Method for Preparing a Complex Cyclic Compound

Abstract

This specification provides a method for preparing Compound 101. Also provided are intermediate compounds useful in the preparation of Compound 101 and methods for preparing those intermediate compounds. TIFF2025523682000062.tif48165

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Patent Application No. 63 / 388,344, filed on July 12, 2022, the content of which is hereby incorporated by reference in its entirety.

Background Art

[0002] Background Cbl - b is an E3 ubiquitin - protein ligase that functions as a negative regulator of T - cell activation. The regulation of Cbl - b has been shown to be a therapeutic target for diseases and disorders. There is still a need for an efficient means to prepare compounds that inhibit Cbl - b.

Summary of the Invention

[0003] Summary In one aspect, provided herein is a method for producing Compound 101, the method comprising the following steps: a) reacting Compound 19 with X - C(O) - Y (wherein X and Y are each a leaving group) to produce Compound 101 A method is provided that includes TIFF2025523682000002.tif42165.

[0004] In another aspect, Compound 101 An intermediate compound useful for the preparation of TIFF2025523682000003.tif48165, which is selected from the group consisting of Compounds 1 - 19 of Schemes 1 - 3, is provided.

[0005] In yet another aspect, provided herein is a method for producing an intermediate compound useful for the preparation of Compound 101 of TIFF2025523682000004.tif48165, the intermediate compound being selected from the group consisting of Compounds 1 - 19 of Schemes 1 - 3, and the method comprising the steps found in the Examples.

[0006] ​ In yet another aspect, provided herein are methods for synthesizing Compounds 1-19 of Schemes 1-3.

[0007] In yet another aspect, a method for producing Compound 8 having the structure shown below, the following steps: e) Separating the racemic mixture 6 by chiral supercritical fluid chromatography (SFC) to obtain Compound 7 TIFF2025523682000005.tif48165 and f) Reducing Compound 7 to provide Compound 8 A method is provided that includes TIFF2025523682000006.tif42165. DETAILED DESCRIPTION

[0008] Detailed Description The present disclosure provides a method for synthesizing a compound, referred to herein as Compound 101, having the structure shown below: TIFF2025523682000007.tif48165, or a pharmaceutically acceptable salt thereof. Intermediates useful in the synthesis of Compound 101, and methods for synthesizing those intermediates are also provided. Compound 101 is an inhibitor of Cbl-b and has potential utility as an agent for the treatment of certain diseases including cancer.

[0009] In one aspect, provided herein is a method for producing Compound 101, the following steps: a) Reacting Compound 19 with X-C(O)-Y, wherein X and Y are each a leaving group, to produce Compound 101 A method is provided that includes TIFF2025523682000008.tif42165.

[0010] In some embodiments, X and Y are each independently selected from Cl, Br, I, OCCl3, an imidazolyl radical, and a p-nitrophenoxy radical.

[0011] In some embodiments, X-C(O)-Y is phosgene, bis(trichloromethyl) carbonate, p-nitrophenyl chloroformate, or carbonyldiimidazole. In some embodiments, X-C(O)-Y is phosgene or bis(trichloromethyl) carbonate. In some embodiments, X-C(O)-Y is bis(trichloromethyl) carbonate.

[0012] In some embodiments, the method comprises the following steps: a) reacting Compound 19 with bis(trichloromethyl) carbonate (BTC) to produce Compound 101 It includes TIFF2025523682000009.tif42165.

[0013] In some embodiments, the method comprises the following steps: b) reacting Compound 18 with Compound 8 in the presence of a reducing agent to produce Compound 19 It further includes TIFF2025523682000010.tif53165.

[0014] In some embodiments, the reducing agent in step b) is a borohydride such as NaBH(OAc)3 or NaBH3CN.

[0015] In some embodiments, in step b), before contacting with the reducing agent, first Compound 18 and 8 are reacted, and water is removed (using a Dean-Stark trap etc.) to obtain Compound 18’ TIFF2025523682000011.tif42165, and then the reducing agent is reacted with 18’ to obtain Compound 19.

[0016] In some embodiments, the method comprises the following steps: b) reacting Compound 18 with Compound 8 in the presence of NaBH(OAc)3 to produce Compound 19 It further includes TIFF2025523682000012.tif53165.

[0017] In some embodiments, the method comprises the following steps: c) reacting compound 14’ with compound 11 in the presence of catalyst A to produce compound 15’ TIFF2025523682000013.tif42165 and d) reacting compound 15’ with an acid to produce compound 18 further comprising TIFF2025523682000014.tif32165, wherein each R’ is independently C 1~6 alkyl or both R’ groups are taken together as C 1~6 alkylene, and catalyst A is an organometallic catalyst.

[0018] In some embodiments, each R’ is methyl or ethyl, or both R’ groups are taken together to form -CH2-CH2- or -CH2CH2CH2-. In some embodiments, both R’ groups are taken together to form -CH2-CH2-.

[0019] In some embodiments, catalyst A contains palladium atoms, and preferably, catalyst A is suitable for catalyzing the Suzuki reaction. In some embodiments, catalyst A is formed from a combination of a Pd(II) salt (such as Pd(OAc)2) and xphos.

[0020] In some embodiments, the method comprises the following steps: c) reacting compound 14 with compound 11 in the presence of Pd(OAc)2 and xphos to produce compound 15 TIFF2025523682000015.tif42165 and d) reacting compound 15 with an acid to produce compound 18 including TIFF2025523682000016.tif32165.

[0021] In some embodiments, the method comprises the following steps: e) Separating the racemic mixture 6 by chiral supercritical fluid chromatography (SFC) to obtain compound 7 TIFF2025523682000017.tif48165 and f) Reducing compound 7 to provide compound 8 further comprising TIFF2025523682000018.tif42165.

[0022] In some embodiments, the separation in step e) is carried out on a cellulose-SC column. In some embodiments, the separation in step e) is carried out with mobile phase A being CO2 and mobile phase B containing methanol, acetonitrile, and NH3. In some embodiments, mobile phase B is 2:3 to 3:2 methanol:acetonitrile containing 1 to 3 mM of NH3.

[0023] In some embodiments, the reduction in step f) is carried out by catalytic hydrogenation. In some embodiments, the reduction in step f) is carried out using hydrogen and a catalyst containing palladium or platinum. In some embodiments, the reduction in step f) is carried out using hydrogen and platinum on carbon (Pt / C).

