Method for preparing bifunctional compounds

Abstract

The present disclosure relates to the preparation of bifunctional compounds (e.g., Compound 1), intermediates in the preparation of such compounds, and the preparation of such intermediates. Compound 1 [Formula 1] JPEG2024527934000118.jpg5389

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Application No. 63 / 225,858, filed July 26, 2021, the entirety of which is incorporated herein by reference.

[0002] Certain bifunctional compounds can target specific cellular proteins for degradation via the ubiquitin-proteasome system. Examples of such proteolytic targeting chimeric compounds (i.e., "PROTAC® proteolytic agents") that target the estrogen receptor (ER) for ubiquitination and subsequent degradation are disclosed in U.S. Patent No. 10,647,698, which is incorporated herein by reference in its entirety. Such bifunctional molecules exhibit a range of pharmacological activities consistent with ER degradation, including, but not limited to, the treatment or amelioration of disease conditions such as cancer (e.g., breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer), or endometriosis. There is a need in the art for improved processes for preparing such bifunctional compounds. Summary of the Invention

[0003] A bifunctional molecule of particular interest is referred to herein as Compound 1. The present disclosure is directed to (i) processes for preparing Compound 1, (ii) intermediates used in the preparation of Compound 1 (i.e., I-1, I-2, I-2A, I-3, I-3A, I-4, I-5, I-6, I-6A, I-8, and I-9), and (iii) processes for preparing such intermediates.

[0004] In some embodiments, intermediate I-9 is reacted with [ka] Salt intermediate I-8, [ka] Methods for reductive amination with a base and a reducing agent to provide compound 1 are disclosed herein. [ka]

[0005] In some embodiments, the base is an amine base or a carbonate salt.

[0006] In some embodiments, the base is N-methyl-morpholine, trimethylamine, triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, lithium carbonate, sodium carbonate, potassium carbonate, or magnesium carbonate.

[0007] In some embodiments, the molar ratio of base to salt intermediate I-8 is from about 1:1 to about 3:1, preferably from about 1:1 to about 2:1.

[0008] In some embodiments, the molar ratio of base to salt intermediate I-8 is about 1.00:1, about 1.05:1, about 1.10:1, about 1.15:1, about 1.20:1, about 1.25:1, about 1.30:1, about 1.35:1, about 1.40:1, about 1.45:1, about 1.50:1, about 1.55:1, about 1.60:1, about 1.65:1, about 1.66:1, about 1.67:1, about 1.68:1, about 1.69:1, about 1.70:1, about 1.71:1, about 1.72:1, about 1.73:1, about 1.74:1, about 1.75:1, about 1.76:1, about 1.77:1, about 1.78:1, about 1.79:1, about 1.80:1, about 1.81:1, about 1.82:1, about 1.83:1, about 1.84:1, about 1.85:1, about 1.86:1, about 1.87:1, about 1.88:1, about 1.89:1, about 1.90:1, about 1.92:1, about 1.94:1, about 1.96:1, about 1.98:1, about 1.99:1, about 2.00:1, about 2.01:1, about 2.02:1, about 2.03:1, about 2.04:1, about 2.05:1, about 2.06:1, about 2.07:1, about 2.08:1, about 2.09:1, about 2.10:1 5:1, about 1.70:1, about 1.75:1, about 1.80:1, about 1.85:1, about 1.90:1, about 1.95:1, about 2.00:1, about 2.05:1, about 2.10:1, about 2.15:1, about 2.20:1, about 2.25:1, about 2.30:1, about 2.35:1, about 2.40:1, or about 2.45:1.

[0009] In some embodiments, the reducing agent is sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, or hydrogen in the presence of a catalyst.

[0010] In some embodiments, the molar ratio of reducing agent to salt intermediate I-8 is from about 1:1 to about 3:1, preferably from about 1:1 to about 2:1.

[0011] In some embodiments, the molar ratio of reducing agent to salt intermediate I-8 is about 1.00:1, about 1.05:1, about 1.10:1, about 1.15:1, about 1.20:1, about 1.25:1, about 1.30:1, about 1.35:1, about 1.40:1, about 1.45:1, about 1.50:1, about 1.55:1, about 1.60:1, about 1.65:1, about 1.70:1, about 1.75:1, about 1.80:1, about 1.85:1, about 1.90:1, about 1.95:1, about 2.00:1, about 2.05:1, or about 2.10:1.

[0012] In some embodiments, the solvent is a polar solvent.

[0013] In some embodiments, the polar solvent is dimethylacetamide, N-methyl-2-pyrrolidone, or 2-methyltetrahydrofuran.

[0014] In some embodiments, the temperature of the reductive amination is from about -30°C to about 30°C, preferably from about -10°C to about 10°C.

[0015] In some embodiments, the reductive amination temperature is about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, or about 30°C.

[0016] In some embodiments, the method further comprises quenching the reducing agent with water, an alcohol, preferably ethanol, or a combination thereof to form a first solution.

[0017] In some embodiments, further comprising forming a precipitate comprising Compound 1, a second solution of alcohol and water, preferably ethanol and water, is added to the first solution to form a precipitate comprising Compound 1.

[0018] In some embodiments, further comprising forming a precipitate comprising compound 1, a third solution comprising water, an alcohol, preferably ethanol, or a combination thereof is added to the first solution to quench the reducing agent, thereby forming a precipitate comprising compound 1.

[0019] In some embodiments, the temperature of the second solution of alcohol and water is from about 50° C. to about 90° C., preferably from about 60° C. to about 80° C., when the solution of alcohol and water is added to the first solution.

[0020] In some embodiments, the temperature of the second solution is about 70° C. when the second solution is added to the first solution.

[0021] In some embodiments, the second solution has an alcohol:water ratio of about 1:1 (v / v).

[0022] In some embodiments, after adding the second solution to the first solution or the third solution, the resulting suspension is cooled to about 50° C., about 40° C., about 30° C., about 25° C., about 20° C., or about 15° C. The resulting suspension is then filtered and the filtrate is washed with water and alcohol, preferably water and ethanol.

[0023] In some embodiments, the method for preparing compound 1 includes purifying compound 1. In some embodiments, purifying compound 1 includes dissolving compound 1 in a dichloromethane and methanol solution. In some embodiments, the ratio of dichloromethane to methanol in the solution is about 8:1 (v / v) to about 11:1 (v / v). In some embodiments, the ratio of dichloromethane to methanol in the solution is about 9:1 (v / v) to about 11:1 (v / v). In some embodiments, the ratio of dichloromethane to methanol in the solution is about 8:1 (v / v), about 8.5:1 (v / v), about 9:1 (v / v), about 9.1:1 (v / v), about 9.2:1 (v / v), about 9.3:1 (v / v), about 9.4:1 (v / v), about 9.5:1 (v / v), about 9.6:1 (v / v), about 9.7:1 (v / v), about 9.8:1 (v / v), about 9.9:1 (v / v), about 10:1 (v / v), about 10.5:1 (v / v), or about 11:1 (v / v). In some embodiments, the ratio of dichloromethane to methanol in the solution is about 9.4:1 (v / v).

[0024] In some embodiments, purifying compound 1 comprises distillatively exchanging a dichloromethane / methanol solution for a polar protic solvent. In some embodiments, the polar protic solvent is methanol, ethanol, n-propanol, isopropanol, or n-butanol. In some embodiments, the polar protic solvent is n-butanol.

[0025] In some embodiments, intermediate I-6 is reacted with [ka] with an acid in a solvent to provide intermediate I-9. [ka]

[0026] In some embodiments, the solvent comprises water and an ethereal solvent, hi some embodiments, the ethereal solvent is 2-methyltetrahydrofuran or tetrahydrofuran.

[0027] In some embodiments, the acid is hydrochloric acid.

[0028] In some embodiments, the additive is an antioxidant, a radical scavenger, an oxygen scavenger, or a metal chelator.

[0029] In some embodiments, the additive is dibutylhydroxytoluene, ascorbic acid, alpha-tocopherol, or ethylenediaminetetraacetic acid.

[0030] In some embodiments, the method further comprises reacting intermediate I-6 with an acid and optional additives in a solvent at a temperature from about 0° C. to about 40° C., and preferably from about 10° C. to about 30° C.

[0031] In some embodiments, the method further comprises reacting intermediate I-6 with an acid and optional additives in a solvent, followed by adding an aqueous solution to adjust the pH to about pH 7 to about pH 8. In some embodiments, the aqueous solution is an aqueous solution of tripotassium phosphate.

