Crystalline solids of 3-palmitoyl-amido-1,2-propanediol and 3-palmitoyl-amido-2-hydroxy-1-dimethoxytriphenylmethylether-propane and methods of making and using the same

Abstract

This disclosure includes crystalline solids of 3-palmitinyl-phenylamino-1,2-propanediol and 3-palmitinyl-phenylamino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. A method for preparing crystalline solids of 3-palmitinyl-phenylamino-1,2-propanediol and single crystals of 3-palmitinyl-phenylamino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is also provided. A method for preparing 3-palmitinyl-phenylamino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane from crystalline solids of 3-palmitinyl-phenylamino-1,2-propanediol is also described.

Description

Technical Field

[0001] Cross-referencing of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 926,810, filed October 28, 2019, the disclosure of which is incorporated herein by reference.

[0002] This invention relates to crystalline solids of 3-palmitinyl-phenylamino-1,2-propanediol and 3-palmitinyl-phenylamino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane and their manufacturing methods, as well as a method for preparing 3-palmitinyl-phenylamino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane using crystalline solids of 3-palmitinyl-phenylamino-1,2-propanediol. Prior Technology

[0003] Imetelstat is a telomerase inhibitor that binds with high affinity to the template region of the RNA component of telomerase. Studies have shown that imetelstat inhibits telomerase activity and effectively combats cell proliferation in many different cancer cell lines and human tumors. Imetelstat has been used in clinical trials for patients with hematologic malignancies. Clinical trials in patients with bone marrow fibrosis have shown that imetelstat can achieve complete clinical remission in some patients. In these patients, imetelstat induces reversal of secondary myelofibrosis and leads to morphological and molecular remission.

[0004] Imistat's structure comprises an N3'→P5' thiophosphoramidate oligonucleotide. The synthesis of imistat was previously performed via solid-phase oligonucleotide synthesis, in which the first phosphoamine nucleotide is coupled to the support and subsequently sulfurized. Chain elongation of the oligonucleotide component is achieved through repeated reactions of the 3'-amino group bound to the oligonucleotide with other nucleotide phosphoamine monomers. The imistat oligonucleotide is coupled to the solid support via a palmityl-acetylamine linker. Therefore, this fatty acid-acetylamine linker is a component in the synthesis of imistat. Summary of the Invention

[0005] This disclosure includes the crystalline solid form of 3-palmitoyl-amino-1,2-propanediol (Formula I): (I).

[0006] In specific embodiments, the crystalline solid of 3-palmitinyl-amino-1,2-propanediol has an X-ray powder diffraction (XRPD) pattern containing a peak at approximately 8.25° 2Å. In some specific embodiments, the crystalline solid of 3-palmitinyl-amino-1,2-propanediol has an X-ray powder diffraction (XRPD) pattern containing one or more peaks at approximately 2.75° 2Å; approximately 6° 2Å; approximately 3.8° 2Å; approximately 15° 2Å; approximately 26.3° 2Å; approximately 30.5° 2Å; and approximately 33.1° 2Å. In some cases, the crystalline solid of 3-palmitinyl-amino-1,2-propanediol is characterized by a single weight loss step performed by thermogravimetric analysis (TGA). In some cases, the weight loss step begins at approximately 200.5°C. In several specific embodiments, the crystalline solid of 3-palmitinyl-amino-1,2-propanediol exhibits a first endothermic reaction at approximately 79.3°C and a second endothermic reaction at approximately 102.5°C by differential scanning calorimetry (DSC). In these specific embodiments, the second endothermic reaction is a unimodal endothermic reaction.

[0007] A method for preparing the crystalline solid of 3-palmitinyl-nitro-1,2-propanediol is also provided. In certain embodiments, 3-palmitinyl-nitro-1,2-propanediol is contacted with one or more solvents to produce a 3-palmitinyl-nitro-1,2-propanediol composition and precipitated to produce crystalline solid 3-palmitinyl-nitro-1,2-propanediol. In some embodiments, 3-palmitinyl-nitro-1,2-propanediol is contacted with a polar solvent. In other embodiments, 3-palmitinyl-nitro-1,2-propanediol is contacted with a nonpolar solvent. In still other embodiments, 3-palmitinyl-nitro-1,2-propanediol is contacted with a mixture of polar and nonpolar solvents. The solvent may further include organic bases, such as triethylamine. In several specific embodiments, the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethylsulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), or combinations thereof. In some cases, the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, and dichloromethane. In certain cases, the solvent is tetrahydrofuran. In certain specific embodiments, precipitating the crystalline solid of 3-palmitoyl-amino-1,2-propanediol involves heating the 3-palmitoyl-amino-1,2-propanediol composition to produce a thermal composition (e.g., wherein 3-palmitoyl-amino-1,2-propanediol is dissolved in the solvent) and cooling the thermal 3-palmitoyl-amino-1,2-propanediol composition to produce crystalline solid of 3-palmitoyl-amino-1,2-propanediol.

[0008] A method for preparing 3-palmitinyl-amide-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane from 3-palmitinyl-amide-1,2-propanediol is also described. In a method according to certain specific embodiments, a solvent is contacted with a crystalline solid of 3-palmitinyl-amide-1,2-propanediol to produce a precursor composition; and the precursor composition is contacted with a composition containing dimethoxytriphenylmethyl chloride to produce a composition containing 3-palmitinyl-amide-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. In several specific embodiments, the solvent is tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate (iPrOAc), ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), N-methyl-2-pyrrolidone (NMP), or combinations thereof. In some cases, the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP). In some cases, the solvent is selected from methyltetrahydrofuran, tetrahydrofuran, and dichloromethane.

[0009] In several specific embodiments, the precursor composition comprises a base, such as an organic base. For example, the base may be 1,8-bis(dimethylamino)naphthalene (proton sponge), imidazole, 1,8-diacerbicyclo[5.4.0]undec-7-ene (DBU), 2,4,6-trimethylpyridine (Colin base), triethylamine (TEA), potassium carbonate, sodium methoxide, tetramethylethylenediamine (TMEDA), or dimethylaminoethanol. In some cases, the base is selected from 1,8-bis(dimethylamino)naphthalene (proton sponge), tetramethylethylenediamine (TMEDA), and triethylamine (TEA). In some cases, the base is triethylamine.

[0010] In other specific embodiments, the precursor composition includes an additive. For example, the additive may be calcium oxide, magnesium oxide, boric acid, tetrabutylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP), copper chloride (CuCl2), ytterbium(III) chloride (YbCl3), or 1,4-diacylbicyclo[2.2.2]octane (DABCO). In some cases, the additive is selected from tetrabutylammonium fluoride (TBAF), magnesium oxide, and boric acid. In some cases, the additive is magnesium oxide.

[0011] In some cases, the crystalline solid of 3-palmitinyl-amino-1,2-propanediol has an X-ray powder diffraction (XRPD) pattern containing one or more peaks located at approximately 2.75° 2Ɵ; approximately 6° 2Ɵ; approximately 3.8° 2Ɵ; approximately 8.25° 2Ɵ; approximately 15° 2Ɵ; approximately 26.3° 2Ɵ; approximately 30.5° 2Ɵ; and approximately 33.1° 2Ɵ. In some cases, the crystalline solid of 3-palmitinyl-amino-1,2-propanediol is characterized by a single weight loss step performed by thermogravimetric analysis (TGA). In some cases, this weight loss step begins at approximately 200.5ºC. In several specific embodiments, the crystalline solid of 3-palmitoyl-amino-1,2-propanediol exhibited a first endothermic temperature of about 79.3°C and a second endothermic temperature of about 102.5°C by differential scanning calorimetry (DSC).

[0012] In some cases, the method further includes (e.g., by recrystallization) forming one or more single crystals of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. In these specific embodiments, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with a solvent, and the crystalline solid of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is precipitated from the solvent. In some cases, the solvent is a polar solvent. In other cases, the solvent is a nonpolar solvent. In still other cases, the solvent is a mixture of polar and nonpolar solvents. In certain specific embodiments, forming a crystalline solid of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane comprises heating the 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane composition to generate a thermal composition and cooling the thermal composition to generate a crystalline solid of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane, such as one or more single crystals of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.

[0013] This disclosure also includes the crystalline solid of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (Formula II): (II).

[0014] In some cases, the crystalline solid of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is a single crystal of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Depending on the specific embodiment, the crystalline solid system is monoclinic. Each unit lattice in this crystalline solid contains two different configurations of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane, such as a bent configuration and a linear configuration. In a specific embodiment, the 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane configurations (bent and linear) exist in the unit lattice in a 1:1 ratio. Each unit lattice in this crystalline solid contains four molecules of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. In several specific embodiments, the size of the unit lattice is about 8.44 μm x about 26.56 μm x about 10.06 μm, wherein the volume of the unit lattice is about 2254.8 μm³. The density of the target 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane crystalline solid is about 1.2 g / cm³ to about 1.3 g / cm³, and its polymorph purity is 95% or higher.

[0015] A method for preparing crystalline solids of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is also provided. In certain embodiments, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with one or more solvents to produce a 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane composition and precipitation to produce crystalline solids of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane, such as one or more single crystals of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. In several embodiments, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with a polar solvent. In other specific embodiments, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with a nonpolar solvent. In other specific embodiments, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with a mixture of a polar solvent and a nonpolar solvent. In some cases, the polar solvent is dichloromethane, and the nonpolar solvent is pentane. In certain specific embodiments, precipitating a crystalline solid of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane comprises heating the 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane composition to produce a thermal composition (e.g., wherein 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is dissolved in the solvent), and cooling the thermal 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane composition to produce a crystalline solid of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Simple Explanation of the Diagram

[0016] Figure 1 shows the X-ray powder diffraction pattern of the homomorphic polymorphic solid of 3-palmitoyl-acetamino-1,2-propanediol formed from solutions of (b) THF, (c) 2-methyl THF and (d) DCM, and a comparison with the (a) 3-palmitoyl-acetamino-1,2-propanediol starting material.

[0017] Figure 2 shows the thermogravimetric analysis (TGA) temperature records of the homopolymorphic crystalline solid of 3-palmitinyl-amino-1,2-propanediol formed from THF solution according to certain specific embodiments. The graph in Figure 2 also depicts the differential scanning calorimetry (DSC) plot of the homopolymorphic crystalline solid of 3-palmitinyl-amino-1,2-propanediol formed from THF according to certain specific embodiments.

[0018] Figure 3 depicts a comparison of the DSC diagram of the homopolymorphic crystalline solid of 3-palmitoyl-amino-1,2-propanediol formed from THF with the initial DSC diagram of 3-palmitoyl-amino-1,2-propanediol.

[0019] Figure 4A depicts the Oak Ridge thermal ellipsoid (ORTEP) plot of two different configurations of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane as determined by X-ray crystallography. Figure 4B depicts the unit lattice of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Figure 4C depicts the crystal packing view of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane along the first axis. Figure 4D depicts the crystal packing of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane along the second axis. Figure 4E depicts the intermolecular hydrogen bonds between isomer A and isomer B along the second crystallographic axis. Implementation

[0020] Unless otherwise indicated, the following terms shall have the following meanings. Any undefined term shall have its technically accepted meaning.

[0021] As used herein, the terms “phosphate ester” and “phosphate ester group” are intended to encompass both thiophosphate groups and oxophosphate groups.

[0022] As used herein, the term "phosphatamidoamine group" refers to the amino group -NR4R5 that connects the phosphorus atom to the phosphatamidoamine group, and the term "phosphatamidonitrogen" refers to the nitrogen atom of the phosphatamidoamine group.

[0023] "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, such as 1 to 6 carbon atoms (e.g., "alkyl of 1 to 6 carbon atoms"), or 1 to 5 carbon atoms (e.g., "alkyl of 1 to 5 carbon atoms"), or 1 to 4 carbon atoms (e.g., "alkyl of 1 to 4 carbon atoms"), or 1 to 3 carbon atoms (e.g., "alkyl of 1 to 3 carbon atoms"). This term includes, for example, straight-chain and branched hydrocarbon groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), secondary butyl ((CH3)(CH3CH2)CH-), tertiary butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0024] The term "substituted alkyl" refers to an alkyl group as defined herein and having 1 to 5 substituents, wherein one or more carbon atoms in the alkyl chain are, where appropriate, substituted with heteroatoms such as -O-, -N-, -S-, -S(O)n- (where n is 0 to 2), -NR- (where R is hydrogen or alkyl), the substituent being selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acetyl, acetamino, acetoxy, amino, aminoacetyl, aminoacetoxy, oxoamineacetyl, azide, cyano, halogen, hydroxy, sideoxy, The group consisting of thionyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclic, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamine, alkoxyamine, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl and -NRaRb, wherein Ra and Rb may be the same or different and are selected from hydrogen, and where applicable, substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. In some cases, “substituted alkyl” means an alkyl group having 1 to 5 substituents as defined herein, wherein the substituents are selected from the group consisting of alkoxy, cycloalkyl, cycloalkenyl, acetyl, acetamino, acetoxy, amino, aminoacetyl, aminoacetoxy, oxoamineacetyl, azide, cyano, halogen, hydroxy, carboxyl, carboxylalkyl, thiol, thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, sulfonamide and -NRaRb, wherein Ra and Rb may be the same or different, and are selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

[0025] "Alkyl" refers to a divalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, wherein the hydrocarbon group is straight-chain or branched and, where appropriate, interrupted by one or more groups selected from -O-, -NR10-, -NR10C(O)-, -C(O)NR10- and similar groups. This term includes, for example, methylene (-CH2-), ethyl (-CH2CH2-), propyl (-CH2CH2CH2-), isopropyl (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-) and similar groups.

[0026] "Substituted alkyl" refers to an alkyl group having one to three hydrogen atoms substituted with substituents, wherein such substituents are as described for carbon in the definition of "substituted" below.

[0027] The term "alkane" refers to alkyl groups and alkyl groups as defined herein.

[0028] The terms “alkylaminoalkyl”, “alkylaminoalkenyl” and “alkylaminoynyl” refer to the R'NHR”- group, where R' is an alkyl group as defined herein and R” is an alkylene, alkenyl or alkyne group as defined herein.

[0029] The terms “alkylaryl” or “aryl” refer to -alkyl-aryl and -substituted alkyl-aryl groups, wherein alkyl, substituted alkyl and aryl are as defined herein.

[0030] "Alkoxy" refers to an -O-alkyl group, where the alkyl group is as defined herein. Alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tertiary butoxy, secondary butoxy, n-pentoxy, and similar groups. The term "alkoxy" also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and ynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and ynyl groups are as defined herein.

[0031] The term “substituted alkoxy” refers to substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O- and substituted alkynyl-O- groups, wherein the substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl groups are as defined herein.

[0032] The term "alkoxyamine" refers to the -NH-alkoxy group, where alkoxy is as defined herein.

[0033] The term “haloalkoxy” refers to an alkyl-O- group in which one or more hydrogen atoms of the alkyl group have been replaced by a halogen group and include (for example) groups such as trifluoromethoxy and similar groups.

[0034] The term "haloalkyl" refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms of the alkyl group have been replaced by a halogen group. Examples of such groups include (but are not limited to) fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl and similar groups.

[0035] The term “alkylalkoxy” refers to -alkyl-O-alkyl, alkyl-O-substituted alkyl, substituted alkyl-O-alkyl and substituted alkyl-O-substituted alkyl groups, wherein alkyl, substituted alkyl, alkyl and substituted alkyl are as defined herein.

[0036] The term “alkoxy-thioalkoxy” refers to -alkyl-S-alkyl, alkyl-S-substituted alkyl, substituted alkyl-S-alkyl, and substituted alkyl-S-substituted alkyl groups, wherein the alkyl, substituted alkyl, alkyl and substituted alkyl groups are as defined herein.

[0037] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms and having at least one, more preferably 1 to 2, unsaturated double bond sites. This term includes, for example, di-vinyl, allyl, and but-3-en-1-yl. This term includes cis and trans isomers or mixtures of such isomers.

[0038] The term "substituted alkenyl" refers to an alkenyl group having 1 to 5 substituents or 1 to 3 substituents as defined herein, wherein the substituents are selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acetyl, acetamino, acetoxy, amino, substituted amino, aminoacetyl, aminoacetoxy, oxoamineacetyl, azide, cyano, halogen, hydroxyl, sideoxy, thionyl, and carboxyl. Carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclicoxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamine, alkoxyamine, nitro, SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0039] "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms and having at least 1, more preferably 1 to 2, triple-bonded unsaturated sites. Examples of such alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH2C≡CH).

[0040] The term "substituted alkynyl" refers to an alkynyl group having 1 to 5 substituents, or 1 to 3 substituents, as defined herein, wherein the substituents are selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acetyl, acetamino, acetoxy, amino, substituted amino, aminoacetyl, aminoacetoxy, oxoamineacetyl, azide, cyano, halogen, hydroxyl, sideoxy, thionyl, and carboxyl. Carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclicoxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamine, alkoxyamine, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0041] "Alkyneoxy group" refers to the -O-alkynyl group, where the alkynyl group is as defined herein. Alkyneoxy groups include, for example, acetyloxy, propynyloxy, and similar groups.

[0042] "Aliyl" refers to HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkenyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-. Groups, including alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycles and substituted heterocycles as defined herein. For example, acetyl includes the "acetyl" group CH3C(O)-.

[0043] "Acidylamino" refers to -NR20C(O)alkyl, -NR20C(O)substituted alkyl, NR20C(O)cycloalkyl, -NR20C(O)substituted cycloalkyl, -NR20C(O)cycloalkenyl, -NR20C(O)substituted cycloalkenyl, -NR20C(O)alkenyl, -NR20C(O)substituted alkenyl, -NR20C(O) ynyl, -NR20C(O) substituted alkenyl, -NR20C(O) heteroaryl, -NR20C (O) substituted heteroaryl, -NR20C(O) heterocycle and -NR20C(O) substituted heterocyclic group, wherein R20 is hydrogen or alkyl, and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0044] "Aminocarbonyl" or the term "aminoacetyl" refers to the -C(O)NR21R22 group, wherein R21 and R22 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, and wherein R21 and R22 are, where appropriate, linked to the nitrogen to which they are attached to form a heterocycle or substituted heterocycle group, and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0045] "Aminocarbonylamino" refers to the –NR21C(O)NR22R23 group, wherein R21, R22 and R23 are independently selected from hydrogen, alkyl, aryl or cycloalkyl, or two of the R groups are linked to form a heterocyclic group.

[0046] The term “alkoxycarbonylamine” refers to a -NRC(O)OR group, wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic, wherein the alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic groups are as defined herein.

