Synthesis of vinyl alcohol intermediates

Abstract

Provided herein are processes for synthesizing intermediates useful for preparing Mcl-1 inhibitors. In particular, provided herein are processes for synthesizing compound (E), comprising: 1 Compound (E) may be useful for synthesizing compound (A1), or a salt or solvate thereof, and compound (A2), or a salt or solvate thereof. TIFF2023524261000077.tif72170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 020,888, 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 (1S,3'R,6'R,7'R,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-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 This invention relates to a process for synthesizing intermediates useful for preparing pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (compound A2; AMG 397), a salt or solvate 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) is useful as an inhibitor of myeloid cell leukemia 1 (Mcl-1): [ka]

[0004] The compound (1S,3'R,6'R,7'R,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-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) is useful as an inhibitor of myeloid cell leukemia 1 (Mcl-1): [ka]

[0005] One common characteristic of human cancers is the overexpression of Mcl-1, which prevents cancer cells from undergoing programmed cell death (apoptosis), allowing them 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 (such as BAX and BAK), which form homo-oligomers within the outer mitochondrial membrane shortly after activation, leading to pore formation and mitochondrial content evacuation, a process that triggers apoptosis. Anti-apoptotic members of the Bcl-2 family (such as Bcl-2, Bcl-XL, and Mcl-1) block the activity of BAX and BAK. Other proteins (such as BID, BIM, BIK, and BAD) exhibit 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.

[0007] U.S. Patent No. 9,562,061 (incorporated herein by reference in its entirety) discloses compound A1 as an Mcl-1 inhibitor and provides a method for its preparation. However, improved synthetic methods that result in higher yields and purity of compound A1 are desirable, particularly for commercially producing compound A1.

[0008] U.S. Patent No. 10,300,075 (incorporated herein by reference in its entirety) discloses compound A2 as an Mcl-1 inhibitor and provides a method for its preparation. However, improved synthetic methods that result in higher yields and purity of compound A2 are desirable, particularly for commercially producing compound A2. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 9,562,061 [Patent Document 2] U.S. Patent No. 10,300,075 Summary of the Invention [Means for solving the problem]

[0010] Provided herein is a process for synthesizing compound E, or a salt or solvate thereof, comprising: [ka] Compound C, Compound D, [ka] and Zn(X 3 ) mixing 2 in an organic solvent to form compound E: [ka] In the formula, R 1 is C 1~6 alkyl; R 2 is H or C 1~3 Alkoxy; X 1 is MgCl, MgBr, MgI, Li, CuLi, ZnX 2 , In(I), or In(X 2 ) 2; each X 2 is independently Cl, Br, or I; each X 3 are independently Cl, Br, I, OTf, OTs, OAc, or acac.

[0011] In various embodiments, R 1 is methyl, ethyl, propyl, n-butyl, or tert-butyl. 1 is methyl, ethyl, or tert-butyl.

[0012] In various embodiments, R 2 is H. In various embodiments, R 2 is C 1~3 In some cases, R 2 is methoxy.

[0013] In various embodiments, X 1 is MgCl. In various embodiments, X 1is MgBr or MgI. In various embodiments, X 1 is Li. In various embodiments, X 1 is CuLi. In various embodiments, X 1 is In(I) or In(X 2 )2. In various embodiments, X 1 is ZnCl or ZnBr.

[0014] In various embodiments, Zn(X 3 )2 is ZnCl2. In various embodiments, Zn(X 3 )2 is ZnBr2. In various embodiments, Zn(X 3 )2 is ZnI2. In various embodiments, Zn(X 3 ) is Zn(OTf) or Zn(OTs). In various embodiments, Zn(X 3 )2 is Zn(OAc)2 or Zn(acac)2.

[0015] In various embodiments, the organic solvent is degassed prior to mixing. In various embodiments, the organic solvent comprises an ethereal solvent or acetonitrile. Optionally, the organic solvent is selected from the group consisting of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether, acetonitrile, 1,2-dimethoxyethane (1,2-DME), methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), and combinations thereof. Optionally, the organic solvent is acetonitrile.

[0016] In various embodiments, the mixing is carried out at a temperature of 10 to 35°C.

[0017] In various embodiments, the mixing comprises: (a) compound C and Zn(X 3 (b) mixing 2 in an organic solvent to form a suspension; [ka] (c) adding compound D to the suspension to form a solution; and (c) adding compound E to the solution to form compound E. Optionally, the suspension of step (a) comprises: [ka] Before adding the solution, the solution is cooled to a temperature of -15°C to -5°C. [ka] is added to the suspension as a solution in an ethereal solvent. In some embodiments, the ethereal solvent is THF. [ka] is added to the suspension at a temperature between -10°C and 0°C. Optionally, the solution of step (b) is brought to a temperature between 10°C and 35°C before adding compound D. Optionally, compound D is added as a solution in an organic solvent selected from the group consisting of THF, 2-MeTHF, diethyl ether, acetonitrile, 1,2-DME, MTBE, CPME, and combinations thereof. Optionally, the organic solvent comprises acetonitrile.

[0018] In various embodiments, Compound D and [ka] are present in a molar ratio of 1:2.5 to 1:4.5. [ka] The molar ratio of HCl to HCl is 1:3.2.

[0019] In various embodiments, compound D and Zn(X 3 )2 is present in a molar ratio of 1:2.5 to 1:4.0. In various cases, the Zn(X 3 The molar ratio of 2 to 2 is 1:3.1.

[0020] In various embodiments, Compound D and Compound C are present in a molar ratio of 1:1 to 1:2. In some cases, the molar ratio of Compound D to Compound C is 1:1.4.

[0021] In various embodiments, compound D is reacted with compound B: [ka] Optionally, the oxidation occurs under an inert atmosphere.

[0022] In various embodiments, Compound B is provided as a solution in an organic solvent selected from the group consisting of dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethylformamide (DMF), THF, 2-MeTHF, acetonitrile, toluene, 1,2-DME, MTBE, 1,2-dichloroethane (DCE), chloroform, and combinations thereof. In some embodiments, the organic solvent is DCM.

[0023] In various embodiments, the oxidizing agent is selected from the group consisting of oxalyl chloride, bleach, SO3 / pyridine, iodobenzene diacetate, trifluoroacetic anhydride, N-chlorosuccinimide (NCS), 2-iodoxybenzoic acid (IBX), N-methylmorpholine N-oxide (NMO), ceric ammonium nitrate (CAN), Dess-Martin periodinane (DMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), tetrapropylammonium perruthenate (TPAP) / NMO, NCS / dimethyl sulfide, NCS / dodecyl sulfide, and combinations thereof. In some embodiments, the oxidizing agent is oxalyl chloride.

[0024] In various embodiments, the oxidation is carried out in the presence of a base selected from the group consisting of triethylamine, diisopropylethanolamine, N-methylpyrrolidine, N-ethylpiperidine, pyridine, 2,2,6,6-tetramethylpiperidine (TMP), pempidine, 2,6-lutidine, and combinations thereof. In some embodiments, the base is triethylamine.

[0025] In various embodiments, compound B and the oxidizing agent are present in a molar ratio of 1:1 to 1:3. In some cases, the molar ratio of compound B to the oxidizing agent is 1:1.5.