[0032] In some embodiments, the method further comprises separating the organic and aqueous layers after adjusting the pH with the aqueous solution. In some embodiments, the aqueous layer is extracted with an ether solvent to form an organic extract, which is then concentrated. In some embodiments, the ether extracting solvent is 2-methyltetrahydrofuran.

[0033] In some embodiments, the concentration of the organic extract is carried out under vacuum at a temperature of about 20° C. to about 70° C. In some embodiments, the concentration of the organic extract is carried out under vacuum at a temperature of about 35° C. to about 55° C.

[0034] In some embodiments, the concentrated organic extract is combined with dimethylacetamide and reconcentrated under vacuum.

[0035] In some embodiments, after reconcentration of the organic extract and dimethylacetamide under vacuum, the molar ratio of the ethereal solvent to intermediate I-9 in the reconcentrated organic extract is about 0.1:1 or less. In some embodiments, the ethereal solvent is 2-methyltetrahydrofuran.

[0036] In some embodiments, (a) reacting the racemic intermediate I-5 with [ka] combining an additive in a solvent to form a first reaction mixture; (b) heating the first reaction mixture to reflux to prepare a fourth solution, followed by cooling the fourth solution to a temperature of about 50° C. to about 100° C., preferably, the temperature is about 65° C. to about 75° C.; (c) combining (R)-proline and water to prepare a second solution, the molar ratio of (R)-proline to the total amount of intermediate I-5 being about 0.40:1 to about 1.00:1; (d) adding about 1% to less than about 50% by volume, preferably about 5% to about 25% by volume, of the second solution to the first solution to prepare a second reaction mixture; (e) adding a first amount of a nucleation-inducing agent to the second reaction mixture to form a third reaction mixture; (f) adding from about 1% to less than about 50% by volume, preferably from about 5% to about 25% by volume, of the second solution to the third reaction mixture to prepare a fourth reaction mixture; (g) adding a second amount of a nucleation inducing agent to the fourth reaction mixture to form a fifth reaction mixture; (h) adding the remainder of the second solution to the fifth reaction mixture to prepare a sixth reaction mixture comprising intermediate I-6.

[0037] In some embodiments, the first reaction mixture comprises a mixture of an alcohol solvent and an ether solvent, hi some embodiments, the first reaction mixture comprises a mixture of 2-propanol and 2-methyl-tetrahydrofuran.

[0038] In some embodiments, the agent that induces nucleation is a crystallization promoter, preferably the crystallization promoter is a seed crystal comprising intermediate I-6.

[0039] In some embodiments, the molar ratio of the total amount of crystallization promoter compared to intermediate I-5 is from about 0.0001:1 to about 0.01:1, preferably, the molar ratio is from about 0.0005:1 to about 0.005:1.

[0040] In some embodiments, the molar ratio of the total amount of crystallization promoter compared to intermediate I-5 is about 0.0008:1, about 0.0009:1, about 0.0010:1, about 0.0011:1, about 0.0012:1, about 0.0013:1, about 0.0014:1, about 0.0015:1, about 0.0016:1, about 0.0017:1, or about 0.0018:1.

[0041] In some embodiments, the first amount of the nucleation-inducing agent is about equal to the second amount of the nucleation-inducing agent, hi some embodiments, the first amount of the crystallization promoter is about equal to the second amount of the crystallization promoter.

[0042] In some embodiments, the molar ratio of the first amount of crystallization promoter compared to intermediate I-5 is about 0.0008:1, about 0.0009:1, about 0.0010:1, about 0.0011:1, about 0.0012:1, about 0.0013:1, about 0.0014:1, about 0.0015:1, about 0.0016:1, about 0.0017:1, or about 0.0018:1. In some embodiments, the molar ratio of the second amount of crystallization promoter compared to intermediate I-5 is about 0.0008:1, about 0.0009:1, about 0.0010:1, about 0.0011:1, about 0.0012:1, about 0.0013:1, about 0.0014:1, about 0.0015:1, about 0.0016:1, about 0.0017:1, or about 0.0018:1.

[0043] In some embodiments, the additive is an antioxidant, a radical scavenger, an oxygen scavenger, or a metal chelator.

[0044] In some embodiments, the additive is dibutylhydroxytoluene, ascorbic acid, alpha-tocopherol, or ethylenediaminetetraacetic acid.

[0045] In some embodiments, the molar ratio of the total amount of (R)-proline used in the process to the total amount of intermediate I-5 used in the process is from about 0.40:1 to about 0.90:1, preferably from about 0.50:1 to about 0.75:1.

[0046] In some embodiments, the molar ratio of the total amount of (R)-proline used in the process to the total amount of intermediate I-5 used in the process is about 0.50:1, about 0.51:1, about 0.52:1, about 0.53:1, about 0.54:1, about 0.55:1, about 0.56:1, about 0.57:1, about 0.58:1, about 0.59:1, about 0.60:1, about 0.61:1, about 0.62:1, about 0.63:1, about 0.64:1, about 0.65:1, about 0.66:1, about 0.67:1, about 0.68:1, about 0.69:1, or about 0.70:1.

[0047] In some embodiments, upon completion of the reaction to prepare intermediate I-6, the completed reaction is cooled from a temperature of about 50° C. to about 100° C., preferably about 65° C. to about 75° C., to a temperature of about 25° C. at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

[0048] In some embodiments, upon cooling of the completed reaction, intermediate I-6 is recovered by filtration, washed with a solvent, and dried.

[0049] In some embodiments, the solvent used to wash intermediate I-6 is 2-propanol.

[0050] In some embodiments, intermediate I-6 is dried under vacuum at a temperature of about 30° C. to about 60° C. In some embodiments, intermediate I-6 is dried under vacuum at a temperature of about 40° C. to about 50° C.

[0051] In some embodiments, intermediate I-4 in a solvent, [ka] and camphorsulfonic acid to provide a salt intermediate I-8, [ka] and providing one or more by-products.

[0052] In some embodiments, the molar ratio of camphorsulfonic acid to intermediate I-4 in the reaction mixture is from about 1:1 to about 3:1, preferably from about 1.5:1 to about 2.5:1.

[0053] In some embodiments, the molar ratio of camphorsulfonic acid to intermediate I-4 in the reaction mixture is about 1.90:1, about 1.95:1, about 2.00:1, about 2.05:1, about 2.10:1, about 2.15:1, about 2.20:1, about 2.25:1, about 2.30:1, or about 2.35:1.

[0054] In some embodiments, the camphorsulfonic acid is (+)-camphorsulfonic acid.

[0055] In some embodiments, the solvent comprises acetonitrile, dimethylformamide, or a mixture thereof.

[0056] In some embodiments, the solvent comprises acetonitrile and dimethylformamide in a ratio of about 1:1 (v / v) to about 8:1 (v / v), preferably about 2:1 (v / v) to about 6:1 (v / v).

[0057] In some embodiments, the method further comprises heating intermediate I-4 and camphorsulfonic acid in a solvent at a temperature from about 70° C. to about 100° C., preferably, the temperature is from about 85° C. to about 100° C.

[0058] In some embodiments, the method further comprises heating intermediate I-4 and camphorsulfonic acid in a solvent at a temperature of about 90°C, about 95°C, or about 100°C.

[0059] In some embodiments, the solvent and one or more by-products of the reaction are removed azeotropically.

[0060] In some embodiments, the one or more by-products of the reaction that are azeotropically removed from the reaction mixture include water and tert-butanol.

[0061] In some embodiments, intermediate I-3 is reacted with [ka] Reacting with intermediate I-3A in a solvent in the presence of a reducing agent, [ka] Disclosed herein is a process that includes providing intermediate I-4. [ka]

[0062] In some embodiments, the solvent comprises an alcohol, preferably the solvent comprises methanol.

[0063] In some embodiments, the solvent further comprises an acid, preferably the acid is acetic acid.

[0064] In some embodiments, the method further comprises adding the reducing agent as a solution in methanol.

[0065] In some embodiments, prior to beginning the addition of the reducing agent solution, the method includes cooling intermediate I-3, intermediate 3A, and the solvent to a temperature of about 0° C. to about 30° C., and preferably, the method includes cooling intermediate I-3, intermediate 3A, and the solvent to a temperature of about 0° C. to about 10° C. In some embodiments, the temperature of the reaction mixture is preferably maintained at that temperature throughout the addition of the reducing agent solution.

[0066] In some embodiments, after adding the reducing agent solution, the method further comprises warming the temperature of intermediate I-3, intermediate 3A, and the reducing agent to between about 15° C. and about 35° C. In some embodiments, the method further comprises warming the temperature of intermediate I-3, intermediate 3A, and the reducing agent, preferably between about 20° C. and about 30° C.

