag from the dialysis device and extract the LNP sample using a sterile pipette tip.

[1420] 30. Dilute the sample to 1 ml with sterile 1x PBS and measure the zeta potential, size and PDI using a DLS instrument.

[1421] Measurement of size and size distribution using dynamic light scattering (Method A)

[1422] Turn on the DLS (Dynamic Light Scattering) machine 30 minutes before use. This allows the laser to heat up and the sample station to equilibrate to the set operating temperature (usually room temperature).

[1423] 1. Optionally, if mass production is carried out in discrete batches (i.e., processed in multiple dialysis cassettes), the individual formulations of each unique construct are pooled together.

[1424] 2. Disassemble the folded capillary cells (DTS1070), using one sample per construct.

[1425] 3. Rinse the cuvette by inverting it (with the injection port down) and injecting 1 ml of H2O into one port. This will distribute the fluid through the cells and allow it to flow out from the other port.

[1426] 4. Repeat this step with a syringe filled with 1 ml of air, which will dry any excess water that may remain in the cells after rinsing.

[1427] 5. Invert the cuvette so that the injection port is at the top.

[1428] 6. Dilute 10 μl of the dialyzed LNP preparation into 690 μl of 1x PBS buffer, pH 7.4.

[1429] 7. Add the sample to the cells using a clean syringe, being careful not to exceed the "maximum fill" line on the cuvette.

[1430] 8. In the "Method Builder" of the "ZS Explorer" software, select the "Size & ζ" option and measure the sample to determine the size, PDI, and ζ potential.

[1431] Packaging efficiency (Method A)

[1432] Required solution:

[1433] 1. Preparation of sample stock solution: In the top row (row A) of a 96-well plate, use a multichannel pipette to add 297 μL of pH 7.4 TE buffer to each sample well and a PBS blank well.

[1434] 2. Add 3 μL of sample (0.5 mg / mL) to these wells to make a final volume of 300 μL. Add 3 μL of PBS to the blank wells. Mix using a pipette. These are the stock solutions for each sample. The final RNA concentration of these stock solutions should be approximately 4-7 μg / mL.

[1435] 3. mRNA-LNP sample setup:

[1436] a. Add 50 μL of pH 7.5 TE buffer to the two wells directly below each sample (rows B and C in the plate).

[1437] b. Add 50 μL of the stock solution from row A to the wells in rows B and C (this assay should be performed twice. All liquid handling should be done using a multichannel pipette).

[1438] c. Add 50 μL of Triton buffer to the wells in rows D and E (in the plate) below each sample.

[1439] d. Add 50 μL of the original sample solution from row A to the wells in rows D and E.

[1440] 4. RiboGreen RNA Standard Curve Setup: Dilute the RNA standard to produce a final concentration of 20 μg / mL RNA stock solution in TE buffer at pH 7.4. The final volume should be 150 μL. Establish a standard curve (twice) using the RNA stock solution (20 μg / mL siRNA), TE buffer at pH 7.5, and Triton buffer, according to Table 2 below.

[1441] Table 2. Preparation of RiboGreen RNA Standard Curve

[1442] Final mRNA concentration RNA stock solution (μl) TE buffer (μl) Triton buffer (μl) Total volume (μl) 2.5 25 25 50 100 1 10 40 50 100 0.5 5 45 50 100 0.25 2.5 47.5 50 100 0.1 1 49 50 100

[1443] 5. Once the samples and standard curve are prepared, incubate the plate at 37°C for 10 minutes to lyse the mRNA-LNP in the presence of Triton X-100.

[1444] 6. Simultaneously, prepare the RiboGreen solution: Add the total number of sample wells and standard curve wells. Add 3 to this number, then multiply the total by 100. This is the total volume of RiboGreen solution required for this assay, in μL. Dilute the RiboGreen reagent 1:100 in pH 7.5 TE buffer in a 15 mL RNase-free Falcon tube to achieve the calculated total volume.