[0026] In various embodiments, compound B and the base are present in a molar ratio of 1:3 to 1:10. In some cases, the molar ratio of compound B to base is 1:5.

[0027] In various embodiments, the oxidation occurs in an organic solvent selected from the group consisting of dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethylformamide (DMF), THF, 2-MeTHF, acetonitrile, MTBE, 1,2-DME, toluene, DCE, CPME, and combinations thereof. In some cases, the organic solvent is DMSO.

[0028] In various embodiments, the oxidation occurs at a temperature of -80°C to -20°C. In some cases, the oxidation occurs at a temperature of -40°C.

[0029] In various embodiments, the process further comprises hydrolyzing compound E to produce compound F: [ka] or forming a salt thereof.

[0030] In various embodiments, the hydrolysis comprises combining a solution of compound E in an organic solvent and a hydroxide base in water to form compound F.

[0031] In various embodiments, the hydroxide base is selected from the group consisting of NaOH, KOH, LiOH, potassium trimethylsilanolate (TMSOK), and combinations thereof.

[0032] In various embodiments, compound E and the hydroxide base are present in a molar ratio of 1:1 to 1:100. In some cases, the molar ratio of compound E to the hydroxide base is 1:3.

[0033] In various embodiments, the organic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, THF, diethyl ether, acetone, acetonitrile, 2-MeTHF, sec-butanol, and combinations thereof. In some embodiments, the organic solvent is ethanol.

[0034] In various embodiments, the hydrolysis occurs at a temperature between 20°C and 60°F.

[0035] In various embodiments, Compound F is in the form of a salt. In some cases, the salt of Compound F comprises an ammonium cation or an alkali metal cation. In some cases, the ammonium cation is selected from the group consisting of benzylammonium, methylbenzylammonium, trimethylammonium, triethylammonium, morpholinium, pyridinium, piperidinium, picolinium, dicyclohexylammonium, protonated N,N'-dibenzylethylenediamine, 2-hydroxyethylammonium, bis-(2-hydroxyethyl)ammonium, tri-(2-hydroxyethyl)ammonium, protonated procaine, dibenzylpiperidium, dehydroabietylammonium, N,N'-bisdehydroabietylammonium, protonated glucamine, protonated N-methylglucamine, protonated collidine, protonated quinine, protonated quinoline, protonated lysine, protonated arginine, protonated 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-diisopropylethylammonium, and combinations thereof. In some cases, the ammonium cation is [ka] In some cases, the alkali metal cation is selected from the group consisting of lithium, sodium, potassium, and combinations thereof.

[0036] In various embodiments, the salt of Compound F is prepared by combining Compound F, in its free acid form (Compound F free acid), with an amine base or an alkali metal base in a non-polar organic solvent to form the salt of Compound F.

[0037] In various embodiments, Compound F free acid and the amine base or alkali metal base are present in a molar ratio of 1:1 to 1:2. In some cases, the molar ratio of Compound F free acid to the amine base or alkali metal base is 1:1.2.

[0038] In various embodiments, the non-polar organic solvent is selected from the group consisting of ethyl acetate, toluene, isopropyl acetate, MTBE, and combinations thereof. In some embodiments, the non-polar organic solvent is ethyl acetate.

[0039] In various embodiments, the combining (of Compound F free acid and the amine base or alkali metal base) occurs at a temperature of 50° C. to 60° C. In some cases, the combining occurs under an inert atmosphere.

[0040] In various embodiments, the process further includes synthesizing Compound A1, or a salt or solvate thereof, using Compound E: [ka]

[0041] In various embodiments, the process further includes using compound E to synthesize compound A2, or a salt or solvate thereof: [ka]

[0042] Further aspects and advantages will be apparent to those skilled in the art from a review of the following detailed description. The following description includes specific embodiments, with the understanding that this disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. DETAILED DESCRIPTION OF THE INVENTION

[0043] Provided herein are processes for synthesizing Mcl-1 inhibitors and the corresponding vinyl alcohol intermediates. In particular, (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, was synthesized, and (1S,3'R,6'R,7'R,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-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, is provided: [ka]

[0044] U.S. Patent No. 9,562,061 (incorporated herein by reference in its entirety) discloses compound A1, or a salt or solvate thereof, as an Mcl-1 inhibitor and provides a process for preparing the same. This patent also discloses a process for synthesizing the vinyl alcohol intermediate compound shown below, which is used in the synthesis of compound A1. [ka] Vinyl alcohol intermediates of the '061 patent

[0045] U.S. Patent No. 10,300,075 (incorporated herein by reference in its entirety) discloses Compound A2, or a salt or solvate thereof, as an Mcl-1 inhibitor and provides a process for preparing the same. The disclosure of salts and solvates of Compound A2 from U.S. Patent No. 10,300,075 is incorporated by reference in its entirety. This patent also discloses a process for synthesizing the vinyl alcohol intermediate compound shown above, which is used in the synthesis of Compound A2.

[0046] The '061 patent generally describes a procedure for preparing a vinyl alcohol intermediate, as shown in Scheme 1 below, which is an excerpt from the disclosure in col. 49 of the '061 patent. The '061 patent describes combining a cyclobutanecarbaldehyde (intermediate II) with an oxazepine (intermediate I) in a solvent at a temperature below room temperature, preferably 0° C. Sodium cyanoborohydride is added, and the mixture is added to a sodium hydroxide solution to provide intermediate III. Advantageously, the process described herein represents an improved synthetic route compared to General Procedure 1 of the '061 patent, as it can be carried out under ambient conditions (e.g., room temperature) and uses milder reagents.

[0047] Scheme 1 - General Procedure 1 of the '061 Patent [ka] The '061 patent further describes a process for synthesizing a vinyl alcohol intermediate, including the use of a divinylzinc reagent in the conversion of an aldehyde intermediate to the vinyl alcohol intermediate. Scheme 2, below, represents the general process for synthesizing vinyl alcohol described in the '061 patent.

[0048] Scheme 2 - Synthesis of the vinyl alcohol intermediate of the '061 patent [ka] The process of the '061 patent has several disadvantages. Importantly, the divinylzinc reagent is not commercially available and must be synthesized prior to use in the reaction. The preparation of divinylzinc requires a filtration step to remove inorganic salts, which is not scalable due to fines clogging. In addition, the ligand [ka] must also be synthesized prior to use in the reaction. Furthermore, the reaction requires unsuitably low temperatures and is air- and water-sensitive.

[0049] Advantageously, the processes described herein utilize more favorable reaction conditions (i.e., can be carried out at or near room temperature) and reagents are more commercially available. For example, cinchonidine and vinyl Grignard reagents are available from natural and / or commercial sources. Furthermore, the process can be carried out in a single reactor without isolation of intermediates between steps. Also, higher, scalable yields of the final product can be obtained compared to the process of the '061 patent because the difficulties associated with preparing and storing divinyl zinc and ligands, as well as unfavorable reaction conditions, are eliminated.