[0024] In some embodiments, the method comprises the following steps: g) Reacting compound 3 with methyl isothiocyanate to obtain compound 4 TIFF2025523682000019.tif42165 h) Reacting compound 4 with a base to provide compound 5 TIFF2025523682000020.tif48165 and i) Reacting compound 5 with sodium nitrite and an acid to produce compound 6 further comprising TIFF2025523682000021.tif42165.

[0025] In some embodiments, the base in step h) is sodium hydroxide.

[0026] In some embodiments, the acid in step i) is nitric acid.

[0027] In some embodiments, the method comprises the following steps: g) reacting compound 3 with methyl isothiocyanate to obtain compound 4 TIFF2025523682000022.tif42165 h) reacting compound 4 with a base to provide compound 5 TIFF2025523682000023.tif48165 and i) reacting compound 5 with sodium nitrite and an acid to produce compound 6 TIFF2025523682000024.tif42165 and further comprises.

[0028] In some embodiments, compound 101 is crystallized from a mixture of isopropyl acetate and heptane.

[0029] In some embodiments, compound 101 is at least 95% pure by HPLC.

[0030] In another aspect, compound 101 TIFF2025523682000025.tif48165 provides an intermediate compound useful for the preparation of, and the intermediate compound is selected from the group consisting of compounds 1-19 of Schemes 1-3.

[0031] In some embodiments, the intermediate compound has the following structure TIFF2025523682000026.tif32165

[0032] In some embodiments, the intermediate compound has the following structure TIFF2025523682000027.tif37165

[0033] In yet another aspect, provided herein is a method for producing compound 8 having the structure shown below, the method comprising the following steps: e) Separating the racemic mixture 6 by chiral supercritical fluid chromatography (SFC) to obtain compound 7 TIFF2025523682000028.tif48165 and f) Reducing compound 7 to provide compound 8 There is provided a method further comprising TIFF2025523682000029.tif42165

[0034] In some embodiments of the method for producing compound 8, the separation in step e) is carried out on a cellulose-SC column

[0035] In some embodiments of the method for producing compound 8, the separation in step e) is carried out with mobile phase A being CO2 and mobile phase B containing methanol, acetonitrile, and NH3

[0036] In some embodiments of the method for producing compound 8, mobile phase B is 2:3 to 3:2 methanol:acetonitrile containing 1 to 3 mM NH3

[0037] In some embodiments of the method for producing compound 8, the reduction in step f) is carried out by catalytic hydrogenation, such as using hydrogen and a catalyst containing palladium or platinum

[0038] In some embodiments of the method for producing compound 8, the method comprises the following steps: g) Reacting compound 3 with methyl isothiocyanate to obtain compound 4 TIFF2025523682000030.tif42165 h) Reacting compound 4 with a base to provide compound 5 TIFF2025523682000031.tif48165 and i) Reacting compound 5 with sodium nitrite and an acid to produce compound 6 There is further included TIFF2025523682000032.tif42165

[0039] In yet another aspect, provided herein are methods for synthesizing Compounds 1-19 of Schemes 1-3.

[0040] Definitions The term "alkyl" refers to a straight-chain or branched-chain alkyl group. "C1 -6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0041] The term "alkylene" refers to a divalent straight-chain or branched-chain hydrocarbon group. "C1 -6 alkylene" refers to an alkylene group having 1 to 6 carbon atoms. Exemplary alkylene groups are -CH2CH2-, -CH2CH2CH2-, and -CH2CH(CH3)CH2-.

[0042] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts of amino groups formed by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate.

[0043] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N(C 1~4It includes (alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acids, and aryl sulfonic acids.

[0044] As used herein, "reducing agent" refers to a chemical composition or combination thereof that can effect the chemical reduction of a substrate from an oxidized form to a reduced form. Reducing agents include aluminum hydrides such as lithium aluminum hydride and diisobutylaluminum hydride, and hydride-based reagents including borohydrides such as sodium borohydride, NaBH(OAc)3, and NaBH3CN. Particularly preferred reducing agents for reductive amination reactions include NaBH(OAc)3 and NaBH3 CN. Reducing agents may also include agents for catalytic hydrogenation.

[0045] As used herein, "catalytic hydrogenation" is a reaction in which the chemical reduction of a substrate is effected by the use of hydrogen gas and a catalyst. The catalyst may contain metal atoms such as Pd, Pt, or Ni, which may be in a charged or neutral state. The catalyst may contain salts of metal atoms or coordination complexes of metal atoms and non-metal ligands. Examples of catalysts for catalytic hydrogenation include Pd carbon, Pt carbon, and Raney Ni.

[0046] As used herein, "leaving group" refers to a chemical group that can readily break the chemical bond that attaches them to a molecule and leaves along with the electrons involved in that bond. Leaving groups can be described as radicals (i.e., they are attached to the molecule by a chemical bond that is not part of the leaving group), but often leave as anions. Examples of leaving groups include the halogens Cl, Br, and I, alkoxy such as trichloromethoxy, phenoxy such as p-nitrophenoxy, and other groups that can stabilize anions such as imidazolyl.

[0047] The "Suzuki reaction" is a chemical coupling reaction between an organic group containing a halogen or certain other leaving group and a molecule containing a boron group such as boronic acid or a boron salt. Suitable catalysts for the Suzuki reaction include various organometallic catalysts, for example, those containing palladium and an organic ligand (xphos). A number of catalysts and substrates are known. (See, for example, R. Martin and S. Buchwald, Acc. Chem. Res., 2008, 41(11):1461 - 1473).

Examples

[0048] The invention outlined herein will be more readily understood by reference to the following examples. The following examples are included for the purpose of merely illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0049] TIFF2025523682000033.tif151165

[0050] The reaction temperature is reported as the internal temperature unless otherwise specified. Chemical intermediates, reagents, and solvents were obtained from commercial sources.

[0051] NMR: 1The H spectrum was recorded with a spectrometer of 300 MHz or higher. The chemical shift was referenced to the residual solvent signal at δ 2.50 (DMSO-d6) with respect to TMS as the internal standard whenever applicable.