[0047] The term “aceoxy” refers to alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O- and heterocyclic-C(O)O- groups, wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0048] "Aminosulfonyl" refers to the -SO2NR21R22 group, wherein R21 and R22 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R21 and R22 are, where appropriate, linked to a nitrogen to form a heterocycle or substituted heterocycle group, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0049] "Sulfoamino" refers to the -NR21SO2R22 group, wherein R21 and R22 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, and wherein R21 and R22 are, where appropriate, linked with the atoms to form a heterocycle or substituted heterocycle group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0050] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group having 6 to 18 carbon atoms and a monocyclic ring (such as a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthracene, and dihydroindenyl), wherein the condensed ring may be aromatic or non-aromatic if the link is via an atom of an aromatic ring. This term includes, for example, phenyl and naphthyl. Unless otherwise limited by the definition of the aryl substituent, such aryl groups may be substituted with 1 to 5 substituents, or 1 to 3 substituents selected from acetoxy, hydroxy, thiol, acetyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacetyl, acetylaminyl, alkylaryl, aryl aryl group, azide, carboxyl, carboxyalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, aminoalkyloxy, oxoamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalomethyl. In this case, an aryl group substituted with 1 to 5 substituents (e.g., as described herein) is called a "substituted aryl".

[0051] "Aryloxy" refers to an -O-aryl group, wherein the aryl group is as defined herein and includes (for example) phenoxy, naphthoxy and similar groups, including aryl groups that are substituted as defined herein.

[0052] "Amino group" refers to the -NH2 group.

[0053] The term “substituted amino group” refers to a -NRR group, wherein if at least one R is not hydrogen, each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic.

[0054] The term "azido group" refers to the -N3 group.

[0055] "Carboxyl group" or "carboxylate" refers to -CO2H or its salt.

[0056] "Carboxylate" or the term "carboxyalkyl" refers to -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-ynyl, -C(O)O-substituted alkenyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C( O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic and -C(O)O-substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocyclic systems are as defined herein.

[0057] "(Carboxylate)oxy" or "carbonate" refers to -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-ynyl, -OC(O)O-substituted alkenyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-cycloalkenyl, -OC(O)O-substituted cycloalkenyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic and -OC(O)O-substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocyclic systems are as defined herein.

[0058] "Cyano" or "nitrile" refers to -CN.

[0059] "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms and possessing a monocyclic or multiple cyclic rings (including fused rings, bridged rings, and spirocyclic systems). Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and similar groups. Such cycloalkyl groups include, for example, monocyclic structures (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and similar groups) or polycyclic structures (such as adamantyl and similar groups).

[0060] The term "substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5 substituents, or 1 to 3 substituents, wherein the substituent is selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acetyl, acetamino, acetoxy, amino, substituted amino, aminoacetyl, aminoacetoxy, oxoamineacetyl, azide, cyano, halogen, hydroxyl, side oxygen, thionyl Carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclicoxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamine, alkoxyamine, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0061] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group with 3 to 10 carbon atoms and having a monocyclic or polycyclic structure and at least one double bond, preferably having 1 to 2 double bonds.

[0062] The term "substituted cycloalkenyl" refers to a cycloalkenyl group having 1 to 5 substituents, or 1 to 3 substituents, wherein the substituent is selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acetyl, acetamino, acetoxy, amino, substituted amino, aminoacetyl, aminoacetoxy, oxoamineacetyl, azide, cyano, halogen, hydroxyl, ketone, thionyl, carboxyl, carboxyl alkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclicoxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamine, alkoxyamine, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0063] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group with 5 to 10 carbon atoms and having a monocyclic or polycyclic structure and at least one triple bond.

[0064] “Cycloalkoxy” refers to -O-cycloalkyl.

[0065] "Cycloalkenyl group" refers to -O-cycloalkenyl group.

[0066] "Halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0067] "Hydroxy" refers to the -OH group.

[0068] "Heteroaryl" refers to an aromatic group with 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Such heteroaryl groups may have a monocyclic ring (such as pyridyl, imidazolyl, or furanyl) or multiple condensed rings (e.g., groups such as indolizinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothiaphenyl) in the ring system, wherein if the linking point is via an atom of an aromatic ring, at least one ring in the ring system is aromatic and at least one ring in the ring system is aromatic. In certain embodiments, the nitrogen and / or sulfur ring atoms of the heteroaryl group are, where appropriate, oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. This term includes, for example, pyridyl, pyrroleyl, indolyl, phenylthio, and furanyl. Unless otherwise limited by the definition of the heteroaryl substituent, such heteroaryl groups may be substituted with 1 to 5 substituents, or 1 to 3 substituents, wherein the substituents are selected from acetoxy, hydroxy, thiol, acetyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacetyl, acetylamino, and alkylaryl. aryl, aryloxy, azide, carboxyl, carboxyalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, aminoalkyloxy, oxoamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl and trihalomethyl. In this case, a heteroaryl group substituted with 1 to 5 substituents (e.g., as described herein) is called a "substituted heteroaryl".

[0069] The term “heteroaryl” refers to an -alkyl-heteroaryl group, wherein alkyl and heteroaryl are as defined herein. This term includes, for example, pyridylmethyl, pyridylethyl, indolylmethyl and similar groups.

[0070] "Heteroaryl group" refers to -O-heteroaryl group.

[0071] "Heterocyclic," "heterocyclic alkyl," and "heterocyclic group" refer to a saturated or unsaturated group having a monocyclic or multiple condensed rings (including fused rings, bridged rings, and spirocyclic systems) and 3 to 20 ring atoms (including 1 to 10 heteroatoms). These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, wherein, if the linking point is via a non-aromatic ring, one or more of these rings in a fused ring system may be cycloalkyl, aryl, or heteroaryl. In certain embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are, where appropriate, oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety.

[0072] Examples of heterocyclic and heteroaryl compounds include (but are not limited to) tetrahydroacrylamide, pyrrole, imidazole, pyrazole, pyridine, pyridine, pyrimidine, pyrazine, indoleazine, isoindole, indole, dihydroindole, indazole, purine, quinazine, isoquinoline, quinoline, pyrazine, naphthylpyridine, quinoline, quinazoline, phenoline, pteridine, carbazole, caroline, phenidine, acridine, phenoline, isothiazole, phenidine, isothiazole, phenidine, phenothiazide, imidazoline, piperidine, piperidine, dihydroindole, phthalimide 1,2,3,4-Tetrahydroisoquinoline, 4,5,6,7-Tetrahydrobenzo[b]thiophene, thiazole, tetrahydrothiazole, thiophene, benzo[b]thiophene, thiomorpholinyl, thiomorpholinyl (also known as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl and similar groups.

[0073] Unless otherwise limited by the definition of the heterocyclic substituent, such heterocyclic groups may be substituted with 1 to 5, or 1 to 3, substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acetyl, acetamino, acetoxy, amino, substituted amino, aminoacetyl, aminoacetoxy, oxoamineacetyl, azide, cyano, halogen, hydroxyl, sideoxy, thionyl, carboxyl alkyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclicoxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamine, alkoxyamine, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl and fused heterocycles.

[0074] "Heterocyclic group" refers to the -O-heterocyclic group.

[0075] The term "heterocyclic thio group" refers to a heterocyclic -S- group.

[0076] The term “heterocyclene” refers to a biradical group formed from a heterocycle, as defined herein.

[0077] The term "hydroxylamine" refers to the -NHOH group.

[0078] "Nitro" refers to the -NO2 group.

[0079] "Side oxygen group" refers to an atom (=O).

[0080] "Sulfoyl" refers to SO2-alkyl, SO2-substituted alkyl, SO2-alkenyl, SO2-substituted alkenyl, SO2-cycloalkyl, SO2-substituted cycloalkyl, SO2-cycloalkenyl, SO2-substituted cycloalkenyl, SO2-aryl, SO2-substituted aryl, SO2-heteroaryl, SO2-substituted heteroaryl, SO2-heterocyclic, and SO2-substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Sulfoyl includes (for example) methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0081] “Sulfooxy” refers to -OSO2-alkyl, OSO2-substituted alkyl, OSO2-alkenyl, OSO2-substituted alkenyl, OSO2-cycloalkyl, OSO2-substituted cycloalkyl, OSO2-cycloalkenyl, OSO2-substituted cycloalkenyl, OSO2-aryl, OSO2-substituted aryl, OSO2-heteroaryl, OSO2-substituted heteroaryl, OSO2-heterocyclic and OSO2-substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0082] The term “aminocarbonyloxy” refers to the -OC(O)NRR group, wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic, wherein the alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0083] "Thiol" refers to the -SH group.

[0084] "Thioxo" or the term "thioketo" refers to the atom (=S).

[0085] "Alkylthio" or the term "thioalkoxy" refers to an -S-alkyl group, where the alkyl is as defined herein. In certain embodiments, sulfur can be oxidized to -S(O)-. The sulfoxide can exist in the form of one or more stereoisomers.

[0086] The term "substituted thioalkoxy" refers to an -S-substituted alkyl group.

[0087] The term "thioaryloxy" refers to an aryl-S- group, where the aryl is as defined herein, including a substituted aryl group as defined herein as appropriate.

[0088] The term "thioheteroaryloxy" refers to a heteroaryl-S- group, where the heteroaryl is as defined herein, including a substituted aryl as defined herein as appropriate.

[0089] The term "thioheterocyclyloxy" refers to a heterocyclyl-S- group, where the heterocyclyl group is as defined herein, including a substituted heterocyclyl group as defined herein as appropriate.

[0090] Except as disclosed herein, when the term "substituted" is used to modify a specified group or radical, it may also mean that one or more hydrogen atoms in the specified group or radical are independently replaced by the same or different substituents as defined below.

[0091] Unless otherwise specified, substituents used to replace one or more hydrogens on a saturated carbon atom of the designated group or groups, in addition to the groups disclosed for individual terms herein, (any two hydrogens on a single carbon may be replaced by =O, =NR70, =N-OR70, =N2 or =S) are -R60, halo, =O, -OR70, -SR70, -NR80R80, trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R70, -SO2O-M+, -SO2OR70, -OSO2R70, -OSO2O-M+, -OSO2OR70, -P(O)(O-)2(M+)2, -P(O)(OR70)O-M+, -P(O)(OR70)2, -C(O)R70, -C(S)R70, -C(NR70)R70, -C(O)O-M+, -C(O)OR70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OC(O)O-M+, -OC(O)OR70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2-M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70 and -NR70C(NR70)NR80R80, where R60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heteroalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R70 is independently hydrogen or R60; each R80 is independently R70, or two R80s together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered heteroalkyl group, where the heteroalkyl group may optionally contain 1 to 4 additional heteroatoms the same or different selected from the group consisting of O, N and S, where N may have a -H or C1-C3 alkyl substituent; and each M+ is a counter ion with a net single positive charge. Each M+ may independently be (for example) an alkali metal ion (such as K+, Na+, Li+); an ammonium ion (such as +N(R60)4) or an alkaline earth metal ion (such as [Ca2+]0.5, [Mg2+]0.5 or [Ba2+]0.5) (the subscript 0.5 indicates that one counter ion of such divalent alkaline earth metal ions may be the ionized form of the compounds of the invention, and the other counter ion (such as chloride) or two ionized compounds disclosed herein may be used as the counter ion of such divalent alkaline earth metal ions, or the doubly ionized compounds of the invention may be used as the counter ion of such divalent alkaline earth metal ions).As a specified example, -NR80R80 is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperidyl, 4N-methyl-piperid-1-yl, and N-quinolyl.

[0092] In addition to the disclosures herein, unless otherwise indicated, the substituent groups for the hydrogens on the unsaturated carbons in "substituted" alkene, alkyne, aryl, and heteroaryl groups are -R60, halo, -O-M+, -OR70, -SR70, S-M+, -NR80R80, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R70, -SO3 -M+, -SO3R70, -OSO2R70, -OSO3 -M+, -OSO3R70, -PO3 -2(M+)2, -P(O)(OR70)O-M+, -P(O)(OR70)2, -C(O)R70, -C(S)R70, -C(NR70)R70, -CO2 -M+, -CO2R70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OCO2 -M+, -OCO2R70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2 -M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70, and -NR70C(NR70)NR80R80, where R60, R70, R80, and M+ are as previously defined, provided that in the case of a substituted alkene or alkyne, these substituents are not -O-M+, -OR70, -SR70, or -S-M+.

[0093] Except for the groups disclosed for the individual terms herein, unless otherwise indicated, the substituents on the hydrogen on the nitrogen atom in a "substituted" heteroalkyl and cycloheteroalkyl group are -R60, -O-M+, -OR70, -SR70, -S-M+, -NR80R80, trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R70, -S(O)2O-M+, -S(O)2OR70, -OS(O)2R70, -OS(O)2O-M+, -OS(O)2OR70, -P(O)(O-)2(M+)2, -P(O)(OR70)O-M+, -P(O)(OR70)(OR70), -C(O)R70, -C(S)R70, -C(NR70)R70, -C(O)OR70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OC(O)OR70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70C(O)OR70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70 and -NR70C(NR70)NR80R80, wherein R60, R70, R80 and M+ are as previously defined.

[0094] Except as disclosed herein, in certain embodiments, a substituted group has 1, 2, 3 or 4 substituents, 1, 2 or 3 substituents, 1 or 2 substituents or 1 substituent.

[0095] Unless otherwise indicated, the naming of substituents not specifically defined herein is accomplished by naming the terminal portion of the functionality, followed by naming the adjacent functionality toward the point of attachment. For example, the substituent "arylalkoxycarbonyl" refers to the (aryl)-(alkyl)-O-C(O)- group.

[0096] With respect to any group disclosed herein that contains one or more substituents, it should of course be understood that such groups do not contain any substitutions or substitution patterns that are spatially unfeasible and / or synthetically infeasible. In addition, the subject compounds include all stereochemical isomers resulting from the substitution of such compounds.

[0097] "Stereoisomers" refer to compounds having the same atomic connectivity but different spatial arrangements of atoms. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers and diastereomers.

[0098] It will be understood that the term "or its salts or solvates or stereoisomers" is intended to include all permutations of salts, solvates, and stereoisomers, such as solvates of pharmaceutically acceptable salts of stereoisomers of the target compound. The term "or its salts" is intended to include all permutations of salts. The term "or its pharmaceutically acceptable salts" is intended to include all permutations of salts. The term "or its solvates" is intended to include all permutations of solvates. The term "or its stereoisomers" is intended to include all permutations of stereoisomers. The term "or its tautomers" is intended to include all permutations of tautomers. Therefore, (for example) it is thus understood that it is intended to include solvates of pharmaceutically acceptable salts of tautomers of stereoisomers of the target compound.

[0099] As used herein, the term "isolated" is intended to describe a compound of interest in an environment different from that of a naturally occurring compound. "Isolated" is intended to include compounds in samples substantially rich in the compound of interest and / or wherein the compound of interest has been partially or substantially purified.

[0100] Before further describing the invention, it should be understood that the invention is not limited to the specific embodiments described, and therefore variations are possible. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting, as the scope of the invention is limited only by the scope of the appended patent applications.

[0101] When providing numerical ranges, it should be understood that, unless the context explicitly indicates otherwise, all intermediate values ​​between the upper and lower limits of the range up to one-tenth of the lower limit, as well as any other specified or intermediate values ​​within the specified range, are included in this invention. The upper and lower limits of such smaller ranges may be independently included within those smaller ranges and are also included in this invention, subject to any express exclusions within the specified range. When the specified range includes one or both of these limits, the range excluding one or both of those included limits is also included in this invention.

[0102] It should be understood that certain features of the invention described in the context of a single embodiment for clarity may also be provided in combinations of single embodiments. Conversely, for brevity, various features of the invention described in the context of a single embodiment may also be provided individually or in any suitable sub-combination. The invention specifically covers all combinations of embodiments of the invention, and discloses them herein as individually and exhaustively as each combination covers the subject matter, wherein the subject matter is, for example, a compound of a stable compound (i.e., a compound that can be manufactured, isolated, characterized, and tested for biological activity). Furthermore, the invention also specifically covers all sub-combinations of various embodiments and their elements (e.g., elements of chemical groups listed in embodiments describing such variables), and discloses them herein as individually and exhaustively as each such sub-combination is disclosed herein.

[0103] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention pertains. While any similar or equivalent methods and materials described herein may also be used in the practice or testing of this invention, methods and materials of interest are described here. All publications mentioned herein are incorporated herein for reference in order to disclose and describe methods and / or materials relating to the cited publications.

[0104] It must be noted that, as used herein and in the appended claims, the singular forms “a” and “the” include the plural references unless the context clearly indicates otherwise. It should also be noted that the claims may be designed to exclude any selected technical elements. Therefore, this statement is intended as a priori basis for the use of specialized terms such as “unique,” ​​“only,” and similar words relating to the detailed description of the technical features of the claims, or for the use of negative limiting terms.

[0105] It should be recognized that certain features of the invention described in the context of individual embodiments for clarity may also be provided in combinations of individual embodiments. Conversely, various features of the invention described in the context of individual embodiments for brevity may also be provided individually or in any suitable sub-combination.

[0106] The publications discussed herein provide only their disclosures prior to the date of this application. Nothing herein should be construed as an admission that the invention is not entitled to pre-existing inventions. Furthermore, the publication dates provided may differ from the actual publication dates, which may require independent verification.

[0107] Unless otherwise specified, the methods and techniques of this particular embodiment are generally based on those well-known in the art and as described in the various general and more specific references cited and discussed throughout this specification. See, for example, Loudon, Organic Chemistry, 4th Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, Wiley-Interscience, 2001.

[0108] The nomenclature used to name the target compounds in this document is described in the examples herein. Where possible, this nomenclature was generally obtained using commercially available AutoNom software (MDL, San Leandro, Calif.).

[0109] Numerous general references are available to provide well-known chemical synthetic schemes and conditions that can be used to synthesize the revealed compounds (see, for example, Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, 4th ed., New York: Longman, 1978).

[0110] The compounds described herein can be purified by any method known in the art, including chromatographic methods such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases and ion exchange resins. See, for example, Introduction to Modern Liquid Chromatography, 2nd edition, edited by LR Snyder and JJ Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, edited by Stahl, Springer-Verlag, New York, 1969.

[0111] During any procedure for preparing the disclosed compounds, it may be necessary and / or desirable to protect any sensitive or reactive groups on the relevant molecules. This can be achieved through standard work such as that of TW Greene and PGM Wuts. [, , This is achieved using the conventional protecting groups described in "Protective Groups in Organic Synthesis", 4th Edition, Wiley, New York 2006. These protecting groups can be removed using methods known in the art at appropriate subsequent stages.

[0112] The compounds described herein may contain one or more palmar centers and / or double bonds, and therefore may exist in stereoisomers, such as double-bonded isomers (i.e., geometric isomers), enantiomers, or diastereomers. Therefore, all possible enantiomers and stereoisomers of these compounds, including pure stereoisomers (e.g., pure geometric, pure enantiomers, or pure diastereomers) and mixtures of enantiomers and stereoisomers, are included in the description of the compounds herein. Mixtures of enantiomers and stereoisomers can be resolved into their component enantiomers or stereoisomers using separation techniques or palmar synthesis techniques well known to those skilled in the art. These compounds may also exist in several tautomeric forms, including enol forms, ketone forms, and mixtures thereof. Therefore, the chemical structures described herein cover all possible tautomeric forms of the compounds described. The compounds described also include isotopically labeled compounds, in which the atomic masses of one or more atoms differ from those conventionally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include (but are not limited to) 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, etc. The compounds may exist in solvated and solvent forms, including hydrated forms. Generally, the compounds may be hydrated or solvated. Some compounds may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the purposes contemplated herein and are intended to be within the scope of this disclosure.

