Methods for the synthesis of diazabicyclo[6.2.0]decane-related compounds

Abstract

To provide a method for synthesis of diazabicyclo[6.2.0]decane compounds.SOLUTION: The synthesis proceeds by stereoselective synthesis of a chiral lactone followed by azetidine formation via a series of chemoselective reactions. Bicyclization results with the formation of diazobicyclo[6.2.0]decane related compounds.SELECTED DRAWING: None

Description

Description of Government Support

[0001] This invention was made with government support under Award Number W81XWH-16-1-0719 awarded by the United States Department of Defense under a peer-reviewed medical research program. The government has certain rights in this invention. Cross-reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 790,340, filed on January 9, 2019, which is incorporated herein by reference.

Technical Field

[0003] The present invention relates to stereochemically defined syntheses for generating 1,6-diazabicyclo[6.2.0]decane.

Background Art

[0004] Malaria is an infectious disease caused by parasitic protozoa of the genus Plasmodium. Eradicating malaria has been difficult due to the complex life cycle of Plasmodium and the emergence of parasite resistance. Diversity-oriented synthesis (DOS) has been used to identify antimalarial compounds. For example, the phenylalanyl-tRNA synthetase inhibitor BRD7929 was identified. BRD7929 exhibits activity at all stages of the parasite life cycle.

[0005] BRD7929, having the chemical name (8R,9S,10S)-10-[(dimethylamino)methyl]-N-(4-methoxyphenyl)-9-[4-(2-phenylethynyl)phenyl]-1,6-diazabicyclo[6.2.0]decane-6-carboxamide, is reported in U.S. Patent Application Publication No. 2016 / 0289235, which is incorporated herein by reference. BRD7929 has the following structure:

Chemical Formula

[0006] Similarly, compounds represented by the following structure (Formula XIV, or Compound 22) have also been identified as useful in the treatment and / or prevention of diseases transmitted by parasites, including malaria and cryptosporidiosis:

Chemical formula

[0007] Furthermore, additional related compounds and their syntheses described as useful in the treatment for combating diseases transmitted by parasites (including, for example, malaria and cryptosporidiosis) can be found in International Publication No. 2018 / 175385; Lowe, J. T. et al., Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries, J. Org. Chem. 77, 7187 - 7211 (2012); Maetani, M. et al., Synthesis of a Bicyclic Azetidine with In Vivo Antimalarial Activity Enabled by Stereospecific, Directed C(sp : 3 )-H Arylation, J. A. C. S. 139, 11300 - 11306 (2017); and Kato, N. et al., Diversity-oriented synthesis yields novel multistage antimalarial inhibitors, Nature 538, 344 - 349 (2016), all of which are relied upon herein and incorporated herein by reference in their entirety.

[0008] Additional references relating to the preparation and treatment of compounds for parasitic diseases include: International Publication No. 2015070204, International Publication No. 2015002755, International Publication No. 2016172631, and U.S. Patent Application Publication No. 2018 / 0194768, all of which are relied upon and incorporated herein by reference.

[0009] However, the long, low-yielding, and / or costly synthetic routes limit the usefulness of this compound. While BRD7929, formula XIV, and related compounds are known to have therapeutic value, improvements to the synthetic routes to their production would simultaneously provide further medicinal chemical exploration of this class of compounds and reduce their production costs, thereby making the development and / or widespread delivery of these therapeutics more feasible. Therefore, there is a need for improved synthesis to produce these potential antimalarial compounds. [Overview of the Initiative]

[0010] One embodiment is given by formula I: [ka] This paper focuses on methods for forming solid compounds as shown by [the relevant method].

[0011] In formula I, R1 is -I, -Cl, -Br, or [ka] R2 is C(O)R3; R3 is -O - The method involves formula II; a positive counterion ionically bonds with formula I; and P1 is a nitrogen protecting group. [ka] This method includes reacting the reactants with a base and dividing the racemic mixture by crystallization using a chiral reagent.

[0012] In one embodiment, R1 is [ka] That is the case.

[0013] In another embodiment, P1 is selected from the group consisting of -C(O)CF3, -C(O)OC(CH3)3, and -C(O)OCH2Ph.

[0014] In another embodiment, P1 is -C(O)CF3.

[0015] In another embodiment, the step of reacting with a base is lithium diisopropylamine in the presence of ZnCl2.

[0016] In another embodiment, the chiral reagent is (R)-(+)-1-phenylethylamine.

[0017] In another embodiment forming the compound represented by formula I, R1 is -I, -Cl, -Br, or [ka] The formula is C(O)R3; R3 is -O alkyl; and P1 is a nitrogen protecting group. [ka] (In the formula, X1 is a halogen atom.) This involves reacting the reactant with a chiral sulfinylimine.

[0018] In one embodiment, R1 and X1 are each -Br, and the chiral sulfinylimine is [ka] R4 and R5 are linear or branched alkyl groups.

[0019] In another embodiment, R4 is -C(CH3)3 and R5 is -CH2CH3.

[0020] In another embodiment, the reaction is carried out in the presence of Zn.

[0021] Another embodiment is given by formula IV: [ka] This may refer to methods for forming the compounds shown by.

[0022] In formula IV, R1 is -I, -Cl, -Br, or [ka] The formula is V: [ka] The lactone of formula I [ka] (In the formula, R2 is C(O)R3; R3 is -OH, -O alkyl, -O - And R3 is -O - In this case, the positive counterion forms an ionic bond with formula I; P1 is a nitrogen protecting group. Formation from the compound of formula V to the lactone of formula VI: [ka] This includes reducing the compound to a compound of formula VI, and converting the alcoholic group covalently bonded to the unsaturated carbon of formula VI into a leaving group, thereby forming an intermediate that reacts with a nitrogen nucleophile to produce the compound of formula IV.

[0023] In one embodiment, the nitrogen nucleophile is phthalimide.

[0024] In another embodiment, R1 is [ka] And R2 is -C(O)O - Therefore, P1 is -C(O)CF3.

[0025] In another embodiment, the lactone of formula V is formed by reacting the compound of formula I with an electropositive halogen source in a polar solvent.

[0026] In another embodiment, the halogen electropositive source is I2, and the polar solvent is an aqueous mixture of CH3CN. Those skilled in the art will readily recognize a variety of polar solvents that can be used, including, but not limited to, water, aqueous solutions of THF, DMF, or other polar protic or polar aprotic water miscible solvents.

[0027] In another embodiment, the lactone of formula V is formed by reacting the compound of formula I with I2 in a polar solvent to form a first product, and then reacting the first product with NaN3 to form the compound of formula V.

[0028] In another embodiment, the reduction is carried out using NaBH4.

[0029] In another embodiment, the leaving group is a mesylate group, and the intermediate has the following structure: [ka] It is indicated by one or both of the following.

[0030] In another embodiment, P1 is derived from -C(O)CF3 with the following structure: [ka] It will be converted.

[0031] In another embodiment, R1 is -Br, R2 is -C(O)OCH2CH3, and P1 is -S(O)C(CH3)3.

[0032] In another embodiment, P1 has the following structure derived from -S(O)C(CH3)3: [ka] It will be converted.

[0033] In another embodiment, the lactone of formula V is formed by reacting the compound of formula I with an electropositive halide source in a polar solvent to form a first product, and then reacting the first product with NaN3 to form the compound of formula V.

[0034] In another embodiment, the lactone of formula V is reduced with NaBH4 to form the following compound: [ka] It forms.

[0035] In another embodiment, the leaving group is a mesylate group, and the intermediate has the following structure: [ka] It is indicated by one or both of the following.

[0036] Another embodiment is given by formula VIII: [ka] This may involve methods for producing compounds represented by their structure.

[0037] In formula VIII, R1 is -I, -Cl, -Br, or [ka] R6 and R7 are independently the same or different, selected from -H, alkyl, or -O alkyl, or R6 and R7, together with the atom to which they are bonded, form a ring; R8 and R9 are independently the same or different, selected from -H, -alkyl, -C(O)alkyl, or -S(O)2alkyl, or R8 and R9, together with the N to which they are bonded, form a monocyclic or bicyclic ring system; R 10 The alkyl, aryl, and heteroaryl atoms are optionally substituted with one or more halogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms. The method is based on formula IV: [ka] This involves reacting the compound shown with a substituted γ-hydroxyaldehyde and carrying out bicyclization.

[0038] In one embodiment, γ-hydroxyaldehyde has the following structure: [ka] (In the formula, R 11 R is a -H or oxygen protecting group; 12 (This is -H or -CH2OH) This is shown by.

[0039] In another embodiment, γ-hydroxyaldehyde is [ka] The compound of formula VIII is the following intermediate: [ka] It is produced through the following process.

[0040] In another embodiment, the method further comprises oxidation, wherein the compound of formula VIII is the following intermediate: [ka] It is produced through the following process.

[0041] In another embodiment, the method further comprises reduction and bicyclization, wherein the compound of formula VIII is the following intermediate: [ka] It is produced through the following process.

[0042] In another embodiment, the method comprises further reduction, wherein the compound of formula VIII is obtained as the following intermediate: [ka] It is produced through the following process.

[0043] In another embodiment, the compound of formula XIII reacts with 4-methoxyphenyl isocyanate, and the compound of formula VIII has the following structure: [ka] This is shown by.

[0044] Another object of the present invention is formula IV [ka] This study focuses on methods for forming compounds shown by [the specified method].

[0045] In formula IV, R1 is -I, -Cl, -Br, or [ka] The formula is VI; P1 and P2 are the same or different and represent a nitrogen protecting group. [ka] This process involves converting an alcoholic group covalently bonded to an unsaturated carbon atom into a leaving group, thereby forming an intermediate that reacts with a nitrogen nucleophile to produce the compound of formula IV.

[0046] In one embodiment, the leaving group is a mesylate group, and the intermediate has the following structure: [ka] It is indicated by one or both of the following.

[0047] In another embodiment, the nitrogen nucleophile is phthalimide.

[0048] One beneficial discovery of the present invention is a chemoselective tandem process for preparing substituted azetidines. This may be the first example or one of the first examples of a bespoke nucleophilic aziridine that opens in preference to oxygen leaving group substitution, highlighting the importance of reducing ring strain energy in tuning chemical reactivity. Another beneficial discovery of the present invention is the application of an Aza-Wittig / reducing sequence to construct an 8-membered ring directly from an azido-aldehyde.

[0049] Another embodiment is directed to a compound represented by Formula I:

Chem.

Chem.

[0050] Another embodiment is directed to a compound represented by Formula IV:

Chem.

[0051] ; P1 and P2 are the same or different and represent a nitrogen protecting group or -H.

Chem.

[0052] wherein in Formula V, R1 is -I, -Cl, -Br, or

Chem.

[0053] Another embodiment is directed to a compound represented by Formula VI:

Chem.

[0054] <于 Another embodiment is directed to a compound represented by Formula VI: ]>

[0055]

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[0058] <00005;> [[ID=];>

[0059] <00;

[0060]

[0061] <00;

[0062]

[0063]

[0064] <000056;> [ka] The compounds shown are the target compounds.

[0055] In formula VI, R1 is -I, -Cl, -Br, or [ka] P1 is a nitrogen protecting group or -H.