[0050] Described herein is a process for synthesizing compound E, or a salt or solvate thereof, comprising: [ka] E: compound C, compound D, [ka] , and Zn(X 3 )2 in an organic solvent to produce compound E, which is discussed in detail below: [ka] As will be appreciated, the disclosed processes encompass the formation of a vinyl alcohol intermediate by addition of a vinyl group across the carbonyl of the corresponding aldehyde intermediate. The processes disclosed herein for forming intermediate compounds (e.g., compounds D, E, and F, described in more detail below) can be carried out sequentially in a single reactor without the need to isolate the intermediates between steps.

[0051] A general reaction scheme for the processes described herein is provided below in Scheme 3:

[0052] Scheme 3 - General process for the synthesis of vinyl alcohol intermediates [ka]

[0053] oxidation The processes of the present disclosure can include oxidizing compound B to provide compound D. In particular, the primary alcohol of compound B can be oxidized to form the aldehyde of compound D. In some embodiments, the oxidation occurs under an inert atmosphere, for example, under nitrogen or argon gas. In some embodiments, the oxidation occurs under nitrogen gas.

[0054] Compound B provided herein is [ka] and compound D has the structure [ka] wherein R 1 is C 1~6 The term "alkyl" as used herein refers to a linear, branched, saturated hydrocarbon group. n means that the group has "n" carbon atoms. For example, C3 alkyl refers to an alkyl group having 3 carbon atoms. C 1~6Alkyl refers to alkyl groups having a number of carbon atoms (i.e., 1 to 6 carbon atoms) throughout the range and all subgroups (e.g., 2 to 6, 1 to 5, 1 to 4, 3 to 6, 3 to 5, 1, 2, 3, 4, 5, and 6 carbon atoms). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), tert-butyl (1,1-dimethylethyl), n-pentyl, and n-hexyl. In some embodiments, R 1 is methyl, ethyl, n-propyl, or tert-butyl. 1 is methyl, ethyl, or tert-butyl. 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is tert-butyl.

[0055] In some embodiments, compound B is provided as a solution in an organic solvent, for example, when added to a reactor for oxidation reaction. Organic solvents are generally known in the art. Non-limiting examples of organic solvents that can be used throughout the processes described herein include acetonitrile, toluene, benzene, xylene, chlorobenzene, fluorobenzene, naphthalene, benzotrifluoride, tetrahydrofuran (THF), tetrahydropyran, dimethylformamide (DMF), tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethyl sulfoxide (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.

[0056] In some embodiments, compound B is provided as a solution in an organic solvent selected from the group consisting of dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethylformamide (DMF), THF, 2-MeTHF, acetonitrile, toluene, 1,2-DME, MTBE, 1,2-dichloroethane (1,2-DCE), chloroform, and combinations thereof. In some embodiments, the organic solvent is DCM. That is, in some embodiments, compound B is provided as a DCM solution.

[0057] The oxidation of compound B is carried out with an oxidizing agent. Oxidizing agents capable of oxidizing primary alcohols to aldehydes are generally known in the art. Non-limiting examples of oxidizing agents include, but are not limited to, chromium-based reagents such as Collins' reagent (CrO3·Py2), pyridinium chlorochromate (PCC), and pyridinium dichromate (PDC); sulfonium species ("activated DMSO" derived from the reaction of DMSO with an electrophile such as oxalyl chloride, carbodiimide, or SO3·Py); hypervalent iodine compounds such as Dess-Martin periodinane (DMP) or 2-iodoxybenzoic acid (IBX); catalytic tetrapropylammonium perruthenate (TPAP) in the presence of N-methylmorpholine N-oxide (NMO); and catalytic 2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) in the presence of NaOCl (bleach).

[0058] In some embodiments, the oxidizing agent is selected from the group consisting of oxalyl chloride, bleach, SO3 / pyridine, iodobenzene diacetate, trifluoroacetic anhydride, N-chlorosuccinimide (NCS), 2-iodoxybenzoic acid (IBX), N-methylmorpholine N-oxide (NMO), ceric ammonium nitrate (CAN), Dess-Martin periodinane (DMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), tetrapropylammonium perruthenate (TPAP) / NMO, NCS / dimethyl sulfide, NCS / dodecyl sulfide, and combinations thereof. In some embodiments, the oxidizing agent is oxalyl chloride.

[0059] Compound B and the oxidizing agent may be present in a molar ratio of 1:1 to 1:3, e.g., at least 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, or 1:2.25, and / or at most 1:3, 1:2.75, 1:2.5, 1:2.25, 1:2, or 1:1.75, e.g., 1:1 to 1:2.5, 1:1 to 1:2, 1:1 to 1:1.5, 1:1.25 to 1:2, or 1:1.25 to 1:1.75. In some embodiments, the molar ratio of compound B to oxidizing agent is 1:1.5.

[0060] The oxidation of compound B occurs in the presence of an organic solvent. The organic solvent may be the same as or different from the organic solvent used in the solution with compound B. In some embodiments, the oxidation occurs in the presence of an organic solvent selected from the group consisting of dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethylformamide (DMF), THF, 2-MeTHF, acetonitrile, MTBE, 1,2-DME, toluene, 1,2-DCE, CPME, and combinations thereof. In some embodiments, the oxidation occurs in the presence of DMSO. In some embodiments, the oxidation occurs in the presence of DMSO and DCM.

[0061] The organic solvent may be present in an amount from 5 L / kg of compound B to 50 L / kg of compound B, e.g., at least 5, 10, 15, 20, 25, or 30 L / kg of compound B, and / or up to 50, 45, 40, 35, 30, 25, or 20 L / kg of compound B, e.g., 10 to 40 L / kg of compound B, 15 to 30 L / kg of compound B, or 15 L / kg to 20 L / kg of compound B.

[0062] The oxidation of compound B can be carried out in the presence of a base, for example, an amine base (e.g., mono-, di-, or trialkylamine, substituted or unsubstituted piperidine, substituted or unsubstituted pyridine, etc.). In some embodiments, the base is selected from the group consisting of triethylamine, diisopropylethanolamine, N-methylpyrrolidine, N-ethylpiperidine, pyridine, 2,2,6,6-tetramethylpiperidine (TMP), pempidine, 2,6-lutidine, and combinations thereof. In some embodiments, the base is triethylamine.

[0063] When a base is present in the oxidation of compound B, compound B and the base can be present in a molar ratio of 1:3 to 1:10, e.g., at least 1:3, 1:4, 1:5, 1:6, or 1:7, and / or at most 1:10, 1:9, 1:8, 1:7, or 1:6, e.g., 1:3 to 1:9, 1:5 to 1:10, 1:4 to 1:8, or 1:4 to 1:6. In some embodiments, the molar ratio of compound B to base is 1:5.

[0064] The oxidation of compound B can occur at a temperature of -80°C to -20°C, e.g., at least -80, -70, -60, -55, -50, -45, or -40°C, and / or at most -20, -25, -30, -35, -40, -50, or -60°C, e.g., -70°C to -25°C, -60°C to -30°C, -50°C to -30°C, or -45°C to -35°C. In some embodiments, the oxidation occurs at a temperature of -40°C.