[0113] This disclosure includes the crystalline solid form of 3-palmitoyl-amino-1,2-propanediol (Formula I): (I).

[0114] The term "crystallization" is used herein in its conventional sense to refer to a solid material in which the molecules forming the solid are arranged in a highly ordered microscopic geometry (e.g., forming an ordered lattice structure) extending along three dimensions. In specific embodiments, the crystalline solids described herein are crystalline, characterized by an undefined structural order and microscopic configuration lacking a regular geometric arrangement in three dimensions.

[0115] In specific embodiments, the crystalline solid of 3-palmitinyl-amino-1,2-propanediol has a polymorph purity (i.e., as demonstrated by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC), described in more detail below), with a polymorph purity of 90% or greater, such as 95% or greater, such as 97% or greater, such as 99% or greater, including 99.9% or greater. In several specific embodiments, the polymorphic crystal system of 3-palmitinyl-amino-1,2-propanediol described herein exists in the crystalline solid with 100% purity. In several specific embodiments, compared to other polymorphs of crystalline and amorphous 3-palmitoyl-amino-1,2-propanediol, the polymorph of the crystalline solid of 3-palmitoyl-amino-1,2-propanediol provided herein exhibits improved solubility and reactivity.

[0116] In the specific embodiment, the isopolymorphic crystal form of the crystalline solid of 3-palmitoyl-amino-1,2-propanediol exhibits an X-ray powder diffraction (XRPD) pattern containing a peak located at approximately 8.25° 2Å. For a given crystal form, the relative intensity of this diffraction peak can vary due to the orientation of the crystal relative to X-rays, such as due to the crystal morphology. In the specific embodiment, the intensity of the X-ray powder diffraction peak at 2Å can vary with different crystals, but the characteristic peak position of the isopolymorphic crystal form will remain the same. In certain specific embodiments, the isopolymorphic crystal form of the 3-palmitinyl-amino-1,2-propanediol crystalline solid has an X-ray powder diffraction (XRPD) pattern containing one or more peaks located at approximately 2.75° 2Å; approximately 6° 2Å; approximately 3.8° 2Å; approximately 15° 2Å; approximately 26.3° 2Å; approximately 30.5° 2Å; and approximately 33.1° 2Å. In some cases, the isopolymorphic crystal form of the 3-palmitinyl-amino-1,2-propanediol crystalline solid provided herein is characterized by a single weight loss step performed by thermogravimetric analysis (TGA). In some cases, this weight loss step begins at approximately 200.5ºC.

[0117] Differential scanning calorimetry (DSC) measures the transition temperature of a crystalline solid as it absorbs or releases heat due to structural changes or melting. DSC is used to distinguish different crystal forms (e.g., different polymorphs). Different crystal forms can be identified based on their distinct characteristic transition temperatures. In several specific embodiments, by differential scanning calorimetry (DSC), the polymorph of the 3-palmitinyl-amino-1,2-propanediol crystalline solid provided herein exhibits a first endothermic reaction at approximately 79.3 °C and a second endothermic reaction at approximately 102.5 °C. In these specific embodiments, the second endothermic reaction is a single-peak endothermic reaction.

[0118] A method is also provided for preparing the homopolymorphic crystal form of the crystalline solid of 3-palmitinyl-amino-1,2-propanediol. In carrying out the method according to certain embodiments, 3-palmitinyl-amino-1,2-propanediol is contacted with one or more solvents to produce a 3-palmitinyl-amino-1,2-propanediol composition and precipitated to produce a crystalline solid of 3-palmitinyl-amino-1,2-propanediol. In some embodiments, the solvent is a polar solvent. In other embodiments, the solvent is a non-polar solvent. In still other embodiments, the solvent is a mixture of polar and non-polar solvents. Solvents of interest may include (but are not limited to) tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethylsulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), and combinations thereof. In some cases, the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, and dichloromethane. In some cases, the solvent is tetrahydrofuran.

[0119] In certain specific embodiments, the 3-palmitinyl-amino-1,2-propanediol system is contacted with the solvent in the presence of a base. In some cases, the base is an organic base. Among other organic bases, the organic base used may include (but is not limited to) triethylamine, triethanolamine, ammonia, arginine, benzylethylenediamine, ethylenediamine, meglumine, procaine, N-methylreduced glucosamine, piperazine, trimethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, ethanolamine, diisopropylamine, diisopropylethylamine, 1,8-bis(dimethylamino)naphthalene (proton sponge), imidazole, 1,8-diacrylbicyclo[5.4.0]undec-7-ene (DBU), 2,4,6-trimethylpyridine (Colin base), potassium carbonate, sodium methoxide, tetramethylethylenediamine (TMEDA), and dimethylaminoethanol. In some cases, the base is selected from tetramethylethylenediamine (TMEDA), 1,8-bis(dimethylamino)naphthalene (proton sponge), and triethylamine. In some cases, the base is triethylamine. The amount of base in contact with the 3-palmitinyl-amino-1,2-propanediol can vary from 1 equivalent to 4 equivalents of the base relative to the 3-palmitinyl-amino-1,2-propanediol system, such as from 1.5 equivalents to 3.5 equivalents, including about 3 equivalents of the base relative to 3-palmitinyl-amino-1,2-propanediol.

[0120] To precipitate the crystalline solid of 3-palmitinyl-amino-1,2-propanediol, the 3-palmitinyl-amino-1,2-propanediol solvent composition (with or without an alkali) can be heated to generate a hot 3-palmitinyl-amino-1,2-propanediol solvent composition, followed by cooling to form the crystalline solid of 3-palmitinyl-amino-1,2-propanediol. The 3-palmitinyl-amino-1,2-propanediol solvent composition can be heated to temperatures ranging from 10°C to 60°C, such as 15°C to 55°C, such as 25°C to 55°C, including 50°C. The thermal composition can be maintained at a relatively high temperature for a variable period of time, such as 1 minute or longer, such as 2 minutes or longer, such as 5 minutes or longer, such as 10 minutes or longer, such as 15 minutes or longer, such as 30 minutes or longer, including 60 minutes or longer. In some specific embodiments, the 3-palmitoyl-amino-1,2-propanediol solvent is heated to a temperature sufficient to dissolve the 3-palmitoyl-amino-1,2-propanediol in the solvent. All or part of the 3-palmitinyl-phenylamine-1,2-propanediol may be dissolved in the solvent (e.g., the 3-palmitinyl-phenylamine-1,2-propanediol solvent composition may change from a clear solution to a slurry composition when viewed with the naked eye), such as 25% by weight or more of the 3-palmitinyl-phenylamine-1,2-propanediol may be dissolved in the solvent, such as 50% or more, such as 75% or more, such as 90% or more, such as 95% or more, such as 97% or more, including 99% or more.

[0121] In specific embodiments, the crystalline solid system of 3-palmitinyl-nitro-1,2-propanediol is precipitated by cooling the hot 3-palmitinyl-nitro-1,2-propanediol solvent composition. The composition can be cooled to 20°C to 40°C, such as from 15°C to 35°C, including temperatures of about 30°C. In some specific embodiments, the method includes removing a certain amount of solvent from the composition, such as by rotary evaporation or by precipitating the crystalline solid of 3-palmitinyl-nitro-1,2-propanediol under an inert gas (N2 or argon).

[0122] In some specific embodiments, the crystalline solid system of 3-palmitinyl-amino-1,2-propanediol is separated by filtration (e.g., vacuum filtration), or the solvent can be removed by heating or rotary evaporation. In some specific embodiments, the crystalline solid system of 3-palmitinyl-amino-1,2-propanediol is separated by drying under a nitrogen atmosphere at room temperature or under vacuum.

[0123] This disclosure also includes the crystalline solid of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (Formula III): (III) DMTr stands for dimethoxytriphenylmethyl.

[0124] In some cases, the crystalline solid of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is a single crystal of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. The term "single crystal" is used herein in its conventional sense to refer to a single-crystal solid in which the crystal lattice of the entire sample is continuous and unbroken to the sample edge, without grain boundaries. In certain specific embodiments, the single crystal of interest is a single-crystal solid of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane of sufficient size and quality for X-ray crystallography (XRC) and X-ray crystal structure determination.

[0125] In specific embodiments, the purity of the crystalline solid of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (e.g., a single crystal of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane) is 90% or greater, such as 95% or greater, such as 97% or greater, such as 99% or greater, including 99.9% or greater. In several specific embodiments, 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is present in the crystalline solid with 100% purity. In several specific embodiments, the crystalline solids of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (e.g., single crystals of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane) provided herein exhibit improved solubility and reactivity compared to other crystalline forms (e.g., powders) or amorphous solids of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.

[0126] According to a specific embodiment, the crystalline solid system of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is monoclinic. Each unit lattice in this crystalline solid contains two different configurations of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (e.g., curved and linear configurations). In the specific embodiment, the 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane configurations (curved and linear) exist in a 1:1 ratio within the unit lattice. Each unit lattice in this crystalline solid contains four 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane molecules. In several specific embodiments, the unit lattice dimensions are approximately 8.44 μm x approximately 26.56 μm x approximately 10.06 μm, with a unit lattice volume of approximately 2254.8 μm³. The target 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane crystalline solid has a density of approximately 1.2 g / cm³ to approximately 1.3 g / cm³ and a purity of 95% or higher.

[0127] A method is also provided for preparing crystalline solids (e.g., single crystals) of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. In carrying out the method according to certain specific embodiments, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is contacted with one or more solvents to produce a 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane composition and precipitated to produce crystalline solids of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane, such as one or more single crystals of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.

[0128] In some specific embodiments, the solvent is a polar solvent. In other specific embodiments, the solvent is a nonpolar solvent. In still other specific embodiments, the solvent is a mixture of polar and nonpolar solvents. Among other solvents, solvents of interest may include (but are not limited to) methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, terbutanol, dichloromethane, trichloromethane, carbon tetrachloride, 1,4-dimethylalkanes, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, 2-methylbut-2-ol (tAmOH), dimethyl sulfoxide, pentane, hexane, heptane, and octane. In some specific embodiments, the solvent is a mixture of dichloromethane and pentane.

[0129] To precipitate the 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane crystalline solid, the 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane solvent composition can be first heated to generate a thermal 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane solvent composition, and then cooled to form the 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane crystalline solid. The 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane solvent composition can be heated to temperatures ranging from 10°C to 60°C, such as from 15°C to 55°C, such as from 25°C to 55°C, including 50°C. The thermal composition can be maintained at a higher temperature for a variable period of time, such as 1 minute or longer, such as 2 minutes or longer, such as 5 minutes or longer, such as 10 minutes or longer, such as 15 minutes or longer, such as 30 minutes or longer, including 60 minutes or longer. In certain specific embodiments, the 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane solvent is heated to a temperature sufficient to dissolve the 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane in the solvent.

[0130] In other specific embodiments, the crystalline solid system of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is precipitated by cooling the hot 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane solvent composition. The composition can be cooled to temperatures ranging from -20°C to 20°C, such as from -19°C to 19°C, such as from -18°C to 18°C, such as from -17°C to 17°C, such as from -16°C to 16°C, such as from -15°C to 15°C, such as from -14°C to 14°C, such as from -13°C to 13°C, such as from -12°C to 12°C, such as from -11°C to 11°C, including temperatures from -10°C to 10°C. In some specific embodiments, the method includes removing the solvent by the composition, such as by rotary evaporation or under an inert gas (N2 or argon), to precipitate the crystalline solid of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.

[0131] The crystalline solid of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane can be separated by filtration (e.g., vacuum filtration), or by removing the solvent through heating or rotary evaporation. In certain embodiments, the crystalline solid system of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is separated by drying under a nitrogen atmosphere at room temperature or under vacuum.

[0132] A method for preparing 3-palmitinyl-amide-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane from 3-palmitinyl-amide-1,2-propanediol is also described. In carrying out the method according to certain specific embodiments, a solvent is contacted with a crystalline solid of 3-palmitinyl-amide-1,2-propanediol to produce a precursor composition; and the precursor composition is contacted with a composition containing dimethoxytriphenylmethyl chloride to produce a composition having 3-palmitinyl-amide-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.

[0133] In specific embodiments, solvents of interest may include (but are not limited to) tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate (iPrOAc), ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), N-methyl-2-pyrrolidone (NMP), or combinations thereof. In some cases, the solvent system is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP). In some cases, the solvent system is selected from methyltetrahydrofuran, tetrahydrofuran, and dichloromethane.

[0134] In several specific embodiments, the precursor composition includes an additive. For example, the additive may be calcium oxide, magnesium oxide, boric acid, tetrabutylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP), copper chloride (CuCl2), ytterbium(III) chloride (YbCl3), or 1,4-diacylbicyclo[2.2.2]octane (DABCO). In some cases, the additive is selected from tetrabutylammonium fluoride (TBAF), magnesium oxide, and boric acid. In some cases, the additive is magnesium oxide. The amount of the additive in the precursor composition can vary, ranging from 0.05 equivalents to 1 equivalent of 3-palmitinyl-amino-1,2-propanediol, such as from 0.1 equivalents to 0.5 equivalents, including about 0.3 equivalents of the additive relative to 3-palmitinyl-amino-1,2-propanediol.

[0135] In several specific embodiments, the precursor composition is further contacted with a base. In some cases, the base is an organic base. In several specific embodiments, the precursor composition is contacted with the protecting group in the presence of a base selected from 1,8-bis(dimethylamino)naphthalene (proton sponge), imidazole, 1,8-diacabisocyclo[5.4.0]undec-7-ene (DBU), 2,4,6-trimethylpyridine (Colin base), triethylamine (TEA), potassium carbonate, sodium methoxide, tetramethylethylenediamine (TMEDA), dimethylaminoethanol, and combinations thereof. In several cases, the base is selected from 1,8-bis(dimethylamino)naphthalene (proton sponge), tetramethylethylenediamine (TMEDA), and triethylamine (TEA). In some cases, the base is triethylamine.

[0136] The amount of base in contact with the 3-palmitinyl-amino-1,2-propanediol precursor composition can vary, ranging from 0.5 equivalents to 3.5 equivalents of base relative to the 3-palmitinyl-amino-1,2-propanediol system, such as from 0.75 equivalents to 1.95 equivalents, such as from 1 equivalent to 1.9 equivalents, such as from 1.1 equivalents to 1.85 equivalents, such as from 1.15 equivalents to 1.80 equivalents, such as from 1.25 equivalents to 1.75 equivalents, including contact of 3-palmitinyl-amino-1,2-propanediol with 1.5 equivalents of base.

[0137] In several embodiments, the precursor composition is formed and maintained at ambient temperature. In other embodiments, the precursor composition is formed and maintained at higher temperatures, such as from 25°C to 40°C, such as from 27.5°C to 45°C, including from 30°C to 35°C, such as about 30°C. In some embodiments, the precursor composition is formed at a first temperature and then changed to a second temperature. In one embodiment, the precursor composition is formed at ambient temperature and then changed to a higher temperature, such as from 25°C to 40°C, such as from 27.5°C to 45°C, including from 30°C to 35°C, such as at about 30°C. In another embodiment, the precursor composition is formed at a higher temperature (e.g., about 50°C or higher) and cooled to a lower temperature (e.g., about 30°C) before being brought into contact with the protecting group.

[0138] In a specific embodiment, the precursor composition is contacted with a hydroxyl protecting group to produce 3-palmitoyl-amino-2-hydroxy-1-(protected hydroxyl)-propane. The hydroxyl protecting group can vary, and in some cases, it includes (but is not limited to): 1) alkyl ether type protecting groups, such as alkyl ethers, allyl ethers, triphenylmethyl ethers, dimethoxy-triphenylmethyl ethers, benzyl ethers, or p-methoxybenzyl ether protecting groups; 2) ester and carbonate type protecting groups, such as acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, neopentanoate, benzoate, p-methoxybenzoate, p-bromobenzoate, methyl carbonate, 9-(fluorenylmethyl)carbonate (Fmoc), allyl carbonate (Alloc), 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (Teoc), benzyl carbonate (Cbz), tributyl carbonate (Boc), or dimethylthiocarbamate (DMTC) protecting groups; 3) Acetal-type protecting groups, such as methoxymethyl ether (MOM), benzyloxymethyl ether (BOM), 2,2,2-trichloroethoxymethyl ether, 2-methoxymethyl ether (MEM), methyl thiomethyl ether (MTM), p-methoxybenzyloxymethyl ether (PMBM), 2-(trimethylsilyl)ethoxymethyl ether (SEM), tetrahydropiperanyl ether (THP) protecting groups; and 4) silicone ether-type protecting groups, such as trimethylsilyl (TMS), triethylsilyl (TES), isopropyl dimethylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), tributyldimethylsilyl (TBS), tributyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), tetraisopropyldisyloalkylene (TIPDS), or di-tert-butylsilane (DTBS) protecting groups. In some specific embodiments, the hydroxyl protecting group is a dimethoxy-triphenylmethyl protecting group.

[0139] The amount of hydroxyl protecting group in contact with the precursor composition can vary, ranging from 0.5 equivalents to 2 equivalents relative to 3-palmitoyl-amino-1,2-propanediol, such as from 0.75 equivalents to 1.5 equivalents, including about 1.4 equivalents of hydroxyl protecting group relative to 3-palmitoyl-amino-1,2-propanediol.

[0140] In several specific embodiments, the 3-palmitoyl-amino-1,2-propanediol used in the method for preparing 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is a crystalline solid of 3-palmitoyl-amino-1,2-propanediol. In certain specific embodiments, 3-palmitinyl-amino-1,2-propanediol is an allotropic crystal form of the crystalline solid of 3-palmitinyl-amino-1,2-propanediol, exhibiting X-ray powder diffraction (XRPD) patterns with one or more peaks at approximately 2.75° 2Ɵ; approximately 6° 2Ɵ; approximately 3.8° 2Ɵ; approximately 8.25° 2Ɵ; approximately 15° 2Ɵ; approximately 26.3° 2Ɵ; approximately 30.5° 2Ɵ and approximately 33.1° 2Ɵ.

[0141] The components used in the various steps of the method described herein may be purified or crude compositions, if required. The term "purified" is used in its conventional sense to refer to a composition that has undergone at least several separation or purification procedures, such as filtration or aqueous post-treatment of the reaction mixture. In some cases, purification includes liquid chromatography, recrystallization, distillation (e.g., azeotropic distillation), or other types of compound purification. In several specific embodiments, the reaction mixture is used in subsequent steps as a crude mixture in the method described herein, wherein the crude mixture has not undergone purification or other post-treatment of the reaction mixture. In some cases, the crude composition reaction mixture contains a compound of sufficient purity, such as 90% or higher, 95% or higher, 97% or higher, including 99% or higher, wherein the purity is determined by high-performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy (1H NMR), or a combination thereof.

[0142] The subject matter aspects (including specific embodiments) described herein may benefit individually or in combination with one or more other aspects or specific embodiments. Without limiting the description, certain non-limiting aspects of disclosure numbers 1-66 are provided below. Those skilled in the art will readily understand, upon reading this disclosure, the individual aspects numbered, or their combinations with any of the preceding or following individual aspects numbered. This is intended to support all combinations of such aspects, and is not limited to the combinations of aspects explicitly provided below:

[0143] 1. A crystalline solid of a compound of formula I: (I).