[0056] Another embodiment is formula VII: [ka] The compounds shown are the target compounds.

[0057] In formula VII, R1 is -I, -Cl, -Br, or [ka] P1 is a nitrogen protecting group or -H.

[0058] Another embodiment is given by formula VIIb: [ka] The compounds shown are the target compounds.

[0059] In formula VIIb, R1 is -I, -Cl, -Br, or [ka] P1 is a nitrogen protecting group or -H.

[0060] Another embodiment is given by formula VIII: [ka] The compounds shown are the target compounds.

[0061] In formula VIII, R1 is -I, -Cl, -Br, or [ka] R6 and R7 are independently the same or different, selected from -H, alkyl, or -Oalkyl, or R6 and R7, together with the atom to which they are bonded, form a ring; R8 and R9 are independently the same or different, selected from -H, -alkyl, -C(O)alkyl, or -S(O)2alkyl, or R8 and R9, together with the N to which they are bonded, form a monocyclic or bicyclic ring system; R 10 These are -H, linear or branched alkyl, -C(O)alkyl, -C(O)O-alkyl, -C(O)NH-alkyl, -C(O)aryl, -C(O)O-aryl, -C(O)NH-aryl, -C(O)heteroaryl, -C(O)O-heteroaryl, and -C(O)N-heteroaryl, where alkyl, aryl, and heteroaryl are substituted with one or more hydrogen atoms, halogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms.

[0062] Another embodiment is given by formula X: [ka] The compounds shown are the target compounds.

[0063] In formula X, R1 is -I, -Cl, -Br, or [ka] R8 and R9 are independently the same or different, selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9, together with the N to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl is substituted with one or more hydrogen atoms, halogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms.

[0064] Another embodiment is given by formula XI: [ka] The compounds shown are the target compounds.

[0065] In formula XI, R1 is -I, -Cl, -Br, or [ka] R8 and R9 are independently the same or different, selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9, together with the N to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl is substituted with one or more hydrogen atoms, halogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms.

[0066] Another embodiment is given by formula XII: [ka] The compounds shown are the target compounds.

[0067] In equation XII, R1 is -I, -Cl, -Br, or [ka] R8 and R9 are independently the same or different, selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9, together with the N to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl is substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms.

[0068] Another embodiment is given by formula XIII: [ka] The compounds shown are the target compounds.

[0069] For equation XIII, R1 is -I, -Cl, -Br, or [ka] R8 and R9 are independently the same or different, selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9, together with the N to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl is substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms.

[0070] Another embodiment is given by formula XV: [ka] The compounds shown are the target compounds.

[0071] For equation XV, R1 is -I, -Cl, -Br, or [ka] And, Z is a four-membered nitrogen-containing heterocycle selected from one of the following: [ka] (P1 and P2 are the same or different, and are nitrogen protecting groups or -H); [ka] (R6 and R7 are independently the same or different, selected from -H, alkyl, or -Oalkyl, or R6 and R7, together with the atom to which they are bonded, form a ring; R8 and R9 are independently the same or different, selected from -H, -alkyl, -C(O)alkyl, or -S(O)2alkyl, or R8 and R9, together with the N to which they are bonded, form a monocyclic or bicyclic ring system; R 10 These are -H, linear or branched alkyl, -C(O)alkyl, -C(O)O-alkyl, -C(O)NH-alkyl, -C(O)aryl, -C(O)O-aryl, -C(O)NH-aryl, -C(O)heteroaryl, -C(O)O-heteroaryl, and -C(O)N-heteroaryl, where alkyl, aryl, and heteroaryl are substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms. [ka] (R8 and R9 are independently the same or different, selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9, together with the N to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl is substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms); [ka] (R8 and R9 are independently the same or different, selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9, together with the N to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl is substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms); [ka] (R8 and R9 are independently the same or different, selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9, together with the N to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl is substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms); and [ka] (R8 and R9 are independently the same or different, selected from -H, -alkyl, -C(O)alkyl, -S(O)2alkyl, or R8 and R9, together with the N to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl is optionally substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms.)

[0072] Another embodiment involves a compound represented by formula XV: [ka] [In the formula, R1 is -I, -Cl, -Br, or [ka] And, In equation XV, Z is [ka] (R2 is C(O)R3; R3 is -O - The positive counterion forms an ionic bond with formula XVI, or R3 is -OH; P1 is a nitrogen protecting group or -H. [ka] (P1 is a nitrogen protecting group or -H); [ka] (P1 is a nitrogen protecting group or -H); [ka] (P1 is a nitrogen protecting group or -H); and [ka] (P1 is a nitrogen protecting group or -H) The subject is one of the following [selected from] or a pharmaceutically acceptable salt thereof.

[0073] The compounds provided herein, including but not limited to compounds of formulas I, IV, V, VI, VII, VIIb, VIII, X, XI, XII, XIII, and XV, may be provided as pharmaceutically acceptable salts. “pharmaceutically acceptable salt” as used herein means an acid-added or base-added salt of the compound in this disclosure. A pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not impart any unduly harmful or undesirable effect to the subject to which it is administered or in the context in which it is administered. Examples of pharmaceutically acceptable salts include, but not limited to, metal complexes and salts of both inorganic acids and carboxylic acids. Examples of pharmaceutically acceptable salts include metal salts, such as aluminum salts, calcium salts, iron salts, magnesium salts, manganese salts, and complex salts. In addition, pharmaceutically acceptable salts include, but are not limited to, acidic salts such as acetate, aspartate, alkyl sulfonate, aryl sulfonate, axetyl, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, butyrate, calcium edetate, camusylate, carbonate, chlorobenzoate, citrate, edetate, edisylate, estrulate, esylate, esilenate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycolyl arsanylate, hexamine, hexylresorcinolate, hydrabaminate, hydrobromide, hydrochloride, and iodine. Examples include hydrochlorides, hydroxynaphthoates, isethionates, lactates, lactobionates, maleates, malates, malons, mandelates, methanesulfons, methylnitrates, methylsulfates, mucoates, muconates, napsylates, nitrates, oxalates, p-nitromethanesulfons, pamonates, pantothenates, phosphates, monohydrogen phosphates, dihydrogen phosphates, phthalates, polygalacturonic acids, propions, salicylates, stearates, succinates, sulfamines, sulfanilates, sulfonates, sulfates, tannates, tartrates, theoclates, and toluenesulfons. Pharmaceutically acceptable salts, including cysteine, can be derived from amino acids, but are not limited to those listed below.Methods for producing compounds as salts are known to those skilled in the art (see, for example, Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH; Verlag Helvetica Chimica Acta, Zurich, 2002; Berge et al., J.Pharm.Sci.66:1, 1977).

[0074] Other aspects and advantages of the present invention are evident from the following description, drawings and appended claims. [Brief explanation of the drawing]

[0075] [Figure 1] This figure shows the ORTEP projection for compound 5. [Figure 2] This figure shows the ORTEP projection for compound 32. Detailed description of the invention

[0076] While the terms used herein are expected to be readily understood by those skilled in the art, their definitions are provided herein for the purpose of facilitating the description of the subject matter disclosed herein.

[0077] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the subject matter disclosed herein belongs. Any methods, apparatus, and materials similar to or equivalent to those described herein may be used in the practice or testing of the subject matter disclosed herein, but representative methods, apparatus, and materials are described herein.

[0078] Any combination of methods or process steps, as used herein, may be carried out in any order unless otherwise specified or clearly implied to be inconsistent by the context in which the referenced combination is made.

[0079] The methods and apparatus of this disclosure, including their components, may include, consist of, or be essential to, the essential elements and limitations of the embodiments described herein, as well as any additional or optional components or limitations described herein or otherwise useful.

[0080] Unless otherwise indicated, all physical dimensions, quantities, reaction conditions, and other properties of components used herein and in the claims should be understood to be modified in all examples by the term “approximately,” and therefore, unless otherwise indicated, the numerical parameters described herein and in the claims are approximations that may vary depending on the desired properties to be obtained by the subject matter now disclosed.

[0081] The term "alkyl" includes branched, linear, and cyclic substituted or unsubstituted saturated aliphatic hydrocarbon groups. Alkyl groups may include about 1 to about 24 carbon atoms ("C1-C24"), about 7 to about 24 carbon atoms ("C7-C24"), about 8 to about 24 carbon atoms ("C8-C24"), or about 9 to about 24 carbon atoms ("C9-C24"). Alkyl groups may also include about 1 to about 8 carbon atoms ("C1-C8"), about 1 to about 6 carbon atoms ("C1-C6"), or about 1 to about 3 carbon atoms ("C1-C3"). Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, cyclopropylmethyl, and neohexyl groups.

[0082] The term "aryl" includes monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ring systems with 6 to 14 members. Examples of aryl groups include phenyl and naphthyl.

[0083] The term "heteroaryl" includes monocyclic, bicyclic, and tricyclic systems, encompassing aromatic heterocycles with 5 to 14 members, and containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, as well as at least one carbon atom. Representative heteroaryls include triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, sinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl, and oxazolyl.

[0084] Examples of oxygen protecting groups, without limitation, include benzyl groups or substituted benzyl groups, silyl groups or substituted silyl groups, acetyl groups or other ester protecting groups, methoxymethyl ethers or other methoxy ethers. Those skilled in the art will recognize other acceptable protecting groups, such as those identified in Greene's Protective Groups in Organic Synthesis, 5th Edition, Peter GMWuts, John Wiley & Sons, Inc. (2014), which is fully incorporated herein by reference.

[0085] Those skilled in the art will recognize a wide variety of nitrogen protecting groups that can be used according to embodiments of the present invention. See also Greene's Protective Groups in Organic Synthesis, 5th Edition, which is fully incorporated herein by reference. Useful nitrogen protecting groups include, but are not limited to, 9-fluorenylmethylcarbamate; t-butylcarbamate; 2-nitrobenzenesulfonyl; 4-nitrobenzenesulfonyl; benzyl carbamate; acetamide; trifluoroacetamide; phthalimide; benzylamine; triphenylmethylamine; benzylideneamine; and p-toluenesulfonamide.

[0086] Abbreviations. XPhos-Pd-G3 (XPhosG3) is (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, XPhos-G3-Palladacycle (Sigma-Aldrich). Des Martinperiodinane is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Sigma-Aldrich). MTBE is a methyl tertiary butyl ether. As used herein, "Ns" or "nosyl" refers to a 2-nitrophenylsulfonyl group; "Ms" or "mesyl" refers to a methanesulfonyl group; and "TFA" refers to a trifluoroacetyl group.

[0087] While only a specific stereoisomer may be represented in any given claim, a person skilled in the art will recognize that enantiomers or other stereoisomers can be produced through the manufacture of appropriate corresponding chiral starting materials or intermediates.