[0052] HPLC for the measurement of chemical purity and chiral purity was as detailed in Example 1. Example 1. HPLC Procedure TIFF2025523682000034.tif142165TIFF2025523682000035.tif136165TIFF2025523682000036.tif142165TIFF2025523682000037.tif136165TIFF2025523682000038.tif110165TIFF2025523682000039.tif105165TIFF2025523682000040.tif105165

[0053] Example 2. Synthesis of Compound 8 TIFF2025523682000041.tif109165Scheme 1: Synthesis of Compound 8 Synthesis of Compound 2 Under a nitrogen atmosphere, DMF (5.0 volumes) was charged into the reactor. The reactants were stirred for at least 5 minutes. A sample was taken for KF. The standard was KF ≤ 0.1%. Cs2CO3 (3.0 equivalents, 118 kg) was charged into the reactor. The reactants were purged with nitrogen for at least 1.0 hour. Methyl 2-(3-nitrophenyl)acetate (Compound 1, 1.0 equivalent, 23.6 kg) was added dropwise to the reactor at 20 ± 5 °C and stirred for at least 1.0 hour. Cyclobutyl bromide (2.0 equivalents, 32.3 kg) was added dropwise to the reactor at 20 ± 5 °C. The temperature was adjusted to 45 ± 5 °C and the reactants were stirred at 45 ± 5 °C for at least 16.0 hours. Samples were taken every 4.0 hours for HPLC until the area % of Compound 1 was 5% or less. IPC = 86.5%.

[0054] The reactants were cooled to 20 ± 5 °C, MTBE (5.0 volumes) was charged into the reactor, and then the reactants were stirred at 20 ± 5 °C for at least 30 minutes. The reactants were filtered, and the cake was washed once with MTBE (15.0 volumes). The mother liquors were combined. Organic phase assay: 25.4 kg, 84.5%. Filter cake assay: 0.04 kg, loss: 0.13%.

[0055] The mother liquors were transferred to the reactor. It was cooled to 5 ± 5 °C, and 1N hydrochloric acid (2.0 volumes) was charged into the reactor. The reactants were stirred at 5 ± 5 °C for at least 30 minutes and then held for at least 30 minutes. The phases were separated, and the organic phase was collected. Aqueous phase assay: 0.31 kg, loss: 1.0%.

[0056] The organic phase was transferred to the reactor, the jacket temperature was maintained below 35 °C, and the organic phase was concentrated to 1 - 2 volumes. MTBE (2.5 volumes) was charged into the reactor, then n - heptane (7.5 volumes) was charged into the reactor, the reactants were stirred at 20 ± 5 °C for at least 30 minutes and then held for at least 30 minutes. The phases were separated, and the organic phase was collected. The organic phases were combined and transferred to the reactor. Soft water (5.0 volumes) was charged into the reactor, stirred at 20 ± 5 °C for at least 30 minutes and then held for at least 30 minutes. The phases were separated, and the organic phase was collected. Organic phase assay: 25.1 kg, 83.4%. Aqueous phase assay: 0.4 kg, loss: 1.3%.

[0057] Soft water (5.0 volumes) was charged into the reactor, stirred at 20 ± 5 °C for at least 30 minutes and then held for at least 30 minutes. The phases were separated, and the organic phase was collected. Organic phase assay: 24.9 kg, 82.7%. Aqueous phase assay: 0.1 kg, loss: 0.3%.

[0058] A 20% aqueous sodium chloride solution (3.0 volumes) was charged into a reactor, stirred at 20 ± 5 °C for at least 30 minutes, and then held for at least 30 minutes. The phases were separated and the organic phase was collected. The organic phase was transferred to the reactor. The jacket temperature was maintained below 45 °C and the organic phase was concentrated to 2 - 3 volumes. The temperature was adjusted to 20 ± 5 °C. n-Heptane (3.0 volumes) was charged into the reactor at 20 ± 5 °C. The temperature was adjusted to 40 ± 5 °C and the reaction mixture was stirred until the solid dissolved. Seed crystals of Compound 2 were charged into the reactor at 38 ± 2 °C and the reaction mixture was stirred until the solid crystallized. The reaction mixture was slowly cooled to 5 ± 5 °C and stirred at 5 ± 5 °C for at least 4.0 hours. The reaction mixture was filtered. The reaction mixture was sampled by HPLC. The filter cake was dried at 20 ± 5 °C, P ≤ -0.08 MPa for at least 16.0 hours. The cake was sampled and the LOD was measured.

[0059] For the produced Compound 2, m = 21.9 kg, yield: 72.8%, HPLC purity: 99.3%, LOD: 0.49%. Mother liquor assay: 4.31 kg, loss 14.3%.

[0060] Synthesis of Compound 3 Under a nitrogen atmosphere, methanol (7.0 volumes) was charged into a reactor. Stirring was started and Compound 2 (1.0 equivalent, 21.9 kg) was charged into the reactor. The temperature was adjusted to 45 ± 5 °C and 80% hydrazine hydrate (10.0 equivalents, 54.9 kg) was added dropwise to the reactor at 45 ± 5 °C for at least 1.0 hour. The reaction mixture was stirred at 45 ± 5 °C for at least 16.0 hours. A sample for HPLC was taken and the reaction was carried out until the area% of Compound 2 was 5% or less. IPC = 96.4%.

[0061] The reaction mixture was slowly cooled to 45 ± 3 °C, seed crystals of Compound 3 were charged into the reactor at 45 ± 3 °C and the reaction mixture was stirred until the solid separated. The reaction mixture was slowly cooled to 20 ± 5 °C and soft water (7.0 volumes) was added dropwise to the reactor at 20 ± 5 °C for at least 1.0 hour. Stirring was continued at 20 ± 5 °C for at least 4.0 hours. The reaction mixture was filtered and the cake was washed once with soft water (10.0 volumes). Mother liquor assay: 0.6 kg, loss 2.7%. A sample was taken and HPLC was performed. HPLC purity: 98.6%.

[0062] The filter cake was dried at 60 ± 5 °C and P ≤ -0.08 MPa for at least 16.0 hours. Samples were taken at least every 4.0 hours to measure KF, and drying was stopped when KF ≤ 0.2%. Produced Compound 3: m = 20.7 kg, yield: 94.7%, HPLC purity: 99.4%, KF: 0.02%.

[0063] Synthesis of Compound 4 Under a nitrogen atmosphere, THF (10.0 volumes) was charged into the reactor. Stirring was started and continued for at least 5 minutes. Samples were taken for KF. The criterion was KF ≤ 0.1%. Compound 3 (1.0 equivalent, 18.72 kg) was charged into the reactor. Methyl isothiocyanate (1.2 equivalents, 6.95 kg) was added dropwise to the reactor at 25 ± 5 °C for at least 2.0 hours and reacted at 25 ± 5 °C. The reaction mixture was stirred at 25 ± 5 °C for at least 16.0 hours. Samples were taken every 4.0 hours for HPLC until the area% of Compound 3 (1.0 equivalent) was 1% or less. IPC: 96.3%.