[0144] 2. The crystalline solid as described in item 1, having an X-ray powder diffraction (XRPD) pattern containing a peak located at approximately 8.25° 2 Å.

[0145] 3. The crystalline solid described in any of items 1-2 has an XRPD spectrum containing one or more peaks located at approximately 2.75° 2Ɵ; approximately 6° 2Ɵ; approximately 3.8° 2Ɵ; approximately 15° 2Ɵ; approximately 26.3° 2Ɵ; approximately 30.5° 2Ɵ; and approximately 33.1° 2Ɵ.

[0146] 4. A crystalline solid as described in any of items 1-3, wherein the thermogravimetric analysis (TGA) of the crystalline solid is characterized by a single weight loss step.

[0147] 5. The crystalline solid as described in item 4, wherein the weight loss step begins at approximately 200.5°C.

[0148] 6. The crystalline solid of any one of items 1-5, by differential scanning calorimetry (DSC), has a first endothermic temperature of about 79.3°C and a second endothermic temperature of about 102.5°C.

[0149] 7. As in item 6, the crystalline solid, wherein the second endothermic reaction is a single-peak endothermic reaction.

[0150] 8. A method comprising:

[0151] Contact the solvent with the compound of formula I: (I) To produce a precursor composition; and The precursor composition produces a crystalline solid of the compound of formula I.

[0152] 9. The method of paragraph 8, wherein the solvent is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP) and combinations thereof.

[0153] 10. The method of paragraph 9, wherein the solvent is selected from tetrahydrofuran, methyltetrahydrofuran and dichloromethane.

[0154] 11. The method of item 10, wherein the solvent is tetrahydrofuran.

[0155] 12. The method of any one of items 8-11, wherein the crystalline solid of compound I is produced comprises: The precursor composition is heated to a temperature of approximately 45°C to approximately 65°C; and The heated precursor composition is cooled to a temperature of about 25°C to about 35°C to produce a crystalline solid of the compound of formula I.

[0156] 13. The method of claim 12, wherein producing a crystalline solid of the compound of formula I comprises heating the precursor composition to a temperature of about 50°C and cooling the heated precursor composition to a temperature of about 30°C to produce a crystalline solid of formula I.

[0157] 14. The method of any one of items 8-13, wherein the compound of formula I is contacted with the solvent in the presence of a base.

[0158] 15. The method as described in item 14, wherein the base is triethylamine (TEA).

[0159] 16. The method of any one of items 8-15, wherein the crystalline solid of the compound of formula I has an X-ray powder diffraction (XRPD) pattern containing a peak located at about 8.25° 2 Å.

[0160] 17. The method of any one of items 8-16, wherein the crystalline solid of the compound of formula I has an XRPD spectrum containing one or more peaks located at about 2.75° 2Ɵ; about 6° 2Ɵ; about 3.8° 2Ɵ; about 15° 2Ɵ; about 26.3° 2Ɵ; about 30.5° 2Ɵ and about 33.1° 2Ɵ.

[0161] 18. The method of any one of items 8-17, wherein the crystalline solid of the compound of formula I is characterized by a single weight loss step performed by thermogravimetric analysis (TGA).

[0162] 19. The method of item 18, wherein the weightlessness step begins at approximately 200.48°C.

[0163] 20. The method of any one of items 8-19, wherein the crystalline solid of the compound of formula I exhibits a first endothermic temperature of about 79.3°C and a second endothermic temperature of about 102.5°C by differential scanning calorimetry (DSC).

[0164] 21. The method of item 20, wherein the second endothermic reaction is a single-peak endothermic reaction.

[0165] 22. A method comprising: Contact the solvent with the crystalline solid of compound I: (I) To produce a precursor composition; and The precursor composition is contacted with a composition containing dimethoxytriphenylmethyl chloride to produce a composition containing a compound of formula II: (II), DMTr stands for dimethoxytriphenylmethyl.

[0166] 23. The method of claim 22, wherein the precursor composition is contacted with dimethoxytriphenylmethyl chloride in the presence of a base.

[0167] 24. The method as described in item 23, wherein the base is an organic base.

[0168] 25. The method of paragraph 23, wherein the base system is selected from the group consisting of 1,8-bis(dimethylamino)naphthalene (proton sponge), imidazole, 1,8-diacabirocyclo[5.4.0]undec-7-ene (DBU), 2,4,6-trimethylpyridine (Colin base), triethylamine (TEA), potassium carbonate, sodium methoxide, tetramethylethylenediamine (TMEDA) and dimethylaminoethanol.

[0169] 26. The method of item 23, wherein the base is selected from 1,8-bis(dimethylamino)naphthalene (proton sponge), tetramethylethylenediamine (TMEDA), and triethylamine (TEA).

[0170] 27. The method as described in item 23, wherein the base is triethylamine (TEA).

[0171] 28. The method of any one of 22-27, wherein the precursor composition is contacted with dimethoxytriphenylmethyl chloride in the presence of an additive.

[0172] 29. The method of item 28, wherein the additive is selected from the group consisting of calcium oxide, magnesium oxide, boric acid, tetrabutylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP), copper chloride (CuCl2), ytterbium(III) chloride (YbCl3) and 1,4-diacylbicyclo[2.2.2]octane (DABCO).

[0173] 30. The method of item 29, wherein the additive is selected from tetrabutylammonium fluoride (TBAF), magnesium oxide and boric acid.

[0174] 31. The method of item 29, wherein the additive is magnesium oxide.

[0175] 32. The method of any one of items 22-31, wherein the solvent is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP) and combinations thereof.

[0176] 33. The method of item 32, wherein the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, acetonitrile, toluene, 2-methylbut-2-ol (tAmOH) and N-methyl-2-pyrrolidone (NMP).

[0177] 34. The method of item 32, wherein the solvent is selected from methyltetrahydrofuran, tetrahydrofuran and dichloromethane.

[0178] 35. The method of any one of items 22-34, wherein the crystalline solid of the compound of formula I has an X-ray powder diffraction (XRPD) pattern containing a peak located at about 8.25° 2 Å.

[0179] 36. The method of any one of items 22-35, wherein the crystalline solid of the compound of formula I has an XRPD spectrum containing one or more peaks located at about 2.75° 2Ɵ; about 6° 2Ɵ; about 3.8° 2Ɵ; about 15° 2Ɵ; about 26.3° 2Ɵ; about 30.5° 2Ɵ and about 33.1° 2Ɵ.

[0180] 37. The method of any one of items 22-36, wherein the crystalline solid of the compound of formula I is characterized by a single weight loss step performed by thermogravimetric analysis (TGA).

[0181] 38. The method of item 37, wherein the weightlessness step begins at approximately 200.48°C.

[0182] 39. The method of any one of items 22-38, wherein the crystalline solid of the compound of formula I exhibits a first endothermic reaction at 79.3 °C and a second endothermic reaction at about 102.5 °C by differential scanning calorimetry (DSC).

[0183] 40. The method of item 39, wherein the second endothermic reaction is a single-peak endothermic reaction.

[0184] 41. A crystalline solid of a compound of formula II: (II), DMTr stands for dimethoxytriphenylmethyl.

[0185] 42. A crystalline solid as described in item 41, wherein the crystalline solid system of formula II is monoclinic.

[0186] 43. A crystalline solid as described in any of items 40-42, wherein each unit lattice in the crystalline solid contains two different configurations of the compound of formula II.

[0187] 44. A crystalline solid as described in item 43, wherein each unit lattice contains extended and bent configurations of the compound of formula II.

[0188] 45. A crystalline solid as described in any of items 43-44, wherein the configurations of the compound of formula II are present in a 1:1 ratio.

[0189] 46. ​​A crystalline solid as described in any of items 41-45, wherein each unit lattice of the crystalline solid contains four molecules of compound II.

[0190] 47. A crystalline solid as described in item 46, wherein the size of the unit lattice is approximately 8.44 μm × approximately 26.56 μm × approximately 10.06 μm.

[0191] 48. A crystalline solid as described in item 47, wherein the volume of the unit lattice is approximately 2254.8 oz.

[0192] 49. The crystalline solid of item 48 has a density of about 1.2 g / cm³ to about 1.3 g / cm³.

[0193] 50. A crystalline solid as described in any of items 41-49, wherein the compound of formula II has a polymorph purity of 95% or higher.

[0194] 51. A method comprising: Contact a composition containing one or more solvents with a compound of formula III: (II); and To form single crystals of one or more compounds of formula II.

[0195] 52. The method of claim 51, wherein the composition comprises two different solvents.

[0196] 53. The method of claim 52, wherein the composition comprises a polar solvent and a nonpolar solvent.

[0197] 54. The method of item 53, wherein the polar solvent is dichloromethane.

[0198] 55. The method of any one of items 53-54, wherein the nonpolar solvent is pentane.

[0199] 56. The method of any one of claims 51-55, wherein the composition is contacted with the compound of formula II at a temperature of about 10°C to about 75°C.

[0200] 57. The method of claim 56, wherein the method comprises heating the composition sufficiently to dissolve the compound of formula II, and cooling the heated composition after dissolving the compound of formula II.

[0201] 58. The method of any one of items 51-57, wherein one or more of the single crystal systems formed are monoclinic.

[0202] 59. The method of any one of items 51-58, wherein each single crystal contains two different configurations of the compound of formula II.

[0203] 60. The method of paragraph 59, wherein each unit lattice of the single crystal contains extended and bent configurations of the compound of formula II.

[0204] 61. The method of any one of items 59-60, wherein each configuration of the compound of formula II exists in each unit lattice in a 1:1 ratio.

[0205] 62. The method of any one of items 51-61, wherein the unit lattice of each single crystal contains four molecules of compound of formula II.

[0206] 63. The method of item 62, wherein the size of the unit lattice is about 8.44 μm × about 26.56 μm × about 10.06 μm.

[0207] 64. The method of item 63, wherein the volume of the unit lattice is approximately 2254.8 oz.

[0208] 65. The method of any one of items 51-64, wherein the density of each formed single crystal is about 1.2 g / cm³ to about 1.3 g / cm³.

[0209] 66. The method of any one of items 51-65, wherein each formed single crystal has a polymorph purity of 95% or higher of the compound of formula II. [Example]

[0210] The following embodiments are provided to provide a complete disclosure and description of how to make and use the invention for those skilled in the art, and are not intended to limit the scope of the invention, or to represent all or a single experiment performed. Every effort has been made to ensure the accuracy of the figures used (e.g., amounts, temperatures, etc.), but some experimental errors and biases should be taken into account. Unless otherwise indicated, parts are by weight, molecular weights are by weight average, temperatures are expressed in Celsius, and pressures are at or near atmospheric pressure. “Average” means arithmetic mean. Standard abbreviations may be used, such as bp, base pair; kb, kilobase; pl, picoliter; s or sec, second; min, minute; h or hr, hour; aa, amino acid; kb, kilobase; bp, base pair; nt, nucleotide; im, intramuscular; ip, intraperitoneal; sc, subcutaneous; and similar abbreviations. [ ] [General Synthesis Procedure]

[0211] Numerous general references are available to provide well-known chemical synthesis schemes and conditions that can be used to synthesize the revealed compounds (see, for example, Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, 4th ed., New York: Longman, 1978).

[0212] The compounds described herein can be purified by any purification method known in the art, including chromatography, such as HPLC, preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases and ion exchange resins. In some specific embodiments, the disclosed compounds were purified by silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd edition, edited by LR Snyder and JJ Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, edited by E. Stahl, Springer-Verlag, New York, 1969.

[0213] During any procedure for preparing the target compound, it may be necessary and / or desirable to protect any sensitive or reactive groups on the relevant molecule. This can be achieved by conventional protecting groups such as those described in the following standard works: JFW McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; and TW Greene and PGM Wuts. [, ,, ] “Protective Groups in Organic Synthesis”, 3rd edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (edited by E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in “Methoden der organic Chemie”, Houben-Weyl, 4th edition, Volume 15 / 1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide, Proteine”, Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and / or in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide and Derivate”, Georg Thieme Verlag, Stuttgart 1974. These protective bases can be removed using methods known in the art at appropriate subsequent stages.

[0214] The target compound can be synthesized using commercially available starting materials and / or starting materials prepared by conventional synthetic methods through various synthetic routes. Examples of synthetic routes that can be used to synthesize the compound disclosed herein are described below. Example 1 - Preparation and Analysis of Crystalline Polymorphs of 3-Palmazyl-Ami-1,2-Propanediol

[0215] The solubility of 3-palmitinyl-amino-1,2-propanediol was screened using various solvents and solvent mixtures. Tetrahydrofuran (THF), 2-methyl-THF, dichloromethane (DCM), N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAc), toluene, 2-methylbut-2-ol (tAmOH), isopropyl acetate (iPrOAc), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF) were identified as solvents for this study. The effect of triethylamine on the solubility was also evaluated. It was shown that triethylamine had little effect on the solubility of 3-palmitinyl-amino-1,2-propanediol in these solvents. Dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and dimethylformamide (DMF) were determined to have moderate solubility in 3-palmitoyl-acetamido-1,2-propanediol.

[0216] During hot / cold induced crystallization, the crystalline solid was identified as a novel allopolyform of 3-palmitinyl-amino-1,2-propanediol using THF, 2-methyl-THF, or DCM with triethylamine. This hot / cold crystallization involved dissolving 3-palmitinyl-amino-1,2-propanediol in a THF solution, heating the composition, and maintaining it overnight at 50°C. For 2-methyl-THF or DCM, the solution containing palmitinyl-amino-1,2-propanediol was heated overnight to 60°C to produce a solution. After cooling the sample to 30°C, the crystalline solid system formed as a slurry in a solution of THF, 2-methyl-THF, and DCM.

[0217] The homopolymorph of 3-palmitoyl-amino-1,2-propanediol exhibits faster solubility and greater reaction selectivity when used as a matrix for the preparation of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.

[0218] The analysis of the crystalline solid was performed by X-ray powder diffraction (in the form of slurry droplets), thermogravimetric analysis, differential scanning calorimetry, and nuclear magnetic resonance spectroscopy. Figure 1 depicts the X-ray powder diffraction (XRPD) pattern of the crystalline solid formed from solutions of (b) THF, (c) 2-methyl THF, and (d) DCM, and compares these peaks with those of the (a) 3-palmitinyl-amino-1,2-propanediol starting material. As shown in Figure 1, the crystalline solid formed from THF, 2-methylTHF, and DCM exhibits peaks different from those of the 3-palmitinyl-amino-1,2-propanediol initiator (e.g., at approximately 2.75° 2Ɵ; approximately 6° 2Ɵ; approximately 3.8° 2Ɵ; approximately 8.25° 2Ɵ; approximately 15° 2Ɵ; approximately 26.3° 2Ɵ; approximately 30.5° 2Ɵ and approximately 33.1° 2Ɵ).

[0219] Figure 2 depicts the thermogravimetric analysis (TGA) of the crystalline solid formed from THF solution. The TGA characteristic of the isomorph of 3-palmitinyl-amino-1,2-propanediol formed from THF is a single weight loss step, which begins at approximately 200.5 °C. The graphs in Figure 2 also depict the differential scanning calorimetry (DSC) of the crystalline solid formed from THF solution. Figure 2 also depicts the DSC spectrum of the isomorph of 3-palmitinyl-amino-1,2-propanediol formed from THF, showing two endothermic peaks: a first endothermic peak at approximately 79.9 °C and a second endothermic peak at approximately 102.5 °C. The second endothermic peak at approximately 102.5 °C is a singlet endothermic peak. Figure 3 depicts the DSC spectrum of the isomorph of 3-palmitinyl-amino-1,2-propanediol formed from THF, compared with that of the 3-palmitinyl-amino-1,2-propanediol starting material. The 3-palmitinyl-amino-1,2-propanediol starting material exhibits a first endothermic reaction at approximately 79.3 °C and a second endothermic reaction at approximately 102.5 °C. Example 2 - Preparation of 3-palmitinyl-phenylamine-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (Compound B) from 3-palmitinyl-phenylamine-1,2-propanediol (Compound A)

[0220] The reaction of 3-palmitinyl-nitro-1,2-propanediol (CMPD-A) with 4,4'-dimethoxytriphenylmethyl chloride was tested in different bases and solvents. The reaction mixture with different additives was also tested. Table 1 summarizes the reaction products formed: 3-palmitinyl-nitro-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (CMPD-B), 3-palmitinyl-nitro-1-hydroxy-2-dimethoxytriphenylmethyl ether-propane (CMPD-B-Reg), and 3-palmitinyl-nitro-1,2-dimethoxytriphenylmethyl ether-propane (Bis-DMTr). For each reaction, 3-palmitinyl-nitro-1,2-propanediol was added to a three-necked round-bottom flask containing the solvent at 30°C and stirred for 1 hour. 3.0 equivalents of alkali were added to the 3-palmitinyl-amino-1,2-propanediol solvent composition, and the mixture was stirred at 30°C. When using an additive, 0.3 equivalents of the additive were brought into contact with the reaction mixture. 1.4 equivalents of 4,4'-dimethoxytriphenylmethyl chloride were added, and the resulting suspension was stirred at 30°C for approximately 17.3 hours. Samples were periodically taken from the reaction mixture (every 2 hours, 4 hours, etc.), and the reaction products were characterized by HPLC. [surface]

[0001] [solvent] [Alkali] [additive] [AP, , CMPD] [-A] [AP, , DMTr] [-OH] [AP, , DMTr-] [OMe] [AP, , CMPD] [-B] [AP, , CMPD] [B-] [Reg] [AP, Bis-DMTr] [AP, , DMTr] [-OR] [sum] [CMPD-B] [ / , , Bis-] [DMTr] [Known] [AP] [sum] THF TMEDA TBAF 5.8 3.5 22.7 60.8 0.4 4.2 26.2 14.4 97.5 THF TEA TBAF 13.2 3.4 21.5 54.8 0.5 3.0 24.9 18.3 96.5 THF Proton sponge TBAF 6.0 2.8 21.6 59.1 0.5 4.3 24.4 13.6 94.3[[ID=S67]] Me-THF TMEDA TBAF 0.1 5.0 23.9 53.7 0.0 13.3 28.9 4.0 96.1 Me-THF TEA TBAF 10.0 7.4 19.7 55.1 0.4 4.1 27.1 13.4 96.7 Me-THF Proton Sponge TBAF 23.7 3.9 18.5 45.8 0.5 2.8 22.4 16.3 95.1 THF TMEDA MgO 0.0 2.1 2.3 76.0 0.1 15.1 4.5 5.0 95.6 THF TEA MgO 0.0 2.3 6.2 50.3 0.0 35.1 8.6 1.4 94.0 THF Proton Sponge MgO 0.0 1.5 4.2 60.2 0.0 27.7 5.8 2.2 93.6 Me-THF TMEDA MgO 0.1 4.0 8.1 47.9 0.0 34.4 12.0 1.4 94.5 Me-THF TEA MgO 0.0 4.1 3.8 54.6 0.0 29.7 7.9 1.8 92.3 THF TMEDA B(OH)3 0.0 32.7 1.0 61.1 2.1 0.9 33.7 66.4 97.8 THF TEA B(OH)3 22.8 25.0 0.8 46.8 1.5 1.1 25.8 41.8 98.0 THF Proton sponge B(OH)3 33.8 14.2 0.4 41.7 0.3 3.5 14.7 12.1 93.9 Me-THF TMEDA B(OH)3 62.2 11.3 0.5 22.2 0.7 0.7 11.8 29.7 97.6 Me-THF TEA B(OH)3 32.0 20.2 0.7 40.9 1.1 2.5 20.9 16.2 97.5 Me-THF Proton Sponge B(OH)3 0.8 28.0 1.0 51.7 0.2 12.3 29.0 4.2 94.0 THF TMEDA 0.0 1.6 4.9 63.5 0.0 25.0 6.6 2.5 95.0 THF TEA 0.0 1.9 4.8 55.1 0.0 32.1 6.7 1.7 93.9 THF Proton Sponge 0.0 1.1 6.7 50.7 0.0 34.7 7.8 1.5 93.2 Me-THF TMEDA 0.0 4.4 2.0 73.5 0.3 15.4 6.4 4.8 95.5 Me-THF TEA 0.0 4.1 2.4 58.9 0.1 30.1 6.5 2.0 95.6 Me-THF Proton Sponge 0.0 3.2 8.0 41.3 0.0 40.6 11.3 1.0 93.2 Example 3 - Preparation of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (compound B) from 3-palmitinyl-amino-1,2-propanediol (compound A) with methyl THF and TEA.