[0067] In some embodiments, the reducing agent is sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, or hydrogen in the presence of a catalyst.

[0068] In some embodiments, the reducing agent is sodium cyanoborohydride.

[0069] In some embodiments, intermediate I-2 is reacted with [ka] Provided herein is a process that includes reacting with a reducing agent in a solvent, followed by heating the reaction mixture to provide intermediate I-3. [ka]

[0070] In some embodiments, the solvent comprises water, an acid, pyridine, or a combination thereof, In some embodiments, the solvent comprises water, an acid, 2,6-lutidine, or a combination thereof.

[0071] In some embodiments, the acid is propionic acid or acetic acid. In some embodiments, the acid is propionic acid. In some embodiments, the acid is acetic acid.

[0072] In some embodiments, the reducing agent is Raney nickel.

[0073] In some embodiments, the method further comprises maintaining the temperature of intermediate 2, the reducing agent, and the solvent at about 15° C. to about 30° C., preferably, the temperature is maintained at about 20° C. to about 30° C.

[0074] In some embodiments, the method further comprises heating intermediate 2, the reducing agent, and the solvent to a temperature of about 40° C. to about 70° C. In some embodiments, the method further comprises heating intermediate 2, the reducing agent, and the solvent to a temperature of about 50° C. to about 60° C.

[0075] In some embodiments, intermediate I-2A, [ka] Disclosed herein is a process that includes reacting a hydrogen source and, optionally, a catalyst in a solvent to provide intermediate I-3A. [ka]

[0076] In some embodiments, the catalyst comprises a transition metal, hi some embodiments, the transition metal is palladium, rhodium, ruthenium, iridium, or copper.

[0077] In some embodiments, the catalyst is Pd(OH) 2 .

[0078] In some embodiments, the hydrogen source is hydrogen gas.

[0079] In some embodiments, the pressure of the hydrogen gas is maintained at about 0.5 MPa to about 1.5 MPa, and preferably, the pressure of the hydrogen gas is maintained at about 0.75 MPa to about 1.25 MPa.

[0080] In some embodiments, intermediate I-9 is intermediate I-6, [ka] and an acid in a solvent to provide intermediate I-9. [ka]

[0081] In some embodiments, intermediate I-6 is (a) reacting the racemic intermediate I-5 with [ka] combining an additive in a solvent to form a first reaction mixture; (b) heating the first reaction mixture at reflux to prepare a first solution, and subsequently cooling the first solution to a temperature of about 50° C. to about 100° C., preferably about 65° C. to about 75° C.; (c) combining (R)-proline and water to prepare a second solution, the molar ratio of (R)-proline to the total amount of intermediate I-5 being about 0.40:1 to about 1.00:1; (d) adding about 1% to less than about 50% by volume, preferably about 5% to about 25% by volume, of the second solution to the first solution to prepare a second reaction mixture; (e) adding a first amount of a nucleation-inducing agent to the second reaction mixture to form a third reaction mixture; (f) adding from about 1% to less than about 50% by volume, preferably from about 5% to about 25% by volume, of the second solution to the third reaction mixture to prepare a fourth reaction mixture; (g) adding a second amount of a nucleation inducing agent to the fourth reaction mixture to form a fifth reaction mixture; (h) adding the remainder of the second solution to said fifth reaction mixture to prepare a sixth reaction mixture to prepare intermediate I-6. [ka]

[0082] In some embodiments, intermediate I-8 is a reaction product of intermediate I-4, [ka] and camphorsulfonic acid in a solvent to give intermediate I-8, [ka] and providing one or more by-products.

[0083] In some embodiments, intermediate I-4 is intermediate I-3, [ka] Reacting with intermediate I-3A in a solvent in the presence of a reducing agent, [ka] It is prepared by a process comprising providing intermediate I-4. [ka]

[0084] In some embodiments, intermediate I-3 is intermediate I-2, [ka] and a reducing agent in a solvent to provide intermediate I-3. [ka]

[0085] In some embodiments, intermediate I-3A is intermediate I-2A, [ka] Intermediate I-3A is prepared by a process comprising reacting a hydrogen source, and optionally a catalyst, in a solvent to provide intermediate I-3A. [ka]

[0086] In some embodiments, (a) Intermediate I-2A, [ka] reacting a hydrogen source and, optionally, a catalyst in a solvent to provide intermediate I-3A; [ka] (b) reducing intermediate I-2 in the presence of a reducing agent in a solvent, [ka] Providing an intermediate I-3; [ka] (c) reacting intermediate I-3 with [ka] Reacting with intermediate I-3A in a solvent in the presence of a reducing agent, [ka] Providing an intermediate I-4; [ka] (d) intermediate I-4, [ka] and camphorsulfonic acid in a solvent to give salt intermediate I-8, [ka] and providing one or more by-products. (e1) racemic intermediate I-5, [ka] combining an additive in a solvent to form a first reaction mixture; (e2) heating the first reaction mixture at reflux to prepare a first solution, and subsequently cooling the first solution to a temperature of about 50° C. to about 100° C.; (e3) combining (R)-proline and water to prepare a second solution, wherein the molar ratio of (R)-proline to the total amount of intermediate I-5 is from about 0.40:1 to about 1.00:1; (e4) adding about 1% to less than about 50% by volume of the second solution to the first solution to prepare a second reaction mixture; (e5) adding a first amount of a nucleation-inducing agent to the second reaction mixture to form a third reaction mixture; (e6) adding about 1% to less than about 50% by volume of the second solution to the third reaction mixture to prepare a fourth reaction mixture; (e7) adding a second amount of a nucleation inducing agent to the fourth reaction mixture to form a fifth reaction mixture; (e8) adding the remainder of the second solution to a fifth reaction mixture to prepare a sixth reaction mixture to prepare intermediate I-6; [ka] (h) reacting intermediate I-6 with [ka] with an acid to provide intermediate I-9; [ka] (i) reacting intermediate I-9 with [ka] reductive amination with salt intermediate I-8 in the presence of a base and a reducing agent; [ka] Provided herein is a method that includes providing Compound 1 in the presence of a base and a reducing agent. [ka] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0087] In one aspect, the present disclosure is directed to a method for preparing compound 1.

[0088] In some embodiments, a method for preparing compound 1 includes providing a mixture comprising intermediate I-9, salt intermediate I-8, a base, and a reducing agent, and reductively amminating intermediate I-9 with salt intermediate I-8 to provide compound 1. [ka]

[0089] In some embodiments, the base used in the method for preparing Compound 1 is an amine base or a carbonate salt.

[0090] In some embodiments, the base used in the method for preparing compound 1 is an amine base.

[0091] In some embodiments, the base used in the method for preparing compound 1 is N-methyl-morpholine.

[0092] In some embodiments, the base used in the method for preparing compound 1 is trimethylamine.

[0093] In some embodiments, the base used in the method for preparing compound 1 is triethylamine.

[0094] In some embodiments, the base used in the method for preparing compound 1 is N,N-diisopropylethylamine.

[0095] In some embodiments, the base used in the method for preparing compound 1 is N,N-dimethylaniline.

[0096] In some embodiments, the base used in the method for preparing Compound 1 is a carbonate salt.

[0097] In some embodiments, the base used in the method for preparing Compound 1 is lithium carbonate, sodium carbonate, potassium carbonate, or magnesium carbonate.

[0098] In some embodiments, the base used in the method for preparing compound 1 is lithium carbonate.

[0099] In some embodiments, the base used in the method for preparing compound 1 is sodium carbonate.

[0100] In some embodiments, the base used in the method for preparing compound 1 is potassium carbonate.

[0101] In some embodiments, the base used in the method for preparing Compound 1 is magnesium carbonate.

[0102] In some embodiments, the base used in the method for preparing compound 1 is N-methyl-morpholine, trimethylamine, triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, lithium carbonate, sodium carbonate, potassium carbonate, or magnesium carbonate.

[0103] In some embodiments, the base used in the method for preparing compound 1 is present in a ratio of base to salt intermediate I-8 in the reaction mixture of about 1:1 to about 3:1, preferably about 1:1 to about 2:1.

[0104] In some embodiments, the base used in the method for preparing Compound 1 is about 1.00:1, about 1.05:1, about 1.10:1, about 1.15:1, about 1.20:1, about 1.25:1, about 1.30:1, about 1.35:1, about 1.40:1, about 1.45:1, about 1.50:1, about 1.55:1, about 1.60:1, about 1.65:1, about The base is present in a molar ratio of about 1.70:1, about 1.75:1, about 1.80:1, about 1.85:1, about 1.90:1, about 1.95:1, about 2.00:1, about 2.05:1, about 2.10:1, about 2.15:1, about 2.20:1, about 2.25:1, about 2.30:1, about 2.35:1, about 2.40:1, or about 2.45:1 of the base to salt intermediate I-8.