[0064] Absolute ethanol (5 volumes) was charged into the reactor at 25 ± 5 °C. The jacket temperature was maintained below 35 °C, and the organic phase was concentrated to 4 - 6 volumes. Absolute ethanol (10.0 volumes) was charged into the reactor at 25 ± 5 °C. The temperature was adjusted to 60 ± 5 °C and stirring was continued for at least 1.0 hour. The reaction mixture was cooled to 25 ± 5 °C and stirred at 25 ± 5 °C for at least 4.0 hours. Area% of tetrahydrofuran: 9.1%.

[0065] The reaction mixture was filtered, and the cake was washed once with absolute ethanol (4.0 volumes). Mother liquor assay: 1.0 kg, loss: 3.9%.

[0066] Samples were taken to measure LOD, and samples were taken to measure HPLC purity. The produced Compound 4 was kept in a well-sealed container at room temperature. Wet cake: 45.1 kg, LOD: 47.7%, content 23.6 kg, yield: 92.2%, HPLC purity: 99.2%.

[0067] Synthesis of Compound 5 In a nitrogen atmosphere, soft water (10 volumes) was charged into a reactor and stirring was started. The temperature was adjusted to 20 ± 5 °C, and sodium hydroxide (1.50 equivalents, 4.4 kg) was charged into the reactor at 20 ± 10 °C. The reactants were stirred for at least 30 minutes until the solid dissolved. The reactants were cooled to 5 ± 5 °C, and the solid of Compound 4 (1.00 equivalent, 45.1 kg) was charged into the reactor in batches at 5 ± 5 °C. The reactants were stirred at 5 ± 5 °C for at least 4.0 hours. The temperature was adjusted to 20 ± 5 °C, and the reactants were stirred at 20 ± 5 °C for at least 6.0 hours. Samples were taken and HPLC was performed until the area percentage of Compound 4 was 3% or less. IPC: 99.4%.

[0068] The temperature of the system was adjusted to 10 ± 5 °C. A 1N hydrochloric acid solution was added dropwise to the reactor at 10 ± 5 °C to adjust the pH value of the reaction system to 3 - 6.

[0069] The reaction mixture was filtered, and the filter cake was washed once with soft water (2.0 volumes). The filter cake was collected. Soft water (10.0 volumes) was charged into the reactor. Stirring was started, and the filter cake was charged into the reactor. The temperature was adjusted to 20 ± 5 °C, and the reactants were stirred at 20 ± 5 °C for at least 2.0 hours.

[0070] The reaction mixture was filtered, and the filter cake was washed with soft water (2.0 volumes). Loss of mother liquor: 0%.

[0071] The filter cake was collected. Samples were taken to measure the LOD, and samples were taken to perform HPLC. In the case of the produced Compound 5, wet cake: 59.9 kg, LOD: 63.5%, content: 21.9 kg, yield: 98.3%, HPLC purity: 99.6%.

[0072] Synthesis of Compound 6 Under a nitrogen atmosphere, dichloromethane (5.0 volumes) was charged into the reactor, and then soft water (5.0 volumes) was charged into the reactor. Stirring was started, and Compound 5 (1.0 equivalent, 16.5 kg) was charged into the reactor. Sodium nitrite (4.0 equivalents) was charged into the reactor. The reaction mixture was cooled to 5 ± 5 °C, and a 2N aqueous nitric acid solution (2.0 equivalents) was added dropwise to the reactor at 5 ± 5 °C for at least 12.0 hours. The temperature was adjusted to 20 ± 5 °C, and the reaction mixture was stirred at 20 ± 5 °C for at least 6.0 hours. Samples were taken at least every 4.0 hours until the area percentage of Compound 5 was 2% or less, and HPLC was performed. IPC: 97.5%.

[0073] The temperature was adjusted to 20 ± 5 °C. A 15% aqueous sodium carbonate solution (about 2.1 volumes) was charged into the reactor at 20 ± 5 °C to adjust the pH value of the reaction system to 7 - 8. The reaction mixture was stirred at 20 ± 5 °C for at least 30 minutes and then held for at least 30 minutes. The phases were separated, and the organic phase was collected. Dichloromethane (5.0 volumes) was charged into the reactor together with the aqueous phase, the reaction mixture was stirred at 20 ± 5 °C for at least 30 minutes and then held for at least 30 minutes. The phases were separated, and the organic phase was collected. The organic phase was transferred to the reactor. Soft water (4.0 volumes) was charged into the reactor, stirred at 20 ± 5 °C for at least 30 minutes and then held for at least 30 minutes. The phases were separated, and the organic phase was collected. A 20% aqueous sodium chloride solution (4.0 volumes) was charged into the reactor, the reaction mixture was stirred at 20 ± 5 °C for at least 30 minutes and then held for at least 30 minutes. The phases were separated, and the organic phase was collected. Loss of aqueous phase: 0.1%.

[0074] The organic phase was transferred to the reactor. The jacket temperature was maintained below 40 °C, and the organic phase was concentrated to 3 - 5 volumes. Methyl tert-butyl ether (10.0 volumes) was charged into the reactor at 20 ± 5 °C. The jacket temperature was maintained below 40 °C, and the organic phase was concentrated to 3 - 5 volumes. The reaction mixture was filtered, and the filter cake was washed once with methyl tert-butyl ether (1.0 volume). Loss of mother liquor: 0.6%.

[0075] Samples were taken to measure the LOD, and samples were taken to measure the HPLC purity. Compound 6 was generated: m = 4.93 kg, yield: 98.3%, HPLC purity: 99.6%.

[0076] Synthesis of Compound 7 The enantiomers of Compound 6 (10 kg) were separated by SFC chromatography under the following conditions to obtain Compound 7. Column: CHIRAL ART Cellulose-SC, 7 * 25 cm, 10 μm, Mobile phase A: CO2, Mobile phase B: MeOH:ACN = 1:1 (2 mM NH3-MeOH), Flow rate: 250 mL / min, Gradient: Isocratic 36% B, Column temperature (°C): 35, Back pressure (bar): 100, Wavelength: 220 nm, Retention time 1 (min): 8.59, Retention time 2 (min): 11.68, Compound 7 was obtained (3.8 kg, HPLC purity 99.6%, chiral purity 99.9%).