[0221] 3-Palmazinyl-Ami-1,2-propanediol was charged into a three-necked round-bottom flask containing methyl THF at 30°C to produce a white suspension, and stirred at 30°C for 1 hour. The flask was equipped with a top stirrer, thermocouple, nitrogen inlet, and glass stopper. 3.0 equivalents of triethylamine were added and stirred at 30°C for 0.5 hours. Simultaneously, 1.4 equivalents of 4,4'-dimethoxytriphenylmethyl chloride were added to the white suspension. The resulting yellow suspension was stirred at 30°C for 23 hours. Samples were analyzed at 2 hours, 4 hours, 20 hours, and 23 hours to confirm the progress of the triphenylmethylation reaction and the formation of any impurities (e.g., unwanted positional isomers and bis(triphenylmethylated) compounds). After 2 hours of reaction, 3-palmazinyl-Ami-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 63.2% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was formed in 0.4% yield, and the bis-triphenylmethylated compound showed a yield of 7.8%. After 4 hours of reaction, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 65.8% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was formed in 0.2% yield, and the bis-triphenylmethylated compound increased to 11.2% yield. After 20 hours of reaction, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 62.4% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was formed in 0.1% yield, and the bis-triphenylmethylated compound was increased to 16.6% yield. After 23 hours, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 62.6% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was formed in 0.1% yield, and the bis-triphenylmethylated compound remained in 16.6% yield. Example 4 - Preparation of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (compound B) from 3-palmitinyl-amino-1,2-propanediol (compound A) with methyl-THF, TEA, and magnesium oxide.

[0222] 3-Palmazinyl-Ami-1,2-propanediol and 0.3 equivalents of magnesium oxide were charged into a three-necked round-bottom flask containing methyl THF at 30 °C. The flask was equipped with a top stirrer, thermocouple, nitrogen inlet, and glass stopper. The white suspension was stirred at 30 °C for 1 hour. 3.0 equivalents of triethylamine were added and the mixture was stirred at 30 °C for 0.5 hours. Simultaneously, 1.4 equivalents of 4,4'-dimethoxytriphenylmethyl chloride were added. The resulting yellow-green suspension was stirred at 30 °C for 23 hours. Samples were analyzed at 2, 4, 20, and 23 hours to confirm the progress of the triphenylmethylation reaction and the formation of any impurities (e.g., unwanted positional isomers and bis(triphenylmethylated) compounds). After 2 hours of reaction, 3-palmazinyl-Ami-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 63.2% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was formed in 0.4% yield, and the bis-triphenylmethylated compound showed a yield of 7.7%. After 4 hours of reaction, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 65.7% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was formed in 0.3% yield, and the bis-triphenylmethylated compound increased to 11.0% yield. After 20 hours of reaction, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 63.2% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane no longer appears, and the yield of the bis-triphenylmethylated compound increases to 16.7%. After 23 hours, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane is formed in 62.6% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane is formed in 0.1% yield, and the yield of the bis-triphenylmethylated compound increases slightly to 16.9%. Example 5 - Preparation of 3-palmitinyl-amino-1,2-propanediol (compound A) with methyl-THF, TEA, and magnesium oxide by heating (compound A) to produce 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane (compound B).

[0223] At ambient temperature, 3-palmitinyl-amino-1,2-propanediol, 0.3 equivalents of magnesium oxide, and 3.0 equivalents of triethylamine were charged into a three-necked round-bottom flask containing methyl THF. The flask was equipped with a top stirrer, thermocouple, nitrogen inlet, and glass stopper. The composition was heated to 48°C to produce a white suspension and stirred at 48°C for 1 hour. The composition was further heated to 55°C and stirred for another hour. The reaction was then heated again to 60°C and stirred for another 30 minutes. The reaction was cooled to 30°C over 70 minutes, and 1.4 equivalents of 4,4'-dimethoxytriphenylmethyl chloride were simultaneously added to the resulting white suspension. The resulting pale green suspension was stirred at 30°C for 23 hours. Samples were analyzed at 2 hours, 4 hours, 20 hours, and 23 hours to confirm the progress of the triphenylmethylation reaction and the formation of any impurities (e.g., unwanted positional isomers and bis(triphenylmethylated) compounds). After 2 hours of reaction, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 67.0% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was formed in 0.2% yield, and the bis(triphenylmethylated) compound showed a yield of 8.3%. After 4 hours of reaction, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 66.2% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was formed in 0.1% yield, and the bis(triphenylmethylated) compound increased to 11.6% yield. After 20 hours of reaction, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 63.2% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was no longer present, and the yield of the bis-triphenylmethylated compound increased to 18.1%. After 23 hours, 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane was formed in 63.0% yield. The positional isomer impurity 3-palmitinyl-amino-2-dimethoxytriphenylmethyl ether-1-hydroxy-propane was no longer present, and the yield of the bis-triphenylmethylated compound increased slightly to 18.2%. Example 6 - X-ray crystallography of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane

[0224] Single crystals of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane are prepared by recrystallization of a composition of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane in various solvents and solvent mixtures. Single crystals formed from dichloromethane / pentane are used in X-ray diffraction studies.

[0225] X-ray diffraction was performed on a single crystal in its pure form at -100°C. The X-ray crystallography analysis used a monoclinic plate-shaped sample with approximate dimensions of 0.080 mm × 0.130 mm × 0.130 mm. The X-ray structure was studied using a Bruker D8 QUEST single-crystal X-ray diffractometer equipped with a high-brightness 1µS 3.0 microjoule (50 kilovolts x 1 milliampere) detector for Cu radiation (λ = 1.54178 Å) and a PHOTON II charge-integrating pixel array detector with excellent speed, sensitivity, and accuracy for crystal screening / evaluation and diffraction data collection. A Cryostream 800 cryogenic device was used to cool the crystal at 173 K (-100°C) to provide a sample temperature between 80 K and 500 K. The Bruker APEX3 software suite, including SHELXTL, is used for data collection and integration, as well as analysis, refinement, and presentation of structural results in diffraction experiments.

[0226] A total of 1346 frames were collected. The total exposure time was 12.76 hours. These frames were obtained by integration using narrow frame operations with the Bruker SAINT software suite. Data integration using triclinic unit lattice produced a total of 30535 reflections with a maximum θ angle of 65.20° (0.85 Å resolution), of which 12077 were independent (average redundancy information 2.528, integrity = 96.7%, Rint = 3.33%, Rsig = 3.88%) and 10927 (90.48%) were greater than 2σ(F2). Based on 9845 reflections of the XYZ-center refined to 20σ(I) and 6.873°<2θ<130.4°, the final lattice constants are a = 8.6815(6) Å, b = 12.9371(9) Å, c = 32.676(2) Å, α = 83.787(3)°, β = 87.487(3)°, γ = 89.930(3)°, and volume = 3644.9(4) ų. Absorption effects in the data were corrected using the Multi-Scan method (SADABS). The minimum relative to the maximum apparent transmittance is 0.853. The calculated minimum and maximum transmittance coefficients (based on crystal size) are 0.9280 and 0.9550, respectively. The structure was analyzed and refined using the Bruker SHELXTL software suite with space group P-1 and the chemical formula unit C40H57NO5 at Z = 4. The final anisotropic full-matrix least-squares refined system with F2 of 838 variables converged at R1 = 11.45% (observed data) and wR2 = 26.68% (all data). The fitness was 1.106. The maximum peak in the final differential electron density synthesis was 0.692 e⁻ / ų, and the maximum void was -0.510 e⁻ / ų, with an RMS bias of 0.073 e⁻ / ų. Based on the final model, the calculated density was 1.151 g / cm³. Table 2 provides the atomic coordinates and equivalent isotropic atomic displacement parameters (Ų) as measured from the crystal structure of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Table 3 provides the measured bond lengths (Å) as measured from the crystal structure of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Table 4 provides the measured bond angles (°) as measured from the crystal structure of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Table 5 provides the measured torsion angles (°) as measured from the crystal structure of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Table 6 provides the anisotropic atomic shift parameters (Å2) as measured from the crystal structure of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane.Table 7 provides the hydrogen atom coordinates and isotropic atomic displacement parameters (Å2) as measured from the crystal structure of 3-palmitoyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. [ ]

