Synthesis of sulfonamide intermediates

Abstract

Provided herein are methods for synthesizing Mcl-1 inhibitors and intermediates that can be used to prepare the Mcl-1 inhibitors, such as compound Z. Specifically, provided herein are methods for synthesizing compound A1 and salts or solvates thereof, and compound A2 and salts and solvates thereof. TIFF2023524262000057.tif86170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 020,951, filed May 6, 2020, which is incorporated by reference in its entirety for all purposes as if fully set forth herein.

[0002] The present disclosure relates to (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24 ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (compound A1; AMG 176), its salts or solvates, and the preparation of (1S,3'R,6'R,7'R,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dinethyl-7'-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'-

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24 The present invention relates to a process for the synthesis of intermediates useful in the preparation of pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (compound A2; AMG 397), salts or solvates thereof. These compounds are inhibitors of myeloid cell leukemia 1 protein (Mcl-1). [Background technology]

[0003] The compound (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24 ]Pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Compound A1): [ka] are useful as inhibitors of myeloid cell leukemia 1 (Mcl-1).

[0004] The compound (1S,3'R,6'R,7'R,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dinetyl-7'-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'-

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24 ]Pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (compound A2): [ka] are useful as inhibitors of myeloid cell leukemia 1 (Mcl-1).

[0005] One common characteristic of human cancers is overexpression of Mcl-1, which prevents cancer cells from undergoing programmed cell death (apoptosis) and allows the cells to survive despite extensive genetic damage.

[0006] Mcl-1 is a member of the Bcl-2 family of proteins. The Bcl-2 family includes pro-apoptotic members (e.g., BAX and BAK), which upon activation form homo-oligomers in the outer mitochondrial membrane, leading to pore formation and mitochondrial content escape, the steps that trigger apoptosis. Anti-apoptotic members of the Bcl-2 family (e.g., Bcl-2, Bcl-XL, and Mcl-1) block the activity of BAX and BAK. Other proteins (e.g., BID, BIM, BIK, and BAD) show additional regulatory functions. Studies have shown that Mcl-1 inhibitors may be useful for the treatment of cancer. Mcl-1 is overexpressed in many cancers. Summary of the Invention [Problem to be solved by the invention]

[0007] US Patent No. 9,562,061, the entirety of which is incorporated herein by reference, discloses compound A1 as an Mcl-1 inhibitor and provides a method for its preparation.However, an improved synthesis method is desired that provides higher yield and purity of compound A1, especially for commercial production of compound A1.

[0008] US Patent No. 10,300,075, the entirety of which is incorporated herein by reference, discloses compound A2 as an Mcl-1 inhibitor and provides a method for its preparation. However, improved synthetic methods that provide higher yields and purity of compound A2 are desirable, especially for commercial production of compound A2. [Means for solving the problem]

[0009] Provided herein is compound Z [ka] or a salt thereof, comprising: (a) combining (2S,3S)-butane-2,3-diol, a bromide source, and acetic acid to form compound I; [ka] (b) combining compound I and a non-nucleophilic base to form compound J; [ka] (c) combining compound J and an aryl nucleophile to form compound K [ka] (d) combining compound K, a leaving group reagent, and an amine base to form compound L [ka] (e) reacting a compound L, a non-nucleophilic base, and Ar 1 -SH was mixed to obtain compound M [ka] wherein Ar 1 is a 5-12 membered heteroaryl containing 1-3 ring heteroatoms selected from O, N, and C; (f) oxidizing compound M to form compound N [ka] and (g) combining compound N, a base, and hydroxylamine-O-sulfonic acid to form compound Z.

[0010] Also provided herein is a method for the preparation of compound A1, or a salt or solvate thereof, or compound A2, or a salt or solvate thereof, using compound Z: [ka] The method includes synthesizing

[0011] Further aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description. The description herein below includes specific embodiments, with the understanding that the disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Provided herein are methods for synthesizing Mcl-1 inhibitors and corresponding sulfonamide Mcl-1 inhibitor intermediates, specifically, the sulfonamide intermediates can be synthesized by reacting (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24 ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (compound A1) or a salt or solvate thereof, and a method for synthesizing (1S,3'R,6'R,7'R,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dinethyi-7'-((9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylmethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'-

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24 ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (compound A2) or a salt or solvate thereof may be used in the process for synthesizing: [ka]

[0013] US Patent No. 9,562,061, the entirety of which is incorporated herein by reference, discloses compound A1 or a salt or solvate thereof as an Mcl-1 inhibitor, and provides methods for preparing the same. US Patent No. 9,562,061 also discloses methods for synthesizing sulfonamide Mcl-1 inhibitor intermediates used in the synthesis of compound A1.

[0014] U.S. Patent No. 10,300,075, the entirety of which is incorporated herein by reference, discloses compound A2 or a salt or solvate thereof as an Mcl-1 inhibitor and provides methods for preparing the same. U.S. Patent No. 10,300,075 also discloses methods for synthesizing sulfonamide Mcl-1 inhibitor intermediates used in the synthesis of compound A2.

[0015] Specifically, the '061 patent provides a sulfonamide intermediate, compound Z, shown in Scheme 1: [ka] A process for synthesizing is described.

[0016] Scheme 1 - Synthesis of sulfonamide Mcl-1 inhibitor intermediates from the '061 patent [ka] The '061 patent describes the isolation of each of the intermediate compounds prior to use in the next step of the synthesis. Additionally, the '061 patent describes the process from (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide to (2S,3S)-3-methylhex-5-en-2-ol resulting in a synthesis with variable levels of chemical and chiral purity, which may require laborious work-up steps such as chromatography, resulting in significantly reduced yields. Advantageously, the use of a different synthetic strategy from the starting butanediol described herein allows for the production of crystalline intermediates (e.g., compounds N, Ar 1= pyridyl or pyrimidinyl) and isolation of the crystalline target compound (Z) provide high yields, improved efficiency, and high purity products. The methods described herein avoid the formation of dimeric sulfur-based impurities that are difficult to remove, improve chemical and chiral purity, improve safety, and provide flexibility for both small-scale (e.g., less than 1 gram) and large-scale (e.g., several kg) production.

[0017] Provided herein is a compound Z: [ka] or a salt thereof, comprising the steps of: (a) (2S,3S)-butane-2,3-diol, a bromide source, and acetic acid are mixed to obtain compound I [ka] To form; (b) Compound I and a non-nucleophilic base are mixed to obtain Compound J. [ka] To form; (c) Compound J and an allyl nucleophile are mixed to obtain compound K. [ka] To form; (d) Compound K, a leaving group reagent, and an amine base are mixed to obtain compound L. [ka] wherein LG is a leaving group; (e) Compound L, a non-nucleophilic base, and Ar 1 -SH was mixed to obtain compound M [ka] wherein Ar 1is a 5-12 membered heteroaryl containing 1-3 ring heteroatoms selected from O, N, and S; (f) Oxidizing compound M to obtain compound N [ka] To form; (g) combining compound N, a base, and hydroxylamine-O-sulfonic acid to form compound Z.

[0018] The overall reaction scheme for the methods described herein is shown below in Scheme 2. Scheme 2: Overall process for the synthesis of sulfonamide Mcl-1 inhibitor intermediates [ka]

[0019] Bromination and acetylation of 2S,3S-butane-diol to form compound I (step (a)) The disclosed method includes bromination and acetylation of 2S,3S-butane-diol to obtain compound I, which includes combining 2S,3S-butane-diol, a bromide source, and acetic acid.

[0020] The term "bromide source" as used herein refers to a bromide source used to replace a hydroxyl group on butane-diol. In some embodiments, the bromide source herein comprises HBr, PBr3, or a combination thereof. In some embodiments, the bromide source herein comprises HBr.

[0021] In some embodiments, the bromide source is provided in an acetic acid solution. In some embodiments, the bromide source may be present in acetic acid in an amount of 20 w / w% to 50 w / w%. For example, the bromide source may be present in acetic acid in an amount of 25 w / w% to 40 w / w%, 25 w / w% to 35 w / w%, or 30 w / w% to 35 w / w%, such as 20 w / w%, 25 w / w%, 30 w / w%, 32 w / w%, 33 w / w%, 34 w / w%, 35 w / w%, 40 w / w%, 45 w / w%, or 50 w / w%. In some embodiments, HBr may be present in acetic acid. In some embodiments, HBr may be present as a 33 w / w% solution in acetic acid.