[0088] If there is a discrepancy between the illustrated structure and the name given to it, the illustrated structure prevails. In addition, if the stereochemistry of a structure or part of a structure is not indicated, for example, by a thick or dashed line, that structure or part of a structure should be interpreted as encompassing all of its stereoisomers. [Examples]

[0089] Path A synthesis Esterification of 4-bromocinnamic acid to obtain (methyl(E)-3-(4-bromophenyl)acrylate)1 [ka]

[0090] Thionyl chloride (176 mL, 2422 mmol) was added dropwise over 20 minutes to a white suspension of 4-bromodinamic acid (500 g, 2202 mmol) in methanol (3000 mL), while the reaction temperature remained below 40°C. The mixture was then heated under reflux for 1 hour, during which time the mixture became homogenized. The solution was slowly allowed to cool to room temperature to obtain a white suspension. The suspension was filtered, and the filter cake was washed twice with cold methanol to obtain compound 1 as a white solid. The filtrate was concentrated to half its original volume, filtered again, and the filter cake was washed with cold methanol. This procedure was repeated two more times to obtain an additional compound 1 (523 g in total, 98% yield). 1 H NMR(400 MHz, CDCl3) δ 7.62 (d, J = 16.0 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2 H), 7.38 (d, J = 8.6 Hz, 2 H), 6.43 (d, J = 16.0 Hz,1 H), 3.81 (s, 3 H); 13 C NMR (75 MHz, CDCl3) δ 167.1, 143.4, 133.2, 132.1, 129.4, 124.5, 118.5, 51.8.

[0091] Sonogashira reaction 1 to obtain (methyl(E)-3-(4-(phenylethynyl)phenyl)acrylate)2 [ka]

[0092] A clear, homogeneous solution was obtained by dissolving 1 (285 g, 1180 mmol) in diisopropylamine (2500 ml). After sparging the solution with nitrogen gas for 30 minutes, copper(I) iodide (0.169 g, 0.885 mmol), bis(benzonitrile) palladium(II) chloride (0.453 g, 1.18 mmol), and tri-tert-butylphosphonium tetrafluoroborate (0.685 g, 2.36 mmol) were added. After heating the mixture to 80°C, the reaction was initially initiated by adding phenylacetylene (136 mL, 1239 mmol) in small amounts, as indicated by the increase in internal temperature and precipitate formation up to reflux, and then reflux of the exothermic reaction was maintained. After the addition was complete, the mixture was stirred at 80°C for a further 1 hour, then slowly reduced to 50°C, and the reactants were quenched with water (2000 mL). The mixture was brought to room temperature while stirring, and then filtered. The filter cake was washed with water (200 mL x 3), and then dried under vacuum at 40°C to obtain pure 2 (296 g, 96%) as a white solid, based on the NMR spectrum. 1 H NMR(400 MHz, CDCl3) δ 7.69 (d, J = 16.0 Hz, 1H), 7.56 - 7.50 (m, 6 H), 7.38 - 7.35 (m, 3 H), 6.46 (d, J = 16.0 Hz, 1 H),3.83 (s, 3 H); 13 C NMR (75 MHz, CDCl3) δ 167.2, 143.9, 134.1, 132.0, 131.6, 128.5, 128.4, 128.0, 125.2,122.9, 118.4, 91.6, 89.0, 51.7.

[0093] Reduction 2 to obtain ((E)-3-(4-(phenylethynyl)phenyl)propa-2-en-1-ol)3 [ka]

[0094] A clear, colorless solution of 2 (210 g, 801 mmol) in dichloromethane (3150 mmol) was cooled to -78°C in a dry ice-acetone bath, during which time the solution became a white suspension. A solution of diisobutylaluminum hydride (25 wt.%, 934 g, 1641 mmol) in toluene was slowly added, and the mixture was then slowly cooled to -20°C over 12 hours. The reaction mixture was carefully quenched with a solution of potassium sodium tartrate tetrahydrate (926 g, 3282 mmol) in water (4200 mL), and the mixture was stirred at room temperature for 12 hours. The two phases were separated, and the aqueous phase was extracted with dichloromethane (1700 mL x 4). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain pure 3 (184 g, 98%) as a white solid, based on the NMR spectrum. 1 H NMR(400 MHz, CDCl3) δ 7.55 - 7.48 (m, 4 H),7.39 - 7.34 (m, 5 H), 6.63 (d, J = 16.1 Hz, 1 H), 6.41 (dt, J = 16.0, 5.4 Hz, 1H), 4.36 (dd, J = 5.5, 1.6 Hz, 2H); 13 C NMR (75 MHz, CDCl3)δ 136.6, 131.8, 131.6, 130.4, 129.5, 128.3, 128.3,126.4, 123.2, 122.4, 90.1, 89.4, 63.6.

[0095] Esterification of 3 using N-(trifluoroacetyl)glycine to obtain ((E)-3-(4-(phenylethynyl)phenyl)allyl(2,2,2-trifluoroacetyl)glycinate)4 [ka]

[0096] A mixture of 3 (184 g, 785 mmol), N-(trifluoroacetyl)glycine (136 g, 793 mmol), and 4-(dimethylamino)pyridine (9.59 g, 78.5 mmol) was added to dichloromethane (1840 mL) to obtain a yellow suspension. The suspension was cooled to 10°C in an ice bath, during which time N,N'-diisopropylcarbodiimide (128 mL, 825 mmol) was added in small amounts while maintaining the internal temperature below 15°C. The mixture was slowly brought to room temperature and stirred overnight. The mixture was filtered, and the filter cake was washed with methylene chloride (50 mL x 3). The filtrate was placed in a mixed solvent of ethyl acetate / methyl tert-butyl ether (1:1, 3680 mL) and washed with aqueous sodium bicarbonate (400 mL x 2) and brine (400 mL). The organic phase was dried on anhydrous sodium sulfate and concentrated. By crystallizing the residue in isopropanol, 4 (240g, 79%) was obtained as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.56 - 7.50 (m, 4 H),7.40 - 7.34 (m, 5 H), 6.90 (br s, 1 H), 6. 6.69 (d, J = 15.6 Hz, 1 H), 6.31(dt, J = 16.0, 6.6 Hz, 1 H), 4.88 (dd, J = 6.6, 1.1 Hz, 2 H), 4.19 (d, J = 5.0Hz, 1 H); 13 C NMR (75 MHz, CDCl3) δ 168.0, 135.5, 134.9, 131.9, 131.6, 128.4, 126.6, 123.3,123.1,122.5, 90.5, 89.1, 66.6, 41.4.

[0097] Claisen rearrangement of 4 and chiral resolution using (R)-(+)-1-phenylethylamine to obtain ((R)-1-phenylethane-1-aminium(2S,3S)-3-(4-(phenylethynyl)phenyl)-2-(2,2,2-trifluoroacetamide)penta-4-enoic acid)5 [ka]

[0098] Preparation of lithium diisopropylamide (LDA): A solution of diisopropylamine (22.8 mL, 160 mmol) in tetrahydrofuran (130 mL) was cooled in an ice bath and slowly treated with a solution of n-butyllithium (2.5 M in hexane, 62.0 mL, 155 mmol) while maintaining the internal temperature below 20°C. The ice bath was removed and the mixture was stirred at room temperature for 30 minutes.

[0099] In separate containers, a solution of 4 (20.0 g, 51.6 mmol) in tetrahydrofuran (140 mL) was cooled in a dry ice-acetone bath to obtain a yellow suspension. The suspension was treated with a solution of zinc chloride (1.9 M, 40.8 mL, 77.4 mmol in 2-methyltetrahydrofuran) while maintaining an internal temperature below -60°C. The LDA solution was slowly added to this mixture while maintaining an internal temperature below -65°C, during which time the mixture became a dark blue homogeneous solution towards the end of the addition. The reaction mixture was maintained at this temperature for 60 minutes. The cooling bath was removed, and the reaction mixture was slowly brought to room temperature, during which time the mixture turned dark orange. The reaction product was quenched with hydrochloric acid (1 M, 336 mL, 336 mmol), during which time the internal temperature rose to 35°C. The two phases were separated, and the aqueous phase was extracted with methyl tert-butyl ether (160 mL × 2). The combined organic phases were concentrated, and the residue was placed in methyl tert-butyl ether (160 mL). The mixture was heated to reflux temperature to obtain a nearly clear solution. Treatment of the solution with (R)-(+)-1-phenylethylamine (12.5 g, 103 mmol) yielded a clear solution, from which a precipitate immediately began to form. The mixture was slowly brought to room temperature with stirring, and then cooled in an ice bath. The product was filtered, washed with methyl tert-butyl ether (20 mL x 2), and dried under vacuum to obtain 5 (10.7 g, 40.8% yield, er=16.8:1) as a white solid. 1 H NMR(400 MHz, MeOH-d4) δ 7.52 - 7.49 (m, 2 H),7.46 - 7.39 (m, 7 H), 7.39 - 7.34 (m, 3 H), 7.28 (d, J = 8.2 Hz, 2 H), 6.24 -6.14 (m, 1 H), 5.13 - 5.09 (m, 2 H), 4.70 (d, 8.2 Hz, 1 H), 4.44 (q, J = 7.0Hz, 1 H), 3.86 (t, J = 8.2 Hz, 1 H), 1.63 (d, J = 7.0 Hz, 3 H); 13CNMR (75 MHz, MeOH-d4) δ 175.5, 142.2, 140.1,139.1, 132.7, 132.6, 130.5, 130.3, 130.0, 129.7, 129.5, 127.7, 124.9, 123.2,117.4, 90.2, 90.1, 61.0, 54.3, 52.5, 21.0.

[0100] Iodlactonization of 5 and substitution with sodium azide to obtain (N-((3S,4S,5S)-5-(azidomethyl)-2-oxo-4-(4-(phenylethynyl)phenyl)tetrahydrofuran-3-yl)-2,2,2-trifluoroacetamide)7 [ka]

[0101] A white emulsion suspension of 5 (30.9 g, 60.8 mmol) in acetonitrile (494 mL) and water (124 mL) was cooled to 0°C and treated with iodine (30.8 g) to obtain a dark red solution, which was stirred at the same temperature for 1 hour. The mixture was quenched by treating it with sodium thiosulfate (28.8 g, 182 mmol) and stirring for 10 minutes, during which time the reaction mixture turned pale yellow. The mixture was placed in methyl tert-butyl ether (500 mL) and the two phases were separated. The organic phase was washed with 1 M hydrochloric acid (150 mL) and brine (150 mL). The aqueous phase was back-extracted with methyl tert-butyl ether. The combined organic phases were dried on anhydrous sodium sulfate and concentrated to obtain the crude product (2,2,2-trifluoro-N-((3S,4S,5S)-5-(iodomethyl)-2-oxo-4-(4-(phenylethynyl)phenyl)tetrahydrofuran-3-yl)acetamide)6 as a red, rubbery substance.

[0102] Crude product 6 was placed in N,N-dimethylformamide (185 mL) and treated with sodium azide (15.8 g, 243 mmol). The mixture was stirred at room temperature for 12 hours, then heated to 45°C and stirred for another 12 hours. The mixture was placed in methyl tert-butyl ether (400 mL) and washed with water (300 mL) and brine (300 mL). The aqueous phase was back-extracted with methyl tert-butyl ether (300 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was passed through a short pad of silica gel (130 g) eluted with 50% ethyl acetate in heptane (100 mL). By concentrating the filtrate, product 7 was obtained as a pale yellow foamy solid, which was used without purification.