[0077] Synthesis of Compound 8 MeOH (10 L, 10 volumes), Pt / C (50 g, 5 wt%), and NH4VO3 (21.5 g, 0.05 eq) were charged into a 20 L high-pressure reactor at room temperature under a N2 atmosphere. Compound 7 (1,000 g, 1.0 eq) was charged into the reactor at room temperature under a N2 atmosphere. (Two other batches were carried out, one using 1082 g of Compound 7 and the other using 15 g of Compound 7, and the final yield reflects the combination of all three batches). The system was purged three times with N2 and then three times with H2. Subsequently, the reaction system was maintained at 20 atm. After addition, the reaction mixture was stirred at 55 - 65 °C for 12 h while maintaining the H2 pressure at 10 - 20 atm. When a sample was taken, it showed less than 1.0% residual Compound 7.

[0078] The solvent was filtered, and the filter cake was washed three times with MeOH (3 * 10 volumes). All the filtrates were combined, and this was combined with the mother liquors of the two other batches for concentration. Then, the combined solution was concentrated to 1 - 2 volumes at 40 °C under vacuum.

[0079] MTBE (20.4 L, 10 volumes) was added to the residue, and the mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the filter cake was collected to obtain Compound 8 as a white solid. Compound 8 was dried under vacuum at 40 °C for 2 hours to obtain 1,818 g of a white solid. HPLC purity: 97.1%. Ee: 98.58%, Isolated yield: 96%.

[0080] Example 3. Synthesis of Compound 11 TIFF2025523682000042.tif37165Scheme 2: Synthesis of Compound 11 Synthesis of Compound 11 Under a nitrogen atmosphere, tetrahydrofuran (20.0 volumes) was charged into the reactor. Stirring was started and continued for at least 5 minutes. A sample was taken for KF analysis (Test: 0.0143%).

[0081] (S)-3-Methylpiperidine hydrochloride (Compound 10, 1.0 equivalent, 7.00 kg), potassium (bromomethyl)trifluoroborate (Compound 9, 1.1 equivalents), potassium bicarbonate (2.1 equivalents), and potassium iodide (0.1 equivalent) were charged into the reactor. The temperature was adjusted to 30 ± 5 °C, and the reaction mixture was stirred for at least 1 hour. The temperature was adjusted to 40 ± 5 °C, and the reaction mixture was stirred for at least 1 hour. The temperature was adjusted to 50 ± 5 °C, and the reaction mixture was stirred for at least 1 hour. Then, the reaction mixture was heated to 60 - 65 °C and maintained at 60 - 65 °C while stirring for at least 6 hours. The reaction mixture was cooled to below 30 °C until the chemical shift ratio of 2.6 ppm:2.5 ppm was ≤ 0.13:1 1 A sample for 1H-NMR was taken. (Test: 0.05:1).

[0082] The temperature was adjusted to 25 ± 5°C. The temperature was maintained at 25 ± 5°C, and the reactants were stirred for at least 0.5 h. The reaction mixture was filtered, and the filter cake was washed twice with THF (2 × 2 volumes). All the filtrates were combined and concentrated to 3 - 4 volumes under vacuum. Under a nitrogen atmosphere, acetone (2 × 7.0 volumes) was charged into the reactor at 25 ± 5°C. The internal temperature was maintained below 50°C, and the jacket temperature was maintained below 70°C. Subsequently, the organic phase was concentrated to 3 - 4 volumes. Under a nitrogen atmosphere, the organic phase was transferred to the reactor through a fluid filter. The internal temperature was maintained below 50°C, and the jacket temperature was maintained below 70°C. The organic phase was concentrated to 3 - 4 volumes. The organic phase was transferred to a 50 L rotary steam bottle and concentrated to 1 - 2 volumes under vacuum. 3 volumes of purified water were charged into the bottle, and the mixture was concentrated to 3 volumes. 29.4 Kg of the aqueous phase was obtained, 1 confirmed by 1H-NMR. Proton 2.3 ppm: 2.1 ppm = 1:0.39, assay of Compound 11: 32.4%, yield: 84.2%.

[0083] Example 4. Synthesis of Compound 101 TIFF2025523682000043.tif187165Scheme 3. Synthesis of Compound 101 Synthesis of Compound 14 Under a nitrogen atmosphere, toluene (10.0 volumes) was charged into the reactor and stirred for at least 5 min. A sample was taken for KF. The criterion was KF ≤ 0.05%. (Result: KF = 0.003%).

[0084] Stirring was started, and Compound 12 (1.00 equivalent, 100 g) was charged into the reactor. The temperature was adjusted to -77 ± 5°C. The temperature was maintained at -77 ± 5°C, then n-BuLi (1.10 equivalents) was added dropwise to the reactor (preferably added over at least 2 h), and the reactants were stirred for at least 0.5 h. The temperature was maintained at -77 ± 5°C, and samples were taken and analyzed by HPLC until the area% of Compound 12 was 4.0% or less.

[0085] The temperature was maintained at -77 ± 5 °C, and NFM (1.5 equivalents, 56.6 g) was added dropwise to the reactor. The temperature was controlled at -77 ± 5 °C, and sampling was sent to HPLC for testing until two consecutive samples showed a purity change of 2.0% or less (result: the HPLC purity change between the two samples was 0.1% or less). HPLC purity at 1 hour: 93.8%, HPLC purity at 2 hours: 93.8%.

[0086] Under a N2 atmosphere, the reaction mass was warmed to 10 ± 20 °C, and an aqueous 18.0% citric acid solution was charged into the reactor and adjusted to pH = 3 - 6 (pH = 4). The reaction mixture was maintained at 15 - 25 °C and stirred for at least 30 minutes. The reaction mixture was transferred to an enamel reactor, stirred for at least 0.5 hour, and held for at least 0.5 hour. The phases were separated, and the aqueous and organic phases were collected. The aqueous phase was extracted once with toluene (4.00 volumes) at 20 ± 10 °C, and the toluene phase was combined with the organic phase. Soft water (5.00 volumes) was charged into the reactor containing the organic phase at 20 ± 10 °C. The reaction mixture was stirred for at least 0.5 hour and held for at least 0.5 hour. The phases were separated, the organic phase was collected and held for a second wash. Under a N2 atmosphere, soft water (5.00 volumes) was charged into the reactor at 20 ± 5 °C. The reaction mixture was stirred for at least 0.5 hour and held for at least 0.5 hour. The phases were separated, and the organic phase was held for a third wash. Under a nitrogen atmosphere, an aqueous sodium chloride solution was charged into the reactor, and the reaction mixture was stirred at 20 ± 5 °C for at least 30 minutes and then held for at least 30 minutes. The phases were separated, and the organic phase was recovered. 1% of the material was lost in the aqueous phase.