[1445] 7. Add RiboGreen solution and read samples: Remove the 96-well plate from the 37°C incubator and allow it to cool to room temperature, as RiboGreen binding is temperature-dependent. Add 100 μL of RiboGreen solution to each well. Puncture any air bubbles with a needle. Read the samples using a fluorescent plate reader (excitation = 480, emission = 525).

[1446] 8. Sample Analysis: The concentration of mRNA was calculated using data generated from the RiboGreen standard curve.

[1447] Luciferase-mRNA transfection efficiency (Method A)

[1448] Control transfection preparation:

[1449] 1. An mRNA solution was prepared by adding 100 ng mRNA (SecNLuc, #P009024, RiboPro) to 5 μl of Opti-MEM.

[1450] a. Multiply by the number of pores, including different concentrations, and add an extra 10%.

[1451] b. Our standard setup is 100ng-50ng-10ng mRNA per well (three copies), which will require 528ng mRNA (including 10% extra).

[1452] Transfection:

[1453] 2. (If applicable) Prepare different concentrations (e.g., 100 / 50 / 10 ng) in Opti-MEM.

[1454] 3. Add 10 μl to each well and stir carefully with a pipette.

[1455] 4. Stir by rotating the plate horizontally at a moderate speed. Rotate in the opposite direction 3 times.

[1456] 5. Incubate for 24 hours (using an incubator).

[1457] Nano-Glo determination

[1458] background:

[1459] This protocol was applied to measure the luciferase activity of secreted NanoLuc, and is based on Promega (Nano- The protocol for the luciferase assay system (#N1110-1150) is designed for 384-well plates, but the volume can be adjusted accordingly for other plates.

[1460] program:

[1461] 1. Place the cells (HeLa) in a 96-well plate, grow to 80% confluence, transfect with SecNanoLuc mRNA, and incubate for the required time (24h).

[1462] 2. After incubation, the translated proteins accumulate in the culture medium. Transfer the medium to a new plate or tube.

[1463] 3. Transfer 12 μl of each sample to a 384-well plate with black walls and a transparent bottom.

[1464] a. Black side panels are important to prevent light from penetrating from other apertures; or, multiple apertures between samples can leave gaps.

[1465] 4. Set up the board reader

[1466] 5. Add 1 volume of Nano- Luciferase assay substrate and 50 volumes of Nano- Combined with luciferase assay buffer, the required amount of Nano- Luciferase assay reagent

[1467] a. Composition: 100mM MES pH 6; 1mM EDTA; 0.5% NP-50; 150mM KCl; 1mM DTT; 35mM thiourea

[1468] b. Briefly rotate the tube containing the substrate in a microcentrifuge before use.

[1469] 6. Add and mix 12 μl Nano- to each well (by pipetting) Luciferase assay reagent

[1470] a. Wait approximately 3 minutes before measuring the luminescence. The luminescence intensity will gradually decrease, with a signal half-life of approximately 120 minutes at room temperature.

[1471] 7. Use a standard luciferase assay plate reader to measure the luminescence (this includes mixing the samples in the plate reader).

[1472] Remark

[1473] Nano- Thaw the luciferase assay buffer to room temperature, but do not exceed 25°C at any time during the procedure.

[1474] Assessing cell viability using the rezinometer assay (Method A)

[1475] background:

[1476] This protocol is used to determine cellular metabolic activity as a measure of cellular viability after exposure to potentially toxic substances. Resazurin is reduced to resorufin in mitochondria, which exhibits higher fluorescence at ~600 nm compared to unconverted resazurin. Lower amount / percentage conversion rates are associated with reduced cellular metabolism and indirectly with cell death and toxicity. Readings must be interpreted with caution, as a 50% reduction in resazurin conversion could mean a 50% reduction in cellular metabolism or 50% cell death in 100% of viable cells, or any combination thereof.