[0065] In some embodiments, Compound B and / or Compound D are salts. A salt of Compound B, Compound D, or any other compound described herein can be, for example, a salt of a compound in its free acid form (e.g., R 1 is H) with a suitable organic or inorganic base and, optionally, isolating the salt thus formed. Non-limiting examples of suitable salts include salts with alkali metal cations, such as lithium, sodium, potassium, and combinations thereof, or ammonium cations, such as benzylammonium, methylbenzylammonium, trimethylammonium, triethylammonium, morpholinium, pyridinium, piperidinium, picolinium, dicyclohexylammonium, protonated N,N'-dibenzylethylenediamine, 2-hydroxyethylammonium, bis-(2-hydroxyethyl)ammonium, tri-(2-hydroxyethyl)ammonium, protonated procaine, dibenzylpiperidium, dehydroabietylammonium, N,N'-bisdehydroabietylammonium, protonated glucamine, protonated N-methylglucamine, protonated collidine, protonated quinine, protonated quinoline, protonated lysine, protonated arginine, protonated 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-diisopropylethylammonium, and amino acid salts. In some embodiments, Compound B, Compound D, or any other compound described herein can be prepared, for example, by reacting the compound in its free form with a suitable organic or inorganic acid and, optionally, isolating the salt thus formed. Non-limiting examples of suitable acid salts include hydrobromide, hydrochloride, sulfate, bisulfate, sulfonate, camphorsulfonate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, and amino acid salts.

[0066] Oxidation of compound B can provide compound D, which can be through-processed directly to the next step without the need for separation.

[0067] Vinyl alcohol formation The process of the present disclosure comprises reacting Compound C, Compound D (e.g., as prepared in Step 1), [ka] and Zn(X 3 ) mixing 2 in an organic solvent to form compound E: [ka] In the formula, R 1 is as previously described, and X 1 is MgCl, MgBr, MgI, Li, CuLi, ZnX 2 , In(I), or In(X 2 ) 2; each X 2 is independently Cl, Br, or I; each X 3 are independently Cl, Br, I, triflate (OTf), tosylate (OTs), acetate (OAc), or 2,4-acetylacetonate (acac).

[0068] Advantageously, the process of the present disclosure can eliminate the additional and separate synthesis of divinylzinc used, for example, in the process of U.S. Pat. No. 9,562,061, by using commercially available reagents for the synthesis of vinyl alcohol intermediates (e.g., Compound E) from the corresponding aldehydes (e.g., Compound D).

[0069] Compound C provided herein is [ka] wherein R 2 is H or C 1~3 In some embodiments, R2 is H (i.e., compound C is cinchonidine). In some embodiments, R 2 is C 1~3 The term "alkoxy" as used herein is defined as -OR, where R is an alkyl group. For example, R 2 can be methoxy (-OCH), ethoxy (-OCHCH), n-propoxy (-OCHCHCH), or isopropoxy (-OCH(CH)). In some embodiments, R 2 is methoxy (i.e., compound C is quinine).

[0070] Vinyl Reagents [ka] can be any one of a Grignard, organolithium, organocuprate, organozinc, or organoindium reagent suitable for addition of a vinyl group across the aldehyde of compound D.

[0071] In some embodiments, [ka] is a Grignard reagent. "Grignard reagent" is a 1 means that X includes magnesium with a halogen, for example, Cl, Br, or I. 1 is MgCl. In some embodiments, X 1 is MgBr or MgI.

[0072] In some embodiments, [ka] is an organolithium reagent. For example, in some embodiments, X 1 is Li. In some embodiments, [ka] is an organocuprate reagent. For example, in some embodiments, X 1 is CuLi. In some embodiments, [ka] is an organoindium reagent. For example, in some embodiments, X 1 is In(I) or In(X 2 )2. In some embodiments, X 1 is In(I). In some embodiments, X 1 is In(X 2 )2, and each X 2 is independently Cl, Br, or I. In some embodiments, X 1 is InCl. In some embodiments, X 1 is InBr. In some embodiments, X 1 is InI. In some embodiments, [ka] is an organozinc reagent. For example, in some embodiments, X 1 ZnX 2 and X 2 is as described herein. In some embodiments, X 1 is ZnCl or ZnBr. 1 is ZnCl. In some embodiments, X 1 is ZnBr.

[0073] Compound D and [ka] may be present in a molar ratio of 1:2.5 to 1:4.5, e.g., at least 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, or 1:3.75, and / or at most 1:4.5, 1:4.0, 1:3.75, 1:3.5, 1:3.25, or 1:3, e.g., 1:2.5 to 1:4, 1:3 to 1:4.5, 1:3 to 1:4, or 1:3 to 1:3.5. In some embodiments, compound D [ka] The molar ratio of HCl to HCl is 1:3.2.

[0074] The process provided herein involves the production of Zn(X 3 ) 2 with Compound C, Compound D, and [ka] In some embodiments, Zn(X 3 )2 is ZnCl2. In some embodiments, Zn(X 3 )2 is ZnBr2. In some embodiments, Zn(X 3 )2 is ZnI2. In some embodiments, Zn(X 3 ) is Zn(OTf). In some embodiments, Zn(X 3 )2 is Zn(OTs)2. In some embodiments, Zn(X 3 ) is Zn(OAc). In some embodiments, Zn(X 3 )2 is Zn(acac)2.

[0075] Compounds D and (X 3 )2 may be present in a molar ratio of 1:2.5 to 1:4, e.g., at least 1:2.5, 1:2.75, 1:3, or 1:3.25, and / or at most 1:4, 1:3.75, 1:3.5, 1:3.25, or 1:3, e.g., 1:2.5 to 1:3.5, 1:2.75 to 1:3.5, 1:3 to 1:4, or 1:3 to 1:3.5. In some embodiments, the Zn(X 3 The molar ratio of 2 to 2 is 1:3.1.

[0076] Compound C, Compound D, [ka] and Zn(X 3 The mixing of 2) occurs in an organic solvent. In some embodiments, the organic solvent is an ethereal solvent or acetonitrile. Non-limiting examples of ethereal solvents include tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), tetrahydropyran, tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), 1,2-dimethoxyethane, 1,4-dioxane, 2-methyl-THF, and cyclopentyl methyl ether. In some embodiments, the organic solvent is selected from the group consisting of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether, 1,2-dimethoxyethane (1,2-DME), methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), and combinations thereof. In some embodiments, the organic solvent is acetonitrile.

[0077] Mixing may occur at a temperature of from 10°C to 35°C, for example at least 10, 15, 20, or 25°C, and / or at most 35, 30, 25, or 20°C, for example from 15°C to 30°C or from 20°C to 25°C.

[0078] In some embodiments, the mixing comprises: (a) mixing a compound C and Zn(X 3 (b) mixing 2 in an organic solvent to form a suspension; [ka] to the suspension to form a solution; and (c) adding compound D to the solution to form compound E.

[0079] In some embodiments, the suspension of step (a) comprises: [ka] For example, the suspension of step (a) may be cooled to a temperature of -12°C to -7°C or -10°C to -8°C. In some embodiments, the suspension of step (a) is cooled to a temperature of -15°C to -5°C before adding [ka] Before addition, the solution is cooled to a temperature of -10°C.

[0080] In some embodiments, [ka] is added to the suspension as a solution in an ether solvent, for example, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), tetrahydropyran, tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), 1,2-dimethoxyethane, 1,4-dioxane, 2-methyl-THF, or cyclopentyl methyl ether. [ka] is added to the suspension as a solution in THF.