[0103] Preparation of aminodiol 9 from azidlactone ((2S,3S,4S)-2-amino-5-azido-3-(4-(phenylethynyl)phenyl)pentan-1,4-diol)7 [ka]

[0104] The crude product 7 (26.0 g, 60.8 mmol) described above was added to ethanol (260 mL) to obtain a colorless solution. The solution was cooled in an ice bath and treated with sodium borohydride (2.76 g, 73.0 mmol). The mixture was stirred at this temperature for 2 hours to obtain a white suspension. The ice bath was removed, and the mixture was then allowed to rise to room temperature, and then to 45°C, at which point the foaming stopped and the mixture became homogeneous. The solution was treated with potassium carbonate (25.2 g, 182 mmol) and water (13 mL) and stirred at this temperature for 24 hours. The mixture was concentrated, and the residue was added to methylene chloride (390 mL). This mixture was treated with Celite (26 g), filtered through a Celite pad, and rinsed with methylene chloride (260 mL x 2). The filtrate was concentrated to obtain an orange solid, which was filtered through a silica gel (160 g) pad eluted with 20% methanol in dichloromethane (conditioned in 1% aqueous ammonia, 2000 mL). The filtrate was concentrated, and the residue was crystallized (isopropyl acetate / isopropanol = 3:1, concentrated mother liquor, further crystallized acetonitrile, then in ethyl acetate) to obtain 9 as a white solid (7.01 g). Another fraction of 9 was obtained as a crude product in the mother liquor (7.84 g based on 9.8 g of concentrate with 80% purity as indicated by ELSD, with a combined yield of 5-73%). 1 H NMR(400 MHz, MeOH-d4) δ 7.53 - 7.49 (m, 4 H),7.40 - 7.36 (m, 3 H), 7.30 (d, J = 8.2 Hz, 2 H), 4.31 (ddd, J = 9.8, 6.2, 2.7Hz, 1 H), 3.49 - 3.45 (m, 1 H), 3.40 (dd, J = 10.6, 6.3 Hz, 1 H), 3.33 - 3.32(m, 1 H), 3.29 (dd, J = 10.5, 7.4 Hz, 1 H), 3.15 (dd, J = 12.7, 3.0 Hz, 1 H),3.03 (dd, J = 12.5, 6.6 Hz, 1 H), 3.00 (dd, J = 9.7, 3.5 Hz, 1 H); 13CNMR (75 MHz, MeOH-d4) δ 138.4, 131.2, 131.1,129.4, 128.1, 128.0, 123.1, 122.0, 88.9, 88.4, 70.8, 64.4,55.6, 52.4, 50.1.

[0105] One-pot N-nosylation and bis-O-mesylation of 9 to obtain azetidine (2-(((2S,3S,4R)-4-(azidomethyl)-1-((2-nitrophenyl)sulfonyl)-3-(4-(phenylethynyl)phenyl)azetidine-2-yl)methyl)isoindoline-1,3-dione)12; tandem N-nucleophilic substitution [ka]

[0106] A suspension of 9 (2.00 g, 5.95 mmol) and triethylamine (4.97 mL, 35.7 mmol) in dichloromethane (20 mL) was cooled in an ice bath and treated with a solution of 2-nitrobenzenesulfonyl chloride (1.98 g, 8.92 mmol) in dichloromethane (10 mL) while maintaining an internal temperature below 6°C. The mixture was stirred at this temperature for 30 minutes until homogenized. The solution was then treated with methanesulfonyl chloride (1.39 mL, 17.8 mmol) and stirred at this temperature for 30 minutes. The reaction product was quenched with aqueous sodium hydroxide solution (1 M, 100 mL) and the mixture was placed in ethyl acetate (300 mL). The organic phase was separated, washed with brine (50 mL), and concentrated to obtain a crude product consisting of bis-mesylate 11 and an aziridine intermediate.

[0107] The crude product described above was placed in N,N-dimethylformamide (20 mL), treated with potassium carbonate (2.47 g, 17.8 mmol) and potassium phthalimide (1.65 g, 8.92 mmol), and stirred at room temperature for 60 hours. The reaction mixture was placed in ethyl acetate (400 mL), washed with water (100 mL) and brine (100 mL), and concentrated. The residue was placed in isopropanol (30 mL) and brought to a boil to obtain a homogeneous solution. This solution was slowly brought to room temperature while stirring, during which time the product precipitated. The product was filtered, washed with isopropanol (10 mL x 2), and dried under vacuum to obtain 12 (3.14 g, 83% yield) as an off-white solid. 1 H NMR(400 MHz, CDCl3) δ 8.15 (dd, J = 7.8, 1.5Hz, 1 H), 7.85 - 7.75 (m, 4 H), 7.72 - 7.69 (m, 3 H), 7.61 (d, J = 8.6 Hz, 2H), 7.57 - 7.54 (m, 2 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.39 - 7.35 (m, 3 H), 4.93(dt, J = 8.2, 6.7 Hz, 1 H), 4.55 (dt, J = 9.3, 3.9 Hz, 1 H), 4.23 (dd, J =14.4, 6.2 Hz, 1 H), 3.79 (t, J = 8.6 Hz, 1 H), 3.75 (dd, J = 14.4, 6.6 Hz, 1H), 3.71 (dd, J = 12.9, 5.1 Hz, 1 H), 3.60 (dd, J = 12.8, 9.3 Hz, 1 H); 13 CNMR (75 MHz, CDCl3) δ 167.6, 149.3, 134.8,134.0, 132.6, 132.2, 132.0, 131.8, 131.7, 131.6, 130.5, 128.4, 128.3, 127.4,124.3, 123.5, 123.3, 123.1, 90.4, 88.8, 62.5, 61.9, 48.7, 42.4, 37.5.

[0108] Preparation of (2-(((2S,3S,4R)-4-(azidomethyl)-1-(((4S,5R)-5-((R)-1,2-dihydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(4-(phenylethynyl)phenyl)azetidine-2-yl)methyl)isoindoline-1,3-dione)15 by deprotection and reductive amination of 12 [ka]

[0109] A clear, colorless solution of 12 (5.84 g, 9.23 mmol) and 1-dodecanethiol (2.65 mL, 11.1 mmol) in tetrahydrofuran (70 mL) was cooled to an internal temperature of 4°C in an ice bath. A solution of potassium tert-butoxide (1 M in THF, 11.1 mL, 11.1 mmol) was added dropwise while maintaining the internal temperature below 10°C, during which time the mixture turned dark red. The ice bath was removed and the mixture was allowed to rise to room temperature. The mixture was stirred at this temperature for 1 hour, then quenched with aqueous sodium bicarbonate solution (100 mL), and placed in ethyl acetate (200 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (150 mL x 3). The combined organic phases were dried on anhydrous sodium sulfate and then concentrated to obtain crude product 13 as a yellow, rubbery substance.

[0110] The crude product 13 was combined with 14 (2.11 g, 11.1 mmol) and placed in methanol (70 mL) to obtain a yellow solution, which was treated with acetic acid (2.64 mL, 46.2 mmol) and sodium cyanoborohydride (0.696 g, 11.1 mmol). After stirring the solution at room temperature for 24 hours, it was treated with additional acetic acid (2.64 mL, 46.2 mmol) and sodium cyanoborohydride (0.300 g, 4.78 mmol). After 12 hours, a third portion of sodium cyanoborohydride (0.300 g, 4.78 mmol) was added and the mixture was stirred for an additional 6 hours. The reaction mixture was placed in ethyl acetate (200 mL) and washed with 1 M sodium hydroxide (100 mL). The aqueous phase was separated and back-extracted with ethyl acetate (200 mL). The combined organic phases were washed with brine (100 mL) and concentrated. The residue was filtered through a silica gel (140 g) column and eluted with methylene chloride (700 mL) and then ethyl acetate (700 mL). Concentration of the ethyl acetate filtrate gave 15 (5.34 g, 93%) as a pale yellow foamy solid, which was used without further purification.

[0111] Oxidative cleavage of the 1,2-diol of 15 to give ((4S,5S)-5-(((2R,3S,4S)-2-(azidomethyl)-4-((1,3-dioxoisoindolin-2-yl)methyl)-3-(4-(phenylethynyl)phenyl)azetidin-1-yl)methyl)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde) 16

Chemical formula

[0112] A clear, colorless solution of 15 (5.34 g, 8.59 mmol) in tetrahydrofuran (64 mL) and water (6.4 mL) was treated with sodium periodate (2.76 g, 12.9 mmol). The mixture was stirred at room temperature for 2 hours, during which time the mixture became a white, milky suspension. The suspension was poured into ethyl acetate (500 mL) and washed successively with aqueous sodium thiosulfate (50 mL) and brine (50 mL). The organic phase was separated and dried over anhydrous sodium sulfate. Concentration of the organic phase afforded 16 as a white, foamy solid, which was used without purification.

[0113] Conversion of 16 to (2-(((3aR,6aR,7R,8S,10aS)-2,2-dimethyl-7-(4-(phenylethynyl)phenyl)octahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazocin-8-yl)methyl)isoindoline-1,3-dione) 18 using an aza-Wittig reaction followed by reduction

Chemical formula

[0114] The above crude 16 was taken up in methanol (30 mL) to give a clear, colorless solution. The solution was slowly added dropwise over 8 hours at room temperature to a stirred, white suspension of triphenylphosphine (2.70 g, 10.3 mmol) in methanol (50 mL), during which time the mixture became a colorless, homogeneous solution. The solution was stirred at this temperature for an additional 6 hours, after which acetic acid (2.46 mL, 43.0 mmol) and sodium cyanoborohydride (0.648 g, 10.3 mmol) were added. The mixture was stirred at this temperature for 4 hours and then concentrated. The residue was taken up in ethyl acetate (400 mL) and washed with 1 M sodium hydroxide (40 mL) and brine (40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to afford crude 18 as a colorless, gummy material.

[0115] Conversion from 18 to ((3aR,6aR,7S,8S,10aS)-8-((1,3-dioxoisoindoline-2-yl)methyl)-N-(4-methoxyphenyl)-2,2-dimethyl-7-(4-(phenylethynyl)phenyl)octahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazosin-5-carboxamide)19 [ka]

[0116] Crude product 18 was placed in dichloromethane (57 mL) and treated with 4-methoxyphenyl isocyanate (1.34 mL, 10.3 mmol). The mixture was maintained at room temperature for 30 minutes and then concentrated. Crystallization of the residue in a mixed solvent of isopropanol / acetonitrile (1:1, 100 mL) yielded 19 (1.60 g) as a white solid. The mother liquor was concentrated and purified using silica gel column chromatography eluted with 50%–60% ethyl acetate in heptane to obtain an additional 19 (1.0 g, combined yield of 12–43%). 1 H NMR(400 MHz, DMF-d7) δ 8.44 (s, 1H), 7.88 (s,4H), 7.74 (d, J = 8.2 Hz, 2H), 7.64 - 7.61 (m, 4 H), 7.51 - 7.44 (m, 3 H), 7.37- 7.33 (m, 2 H), 6.87 - 6.83 (m, 2 H), 4.50 - 4.47 (m, 1 H), 4.34 - 4.29 (m, 1H), 4.08 (br dd, J = 16.0, 5.0 Hz, 1 H), 3.97 (br dd, J = 16.0, 2.8 Hz, 1 H),3.87 - 3.65 (m, 6 H), 3.75 (s, 3 H), 3.52 (dd, J = 14.0, 4.6 Hz, 1 H), 3.48 (s,1 H), 3.10 (br t, J = 2.1 Hz, 1 H), 1.39 (s, 3 H), 1.37 (s, 3 H); 13CNMR (75 MHz, DMF-d7) δ 168.9, 163.3, 157.5,156.1, 138.5, 135.5, 135.0, 133.1, 132.6, 132.4, 132.3, 129.9, 129.8, 124.1,124.1, 122.4, 122.1, 114.8, 108.1, 90.5, 90.5, 78.9, 77.4, 68.0, 66.5, 59.0,56.1, 50.7, 47.4, 45.0, 39.7, 28.9, 26.3.