[1477] program:

[1478] 1. Prepare a 0.25 mg / ml stock solution of resazurin in fresh cell culture medium. Resazurin decreases spontaneously over time in solution, especially in culture medium, and a fresh stock solution should be prepared every 2-3 days. The stock solution should be stored at 4°C and protected from light. For HeLa cells, use DMEM / F12 containing 10% FCS.

[1479] 2. Dilute the stock solution 10x to 0.025 mg / ml in fresh cell culture medium -> ready for application to cells. For HeLa cells, use DMEM / F12 containing 10% FCS.

[1480] 3. Collect the 96-well plates and replace the waste cell culture medium with 100 μl of rezin solution per well. Add some rezin solution to the cell-free wells for background measurement.

[1481] 4. Incubate for 50 minutes in an incubator at 37°C, 5% CO2, and 95% RH.

[1482] 5. Transfer the azadirachtin solution to a new 96-well or 384-well plate.

[1483] 6. Use the standard settings (PTM low / OD-1.0) to perform measurements using 540 / 25nm (excitation) and 610 / 40nm (emission) on the plate reader.

[1484] 7. Subtract the mean background measurement from all samples. Set the mean of the negative controls (only those receiving good OptiMEM during transfection) to 100%, and express all values ​​as a percentage of control activity. Generally, lower treatment levels show increased metabolic activity, while for toxic substances, an S-shaped curve is obtained at toxic concentrations, with lower activity indicating higher toxicity.

[1485] Method B

[1486] LNP formulation (Method B)

[1487] Required solution:

[1488] 0.33 μg / μL of mRNA (RiboPro, finished mRNA; eGFP containing Cap1) in DEPC-treated water

[1489] 0.04 μg / μL of mRNA (RiboPro, finished mRNA; containing Cap1-containing eGFP) in DEPC-treated water.

[1490] Table 3. Lipid formulation solutions in anhydrous ethanol

[1491] reagents mol / L lipids tested 7.36E-03 ALC-0159 (CAS#1849616-42-7) 2.54E-04 DSPC (CAS#4539-70-2) 1.49E-03 Chol (CAS#57-88-5) 7.36E-03 DOTAP (CAS#132172-61-3) 7.36E-03

[1492] MEM (Sigma, cat#M5650-500mL)

[1493] Diluent: 10 mL MEM + 0.036 mL ethanol

[1494] Liposome solution (Thermo Fisher Scientific / Invitgen, CAT#11668-019, 1 mg / mL solution)

[1495] program:

[1496] 1. Negative control:

[1497] a.) Place 360 ​​μL of diluent into an Epdorf tube.

[1498] 2. The lipid formulation being tested:

[1499] In a 1.5 mL Epdorf tube:

[1500] a) Place 2.9 μL of 0.33 μg / μL mRNA solution into an Ependorf tube.

[1501] b) Add 1.94 μL of the supplied ethanol solution of the test lipid and immediately mix by pipetting up and down several times (pipette the solution up and down several times before transferring it to a pipette tip saturated with ethanol vapor).

[1502] c) Incubate for 15 minutes.

[1503] d) Add 536 μL of MEM. Mix the solution by vortexing.

[1504] e) Incubate for 30 minutes.

[1505] 3. Liposome-50 control formulation (according to manufacturer's instructions)

[1506] a) Place 13.5 μL of 0.04 μg / μL mRNA solution into a 1.5 mL sterile Eppendorf tube.

[1507] b) Add 527 μL MEM

[1508] c) Add 2.16 μL of liposome stock solution. Vortex.

[1509] d) Incubate for 15 minutes

[1510] 4. Liposome-6 control formulation:

[1511] a) Place 45 μL of liposome-50 solution into a 1.5 mL sterile Ependorf tube.

[1512] b) Add 315 μL MEM. Vortex.

[1513] c) Incubate for 15 minutes

[1514] Measurement of size and size distribution using dynamic light scattering (Method B)

[1515] 1. Transfer 100 μL of freshly prepared LNP formulation to a DLS microcapsule container.

[1516] 2. Place the formulation into a Zetasizer preheated to 37°C.