[0227] Figure 4A depicts the Oak Ridge thermal ellipsoid (ORTEP) plots of two different configurations of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane as determined by X-ray crystallography. Configurational isomer A shows the linear configuration of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Configurational isomer B shows the curved configuration of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane. Figure 4B depicts a unit crystal lattice of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane, where each unit lattice contains four 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane molecules (two isomer A molecules and two isomer B molecules). Figure 4C depicts a crystal packing view of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane along the first axis. Figure 4D depicts the crystal packing of 3-palmitinyl-amino-2-hydroxy-1-dimethoxytriphenylmethyl ether-propane along the second axis. Figure 4E depicts the intermolecular hydrogen bonds between isomer A and isomer B along this second crystallographic axis. [ ] [ ] [surface] [ 2 - ] [Atomic coordinates and equivalent isotropic atomic displacement parameters] [ ] [x / a] [y / b] [z / c] [U(] [equivalent)] C1A 0.3510(10) 0.7692(7) 0.3604(3) 0.089(3) C2A 0.2495(8) 0.8404(5) 0.3833(2) 0.0613(17) C3A 0.3331(7) 0.8953(5) 0.4147(2) 0.0547(15) C4A 0.2303(7) 0.9690(5) 0.43662(19) 0.0543(15) C5A 0.3122(7) 0.0278(5) 0.4674(2) 0.0573(16) C6A 0.2061(7) 0.1025(5) 0.48786(19) 0.0561(16) C7A 0.2829(7) 0.1618(5) 0.5193(2) 0.0571(16) C8A 0.1738(7) 0.2369(5) 0.5384(2) 0.0564(16) C9A 0.2451(7) 0.2973(5) 0.57015(19) 0.0560(16) C10A 0.1340(7) 0.3721(5) 0.58881(19) 0.0557(16) O1A 0.8579(3) 0.7210(3) 0.75600(12) 0.0408(9) N1A 0.0410(5) 0.8405(4) 0.75844(15) 0.0504(13) C11A 0.2017(7) 0.4325(5) 0.62082(19) 0.0531(15) C12A 0.0889(7) 0.5070(5) 0.63866(18) 0.0515(15) C13A 0.1533(6) 0.5644(4) 0.67235(18) 0.0471(13) C14A 0.0420(6) 0.6406(4) 0.68957(17) 0.0458(13) C15A 0.1085(5) 0.6886(4) 0.72582(16) 0.0371(11) C16A 0.9924(5) 0.7525(4) 0.74799(15) 0.0343(11) C17A 0.9406(6) 0.9132(5) 0.7791(2) 0.0557(16) C18A 0.0278(5) 0.9735(4) 0.80583(18) 0.0400(12) O2A 0.1483(4) 0.0319(3) 0.78391(14) 0.0563(11) C19A 0.9269(5) 0.0537(4) 0.82453(16) 0.0347(11) O3A 0.7935(3) 0.0018(2) 0.84425(10) 0.0305(7) C20A 0.6767(5) 0.0702(3) 0.85979(14) 0.0278(10) C21A 0.7402(5) 0.1203(3) 0.89624(14) 0.0264(9) C22A 0.8470(5) 0.0650(4) 0.92084(14) 0.0302(10) C23A 0.8986(5) 0.1026(4) 0.95569(15) 0.0343(11) C24A 0.8469(5) 0.1983(4) 0.96695(14) 0.0303(10) O4A 0.9087(4) 0.2306(3) 0.00150(10) 0.0428(9) C25A 0.8669(8) 0.3313(5) 0.01188(18) 0.0574(16) C26A 0.7392(5) 0.2523(4) 0.94361(14) 0.0294(10) C27A 0.6851(5) 0.2136(3) 0.90873(13) 0.0265(9) C28A 0.6225(5) 0.1445(3) 0.82374(14) 0.0269(10) C29A 0.5262(5) 0.1041(4) 0.79597(15) 0.0321(10) C30A 0.4806(5) 0.1635(4) 0.76086(15) 0.0360(11) C31A 0.5260(5) 0.2661(4) 0.75301(14) 0.0333(11) C32A 0.5312(8) 0.4222(5) 0.70629(18) 0.0560(16) C33A 0.6214(5) 0.3089(4) 0.77977(14) 0.0327(10) O5A 0.4710(4) 0.3205(3) 0.71806(11) 0.0440(9) C34A 0.6712(5) 0.2460(3) 0.81424(14) 0.0304(10) C35A 0.5428(5) 0.9986(3) 0.87697(14) 0.0267(9) C36A 0.4127(5) 0.0424(4) 0.89437(17) 0.0407(12) C37A 0.2875(6) 0.9821(4) 0.90975(18) 0.0464(14) C38A 0.2914(6) 0.8750(4) 0.90881(15) 0.0383(12) C39A 0.4193(6) 0.8308(4) 0.89148(16) 0.0375(11) C40A 0.5444(5) 0.8916(3) 0.87551(14) 0.0301(10) C1B 0.8259(9) 0.9773(5) 0.3541(2) 0.0705(19) C2B 0.8579(10) 0.0767(6) 0.3684(3) 0.093(3) C3B 0.7945(8) 0.1091(6) 0.4062(2) 0.0690(19) C4B 0.8239(8) 0.2065(5) 0.4211(2) 0.0644(18) C5B 0.7582(9) 0.2397(6) 0.4589(3) 0.084(3) C6B 0.7856(7) 0.3380(5) 0.4734(2) 0.0600(17) C7B 0.7172(10) 0.3726(6) 0.5105(3) 0.095(3) C8B 0.7422(8) 0.4728(5) 0.5245(2) 0.0644(18) C9B 0.6756(10) 0.5066(6) 0.5618(3) 0.091(3) C10B 0.6983(8) 0.6065(5) 0.5749(2) 0.0678(19) C11B 0.6325(9) 0.6422(6) 0.6125(2) 0.080(2) C12B 0.6576(9) 0.7434(6) 0.6246(2) 0.076(2) C13B 0.6024(7) 0.7803(5) 0.6623(2) 0.0595(17) C14B 0.6214(12) 0.8837(6) 0.6724(3) 0.108(4) C15B 0.6000(8) 0.9258(4) 0.71007(18) 0.0535(15) C16B 0.4896(5) 0.8692(3) 0.74247(15) 0.0302(10) O1B 0.3551(4) 0.8951(3) 0.74538(15) 0.0585(12) N1B 0.5490(4) 0.7896(3) 0.76518(12) 0.0331(9) C17B 0.4546(9) 0.7164(5) 0.7920(2) 0.071(2) C18B 0.5183(8) 0.6233(4) 0.8063(3) 0.087(3) O2B 0.6309(4) 0.5760(3) 0.78120(13) 0.0517(11) C19B 0.4253(5) 0.5379(4) 0.82776(16) 0.0344(11) O3B 0.2917(3) 0.5769(2) 0.84798(10) 0.0314(7) C20B 0.1761(5) 0.5000(3) 0.86421(14) 0.0274(10) C21B 0.2428(5) 0.4288(3) 0.90012(14) 0.0276(10) C22B 0.3474(5) 0.4693(3) 0.92516(15) 0.0310(10) C23B 0.4017(5) 0.4108(4) 0.95886(15) 0.0355(11) C24B 0.3528(5) 0.3084(4) 0.96926(14) 0.0306(10) O4B 0.4172(4) 0.2551(3) 0.00264(10) 0.0395(8) C25B 0.3830(8) 0.1469(4) 0.01037(19) 0.0589(17) C26B 0.2454(5) 0.2675(4) 0.94524(14) 0.0309(10) C27B 0.1891(5) 0.3283(3) 0.91125(14) 0.0284(10) C28B 0.1200(5) 0.4431(3) 0.82883(14) 0.0275(10) C29B 0.1884(5) 0.3527(4) 0.81682(15) 0.0317(10) C30B 0.1415(5) 0.3082(4) 0.78236(15) 0.0348(11) C31B 0.0272(5) 0.3560(4) 0.75873(15) 0.0357(11) O5B 0.9746(4) 0.3213(3) 0.72353(12) 0.0483(9) C32B 0.0491(8) 0.2333(5) 0.70900(19) 0.0574(16) C33B 0.9574(6) 0.4447(4) 0.77055(16) 0.0388(12) C34B 0.0021(6) 0.4872(4) 0.80505(15) 0.0349(11) C35B 0.0431(5) 0.5642(3) 0.88157(14) 0.0281(10) C36B 0.0391(5) 0.6713(3) 0.87462(15) 0.0306(10) C37B 0.9152(6) 0.7259(4) 0.89021(16) 0.0376(11) C38B 0.7944(6) 0.6744(4) 0.91274(16) 0.0406(12) C39B 0.7992(6) 0.5674(4) 0.91935(18) 0.0483(14) C40B 0.9210(6) 0.5127(4) 0.90414(17) 0.0405(12) [, , ] [surface] [ 3 - ] [Key Length] [ ] key length key length C1A-C2A 1.509(9) C1A-H1AA 0.98 C1A-H1AB 0.98 C1A-H1AC 0.98 C2A-C3A 1.520(8) C2A-H2AA 0.99 C2A-H2AB 0.99 C3A-C4A 1.519(8) C3A-H3AA 0.99 C3A-H3AB 0.99 C4A-C5A 1.525(8) C4A-H4AA 0.99 C4A-H4AB 0.99 C5A-C6A 1.521(8) C5A-H5AA 0.99 C5A-H5AB 0.99 C6A-C7A 1.522(8) C6A-H6AA 0.99 C6A-H6AB 0.99 C7A-C8A 1.519(8) C7A-H7AA 0.99 C7A-H7AB 0.99 C8A-C9A 1.519(8) C8A-H8AA 0.99 C8A-H8AB 0.99 C9A-C10A 1.520(8) C9A-H9AA 0.99 C9A-H9AB 0.99 C10A-C11A 1.511(8) C10A-H10A 0.99 C10A-H10B 0.99 O1A-C16A 1.244(6) N1A-C16A 1.299(6) N1A-C17A 1.478(6) N1A-H1A 0.88 C11A-C12A 1.516(8) C11A-H11A 0.99 C11A-H11B 0.99 C12A-C13A 1.519(8) C12A-H12A 0.99 C12A-H12B 0.99 C13A-C14A 1.514(7) C13A-H13A 0.99 C13A-H13B 0.99 C14A-C15A 1.530(7) C14A-H14A 0.99 C14A-H14B 0.99 C15A-C16A 1.512(6) C15A-H15A 0.99 C15A-H15B 0.99 C17A-C18A 1.466(8) C17A-H17A 0.99 C17A-H17B 0.99 C18A-O2A 1.413(6) C18A-C19A 1.519(6) C18A-H18A 1.0 O2A-H2A 0.84 C19A-O3A 1.432(5) C19A-H19A 0.99 C19A-H19B 0.99 O3A-C20A 1.456(5) C20A-C28A 1.528(6) C20A-C35A 1.535(6) C20A-C21A 1.539(6) C21A-C27A 1.393(6) C21A-C22A 1.399(6) C22A-C23A 1.378(7) C22A-H22A 0.95 C23A-C24A 1.397(7) C23A-H23A 0.95 C24A-C26A 1.374(6) C24A-O4A 1.376(6) O4A-C25A 1.423(7) C25A-H25A 0.98 C25A-H25B 0.98 C25A-H25C 0.98 C26A-C27A 1.393(6) C26A-H26A 0.95 C27A-H27A 0.95 C28A-C34A 1.378(6) C28A-C29A 1.402(6) C29A-C30A 1.383(7) C29A-H29A 0.95 C30A-C31A 1.380(7) C30A-H30A 0.95 C31A-O5A 1.378(6) C31A-C33A 1.388(7) C32A-O5A 1.424(7) C32A-H32A 0.98 C32A-H32B 0.98 C32A-H32C 0.98 C33A-C34A 1.401(7) C33A-H33A 0.95 C34A-H34A 0.95 C35A-C36A 1.390(6) C35A-C40A 1.390(6) C36A-C37A 1.383(7) C36A-H36A 0.95 C37A-C38A 1.391(7) C37A-H37A 0.95 C38A-C39A 1.376(7) C38A-H38A 0.95 C39A-C40A 1.391(6) C39A-H39A 0.95 C40A-H40A 0.95 C1B-C2B 1.447(9) C1B-H1BA 0.98 C1B-H1BB 0.98 C1B-H1BC 0.98 C2B-C3B 1.433(9) C2B-H2B1 0.99 C2B-H2B2 0.99 C3B-C4B 1.425(9) C3B-H3B1 0.99 C3B-H3B2 0.99 C4B-C5B 1.446(8) C4B-H4B1 0.99 C4B-H4B2 0.99 C5B-C6B 1.427(9) C5B-H5B1 0.99 C5B-H5B2 0.99 C6B-C7B 1.442(8) C6B-H6B1 0.99 C6B-H6B2 0.99 C7B-C8B 1.441(9) C7B-H7B1 0.99 C7B-H7B2 0.99 C8B-C9B 1.435(8) C8B-H8B1 0.99 C8B-H8B2 0.99 C9B-C10B 1.422(9) C9B-H9B1 0.99 C9B-H9B2 0.99 C10B-C11B 1.453(8) C10B-H10C 0.99 C10B-H10D 0.99 C11B-C12B 1.427(9) C11B-H11C 0.99 C11B-H11D 0.99 C12B-C13B 1.431(8) C12B-H12C 0.99 C12B-H12D 0.99 C13B-C14B 1.425(9) C13B-H13C 0.99 C13B-H13D 0.99 C14B-C15B 1.403(9) C14B-H14C 0.99 C14B-H14D 0.99 C15B-C16B 1.523(7) C15B-H15C 0.99 C15B-H15D 0.99 C16B-O1B 1.217(6) C16B-N1B 1.321(6) N1B-C17B 1.449(7) N1B-H1B 0.88 C17B-C18B 1.368(8) C17B-H17C 0.99 C17B-H17D 0.99 C18B-O2B 1.427(6) C18B-C19B 1.466(7) C18B-H18B 1.0 O2B-H2BA 0.98(7) C19B-O3B 1.428(5) C19B-H19C 0.99 C19B-H19D 0.99 O3B-C20B 1.456(5) C20B-C28B 1.533(6) C20B-C21B 1.544(6) C20B-C35B 1.545(6) C21B-C27B 1.387(6) C21B-C22B 1.389(7) C22B-C23B 1.369(7) C22B-H22B 0.95 C23B-C24B 1.393(7) C23B-H23B 0.95 C24B-O4B 1.366(6) C24B-C26B 1.386(7) O4B-C25B 1.424(7) C25B-H25D 0.98 C25B-H25E 0.98 C25B-H25F 0.98 C26B-C27B 1.396(6) C26B-H26B 0.95 C27B-H27B 0.95 C28B-C34B 1.397(7) C28B-C29B 1.397(6) C29B-C30B 1.395(7) C29B-H29B 0.95 C30B-C31B 1.387(7) C30B-H30B 0.95 C31B-O5B 1.375(6) C31B-C33B 1.382(7) O5B-C32B 1.424(7) C32B-H32D 0.98 C32B-H32E 0.98 C32B-H32F 0.98 C33B-C34B 1.377(7) C33B-H33B 0.95 C34B-H34B 0.95 C35B-C36B 1.379(6) C35B-C40B 1.392(6) C36B-C37B 1.394(6) C36B-H36B 0.95 C37B-C38B 1.383(7) C37B-H37B 0.95 C38B-C39B 1.379(7) C38B-H38B 0.95 C39B-C40B 1.376(7) C39B-H39B 0.95 C40B-H40B 0.95 [surface] [4] [ - ] [Keyboard Corner] key Angle (º) key Angle (º) C2A-C1A-H1AA 109.5 C2A-C1A-H1AB 109.5 H1AA-C1A-H1AB 109.5 C2A-C1A-H1AC 109.5 H1AA-C1A-H1AC 109.5 H1AB-C1A-H1AC 109.5 C1A-C2A-C3A 113.9(6) C1A-C2A-H2AA 108.8 C3A-C2A-H2AA 108.8 C1A-C2A-H2AB 108.8 C3A-C2A-H2AB 108.8 H2AA-C2A-H2AB 107.7 C4A-C3A-C2A 113.1(5) C4A-C3A-H3AA 108.9 C2A-C3A-H3AA 108.9 C4A-C3A-H3AB 108.9 C2A-C3A-H3AB 108.9 H3AA-C3A-H3AB 107.8 C3A-C4A-C5A 114.4(5) C3A-C4A-H4AA 108.7 C5A-C4A-H4AA 108.7 C3A-C4A-H4AB 108.7 C5A-C4A-H4AB 108.7 H4AA-C4A-H4AB 107.6 C6A-C5A-C4A 112.6(5) C6A-C5A-H5AA 109.1 C4A-C5A-H5AA 109.1 C6A-C5A-H5AB 109.1 C4A-C5A-H5AB 109.1 H5AA-C5A-H5AB 107.8 C5A-C6A-C7A 114.3(5) C5A-C6A-H6AA 108.7 C7A-C6A-H6AA 108.7 C5A-C6A-H6AB 108.7 C7A-C6A-H6AB 108.7 H6AA-C6A-H6AB 107.6 C8A-C7A-C6A 112.6(5) C8A-C7A-H7AA 109.1 C6A-C7A-H7AA 109.1 C8A-C7A-H7AB 109.1 C6A-C7A-H7AB 109.1 H7AA-C7A-H7AB 107.8 C9A-C8A-C7A 114.5(5) C9A-C8A-H8AA 108.6 C7A-C8A-H8AA 108.6 C9A-C8A-H8AB 108.6 C7A-C8A-H8AB 108.6 H8AA-C8A-H8AB 107.6 C8A-C9A-C10A 113.6(5) C8A-C9A-H9AA 108.8 C10A-C9A-H9AA 108.8 C8A-C9A-H9AB 108.8 C10A-C9A-H9AB 108.8 H9AA-C9A-H9AB 107.7 C11A-C10A-C9A 114.7(5) C11A-C10A-H10A 108.6 C9A-C10A-H10A 108.6 C11A-C10A-H10B 108.6 C9A-C10A-H10B 108.6 H10A-C10A-H10B 107.6 C16A-N1A-C17A 123.2(4) C16A-N1A-H1A 118.4 C17A-N1A-H1A 118.4 C10A-C11A-C12A 113.6(5) C10A-C11A-H11A 108.8 C12A-C11A-H11A 108.8 C10A-C11A-H11B 108.8 C12A-C11A-H11B 108.8 H11A-C11A-H11B 107.7 C11A-C12A-C13A 114.0(5) C11A-C12A-H12A 108.7 C13A-C12A-H12A 108.7 C11A-C12A-H12B 108.7 C13A-C12A-H12B 108.7 H12A-C12A-H12B 107.6 C14A-C13A-C12A 114.1(5) C14A-C13A-H13A 108.7 C12A-C13A-H13A 108.7 C14A-C13A-H13B 108.7 C12A-C13A-H13B 108.7 H13A-C13A-H13B 107.6 C13A-C14A-C15A 111.5(5) C13A-C14A-H14A 109.3 C15A-C14A-H14A 109.3 C13A-C14A-H14B 109.3 C15A-C14A-H14B 109.3 H14A-C14A-H14B 108.0 C16A-C15A-C14A 113.2(4) C16A-C15A-H15A 108.9 C14A-C15A-H15A 108.9 C16A-C15A-H15B 108.9 C14A-C15A-H15B 108.9 H15A-C15A-H15B 107.8 O1A-C16A-N1A 122.3(4) O1A-C16A-C15A 121.1(4) N1A-C16A-C15A 116.6(4) C18A-C17A-N1A 111.6(4) C18A-C17A-H17A 109.3 N1A-C17A-H17A 109.3 C18A-C17A-H17B 109.3 N1A-C17A-H17B 109.3 H17A-C17A-H17B 108.0 O2A-C18A-C17A 112.2(5) O2A-C18A-C19A 104.7(4) C17A-C18A-C19A 111.5(4) O2A-C18A-H18A 109.4 C17A-C18A-H18A 109.4 C19A-C18A-H18A 109.4 C18A-O2A-H2A 109.5 O3A-C19A-C18A 108.3(3) O3A-C19A-H19A 110.0 C18A-C19A-H19A 110.0 O3A-C19A-H19B 110.0 C18A-C19A-H19B 110.0 H19A-C19A-H19B 108.4 C19A-O3A-C20A 114.8(3) O3A-C20A-C28A 108.6(3) O3A-C20A-C35A 105.4(3) C28A-C20A-C35A 109.4(4) O3A-C20A-C21A 109.0(3) C28A-C20A-C21A 116.5(4) C35A-C20A-C21A 107.3(3) C27A-C21A-C22A 117.6(4) C27A-C21A-C20A 123.2(4) C22A-C21A-C20A 118.8(4) C23A-C22A-C21A 121.2(4) C23A-C22A-H22A 119.4 C21A-C22A-H22A 119.4 C22A-C23A-C24A 120.5(4) C22A-C23A-H23A 119.8 C24A-C23A-H23A 119.8 C26A-C24A-O4A 124.9(4) C26A-C24A-C23A 118.9(4) O4A-C24A-C23A 116.1(4) C24A-O4A-C25A 117.3(4) O4A-C25A-H25A 109.5 O4A-C25A-H25B 109.5 H25A-C25A-H25B 109.5 O4A-C25A-H25C 109.5 H25A-C25A-H25C 109.5 H25B-C25A-H25C 109.5 C24A-C26A-C27A 120.6(4) C24A-C26A-H26A 119.7 C27A-C26A-H26A 119.7 C21A-C27A-C26A 121.0(4) C21A-C27A-H27A 119.5 C26A-C27A-H27A 119.5 C34A-C28A-C29A 117.0(4) C34A-C28A-C20A 125.2(4) C29A-C28A-C20A 117.6(4) C30A-C29A-C28A 121.6(4) C30A-C29A-H29A 119.2 C28A-C29A-H29A 119.2 C31A-C30A-C29A 120.1(4) C31A-C30A-H30A 120.0 C29A-C30A-H30A 120.0 O5A-C31A-C30A 116.2(4) O5A-C31A-C33A 123.9(4) C30A-C31A-C33A 119.9(4) O5A-C32A-H32A 109.5 O5A-C32A-H32B 109.5 H32A-C32A-H32B 109.5 O5A-C32A-H32C 109.5 H32A-C32A-H32C 109.5 H32B-C32A-H32C 109.5 C31A-C33A-C34A 118.9(4) C31A-C33A-H33A 120.5 C34A-C33A-H33A 120.5 C31A-O5A-C32A 117.4(4) C28A-C34A-C33A 122.3(4) C28A-C34A-H34A 118.8 C33A-C34A-H34A 118.8 C36A-C35A-C40A 118.1(4) C36A-C35A-C20A 118.8(4) C40A-C35A-C20A 123.1(4) C37A-C36A-C35A 121.4(5) C37A-C36A-H36A 119.3 C35A-C36A-H36A 119.3 C36A-C37A-C38A 120.0(5) C36A-C37A-H37A 120.0 C38A-C37A-H37A 120.0 C39A-C38A-C37A 119.1(4) C39A-C38A-H38A 120.5 C37A-C38A-H38A 120.5 C38A-C39A-C40A 120.9(5) C38A-C39A-H39A 119.5 C40A-C39A-H39A 119.5 C35A-C40A-C39A 120.5(4) C35A-C40A-H40A 119.8 C39A-C40A-H40A 119.8 C2B-C1B-H1BA 109.5 C2B-C1B-H1BB 109.5 H1BA-C1B-H1BB 109.5 C2B-C1B-H1BC 109.5 H1BA-C1B-H1BC 109.5 H1BB-C1B-H1BC 109.5 C3B-C2B-C1B 124.0(7) C3B-C2B-H2B1 106.3 C1B-C2B-H2B1 106.3 C3B-C2B-H2B2 106.3 C1B-C2B-H2B2 106.3 H2B1-C2B-H2B2 106.4 C4B-C3B-C2B 125.2(6) C4B-C3B-H3B1 106.0 C2B-C3B-H3B1 106.0 C4B-C3B-H3B2 106.0 C2B-C3B-H3B2 106.0 H3B1-C3B-H3B2 106.3 C3B-C4B-C5B 125.2(6) C3B-C4B-H4B1 106.0 C5B-C4B-H4B1 106.0 C3B-C4B-H4B2 106.0 C5B-C4B-H4B2 106.0 H4B1-C4B-H4B2 106.3 C6B-C5B-C4B 125.1(6) C6B-C5B-H5B1 106.0 C4B-C5B-H5B1 106.0 C6B-C5B-H5B2 106.0 C4B-C5B-H5B2 106.0 H5B1-C5B-H5B2 106.3 C5B-C6B-C7B 125.3(6) C5B-C6B-H6B1 106.0 C7B-C6B-H6B1 106.0 C5B-C6B-H6B2 106.0 C7B-C6B-H6B2 106.0 H6B1-C6B-H6B2 106.3 C8B-C7B-C6B 125.2(6) C8B-C7B-H7B1 106.0 C6B-C7B-H7B1 106.0 C8B-C7B-H7B2 106.0 C6B-C7B-H7B2 106.0 H7B1-C7B-H7B2 106.3 C9B-C8B-C7B 125.1(6) C9B-C8B-H8B1 106.0 C7B-C8B-H8B1 106.0 C9B-C8B-H8B2 106.0 C7B-C8B-H8B2 106.0 H8B1-C8B-H8B2 106.3 C10B-C9B-C8B 124.8(6) C10B-C9B-H9B1 106.1 C8B-C9B-H9B1 106.1 C10B-C9B-H9B2 106.1 C8B-C9B-H9B2 106.1 H9B1-C9B-H9B2 106.3 C9B-C10B-C11B 125.7(6) C9B-C10B-H10C 105.9 C11B-C10B-H10C 105.9 C9B-C10B-H10D 105.9 C11B-C10B-H10D 105.9 H10C-C10B-H10D 106.2 C12B-C11B-C10B 124.0(6) C12B-C11B-H11C 106.3 C10B-C11B-H11C 106.3 C12B-C11B-H11D 106.3 C10B-C11B-H11D 106.3 H11C-C11B-H11D 106.4 C11B-C12B-C13B 126.1(6) C11B-C12B-H12C 105.8 C13B-C12B-H12C 105.8 C11B-C12B-H12D 105.8 C13B-C12B-H12D 105.8 H12C-C12B-H12D 106.2 C14B-C13B-C12B 124.8(6) C14B-C13B-H13C 106.1 C12B-C13B-H13C 106.1 C14B-C13B-H13D 106.1 C12B-C13B-H13D 106.1 H13C-C13B-H13D 106.3 C15B-C14B-C13B 130.9(6) C15B-C14B-H14C 104.5 C13B-C14B-H14C 104.5 C15B-C14B-H14D 104.5 C13B-C14B-H14D 104.5 H14C-C14B-H14D 105.7 C14B-C15B-C16B 117.5(5) C14B-C15B-H15C 107.9 C16B-C15B-H15C 107.9 C14B-C15B-H15D 107.9 C16B-C15B-H15D 107.9 H15C-C15B-H15D 107.2 O1B-C16B-N1B 123.8(4) O1B-C16B-C15B 120.8(5) N1B-C16B-C15B 115.4(4) C16B-N1B-C17B 122.4(4) C16B-N1B-H1B 118.8 C17B-N1B-H1B 118.8 C18B-C17B-N1B 118.3(5) C18B-C17B-H17C 107.7 N1B-C17B-H17C 107.7 C18B-C17B-H17D 107.7 N1B-C17B-H17D 107.7 H17C-C17B-H17D 107.1 C17B-C18B-O2B 119.8(6) C17B-C18B-C19B 122.1(5) O2B-C18B-C19B 106.1(5) C17B-C18B-H18B 101.7 O2B-C18B-H18B 101.7 C19B-C18B-H18B 101.7 C18B-O2B-H2BA 109.5 O3B-C19B-C18B 110.8(4) O3B-C19B-H19C 109.5 C18B-C19B-H19C 109.5 O3B-C19B-H19D 109.5 C18B-C19B-H19D 109.5 H19C-C19B-H19D 108.1 C19B-O3B-C20B 116.1(3) O3B-C20B-C28B 109.1(3) O3B-C20B-C21B 109.2(3) C28B-C20B-C21B 114.8(3) O3B-C20B-C35B 104.6(3) C28B-C20B-C35B 109.9(4) C21B-C20B-C35B 108.6(4) C27B-C21B-C22B 118.1(4) C27B-C21B-C20B 122.1(4) C22B-C21B-C20B 119.5(4) C23B-C22B-C21B 121.3(4) C23B-C22B-H22B 119.4 C21B-C22B-H22B 119.4 C22B-C23B-C24B 120.9(4) C22B-C23B-H23B 119.6 C24B-C23B-H23B 119.6 O4B-C24B-C26B 124.8(4) O4B-C24B-C23B 116.6(4) C26B-C24B-C23B 118.6(4) C24B-O4B-C25B 117.0(4) O4B-C25B-H25D 109.5 O4B-C25B-H25E 109.5 H25D-C25B-H25E 109.5 O4B-C25B-H25F 109.5 H25D-C25B-H25F 109.5 H25E-C25B-H25F 109.5 C24B-C26B-C27B 120.1(4) C24B-C26B-H26B 119.9 C27B-C26B-H26B 119.9 C21B-C27B-C26B 121.0(4) C21B-C27B-H27B 119.5 C26B-C27B-H27B 119.5 C34B-C28B-C29B 117.4(4) C34B-C28B-C20B 118.9(4) C29B-C28B-C20B 123.5(4) C30B-C29B-C28B 121.5(4) C30B-C29B-H29B 119.3 C28B-C29B-H29B 119.3 C31B-C30B-C29B 119.5(4) C31B-C30B-H30B 120.2 C29B-C30B-H30B 120.2 O5B-C31B-C33B 115.6(4) O5B-C31B-C30B 124.9(4) C33B-C31B-C30B 119.5(5) C31B-O5B-C32B 117.5(4) O5B-C32B-H32D 109.5 O5B-C32B-H32E 109.5 H32D-C32B-H32E 109.5 O5B-C32B-H32F 109.5 H32D-C32B-H32F 109.5 H32E-C32B-H32F 109.5 C34B-C33B-C31B 120.7(5) C34B-C33B-H33B 119.7 C31B-C33B-H33B 119.7 C33B-C34B-C28B 121.3(4) C33B-C34B-H34B 119.3 C28B-C34B-H34B 119.3 C36B-C35B-C40B 118.6(4) C36B-C35B-C20B 122.2(4) C40B-C35B-C20B 119.2(4) C35B-C36B-C37B 120.2(4) C35B-C36B-H36B 119.9 C37B-C36B-H36B 119.9 C38B-C37B-C36B 121.0(4) C38B-C37B-H37B 119.5 C36B-C37B-H37B 119.5 C39B-C38B-C37B 118.3(4) C39B-C38B-H38B 120.8 C37B-C38B-H38B 120.8 C40B-C39B-C38B 121.2(5) C40B-C39B-H39B 119.4 C38B-C39B-H39B 119.4 C39B-C40B-C35B 120.7(5) C39B-C40B-H40B 119.6 C35B-C40B-H40B 119.6 [surface] [ 5 - ] [Twist Angle] [ ] key Angle (º) key Angle (º) C2A-C1A-H1AA 109.5 C2A-C1A-H1AB 109.5 H1AA-C1A-H1AB 109.5 C2A-C1A-H1AC 109.5 H1AA-C1A-H1AC 109.5 H1AB-C1A-H1AC 109.5 C1A-C2A-C3A 113.9(6) C1A-C2A-H2AA 108.8 C3A-C2A-H2AA 108.8 C1A-C2A-H2AB 108.8 C3A-C2A-H2AB 108.8 H2AA-C2A-H2AB 107.7 C4A-C3A-C2A 