[0087] Under a nitrogen atmosphere, the organic phase was transferred to the reactor, the internal temperature was maintained at 55 °C or below, or the jacket temperature was maintained at 75 °C or below, and the reaction mixture was concentrated to 2.5 - 3.5 volumes. The reaction mixture was cooled to 20 - 30 °C, and 5 volumes of toluene were charged into the reactor. The reaction mixture was concentrated under vacuum to obtain 2.0 - 3.0 volumes (35.65 Kg) of crude compound 13 in solution. HPLC purity: 97.1%. Assay yield: 85%. The crude product 13 was then used in the next step for acetal formation.

[0088] In a nitrogen atmosphere, 13 of toluene solution, 28.9 Kg of toluene, ethylene glycol (5.0 equivalents), and p-toluenesulfonic acid monohydrate (0.05 equivalents) were all charged into a reactor, and the reactants were heated to 110 - 115 °C. The reactants were maintained at 110 - 115 °C and stirred for at least 12 hours. Samples were taken until the area percentage of compound 13 was 0.5% or less and HPLC was performed. After 16 hours of IPC, a residue of 0.3% of compound 13.

[0089] The reactants were cooled to 20 - 30 °C, the phases were separated, the lower phase was extracted with MTBE (0.4 volume), and the organic phases were combined. The organic phase was added to 5% aqueous NaHCO3 solution (7 volumes), stirred at 15 - 30 °C for 20 - 30 minutes, and left to stand for 10 - 20 minutes. The phases were separated, and the organic phase was washed twice with purified water (4 volumes) and once with brine (4 volumes). There was a 1% loss in the aqueous phase.

[0090] The obtained organic phase was mixed with activated carbon (20 wt%) and stirred at 15 - 30 °C for at least 12 hours. The mixture was filtered, and the filter cake was washed twice with toluene (2 volumes). There was a 1 - 2% loss in the filter cake.

[0091] The filtrate was transferred into the reactor and concentrated to 1.0 - 2.0 volumes under vacuum. Heptane (4 volumes) was charged into the reactor and concentrated to 1.0 - 2.0 volumes twice. Heptane (0.8 volume) was charged into the reactor, the mixture was heated to 45 - 50 °C, and stirred for 2 - 3 hours. No solid was observed, and the product was dissolved in heptane. The solution was cooled to 15 - 30 °C and stirred for 1 - 2 hours. Solids were gradually formed. The mixture was cooled to - 5 - 5 °C and stirred for 2 hours. The mixture was filtered, and the filter cake was dried under nitrogen at 15 - 30 °C. After drying, 10.23 Kg of compound 14 was obtained as a yellow solid, HPLC purity: 99.3%, NMR assay: 95.0%. Yield in two steps: 66.9%. A 15% loss in the mother liquor.

[0092] Synthesis of Compound 15 An aqueous solution of Compound 11 (1.5 equivalents, 6000 g), Cs2CO3 (3.0 equivalents), Pd(OAc)2 (0.05 equivalent), Xphos (0.1 equivalent), and 2-MeTHF (7 volumes) were charged into a reactor. The system was purged with N2 for 3 minutes, and then a solution of Compound 14 (6.0 kg, 1.0 equivalent) in 2-MeTHF (1 volume) was added dropwise to the reactor at 70 - 80 °C over 1 hour. The reaction mixture was stirred at 70 - 80 °C overnight under a N2 atmosphere. Samples were taken for IPC, and less than 0.5% of residual Compound 14 was shown. IPC: No residue of Compound 14.

[0093] The reaction system was cooled to room temperature, then filtered, and the filter cake was washed with 2-MeTHF (2 volumes). There was no material loss of the filter cake. All the filtrates were combined, and purified water (5 volumes) was added to the filtrate. The phases were separated, and the organic phase was washed with 10% brine (5 volumes). All the aqueous phases were combined, and a 1% loss was observed in the aqueous phase. The organic phase was extracted three times with 5% citric acid (3 * 30 mL, 3 * 6 volumes). All the acidic phases were combined and washed with 2-MeTHF (5 volumes). All the organic phases were combined, and a 6.7% loss was observed in the organic phase. Samples of the acidic phase were taken, and the HPLC purity was shown to be 99.3%.

[0094] The acidic phase was transferred to a reactor, maintained at T = 15 - 30 °C, and saturated aqueous Na2CO3 was added to adjust the pH to 8 - 9. The aqueous phase was extracted twice with 2-MeTHF (2 * 5 volumes), and all the 2-MeTHF phases were combined. No material loss was observed in the aqueous phase. The 2-Me-THF phase was concentrated under vacuum at a temperature below 40 °C to obtain Compound 15 as a brown oil. HPLC purity: 99.4%, NMR assay: 97.0%, yield: 82%. The crude Compound 15 was used directly in the next step.

[0095] Synthesis of Compound 17 H2O (5 volumes) was charged into a reactor at room temperature under a N2 atmosphere, and stirring was started. The reaction mixture was cooled to 0 - 10 °C, and concentrated H2SO4 (1 volume) and Compound 15 (5.46 Kg, 1.0 equivalent) were charged into the reactor. The reaction mixture was stirred at 60 °C for 16 hours. Samples were taken for IPC. By testing, 3.3% residue of Compound 15 was found.