[1517] 3. Allow the sample to equilibrate for 5 minutes.

[1518] 4. Perform three dimensional measurements (settings: position and automatic gain).

[1519] 5. For QC, check the relevant curves for interference-free conditions. Report the Z-mean and PDI based on the cumulative values.

[1520] Packaging efficiency (Method B)

[1521] Required solution:

[1522] Ribogreen (Invitgen / Thermo Fisher Scientific, CAT#10207502)

[1523] Table 4. Lipid formulation ethanol solution

[1524] reagents mol / L lipids tested 7.36E-03 ALC-0159 (CAS#1849616-42-7) 2.54E-04 DSPC (CAS#4539-70-2) 1.49E-03 Chol (CAS#57-88-5) 7.36E-03 DOTAP (CAS#132172-61-3) 7.36E-03

[1525] A 0.33 μg / μL mRNA solution (RiboPro, finished mRNA; eGFP containing Cap1) in DEPC-treated water.

[1526] 1X TE (Tris-EDTA) buffer solution (10mM Tris-HCl, 1mM EDTA, pH 7.5)

[1527] 0.1% Triton X-100 in 1X TE (Tris-EDTA) buffer solution

[1528] program:

[1529] 1. Preparation of RiboGreen working solution:

[1530] a) Dilute RiboGreen reagent in 1X TE buffer (1:200 dilution) according to the manufacturer's instructions.

[1531] 2. Preparation of RNA standards:

[1532] a) Dilute known concentrations of RNA standards in 1X TE buffer to create a series of standards with different RNA concentrations, ranging from 0.1 to 1,000 ng / mL.

[1533] b) Divide 100 μL of each standard into different wells of a black 96-well plate.

[1534] 3. Preparation of liposome samples:

[1535] a) Place 2.9 μL of 0.33 μg / μL mRNA solution into an Ependorf tube.

[1536] b) Add 1.94 μL of the lipid formulation ethanol solution and immediately mix by moving the pipette up and down several times (Note! Pipette the solution up and down several times before transferring it to a pipette tip saturated with ethanol vapor).

[1537] c) Incubate for 15 minutes.

[1538] d) Add 268 μL of 1x TE buffer. Mix the solution by vortexing.

[1539] e) Incubate for 30 minutes.

[1540] Transfer the 100 µL sample obtained to a separate Ependorf tube and dilute with an additional 100 µL of 1x TE buffer. Brief vortex = control sample.

[1541] g) Transfer 100 μL of the obtained sample to a separate Eppendorf tube and dilute with 100 μL of 0.1% Triton X-100 solution. Briefly vortex and incubate at 37 °C for 15 min = lyse the sample.

[1542] h) Divide 100 μL of control sample and lysed sample into different wells of a black 96-well plate.

[1543] 4. Perform RiboGreen assay:

[1544] a) Add 100 μL RiboGreen working solution to each well containing RNA standards and liposome samples.

[1545] b) Gently mix the contents of the orifice by moving the liquid up and down or by shaking the plate on the track oscillator.

[1546] c) Incubate the plate in the dark at room temperature for 5-10 minutes.

[1547] d) Use a fluorescent microplate reader to measure the fluorescence intensity of each well, with an excitation wavelength of 480 nm and an emission wavelength of 525 nm.

[1548] e) Record the fluorescence values ​​of RNA standards and liposome samples.

[1549] 5. Calculate mRNA encapsulation efficiency:

[1550] a) Plot an RNA standard curve by plotting RNA concentration (ng / mL) on the x-axis and the corresponding fluorescence intensity on the y-axis. Fit the data to a linear regression model.

[1551] b) The concentration of mRNA in liposome samples was determined by interpolating the fluorescence values ​​on a standard curve.