[0117] Hydrolysis of 19 phthalimides to obtain ((3aR,6aR,7S,8S,10aS)-8-(aminomethyl)-N-(4-methoxyphenyl)-2,2-dimethyl-7-(4-(phenylethynyl)phenyl)octahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazosin-5-carboxamide)20 [ka]

[0118] A white suspension of 19 (2.30 g, 3.30 mmol) in methanol (23 mL) was treated with ethanolamine (2.00 mL, 33.0 mmol). The mixture was stirred at 55°C for 12 hours, then refluxed for 12 hours, during which time the mixture became a homogeneous solution. The solution was treated with ethanolamine (1.50 mL, 24.8 mmol) and refluxed for 24 hours. By concentrating the solution, a colorless rubbery substance was obtained. This rubbery substance was placed in dichloromethane (300 mL), washed with water (50 mL x 2) and brine (50 mL), and dried on anhydrous sodium sulfate. By concentrating the rubbery substance, crude product 20 was obtained as a white waxy solid, and this crude product was used without purification.

[0119] Reductive amination and acetonide removal of 20 to obtain ((3S,4R,8R,9S,10S)-10-((dimethylamino)methyl)-3,4-dihydroxy-N-(4-methoxyphenyl)-9-(4-(phenylethynyl)phenyl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamide)22 [ka]

[0120] The crude product 20 described above was placed in methanol (18.7 mL) to obtain a suspension, which was then treated with formaldehyde (37%, 3.69 mmol, 49.5 mmol), acetic acid (1.13 mL, 19.8 mmol), and sodium borohydride cyanohydride (0.622 g, 9.90 mmol). The mixture was stirred at room temperature for 2 hours, then placed in ethyl acetate (150 mL), washed with aqueous sodium bicarbonate solution (10 mL) and brine (10 mL), dried on anhydrous sodium sulfate, and concentrated. The residue was passed through a silica gel pad eluted with 15% methanol in dichloromethane and concentrated to obtain the crude product ((3aR,6aR,7S,8S,10aS)-8-((dimethylamino)methyl)-N-(4-methoxyphenyl)-2,2-dimethyl-7-(4-(phenylethynyl)phenyl)octahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazosin-5-carboxamide)21 as a colorless, rubbery substance, which was used without further purification.

[0121] The crude product 21 described above was placed in a mixed solvent of tetrahydrofuran (14 mL) and 1 M hydrochloric acid (14 mL, 14 mmol) to obtain a colorless solution, which was stirred at 50°C for 12 hours. The solution was placed in ethyl acetate (300 mL), washed with 1 M sodium hydroxide (50 mL) and brine (50 mL), dried on anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (conditioned with 0.1% 7 M ammonia in methanol) eluting with 20-30% methanol in dichloromethane to obtain 22 (0.86 g, 52%) as a white waxy solid. 1 H NMR(400 MHz, MeOH-d4) δ 7.56 -7.51 (m, 6 H),7.42 - 7.36 (m, 3 H), 7.16 (d, J = 9.0 Hz, 2 H), 6.84 (d, J = 8.9 Hz, 2 H),4.19 (dd, J = 15.6, 6.6 Hz, 1 H), 4.14 - 4.10 (m, 1 H),3.83 - 3.78 (m, 2 H),3.76 (s, 3 H), 3.65 (dd, J = 14.4, 7.6 Hz, 1 H), 3.60 (br t, J = 7.1 Hz, 1 H),3.40 (br t, J = 8.8 Hz, 1 H), 3.30 (d, J = 10.5 Hz, 1 H), 2.84 (dd, J = 13.5,9.2 Hz, 1 H), 2.75 (dt, J = 15.2, 3.0 Hz, 1 H), 2.55 (dd, J = 13.3, 8.6 Hz, 1H), 2.45 (dd, J = 13.3, 2.4 Hz, 1 H), 2.05 (s, 6 H); 13 C NMR (75MHz, MeOH-d4) δ 160.2, 157.3, 138.7, 134.2,132.7, 132.5, 132.3, 129.7, 129.6, 124.8, 123.5, 123.3, 115.1, 90.5, 90.2,77.0, 74.0, 71.3, 66.8, 58.2, 57.7, 56.0, 53.0, 52.1, 46.9, 46.0

[0122] Path B synthesis Reduction of methyl 4 - bromocinnamate 1 to obtain 4 - bromocinnamyl alcohol 23

Chem.

[0123] Into a 3 L three - necked round - bottom flask, methyl 4 - bromocinnamate (1, 100 g, 414 mmol) and dichloromethane (1.1 L) were charged to obtain a clear solution. The solution was cooled in a dry ice - acetone bath to obtain an emulsion mixture. The mixture was treated with a solution of diisobutylaluminum hydride (25 wt% in toluene, 586 mL, 871 mmol) to obtain a pale green - tinged solution. The mixture was slowly brought to - 5 °C and carefully quenched in an ice bath with a solution of potassium sodium tartrate tetrahydrate (351 g, 1.24 mol) in water (800 mL). The mixture was stirred at room temperature overnight, treated with water (2 L), and extracted with methyl tert - butyl ether (1 L × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain 4 - bromocinnamyl alcohol (23, 87.5 g, 99%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.46 - 7.44 (m, 2 H),7.27 - 7. 25 (m, 2 H), 6.58 (d, J = 16.0 Hz, 1 H), 6.37 (dt, J = 15.6, 5.5 Hz,1 H), 4.33 (dd, J = 5.8, 1.5 Hz, 2 H)

[0124] Bromination of 4 - bromocinnamyl alcohol 23 to obtain 4 - bromocinnamyl bromide 24

Chem.

[0125] 4-bromosinamyl alcohol (23, 329 g, 1.54 mol) and diethyl ether (3 L) were added to a 5 L three-necked round-bottom flask. The mixture was cooled to 5°C using an ice bath, during which time the solution became slightly cloudy. A solution of tribromophosphan (72.6 mL, 772 mmol) in diethyl ether (200 mL) was added dropwise to the mixture while maintaining the internal temperature below 12°C, until a nearly clear solution was obtained at the end of the addition. The mixture was stirred in an ice bath for 1 hour, and then quenched by the slow addition of a solution of sodium bicarbonate (133 g, 1.57 mol) in water (1.5 L). The organic phase was separated and washed with brine (300 mL). The aqueous phase was extracted with methyl tert-butyl ether (1 L x 2). The combined organic phases were dried on anhydrous sodium sulfate and concentrated to obtain pure 24 (404g, 95%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.48 - 7. 45 (m, 2 H),7.25 - 7.24 (m, 2 H), 6.59 (d, J = 15.6 Hz, 1 H), 6.40 (dt, J = 15.6, 7.4 Hz, 1H), 4.15 (dt, J = 7.8, 0.7Hz, 2H)

[0126] Preparation of (ethyl(S,E)-2-((tert-butylsulfinyl)imino)acetate)25 [ka]

[0127] Zinc-mediated clotylation of 25 to obtain (ethyl(2S,3S)-3-(4-bromophenyl)-2-(((S)-tert-butylsulfinyl)amino)penta-4-enoic acid)26 [ka]

[0128] In a 5L three-necked round-bottom flask, 4-bromosinnamyl bromide (24, 175g, 6363 mmol), 25 (87g, 424 mmol), and N,N-dimethylformamide (1.3L) were added. The solution was sparged with nitrogen gas while stirring for 30 minutes. Zinc dust (55.4g, 848 mmol) was added in small amounts while maintaining the internal temperature below 48°C. The mixture initially turned green, then brown towards the end of the addition. After stirring the mixture at ambient temperature for 2 hours, the reactants were quenched with water (1.3L). The mixture was filtered through a Celite pad and rinsed with methyl tert-butyl ether. The filtrate was added to water (1.3L), and the aqueous phase was extracted with methyl tert-butyl ether (870mL x 2). The combined organic phases were concentrated, filtered through a Celite pad, and rinsed with a small amount of methyl tert-butyl ether. The filtrate was concentrated, and the residue was purified by silica gel column chromatography using ethyl acetate in heptane to obtain 26 (111 g, 65.2%) as a pale yellow oil. 1 H NMR(400 MHz, CDCl3) δ 7.44 - 7.40 (m, 2 H),7.05 - 7.03 (m, 2 H), 6.05 - 5.96 (m, 1 H), 5.17 - 5.11 (m, 2 H), 4.20 - 4.12(m, 3 H), 3.91 (d, J = 9.4 Hz, 1 H), 3.67 (t, J = 7.8 Hz, 1 H), 1.25 (s, 3 H)

[0129] Conversion of sulfinamide 26 to (ethyl(2S,3S)-3-(4-bromophenyl)-2-((2-nitrophenyl)sulfonamide)penta-4-enoic acid) 27 [ka]

[0130] A solution of 26 (2.48 g, 5.30 mmol) in tetrahydrofuran (21 mL) was treated with concentrated hydrogen chloride (37%, 2.18 mL, 26.5 mmol) and stirred at room temperature for 2 hours. The reaction mixture was quenched with aqueous sodium bicarbonate (20 mL), followed by solid sodium bicarbonate, and the mixture was no longer acidic. The mixture was extracted with methyl tert-butyl ether (200 mL x 3), dried on anhydrous sodium sulfate, and concentrated to obtain a dark yellow oil.