[0096] The reactants were cooled to -5 to 5 °C, and the pH value of the system was adjusted to 8 to 9 slowly at -5 to 5 °C using 12% aqueous NaOH solution (about 12 volumes). 2-MeTHF (5 volumes) was added to the reactants, and the reactants were warmed to 15 to 30 °C and stirred for 30 minutes. Part of Na2SO4 did not dissolve in the aqueous phase. The reactants were filtered, the filtrate was transferred to a reactor, and the phases were separated. The filter cake was washed with 2-MeTHF (5 volumes), and the aqueous phase was extracted as described above. Loss in the aqueous phase: 0.2%, no loss in the filter cake. The 2-MeTHF phases from the two-phase separation were combined. The 2-MeTHF phase was concentrated to 1 to 2 volumes under vacuum at less than 50 °C. The residual 2-MeTHF was exchanged once with EA (5 volumes). The residue was dissolved in EA (10 volumes), the EA solution was charged into the reactor, and then anhydrous oxalic acid (2.0 equivalents) was added to the system to form a salt at 15 to 30 °C. KF of the EA solution: 0.0144%. The reaction mixture was stirred at 15 to 30 °C for 2 hours. When the mother liquor was sampled and IPC was performed, residual compound 16 was shown. No loss in ML. The filter cake was filtered and washed once with EA (2 volumes). The filter cake was collected and dried under a stream of N2 to obtain compound 17 as a pale yellow solid. 7.9 Kg of pale yellow solid, HPLC purity: 97.0%, LOD: 0.22, yield 6.16 kg.

[0097] Synthesis of Compound 18 H2O (15.6 L, 5 volumes) and compound 18 (3.12 kg) were charged into a 50 L reactor at room temperature under a N2 atmosphere. The reactants were stirred at room temperature for 30 minutes. The pH value of the system was adjusted to 8 to 9 with saturated 5% aqueous Na2CO3 solution (8 to 9 volumes). The aqueous phase was extracted twice with 2-MeTHF (2 * 15.6 L, 2 * 5 volumes), and all the 2-MeTHF phases were combined. The 2-MeTHF phase was separated and washed once with water (15.6 L, 5 volumes). The 2-MeTHF phase was separated and washed once with 10% brine (6.24 L, 2 volumes). The 2-Me-THF phase was concentrated under vacuum at less than 40 °C to obtain compound 18 (2.2 kg) as a brown oil. KF: 0.104%. Yield: 92.8%.

[0098] Synthesis of Compound 19 Compound 8 (1,737.4 g, 1.0 equivalent), compound 18 (2,463.8 g, 1.2 equivalents), TsOH (0.05 equivalent), and 2-MeTHF (20 volumes) were charged into a 50 L reactor at 20 °C under a N2 atmosphere. The reaction mixture was refluxed for 10 h (85 - 90 °C) under a N2 atmosphere, and water was removed by a Dean-Stark trap. Samples were taken and 1 IPC was performed by 1H-NMR (d6-DMSO), and peaks were shown at 8.91 ppm:6.41 ppm > 1:0.06.

[0099] The reaction solvent was concentrated to 3 - 4 volumes at 40 - 50 °C under vacuum, and 2-MeTHF was exchanged with DCM (17.3 L, 10 volumes). Then, the mixture was concentrated to 3 - 4 volumes. DCM (22.5 L, 13 volumes) was charged into the reaction mixture, and the reaction mixture was stirred for 0.5 h. Then, the reaction mixture was cooled to 5 °C.

[0100] NaBH(OAc)3 (3,048 g, 2.0 equivalents) was added to the residual mixture in 4 portions over 2 h at 0 - 10 °C. The reaction mixture was stirred at 5 °C for 2 h and then warmed to 20 °C. The reaction mixture was stirred overnight, and sampling and IPC were performed, showing less than 3% of residual compound 8. The reaction was quenched by adding the reaction system to H2O (17.4 L, 10 volumes) at 30 °C and stirred for 2.0 h. The organic phase was separated and washed once with H2O (1 × 17.4 L, 1 × 10 volumes). The organic phase was separated and washed once with an aqueous Na2CO3 solution (1 × 17.4 L, 1 × 10 volumes). The organic phase was separated and washed once with brine (1 × 17.4 L, 1 × 10 volumes). The organic phase was concentrated to 2 - 3 volumes at 40 - 50 °C under vacuum, and DCM was exchanged with MTBE (3 × 17.4 L, 3 × 10 volumes) three times. The residue was slurried with MTBE (5 volumes) at room temperature (20 ± 5 °C) for 2.0 h. The reaction mixture was filtered, and the filter cake was collected to obtain 3,103 g of compound 19 as a solid, HPLC purity: 97.4%, 135 g of solid was recovered from the mother liquor, HPLC purity: 95.2%, total yield: 88.1%.

[0101] Synthesis of Compound 101 Compound 19 (1.0 equivalent) and DCM (7 volumes) were charged into reactor A at room temperature under a nitrogen atmosphere. The reaction mixture was maintained at 25 °C, and then 1-methyl-1H-imidazole (3.0 equivalents) was charged into the reactor, and the reaction mixture was stirred at 25 °C for 0.5 h. The mixture was a clear solution. A solution of BTC (0.35 equivalent) in DCM (3 volumes) was added dropwise at 25 - 30 °C over 90 min. After the addition, the reaction mixture was stirred at 25 - 30 °C for 30 min. Samples were taken for IPC, which showed less than 3.0% residual compound 19. If the residual compound 19 was more than 3.0%, an appropriate amount of BTC in DCM solution was added, the reaction mixture was stirred for 30 min, sampled, and less than 3.0% compound 19 was obtained. (Actual: 0.1A% compound 19)

[0102] H2O (15 volumes) was added to the reaction mixture at 25 - 30 °C. The reaction mixture was stirred for 60 min, and the phases were separated. The aqueous phase was extracted once with DCM (5 volumes). The organic phases were combined, and 5% aqueous NaHCO3 solution was added to the reaction mixture. The reaction mixture was stirred for 60 min, the phases were separated, and the organic phase was collected. (Total aqueous phase loss: 135 g). The organic phase was washed twice with H2O (2 * 5 volumes), and the organic phase was collected. Optionally, to detect the influence of contaminants, 9 g of the (S,S) isomer of 101, 5 g of the (R,R) isomer of 101, 4.4 g of the (R,S) isomer of 101, and compound 19 (50 g. 1.2A% of the material remained after spiking) were added to the organic phase and stirred to obtain a clear solution (this step may be excluded during synthesis; in this run, these contaminants were removed in the final purification).

[0103] The solution was polished and filtered through a microporous filter, and the filtrate was collected in reactor B. The organic phase was concentrated under vacuum while maintaining the jacket temperature at 38 °C to 3 - 4 volumes, and DCM was exchanged with iPrOAc (2 * 7 volumes) previously filtered through a microporous filter. The reaction mixture was adjusted to 6 volumes with iPrOAc (previously filtered through a microporous filter). The internal temperature was maintained at 38 ± 1 °C, and 0.5 wt% of A-form crystals were added as seeds. The mixture was stirred at 38 ± 1 °C for 40 min.