[1552] c) mRNA encapsulation efficiency is calculated as the percentage of mRNA content in the liposome control sample relative to the liposome lysate sample. GFP-mRNA transfection efficiency (Method B)

[1553] Required solution:

[1554] MEM (Sigma, cat#M5650-500mL)

[1555] Fetal bovine serum, FBS (Sigma, CAT#F7524-500 ml)

[1556] The formulation solution (see above)

[1557] Diluent: 10 mL MEM + 0.036 mL ethanol

[1558] Phosphate-buffered saline, PBS

[1559] program:

[1560] 1. Fill the edge wells of the 96-well plate with 100 μL of medium.

[1561] 2. Place 10,000 HeLa cells in each well of a 96-well plate. Do not use the edge wells. A total of 60 wells are required for seeding. Incubate at 37°C in MEM + 10% FBS under a humid atmosphere containing 5% CO2 for 24 hours.

[1562] 3. Examine under a microscope. The degree of fusion must be equal to or close to 80%.

[1563] 4. Gently remove the medium (absorption). Add 50 μL of the following formulation:

[1564] a) 6 wells, diluent-negative control

[1565] b) 6-well, Liposome-50 positive control

[1566] c) 6-well, Liposome-6-secondary positive control

[1567] d) 6 wells for each formulation - test sample.

[1568] 5. Incubate the plate at 37°C for 1 hour.

[1569] 6. Add 50 μL MEM + 20% FBS (diluted to 10%).

[1570] 7. Place the plate in an incubator and incubate at 37°C in a humid atmosphere containing 5% CO2 for 23 hours (total incubation for 24 hours).

[1571] After 8.24 hours, aspirate the medium without disturbing the cells. Gently wash the cells with 100 μL of warm PBS. Aspirate the PBS.

[1572] 9. Add 100 μL of fresh PBS to the washed cells and read the GFP fluorescence on a plate reader.

[1573] 10. After this, viability can be assessed using the MTT assay.

[1574] Evaluation of cell viability using the MTT assay (Method B)

[1575] Required solution:

[1576] MEM (Sigma, cat#M5650-500mL)

[1577] Fetal bovine serum, FBS (Sigma, CAT#F7524-500 ml)

[1578] Thiazole blue tetrazolium bromide, MTT (TCI Chemicals, CAT#D0801-5G)

[1579] The formulation solution (see the "Preparation of LNPs Loaded with GFP mRNA" protocol).

[1580] Diluent: 10 mL MEM + 0.036 mL ethanol

[1581] Phosphate-buffered saline, PBS

[1582] program:

[1583] 1. Place 10,000 HeLa cells in each well of a 96-well plate. Do not use edge wells. A total of 60 wells are required for seeding. Incubate at 37°C in MEM + 10% FBS under a humid atmosphere containing 5% CO2 for 24 hours.

[1584] 2. Examine under a microscope. The degree of fusion must be equal to or close to 80%.

[1585] 3. Gently remove the medium (absorption). Add 50 μL of the following formulation:

[1586] a) 6 wells, diluent-negative control

[1587] b) 6-well, Liposome-50 positive control

[1588] c) 6-well, Liposome-6-secondary positive control

[1589] d) 6 wells for each formulation - test sample.

[1590] 4. Incubate the plate at 37°C for 1 hour.

[1591] 5. Add 50uL MEM + 20% FBS (diluted to 10%).

[1592] 6. Place the plate in an incubator and incubate at 37°C for 23 hours (total incubation time: 24 hours).

[1593] 7. Prepare a 1 mg / mL MTT solution in sterile PBS. Filter – Sterilize the solution using a 0.22 μm filter and protect it from light. This solution needs to be freshly prepared before assay.

[1594] 8. After processing time, carefully remove the processing medium from each hole.

[1595] a. Add 100 μL of MTT solution to each well.

[1596] b. Incubate the plates at 37°C in a humid atmosphere containing 5% CO2 for 2-4 hours.

[1597] 9. After incubation, carefully remove the MTT solution from each well without disturbing the formazan crystals. Add 100-150 μL of solubilizing solution (isopropanol containing 0.04 M HCl) to each well to dissolve the formazan crystals. Gently pipette up and down or shake the plate on a track shaker for 5-10 minutes to ensure complete dissolution.