[0131] The oil was placed in dichloromethane (16 mL) and treated with 2-nitrobenzenesulfonyl chloride (1.29 g, 5.83 mmol) and triethylamine (1.11 mL, 7.95 mmol) to obtain an orange solution, which was stirred overnight at room temperature. The mixture was placed in methyl tert-butyl ether (200 mL) and washed with 1 M sodium hydroxide (30 mL). The aqueous phase was extracted with methyl tert-butyl ether (50 mL). The combined organic phase was dried on anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography eluted with ethyl acetate in heptane at a concentration of 15-40%, yielding 27 (2.29 g, 89%) as a pale yellow, rubbery substance. 1 H NMR(400 MHz, MeOH-d4) δ 7.50 - 7.32 (m, 3 H),7.23 - 7.19 (m, 2 H), 7.10 - 7.07 (m, 2 H), 5.97 - 5.88 (m, 1 H), 5.01 (dd, J =17.0, 1.0 Hz, 1 H), 4.95 (dd, J = 10.1, 1.3 Hz, 1 H), 4.06 (d, J = 10.5 Hz, 1H), 4.03 - 3.92 (m, 2 H), 3.58 (t, J = 9.8 Hz, 1 H), 1.76 (t, J = 7.0 Hz, 3 H)

[0132] Iodlactonization and azido substitution of 27 to obtain (N-((3S,4S,5S)-5-(azidomethyl)-4-(4-bromophenyl)-2-oxotetrahydrofuran-3-yl)-2-nitrobenzenesulfonamide)29 [ka]

[0133] A solution of 27 (10.0 g, 20.7 mmol) in acetonitrile (80 mL) and water (3.2 mL) was treated with iodine (10.5 g, 41.3 mmol) to obtain a dark red solution. When this solution was stirred at room temperature, all the starting materials were consumed. The reactants were quenched with an excess aqueous sodium thiosulfate solution and stirred at room temperature, resulting in a pale yellow mixture. The mixture was placed in methyl tert-butyl ether, washed with brine, dried on anhydrous sodium sulfate, and concentrated to obtain the crude product (N-((3S,4S,5S)-4-(4-bromophenyl)-5-(iodomethyl)-2-oxotetrahydrofuran-3-yl)-2-nitrobenzenesulfonamide) 28 (12 g) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.89 (dd, J = 8.1, 1.4Hz, 1 H), 7.81 (dd, J = 8.0, 1.4 Hz, 1 H), 7.72 (dt, J = 7.8, 1.5 Hz, 1 H),7.62 (dt, J = 7.8, 1.2 Hz, 1 H), 7.44 - 7.41 (m, 2 H), 7.15 - 7.12 (m, 2 H),6.25 (d, 9.0 Hz, 1 H), 4.81 (dd, J = 12.1, 9.0 Hz, 1 H), 4.27 - 4.22 (m, 1 H),3.48 - 3.41 (m, 2 H), 3.24 (dd, J = (11.9, 4.9 Hz, 1 H)

[0134] Crude product 28 was placed in N,N-dimethylformamide (65 mL) and treated with sodium azide (2.02 g, 31.0 mmol) to obtain a yellow suspension, which was stirred overnight at room temperature. The mixture was placed in methyl tert-butyl ether, washed with water and brine, dried on anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluted with ethyl acetate in heptane to obtain 29 (7.90 g, 77%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.84 (dd, J = 8.0, 0.9Hz, 1 H), 7.75 (dd, J = 7.8, 1.2 Hz, 1 H), 7.69 (dt, J = 7.6, 1.3 Hz, 1 H),7.57 (dt, J = 7.6, 1.2 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 2 H), 7.09 (d, J = 8.6Hz, 2 H), 6.46 (d, J = 9.0 Hz, 1 H), 4.79 (dd, J = 12.1, 9.0 Hz, 1 H), 4.58 -4.53 (m, 1 H), 3.63 - 3.53 (m, 2 H), 3.38 (dd, J = 13.9, 4.9 Hz, 1H)

[0135] Reduction of 29 to obtain (N-((2S,3S,4S)-5-azido-3-(4-bromophenyl)-1,4-dihydroxypentan-2-yl)-2-nitrobenzenesulfonamide)30 [ka]

[0136] A yellow solution of 29 (9.10 g, 18.3 mmol) in ethanol (80 mL) was treated with small amounts of sodium borohydride (1.04 g, 27.5 mmol), during which the mixture turned dark purple. The reaction mixture was stirred at room temperature for 1 hour, and then quenched with 1 M HCl. The mixture was placed in methyl tert-butyl ether, washed with water and brine, dried on anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluting with 50-80% ethyl acetate in heptane to obtain 30 (8.20 g, 89%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 8.17 - 8.15 (m, 1 H),7.92 - 7.89 (m, 1 H), 7.80 - 7.75 (m, 2 H), 7.48 (d, J = 8.6 Hz, 2 H), 7.10 (d,J = 8.2 Hz, 2 H), 5.45 (d, J = 9.0 Hz, 1 H), 4.41 - 4.37 (m, 1 H), 4.16 - 4.11(m, 1 H), 3.72 (brs, 1 H), 3.44 (dd, J = 11.4, 5.5 Hz, 1 H), 3.30 (dd, J =11.3, 7.0 Hz, 1 H), 3.23 (dd, J = 12.9, 2.7 Hz, 1 H), 3.00 - 2.91 (m, 2 H)

[0137] Bis-mesylation and tandem N-nucleophilic substitution to convert 30 to azetidine (2-(((2S,3S,4R)-4-(azidomethyl)-3-(4-bromophenyl)-1-((2-nitrophenyl)sulfonyl)azetidine-2-yl)methyl)isoindoline-1,3-dione)32 [ka]

[0138] A solution of 30 (5.37 g, 10.7 mmol) and triethylamine (5.98 mL, 42.9 mmol) in dichloromethane (50 mL) was cooled to 0°C and treated dropwise with methanesulfonyl chloride (2.08 mL, 26.8 mmol). The pale yellow, turbid mixture was stirred at this temperature for 2 hours, and then the reaction was quenched with an aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried on anhydrous sodium sulfate and concentrated to obtain a crude product consisting of 31 and an aziridine intermediate.

[0139] The residue was placed in N,N-dimethylformamide (35 mL), treated with potassium carbonate (4.45 g, 32.2 mmol) and potassium phthalimide (2.39 g, 12.9 mmol), and stirred at room temperature for 84 hours. The mixture was placed in ethyl acetate, washed with water and brine, dried on anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate in heptane, yielding 32 (4.92 g, 75%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 8.14 (dd, J = 7.9, 1.6Hz, 1 H), 7.83 - 7.70 (m, 7 H), 7.58 (d, J = 8.6 Hz, 2 H), 7.33 (d, J = 8.2 Hz,2 H), 4.91 (dd, J = 14.9, 6.7 Hz, 1 H), 4.56 - 4.50 (m, 1 H), 4.18 (dd, J =17.7, 6.0 Hz, 1 H), 3.77 - 3.68 (m, 3 H), 3.55 (dd, J = 12.7, 9.6 Hz, 1 H)

[0140] Deprotection and reductive amination to convert 32 to (2-(((2S,3S,4R)-4-(azidomethyl)-3-(4-bromophenyl)-1-(((4S,5R)-5-((R)-1,2-dihydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)azetidine-2-yl)methyl)isoindoline-1,3-dione)35 [ka]

[0141] A solution of 32 (1.35 g, 2.21 mmol) and 1-dodecanethiol (0.635 mL, 2.65 mmol) in tetrahydrofuran (10 mL) was treated dropwise with a solution of potassium tert-butoxide (1 M in tetrahydrofuran, 2.65 mL, 2.65 mmol) at room temperature, and then stirred for 5 hours. The mixture was placed in ethyl acetate, washed with brine, dried on anhydrous sodium sulfate, and concentrated to obtain the crude product (2-(((2S,3S,4R)-4-(azidomethyl)-3-(4-bromophenyl)azetidine-2-yl)methyl)isoindoline-1,3-dione)33 as a yellow, rubbery substance.

[0142] Crude product 33 (0.469 g, 1.10 mmol) and a mixture of ((3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofl[3,4-d][1,3]dioxol-4-ol) 34 (0.29 g, 1.53 mmol) were placed in methanol (5 mL), treated with acetic acid (0.315 mL, 5.50 mmol) and sodium borohydride cyanohydride (0.104 g, 1.65 mmol), and stirred at room temperature until the reaction was complete. The mixture was placed in ethyl acetate, washed with 1 M sodium hydroxide and brine, dried on anhydrous sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography eluting with methanol in dichloromethane to obtain 35 (365 mg, 55%) as a colorless oil. 1H NMR(400 MHz, CDCl3) δ 7.77 - 7.74 (m, 2 H),7.71 - 7.67 (m, 2 H), 7.52 (d, J = 8.2 Hz, 2 H), 7.19 (d, J = 8.6 Hz, 2 H),6.11 (brs, 1 H), 4.53 - 4.48 (m, 1 H), 4.31 (dd, J = 9.3, 6.2 Hz, 1 H), 3.93 -3.75 (m, 7 H), 3.58 (dd, J = 13.9, 7.3 Hz, 1 H), 3.51 -3.46 (m, 1 H), 3.32 -3.24 (m, 2 H), 2.77 (dd, J = 12.5, 3.9Hz, 1H), 2.49 (brs, 1H), 1.41 (s, 3H), 1.33 (s, 3H)

[0143] Reductive amination of 33 using ((3aR,6aR)-2,2-dimethyltetrahydrofl[3,4-d][1,3]dioxol-4-ol)36 to obtain (2-(((2S,3S,4R)-4-(azidomethyl)-3-(4-bromophenyl)-1-(((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)azetidine-2-yl)methyl)isoindoline-1,3-dione)37 [ka]

[0144] Crude products 35 (2.72 g, 6.38 mmol) and 36 (1.53 g, 9.57 mmol) were placed in methanol (40 mL) and acetic acid (1.83 mL, 31.9 mmol), and treated with sodium borohydride cyanohydride (0.601 g, 9.57 mmol). The mixture was stirred at room temperature, and the reaction was completed. The mixture was placed in methyl tert-butyl ether (500 mL) and washed with 1 M sodium hydroxide (50 mL) and brine (50 mL). The aqueous phase was back-extracted with methyl tert-butyl ether (100 mL x 2). The combined organic phase was dried on anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (conditioned with 70 mM ammonia) eluted with methanol in dichloromethane to obtain 37 (2.34 g, 64%) as a white foamy solid. 1 H NMR(400 MHz, CDCl3) δ 7.75 - 7.71 (m, 2 H),7.68 - 7.64 (m, 2 H), 7.48 - 7.45 (m, 2 H), 7.23 - 7.21 (m, 2 H), 4.43 - 4.34(m, 2 H), 4.01 (brs, 1 H), 3.81 - 3.66 (m, 6 H), 3.50 (dd, J = 13.7, 6.6 Hz, 1H), 3.42 (dd, J = 12.7, 6.5 Hz, 1 H), 3.21 (dd, 12.7, 6.5 Hz, 1 H), 3.08 (dd,12.9, 7.8Hz, 1H), 2.76 (dd, J = 12.9, 5.1 Hz, 1 H), 1.41 (s, 3 H), 1.31 (s, 3H)

[0145] Oxidative cleavage of 35 to obtain ((4S,5S)-5-(((2R,3S,4S)-2-(azidomethyl)-3-(4-bromophenyl)-4-((1,3-dioxoisoindolin-2-yl)methyl)azetidine-1-yl)methyl)-2,2-dimethyl-1,3-dioxolan-4-carbaldehyde)38 [ka]

[0146] A solution of 35 (2.73 g, 4.55 mmol) in tetrahydrofuran (33 mL) and water (3.6 mL) was treated with sodium periodate (1.46 g, 6.82 mmol) and stirred at room temperature for 2 hours to obtain a white suspension. The mixture was placed in methyl tert-butyl ether (500 mL) and washed with aqueous sodium thiosulfate (100 mL) and aqueous sodium bicarbonate (100 mL). The combined aqueous phase was back-extracted with methyl tert-butyl ether (150 mL x 2). The combined organic phase was dried on anhydrous sodium sulfate and concentrated to obtain 38 as a colorless rubbery substance, which was used without purification. 1 H NMR(400 MHz, CDCl3) δ 9.79 (d, J = 2.7 Hz, 1H), 7.78 - 7.75 (m, 2 H), 7.71 - 7.68 (m, 2 H), 7.52 - 7.49 (m, 2 H), 7.31 -7.29 (m, 2 H), 4.54 - 4.51 (m, 1 H), 4.47 - 4.44 (m, 2 H), 3.79 - 3.3.61 (m, 4H), 3.46 - 3.40 (m, 2 H), 3.21 - 3.19 (m, 1 H), 2.96 (dd, J = 13.7, 4.7 Hz, 1H), 2.80 (dd, J = 13.7, 5.5Hz, 1H), 1.60 (s, 3H), 1.41 (s, 3H)

[0147] Oxidation of 37 to obtain 38 [ka]

[0148] A solution of 37 (900 mg, 1.58 mmol) in dichloromethane (10 mL) was treated with Dess Martin periodinane (803 mg, 1.89 mmol) and stirred at room temperature for 3 hours. The mixture was placed in ethyl acetate, washed with aqueous sodium thiosulfate solution, 1 M sodium hydroxide, and brine, dried on anhydrous sodium sulfate, and concentrated to obtain 38 as a colorless, rubbery substance, which was used without purification.