[0022] The 2S,3S-butane-diol and the bromide source may be present in a molar ratio of 1:1 to 1:6, for example, at least 1:1, 1.05, 1:1.2, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:3, 1:4, and / or at most 1:6, 1:5, 1:4, 1:3, 1:2.75, 1:2.5, 1:2.25, 1:2, or 1:1.5, for example, at least 1:1 to 1:3.5, 1:2 to 1:4, 1:2 to 1:5, or 1:1.5 to 1:3.5. In some embodiments, the molar ratio of compound I to the non-nucleophilic base is 1:3.5.

[0023] The bromination of butanediol may be carried out at a temperature between -20°C and 10°C, for example at a minimum of -20, -15, -10, -5, 0, 5, or 10, and / or at a maximum of 10, 5, 0, or -10, for example at a temperature between -15°C and 10°C, between -10°C and 10°C, between -5°C and 10°C, or between 0°C and 10°C. In some embodiments, the bromination is carried out at a temperature of 10°C.

[0024] In some embodiments, the mixing in step (a) may occur for 1 hour to 24 hours. In some embodiments, the mixing in step (a) may occur for 15 hours to 20 hours, or 10 hours to 24 hours, or 12 hours to 24 hours, or 14 hours to 21 hours. For example, the mixing in step (a) may occur for 1 hour, 5 hours, 10 hours, 12 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, or 24 hours.

[0025] Bromination / acetylation of butanediol gives compound I, which can be directly processed to the next step without the need for substantial purification. As used herein, the term "substantial purification" refers to any purification method other than solvent washing and / or distillation, such as chromatography (e.g., column chromatography), crystallization, filtration, or a combination thereof. In embodiments, neutralization of any remaining acid (e.g., acetic acid and / or HBr) during the formation of compound I can be achieved by mixing with a base such as potassium carbonate in water, and compound I can be extracted with an organic solvent such as tert-butyl methyl ether (MTBE). In embodiments, the extracted compound I can be used in step (b) described below, or can be used after removal of the solvent used for extraction (e.g., "solvent-free").

[0026] In some embodiments where compound I is directly processed to the next step, compound I may be provided in a solution comprising an organic solvent. Organic solvents are well known in the art. Non-limiting examples of contemplated organic solvents include acetonitrile, toluene, benzene, xylene, chlorobenzene, fluorobenzene, naphthalene, benzotrifluoride, tetrahydrofuran (THF), tetrahydropyran, dimethylformamide (DMF), tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, dimethyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane (1,2-DME), 1,2-dichloroethane (1,2-DCE), 1,4-dioxane, cyclopentyl methyl ether (CPME), chloroform, carbon tetrachloride, dichloromethane (DCM), methanol, ethanol, propanol, and 2-propanol. In some embodiments, the organic solvent comprises MTBE. The organic solvent may be present in an amount of 0.1 L / kg to 10 L / kg of 2S,3S-butane-diol, for example a minimum of 0.5, 1, 1.5, 2, 3, 5, 7.5, or 10 L / kg of 2S,3S-butane-diol, and / or a maximum of 10, 7.5, 5, 3.5, 1.5, or 0.5 L / kg of 2S,3S-butane-diol, for example 1 to 4 L / kg of 2S,3S-butane-diol, 1.5 to 10 L / kg of 2S,3S-butane-diol, or 5 L / kg to 10 L / kg of 2S,3S-butane-diol.

[0027] Epoxidation of Compound I to Form Compound J (Step (b)) The methods of the disclosure can include epoxidizing compound I to obtain compound J. The methods herein can include synthesizing compound J by combining compound I and a non-nucleophilic base to form compound J. As provided herein, compound J can be represented by the formula: [ka] It has the structure:

[0028] Non-nucleophilic base, as used herein, can be any suitable non-nucleophilic base known to those skilled in the art.Contemplated non-nucleophilic bases include, for example, lithium hexamethyldisilazide ("HMDS"), sodium HMDS, potassium HMDS, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-amylate, sodium tert-amylate, potassium tert-amylate, 2,2,6,6-tetramethylpiperidine (TMP), LiTMP, 1,1,3,3-tetramethylguanidine (TMG), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene, and any combination thereof. In some embodiments, the non-nucleophilic base comprises lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof. In some embodiments, the non-nucleophilic base is potassium tert-butoxide. In some embodiments, the non-nucleophilic base is sodium tert-butoxide. In some embodiments, the non-nucleophilic base is sodium tert-amylate. In some embodiments, the non-nucleophilic base is potassium tert-amylate.

[0029] Compound I and the non-nucleophilic base may be present in a molar ratio of 1:1 to 1:5, for example, at least 1:1, 1.05, 1:1.2, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:3, 1:4, and / or at most 1:5, 1:4, 1:3, 1:2.75, 1:2.5, 1:2.25, 1:2, or 1:1.5, for example, at least 1:1 to 1:2.5, 1:1 to 1:3, 1:1 to 1:4, 1:1.25 to 1:3, or 1:1.1 to 1:2.5. In some embodiments, the molar ratio of compound I and the non-nucleophilic base is 1:2.5.

[0030] In some embodiments, step (b) further comprises monoethylene glycol. In some embodiments, step (b) comprises monoethylene glycol and potassium tert-butoxide. In some embodiments, step (b) comprises monoethylene glycol and sodium tert-butoxide.

[0031] Monoethylene glycol may be present in an amount of 2 L / kg compound I to 5 L / kg compound I, for example, a minimum of 2, 2.5, 3, 5 L / kg compound I, and / or a maximum of 5, 3.5, or 3 L / kg compound I, for example, 2 to 4 L / kg compound I, 2.5 to 5 L / kg compound I, or 3 L / kg to 4 L / kg compound I.

[0032] In some embodiments, the mixing in step (b) can be carried out in an organic solvent. In some embodiments, the organic solvent comprises tert-butyl methyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, or a combination thereof. In some embodiments, the organic solvent comprises tert-butyl methyl ether.

[0033] In some embodiments, monoethylene glycol and the non-nucleophilic base are mixed together and then mixed with compound I. This mixing of monoethylene glycol and the non-nucleophilic base may be performed such that the non-nucleophilic base is added to the monoethylene glycol in a manner that maintains the temperature of the resulting mixture between 20° C. and 40° C. In some embodiments, the non-nucleophilic base is added to the monoethylene glycol over a period of 3-7 hours or over a period of 4-6 hours. After all of the non-nucleophilic base has been added to the monoethylene glycol, the mixture may be subjected to a temperature of 70-120° C. under reduced pressure (e.g., a pressure of 400 mmHg) to remove the resulting by-product of protonated non-nucleophilic base (e.g., if the non-nucleophilic base is t-butoxide, t-butanol is produced), leaving behind deprotonated monoethylene glycol. Compound I may then be added to the deprotonated monoethylene glycol at a temperature between 20° C. and 40° C. (e.g., 30° C.) and mixed for 15 minutes to 120 minutes (e.g., 15 minutes to 60 minutes, or 30 minutes). In some embodiments, the resulting epoxide, compound J, may be isolated from the reaction mixture by distillation.

[0034] Epoxidation of compound I gives compound J, which can be directly carried on to the next step without the need for isolation.

[0035] Allylic Addition to Compound J to Form Compound K (Step (C)) The methods of the disclosure include an allylic addition to compound J to provide compound K. The methods herein can include synthesizing compound K by combining compound J and an allylic nucleophile to form compound K. As provided herein, compound K can be represented by the formula: [ka] It has the structure:

[0036] Allylic nucleophiles are [ka] wherein X 1is MgCl, MgBr, MgI, Li, CuLi, ZnX 3 , In(I), or In(X 2 ) 2; each X 2 are independently Cl, Br, or I; X 3 is Cl, Br, I, OTf, OTs, OAc, or acac. 1 is MgCl, MgBr, or MgI. 1 is MgCl. In some embodiments, X 1 is MgBr or MgI.

[0037] In some embodiments, X 1 In some embodiments, X is Li. 1 is CuLi.

[0038] In some embodiments, X 1 ZnX 3 Wherein X 3 is Cl, Br, I, OTf, OTs, OAc, or acac. 1 is ZnCl or ZnBr. 1 is ZnCl. In some embodiments, X 1 In some embodiments, X is ZnBr. 1 is ZnOTf or ZnOTs. In some embodiments, X 1 is ZnOAc or Zn(acac). 1 is In(I), or InCl, or InBr, or InI.