[0081] In some embodiments, [ka] is added to the suspension at a temperature of -10°C to 0°C, e.g., at least -10, -9, -8, -7, -6, -5, or -4, and / or at most 0, -1, -2, -3, -4, -5, or -6°C, e.g., -8°C to 0°C, -6°C to -2°C, or -6°C to -4°C. [ka] is added to the suspension at a temperature of −5° C. The solution of step (b) is added to the suspension at a temperature of −5° C. before adding compound D (e.g. [ka] The solution in step (b) may be brought to a temperature of 10° C. to 35° C. (after addition of Compound D). For example, the solution in step (b) may be brought to a temperature of 10, 15, 20, 25, or 30° C., and / or up to 35, 30, 25, 20, or 15° C., e.g., 15° C. to 30° C., 15° C. to 25° C., or 20° C. to 25° C., before addition of Compound D. In some embodiments, the solution in step (b) is brought to a temperature of 20° C. before addition of Compound D.

[0082] In step (c), compound D may be added as a solution in an organic solvent. For example, compound D may be added as a solution in an organic solvent selected from the group consisting of THF, 2-MeTHF, diethyl ether, acetonitrile, 1,2-DME, MTBE, CPME, and combinations thereof. In some embodiments, compound D is added as an acetonitrile solution.

[0083] The organic solvent can be present in an amount from 5 L / kg of compound D to 30 L / kg of compound D, e.g., at least 5, 7, 10, 12, 15, 17, 20, or 22 L / kg of compound D, and / or up to 30, 27, 25, 22, 20, or 15 L / kg of compound D, e.g., 10-30 L / kg of compound D, 15-30 L / kg of compound D, or 10 L / kg to 20 L / kg of compound D.

[0084] In some embodiments, Compound E is a salt. The salts of Compound E can be similar to those described herein for Compounds B or D.

[0085] Compound E: [ka] In the formula, R 1 is as described herein and can be processed straight through to the next step without the need for separation.

[0086] Ester Hydrolysis and Salt Formation The process of the present disclosure further comprises hydrolyzing ester compound E to produce compound F: [ka] or forming a salt thereof.

[0087] In some embodiments, the hydrolysis comprises using an enzyme (e.g., enzymatic hydrolysis). In some embodiments, the hydrolysis comprises combining a solution of compound E in an organic solvent and a hydroxide base in water to form compound F. Non-limiting examples of hydroxide bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium trimethylsilanolate (TMSOK). In some embodiments, the hydroxide base is selected from the group consisting of NaOH, KOH, LiOH, TMSOK, and combinations thereof. In some embodiments, the hydroxide base is NaOH.

[0088] Compound E and the hydroxide base can be present in a molar ratio of 1:1 to 1:100, e.g., at least 1:1, 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:40, 1:50, or 1:60, and / or at most 1:100, 1:95, 1:90, 1:80, 1:75, 1:70, 1:60, 1:50, 1:45, or 1:40, e.g., 1:1 to 1:75, 1:1 to 1:50, 1:1 to 1:25, 1:1 to 1:10, or 1:1 to 1:5. In some embodiments, the molar ratio of compound E to hydroxide base is 1:3.

[0089] The hydrolysis can be carried out in the presence of an organic solvent, such as any of the organic solvents described herein, for example, an ether solvent, an alcohol solvent (e.g., methanol, ethanol, propanol, butanol, etc.), or any water-miscible solvent (e.g., THF, acetonitrile, etc.). In some embodiments, the organic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, THF, diethyl ether, acetone, acetonitrile, 2-MeTHF, sec-butanol, and combinations thereof. In some embodiments, the organic solvent is ethanol.

[0090] Hydrolysis can occur at a temperature of 20°C to 60°F, e.g., at least 20, 25, 30, 35, 40, or 45°C, and / or up to 60, 55, 50, 45, 40, or 35°C, e.g., 25°C to 60°C, 30°C to 60°C, 40°C to 60°C, or 50°C to 60°C. In some embodiments, hydrolysis occurs at a temperature of 55°C.

[0091] Once hydrolysis is complete, the solution may be cooled or brought to ambient room temperature (e.g., 15, 20, or 25°C), at which point the reaction may be neutralized to a pH of 6-7 with an acid, such as phosphoric acid.

[0092] Hydrolysis converts compound F into its free acid form: [ka] It can be provided at.

[0093] The process of the present disclosure can further include providing compound F in a salt form. For example, compound F in salt form can be: [ka] It may have the structure:

[0094] In some embodiments, the salt of Compound F can include an ammonium cation or an alkali metal cation. In some embodiments, the salt of Compound F includes an alkali metal cation, such as lithium, sodium, potassium, and combinations thereof. In some embodiments, the salt of compound F comprises an ammonium cation, such as benzylammonium, methylbenzylammonium, trimethylammonium, triethylammonium, morpholinium, pyridinium, piperidinium, picolinium, dicyclohexylammonium, protonated N,N'-dibenzylethylenediamine, 2-hydroxyethylammonium, bis-(2-hydroxyethyl)ammonium, tri-(2-hydroxyethyl)ammonium, protonated procaine, dibenzylpiperidium, dehydroabietylammonium, N,N'-bisdehydroabietylammonium, protonated glucamine, protonated N-methylglucamine, protonated collidine, protonated quinine, protonated quinoline, protonated lysine, protonated arginine, protonated 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-diisopropylethylammonium, and combinations thereof. In some embodiments, the ammonium cation is [ka] is.

[0095] A salt of Compound F can be prepared by combining Compound F, in its free acid form (Compound F free acid), with an amine base or an alkali metal base in a non-polar organic solvent to form a salt of Compound F (Compound F salt form).

[0096] Non-limiting examples of amine bases include alkylamines, such as mono-, di-, or trialkylamines (e.g., monoethylamine, diethylamine, triethylamine, and N,N-diisopropylethylamine), pyridines, such as collidine and 4-diethylaminopyridine (DMAP), and imidazoles, such as N-methylimidazole, as well as benzylamine, methylbenzylamine, morpholine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine, quinine, quinoline, lysine, arginine, 1,4-diazabicyclo[2.2.2]octane (DABCO), and N,N-diisopropylethylamine. Non-limiting examples of alkali metal bases include NaOH, LiOH, and KOH.

[0097] The Compound F free acid and the amine base or alkali metal base can be present in a molar ratio of 1:1 to 1:2, e.g., at least 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, or 1:1.6, and / or at most 1:2, 1:1.9, 1:1.8, 1:1.7, 1:1.6, 1:1.5, or 1:1.4, e.g., 1:1 to 1:7, 1:1 to 1:5, or 1:1 to 1:1.3. In some embodiments, the molar ratio of Compound F free acid to the amine base or alkali metal base is 1:1.2.

[0098] The Compound F free acid can be mixed with an amine base or an alkali metal base in a non-polar organic solvent. In some embodiments, the non-polar organic solvent is selected from the group consisting of ethyl acetate, toluene, isopropyl acetate, MTBE, and combinations thereof. In some embodiments, the non-polar organic solvent is ethyl acetate.