[0104] Heptane (25 volumes), pre-filtered through a microporous filter, was added dropwise at 38 ± 1 °C for at least 2 hours. After the addition, the reaction mixture was stirred for 30 minutes, then cooled to 35 ± 1 °C, stirred for 5 minutes, then cooled to 32 ± 1 °C, stirred for 5 minutes until cooled to 5 ± 1 °C, and then stirred for at least an additional 13 hours.

[0105] The reaction mixture was filtered, and the filter cake was washed with heptane (2 volumes, pre-filtered through a microporous filter) to obtain a yellow solid, which was sampled by HPLC. The filter cake was dried at 40 ± 5 °C and P ≤ -0.08 MPa for at least 16.0 hours. Samples were taken and the LOD was measured. 2.85 kg of the resulting Compound 101 was obtained, HPLC: 98.59 A%, yield: 86.9%, %de: 99.9%, %ee: 99.9%. The product was submitted to QC for release. (ML loss: 149 g).

[0106] LC-MS: (ES, m / z): [M+H] + 540

[0107] 1 1H-NMR: (400 MHz, DMSO-d6, ppm): δ 0.84 - 0.91 (m, 4H), δ 1.38 - 1.95 (m, 12H), δ 2.08 - 2.10 (m, 1H), δ 2.68 - 2.77 (m, 2H), δ 3.19 - 3.25 (m, 3H), δ 3.43 (s, 3H), δ 4.25 - 4.28 (d, 1H), δ 7.01 (s, 1H), δ 7.19 - 7.21 (d 1H), δ 7.32 (s, 1H), δ 7.43 - 7.46 (t, 1H), δ 7.66 - 7.75 (m, 3H), δ 8.34 (s, 1H).

Claims

1. A method for producing Compound 101, comprising: a) reacting Compound 19 with X-C(O)-Y (wherein X and Y are each a leaving group) to produce Compound 101 The method as described above.

2. The method according to Claim 1, wherein X-C(O)-Y is phosgene or bis(trichloromethyl) carbonate.

3. The method according to Claim 1, wherein X-C(O)-Y is bis(trichloromethyl) carbonate.

4. b) reacting Compound 18 with Compound 8 in the presence of a reducing agent to produce Compound 19 The method according to any one of Claims 1 to 3, further comprising the above step.

5. The reducing agent in step b) is NaBH(OAc) ３ or NaBH ３ borohydride such as CN, the method according to claim 4.

6. The method further comprises: c) reacting Compound 14' with Compound 11 in the presence of Catalyst A to produce Compound 15' and d) reacting Compound 15' with an acid to produce Compound 18 The method according to any one of Claims 1 to 5, wherein Catalyst A is an organometallic catalyst. In the formula, each R' is independently C １～６ alkyl, or Both R' groups are C １～６ together as alkylene,

7.

8. each R' is methyl or ethyl, or both R' groups together form -CH ２ -CH ２ - or -CH ２ CH ２ CH ２ - and the method according to claim 6.

9. The method according to claim 7, wherein both R' groups together form -CH ２ -CH ２ -.

10. The method according to any one of Claims 6 to 8, wherein Catalyst A contains palladium atoms and is preferably suitable for catalyzing the Suzuki reaction.

11. The method according to claim 9, wherein the catalyst A is formed from a combination of a Pd(II) salt (such as Pd(OAc)) and xphos. ２ ​

12. e) separating the racemic mixture 6 by chiral supercritical fluid chromatography (SFC) to obtain Compound 7 and f) reducing Compound 7 to provide Compound 8 The method according to any one of Claims 1 to 10, further comprising the above steps.

13. The method according to Claim 11, wherein the separation in step e) is carried out on a cellulose-SC column.

14. The separation in step e) is such that mobile phase A is CO ２ and mobile phase B is methanol, acetonitrile, and NH ３ The method according to claim 12, wherein the separation is carried out including these components.

15. The mobile phase B is 2:3 to 3:2 methanol:acetonitrile containing 1 to 3 mM NH ３ The method according to claim 13, which is

16. The method according to any one of Claims 11 to 14, wherein the reduction in step f) is carried out by catalytic hydrogenation, such as using hydrogen and a catalyst containing palladium or platinum.

17. g) reacting Compound 3 with methyl isothiocyanate to obtain Compound 4 h) reacting Compound 4 with a base to provide Compound 5 and i) reacting Compound 5 with sodium nitrite and an acid to produce Compound 6 The method according to any one of Claims 1 to 15, further comprising the above steps.

18. The method according to any one of Claims 1 to 16, wherein Compound 101 is crystallized from a mixture of isopropyl acetate and heptane.

19. The method according to any one of claims 1 to 17, wherein compound 101 is at least 95% pure by HPLC.

19. Compound 101 An intermediate compound useful for the preparation of, said intermediate compound being selected from the group consisting of Compounds 1 to 19 of Schemes 1 to 3.

20. The following structure: The intermediate compound according to claim 19, having.

21. The following structure: The intermediate compound according to claim 19, having.

22. Compound 101 A method for producing an intermediate compound useful for the preparation of, said intermediate compound being selected from the group consisting of Compounds 1 to 19 of Schemes 1 to 3, said method including the steps found in the Examples.

23. A method for producing Compound 8 having the structure shown below, e) separating the racemic mixture 6 by chiral supercritical fluid chromatography (SFC) to obtain Compound 7 and f) reducing Compound 7 to provide Compound 8 The method including.

24. The method according to claim 23, wherein the separation in step e) is carried out on a cellulose-SC column.

25. The separation in step e) is such that mobile phase A is CO ２ and mobile phase B is methanol, acetonitrile, and NH ３ The method according to claim 24, wherein the method is carried out including

26. The mobile phase B is 2:3 to 3:2 methanol:acetonitrile containing 1 to 3 mM NH ３ The method according to claim 25, wherein the mobile phase B is 2:3 to 3:2 methanol:acetonitrile containing 1 to 3 mM NH

27. The method according to any one of claims 23 to 26, wherein the reduction in step f) is carried out by catalytic hydrogenation, such as using hydrogen and a catalyst containing palladium or platinum.

28. g) reacting Compound 3 with methyl isothiocyanate to obtain Compound 4 h) reacting Compound 4 with a base to provide Compound 5 and i) reacting Compound 5 with sodium nitrite and an acid to produce Compound 6 The method according to any one of claims 23 to 27, further including.

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