113.1(5) C4A-C3A-H3AA 108.9 C2A-C3A-H3AA 108.9 C4A-C3A-H3AB 108.9 C2A-C3A-H3AB 108.9 H3AA-C3A-H3AB 107.8 C3A-C4A-C5A 114.4(5) C3A-C4A-H4AA 108.7 C5A-C4A-H4AA 108.7 C3A-C4A-H4AB 108.7 C5A-C4A-H4AB 108.7 H4AA-C4A-H4AB 107.6 C6A-C5A-C4A 112.6(5) C6A-C5A-H5AA 109.1 C4A-C5A-H5AA 109.1 C6A-C5A-H5AB 109.1 C4A-C5A-H5AB 109.1 H5AA-C5A-H5AB 107.8 C5A-C6A-C7A 114.3(5) C5A-C6A-H6AA 108.7 C7A-C6A-H6AA 108.7 C5A-C6A-H6AB 108.7 C7A-C6A-H6AB 108.7 H6AA-C6A-H6AB 107.6 C8A-C7A-C6A 112.6(5) C8A-C7A-H7AA 109.1 C6A-C7A-H7AA 109.1 C8A-C7A-H7AB 109.1 C6A-C7A-H7AB 109.1 H7AA-C7A-H7AB 107.8 C9A-C8A-C7A 114.5(5) C9A-C8A-H8AA 108.6 C7A-C8A-H8AA 108.6 C9A-C8A-H8AB 108.6 C7A-C8A-H8AB 108.6 H8AA-C8A-H8AB 107.6 C8A-C9A-C10A 113.6(5) C8A-C9A-H9AA 108.8 C10A-C9A-H9AA 108.8 C8A-C9A-H9AB 108.8 C10A-C9A-H9AB 108.8 H9AA-C9A-H9AB 107.7 C11A-C10A-C9A 114.7(5) C11A-C10A-H10A 108.6 C9A-C10A-H10A 108.6 C11A-C10A-H10B 108.6 C9A-C10A-H10B 108.6 H10A-C10A-H10B 107.6 C16A-N1A-C17A 123.2(4) C16A-N1A-H1A 118.4 C17A-N1A-H1A 118.4 C10A-C11A-C12A 113.6(5) C10A-C11A-H11A 108.8 C12A-C11A-H11A 108.8 C10A-C11A-H11B 108.8 C12A-C11A-H11B 108.8 H11A-C11A-H11B 107.7 C11A-C12A-C13A 114.0(5) C11A-C12A-H12A 108.7 C13A-C12A-H12A 108.7 C11A-C12A-H12B 108.7 C13A-C12A-H12B 108.7 H12A-C12A-H12B 107.6 C14A-C13A-C12A 114.1(5) C14A-C13A-H13A 108.7 C12A-C13A-H13A 108.7 C14A-C13A-H13B 108.7 C12A-C13A-H13B 108.7 H13A-C13A-H13B 107.6 C13A-C14A-C15A 111.5(5) C13A-C14A-H14A 109.3 C15A-C14A-H14A 109.3 C13A-C14A-H14B 109.3 C15A-C14A-H14B 109.3 H14A-C14A-H14B 108.0 C16A-C15A-C14A 113.2(4) C16A-C15A-H15A 108.9 C14A-C15A-H15A 108.9 C16A-C15A-H15B 108.9 C14A-C15A-H15B 108.9 H15A-C15A-H15B 107.8 O1A-C16A-N1A 122.3(4) O1A-C16A-C15A 121.1(4) N1A-C16A-C15A 116.6(4) C18A-C17A-N1A 111.6(4) C18A-C17A-H17A 109.3 N1A-C17A-H17A 109.3 C18A-C17A-H17B 109.3 N1A-C17A-H17B 109.3 H17A-C17A-H17B 108.0 O2A-C18A-C17A 112.2(5) O2A-C18A-C19A 104.7(4) C17A-C18A-C19A 111.5(4) O2A-C18A-H18A 109.4 C17A-C18A-H18A 109.4 C19A-C18A-H18A 109.4 C18A-O2A-H2A 109.5 O3A-C19A-C18A 108.3(3) O3A-C19A-H19A 110.0 C18A-C19A-H19A 110.0 O3A-C19A-H19B 110.0 C18A-C19A-H19B 110.0 H19A-C19A-H19B 108.4 C19A-O3A-C20A 114.8(3) O3A-C20A-C28A 108.6(3) O3A-C20A-C35A 105.4(3) C28A-C20A-C35A 109.4(4) O3A-C20A-C21A 109.0(3) C28A-C20A-C21A 116.5(4) C35A-C20A-C21A 107.3(3) C27A-C21A-C22A 117.6(4) C27A-C21A-C20A 123.2(4) C22A-C21A-C20A 118.8(4) C23A-C22A-C21A 121.2(4) C23A-C22A-H22A 119.4 C21A-C22A-H22A 119.4 C22A-C23A-C24A 120.5(4) C22A-C23A-H23A 119.8 C24A-C23A-H23A 119.8 C26A-C24A-O4A 124.9(4) C26A-C24A-C23A 118.9(4) O4A-C24A-C23A 116.1(4) C24A-O4A-C25A 117.3(4) O4A-C25A-H25A 109.5 O4A-C25A-H25B 109.5 H25A-C25A-H25B 109.5 O4A-C25A-H25C 109.5 H25A-C25A-H25C 109.5 H25B-C25A-H25C 109.5 C24A-C26A-C27A 120.6(4) C24A-C26A-H26A 119.7 C27A-C26A-H26A 119.7 C21A-C27A-C26A 121.0(4) C21A-C27A-H27A 119.5 C26A-C27A-H27A 119.5 C34A-C28A-C29A 117.0(4) C34A-C28A-C20A 125.2(4) C29A-C28A-C20A 117.6(4) C30A-C29A-C28A 121.6(4) C30A-C29A-H29A 119.2 C28A-C29A-H29A 119.2 C31A-C30A-C29A 120.1(4) C31A-C30A-H30A 120.0 C29A-C30A-H30A 120.0 O5A-C31A-C30A 116.2(4) O5A-C31A-C33A 123.9(4) C30A-C31A-C33A 119.9(4) O5A-C32A-H32A 109.5 O5A-C32A-H32B 109.5 H32A-C32A-H32B 109.5 O5A-C32A-H32C 109.5 H32A-C32A-H32C 109.5 H32B-C32A-H32C 109.5 C31A-C33A-C34A 118.9(4) C31A-C33A-H33A 120.5 C34A-C33A-H33A 120.5 C31A-O5A-C32A 117.4(4) C28A-C34A-C33A 122.3(4) C28A-C34A-H34A 118.8 C33A-C34A-H34A 118.8 C36A-C35A-C40A 118.1(4) C36A-C35A-C20A 118.8(4) C40A-C35A-C20A 123.1(4) C37A-C36A-C35A 121.4(5) C37A-C36A-H36A 119.3 C35A-C36A-H36A 119.3 C36A-C37A-C38A 120.0(5) C36A-C37A-H37A 120.0 C38A-C37A-H37A 120.0 C39A-C38A-C37A 119.1(4) C39A-C38A-H38A 120.5 C37A-C38A-H38A 120.5 C38A-C39A-C40A 120.9(5) C38A-C39A-H39A 119.5 C40A-C39A-H39A 119.5 C35A-C40A-C39A 120.5(4) C35A-C40A-H40A 119.8 C39A-C40A-H40A 119.8 C2B-C1B-H1BA 109.5 C2B-C1B-H1BB 109.5 H1BA-C1B-H1BB 109.5 C2B-C1B-H1BC 109.5 H1BA-C1B-H1BC 109.5 H1BB-C1B-H1BC 109.5 C3B-C2B-C1B 124.0(7) C3B-C2B-H2B1 106.3 C1B-C2B-H2B1 106.3 C3B-C2B-H2B2 106.3 C1B-C2B-H2B2 106.3 H2B1-C2B-H2B2 106.4 C4B-C3B-C2B 125.2(6) C4B-C3B-H3B1 106.0 C2B-C3B-H3B1 106.0 C4B-C3B-H3B2 106.0 C2B-C3B-H3B2 106.0 H3B1-C3B-H3B2 106.3 C3B-C4B-C5B 125.2(6) C3B-C4B-H4B1 106.0 C5B-C4B-H4B1 106.0 C3B-C4B-H4B2 106.0 C5B-C4B-H4B2 106.0 H4B1-C4B-H4B2 106.3 C6B-C5B-C4B 125.1(6) C6B-C5B-H5B1 106.0 C4B-C5B-H5B1 106.0 C6B-C5B-H5B2 106.0 C4B-C5B-H5B2 106.0 H5B1-C5B-H5B2 106.3 C5B-C6B-C7B 125.3(6) C5B-C6B-H6B1 106.0 C7B-C6B-H6B1 106.0 C5B-C6B-H6B2 106.0 C7B-C6B-H6B2 106.0 H6B1-C6B-H6B2 106.3 C8B-C7B-C6B 125.2(6) C8B-C7B-H7B1 106.0 C6B-C7B-H7B1 106.0 C8B-C7B-H7B2 106.0 C6B-C7B-H7B2 106.0 H7B1-C7B-H7B2 106.3 C9B-C8B-C7B 125.1(6) C9B-C8B-H8B1 106.0 C7B-C8B-H8B1 106.0 C9B-C8B-H8B2 106.0 C7B-C8B-H8B2 106.0 H8B1-C8B-H8B2 106.3 C10B-C9B-C8B 124.8(6) C10B-C9B-H9B1 106.1 C8B-C9B-H9B1 106.1 C10B-C9B-H9B2 106.1 C8B-C9B-H9B2 106.1 H9B1-C9B-H9B2 106.3 C9B-C10B-C11B 125.7(6) C9B-C10B-H10C 105.9 C11B-C10B-H10C 105.9 C9B-C10B-H10D 105.9 C11B-C10B-H10D 105.9 H10C-C10B-H10D 106.2 C12B-C11B-C10B 124.0(6) C12B-C11B-H11C 106.3 C10B-C11B-H11C 106.3 C12B-C11B-H11D 106.3 C10B-C11B-H11D 106.3 H11C-C11B-H11D 106.4 C11B-C12B-C13B 126.1(6) C11B-C12B-H12C 105.8 C13B-C12B-H12C 105.8 C11B-C12B-H12D 105.8 C13B-C12B-H12D 105.8 H12C-C12B-H12D 106.2 C14B-C13B-C12B 124.8(6) C14B-C13B-H13C 106.1 C12B-C13B-H13C 106.1 C14B-C13B-H13D 106.1 C12B-C13B-H13D 106.1 H13C-C13B-H13D 106.3 C15B-C14B-C13B 130.9(6) C15B-C14B-H14C 104.5 C13B-C14B-H14C 104.5 C15B-C14B-H14D 104.5 C13B-C14B-H14D 104.5 H14C-C14B-H14D 105.7 C14B-C15B-C16B 117.5(5) C14B-C15B-H15C 107.9 C16B-C15B-H15C 107.9 C14B-C15B-H15D 107.9 C16B-C15B-H15D 107.9 H15C-C15B-H15D 107.2 O1B-C16B-N1B 123.8(4) O1B-C16B-C15B 120.8(5) N1B-C16B-C15B 115.4(4) C16B-N1B-C17B 122.4(4) C16B-N1B-H1B 118.8 C17B-N1B-H1B 118.8 C18B-C17B-N1B 118.3(5) C18B-C17B-H17C 107.7 N1B-C17B-H17C 107.7 C18B-C17B-H17D 107.7 N1B-C17B-H17D 107.7 H17C-C17B-H17D 107.1 C17B-C18B-O2B 119.8(6) C17B-C18B-C19B 122.1(5) O2B-C18B-C19B 106.1(5) C17B-C18B-H18B 101.7 O2B-C18B-H18B 101.7 C19B-C18B-H18B 101.7 C18B-O2B-H2BA 109.5 O3B-C19B-C18B 110.8(4) O3B-C19B-H19C 109.5 C18B-C19B-H19C 109.5 O3B-C19B-H19D 109.5 C18B-C19B-H19D 109.5 H19C-C19B-H19D 108.1 C19B-O3B-C20B 116.1(3) O3B-C20B-C28B 109.1(3) O3B-C20B-C21B 109.2(3) C28B-C20B-C21B 114.8(3) O3B-C20B-C35B 104.6(3) C28B-C20B-C35B 109.9(4) C21B-C20B-C35B 108.6(4) C27B-C21B-C22B 118.1(4) C27B-C21B-C20B 122.1(4) C22B-C21B-C20B 119.5(4) C23B-C22B-C21B 121.3(4) C23B-C22B-H22B 119.4 C21B-C22B-H22B 119.4 C22B-C23B-C24B 120.9(4) C22B-C23B-H23B 119.6 C24B-C23B-H23B 119.6 O4B-C24B-C26B 124.8(4) O4B-C24B-C23B 116.6(4) C26B-C24B-C23B 118.6(4) C24B-O4B-C25B 117.0(4) O4B-C25B-H25D 109.5 O4B-C25B-H25E 109.5 H25D-C25B-H25E 109.5 O4B-C25B-H25F 109.5 H25D-C25B-H25F 109.5 H25E-C25B-H25F 109.5 C24B-C26B-C27B 120.1(4) C24B-C26B-H26B 119.9 C27B-C26B-H26B 119.9 C21B-C27B-C26B 121.0(4) C21B-C27B-H27B 119.5 C26B-C27B-H27B 119.5 C34B-C28B-C29B 117.4(4) C34B-C28B-C20B 118.9(4) C29B-C28B-C20B 123.5(4) C30B-C29B-C28B 121.5(4) C30B-C29B-H29B 119.3 C28B-C29B-H29B 119.3 C31B-C30B-C29B 119.5(4) C31B-C30B-H30B 120.2 C29B-C30B-H30B 120.2 O5B-C31B-C33B 115.6(4) O5B-C31B-C30B 124.9(4) C33B-C31B-C30B 119.5(5) C31B-O5B-C32B 117.5(4) O5B-C32B-H32D 109.5 O5B-C32B-H32E 109.5 H32D-C32B-H32E 109.5 O5B-C32B-H32F 109.5 H32D-C32B-H32F 109.5 H32E-C32B-H32F 109.5 C34B-C33B-C31B 120.7(5) C34B-C33B-H33B 119.7 C31B-C33B-H33B 119.7 C33B-C34B-C28B 121.3(4) C33B-C34B-H34B 119.3 C28B-C34B-H34B 119.3 C36B-C35B-C40B 118.6(4) C36B-C35B-C20B 122.2(4) C40B-C35B-C20B 119.2(4) C35B-C36B-C37B 120.2(4) C35B-C36B-H36B 119.9 C37B-C36B-H36B 119.9 C38B-C37B-C36B 121.0(4) C38B-C37B-H37B 119.5 C36B-C37B-H37B 119.5 C39B-C38B-C37B 118.3(4) C39B-C38B-H38B 120.8 C37B-C38B-H38B 120.8 C40B-C39B-C38B 121.2(5) C40B-C39B-H39B 119.4 C38B-C39B-H39B 119.4 C39B-C40B-C35B 120.7(5) C39B-C40B-H40B 119.6 C35B-C40B-H40B 119.6 [ ] [surface] [ 6 - ] [Anisotropic Atom Displacement Parameters] [ ] U11 U22 U33 U23 U13 U12 C1A 0.096(6) 0.093(6) 0.091(6) -0.063(5) -0.002(5) 0.014(5) C2A 0.061(4) 0.060(4) 0.069(4) -0.036(3) 0.001(3) 0.000(3) C3A 0.051(3) 0.058(4) 0.059(4) -0.029(3) 0.003(3) -0.001(3) C4A 0.053(3) 0.053(4) 0.059(4) -0.025(3) 0.012(3) -0.010(3) C5A 0.055(4) 0.058(4) 0.064(4) -0.033(3) 0.009(3) -0.010(3) C6A 0.060(4) 0.055(4) 0.057(4) -0.026(3) 0.013(3) -0.013(3) C7A 0.059(4) 0.053(4) 0.064(4) -0.029(3) 0.009(3) -0.017(3) C8A 0.055(4) 0.055(4) 0.063(4) -0.028(3) 0.014(3) -0.014(3) C9A 0.063(4) 0.051(4) 0.057(4) -0.027(3) 0.010(3) -0.009(3) C10A 0.065(4) 0.050(3) 0.055(4) -0.025(3) 0.019(3) -0.017(3) O1A 0.0187(16) 0.0336(18) 0.069(2) -0.0051(17) 0.0063(15) -0.0026(13) N1A 0.028(2) 0.052(3) 0.075(3) -0.038(2) 0.025(2) -0.015(2) C11A 0.060(4) 0.049(3) 0.052(3) -0.021(3) 0.013(3) -0.009(3) C12A 0.055(3) 0.050(3) 0.051(3) -0.020(3) 0.013(3) -0.015(3) C13A 0.042(3) 0.047(3) 0.054(3) -0.021(3) 0.008(3) -0.003(2) C14A 0.041(3) 0.050(3) 0.048(3) -0.017(3) 0.008(2) -0.007(2) C15A 0.027(2) 0.041(3) 0.044(3) -0.012(2) 0.008(2) -0.003(2) C16A 0.028(2) 0.035(3) 0.039(3) -0.006(2) 0.006(2) -0.006(2) C17A 0.032(3) 0.066(4) 0.073(4) -0.035(3) 0.017(3) -0.003(3) C18A 0.027(2) 0.033(3) 0.060(3) -0.013(2) 0.018(2) -0.007(2) O2A 0.040(2) 0.039(2) 0.089(3) -0.013(2) 0.031(2) -0.0074(17) C19A 0.025(2) 0.026(2) 0.051(3) -0.009(2) 0.018(2) -0.0073(18) O3A 0.0236(15) 0.0217(15) 0.0463(19) -0.0107(13) 0.0141(13) -0.0032(12) C20A 0.025(2) 0.023(2) 0.036(2) -0.0083(18) 0.0068(18) -0.0006(17) C21A 0.022(2) 0.023(2) 0.034(2) -0.0028(18) 0.0071(18) -0.0024(17) C22A 0.022(2) 0.027(2) 0.041(3) 0.0004(19) 0.0044(19) 0.0009(18) C23A 0.028(2) 0.037(3) 0.036(3) 0.005(2) -0.003(2) 0.001(2) C24A 0.029(2) 0.034(3) 0.026(2) 0.0012(19) 0.0032(18) -0.0063(19) O4A 0.046(2) 0.052(2) 0.0313(18) -0.0068(16) -0.0056(15) -0.0020(17) C25A 0.084(5) 0.053(4) 0.039(3) -0.017(3) -0.015(3) -0.002(3) C26A 0.028(2) 0.028(2) 0.033(2) -0.0081(19) 0.0047(19) 0.0006(18) C27A 0.022(2) 0.027(2) 0.030(2) -0.0024(18) -0.0011(17) 0.0032(17) C28A 0.021(2) 0.029(2) 0.032(2) -0.0105(19) 0.0088(18) -0.0020(17) C29A 0.030(2) 0.029(2) 0.038(3) -0.008(2) 0.003(2) -0.0045(19) C30A 0.030(2) 0.045(3) 0.035(3) -0.010(2) -0.006(2) -0.001(2) C31A 0.027(2) 0.042(3) 0.030(2) -0.005(2) 0.0037(19) 0.006(2) C32A 0.079(4) 0.047(3) 0.040(3) 0.005(3) -0.007(3) 0.006(3) C33A 0.032(2) 0.032(3) 0.033(3) -0.004(2) 0.003(2) -0.0024(19) O5A 0.046(2) 0.050(2) 0.0347(19) -0.0006(16) -0.0027(16) 0.0020(17) C34A 0.027(2) 0.030(2) 0.035(3) -0.0077(19) 0.0021(19) -0.0034(18) C35A 0.024(2) 0.025(2) 0.032(2) -0.0079(18) 0.0023(18) 0.0000(17) C36A 0.029(3) 0.035(3) 0.060(3) -0.015(2) 0.014(2) -0.002(2) C37A 0.029(3) 0.050(3) 0.061(4) -0.021(3) 0.016(2) -0.009(2) C38A 0.030(3) 0.043(3) 0.040(3) -0.005(2) 0.011(2) -0.014(2) C39A 0.038(3) 0.029(3) 0.045(3) -0.004(2) 0.005(2) -0.008(2) C40A 0.024(2) 0.030(2) 0.036(3) -0.0054(19) 0.0059(19) -0.0001(18) C1B 0.074(5) 0.069(5) 0.073(5) -0.027(4) -0.009(4) 0.013(4) C2B 0.087(6) 0.088(6) 0.111(7) -0.064(5) 0.050(5) -0.026(4) C3B 0.062(4) 0.074(5) 0.075(5) -0.033(4) 0.018(3) -0.014(3) C4B 0.054(4) 0.066(4) 0.077(5) -0.034(4) 0.022(3) -0.014(3) C5B 0.080(5) 0.081(5) 0.095(6) -0.048(4) 0.050(4) -0.038(4) C6B 0.051(4) 0.062(4) 0.069(4) -0.025(3) 0.016(3) -0.011(3) C7B 0.092(6) 0.095(6) 0.104(6) -0.065(5) 0.059(5) -0.052(5) C8B 0.062(4) 0.066(4) 0.067(4) -0.027(3) 0.024(3) -0.014(3) C9B 0.094(6) 0.084(5) 0.101(6) -0.058(5) 0.060(5) -0.052(4) C10B 0.071(4) 0.063(4) 0.071(4) -0.029(4) 0.026(4) -0.013(3) C11B 0.079(5) 0.074(5) 0.090(5) -0.040(4) 0.046(4) -0.028(4) C12B 0.087(5) 0.069(5) 0.075(5) -0.032(4) 0.041(4) -0.026(4) C13B 0.057(4) 0.062(4) 0.061(4) -0.022(3) 0.021(3) -0.014(3) C14B 0.173(9) 0.057(4) 0.091(6) -0.032(4) 0.091(6) -0.056(5) C15B 0.076(4) 0.035(3) 0.047(3) 0.001(2) 0.020(3) -0.011(3) C16B 0.027(2) 0.019(2) 0.045(3) -0.0101(19) 0.004(2) -0.0028(18) O1B 0.0238(19) 0.037(2) 0.116(4) -0.014(2) 0.000(2) 0.0026(15) N1B 0.0226(19) 0.030(2) 0.044(2) 0.0049(17) 0.0077(17) 0.0046(16) C17B 0.095(5) 0.040(3) 0.070(4) 0.012(3) 0.055(4) 0.013(3) C18B 0.057(4) 0.033(3) 0.155(7) 0.031(4) 0.076(5) 0.025(3) O2B 0.035(2) 0.034(2) 0.083(3) -0.0067(19) 0.0280(19) 0.0012(16) C19B 0.024(2) 0.026(2) 0.051(3) -0.001(2) 0.015(2) 0.0051(18) O3B 0.0212(15) 0.0211(15) 0.050(2) -0.0026(14) 0.0151(14) -0.0003(12) C20B 0.023(2) 0.017(2) 0.041(3) -0.0001(18) 0.0070(19) 0.0008(17) C21B 0.021(2) 0.021(2) 0.039(3) -0.0033(18) 0.0079(18) 0.0028(17) C22B 0.028(2) 0.024(2) 0.042(3) -0.009(2) 0.005(2) -0.0010(18) C23B 0.028(2) 0.042(3) 0.038(3) -0.014(2) 0.000(2) -0.003(2) C24B 0.029(2) 0.034(3) 0.028(2) -0.0048(19) 0.0067(19) 0.0033(19) O4B 0.042(2) 0.044(2) 0.0313(18) 0.0009(15) -0.0040(15) 0.0037(16) C25B 0.090(5) 0.041(3) 0.046(3) 0.004(3) -0.018(3) 0.001(3) C26B 0.030(2) 0.026(2) 0.037(3) -0.0024(19) 0.0051(19) -0.0003(18) C27B 0.021(2) 0.028(2) 0.036(2) -0.0025(19) -0.0014(18) 0.0000(17) C28B 0.025(2) 0.021(2) 0.035(2) -0.0009(18) 0.0087(18) -0.0004(17) C29B 0.026(2) 0.031(2) 0.038(3) -0.002(2) 0.0004(19) 0.0031(19) C30B 0.033(3) 0.027(2) 0.043(3) -0.004(2) 0.008(2) 0.0025(19) C31B 0.033(3) 0.035(3) 0.038(3) -0.004(2) 0.006(2) -0.006(2) O5B 0.047(2) 0.052(2) 0.048(2) -0.0158(18) -0.0064(17) 0.0074(18) C32B 0.082(5) 0.045(3) 0.047(3) -0.015(3) 0.000(3) -0.003(3) C33B 0.031(3) 0.042(3) 0.043(3) -0.001(2) -0.005(2) 0.008(2) C34B 0.036(3) 0.026(2) 0.042(3) -0.004(2) 0.005(2) 0.004(2) C35B 0.024(2) 0.026(2) 0.034(2) -0.0019(19) 0.0055(18) 0.0015(18) C36B 0.026(2) 0.024(2) 0.041(3) -0.0020(19) 0.0058(19) 0.0013(18) C37B 0.034(3) 0.025(2) 0.055(3) -0.010(2) 0.003(2) 0.007(2) C38B 0.034(3) 0.041(3) 0.046(3) -0.002(2) 0.010(2) 0.016(2) C39B 0.034(3) 0.046(3) 0.060(4) 0.006(3) 0.025(3) 0.004(2) C40B 0.032(3) 0.026(2) 0.060(3) 0.001(2) 0.016(2) 0.001(2) [ ] [surface] [ 7 - ] [Hydrogen atom coordinates and isotropic atom displacement parameters] [x / a] [y / b] [z / c] [U(] [equivalent)] H1AA 1.2927 -0.2579 0.3388 0.134 H1AB 1.3853 -0.2887 0.3796 0.134 H1AC 1.4410 -0.1919 0.3478 0.134 H2AA 1.1632 -0.2008 0.3976 0.074 H2AB 1.2048 -0.1066 0.3631 0.074 H3AA 1.3749 -0.1576 0.4355 0.066 H3AB 1.4212 -0.0651 0.4006 0.066 H4AA 1.1439 -0.0713 0.4513 0.065 H4AB 1.1857 0.0201 0.4157 0.065 H5AA 1.3544 -0.0229 0.4889 0.069 H5AB 1.3999 0.0673 0.4530 0.069 H6AA 1.1177 0.0627 0.5018 0.067 H6AB 1.1649 0.1532 0.4662 0.067 H7AA 1.3221 0.1115 0.5414 0.069 H7AB 1.3723 0.2011 0.5056 0.069 H8AA 1.1351 0.2870 0.5161 0.068 H8AB 1.0841 0.1973 0.5516 0.068 H9AA 1.3348 0.3372 0.5570 0.067 H9AB 1.2834 0.2475 0.5925 0.067 H10A 1.0964 0.4221 0.5664 0.067 H10B 1.0439 0.3322 0.6016 0.067 H1A 1.1384 0.8576 0.7529 0.06 H11A 1.2922 0.4724 0.6082 0.064 H11B 1.2383 0.3829 0.6435 0.064 H12A 0.9961 0.4676 0.6500 0.062 H12B 1.0562 0.5587 0.6161 0.062 H13A 1.1838 0.5127 0.6951 0.057 H13B 1.2474 0.6025 0.6612 0.057 H14A 0.9443 0.6043 0.6988 0.055 H14B 1.0189 0.6966 0.6676 0.055 H15A 1.1470 0.6322 0.7457 0.045 H15B 1.1973 0.7335 0.7155 0.045 H17A 0.8911 0.9614 0.7580 0.067 H17B 0.8581 0.8735 0.7958 0.067 H18A 1.0716 0.9254 0.8284 0.048 H2A 1.2212 0.9921 0.7785 0.084 H19A 0.9846 1.0877 0.8449 0.042 H19B 0.8955 1.1078 0.8027 0.042 H22A 0.8846 1.0003 0.9134 0.036 H23A 0.9700 1.0632 0.9722 0.041 H25A 0.8974 1.3835 0.9890 0.086 H25B 0.9194 1.3455 1.0366 0.086 H25C 0.7551 1.3340 1.0172 0.086 H26A 0.7013 1.3166 0.9514 0.035 H27A 0.6095 1.2515 0.8932 0.032 H29A 0.4915 1.0342 0.8014 0.039 H30A 0.4180 1.1336 0.7421 0.043 H32A 0.6439 1.4191 0.7036 0.084 H32B 0.5009 1.4676 0.7274 0.084 H32C 0.4902 1.4499 0.6799 0.084 H33A 0.6524 1.3797 0.7748 0.039 H34A 0.7409 1.2743 0.8317 0.037 H36A 0.4098 1.1154 0.8957 0.049 H37A 0.1989 1.0139 0.9210 0.056 H38A 0.2069 0.8328 0.9200 0.046 H39A 0.4223 0.7577 0.8904 0.045 H40A 0.6314 0.8599 0.8635 0.036 H1BA 0.8569 -0.0205 0.3248 0.106 H1BB 0.7153 -0.0378 0.3579 0.106 H1BC 0.8838 -0.0772 0.3699 0.106 H2B1 0.9713 0.0814 0.3698 0.112 H2B2 0.8281 0.1304 0.3462 0.112 H3B1 0.6812 0.1040 0.4048 0.083 H3B2 0.8243 0.0551 0.4282 0.083 H4B1 0.7958 0.2605 0.3988 0.077 H4B2 0.9371 0.2110 0.4230 0.077 H5B1 0.6450 0.2338 0.4572 0.101 H5B2 0.7880 0.1865 0.4812 0.101 H6B1 0.7589 0.3911 0.4507 0.072 H6B2 0.8985 0.3429 0.4758 0.072 H7B1 0.6043 0.3658 0.5084 0.114 H7B2 0.7464 0.3205 0.5333 0.114 H8B1 0.8552 0.4801 0.5262 0.077 H8B2 0.7113 0.5249 0.5019 0.077 H9B1 0.5628 0.4977 0.5605 0.109 H9B2 0.7087 0.4556 0.5845 0.109 H10C 0.6651 0.6572 0.5522 0.081 H10D 0.8113 0.6152 0.5761 0.081 H11C 0.5194 0.6338 0.6116 0.096 H11D 0.6660 0.5921 0.6355 0.096 H12C 0.6183 0.7928 0.6023 0.092 H12D 0.7709 0.7531 0.6236 0.092 H13C 0.4900 0.7663 0.6644 0.071 H13D 0.6480 0.7343 0.6847 0.071 H14C 0.7288 0.9024 0.6631 0.13 H14D 0.5552 0.9265 0.6534 0.13 H15C 0.5629 0.9980 0.7042 0.064 H15D 0.7020 0.9295 0.7223 0.064 H1B 0.6496 0.7808 0.7640 0.04 H17C 0.4194 0.7514 0.8162 0.085 H17D 0.3617 0.7014 0.7771 0.085 H18B 0.5819 0.6437 0.8289 0.105 H2BA 0.715(7) 0.626(4) 0.7726(18) 0.078 H19C 0.3934 0.4909 0.8077 0.041 H19D 0.4882 0.4974 0.8483 0.041 H22B 0.3819 0.5391 0.9188 0.037 H23B 0.4737 0.4403 0.9754 0.043 H25D 0.2741 0.1374 1.0191 0.088 H25E 0.4476 0.1152 1.0321 0.088 H25F 0.4039 0.1137 0.9851 0.088 H26B 0.2100 0.1981 0.9519 0.037 H27B 0.1129 0.3005 0.8955 0.034 H29B 0.2688 0.3208 0.8325 0.038 H30B 0.1874 0.2456 0.7751 0.042 H32D 0.0040 0.2183 0.6833 0.086 H32E 0.0351 0.1730 0.7297 0.086 H32F 0.1594 0.2481 0.7040 0.086 H33B -0.1223 0.4768 0.7547 0.047 H34B -0.0483 0.5478 0.8128 0.042 H36B 0.1210 0.7079 0.8592 0.037 H37B -0.0863 0.7996 0.8853 0.045 H38B -0.2897 0.7119 0.9234 0.049 H39B -0.2830 0.5308 0.9347 0.058 H40B -0.0782 0.4390 0.9091 0.049