[0099] The Compound F free acid and the amine base or alkali metal base can be mixed at a temperature of 50° C. to 60° C., e.g., at least 50, 52, 55, or 57° C., and / or up to 60, 57, 55, or 52° C., e.g., 52° C. to 60° C., 55° C. to 60° C., or 57° C. to 60° C. In some embodiments, the mixing occurs at a temperature of 60° C.

[0100] The mixing can occur under an inert atmosphere, for example under nitrogen or argon gas, hi some embodiments, the mixing is carried out under nitrogen gas.

[0101] Combining Compound F free acid with an amine base or alkali metal base in a non-polar organic solvent provides the Compound F salt form, which can be crystallized for later use, for example, in the synthesis of Compound A1 or A2.

[0102] The process for synthesizing compounds E and F can be used to synthesize compounds A1 and A2 from compounds E and F. As shown in Scheme 4 below, compounds E and F can be used to synthesize compound A1 and its salts and solvates, and as shown in Scheme 5, compounds E and F can also be used to synthesize compound A2 and its salts and solvates.

[0103] Scheme 4 - Conversion of Compound E to Compound A1 [ka] As shown in Scheme 4 and described in U.S. Pat. No. 9,562,061, compounds E and F can be used to synthesize compound A1 and its salts and solvates. The synthesis of sulfonamide EE22 is disclosed in U.S. Pat. No. 9,562,061. As described herein, compound E can be used to prepare compound F by conversion of ester E to carboxylic acid F. As shown in U.S. Pat. No. 9,562,061, compound EE22 and compound F can react to form compound G. As described in U.S. Pat. No. 9,562,061, cyclization of compound G can provide hydroxy compound H, which can be subsequently methylated to provide compound A1.

[0104] Scheme 5 - Conversion of Compound E to Compound A2 [ka] As shown in Scheme 5 and described in U.S. Pat. No. 10,300,075, compounds E and F can be used to synthesize compound A2 and its salts and solvates. As previously described with respect to Scheme 4, the synthesis of sulfonamide EE22 is disclosed in U.S. Pat. No. 9,562,061. Also, as previously described and shown in U.S. Pat. No. 9,562,061, sulfonamide EE22 and compound F can react to form compound G, which can be cyclized to produce hydroxy compound H. Compound H can then be oxidized to provide cyclic enone I, as disclosed in U.S. Pat. No. 10,300,075. Alternatively, compound G can be oxidized to provide the acyclic enone version of compound G, which can then be cyclized to provide cyclic enone I. Enone I can then be converted to epoxide J using procedures disclosed in U.S. Pat. No. 10,300,075. Epoxide J can subsequently be reacted with bicyclic compound K to provide hydroxy compound L. Finally, methylation of compound L can provide compound A2, as disclosed in U.S. Pat. No. 10,300,075.

[0105] In some embodiments, the process further comprises using compound D to synthesize compound A1: [ka] or synthesizing a salt or solvate thereof.

[0106] In some embodiments, the process further comprises using compound D to prepare compound A2: [ka] or synthesizing a salt or solvate thereof.

[0107] 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 intended to be illustrative and not limiting of 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. [Example]

[0108] The following examples are provided for illustrative purposes and are not intended to limit the scope of the present invention.

[0109] Example 1: Oxidation Methyl-(S)-6′-chloro-5-(((1R,2R)-2-formylcyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate) was prepared according to the following reaction scheme. [ka]

[0110] A 1200 L reactor under nitrogen was charged with dichloromethane (125 L, 15 L / kg) and dimethyl sulfoxide (DMSO) (4.265 kg, 3 equiv.). The resulting mixture was cooled to -40°C, and oxalyl chloride (3.465 kg, 1.5 equiv.) was added over 1 hour, maintaining the temperature below -35°C. The resulting solution was stirred at -35°C for 30 minutes, after which a solution of compound B (8.3 kg, 18.2 mol, 1.0 equiv.) in dichloromethane (38 L, 4.6 L / kg) was added over 0.7 hours, maintaining the temperature at -35°C. After 30 minutes of stirring, triethylamine (9.20 kg, 5 equiv.) was introduced over 0.7 hours at -35°C. The suspension was stirred at -35°C for 0.8 hours, and the reaction was monitored by HPLC. Stirring at -35°C was maintained for 0.6 hours, after which additional oxalyl chloride (462 g, 0.2 equiv.) was added at -35°C over 18 minutes to ensure complete conversion. The reaction mixture was warmed to -13°C, and deionized water (41.5 L, 5 L / kg) was added over 16 minutes, maintaining the temperature below 0°C. The resulting biphasic solution was stirred for 20 minutes and then allowed to settle. The layers were separated, and the organic layer was transferred into an enameled 250 L reactor. The solution was washed with 1 N HCl (5 L / kg), followed by sodium bicarbonate solution (5 L / kg), and then sodium chloride solution (5 L / kg). The organic layer was dried over sodium sulfate (8.3 kg, 1 equiv. w / w%), filtered, and the solid was washed with dichloromethane (2 x 25 L, 2 x 3 L / kg). Dichloromethane was removed by atmospheric distillation at 40° C. to a minimum stirring volume, and acetonitrile was added (120 L, 15 L / kg). Concentration continued under vacuum at 40° C. to remove residual water and dichloromethane. Compound D was obtained as an acetonitrile solution in quantitative yield and was processed directly through to the next step.

[0111] Example 2: Vinyl alcohol formation Methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylate (Compound E) was prepared according to the following reaction scheme. [ka]

[0112] A 250 L enameled reactor was charged with acetonitrile (54 L, 13.1 L / kg). The solvent was degassed by bubbling nitrogen and then charged with cinchonidine (3.75 kg, 1.4 equiv.). Zinc chloride (384 g, 3.1 equiv.) was added to the suspension over 1 to 1.5 hours, maintaining the temperature below 28°C. The resulting solution was cooled to -10°C, and a solution of vinylmagnesium chloride in THF (15.10 kg, 3.2 equiv.) was added at -5±5°C over 0.8 to 1.2 hours. The reaction mixture was warmed to 20°C over 0.8 hours, and then a solution of compound D in acetonitrile (23.30 kg, 4.12 kg, pure, 1.0 equiv.) was added over 5 minutes at 20°C. The reaction mixture was stirred at that temperature for 0.5 hours. The reaction was monitored by HPLC. Toluene (26 L, 6.4 L / kg) and 1.5 M citric acid solution were added. The biphasic solution was stirred for 20 minutes, then the layers were allowed to settle. After separation, the organic layer was washed with additional 1.5 M citric acid solution, followed by brine. The solution was concentrated at atmospheric pressure to a residual volume of 80 L. The solution was cooled to 35° C. and then transferred into a cleaned, enameled 250 L reactor. Concentration was continued to a residual volume of 20 L, and ethanol (85 L) was added. Concentration was continued to remove residual acetonitrile and toluene. Compound E was obtained as an ethanol solution and was processed directly through to the next step.