[0039] Compound J and the allylic nucleophile may be present in a molar ratio of 1:1.05 to 1:3, for example, at least 1:1, 1.05, 1:1.2, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, and / or at most 1:3, 1:2.75, 1:2.5, 1:2.25, 1:2, or 1:1.5, for example, at least 1:1, 1:2.5, 1:1 to 1:2, 1:1 to 1:3, 1:1.25 to 1:2, or 1:1.1 to 1:3. In some embodiments, the molar ratio of compound J and the allylic nucleophile is 1:1.2.

[0040] In some embodiments, the mixing of step (c), which is the allylic addition, may be performed in an organic solvent. In some embodiments, the organic solvent comprises tetrahydrofuran (THF), 2-methyltetrahydrofuran, tert-butyl methyl ether (MTBE), cyclopentyl methyl ether, dimethoxyethane, or a combination thereof. In some embodiments, the organic solvent comprises tert-butyl methyl ether. In some embodiments, the organic solvent comprises THF. In some embodiments, the organic solvent comprises THF and MTBE.

[0041] In some embodiments, compound J may be added dropwise to the allyl nucleophile. In some embodiments, compound J is added dropwise to the allyl nucleophile over a period of 1 hour to about 5 hours, for example, over 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours. In some embodiments, compound J is added dropwise to the allyl nucleophile over a period of 3 hours.

[0042] In some embodiments, after compound J and the allylic nucleophile are combined, the two are mixed for a period between 1 hour and 6 hours, such as 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, or 6 hours. In some embodiments, the mixing in step (c) is carried out for 3 hours.

[0043] The mixing in step (C) may be performed at a temperature of -20°C to 10°C, for example, at a minimum of -20, -15, -10, -5, 0, 5, or 10, and / or at a maximum of 10, 7, 5, 0, or -10, for example, at a temperature of -15°C to 10°C, -10°C to 10°C, -5°C to 10°C, 0°C to 10°C, or 7°C to 10°C. In some embodiments, the mixing is performed at a temperature of 7°C to 10°C.

[0044] In some embodiments, the reaction of compound J with an allylic nucleophile may be quenched by the addition of an aqueous solution of citric acid.

[0045] This allylic addition gives compound K which can be carried directly to the next step without the need for substantial purification.

[0046] Addition of a Leaving Group to Compound K to Form Compound L (Step (d)) The methods of the present disclosure include adding a leaving group (LG) to compound K to obtain compound L. The methods herein can include synthesizing compound L by combining compound K, a leaving group reagent, and an amine base to form compound L. As provided herein, compound L can be represented by: [ka] where LG is a leaving group.

[0047] Compound K is reacted with a leaving group reagent and an amine base, which converts the hydroxyl group of compound K into a leaving group to form compound L. Leaving group, as used herein, refers to any suitable atom or functional group that can be displaced by a nucleophile during nucleophilic substitution. Leaving group reagents that can convert a hydroxyl group into a leaving group to favor nucleophilic substitution are known in the art. Non-limiting examples of suitable leaving groups include halides (e.g., F, Cl, Br, or I), or sulfonyls.

[0048] In some embodiments, LG is a sulfonyl leaving group. As used herein, the term "sulfonyl leaving group" refers to a leaving group in which the oxygen atom of a hydroxyl group is bonded to a sulfonyl group. [ka] where RO is derived from the hydroxyl group that has been converted to a leaving group and LG' is derived from the remainder of the sulfonyl leaving group. In some embodiments, the sulfonyl leaving group is selected from the group consisting of mesyl, tosyl, nosyl, and triflyl. In some embodiments, the sulfonyl leaving group comprises mesyl.

[0049] In general, the leaving group reagent can be any suitable leaving group reagent known to those of skill in the art that is used to convert a hydroxyl group to a leaving group. In some embodiments, the leaving group reagent can include mesyl chloride.

[0050] Compound K and the leaving group reagent may be present in a molar ratio of 1:1.2 to 1:2, such as a minimum molar ratio of 1:1.2, 1:1.5, 1:1.6, and / or a maximum molar ratio of 1:2, 1:1.75, 1:1.5, such as a molar ratio of 1:1.2 to 1:1.9, 1:1.2 to 1:7, or 1:1.2 to 1:1.5. In some embodiments, the molar ratio of compound K to the leaving group reagent is 1:1.4.

[0051] The mixing of step (d) can include an amine base (e.g., mono-, di-, or trialkylamine, substituted or unsubstituted piperidine, substituted or unsubstituted pyridine). In some embodiments, the amine base includes pyridine, trimethylamine, triethylamine, aniline, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine, or a combination thereof. In some embodiments, the amine base is triethylamine.

[0052] Compound K and the amine base may be present in a molar ratio of 1:1.8 to 1:3.3, such as a minimum molar ratio of 1:1.8, 1:2, 1:2.5, and / or a maximum molar ratio of 1:3.3, 1:3, 1:2.5, such as a molar ratio of 1:1.8 to 1:3, 1:2 to 1:3, or 1:2 to 1:2.5. In some embodiments, the molar ratio of compound K to the leaving group reagent is 1:2.3.

[0053] In some embodiments, the mixing of step (d), which is the leaving group addition, may be performed in an organic solvent comprising dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, or a combination thereof. In some embodiments, the organic solvent comprises tert-butyl methyl ether. In some embodiments, the organic solvent comprises THF. In some embodiments, the organic solvent does not comprise dichloromethane.

[0054] In some embodiments, the leaving group reagent may be added slowly to the solution of compound K and the amine base. In some embodiments, the leaving group reagent is added to the solution of compound K and the amine base over a period of 2 to 3 hours, for example, over 2 hours, 2.5 hours, or 3 hours. In some embodiments, the leaving group reagent is added to the solution of compound K and the amine base over a period of 2 to 3 hours, and then stirred for 10 minutes to 1 hour. In some embodiments, the leaving group reagent is added to the solution of compound K and the amine base over a period of 2.5 hours. In some embodiments, the leaving group reagent is added to the solution of compound K and the amine base over a period of 2.5 hours, and then stirred for 30 minutes.

[0055] The mixing in step (d) may be performed at a temperature of -10°C to 10°C, for example at a minimum of -10, -5, 0, or 5, and / or at a maximum of 10, 7, 5, 0, or -10, for example at a temperature of -10°C to 5°C, -10°C to 0°C, -5°C to 10°C, 0°C to 10°C. In some embodiments, the mixing is performed at a temperature of 5°C.

[0056] This leaving group addition gives compound L which can be carried directly to the next step without the need for substantial purification.

[0057] Nucleophilic Substitution of Compound L to Form Compound M (Step (e)) The methods of the disclosure include nucleophilic substitution of compound L to give compound M. The methods herein comprise reacting compound L, a non-nucleophilic base, and Ar 1 -SH to form compound M. As provided herein, compound M can be prepared by synthesizing compound M by mixing [ka] wherein Ar 1 is a 5-12 membered heteroaryl containing 1-3 ring heteroatoms selected from O, N, and S.

[0058] As used herein, the term "heteroaryl" refers to a cyclic aromatic ring having a total of 5-12 ring atoms (e.g., a monocyclic aromatic ring having a total of 5-6 ring atoms) and containing 1-3 heteroatoms in the aromatic ring selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted with one or more (e.g., 1-4) substituents selected from, for example, halo, alkyl, alkenyl, OCF3, NO2, CN, NC, OH, alkoxy, amino, CO2H, CO2 alkyl, aryl, and heteroaryl. Optionally, the heteroaryl group is substituted with one or more of alkyl and alkoxy groups. Heteroaryl groups can be isolated (e.g., pyridyl) or fused to another heteroaryl group (e.g., purinyl), a cycloalkyl group (e.g., tetrahydroquinolinyl), a heterocycloalkyl group (e.g., dihydronaphthyridinyl), and / or an aryl group (e.g., benzothiazolyl and quinolyl). Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl. When a heteroaryl group is fused to another heteroaryl group, each ring can contain a total of 5 or 6 ring atoms and 1 to 3 heteroatoms in the aromatic ring.

[0059] In some embodiments, Ar 1 teeth, [ka] In some embodiments, Ar 1 teeth, [ka] It is.