[0105] In some embodiments, the process of method compound 1 includes providing a mixture that includes a reducing agent.

[0106] In some embodiments, the process of method compound 1 includes providing a mixture containing a reducing agent, wherein the reducing agent is sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, or hydrogen in the presence of a catalyst.

[0107] In some embodiments, the process of method compound 1 includes providing a mixture including a reducing agent, wherein the reducing agent is sodium triacetoxyborohydride.

[0108] In some embodiments, the method for preparing compound 1 includes providing a mixture including a reducing agent, wherein the reducing agent is sodium borohydride.

[0109] In some embodiments, the method for preparing compound 1 includes providing a mixture including a reducing agent, where the reducing agent is sodium cyanoborohydride.

[0110] In some embodiments, the method for preparing compound 1 includes providing a mixture including a reducing agent, where the reducing agent is hydrogen in the presence of a catalyst.

[0111] In some embodiments, the reaction mixture used to prepare compound 1 comprises a molar ratio of reducing agent to salt intermediate I-8, wherein the reducing agent is present in a molar ratio of reducing agent to salt intermediate I-8 in the reaction mixture of about 1:1 to about 3:1, preferably about 1:1 to about 2:1.

[0112] In some embodiments, the molar ratio of reducing agent to salt intermediate I-8 in the reaction mixture is about 1.00:1, about 1.05:1, about 1.10:1, about 1.15:1, about 1.20:1, about 1.25:1, about 1.30:1, about 1.35:1, about 1.40:1, about 1.45:1, about 1.50:1, about 1.55:1, about 1.60:1, about 1.65:1, about 1.70:1, about 1.75:1, about 1.80:1, about 1.85:1, about 1.90:1, about 1.95:1, about 2.00:1, about 2.05:1, or about 2.10:1.

[0113] In some embodiments, the reaction to prepare compound 1 is carried out in a polar solvent.

[0114] In some embodiments, the reaction to prepare compound 1 is carried out in a polar solvent, and the polar solvent is dimethylacetamide, N-methyl-2-pyrrolidone, or 2-methyltetrahydrofuran.

[0115] In some embodiments, the reaction to prepare compound 1 is carried out in a polar solvent, and the polar solvent is dimethylacetamide.

[0116] In some embodiments, the reaction to prepare compound 1 is carried out in a polar solvent, and the polar solvent is N-methyl-2-pyrrolidone.

[0117] In some embodiments, the reaction to prepare compound 1 is carried out in a polar solvent, and the polar solvent is 2-methyltetrahydrofuran.

[0118] In some embodiments, the reaction for preparing compound 1 is carried out at a temperature of about -30°C to about 30°C, preferably about -10°C to about 10°C.

[0119] In some embodiments, the reaction to prepare compound 1 is carried out at a temperature of about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, or about 30°C.

[0120] In some embodiments, the reaction to prepare compound 1 is quenched upon completion of the reductive amination reaction and the reaction mixture is quenched by combining the reaction mixture with water.

[0121] In some embodiments, the reaction to prepare compound 1 is quenched upon completion of the reductive amination reaction and the reaction mixture is quenched by combining the reaction mixture with an alcohol.

[0122] In some embodiments, the reaction to prepare compound 1 is quenched upon completion of the reductive amination reaction and the reaction mixture is quenched by combining the reaction mixture with water and an alcohol.

[0123] In some embodiments, the reaction to prepare compound 1 is quenched upon completion of the reductive amination reaction and the reaction mixture is quenched by combining the reaction mixture with a C1-C6 alcohol.

[0124] In some embodiments, the reaction to prepare compound 1 is quenched upon completion of the reductive amination reaction and the reaction mixture is quenched by combining the reaction mixture with ethanol.

[0125] In some embodiments, the reaction to prepare compound 1 is quenched and then the quenched reaction mixture is combined with a solution of alcohol and water to form a precipitate containing compound 1.

[0126] In some embodiments, the reaction to prepare compound 1 is quenched and then the quenched reaction mixture is combined with a solution of ethanol and water to form a precipitate containing compound 1.

[0127] In some embodiments, the reaction to prepare compound 1 is quenched, and then the quenched reaction mixture is combined with a solution of alcohol and water to form a precipitate containing compound 1, and the temperature of the alcohol and water solution is about 50° C. to about 90° C., preferably about 60° C. to about 80° C., when the alcohol and water solution is combined with the quenched reaction mixture. In some embodiments, the alcohol is ethanol.

[0128] In some embodiments, the reaction to prepare compound 1 is quenched and then the quenched reaction mixture is combined with a solution of alcohol and water to form a precipitate that includes compound 1, and the temperature of the alcohol and water solution is about 50° C., about 55° C., about 60° C., about 70° C., about 75° C., or about 80° C. when the alcohol and water solution is combined with the quenched reaction mixture. In some embodiments, the alcohol is ethanol.

[0129] In some embodiments, the reaction mixture to provide compound 1 is quenched and then the quenched reaction mixture is combined with a solution of alcohol and water, where the solution of alcohol and water added to the quenched reaction mixture has an alcohol:water ratio of about 1:100, about 1:50, about 1:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 50:1, or about 100:1 (v:v).

[0130] In some embodiments, the process for preparing compound 1 is quenched and then the quenched reaction mixture is combined with a solution of alcohol and water having an alcohol:water ratio of about 1:1 (v / v).

[0131] In some embodiments, the process for preparing compound 1 includes cooling the precipitate that forms after the quenched reaction mixture is combined with a solution of alcohol and water.

[0132] In some embodiments, the resulting precipitate in the process for preparing Compound 1 is cooled to about 50°C, about 45°C, about 40°C, about 35°C, about 30°C, about 25°C, about 20°C, or about 15°C.

[0133] In some embodiments, the precipitate obtained in the process for preparing Compound 1 is filtered.

[0134] In some embodiments, the precipitate obtained in the process for preparing Compound 1 is washed with water and alcohol. In some embodiments, the alcohol used to wash the filtrate is ethanol.

[0135] In some embodiments, the alcohol:water ratio used to wash the filtrate is the same as the alcohol:water ratio added to the quenched reaction mixture.

[0136] In some embodiments, the alcohol:water ratio used to wash the filtrate is different from the alcohol:water ratio added to the quenched reaction mixture.

[0137] In some embodiments, the alcohol:water ratio used to wash the filtrate is about 1:100, about 1:50, about 1:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 50:1, or about 100:1 (v:v).

[0138] Intermediate I-9 In some embodiments, disclosed herein are methods for preparing intermediate I-9.

[0139] In some embodiments, a method for preparing intermediate I-9 includes providing a mixture comprising intermediate I-6, a solvent, and an acid to provide intermediate I-9. [ka]

[0140] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 comprises a solvent, and the solvent in the reaction mixture comprises water and an ethereal solvent.

[0141] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 comprises a solvent, and the solvent in the reaction mixture comprises water and 2-methyltetrahydrofuran.

[0142] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 comprises a solvent, and the solvent in the reaction mixture comprises water and tetrahydrofuran.

[0143] In some embodiments, the acid used in the process for preparing intermediate I-9 is a strong acid.

[0144] In some embodiments, the acid used in the process for preparing intermediate I-9 is a weak acid.

[0145] In some embodiments, the acid used in the process for preparing intermediate I-9 is HCl.

[0146] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 further comprises an additive that is an antioxidant, a radical scavenger, an oxygen scavenger, or a metal chelator.

[0147] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 further comprises an additive that is an antioxidant.

[0148] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 further comprises an additive that is a radical scavenger.

[0149] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 further comprises an additive that is an oxygen scavenger.

[0150] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 further comprises an additive that is a metal chelating agent.

[0151] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 further comprises an additive that is dibutylhydroxytoluene, ascorbic acid, alpha-tocopherol, or ethylenediaminetetraacetic acid.

[0152] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 further comprises an additive that is dibutylhydroxytoluene.

[0153] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 further comprises an additive that is ascorbic acid.

[0154] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 further comprises an additive that is alpha-tocopherol.

[0155] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 further comprises an additive which is ethylenediaminetetraacetic acid.

[0156] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 is at a temperature of about 0°C to about 40°C, preferably about 10°C to about 30°C.

[0157] In some embodiments, the reaction mixture in the process for preparing intermediate I-9 is at a temperature of about 0° C., about 5° C., about 10° C., about 15° C., about 20° C., about 25° C., about 30° C., about 35° C., or about 40° C., or any range between any two of the foregoing temperatures.