[0149] 38 Aza-Wittig reactions and subsequent reductions to obtain (2-(((3aR,6aR,7R,8S,10aS)-7-(4-bromophenyl)-2,2-dimethyloctahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazosin-8-yl)methyl)isoindoline-1,3-dione)40 [ka]

[0150] A clear solution was obtained by slowly adding a solution of crude product 38 in methanol (39 mL) and tetrahydrofuran (7.8 mL) to a suspension of triphenylphosphan (1.79 g, 6.82 mmol) in methanol (13 mL) over 12 hours. After a further 3 hours, the solution was treated with acetic acid (0.78 mL, 13.6 mmol) and sodium borohydride cyanohydride (0.343 g, 5.46 mmol) and stirred for 3 hours. The mixture was placed in methyl tert-butyl ether, washed with 1 M sodium hydroxide and brine, dried on anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluted with ethyl acetate to obtain 40 (1.88 g, 79%) as a white solid. 1H NMR(400 MHz, CDCl3) δ 7.81 - 7.77 (m, 2 H),7.71 - 7.64 (m, 2 H), 7.46 - 7.44 (m, 2 H), 7.40 - 7.38 (m, 2 H), 4.87 (brs, 3H), 4.39 - 4.34 (m, 1 H), 4.28 - 4.24 (m, 1 H), 3.75 (dd, J = 14.0, 5.5 Hz, 1H), 3.70 - 3.65 (m, 1 H), 3.60 - 3.55 (m, 2 H), 3.47 (dd, J = 14.2, 5. 3 Hz, 1H), 3.28 (dd, J = Hz, 1H), 3.27 (dd, J = 14.6, 9.8 Hz, 1 H), 3.08 (dd, J =14.7, 2.2 Hz, 1 H), 2.90 (dd, J = 13.2, 4.3 Hz, 1 H), 2.79 (dd, J = 13.6, 8.6Hz, 1 H), 2.71 - 2.60 (m, 2 H), 1.36 (s, 3 H), 1.32 (s, 3 H)

[0151] Conversion from 40 to ((3aR,6aR,7S,8S,10aS)-7-(4-bromophenyl)-8-((1,3-dioxoisoindoline-2-yl)methyl)-N-(4-methoxyphenyl)-2,2-dimethyloctahydro-5H-azeto[1,2-a][1,3]dioxolo[4,5-f][1,4]diazosin-5-carboxamide)41 [ka]

[0152] A solution of 40 (70 mg, 0.133 mmol) in dichloromethane (1.5 mL) was treated with 4-methoxyphenyl isocyanate (0.026 mL, 0.199 mmol) and triethylamine (0.028 mL, 0.199 mL) and maintained at room temperature for 2 hours. The mixture was concentrated, and the residue was purified using silica gel column chromatography eluted with approximately 60% ethyl acetate in heptane to obtain 41 (67 mg, 75%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 8.35 (s, 1 H), 7.85 -7.80 (m, 2 H), 7.73 - 7.69 (m, 2 H), 7.51 - 7.45 (m, 4 H), 7.23 - 7.19 (m, 2H), 6.85 - 6.80 (m, 2 H), 4.38 (d, J = 16.8 Hz, 1 H), 4.29 (brs, 2 H), 4.16 -4.10 (m, 1 H), 3.86 - 3.77 (m, 2 H), 3.77 (s, 3 H), 3.65 - 3.47 (m, 4 H), 2.79- 2.73 (m, 1H), 2.64 - 2.61 (m, 2 H), 1.44 (s, 3 H), 1.41 (s, 3 H)

[0153] Hydrolysis of acetonide 41 to obtain ((3S,4R,8R,9S,10S)-9-(4-bromophenyl)-10-((1,3-dioxoisoindolin-2-yl)methyl)-3,4-dihydroxy-N-(4-methoxyphenyl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamide) 42 [ka]

[0154] A solution of 41 (5.0 mg, 0.0074 mmol) in tetrahydrofuran (1 mL) and 1 M HCl (1 mL) was stirred at 50°C for 3 hours. The solution was concentrated, and the residue was purified by reverse-phase preparative HPLC to obtain 42 (3.8 mg, 81%) as a white solid. 1H NMR(400 MHz, CD3OD) δ 7.79 - 7.73 (m, 4 H),7.52 - 7.46 (m, 4 H), 7.11 - 7.07 (m, 2 H), 6.80 - 6.76 (m, 2 H), 4.14 (dd, J =15.5, 6.5 Hz, 1 H), 4.08 - 4.07 (m, 1 H), 3.82 - 3.68 (m, 4 H), 3.71 (s, 3 H),3.33 - 3.27 (m, 2 H), 2.82 - 2.73 (m, 2 H), 2.82 - 2.73 (m, 2 H), 2.67 - 2.63(m, 1H)

[0155] Compound 42 can be converted to compound 22 according to the procedure described above. See, for example, pages 53-55 of International Publication 2018 / 175385, which is incorporated entirely herein by reference. This process is shown in a concise form as follows: [ka]

[0156] The structures of compounds 5 and 32 were confirmed by X-ray crystallography. The ORTEP projections for compounds 5 and 32 are provided in Figures 1 and 2, respectively. ORTEP is an acronym for Oak Ridge thermal ellipsoid plot, which is a representation of molecular structure as determined by X-ray diffraction.

[0157] Further procedures that can be used in combination with or independently of the above procedures are shown below.

[0158] To obtain 13, hydrolysis of 12 o-nitrophenylsulfonamide using thioglycolic acid. [ka]

[0159] Add 12 (1.0 w / w, 1.0 equivalent), methanol (12 v / w), and tetrahydrofuran (4 v / w) to the reactor at room temperature. Add thioglycolic acid (0.221 v / w, 0.291 w / w, 2.0 equivalents) and potassium carbonate (0.874 w / w, 4.0 equivalents) one at a time. Heat the mixture to an internal temperature of 50°C and stir for 3 hours. Monitor the complete consumption of 12 using LCMS / UV on aliquots of the reaction mixture. Pour the reaction mixture into a separation vessel containing ethyl acetate (25 v / w) and water (18 v / w) for extraction. Back-extract the aqueous phase twice with ethyl acetate (12 v / w). Combine with the organic phase and wash with aqueous sodium bicarbonate (12 v / w) and then 50% brine (12 v / w). Dry the organic phase over anhydrous sodium sulfate. Filter the organic phase and evacuate under house vacuum (T bath By concentrating the product using a rotary evaporator (at 37°C), crude product 13 (approximately 0.8 v / w, quantitative) is obtained as a yellow, rubbery substance. Reaction volume: 17 v / w Post-processing volume: 65V / W Expected yield (%): Quantitative Maximum scale: 12g of 20g 1 H NMR(400 MHz, CDCl3) δ 7.84 - 7.82 (m, 2 H),7.72 - 7.67 (m, 2 H), 7.62 - 7.52 (m, 6 H), 7.39 - 7.32 (m, 3 H), 4.50 (dt, J =7.6, 4.5 Hz, 1 H), 4.25 (dd, J = 14.1, 7.0 Hz, 1 H), 3.91 (dd, J = 14.3, 7.8Hz, 1 H), 3.79 (t, J = 7.6 Hz, 1 H), 3.53 (dd, J = 14.2, 4.4 Hz, 1 H), 3.35(dd, J = 12.6, 7.1Hz, 1H), 3.20 (dd, J = 12.6, 6.6 Hz, 1 H); 13CNMR (75 MHz, CDCl3) δ168.2, 135.6, 134.3,134.0, 132.0, 131.6, 131.6, 130.6, 128.4, 128.3, 123.3, 122.5, 89.9, 89.2,57.5, 57.2, 52.0, 46.7, 40.2

[0160] Reductive amination of 13 using 14 to obtain 15-HCl (HCl salt of 15) [ka]

[0161] Crude products 13 (prepared as described above, 1.0 w / w, 1.0 equivalent), 14 (0.850 w / w, 2.0 equivalents), and ethanol (10 v / w) are added to the reactor. To this mixture, acidic acid (0.640 v / w, 0.671 w / w, 5.0 equivalents) and then sodium borohydride cyanohydride (0.281 w / w, 2.0 equivalents) are added all at once at room temperature. 1 Stir the mixture at room temperature for 12-18 hours. Monitor the complete consumption of 13 aliquots of the reactants using LC-MS / UV. Saturated sodium bicarbonate aqueous solution (18v / w), 2 Next, the reaction mixture is quenched with ethyl acetate (35 v / w) and the mixture is stirred at room temperature for 10 minutes. The two phases are separated using a separation vessel, and the aqueous phase is back-extracted twice with ethyl acetate (15 v / w). The organic phases are combined, washed with brine (18 v / w), and dried over anhydrous sodium sulfate. Filter and then (T) under house vacuum. bath The organic phase is concentrated using a rotary evaporator (37°C). Insoluble matter is removed by placing the residue in ethyl acetate (35V / W) and filtering through a silica gel plug. The clarified filtrate is cooled on an ice bath. 3 Slowly add a 4M HCl-dioxane solution (0.071 v / w, 1.05 equivalents) over 10 minutes. Stir the white suspension in an ice bath for 10 minutes, then stop stirring and allow the mixture to precipitate as a white solid for another 20 minutes. 4The mixture is filtered to obtain a clear supernatant first, followed by a suspension of a white solid. The filter cake is washed with ethyl acetate. The filter cake is dried in a house vacuum drying oven at 40°C to obtain 15-HCl (0.813 w / w, 55%) as a white solid. Expected Revenue (%): >55% Maximum scale: 12g of 20g 1 H NMR(400 MHz, MeOH-d4) δ7.83 - 7.78 (m, 4 H),7.57 - 7.51 (m, 6 H), 7.40 - 7.38 (m, 3 H), 5.4208 (dt, J = 9.7, 6.6 Hz, 1 H),4.93 - 4. 85 (m, 1 H), 4.59 (dd, 8.5, 6.5 Hz, 1 H), 4.45 - 4.34 (m, 2 H), 4.21(dd, J = 8.7, 6.4 Hz, 1 H), 4.14 - 3.94 (m, 3 H), 3.76 (d, J = 9.0 Hz, 1 H),3.69 - 3.58 (m, 4 H), 1.48 (s, 3 H), 1.08 (s, 3 H); 13 C NMR (75 MHz,MeOH-d4) δ168.9, 135.7, 133.1, 133.1, 132.6,132.5, 131.9, 131.8, 129.8, 129. 6, 125.2, 124.4, 124.2, 111.6, 91.5, 89.2,77.5, 74.4, 71.0, 69.2, 68.9, 65.0, 59.3, 43.7, 37.5, 28.1, 25.2