[0060] Compounds L and Ar1 -SH may be present in a molar ratio of 1:1.05 to 1:2.5, for example, in a molar ratio of at least 1:1.05, 1:1.25, 1:1.5, 1:1.6, and / or in a molar ratio of at most 1:2.5, 1:2, 1:1.75, 1:1.5, for example, in a molar ratio of 1:1.05 to 1:2.25, 1:1.1 to 1:2, or 1:1.05 to 1:1.2. In some embodiments, compound L and Ar 1 The molar ratio to --SH is 1:1.08.

[0061] Non-nucleophilic base, as used herein, can be any suitable non-nucleophilic base known to those skilled in the art. Suitable non-nucleophilic bases can include, for example, lithium hexamethyldisilazide ("HMDS"), sodium HMDS, potassium HMDS, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-amylate, sodium tert-amylate, potassium tert-amylate, 2,2,6,6-tetramethylpiperidine (TMP), LiTMP, 1,1,3,3-tetramethylguanidine (TMG), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene, and any combination thereof. In some embodiments, the non-nucleophilic base comprises lithium hexamethyldisilazide ("HMDS"), sodium HMDS, potassium HMDS, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-amylate, sodium tert-amylate, potassium tert-amylate, or combinations thereof. In some embodiments, the non-nucleophilic base comprises sodium tert-butoxide, potassium tert-butoxide, or sodium tert-amylate.

[0062] Compound L and the non-nucleophilic base may be present in a molar ratio of 1:1.1 to 1:4, for example, at least 1:1.1, 1:1.2, 1:1.5, 1:2, 1:2.5, and / or at most 1:4, 1:3.5, 1:3, 1:2.5, for example, at least 1:1.1 to 1:3, 1:1.1 to 1:2, or 1:1.1 to 1:1.3. In some embodiments, the molar ratio of compound L and the non-nucleophilic base is 1:1.2.

[0063] In some embodiments, the mixing in step (e) may be carried out in an organic solvent comprising tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, toluene, or a combination thereof. In some embodiments, the organic solvent comprises THF.

[0064] The organic solvent may be present in an amount of from 10 L / kg of compound L to 25 L / kg of compound L, for example, a minimum of 10, 15, 20 L / kg of compound L, and / or a maximum of 25, 20, or 15 L / kg of compound L, for example, from 10 to 20 L / kg of compound L, from 10 to 15 L / kg of compound L, or from 15 to 22 L / kg of compound L.

[0065] In some embodiments, the product L is Ar 1 In some embodiments, compound L may be added slowly to a mixture containing —SH and a non-nucleophilic base. 1 The mixture containing -SH and a non-nucleophilic base is added dropwise over a period of 3 to 6 hours, for example, over a period of 3 hours, 3.5 hours, 4 hours, 5 hours, 5.5 hours, or 6 hours. 1 Add dropwise over 5 hours to the mixture containing --SH and the non-nucleophilic base.

[0066] In some embodiments, the mixing in step (e) is carried out for 3 to 5 hours, e.g., 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours. In some embodiments, the mixing in step (e) is carried out for 4 hours.

[0067] The mixing in step (e) may be performed at a temperature between 60° C. and 80° C., such as a minimum of 60 or 65° C., and / or a maximum of 80, 75, 70, or 68° C., such as between 60° C. and 75° C., between 65° C. and 75° C., or between 65° C. and 80° C. In some embodiments, the mixing is performed at a temperature of 68° C.

[0068] The compound M formed in step (e) may be directly carried to the next step without the need for substantial purification. In some embodiments, compound M is washed 3-5 times with aqueous sodium hydroxide prior to oxidation in step (f). Advantageously, washing compound M 3-5 times (e.g., 5 times) removes residual Ar. 1 -SH is removed, resulting in an improved purity profile and yield as well as avoiding further purification (eg, chromatographic purification).

[0069] Oxidation of Compound M to Form Compound N (Step (f)) The methods of the disclosure include the oxidation of compound M to obtain compound N. The oxidation includes combining compound M and an oxidizing agent to form compound N. As provided herein, compound N can be represented by the formula: [ka] wherein Ar 1 is as defined above.

[0070] Suitable oxidizing agents are well known in the art. Non-limiting examples of oxidizing agents include peracids, such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide, and the like; perchloric acid, such as tetrabutylammonium perchlorate, and the like; chlorates, such as sodium chlorate, and the like; chlorites, such as sodium chlorite, and the like; hypochlorites, such as bleach and the like, periodates, such as sodium periodate, and the like; high valent iodine reagents, such as iodosylbenzene, iodoben, and the like. benzene diacetate and the like; manganese-containing reagents such as manganese dioxide, potassium permanganate and the like; lead, such as lead tetraacetate and the like; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones's reagent and the like; halogen compounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In some embodiments, the oxidizing agent is hydrogen peroxide.

[0071] Compound M and the oxidizing agent may be present in a molar ratio of 1:1.3 to 1:5, for example, a minimum of 1:1.3, 1:1.5, 1:2, or 1:3, and / or a maximum of 1:3, 1:2, 1:1.8, or 1:1.5, for example, a molar ratio of 1:1.3 to 1:4, 1:1.3 to 1:3, 1:1.3 to 1:2, or 1:1.3 to 1:1.8. In some embodiments, the molar ratio of compound M to the oxidizing agent is 1:1.5.

[0072] The oxidation of compound M may further include mixing compound M and an oxidizing agent with an oxidation catalyst. Non-limiting examples of oxidation catalysts include: 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO), tetrapropylammonium perruthenate (TPAP), 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO), metal catalysts (e.g., copper, iron, etc.), 2-azaadamantane-N-oxyl, 1-methyl-2-azaadamantane-N-oxyl, 1,3-dimethyl-2-azaadamantane-N-oxyl, 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate, sodium tungstate dehydrate, and 3-chloroperbenzoic acid. In some embodiments, the oxidation catalyst is sodium tungstate dehydrate, 3-chloroperbenzoic acid, or a combination thereof. In some embodiments, the oxidation catalyst is sodium tungstate dehydrate. In some embodiments, the mixing of step (f) can include hydrogen peroxide and sodium tungstate dehydrate.

[0073] When an oxidation catalyst is present, compound M and the oxidation catalyst may be present in a molar ratio of 1:0.05 to 1:0.5, for example, at least 1:0.05, 0.04, 1:0.1, 1:0.2, 1:0.3, or 1:0.5, and / or at most 1:0.5, 1:0.4, 1:0.3, 1:0.2, or 1:0.1, for example, at a molar ratio of 1:0.05 to 1:0.4, 1:0.05 to 1:0.3, or 1:0.05 to 1:0.2. In some embodiments, the molar ratio of compound M and the oxidation catalyst is 1:0.1.

[0074] In some embodiments, the oxidizing step (f) further comprises acetic acid. Advantageously, when acetic acid is mixed during the oxidation step, it can enhance safety by allowing a reduction in the amount of hydrogen peroxide used, improve the purity profile of compound N, and increase the conversion to product since the acetic acid stabilizes the hydrogen peroxide reagent.

[0075] In some embodiments, the oxidation reaction of step (f) may be carried out in a solvent such as an alcohol solvent (e.g., methanol, ethanol, isopropanol). In some embodiments, the solvent is methanol.

[0076] In some embodiments, the oxidizing of step (f) is carried out for 12 hours to 48 hours, such as 12 hours, 15 hours, 20 hours, 24 hours, 30 hours, 35 hours, 40 hours, or 48 hours. In some embodiments, the mixing of step (f) is carried out for 24 hours.

[0077] In some embodiments, the oxidizing of step (f) may be carried out at a temperature maintained at 25° C.±5° C. In some embodiments, the oxidizing of step (f) is carried out at a temperature between 20° C. and 25° C.

[0078] In some embodiments, compound N may be crystallized from the oxidation in step (f). In some embodiments, compound N may be crystallized by adding water to the oxidation in step (f). Advantageously, compound N is crystallized by adding water to the oxidation in step (f), where direct crystallization of compound N prior to extraction not only improves throughput and yield, but also improves the purity profile of the reaction mixture.