[0158] In some embodiments, the pH of the reaction mixture in the process for preparing intermediate I-9 is adjusted after the reaction is completed.

[0159] In some embodiments, the pH of the reaction mixture in the process for preparing intermediate I-9 is adjusted to about 7 to about 8 after the reaction is completed.

[0160] In some embodiments, the pH of the reaction mixture in the process for preparing intermediate I-9 is adjusted to about 7 to about 8 with an aqueous solution of tripotassium phosphate after the reaction is completed.

[0161] In some embodiments, the pH of the reaction mixture in the process for preparing intermediate I-9 is adjusted to about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8 after the reaction is completed.

[0162] In some embodiments, a pH adjuster may be used to adjust the reaction mixture to an acceptable pH (typically in the pH range of about 5.0 to about 9.0, about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0). The pH adjuster may be a mineral acid or a metal hydroxide base selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. An acidic and / or basic pH modifier may be added to adjust the mixture to a target acceptable pH value or range. A buffering agent may be used to stabilize the pH. If used, the buffer may be any suitable buffer. The buffer may be selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid, or a salt thereof, including disodium tetraborate), citrate buffers (such as citric acid, or a salt thereof, including sodium citrate), ε-aminocaproic acid, and mixtures thereof.

[0163] In some embodiments, the pH of the completed reaction in the process for preparing intermediate I-9 is adjusted, and after adjusting the pH of the completed reaction, an organic layer and an aqueous layer are formed and then separated from each other. The aqueous layer is extracted with an ether solvent, preferably 2-methyltetrahydrofuran, to form an organic extract, and then the organic extract is concentrated.

[0164] In some embodiments, the organic extract containing intermediate I-9 is concentrated under vacuum at a temperature of about 20°C to about 70°C, preferably about 35°C to about 55°C.

[0165] In some embodiments, the organic extract containing intermediate I-9 is concentrated under vacuum at a temperature of about 20° C., about 25° C., about 30° C., about 35° C., about 40° C., about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., or any range between any two of the preceding values.

[0166] In some embodiments, the organic extract containing intermediate I-9 is concentrated, and the concentrated organic extract is combined with dimethylacetamide and reconcentrated under vacuum.

[0167] In some embodiments, after reconcentration of the organic extract and dimethylacetamide under vacuum, the molar ratio of ether solvent to intermediate I-9 in the reconcentrated organic extract is about 0.1:1 or less, about 0.09:1 or less, about 0.08:1 or less, about 0.07:1 or less, about 0.06:1 or less, about 0.05:1 or less, about 0.04:1 or less, about 0.03:1 or less, about 0.02:1 or less, or about 0.01:1 or less.

[0168] In some embodiments, after reconcentration of the organic extract and dimethylacetamide under vacuum, the molar ratio of ether solvent to intermediate I-9 in the reconcentrated organic extract is about 0.1:1 or less.

[0169] In some embodiments, after reconcentration of the organic extract and dimethylacetamide under vacuum, the molar ratio of the ether solvent, preferably 2-methyltetrahydrofuran, to intermediate I-9 in the reconcentrated organic extract is about 0.1:1 or less.

[0170] Intermediate I-6 In some embodiments, disclosed herein is a method for preparing intermediate I-6, the method comprising: [ka] (a) combining racemic intermediate I-5 and an additive with a solvent to prepare a first reaction mixture; (b) heating the first reaction mixture at reflux to prepare a first solution, and subsequently cooling the first solution to a temperature of about 50° C. to about 100° C., preferably about 65° C. to about 75° C.; (c) combining (R)-proline and water to prepare a second solution, the molar ratio of (R)-proline to the total amount of intermediate I-5 being about 0.40:1 to about 1.00:1; (d) adding about 1% to less than about 50% by volume, preferably about 5% to about 25% by volume, of the second solution to the first solution to prepare a second reaction mixture; (e) adding a first amount of a nucleation-inducing agent to the second reaction mixture to form a third reaction mixture; (f) adding from about 1% to less than about 50% by volume, preferably from about 5% to about 25% by volume, of the second solution to the third reaction mixture to prepare a fourth reaction mixture; (g) adding a second amount of a nucleation inducing agent to the fourth reaction mixture to form a fifth reaction mixture; (h) adding the remainder of the second solution to the fifth reaction mixture to prepare a sixth reaction mixture comprising intermediate I-6.

[0171] In some embodiments, the first reaction mixture is heated to prepare a first solution. In some embodiments, the first solution is cooled to a temperature of about 50° C. to about 55° C., about 55° C. to about 60° C., about 60° C. to about 65° C., about 65° C. to about 70° C., about 70° C. to about 75° C., about 75° C. to about 80° C., about 80° C. to about 85° C., about 85° C. to about 90° C., about 90° C. to about 95° C., about 95° C. to about 100° C., or any range selected between any two of the foregoing values.

[0172] In some embodiments, the first reaction mixture is heated to prepare a first solution, hi some embodiments, the first solution is cooled to a temperature of about 65°C to about 75°C.

[0173] In some embodiments, step (c) comprises combining (R)-proline and water to prepare a second solution, wherein the molar ratio of (R)-proline to the total amount of intermediate I-5 is about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, or about 1.0:1.

[0174] In some embodiments, step (c) comprises combining (R)-proline and water to prepare a second solution, wherein the ratio of (R)-proline:water in the second solution is about 1:10 (w / v), about 1:9 (w / v), about 1:8 (w / v), about 1:7 (w / v), about 1:6 (w / v), about 1:5 (w / v), about 1:4 (w / v), about 1:3 (w / v), about 1:2 (w / v), about 1:1 (w / v), about 2:1 (w / v), about 3:1 (w / v), about 4:1 (w / v), about 5:1 (w / v), about 6:1 (w / v), about 7:1 (w / v), about 8:1 (w / v), about 9:1 (w / v), or about 10:1 (w / v).

[0175] In some embodiments, step (d) comprises adding about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 30%, about 35%, about 40%, about 45%, or less than about 50% by volume of the second solution to the first solution to prepare a second reaction mixture.

[0176] In some embodiments, step (d) includes adding about 5% to about 25% by volume of the second solution to the first solution to prepare a second reaction mixture.

[0177] In some embodiments, step (e) comprises adding a first amount of a nucleation-inducing agent to the second reaction mixture to prepare a third reaction mixture.

[0178] In some embodiments, step (f) includes adding from about 1% to less than about 50% by volume, preferably from about 5% to about 25% by volume, of the second solution to the third reaction mixture to prepare a fourth reaction mixture.

[0179] In some embodiments, step (g) includes adding a second amount of a nucleation-inducing agent to the fourth reaction mixture to prepare a fifth reaction mixture.

[0180] In some embodiments, step (h) includes adding the remainder of the second solution to a fifth reaction mixture to prepare a sixth reaction mixture comprising intermediate I-6.

[0181] In some embodiments, the solvent in the first reaction mixture of the process for preparing intermediate I-6 comprises a mixture of an alcohol solvent and an ether solvent.

[0182] In some embodiments, the solvent in the first reaction mixture of the process for preparing intermediate I-6 comprises a mixture of alcoholic and ethereal solvents, where the alcoholic solvent comprises one or more of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and / or 2-methyl-2-propanol.

[0183] In some embodiments, the solvent in the first reaction mixture of the process for preparing intermediate I-6 comprises a mixture of 2-propanol and 2-methyl-tetrahydrofuran.

[0184] In some embodiments, the process for preparing intermediate I-6 includes adding an agent that induces nucleation. In some embodiments, the agent that induces nucleation is a crystallization promoter. In some embodiments, the crystallization promoter is a seed crystal that includes intermediate I-6.

[0185] In some embodiments, the crystallization promoter is added in one or more portions. In some embodiments, the crystallization promoter is added in one, two, three, four, or five portions. In some embodiments, the crystallization promoter is added in equal amounts across all portions. In some embodiments, the crystallization promoter is added in different amounts across all portions. In some embodiments, the crystallization promoter is added in two portions where about 50% is added, followed by about 50%. In some embodiments, the crystallization promoter is added in two portions where about 25% is added, followed by about 75%. In some embodiments, the crystallization promoter is added in two portions where about 75% is added, followed by about 25%. In some embodiments, the crystallization promoter is added in three portions where about 33% is added, followed by about 33% and then about 33%. In some embodiments, the crystallization promoter is added in three portions, where about 1-25% is added, followed by about 1-33%, followed by about 1-65%. In some embodiments, the crystallization promoter is added in three portions, where about 1-65% is added, followed by about 1-33%, followed by about 1-25%. In some embodiments, the crystallization promoter is added in four portions, where about 25% is added in each portion. In some embodiments, the crystallization promoter is added in four unequal portions. In some embodiments, the crystallization promoter is added in five portions, where about 20% is added in each portion. In some embodiments, the crystallization promoter is added in five unequal portions.