[1598] 10. Use a microplate reader to measure the absorbance of each well at 570 nm. Measure the absorbance at a reference wavelength of 650 nm to subtract the background absorbance.

[1599] 11. Calculate relative cell viability (%) by comparison with the blank control (untreated culture).

[1600] The experimental results using the lipids according to the present invention, along with reference compounds, are summarized in Table 5 below.

[1601] Table 5

[1602]

[1603]

[1604]

[1605]

[1606] in conclusion

[1607] The vast potential of the chemical space becomes readily available thanks to the novel modular approach to the novel ionizable cationic lipid library described in this invention. Compounds of formula (I) can be synthesized by utilizing commercially available starting materials and implementing proprietary borane catalysts (as described in WO2022 / 129966).

[1608] Results from LNP formulation and transfection studies provide evidence that novel silicon-containing lipids, as described in this invention, produce nanoparticles with suitable size, polydispersity index (PDI), and zeta potential. Furthermore, apparent pKa values ​​were determined in some cases, consistent with the optimal range.

[1609] Furthermore, lipid nanoparticles formed from formula (I) lipids demonstrated their potential to deliver GFP and luciferase mRNA into cells while exhibiting low to moderate cytotoxicity. Notably, a large number of formula (I) lipids from this study showed comparable or even better transfection efficiencies compared to the reference compound ALC-0315.

Claims

1. A compound having the structure of formula (I) or a salt or stereoisomer thereof, in: G 1 It is an unsubstituted C2-C9 alkylene group, or -(CH2) x -CH=CH-(CH2) y - where x is an integer selected from 1 to 6, y is an integer selected from 1 to 6, and the sum of x + y is an integer selected from 2 to 7. T 1 for in b 1 For G 1 The key, X1 and X2 can be the same or different, and each can independently represent O or S. R1 is Linear C1-C 17 Alkyl, nonlinear C3-C 17 Alkyl groups, in both cases optionally containing an S or O at any position in the carbon chain, provided that the heteroatom is not at the α or Ω position of the carbon chain; C3-C containing a double bond. 17 Alkenyl, provided that at least one -CH2- group exists between the double bond and X2; or a group The group is linked via b. R2 is Linear C1-C 17 Alkyl, nonlinear C3-C 17 Alkyl groups, in both cases optionally containing an S or O atom at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; C3-C containing a double bond. 17 Alkenyl, provided that at least one -CH2- group exists between the double bond and the carbons connecting X1 and X2; or a group The group is linked via a b link, or R1 is attached to R3 via an alkylene or monounsaturated alkenyl group, forming a C5-C... 30 -Meta-ring, or R2 is attached to R3 via an alkylene or monounsaturated alkenyl group to form a C5-C group. 30 Circular ring, or R2 is attached to R1 via an alkylene or monounsaturated alkenyl group, forming a C5-C... 30 ring; R3 is ， R5-b 1 for ， in b 2 For linking with X1, Y1 is either -O- or -CH2-. Each X3 is independently selected from C1-C4 alkyl groups. R4 is a linear C2-C 17 Alkyl or nonlinear C3-C 17 Alkyl groups, in both cases, optionally contain an S or O atom at any position in the carbon chain, provided that the heteroatom is not at the α or Ω position in the carbon chain; C3-C containing a double bond. 20 Alkenyl group, provided that at least one -CH2- group exists between the double bond and Y1; or a group The group is linked via b. D 1 Choose from the following groups in b 4 For nitrogen, R9 is a C1-C6 alkyl group. R 10 and R 11 Independently selected from H and C1-C6 alkyl groups, m is an integer selected from 1 to 6. n is an integer selected from 0 to 6. o is an integer selected from 0 to 6. p is an integer selected from 2 to 6. q is an integer selected from 0 to 6. Cy1 is a C3-C6 cycloalkyl group, or Cy1 is a 4-, 5-, 6-, or 7-membered heterocycle containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, wherein the heterocycle is optionally separated by R. 12 replace, in R 12 The term represents a C1-C6 alkyl, pyranose, or furanose ring, wherein the pyranose or furanose ring is attached to the 4-, 5-, 6-, or 7-membered heterocycle via any one of its ring carbon atoms, wherein the pyranose or furanose ring is optionally substituted with a -NH-CO-CH3 group; P is selected from (i)G 2 -T 2 in G 2 As mentioned above, G 1 As defined, where G 1 and G 2 Can be the same or different; T 2 As mentioned above, T 1 As defined, b 1 It is to G 2 The key, and where T 1 and T 2 Can be the same or different; or (ii) G 2 -T 3 in G 2 As defined above; T 3 for ， in b 5 For G 2 The key, X4 and X5 can be the same or different, and each can be O or S independently. R 13 For linear C2-C 17 Alkyl, nonlinear C3-C 17 Alkyl groups, both optionally containing one of S or O at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; C3-C containing a double bond. 20 Alkenyl group, provided that at least one -CH2- group exists between the double bond and X5; or a group The group is linked via a b link, or R 13 for , where R 23 R 24 R 25 They can be the same or different and each can independently be H, OH, or -C1-C6 alkoxy groups. R 14 For linear C2-C 17 Alkyl, nonlinear C3-C 17 Alkyl groups, both optionally containing one of S or O at any position in the carbon chain, provided that the heteroatom is not in the α or Ω position of the carbon chain; C3-C containing a double bond. 20 Alkenyl group, provided that at least one -CH2- group exists between the double bond and the carbons connecting X4 and X5; or a group The group is linked via a b link, or R 14 for , Among them, R 26 R 27 R 28 They can be the same or different and each independently is H, OH or -C1-C6 alkoxy; And (iii) T 4 ,in T 4 for ， Among them, b 6 For the bond to the nitrogen atom, R 29 R 30 R 31 They can be the same or different, and each is independently H, OH or -C1-C6 alkoxy; C4-C containing a double bond 20 Alkenyl, provided that at least one -CH2- exists between the double bond and N, or Polyunsaturated C8-C 20 Alkenyl group, provided that at least one -CH2- exists between the first double bond and N.