[0113] Example 3: Ester Hydrolysis (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylic acid (Compound F free acid) was prepared according to the following reaction scheme. [ka]

[0114] A 250 L enameled reactor under nitrogen was charged with a solution of compound E (9 kg) in ethanol. The mixture was heated to 55 ± 5°C, and deionized water (9 L, 1 L / kg) was added. A mixture of 30.5 wt% sodium hydroxide solution (7.1 kg, 2.9 equiv.) and deionized water (9 L, 1 L / kg) was added over 15 minutes at 55 ± 5°C. The resulting solution was stirred at 55 ± 5°C for 1.7 hours. After confirming complete conversion by HPLC, the solution was cooled to 20 ± 5°C, and phosphoric acid (74.7%, 1.9 kg, 0.8 equiv.) was added over 15 minutes at 20 ± 5°C until the pH reached 6-7. Ethyl acetate (41 L, 4.7 L / kg) was added, and stirring was continued for 15 minutes. The biphasic mixture was allowed to settle, and the layers were separated. The organic layer was washed twice with brine and then concentrated at atmospheric pressure to a residual volume of 25 L. Ethyl acetate (130 L) was added and azeotropic distillation continued to a residual volume of 25 L. The mixture was filtered through thick filter paper under nitrogen pressure to remove the precipitate. The reactor and filter were rinsed with ethyl acetate (2 x 10 L, 2 x 1.1 L / kg). The filtrates were combined and stored in a drum under nitrogen. Compound F free acid was obtained and processed directly to the next step. 1H NMR(400MHz,DMSO-d6)δ 1.36-2.15(m,9H),2.37-2.55(m,1H)2.61-2.83(m,2H)3.16-3.35(m,2H)3.44(br s,2H)4.00(br d,J=4.15Hz,3H)4.52-4.86(m,1H)4.90-5.03(m,1H)5.09-5.26(m,1H)5.63-5.85(m,1H)6.89(br d,J=8.09Hz,1H)7.02 -7.33(m,3H)7.40(br s,1H)7.62(br d,J=8.50Hz,1H)12.13-12.98(m,1H).LRMS(ESI):C 27 H 30 Calculated for ClNO4 + H: 468.2, Found: 468.2.

[0115] Example 4: Salt formation (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylate, (R)-1-phenylethan-1-aminium salt (Compound F salt form) was prepared according to the following reaction scheme. [ka]

[0116] A 250 L enameled reactor under nitrogen was charged with a solution of Compound F (free acid) in ethyl acetate (44.1 kg, 7.88 kg, pure, 1 equivalent) and ethyl acetate (39 L, adjusted to 10 L / kg). The resulting solution was heated to 60°C, and (R)-(+)-α-methylbenzylamine (2448 g, 1.2 equivalents) was added at that temperature over 13 minutes. When the reaction mixture became slightly cloudy (4 / 5 after the amine addition), Compound F salt form crystallized from the seeds. The resulting solution was stirred at 60±5°C for 1 hour and then cooled to 22±3°C over 45 minutes. The mixture was held for at least 45 minutes before filtering under vacuum. The reactor and filter cake were washed with ethyl acetate (2×8 L, 2×1 L / kg), and the solid was dried overnight under vacuum at 45°C. After sieving, Compound F salt form was obtained. 1 H NMR(400MHz,DMSO-d6)δ 7.60-7.69(m,3H),7.46-7.53(m,3H),7.32-7.39(m,2H),7.29(s,2H),7.20(dd,J=8.50,2.28Hz,1H),7.15(d,J=2.28Hz,1H),6.82(d,J=8.0 9Hz,1H),5.78(ddd,J=17.21,10.47,5.49Hz,1H),5.14-5.21(m,1H),4.94-4.99(m,1H),4.30(q,J=6.63Hz,1H),3.91-4.06(m,3H),3.57(br d,J=12.02Hz,1H),3.41(br d,J=14.10Hz,1H),3.14-3.26(m,2H),2.65-2.81(m,2H),2.41-2.50(m,1H),1.88-2.0 7(m,3H),1.75-1.86(m,2H),1.68-1.77(m,1H),1.50-1.65(m,3H),1.44-1.50(m,3H); 13C NMR(100MHz,DMSO-d6)δ 169.9,150.9,142.5,140.6,140.4,139.6,139.4,131.6,130.8,129.6,128.4,128.2,127.5,126.5,126.0,120.3,1 19.4,117.6,113.4,78.8,75.1,61.3,59.0,50.0,45.0,41.5,36.9,29.7,28.3,25.5,22.4,20.8,18.3.LRMS(ESI):C 27 H 30 Calculated for ClNO4 + H: 468.2, Found: 468.2.

Claims

1. 1. A method of synthesizing compound E, or a salt or solvate thereof, comprising: 【Chemical 1】 Compound C, Compound D, 【Chemistry 2】 and Zn(X ３ ) ２ in an organic solvent to form compound E: 【Chemistry 3】 During the ceremony, R １ is C １～６ is alkyl; R ２ is H or C １～３ is alkoxy; X １ are MgCl, MgBr, MgI, Li, CuLi, ZnX ２ , In(I), In(X ２ ) ２ and Each X ２ is independently Cl, Br, or I; Each X ３ are independently Cl, Br, I, OTf, OTs, OAc, or acac; Compound D and 【Chemistry 4】 are present in a molar ratio of 1:2.5 to 1:4.5; Compound D and Zn(X 3 ) 2 are present in a molar ratio of 1:2.5 to 1:4.0; Compound D and Compound C are present in a molar ratio of 1:1 to 1:2; The method wherein said mixing of compound D is carried out at a temperature of from 10°C to 35°C.

2. R １ The method of claim 1, wherein is methyl, ethyl, propyl, n-butyl, or tert-butyl.

3. R １ The method of claim 2, wherein is methyl, ethyl, or tert-butyl.

4. R ２ The method of claim 1 , wherein

5. R ２ is C １～３ The method of claim 1 , wherein the alkyl group is alkoxy.

6. R ２ The method of claim 5 , wherein is methoxy.

7. X １ 2. The method of claim 1, wherein is MgCl.

8. X １ The method of claim 1 , wherein is MgBr or MgI.

9. X １ The method of claim 1 , wherein is Li.

10. X １ The method of claim 1 , wherein is CuLi.

11. X １ is In(I) or In(X ２ ) ２ The method of claim 1, wherein

12. X １ 2. The method of claim 1, wherein is ZnCl or ZnBr.

13. Zn(X ３ ) ２ is ZnCl ２ The method of claim 1, wherein

14. Zn(X ３ ) ２ is ZnBr ２ The method of claim 1, wherein

15. Zn(X ３ ) ２ is ZnI ２ The method of claim 1, wherein

16. Zn(X ３ ) ２ is Zn(OTf) ２ or Zn(OTs) ２ The method of claim 1, wherein

17. Zn(X ３ ) ２ is Zn(OAc) ２ or Zn(acac) ２ The method of claim 1, wherein

18. The method of claim 1 , wherein the organic solvent is degassed prior to the mixing.

19. The method of claim 1 , wherein the organic solvent comprises an ether solvent or acetonitrile.

20. 20. The method of claim 19, wherein the organic solvent is selected from the group consisting of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether, acetonitrile, 1,2-dimethoxyethane (1,2-DME), methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), and combinations thereof.

21. 21. The method of claim 20, wherein the organic solvent is acetonitrile.