[0186] In some embodiments, crystallization is achieved using any technique known in the art.

[0187] In some embodiments, the method for preparing intermediate I-6 includes adding a crystallization promoter, wherein the molar ratio of the total amount of crystallization promoter compared to intermediate I-6 is from about 0.0001:1 to about 0.01:1, preferably, the molar ratio is from about 0.0005:1 to about 0.005:1.

[0188] In some embodiments, the method for preparing intermediate I-6 comprises adding a crystallization promoter, wherein the molar ratio of the total amount of crystallization promoter compared to intermediate I-6 is about 0.0001:1, about 0.0002:1, about 0.0003:1, about 0.0004:1, about 0.0005:1, about 0.0006:1, about 0.0007:1, about 0.0008:1, about 0.0009:1, about 0.0010:1, about 0.0011:1, about 0.0012:1, about 0.0013:1, about 0.0014:1, about 0.0015:1, about 0.0016:1, about 0.0017:1, about 0.0018:1, about 0.0019:1, about 0.0020:1, about 0.0021:1, about 0.0022:1, about 0.0023:1, about 0.0024:1, about 0.0025:1, about 0.0026:1, about 0.0027:1, about 0.0028:1, about 0.0029:1, about 0.0030:1, about 0.0031:1, about 0.0032:1, about 0.0033:1, about 0.0034:1, about 0.0035:1, about 0.0036:1, about 0.0037:1, about 0.0038:1, about 0.0039:1, about 0.0040:1, about 0.0041:1, about 0.0042:1, about 0.0043 0.0015:1, about 0.0016:1, about 0.0017:1, about 0.0018:1, about 0.0019:1, about 0.0020:1, about 0.0021:1, about 0.0022:1, about 0.0023:1, about 0.0024:1, about 0.0025:1, about 0.0030:1, about 0.0035:1, about 0.0040:1, about 0.0045:1, about 0.0050:1, about 0.0055:1, or about 0.0060:1, or selected from any range between any two of the aforesaid values.

[0189] In some embodiments, the method for preparing intermediate I-6 includes including an additive in the reaction mixture, where the additive is an antioxidant, a radical scavenger, an oxygen scavenger, or a metal chelator.

[0190] In some embodiments, the method for preparing intermediate I-6 includes including an additive in the reaction mixture, where the additive is dibutylhydroxytoluene, ascorbic acid, alpha-tocopherol, or ethylenediaminetetraacetic acid.

[0191] In some embodiments, the method for preparing intermediate I-6 includes including an additive in the reaction mixture, where the additive is dibutylhydroxytoluene.

[0192] In some embodiments, the method for preparing intermediate I-6 includes including an additive in the reaction mixture, where the additive is ascorbic acid.

[0193] In some embodiments, the method for preparing intermediate I-6 includes including an additive in the reaction mixture, where the additive is alpha-tocopherol.

[0194] In some embodiments, the method for preparing intermediate I-6 includes including an additive in the reaction mixture, where the additive is ethylenediaminetetraacetic acid.

[0195] In some embodiments, in the method for preparing intermediate I-6, the molar ratio of the total amount of (R)-proline used in the method to the total amount of intermediate I-5 used in the process is from about 0.40:1 to about 0.90:1, preferably from about 0.50:1 to about 0.75:1.

[0196] In some embodiments, in the method for preparing intermediate I-6, the molar ratio of the total amount of (R)-proline used in the method to the total amount of intermediate I-5 used in the process is about 0.50:1, about 0.51:1, about 0.52:1, about 0.53:1, about 0.54:1, about 0.55:1, about 0.56:1, about 0.57:1, about 0.58:1, about 0.59:1, about 0.60:1, about 0.61:1, about 0.62:1, about 0.63:1, about 0.64:1, about 0.65:1, about 0.66:1, about 0.67:1, about 0.68:1, about 0.69:1, or about 0.70:1.

[0197] In some embodiments, in the method for preparing intermediate I-6, the molar ratio of the total amount of (R)-proline used in the process to the total amount of intermediate I-5 used in the process is about 0.50:1, about 0.51:1, about 0.52:1, about 0.53:1, about 0.54:1, about 0.55:1, about 0.56:1, about 0.57:1, about 0.58:1, about 0.59:1, about 0.60:1, about 0.61:1, about 0.62:1, about 0.63:1, about 0.64:1, about 0.65:1, about 0.66:1, about 0.67:1, about 0.68:1, about 0.69:1, about 0.70:1, about 0.71:1, about 0.72:1, About 0.73:1, about 0.74:1, about 0.75:1, about 0.76:1, about 0.77:1, about 0.78:1, about 0.79:1, about 0.80:1, about 0.81:1, about 0.82:1, about 0.83:1, about 0.84:1, about 0.85:1, about 0.86:1, about 0.87:1, about 0.88:1, about 0.8 9:1, about 0.90:1, about 0.91:1, about 0.92:1, about 0.93:1, about 0.94:1, about 0.95:1, about 0.96:1, about 0.97:1, about 0.98:1, about 0.99:1, about 1.00:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, or about 1.5:1.

[0198] In some embodiments, in the method for preparing intermediate I-6, upon completion of the reaction, the completed reaction is cooled from a temperature of about 50° C. to about 100° C., about 50° C. to about 60° C., about 60° C. to about 70° C., about 70° C. to about 80° C., about 80° C. to about 90° C., or about 90° C. to about 100° C., or any range between any two of the preceding values.

[0199] In some embodiments, in the method for preparing intermediate I-6, upon completion of the reaction, the completed reaction is cooled from a temperature of about 50° C. to about 100° C. to a temperature of about 25° C. at a constant rate of temperature change over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

[0200] In some embodiments, in the process for preparing intermediate I-6, upon cooling of the completed reaction, intermediate I-6 is recovered by filtration, washed with a solvent, and dried.

[0201] In some embodiments, in the process for preparing intermediate I-6, upon cooling of the completed reaction, intermediate I-6 is recovered by filtration and washed with alcohol.

[0202] In some embodiments, in the method for preparing intermediate I-6, upon cooling of the completed reaction, intermediate I-6 is recovered by filtration, washed with 2-propanol, and dried.

[0203] In some embodiments, intermediate I-6 is dried under vacuum.

[0204] In some embodiments, intermediate I-6 is dried under vacuum at a temperature of about 30° C., about 35° C., about 40° C., about 45° C., about 50° C., about 55° C., about 60° C., or selected from any range between any two of the preceding values.

[0205] In some embodiments, intermediate I-6 is dried under vacuum at a temperature of about 40° C. to about 50° C.

[0206] Intermediate I-6A In some embodiments, provided herein is a method for intermediate I-6A, the method including providing intermediate I-5 and performing chiral supercritical chromatography to obtain intermediate I-6A. [ka]

[0207] In some embodiments, intermediate I-6A can be substituted for intermediate I-6 in the preparation of intermediate I-9 in the method of preparing compound 1.

[0208] In some embodiments, a method for preparing intermediate I-9 includes providing a mixture comprising intermediate I-6A, a solvent, and an acid to provide intermediate I-9. [ka]

[0209] Intermediate I-8 In some embodiments, disclosed herein is a method for preparing salt intermediate I-8, comprising providing a mixture comprising intermediate I-4, camphorsulfonic acid, and a solvent to provide salt intermediate I-8. [ka]

[0210] In some embodiments, the molar ratio of camphorsulfonic acid to intermediate I-4 in the reaction mixture is from about 1:1 to about 5:1, from about 1:1 to about 4:1, from about 1:1 to about 3:1, or from about 1:1 to about 2:1.

[0211] In some embodiments, the molar ratio of camphorsulfonic acid to intermediate I-4 in the reaction mixture is from about 1.5:1 to about 2.5:1.

[0212] In some embodiments, the molar ratio of camphorsulfonic acid to intermediate I-4 in the reaction mixture is from about 1:1 to about 3:1, preferably from about 1.5:1 to about 2.5:1.

[0213] In some embodiments, the molar ratio of camphorsulfonic acid to intermediate I-4 in the reaction mixture is about 1.50:1, about 1.55:1, about 1.60:1, about 1.65:1, about 1.70:1, about 1.75:1, about 1.80:1, about 1.85:1, about 1.90:1, about 1.95:1, about 2.00:1, about 2.05:1, about 2.10:1, about 2.15:1, about 2.20:1, about 2.25:1, about 2.30:1, about 2.35:1, about 2.40:1, about 2.45:1, about 2.50:1, or any range between any two of the preceding values.