[0079] Sulfonamidation of Compound N to Form Compound Z The method of the present disclosure includes sulfonamidation of compound N to obtain compound Z (step (g)). This sulfonamidation includes combining compound N, a base, and hydroxylamine-O-sulfonic acid to form compound Z. As provided herein, compound Z can be represented by the formula: [ka] It has the structure:

[0080] In some embodiments, compound N and a base are mixed together in a solvent to form an intermediate compound O, which is then mixed with a hydroxylamino-O-sulfonic acid. As provided herein, compound O is [ka] wherein Q is an alkali metal cation. In some embodiments, Q is lithium, sodium, potassium, or a combination thereof. In some embodiments, Q is sodium. In some embodiments, the compound N and the base are mixed in a solvent. In some embodiments, the solvent comprises tert-butyl methyl ether, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof. In some embodiments, the solvent comprises tert-butyl methyl ether and methanol.

[0081] In some embodiments, the base comprises sodium thiomethoxide, sodium methoxide, potassium carbonate and methanol, or a combination thereof. In some embodiments, the base comprises sodium thiomethoxide.

[0082] In some embodiments, compound N and the base are mixed for 6 hours to 18 hours, such as 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 15 hours, or 18 hours. In some embodiments, compound N and the base are mixed for 12 hours.

[0083] In some embodiments, compound N and the base are mixed at a temperature between 25° C. and 50° C., such as at a minimum of 25, 30, 35, 40° C., and / or at a maximum of 50, 45, 40, or 35° C., such as at a temperature between 25° C. and 45° C., between 30° C. and 45° C., or between 30° C. and 40° C. In some embodiments, compound N and the base are mixed at a temperature of 35° C.

[0084] In some embodiments, mixing compound N and base gives intermediate compound O, which can be directly processed to the addition of hydroxylamine-O-sulfonic acid without the need for substantial purification. In some embodiments, hydroxylamine-O-sulfonic acid is added to intermediate compound O along with sodium acetate, potassium acetate, sodium formate, potassium formate, or a combination thereof. In some embodiments, hydroxylamine-O-sulfonic acid is added to intermediate compound O along with sodium acetate. In some embodiments, hydroxylamine-O-sulfonic acid is added to intermediate compound O along with sodium acetate trihydrate.

[0085] In some embodiments, the intermediate compound O, hydroxylamine-O-sulfonic acid, and sodium acetate are mixed in a solvent. In some embodiments, the solvent includes tert-butyl methyl ether, methanol, 2-methyltetrahydrofuran, or a combination thereof. In some embodiments, the solvent includes tert-butyl methyl ether and methanol. In some embodiments, the solvent can be a biphasic mixture. In some embodiments, the biphasic mixture includes water and an organic solvent such as tert-butyl methyl ether.

[0086] In some embodiments, the mixture of intermediate compound O, hydroxylamine-O-sulfonic acid, and sodium acetate is carried out for 30 minutes to 4 hours, for example, 30 minutes to 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours. In some embodiments, the mixture of intermediate compound O, hydroxylamine-O-sulfonic acid, and sodium acetate is carried out for 2 hours.

[0087] In some embodiments, the intermediate compound O, hydroxylamine-O-sulfonic acid, and sodium acetate are mixed at a temperature between 25° C. and 50° C., such as at a minimum of 25, 30, 35, 40° C., and / or at a maximum of 50, 45, 40, or 35° C., such as at 25° C. to 45° C., 30° C. to 45° C., or 30° C. to 40° C. In some embodiments, the intermediate compound O, hydroxylamine-O-sulfonic acid, and sodium acetate are mixed at a temperature of 35° C.

[0088] In some embodiments, compound Z may be crystallized from the sulfonamidation of step (g). In some embodiments, the crystallization of compound Z includes heating a solution of compound Z, then cooling the solution, and adding a crystallization solvent to the cooled solution to form crystals of compound Z. In some embodiments, the crystallization includes heating a solution of compound Z to 40° C.-45° C., then cooling the solution to 10° C.-15° C., and adding a crystallization solvent to the cooled solution to form crystals of compound Z. In some embodiments, the solution of compound Z includes tert-butyl methyl ether, and the crystallization solvent includes heptane. In some embodiments, the solution of compound Z includes methanol, and the crystallization solvent includes water. Advantageously, the crystallization of compound Z includes heating a solution of compound Z to 40° C.-45° C., which prevents melting of compound Z, controls crystallization, increases yield, and improves purity profile. Additionally, crystallization of compound Z involves heating a solution of compound Z to 40° C.-45° C., which increases the purity of the product, removes chiral impurities, and rejects crystallization of alternative chiral impurities. Crystallization of compound Z advantageously purifies the product without chromatography and its attendant yield losses.

[0089] Compound Z prepared by the methods disclosed herein can be used to synthesize compounds A1 and A2. As shown in Scheme 3, compound Z can be used to synthesize compound A1 and its salts and solvates, and as shown in Scheme 4, compound Z can also be used to synthesize compound A2 and its salts and solvates.

[0090] Scheme 3 - Conversion of compound Z to compound A1 [ka] Compound Z can be used to synthesize compound A1 and its salts and solvates, as shown in Scheme 3 and as described in U.S. Pat. No. 9,562,061. The synthesis of AA11A is disclosed in U.S. Pat. No. 9,562,061. Compound Z and AA11A can be reacted to form compound B, as described in U.S. Pat. No. 9,562,061. Cyclization of compound B gives hydroxy compound C, which is then methylated to give compound A1, as described in U.S. Pat. No. 9,562,061.

[0091] Scheme 4 - Conversion of compound Z to compound A2 [ka] Compound Z can be used to synthesize compound A2 and its salts and solvates, as shown in Scheme 4 and described in U.S. Pat. No. 10,300,075. As described above with respect to Scheme 3, the synthesis of AA11A is disclosed in U.S. Pat. No. 9,562,061. As described above and described in U.S. Pat. No. 9,562,061, sulfonamide Z and AA11A can be reacted to form compound B, which can be cyclized to produce hydroxy compound C. Compound C can then be oxidized to produce cyclic enone D, as disclosed in U.S. Pat. No. 10,300,075. Alternatively, compound B can be oxidized to produce a non-cyclized enone version of compound C, which can then be cyclized to produce cyclic enone D. Enone D can then be converted to epoxide E using the procedure disclosed in U.S. Pat. No. 10,300,075. Epoxide E can then be reacted with bicyclic compound F to produce hydroxy compound G. Finally, methylation of compound G gives compound A2 as disclosed in US Pat. No. 10,300,075.

[0092] While this disclosure is to be read in conjunction with its detailed description, it is to be understood that the foregoing description and the following examples are exemplary and are not intended to limit the scope of the disclosure, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. EXAMPLES

[0093] The following examples are offered for illustrative purposes and are not intended to limit the scope of the invention.

[0094] Example 1: Formation of Compound Z [ka]

[0095] Synthesis of Compound I [ka] (2S,3R)-3-Bromobutan-2-yl acetate (Compound I): A 20 L glass-lined, jacketed reactor was charged with hydrogen bromide (33 w / w% solution in acetic acid, 3.5 kg, 14.3 mol, 3.5 equiv). The solution was cooled to +10° C. and (2S,3S)-butane-2,3-diol (368 g, 4.08 mol, 1.0 equiv) was added slowly while maintaining the temperature below +10° C. (NMT+10° C.). The mixture was stirred at +10° C. for 15-20 hours. The reaction mixture was then added slowly over 8 hours to a pre-cooled stirred solution of potassium carbonate (1.84 kg, 3.26 equiv) in water (3.68 L, 10.0 L / kg) while maintaining the temperature below +10° C. The mixture was diluted with tert-butyl methyl ether (1.84 L, 5.00 L / kg), warmed to +20-+25°C and stirred for at least 30 minutes. The phases were separated and the resulting aqueous layer was washed with tert-butyl methyl ether (1.10 L, 3.00 L / kg). The combined organic layers were washed with a solution of potassium carbonate (644 g, 1.14 equiv.) in water (2.4 L, 6.5 L / kg). The organic layers were washed with water (740 mL, 2.0 L / kg) and diluted under reduced pressure at +45°C. At the end of the distillation, the solution was sampled to ensure low water content and diluted with tert-butyl methyl ether to a total volume of approximately 1.10 L (3 L / kg). Potency-adjusted assay yields were 95-97% and typical GC purities were greater than 95.0 Area%. The resulting solution of compound I in tert-methyl ether was suitable for direct use in the next step of the process.

[0096] A sample of compound I was concentrated in vacuo for characterization by NMR. 1 H NMR(300MHz,CDCl3)δ 4.84-4.78(m,1H),4.16-4.04(m,1H),1.96(s,3H),1.55(d,J=7.1Hz,3H),1.21(d,J=6.9Hz,3H).LRMS(ESI):C6H 11Calculated for Br1O2+Na: 217.0; Found: 217.0.