22. The mixing (a) Compound C and Zn(X ３ ) ２ in the organic solvent to form a suspension; (b) 【Chemistry 5】 to the suspension to form a solution; (c) adding compound D to the solution to form compound E; The method of claim 1 , comprising:

23. The suspension of step (a) comprises 【Chemistry 6】 23. The method of claim 22, wherein the mixture is cooled to a temperature of from -15°C to -5°C before adding

24. 【Chemical 7】 23. The method of claim 22, wherein is added to the suspension as a solution in an ether solvent.

25. 25. The method of claim 24, wherein the ether solvent is THF.

26. [Chemical 8] is added to the suspension at a temperature of from -10°C to 0°C.

27. 23. The method of claim 22, wherein compound D is added as a solution in an organic solvent selected from the group consisting of THF, 2-MeTHF, diethyl ether, acetonitrile, 1,2-DME, MTBE, CPME, and combinations thereof.

28. 28. The method of claim 27, wherein the organic solvent comprises acetonitrile.

29. Compound D, 【Chemistry 9】 The method of claim 1, wherein the molar ratio of

30. Compound D, Zn(X ３ ) ２ The method of claim 1, wherein the molar ratio of

31. 2. The method of claim 1, wherein the molar ratio of compound D to compound C is 1:1.

4.

32. Compound D can be prepared by reacting Compound B: 【Chemistry 10】 2. The method of claim 1, wherein the compound is prepared by oxidizing

33. 33. The method of claim 32, wherein the oxidation is carried out under an inert atmosphere.

34. 33. The method of claim 32, wherein compound B is provided as a solution in an organic solvent selected from the group consisting of dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethylformamide (DMF), THF, 2-MeTHF, acetonitrile toluene, 1,2-DME, MTBE, 1,2-dichloroethane (DCE), chloroform, and combinations thereof.

35. 35. The method of claim 34, wherein the organic solvent is DCM.

36. The oxidizing agent is oxalyl chloride, bleach, SO ３ 33. The method of claim 32, wherein the carboxylic acid is selected from the group consisting of pyridine / pyridine, iodobenzene diacetate, trifluoroacetic anhydride, N-chlorosuccinimide (NCS), 2-iodoxybenzoic acid (IBX), N-methylmorpholine N-oxide (NMO), ceric ammonium nitrate (CAN), Dess-Martin periodinane, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), tetrapropylammonium perruthenate (TPAP) / NMO, NCS / dimethyl sulfide, NCS / dodecyl sulfide, and combinations thereof.

37. 37. The method of claim 36, wherein the oxidizing agent is oxalyl chloride.

38. 33. The method of claim 32, wherein the oxidation is carried out in the presence of a base selected from the group consisting of triethylamine, diisopropylethanolamine, N-methylpyrrolidine, N-ethylpiperidine, pyridine, 2,2,6,6-tetramethylpiperidine (TMP), pempidine, 2,6-lutidine, and combinations thereof.

39. 39. The method of claim 38, wherein the base is triethylamine.

40. 33. The method of claim 32, wherein compound B and the oxidizing agent are present in a molar ratio of 1:1 to 1:

3.

41. 41. The method of claim 40, wherein the molar ratio of compound B to the oxidizing agent is 1:1.

5.

42. 39. The method of claim 38, wherein compound B and the base are present in a molar ratio of 1:3 to 1:

10.

43. 43. The method of claim 42, wherein the molar ratio of compound B to the base is 1:

5.

44. 33. The method of claim 32, wherein the oxidation is carried out in an organic solvent selected from the group consisting of dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethylformamide (DMF), THF, 2-MeTHF, acetonitrile, MTBE, 1,2-DME, toluene, DCE, CPME, and combinations thereof.

45. 45. The method of claim 44, wherein the organic solvent is DMSO.

46. 33. The method of claim 32, wherein the oxidation is carried out at a temperature of from -80°C to -20°C.

47. 47. The method of claim 46, wherein the oxidation is carried out at a temperature of -40°C.

48. Compound E is hydrolyzed to give compound F: 【Chemistry 11】 or a salt thereof.

49. The hydrolysis comprises:

49. The method of claim 48, comprising mixing a solution of compound E in an organic solvent and a hydroxide base in water to form compound F.

50. 50. The method of claim 49, wherein the hydroxide base is selected from the group consisting of NaOH, KOH, LiOH, potassium trimethylsilanolate (TMSOK), and combinations thereof.

51. 50. The method of claim 49, wherein compound E and the hydroxide base are present in a molar ratio of 1:1 to 1:

100.

52. 52. The method of claim 51, wherein the molar ratio of compound E to the hydroxide base is 1:

3.

53. 50. The method of claim 49, wherein the organic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, THF, diethyl ether, acetone, acetonitrile, 2-MeTHF, sec-butanol, and combinations thereof.

54. 54. The method of claim 53, wherein the organic solvent is ethanol.

55. 50. The method of claim 49, wherein the hydrolysis is carried out at a temperature of from 20°C to 60°F.

56. 49. The method of claim 48, wherein compound F is in salt form.

57. 57. The method of claim 56, wherein the salt of compound F comprises an ammonium cation or an alkali metal cation.

58. 58. The method of claim 57, wherein the ammonium cation is selected from the group consisting of benzylammonium, methylbenzylammonium, trimethylammonium, triethylammonium, morpholinium, pyridinium, piperidinium, picolinium, dicyclohexylammonium, protonated N,N'-dibenzylethylenediamine, 2-hydroxyethylammonium, bis-(2-hydroxyethyl)ammonium, tri-(2-hydroxyethyl)ammonium, protonated procaine, dibenzylpiperidium, dehydroabietylammonium, N,N'-bisdehydroabietylammonium, protonated glucamine, protonated N-methylglucamine, protonated collidine, protonated quinine, protonated quinoline, protonated lysine, protonated arginine, protonated 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-diisopropylethylammonium, and combinations thereof.

59. The ammonium cation is 【Chemistry 12】 59. The method of claim 58, wherein:

60. 58. The method of claim 57, wherein the alkali metal cation is selected from the group consisting of lithium, sodium, potassium, and combinations thereof.

61. 58. The method of claim 57, wherein the salt of compound F is prepared by combining compound F, in its free acid form (compound F free acid), with an amine base or an alkali metal base in a non-polar organic solvent to form the salt of compound F.

62. 62. The method of claim 61, wherein the Compound F free acid and the amine base or alkali metal base are present in a molar ratio of 1:1 to 1:

2.

63. 63. The method of claim 62, wherein the molar ratio of Compound F free acid to the amine base or alkali metal base is 1:1.

2.

64. 62. The method of claim 61 , wherein the non-polar organic solvent is selected from the group consisting of ethyl acetate, toluene, isopropyl acetate, MTBE, and combinations thereof.

65. 65. The method of claim 64, wherein the non-polar organic solvent is ethyl acetate.

66. 62. The method of claim 61, wherein the mixing is carried out at a temperature of from 50°C to 60°C.

67. 57. The method of claim 56, wherein the mixing is performed under an inert atmosphere.

68. Compound E was used to synthesize Compound A1 【Chemistry 13】 10. The method of claim 1, further comprising synthesizing the compound of formula (I) or a salt or solvate thereof.

69. Compound E was used to synthesize Compound A2 【Chemistry 14】 10. The method of claim 1, further comprising synthesizing the compound of formula (I) or a salt or solvate thereof.

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