[0162] Oxidative cleavage of 1,2-diol 15-HCl using sodium periodate [ka]

[0163] Add compound 15-HCl (1.0 w / w, 1.0 equivalent), tetrahydrofuran (15 v / w, 13.2 w / w), and water (5 v / w, 5 w / w) to the reactor. Add sodium periodate (0.650 w / w, 2.0 equivalents) one fraction at a time. Stir the mixture at room temperature for 1-2 hours. Monitor the complete consumption of 15 using LCMS / UV on aliquots of the reaction mixture. Pour the mixture into ethyl acetate (36 v / w, 32.4 w / w) and wash with aqueous sodium bicarbonate (12 v / w) and then 50% brine (12 v / w). Dry the organic phase over anhydrous sodium sulfate and filter. (T bath By concentrating the filtrate using a rotary evaporator (at 37°C), crude product 16 (approximately 0.9 w / w, quantitative) is obtained as a colorless oil. Expected yield (%): 100% Maximum scale: 8.3g of 15·HCl 1 H NMR(400 MHz, CDCl3) δ9.82 (d, J = 2.8 Hz, 1 H),7.79 - 7.76 (m, 2 H), 7.71 - 7.67 (m, 2 H), 7.58 - 7.53 (m, 4 H), 7.44 - 7.42(m, 2 H), 7.39 - 7.35 (m, 3 H), 4.55 (dd, J = 11.9, 5.8 Hz, 1 H), 4.48 (dd, J =7.2, 2.8 Hz, 1 H), 3.82 - 3.67 (m, 3 H), 3.50 - 3.41 (m, 2 H), 3.27 - 3.22 (m,1 H), 2.98 (dd, J = 13.6, 4.7 Hz, 1 H), 2.82 (dd, J = 13.6, 5.7 Hz, 1 H), 1.61(s, 3 H), 1.42 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ199.9, 167.8, 135.3, 134.0, 131.8, 131.7, 131.6, 130.6, 128.3,128.2, 123.3, 123.2, 122.4, 110.9, 89.8, 89.2, 81.4, 66.7, 66.4, 56.9, 50.2,44.2, 38.1, 27.3, 22.7

[0164] Tandemstaudinger / Aser-Wittig / reduction for converting 16 to 18·HCl [ka]

[0165] Add triphenylphosphine (0.128 w / w, 1.2 equivalents) and ethanol (7 v / w, 5.52 w / w) to the reactor. To this mixture, slowly add a solution of crude product 16 (prepared as described above, 1.0 w / w, 1.0 equivalent) in ethanol (10 v / w, 7.89 w / w) and tetrahydrofuran (5 v / w, 4.40 w / w) over 1.5 hours at room temperature. Stir the reaction mixture further at room temperature for 12 hours and monitor the complete consumption of 16 using LCMS / UV on aliquots of the reaction mixture. Add sodium borohydride (0.128 w / w, 1.2 equivalents) and acetic acid (0.291 v / w, 0.306 w / w, 3.0 equivalents) in 1 fraction each. 1 Add at room temperature. Stir the mixture at the same temperature for 0.5 to 1 hour and monitor for the complete consumption of the imine intermediate (not shown) using LCMS / UV on aliquots of the reaction mixture. Quench the reactants with aqueous sodium bicarbonate (30 v / w) and extract with ethyl acetate (30 v / w). Extract the aqueous phase twice more with ethyl acetate (12 v / w). Combine the organic phases, wash with brine (12 v / w), and dry on anhydrous sodium sulfate. Filter the organic phase and evaporate under house vacuum (T bathThe solution is concentrated using a rotary evaporator (at 37°C). Insoluble matter is removed by placing the residue in ethyl acetate (35 v / w) and filtering. The solution is cooled in an ice bath. 4M HCl-dioxane solution (0.054 v / w, 0.065 w / w, 1.05 equivalents) is slowly added over 10 minutes with stirring. The resulting white suspension is stirred further in an ice bath for 10 minutes, then the stirring is stopped and the mixture is held for another 20 minutes to allow the precipitation of a white solid. 2 The mixture is filtered, and the filter cake is washed with ethyl acetate. The filter cake is dried in a house vacuum drying oven at 40°C to obtain 18-HCl (0.81 w / w, 82%) as a white solid. Expected yield (%): 80% Maximum scale: 8.3g of 18-HCl 1) Additional spectral data [ka] Compound 18: 1 HNMR (400 MHz, CDCl3) δ7.82 - 7.78 (m, 2 H),7.71 - 7.65 (m, 2 H), 7.55 - 7.49 (m, 6 H), 7.38 - 7.31 (m, 3 H), 4.40 - 4.35(m, 1 H), 4.23 - 4.19 (m, 1 H), 3.79 (dd, J = 14.2, 5.5 Hz, 1 H), 3.70 (dd, J =11.7, 6.0 Hz, 1 H), 3.51 (dd, J = 14.2, 5.2 Hz, 1 H), 3.28 (dd, J = 14.6, 8.5Hz, 1 H), 3.09 (dd, J = 14.6, 2.4 Hz, 1 H), 2.87 - 2.68 (m, 3 H), 2.59 (brd, J= 13.3 Hz, 1 H), 1.74 (brs, 1 H), 1.39 (s, 3 H), 1.33 (s, 3 H); 13CNMR (75 MHz, CDCl3) δ167.9, 136.6, 133.9,131.9, 131.5, 131.2, 130.8, 128.3, 128.1, 123.3, 123.2, 121.8, 106.8, 89.5,89.3, 77.7, 68.2, 65.1, 57.7, 48.7, 45.5, 44.7, 38.5, 27.8, 25.1

Chem.

[0166] While embodiments of the present invention have been described in relation to specific illustrative embodiments and examples, the embodiments disclosed herein are for illustrative purposes only, and it will be acknowledged that various modifications and changes can be made by those skilled in the art without departing from the spirit and scope of the invention as described in the following claims.

Claims

1. Formula IV-1 【Chemistry 1】 (In formula IV-1, R １ is -I, -Cl, -Br, or 【Chemistry 2】 And; P1 is 9-fluorenylmethylcarbamate, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, or -H. A method for forming a compound represented by formula V 【Transformation 3】 The lactone of formula I 【Chemistry 4】 (In equations V and I, R １ is -I, -Cl, -Br, or 【Transformation 5】 And; R ２ is C(O)R ３ And; R ３ is -OH, -O alkyl, -O － And; R ３ ga-O － In this case, the positive counterion forms an ionic bond with formula I; P １ is 9-fluorenylmethyl carbamate or -C(O)CF3) A step of forming from a compound; The lactone of formula V is converted to formula VI 【Transformation 6】 (In formula VI, R １ is -I, -Cl, -Br, or 【Transformation 7】 And; P １ (This is 9-fluorenylmethylcarbamate, -C(O)CF3, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, or -H) The step of reducing to the compound; and A method comprising the step of forming an intermediate that reacts with phthalimide to produce a compound of formula IV-1 by converting the alcoholic group of formula VI to a leaving group.

2. In formula IV-1, R １ but, 【Transformation 8】 The method according to claim 1, wherein P1 is 2-nitrobenzenesulfonyl.

3. The lactone of formula V is used to form compound I. ２ The method according to claim 1, which is formed by reacting with a polar solvent.

4. The aforementioned polar solvent is CH ３ The method according to claim 3, wherein the aqueous mixture is of CN.

5. The lactone of formula V is used to form compound I. ２ The first product is formed by reacting it with a polar solvent, and the first product is converted into NaN ３ The method according to claim 3, wherein the compound of formula V is formed by reacting with [another compound].

6. The aforementioned reduction step is NaBH ４ The method according to claim 1, which is carried out using

7. The leaving group is a mesylate group, and the intermediate has the following structure: 【Chemistry 9】 (In formulas VII and VIIb, R １ is -I, -Cl, -Br, or 【Chemistry 10】 And; P １ (This is 2-nitrobenzenesulfonyl or 4-nitrobenzenesulfonyl.) The method according to claim 1, as shown by one or both of the above.

8. P in equation VI １ However, the structure is as follows: 【Chemistry 11】 The method according to claim 1.

9. In formula I, R １ However, it is -Br, and R ２ The method according to claim 1, wherein the compound is -C(O)OH or -C(O)O-.

10. Compounds of formula XV: 【Chemistry 12】 [In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 13】 And, Z is, 【Chemistry 14】 (wherein P1 is 9-fluorenylmethylcarbamate, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, or -H); is] or a pharmaceutically acceptable salt thereof.

11. Formula XV: 【Chemistry 15】 [In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 16】 And; Z is, 【Chemistry 17】 (In the formula, R ２ is C(O)R ３ And; R ３ is, -O － Therefore, the positive counterion forms an ionic bond with formula XV, or R ３ is -OH; P １ (This is 9-fluorenylmethylcarbamate or -C(O)CF3); [Chemistry 18] (In the formula, P １ (This is 9-fluorenylmethylcarbamate or -C(O)CF3); 【Chemistry 19】 (In the formula, P １ (is 9-fluorenylmethylcarbamate, -C(O)CF3, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, or -H); 【Chemistry 20】 (In the formula, P １ (is 9-fluorenylmethylcarbamate, -C(O)CF3, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl or -H); and 【Chemistry 21】 (In the formula, P １ (wherein this is 9-fluorenylmethylcarbamate, -C(O)CF3, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, or -H) or a pharmaceutically acceptable salt thereof. Selected from the group consisting of: A compound having or a pharmaceutically acceptable salt thereof.

12. Formula I: 【Chemistry 22】 (In the formula, R １ teeth, 【Chemistry 23】 And; R ２ is C(O)R ３ And; R ３ is, -O － Therefore, the positive counterion forms an ionic bond with formula I, or R ３ is -OH; P １ (This is -C(O)CF3) The compound or pharmaceutically acceptable salt thereof according to claim 11.

13. Formula VI: 【Chemistry 24】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 25】 P １ (This is -C(O)CF3 or -H) The compound or pharmaceutically acceptable salt thereof according to claim 11.

14. Formula VII: 【Chemistry 26】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 27】 P １ (This is 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, or -H) The compound or pharmaceutically acceptable salt thereof according to claim 11.

15. Equation VIIb: 【Chemistry 28】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 29】 P １ (This is 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, or -H) The compound or pharmaceutically acceptable salt thereof according to claim 11.

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