2. The compound according to claim 1, wherein, G 1 And if G exists 2 They may be the same or different, and each is independently a linear C4-C9 alkylene group.

3. The compound according to claim 1, wherein, G 1 And if G exists 2 Each is independently linear C5-C9 alkylene or independently linear C5, C6, C7 or C9 alkylene.

4. The compound according to claim 1, wherein, R1 is linear, C1, C2, C4, C6, C7, C8, C9, C 10 Or C 12 Alkyl group, or R1 is a linear C9 alkenyl group, and / or R2 is a linear C1, C3, C5, C6, C7, C8, C9 or C 11 alkyl.

5. The compound according to claim 1, wherein, R1 is a linear equation with C2, C8, and C... 10 Alkyl, or R1 is a linear C9 alkenyl and / or R2 is a linear C1, C3, C7 or C9 alkyl.

6. The compound according to claim 4, wherein, T 1 For (c) and R1 is linear, C2, C4, C6, C7, C8, C9, C 10 Or C 12 Alkyl group, or R1 is a linear C9 alkenyl group, and R2 is a linear C1, C3, C5, C6, C7, C8, C9 or C 11 alkyl.

7. The compound according to claim 5, wherein, T 1 Let (c) and R1 be linear C2, C8, C 10 Alkyl, or R1 is a linear C9 alkenyl, and R2 is a linear C1, C3, C7 or C9 alkyl.