[0214] In some embodiments, the camphorsulfonic acid in the reaction mixture is (+)-camphorsulfonic acid.

[0215] In some embodiments, the solvent comprises acetonitrile.

[0216] In some embodiments, the solvent comprises dimethylformamide.

[0217] In some embodiments, the solvent comprises a mixture of acetonitrile and dimethylformamide.

[0218] In some embodiments, the solvent comprises acetonitrile, dimethylformamide, or a mixture thereof.

[0219] In some embodiments, the solvent comprises acetonitrile and dimethylformamide in a ratio of about 10:1 (v / v), about 9:1 (v / v), about 8:1 (v / v), about 7:1 (v / v), about 6:1 (v / v), about 5:1 (v / v), about 4:1 (v / v), about 3:1 (v / v), about 2:1 (v / v), about 1:1 (v / v), about 1:2 (v / v), about 1:3 (v / v), about 1:4 (v / v), about 1:5 (v / v), about 1:6 (v / v), about 1:7 (v / v), about 1:8 (v / v), about 1:9 (v / v), or about 1:10 (v / v).

[0220] In some embodiments, the solvent comprises acetonitrile and dimethylformamide in a ratio of about 1:1 (v / v) to about 8:1 (v / v), preferably about 2:1 (v / v) to about 6:1 (v / v).

[0221] In some embodiments, the reaction to prepare intermediate I-8 is carried out at a temperature of about 70°C to about 100°C, preferably about 85°C to about 100°C.

[0222] In some embodiments, the reaction to prepare intermediate I-8 is carried out at a temperature of about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, or about 100°C.

[0223] In some embodiments, the reaction to prepare intermediate I-8 is carried out at a temperature of about 85°C to about 100°C.

[0224] In some embodiments, the reaction to prepare intermediate I-8 is carried out at a temperature of about 90°C, about 95°C, or about 100°C.

[0225] In some embodiments, the reaction to prepare intermediate I-8 is carried out under conditions that promote the azeotropic removal of solvent and one or more by-products of the reaction from the reaction mixture. In some embodiments, the one or more by-products of the reaction that are azeotropically removed from the reaction mixture include water and tert-butanol.

[0226] Intermediate I-4 In some aspects, disclosed herein is a method for preparing intermediate I-4, comprising providing a mixture comprising intermediate I-3, intermediate I-3A, and a solvent, to which a reducing agent is added under reaction conditions to obtain intermediate I-4. [ka]

[0227] In some embodiments, the solvent in the process for preparing intermediate I-4 comprises a protic solvent.

[0228] In some embodiments, the solvent in the process for preparing intermediate I-4 comprises a C1-C6 alcohol.

[0229] In some embodiments, the solvent in the process for preparing intermediate I-4 comprises one or more of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol.

[0230] In some embodiments, the solvent in the process for preparing intermediate I-4 comprises methanol.

[0231] In some embodiments, the solvent in the process for preparing intermediate I-4 further comprises an acid, preferably acetic acid.

[0232] In some embodiments, the solvent in the process for preparing intermediate I-4 further comprises acetic acid.

[0233] In some embodiments, the solvent in the process for preparing intermediate I-4 comprises one or more of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and / or 2-methyl-2-propanol, and the solvent further comprises an acid.

[0234] In some embodiments, the solvent in the process for preparing intermediate I-4 comprises one or more of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and / or 2-methyl-2-propanol, and the solvent further comprises acetic acid.

[0235] In some embodiments, the solvent in the process for preparing intermediate I-4 comprises methanol and the solvent further comprises acetic acid.

[0236] In some embodiments, the reducing agent in the method for preparing intermediate I-4 is added to the reaction mixture as a solution in methanol.

[0237] In some embodiments, the reducing agent in the method for preparing intermediate I-4 is added to the reaction mixture as a solution in an alcohol solvent, the reducing agent is about 1% w / w in the alcohol solvent, about 2% w / w in the alcohol solvent, about 3% w / w in the alcohol solvent, about 4% w / w in the alcohol solvent, about 5% w / w in the alcohol solvent, about 6% w / w in the alcohol solvent, about 7% w / w in the alcohol solvent, about 8% w / w in the alcohol solvent, about 9% w / w in the alcohol solvent, about 10% w / w in the alcohol solvent, about 11% w / w in the alcohol solvent, about 12% w / w in the alcohol solvent, about 13% w / w in the alcohol solvent, about 14% w / w in the alcohol solvent, about 15% w / w in the alcohol solvent, about 16% w / w in the alcohol solvent, The alcoholic solvent is present at about 16.1% w / w in the alcoholic solvent, about 16.2% w / w in the alcoholic solvent, about 16.3% w / w in the alcoholic solvent, about 16.4% w / w in the alcoholic solvent, about 16.5% w / w in the alcoholic solvent, about 16.6% w / w in the alcoholic solvent, about 16.7% w / w in the alcoholic solvent, about 16.8% w / w in the alcoholic solvent, about 16.9% w / w in the alcoholic solvent, about 17% w / w in the alcoholic solvent, about 18% w / w in the alcoholic solvent, about 19% w / w in the alcoholic solvent, about 20% w / w in the alcoholic solvent, about 21% w / w in the alcoholic solvent, about 22% w / w in the alcoholic solvent, about 23% w / w in the alcoholic solvent, about 24% w / w in the alcoholic solvent, or about 25% w / w in the alcoholic solvent.

[0238] In some embodiments, the reducing agent in the method for preparing intermediate I-4 is added to the reaction mixture as a solution in an alcohol solvent, the reducing agent is sodium cyanoborohydride, about 1% w / w in alcohol solvent, about 2% w / w in alcohol solvent, about 3% w / w in alcohol solvent, about 4% w / w in alcohol solvent, about 5% w / w in alcohol solvent, about 6% w / w in alcohol solvent, about 7% w / w in alcohol solvent, about 8% w / w in alcohol solvent, about 9% w / w in alcohol solvent, about 10% w / w in alcohol solvent, about 11% w / w in alcohol solvent, about 12% w / w in alcohol solvent, about 13% w / w in alcohol solvent, about 14% w / w in alcohol solvent, about 15% w / w in alcohol solvent, about 16% w / w in alcohol solvent, about 17% w / w in alcohol solvent, about 18% w / w in alcohol solvent, about 19% w / w in alcohol solvent, about 20% w / w in alcohol solvent, about 21% w / w in alcohol solvent, about 22% w / w in alcohol solvent, about 23% w / w in alcohol solvent, about 24% w / w in alcohol solvent, about 25% w / w in alcohol solvent, about 26% w / w in alcohol solvent, about 27% w / w in alcohol solvent, about 28% w / w in alcohol solvent, about 29% w / w in alcohol solvent, about 30% w / w in alcohol solvent, about 31% w / w in alcohol solvent, about 32% w / w in alcohol solvent, about 33% w / w in alcohol solvent, about 34% w / w in alcohol solvent, about 35% w / w in alcohol solvent, about 36% w / w in alcohol solvent, about 37% w / w in alcohol solvent, about 38% w / w in alcohol solvent, about 39% w / w in alcohol solvent, about 40% w / w in about 16% w / w in alcoholic solvent, about 16.1% w / w in alcoholic solvent, about 16.2% w / w in alcoholic solvent, about 16.3% w / w in alcoholic solvent, about 16.4% w / w in alcoholic solvent, about 16.5% w / w in alcoholic solvent, about 16.6% w / w in alcoholic solvent, about 16.7% w / w in alcoholic solvent, about 16.8% w / w in alcoholic solvent, about 16.9% w / w in alcoholic solvent, about 17% w / w in alcoholic solvent, about 18% w / w in alcoholic solvent, about 19% w / w in alcoholic solvent, about 20% w / w in alcoholic solvent, about 21% w / w in alcoholic solvent, about 22% w / w in alcoholic solvent, about 23% w / w in alcoholic solvent, about 24% w / w in alcoholic solvent, or about 25% w / w in alcoholic solvent.

[0239] In some embodiments, the reducing agent in the method for preparing intermediate I-4 is added to the reaction mixture as a solution in methanol, wherein the reducing agent is present at about 1% in methanol, about 2% w / w methanol, about 3% w / w methanol, about 4% w / w in methanol, about 5% w / w in methanol, about 6% w / w in methanol, about 7% w / w in methanol, about 8% w / w in methanol, about 9% w / w in methanol, about 10% w / w in methanol, about 11% w / w in methanol, about 12% w / w in methanol, about 13% w / w in methanol, about 14% w / w in methanol, about 15% w / w methanol, about 16% w / w in methanol, about 17% w / w in methanol, about 18% w / w in methanol, about 19% w / w in methanol, or about 20% w / w in methanol.