[0097] Synthesis of compound J [ka] (2S,3S)-2,3-Dimethyloxirane (Compound J): A 20 L glass-lined, jacketed reactor was charged with monoethylene glycol (1.22 L, 2.88 L / kg). Solid potassium tert-butoxide (612 g, 5.45 mol, 2.50 equiv.) was added in small portions over approximately 5 hours while maintaining the temperature below +40°C. The resulting mixture was distilled under reduced pressure at +90-120°C to remove approximately 500 mL of tert-butanol. Solvent tert-butyl methyl ether (2.13 L, 5.0 L / kg) was added and the mixture was distilled under reduced pressure until the tert-butanol content was determined by GC to be less than 0.4 wt / wt%. After cooling to +30° C., a solution of compound I (425 g, 2.18 mol, 1.0 equiv.) in tert-butyl methyl ether (425 mL, 1.00 L / kg) was added over 30 min, and the liner was then washed with tert-butyl methyl ether (425 mL, 1.00 L / kg). The resulting mixture was stirred at +30° C. for 30 min. The reaction mixture was distilled directly under reduced pressure (condenser setting −15° C.). The product compound J was obtained in a potency-adjusted yield of 75-80% with a typical GC purity of >98.0 Area%. The resulting solution of SS-DMO (with residual tert-butyl methyl ether) was suitable for direct use in the next step of the process. 1 H NMR(300MHz,CDCl3)δ 2.64-2.58(m,2H),1.19-1.15(m,6H).

[0098] Synthesis of compound K [ka] (2S,3S)-3-Methylhex-5-en-2-ol (compound K): A 20 L glass-lined, jacketed reactor was charged with a solution of allylmagnesium chloride in tetrahydrofuran (18% w / w solution, 7.28 mol, 1.20 equiv.) and cooled to +7 to +10 °C. A solution of compound J (438 g, 6.07 mol, 1.00 equiv.) in tert-butyl methyl ether (657 mL, 1.5 L / kg) was added dropwise over 3 hours, maintaining the temperature below +7 °C. The reaction was stirred at +7 to +10 °C for an additional 3 hours. The reaction mixture was added dropwise over 2 to 3 hours to a pre-cooled stirred solution of citric acid monohydrate (1.68 kg, 7.89 mol, 1.3 equiv.) in water (3.50 L, 8.00 L / kg) maintaining the temperature at +5 to +10 °C. The resulting mixture was warmed to +25° C. and stirred for 30 min. The phases were separated and the aqueous layer was washed twice with tert-butyl methyl ether (2×876 mL, 2×2.00 L / kg). The organic layers were combined and washed twice with aqueous sodium bicarbonate (0.8 mol / L solution; 2×2.63 L, 2×6.0 L / kg) and then twice with aqueous sodium chloride (5.3 mol / L solution; 2×876 mL, 2×2.0 L / kg). The organic layers were distilled under reduced pressure at +30° C. to a total volume of 1.3 L (3.0 L / kg). The solvent tetrahydrofuran was added three times (3×1.3 L, 3×3.0 L / kg) and the mixture was distilled under reduced pressure at +30° C. to a final volume of 1.3 L (3.0 kg). The potency adjusted assay yield was 90-95% and the typical GC purity was >88.0 Area%. The resulting solution of compound K in tetrahydrofuran was suitable for use as is in the next step of the process.

[0099] A sample of compound K was concentrated in vacuo for NMR characterization. 1 H NMR(300MHz,CDCl3)δ 5.81-5.67(m,1H),5.02-4.89(m,2H),3.70-3.63(m,1H),2.22-2.10(m,1H),1 .90-1.75(m,2H),1.15(d,J=7.0Hz,3H),0.82(d,J=6.9Hz,3H).LRMS(ESI):C7H 14Calculated for O1+Na: 137.1, Measured: 137.1.

[0100] Synthesis of Compound L (wherein LG is OMs) [ka] (2S,3S)-3-Methylhex-5-en-2-yl methanesulfonate (compound L, where LG was OMs): A 20 L glass-lined jacketed reactor was charged with a solution of compound K (717 g, 4.97 mol, 1.00 equiv.) in tetrahydrofuran (700 mL, 1.0 L / kg) and solvent tert-butyl methyl ether (5.7 L, 8.0 L / kg). The mixture was cooled to 0° C. and charged with triethylamine (2.01 L, 11.4 mol, 2.30 equiv.) followed by tert-butyl methyl ether (700 mL, 1 L / kg). At 0 to +5° C., methanesulfonyl chloride (680 mL, 6.96 mol, 1.40 equiv.) was added slowly over 2.5 hours. The reaction was stirred at +5° C. for 30 minutes. Aqueous hydrochloric acid (1 mol / L solution; 5.0 L, 7.0 L / kg, 1.0 equiv.) was then added over 30 min below 15° C. The biphasic mixture was warmed to +25° C. and stirred for 6 h, then the phases were separated. The aqueous layer was extracted with tert-butyl methyl ether (2.9 L, 4.0 L / kg). The combined organic phases were washed with aqueous hydrochloric acid (1 mol / L solution; 2.9 L, 4.0 L / kg, 0.6 equiv.), washed twice with aqueous sodium chloride (5.7 mol / L solution; 2×1.4 L, 2×3.0 L / kg), and washed with water (1.4 L, 2.0 L / kg). The organic phase was distilled under reduced pressure to a total volume of 2.9 L (4.0 L / kg). Tetrahydrofuran (2.9 L, 4.0 L / kg) was added and the mixture was redistilled under reduced pressure to a total volume of 2.9 L (4.0 L / kg). Potency adjusted assay yields were 93-97% and typical GC purities were >98.0 Are%. The resulting tetrahydrofuran solution of compound L (wherein LG is OMs) was suitable for use as is in the next step of the process.

[0101] Compound M (wherein, Ar 1 Synthesis of (pyridinyl) [ka] 2-(((2R,3S)-3-methylhex-5-en-2-yl)thio)pyridine (compound M, where Ar 1 is pyridinyl): A 20 L glass-lined, jacketed reactor was charged with 2-thiopyridine (637 g, 5.73 mol, 1.08 equiv.) and tetrahydrofuran (10.0 L, 9.0 L / kg) and the resulting mixture was stirred at 15° C. for 30 min. Sodium tert-p-butoxide (612 g, 6.37 mol, 1.20 equiv.) was added in portions over 1 h while maintaining the temperature at NMT+30° C. After addition, the reaction mixture was heated to gentle reflux at +68° C. for 1 h. At this temperature, a solution of compound L (where LG is OMs) (1,020 g, 5.31 mol, 1.00 equiv.) in tetrahydrofuran (1.0 L, 1.0 L / kg) was added dropwise over 5 h. The reaction was stirred for an additional 4 h. The reaction mixture was distilled at atmospheric pressure at +65-+75° C. to remove approximately 6 L of solvent. The mixture was cooled to +20° C. and water (3.0 L, 3.0 L / kg) and ethyl acetate (5.0 L, 5.0 L / kg) were added. The mixture was stirred at +25° C. for 30 min until the solids were totally dissolved. The layers were separated and the aqueous layer was extracted with ethyl acetate (3.0 L, 3.0 L / kg). The combined organic phase was washed five times with aqueous sodium hydroxide (1 mol / L solution; 5×2.2 L, 5×2.2 L / kg) and then once with water (4.0 L, 4.0 L / kg). The organic layer was vacuum distilled to a total volume of 3 L. Methanol was added twice (2×5.0 L, 2×5.0 L / kg) and the mixture was distilled to a total volume of 3 L. The potency adjustment assay yield was 68-75%, and the typical LC purity was greater than 95.0 Area%. 1 The methanolic solution of (is pyridinyl) was suitable for use as is in the next step of the process.

[0102] Compound M (wherein, Ar1 A sample of (is pyridinyl) was concentrated in vacuo for characterization by NMR. 1 H NMR(300MHz,CDCl3)δ 8.30(dd,J=1.2,5.1Hz,1H),7.36(ddd,J=1.2,7.9,8.2Hz,1H),7.08(d,J=7.9Hz,1H),6.85(dd,J=5.1,8.2Hz,1H).LRMS(ESI):C 12 H 17 Calculated for N1S1+Na: 230.1, Found: 230.1.