[0228] none

[0229] none [ ]

Claims

1. A method for manufacturing a composition containing a compound of formula II, comprising: A solvent is contacted with a crystalline solid of a compound of formula I (I) to produce a precursor composition, wherein the crystalline solid of the compound of formula I has an X-ray powder diffraction (XRPD) pattern containing peaks at 8.25° 2Ɵ, 2.75° 2Ɵ, 6° 2Ɵ, 3.8° 2Ɵ, 15° 2Ɵ, 26.3° 2Ɵ, 30.5° 2Ɵ and 33.1° 2Ɵ; and the precursor composition is contacted with a composition containing dimethoxytriphenylmethyl chloride to produce a composition containing a compound of formula II: (II), wherein DMTr is dimethoxytriphenylmethyl.

2. The method of claim 1, wherein the precursor composition is contacted with dimethoxytriphenylmethyl chloride in the presence of a base.

3. The method of claim 2, wherein the base is an organic base.

4. The method of claim 2, wherein the base system is selected from the group consisting of 1,8-bis(dimethylamino)naphthalene (proton sponge), imidazole, 1,8-diacabisocyclo[5.4.0]undec-7-ene (DBU), 2,4,6-trimethylpyridine (Colin base), triethylamine (TEA), potassium carbonate, sodium methoxide, tetramethylethylenediamine (TMEDA), and dimethylaminoethanol.

5. The method of claim 2, wherein the base is selected from 1,8-bis(dimethylamino)naphthalene (proton sponge), tetramethylethylenediamine (TMEDA), and triethylamine (TEA).

6. The method of claim 2, wherein the base is triethylamine (TEA).

7. The method of claim 1, wherein the precursor composition is contacted with dimethoxytriphenylmethyl chloride in the presence of an additive.

8. The method of claim 7, wherein the additive is selected from the group consisting of calcium oxide, magnesium oxide, boric acid, tetrabutylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP), copper chloride (CuCl2), ytterbium(III) chloride (YbCl3) and 1,4-diacrylbicyclo[2.2.2]octane (DABCO).

9. The method of claim 8, wherein the additive is selected from tetrabutylammonium fluoride (TBAF), magnesium oxide and boric acid.

10. The method of claim 8, wherein the additive is magnesium oxide.

11. The method of claim 1, wherein the solvent is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbut-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP) and combinations thereof.

12. The method of claim 11, wherein the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, acetonitrile, toluene, 2-methylbut-2-ol (tAmOH) and N-methyl-2-pyrrolidone (NMP).

13. The method of claim 11, wherein the solvent is selected from methyltetrahydrofuran, tetrahydrofuran and dichloromethane.

14. The method of claim 1, wherein the crystalline solid of the compound of formula I is characterized by a single weight loss step performed by thermogravimetric analysis (TGA).

15. The method of claim 14, wherein the weightlessness step begins at approximately 200.48°C.

16. The method of claim 1, wherein the crystalline solid of the compound of formula I exhibits a first endothermic reaction at 79.3°C and a second endothermic reaction at about 102.5°C by differential scanning calorimetry (DSC).

17. The method of claim 16, wherein the second heat absorption is unimodal heat absorption.

Images