8. The compound according to claim 1, wherein, P is G 2 -T 2 .

9. The compound according to claim 2, wherein, P is G 2 -T 2 .

10. The compound according to claim 3, wherein, P is G 2 -T 2 .

11. The compound according to claim 4, wherein, P is G 2 -T 2 .

12. The compound according to claim 5, wherein, P is G 2 -T 2 .

13. The compound according to claim 8, wherein, G 1 -T 1 and G 2 -T 2 They are the same.

14. The compound according to claim 9, wherein, G 1 -T 1 and G 2 -T 2 They are the same.

15. The compound according to claim 10, wherein, G 1 -T 1 and G 2 -T 2 They are the same.

16. The compound according to claim 11, wherein, G 1 -T 1 and G 2 -T 2 They are the same.

17. The compound according to claim 12, wherein, G 1 -T 1 and G 2 -T 2 They are the same.

18. The compound according to claim 1, wherein, P is G 2 -T 3 .

19. The compound according to claim 2, wherein, P is G 2 -T 3 .

20. The compound according to claim 3, wherein, P is G 2 -T 3 .

21. The compound according to claim 4, wherein, P is G 2 -T 3 .

22. The compound according to claim 5, wherein, P is G 2 -T 3 .

23. The compound according to claim 18, wherein, T 1 -G 1 It has one of the following structures 。 24. The compound according to claim 18, wherein, T 3 It has the following structure Among them, b 5 For G 2 The key.

25. The compound according to claim 23, wherein, T 3 It has the following structure Among them, b 5 For G 2 The key.

26. The compound according to claim 18, wherein, T 3 It has one of the following structures Among them, b 5 For G 2 The key.

27. The compound according to claim 23, wherein, T 3 It has one of the following structures Among them, b 5 For G 2 The key.

28. The compound according to claim 18, wherein, T 3 It has one of the following structures Among them, b 5 For G 2 The key.

29. The compound according to claim 23, wherein, T 3 It has one of the following structures Among them, b 5 For G 2 The key.

30. The compound according to claim 18, wherein, T 3 It has the following structure Among them, b 5 For G 2 The key.

31. The compound according to claim 23, wherein, T 3 It has the following structure Among them, b 5 For G 2 The key.

32. The compound according to claim 1, wherein, P is T 4 .

33. The compound according to claim 32, wherein, T 4 for ， Among them, b 6 For the bond to the nitrogen atom, R 29 R 30 R 31 They can be the same or different, and each can independently be H, OH, or -C1-C6 alkoxy; or Polyunsaturated C8-C 20 Alkenyl group, provided that at least one -CH2- exists between the first double bond and N.

34. The compound according to claim 33, wherein, T 1 -G 1 It has one of the following structures 。 35. The compound according to claim 33, wherein, T 4 It has the following structure Among them, b 6 The bond is to the nitrogen atom.

36. The compound according to claim 1, wherein, D 1 It has one of the following structures: 。 37. The compound according to claim 8, wherein, D 1 It has one of the following structures: 。 38. The compound according to claim 24, wherein, D 1 It has one of the following structures: 。 39. The compound according to claim 26, wherein, D 1 It has one of the following structures: 。 40. The compound according to claim 28, wherein, D 1 It has one of the following structures: 。 41. The compound according to claim 30, wherein, D 1 It has one of the following structures: 。 42. The compound according to claim 1, wherein, D 1 It has one of the following structures: Where q is an integer selected from 1 to 4, and b 4 It is a nitrogen-to-nitrogen bond.

43. The compound according to claim 36, wherein, D 1 It has one of the following structures: 。 44. The compound according to claim 1, wherein the compound has one of the following structures:

45. A lipid nanoparticle comprising a therapeutic agent and a compound according to any one of claims 1 to 20.

46. ​​A lipid nanoparticle comprising a therapeutic agent and the compound according to claim 23.

47. A lipid nanoparticle comprising a therapeutic agent and the compound according to claim 24.

48. A lipid nanoparticle comprising a therapeutic agent and the compound according to claim 26.

49. A lipid nanoparticle comprising a therapeutic agent and the compound according to claim 28.

50. A lipid nanoparticle comprising a therapeutic agent and the compound according to claim 30.

51. A lipid nanoparticle comprising a therapeutic agent and the compound according to claim 44.

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