[0103] Compound N (wherein, Ar 1 Synthesis of (pyridinyl) [ka] 2-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)pyridine (Compound N, where Ar 1 is pyridinyl): In a 10 L glass-lined, jacketed reactor, compound M (wherein Ar 1is pyridinyl) (468 g, 2.26 mol, 1.00 equiv) was charged and the mixture was diluted with methanol (1.4 L, 3.0 L / kg). Acetic acid (136 g, 2.26 mol, 1.00 equiv) was added followed by sodium tungstate dehydrate (75 g, 0.23 mol, 0.10 equiv). The mixture was stirred at +25° C. and hydrogen peroxide (276 g, 2.94 mol, 1.3 equiv) was added over 4.5 hours while maintaining the temperature NMT+25° C. After the addition was complete, the reaction was stirred for 24 hours. Water (2.34 L, 5.0 L / kg) was added over 1 hour to induce crystallization. The crystallization mixture was cooled to 0° C. and stirred for 2 hours. The product was then filtered off at 0° C., and the wet cake was then washed under stirring with aqueous sodium thiosulfate (1.2 mol / L solution; 1.87 L, 4.0 L / kg, 2.26 mol, 1.00 equiv.) at +25° C. The wet cake was washed under stirring with water (1.87 L, 4.0 L / kg) and then with heptane (1.87 L, 4.0 L / kg). The product was dried under vacuum at +30° C. to give compound N (wherein: Ar 1 is pyridinyl) 530 g was obtained as a white crystalline solid (98% yield, 98.6 LC-Area% purity, 99.8 w / w% assay). 1 H NMR(500MHz,DMSO-d6)δ 8.81(dd,J=1.2,5.1Hz,1H),8.18(ddd,J=1.2,7.9,8.2Hz,1H),8.08(d,J=7.9Hz,1H),7.77(dd,J=5.1,8.2Hz,1H),5.68 (m,1H),5.05(m,2H),3.70(m,1H),2.26(m,1H),2.05(m,2H),1.09(d,J=7.2Hz,3H),0.98(d,J=7.2Hz,3H).LRMS(ESI):C 12 H 17 Calculated for N1S1+H: 208.3, found: 208.3. IR (neat) vmax 3086, 2980, 2966, 2934, 1450, 1428, 1304, 1108, 794, 593, 541.

[0104] Synthesis of compound Z [ka] (2R,3S)-3-Methylhex-5-ene-2-sulfonamide (compound Z): In a 10 L glass-lined, jacketed reactor, compound N (Ar 1is pyridinyl) (300 g, 1.25 mol, 1.00 equiv.) and sodium thiomethoxide (105 g, 1.50 mol, 1.20 equiv.). Degassed solvents tert-butyl methyl ether (3.30 L, 11.0 L / kg) and methanol (3.00 L, 1.00 L / kg) were added and the resulting mixture was stirred at +35° C. for 12 hours until the formation of compound O was complete as determined by HPLC. The reaction was cooled to +25° C. and water (3.0 L, 10 L / kg) was added. The phases were separated and the aqueous phase was washed twice with tert-butyl methyl ether (2×1.5 L, 2×5.0 L / kg). The organic layer was discarded. Air was bubbled through the product-rich aqueous layer at +25° C. for 4 hours to consume the remaining sodium thiomethoxide. The aqueous layer was diluted with tert-butyl methyl ether (1.5 L, 5.0 L / kg). To this biphasic mixture, sodium acetate trihydrate (200 g, 1.5 mol, 1.2 eq.) and hydroxylamine-O-sulfonic acid (170 g, 1.5 mol, 1.2 eq.) were added. The biphasic mixture was stirred at +25° C. for 2 h until conversion of the sulfinate to the product compound Z was complete as determined by LC. Aqueous sodium chloride solution (5.5 mol / L solution, 1.35 L, 4.5 L / kg) was added and the mixture was stirred for 30 min. The phases were separated and the aqueous layer was extracted twice with tert-butyl methyl ether (2×1.35 L, 2×4.50 L / kg). The combined organic phase was washed sequentially with aqueous sodium bicarbonate (1 mol / L solution; 900 mL, 3.0 L / kg), aqueous sodium chloride (5.5 mol / L solution, 600 mL, 2.0 L / kg), and water (600 mL, 2.0 L / kg). The organic phase was distilled under low vacuum at +40-45° C. to a total volume of 600 mL. Solvent tert-butyl methyl ether (1.35 L, 4.50 L / kg) was added and the mixture was distilled under low vacuum at +40-45° C. to a total volume of 600 mL. The solution was cooled to +15° C. and n-heptane (1.5 L, 5.0 L / kg) was added slowly over 2 hours to promote crystallization. The slurry was cooled to 0° C. and stirred for 3 hours.The product was filtered off and the wet cake was washed with n-heptane (600 mL, 2.0 L / kg).The product was dried under vacuum at +30° C. to give 168 g of compound Z as a white crystalline solid (76% yield, 99.8 LC-Area% purity, 99.5% GC purity, 100.0 w / w% assay, 99.8% chiral-GC). 1 H NMR(500MHz,DMSO-d6)δ 6.69(s,2H),5.75(m,1H),5.06(m,2H),2.92(m,1H),2.31(m,1H),2.03(m,2H),1.17(d,J=7.2Hz,3H),0.92(d,J=7.2Hz,3H).LRMS(ESI):C7H 15 Calculated for N1O2S1+Na: 200.1, Found: 200.1. IR (neat) vmax 3323, 3255, 2980, 2962, 1556, 1452, 1312, 1165, 11137, 900, 593, 548, 511.

Claims

1. Compound Z 【Chemistry 1】 or a salt thereof, comprising the steps of: (a) (2S,3S)-butane-2,3-diol, a bromide source, and acetic acid are mixed to obtain compound I 【Chemistry 2】 forming (b) mixing compound I and a non-nucleophilic base to obtain compound J; 【Chemistry 3】 forming (c) Compound J and an allyl nucleophile are mixed to obtain Compound K. 【Chemistry 4】 forming (d) Compound K, a leaving group reagent, and an amine base are mixed to obtain Compound L. 【Chemistry 5】 (Wherein LG is a leaving group.) forming (e) Compound L, a non-nucleophilic base, and Ar １ -SH was mixed to obtain compound M 【Chemistry 6】 (In the formula, Ar １ is a 5-12 membered heteroaryl containing 1-3 ring heteroatoms selected from O, N, and S. forming (f) Oxidizing compound M to obtain compound N 【Chemistry 7】 forming and (g) mixing compound N, a base, and hydroxylamine-O-sulfonic acid to form compound Z; The method includes:

2. The bromide source is HBr, PBr ３ or a combination thereof.

3. 3. The method of claim 2, wherein HBr is present in the acetic acid in an amount of 20% to 50% w / w.

4. 4. The method of claim 3, wherein HBr is present as a 33% w / w solution in acetic acid.

5. 2. The method of claim 1, wherein the mixing in step (a) is carried out at a temperature of from -20°C to 10°C.

6. 10. The method of claim 1, wherein the mixing in step (a) is carried out for a period of from 1 hour to 24 hours.

7. 7. The method of claim 6, wherein the mixing in step (a) is carried out for a period of from 15 hours to 20 hours.

8. 10. The method of claim 1, wherein step (b) further comprises monoethylene glycol.

9. 9. The method of claim 8, wherein, for step (b), the non-nucleophilic base and monoethylene glycol are stirred together prior to mixing with compound I.

10. 10. The method of claim 9, wherein the non-nucleophilic base and monoethylene glycol are stirred together at a temperature between 25°C and 40°C.

11. 2. The method of claim 1, wherein the non-nucleophilic base comprises lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate, potassium amylate, or a combination thereof.

12. The method of claim 11 , wherein the non-nucleophilic base comprises potassium tert-butoxide.

13. 10. The method of claim 1, wherein the mixing in step (b) is carried out in an organic solvent comprising tert-butyl methyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, or a combination thereof.

14. The method of claim 13, wherein the organic solvent comprises tert-butyl methyl ether.

15. 10. The method of claim 1, wherein the mixing in step (b) is carried out for a period of from 10 minutes to 2 hours.

16. 16. The method of claim 15, wherein the mixing in step (b) is performed for 30 minutes.

17. 10. The method of claim 1, wherein the mixing in step (b) is carried out at a temperature of from 70°C to 120°C.

18. The allylic nucleophile is 【Chemistry 8】 2. The method of claim 1 , wherein X is a halide.

19. 20. The method of claim 18, wherein X is Cl.

20. 10. The method of claim 1, wherein the combining in step (c) is conducted in an organic solvent comprising tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether (MTBE), cyclopentyl methyl ether, dimethoxyethane, or a combination thereof.

21. 21. The method of claim 20, wherein the organic solvent comprises tetrahydrofuran and MTBE.

22. 2. The method of claim 1, wherein compound J is added dropwise to the allylic nucleophile over a period of 1 hour to 5 hours.

23. 10. The method of claim 1, wherein the mixing in step (c) is carried out for a period of from 1 hour to 6 hours.

24. 24. The method of claim 23, wherein the mixing in step (c) is carried out for 3 hours.

25. 2. The method of claim 1, wherein the mixing in step (c) is carried out at a temperature of from -20°C to 10°C.

26. 2. The method of claim 1, wherein compound J and the allylic nucleophile are present in a molar ratio of from 1:1.05 to 1:

3.

27. 2. The method of claim 1, wherein the leaving group comprises F, Cl, Br, I, mesyl, tosyl, nosyl, or triflyl.

28. 28. The method of claim 27, wherein the leaving group is mesyl.

29. 2. The method of claim 1, wherein the leaving group reagent comprises mesyl chloride, tosyl chloride, nosyl chloride, methanesulfonic anhydride, paratoluenesulfonic anhydride, or a combination thereof.

30. 30. The method of claim 29, wherein the leaving group reagent is mesyl chloride.

31. 10. The method of claim 1, wherein the mixing in step (d) is carried out in an organic solvent comprising dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, or a combination thereof.

32. 32. The method of claim 31 , wherein the organic solvent comprises tetrahydrofuran.

33. 32. The method of claim 31 , wherein the organic solvent does not comprise dichloromethane.

34. The method of claim 1 , wherein the leaving group reagent is added to a solution containing compound K and the amine base.

35. 35. The method of claim 34, wherein the leaving group reagent is added to the solution over a period of 2 to 3 hours, followed by stirring for 10 minutes to 1 hour.

36. 2. The method of claim 1, wherein the amine base in step (d) comprises trimethylamine, pyridine, triethylamine, aniline, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine, or a combination thereof.

37. 37. The method of claim 36, wherein the amine base comprises triethylamine.

38. 2. The method of claim 1, wherein the mixing in step (d) is carried out at a temperature of from -10°C to 10°C.

39. The method of claim 1, wherein the leaving group is present in an amount of 1.2 to 2 molar equivalents based on compound K.

40. 2. The method of claim 1, wherein the amine base is present in an amount of 1.8 to 3.3 molar equivalents based on compound K.

41. With respect to step (e), compound L is reacted with Ar １ The method of claim 1, wherein the -SH is added to a mixture containing the non-nucleophilic base.

42. 42. The method of claim 41, wherein compound L is added dropwise over a period of 3 to 6 hours.

43. 2. The method of claim 1, wherein the non-nucleophilic base in step (e) comprises lithium hexamethyldisilazide ("HMDS"), sodium HMDS, potassium HMDS, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-amylate, sodium tert-amylate, potassium tert-amylate, or combinations thereof.

44. 44. The method of claim 43, wherein the non-nucleophilic base comprises sodium tert-butoxide, potassium tert-butoxide, or sodium tert-amylate.

45. 2. The method of claim 1, wherein compound L and the non-nucleophilic base of step (e) are present in a molar ratio of 1:1.1 to 1:

4.

46. Ar １ teeth, 【Chemistry 9】 The method of claim 1 , wherein the compound is selected from the group consisting of:

47. Ar １ teeth, 【Chemistry 10】 47. The method of claim 46, wherein:

48. Compound L and Ar １ The method of claim 1, wherein the -SH is present in a molar ratio of from 1:1.05 to 1:2.

5.

49. Compound L, Ar １ 2. The method of claim 1, wherein the mixing of step (e) of -SH and non-nucleophilic base is carried out for a period of 3 hours to 5 hours.

50. 10. The method of claim 1, wherein the mixing in step (e) is carried out at a temperature of from 60°C to 80°C.

51. 2. The method of claim 1, wherein compound M is washed with aqueous sodium hydroxide 3-5 times prior to the oxidation in step (f).

52. 10. The method of claim 1, wherein the oxidation in step (f) comprises combining compound M with an oxidation catalyst and hydrogen peroxide.

53. 53. The method of claim 52, wherein the oxidation catalyst is sodium tungstate dehydrate, 3-chloroperbenzoic acid, or a combination thereof.

54. 54. The method of claim 53, wherein the oxidation catalyst is sodium tungstate dehydrate.

55. 53. The method of claim 52, wherein compound M and the oxidation catalyst are present in a molar ratio of from 1:0.05 to 1:0.

5.

56. 53. The method of claim 52, wherein the oxidizing further comprises mixing acetic acid.

57. 53. The method of claim 52, wherein compound M and hydrogen peroxide are present in a molar ratio of 1:1.3 to 1:

5.

58. 10. The method of claim 1, wherein the oxidation in step (f) is carried out in a solvent.

59. 59. The method of claim 58, wherein the solvent comprises methanol or ethanol.

60. 53. The method of claim 52, wherein compound M, the oxidation catalyst, and acetic acid are mixed prior to adding hydrogen peroxide.

61. 61. The method of claim 60, wherein the hydrogen peroxide is added over a period of 3 to 5 hours.

62. 2. The process of claim 1, wherein the oxidation of step (f) is carried out at a temperature of from 20° C. to 25° C.

63. With respect to step (g), compound N and the base are mixed together in a solvent to form intermediate compound O prior to mixing with the hydroxylamino-O-sulfonic acid. 【Chemistry 11】 where Q is an alkali metal cation. The method of claim 1 , further comprising forming

64. 64. The method of claim 63, wherein said combining of compound N and said base is carried out in a solvent comprising tert-butyl methyl ether, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.

65. 65. The method of claim 64, wherein the solvent comprises tert-butyl methyl ether and methanol.

66. 64. The method of claim 63, wherein said mixing of compound N and said base is carried out at a temperature between 25°C and 50°C.

67. 64. The method of claim 63, wherein the base comprises sodium thiomethoxide, sodium methoxide, methanol, and potassium carbonate, or a combination thereof.

68. 68. The method of claim 67, wherein the base is sodium thiomethoxide.

69. 64. The method of claim 63, wherein hydroxylamine-O-sulfonic acid is added to the intermediate compound O along with sodium acetate, potassium acetate, sodium formate, potassium formate, or a combination thereof.

70. 70. The method of claim 69, wherein hydroxylamine-O-sulfonic acid is added to the intermediate compound O along with sodium acetate trihydrate.

71. 70. The method of claim 69, wherein the combining of the intermediate compound O, hydroxylamine-O-sulfonic acid, and sodium acetate is carried out in a solvent comprising tert-butyl methyl ether, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.

72. 64. The method of claim 63, wherein the mixing of the intermediate compound O, hydroxylamine-O-sulfonic acid, and sodium acetate is carried out for a period of from 30 minutes to 4 hours.

73. 73. The method of claim 72, wherein the mixing of the intermediate compound O, hydroxylamine-O-sulfonic acid, and sodium acetate is carried out for 2 hours.

74. 64. The method of claim 63, wherein the mixing of the intermediate compound O, hydroxylamine-O-sulfonic acid, and sodium acetate is carried out at a temperature between 25°C and 50°C.

75. 10. The method of claim 1, further comprising crystallizing compound Z.

76. 76. The method of claim 75, wherein the crystallization comprises heating a solution of compound Z to 40° C. to 45° C., then cooling the solution to 10° C. to 15° C., and adding a crystallization solvent to the cooled solution to form crystals of compound Z.

77. 77. The method of claim 76, wherein the solution of compound Z comprises tert-butyl methyl ether and the crystallization solvent comprises heptane.

78. 77. The method of claim 76, wherein the solution of compound Z comprises methanol and the crystallization solvent comprises water.

79. The method comprises the steps of: 【Chemistry 12】 10. The method of claim 1, further comprising synthesizing the compound,

80. The method comprises the steps of: 【Chemistry 13】 10. The method of claim 1, further comprising synthesizing the compound,

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