[0240] In some embodiments, the reducing agent in the method for preparing intermediate I-4 is added to the reaction mixture as a solution in methanol, and the reducing agent is sodium cyanoborohydride and is present at about 1% in methanol, about 2% w / w methanol, about 3% w / w methanol, about 4% w / w in methanol, about 5% w / w in methanol, about 6% w / w in methanol, about 7% w / w in methanol, about 8% w / w in methanol, about 9% w / w in methanol, about 10% w / w in methanol, about 11% w / w in methanol, about 12% w / w in methanol, about 13% w / w in methanol, about 14% w / w in methanol, about 15% w / w methanol, about 16% w / w in methanol, about 17% w / w in methanol, about 18% w / w in methanol, about 19% w / w in methanol, or about 20% w / w in methanol.

[0241] In some embodiments, the reducing agent in the method of preparing intermediate I-4 is added to the reaction mixture as a solution in methanol, and the reducing agent is sodium cyanoborohydride and is present at about 1% w / w to about 5% w / w in methanol, about 5% w / w to about 10% w / w in methanol, about 10% w / w to about 15% w / w in methanol, or about 15% w / w to about 20% w / w in methanol.

[0242] In some embodiments, the reducing agent used in the method of preparing intermediate I-4 is added to the reaction mixture as a solution in methanol, and the reducing agent is sodium cyanoborohydride and is present at about 1% w / w to about 10% w / w in methanol, or about 5% w / w to about 15% w / w in methanol, or about 10% w / w to about 20% w / w in methanol.

[0243] In some embodiments, in the method for preparing intermediate I-4, the reaction mixture is cooled to a temperature of about 0° C. to about 30° C. prior to the initiation of addition of the reducing agent solution to the reaction mixture.

[0244] In some embodiments, in the method for preparing intermediate I-4, the reaction mixture is cooled to a temperature of about 0° C., about 5° C., about 10° C., about 15° C., about 20° C., about 25° C., or about 30° C. prior to the initiation of addition of the reducing agent solution to the reaction mixture.

[0245] In some embodiments, in the method for preparing intermediate I-4, the reaction mixture is cooled to a temperature of about 0° C. to about 10° C. prior to the initiation of addition of the reducing agent solution to the reaction mixture.

[0246] In some embodiments, in the method for preparing intermediate I-4, prior to the start of the addition of the reducing agent solution to the reaction mixture, the reaction mixture is cooled to a temperature of about 0° C. to about 30° C., and the temperature of the reaction mixture is maintained at that temperature throughout the addition of the reducing agent solution.

[0247] In some embodiments, in the method for preparing intermediate I-4, prior to the start of the addition of the reducing agent solution to the reaction mixture, the reaction mixture is cooled to a temperature of about 0° C., about 5° C., about 10° C., about 15° C., about 20° C., about 25° C., or about 30° C., and the temperature of the reaction mixture is maintained at that temperature throughout the addition of the reducing agent solution.

[0248] In some embodiments, in the method for preparing intermediate I-4, prior to the start of the addition of the reducing agent solution to the reaction mixture, the reaction mixture is cooled to a temperature of about 0° C. to about 10° C., and the temperature of the reaction mixture is maintained at that temperature throughout the addition of the reducing agent solution.

[0249] In some embodiments, in the method for preparing intermediate I-4, upon completion of the addition of the reducing agent solution to the reaction mixture, the reaction mixture is heated to a temperature of about 15° C., about 20° C., about 25° C., about 30° C., about 35° C., or about 40° C.

[0250] In some embodiments, in the method for preparing intermediate I-4, upon completion of the addition of the reducing agent solution to the reaction mixture, the reaction mixture is heated to a temperature of about 20° C. to about 30° C.

[0251] In some embodiments, the reducing agent used in the process for preparing intermediate I-4 is sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, or hydrogen in the presence of a catalyst.

[0252] In some embodiments, the reducing agent used in the process for preparing intermediate I-4 is sodium triacetoxyborohydride.

[0253] In some embodiments, the reducing agent used in the process for preparing intermediate I-4 is sodium borohydride.

[0254] In some embodiments, the reducing agent used in the process for preparing intermediate I-4 is sodium cyanoborohydride.

[0255] In some embodiments, the reducing agent used in the process for preparing intermediate I-4 is hydrogen in the presence of a catalyst.

[0256] Intermediate I-3 In some embodiments, disclosed herein is a method for preparing intermediate I-3, comprising providing a mixture comprising intermediate I-2, a reducing agent, and a solvent, and subsequently heating the mixture to provide intermediate I-3. [ka]

[0257] In some embodiments, the solvent for preparing intermediate I-3 comprises water, an acid, pyridine, or a combination thereof.

[0258] In some embodiments, the solvent for preparing intermediate I-3 comprises water.

[0259] In some embodiments, the solvent for preparing intermediate I-3 comprises water and an acid.

[0260] In some embodiments, the solvent for preparing intermediate I-3 comprises pyridine.

[0261] In some embodiments, the solvent for preparing intermediate I-3 comprises water and pyridine.

[0262] In some embodiments, the solvent for preparing intermediate I-3 comprises an acid.

[0263] In some embodiments, the solvent for preparing intermediate I-3 comprises acetic acid.

[0264] In some embodiments, the solvent for preparing intermediate I-3 comprises water and acetic acid.

[0265] In some embodiments, the reducing agent for preparing intermediate I-3 is Raney nickel.

[0266] In some embodiments, the reaction mixture for preparing intermediate I-3 is at a temperature of about 15°C to about 30°C before heating.

[0267] In some embodiments, the reaction mixture for preparing intermediate I-3 is at a temperature of about 20°C to about 30°C before heating.

[0268] In some embodiments, the reaction mixture for preparing intermediate I-3 prior to heating is at a temperature of about 15° C., about 20° C., about 25° C., about 30° C., about 35° C., or selected from any range between any two of the preceding values.

[0269] In some embodiments, the reaction mixture for preparing intermediate I-3 is at a temperature of about 25° C. before heating.

[0270] In some embodiments, the reaction mixture for preparing intermediate I-3 is heated to a temperature of about 40°C to about 70°C.

[0271] In some embodiments, the reaction mixture for preparing intermediate I-3 is heated to a temperature of about 50°C to about 60°C.

[0272] In some embodiments, the reaction mixture for preparing intermediate I-3 is heated to a temperature of about 40° C., about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., or selected from any range between any two of the preceding values.

[0273] Intermediate I-3A In some embodiments, disclosed herein is a method for preparing intermediate I-3A, comprising providing a mixture comprising intermediate I-2A, a solvent, and a hydrogen source under conditions that provide hydrogenolysis of intermediate I-2A to provide intermediate I-3A. [ka]

[0274] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises a catalyst.

[0275] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises a transition metal catalyst.

[0276] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises a transition metal catalyst, wherein the transition metal is palladium, rhodium, ruthenium, iridium, or copper.

[0277] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises a transition metal catalyst, and the transition metal is palladium.

[0278] In some embodiments, the reaction mixture in the process for preparing intermediate I-3 further comprises a transition metal catalyst, and the transition metal is rhodium.

[0279] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises a transition metal catalyst, and the transition metal is ruthenium.

[0280] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises a transition metal catalyst, and the transition metal is iridium.

[0281] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises a transition metal catalyst, and the transition metal is copper.

[0282] In some embodiments, the reaction mixture in the method for preparing intermediate I-3A further comprises a transition metal catalyst, wherein the catalyst is Pd(OH) 2 .

[0283] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises a hydrogen source, and the hydrogen source in the reaction mixture is hydrogen gas.

[0284] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises a hydrogen source, and the hydrogen source is catalytic transfer hydrogenation.

[0285] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises hydrogen gas, and the hydrogen gas in the reaction mixture is maintained at about 0.5 MPa to about 1.5 MPa.

[0286] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises hydrogen gas, and the hydrogen gas in the reaction mixture is maintained at about 0.5 Mpa, about 0.6 Mpa, about 0.7 Mpa, about 0.8 Mpa, about 0.9 Mpa, about 1.0 Mpa, about 1.1 Mpa, about 1.2 Mpa, about 1.3 Mpa, about 1.4 Mpa, or about 1.5 Mpa, or selected from any range between any two of the preceding values.

[0287] In some embodiments, the reaction mixture in the process for preparing intermediate I-3A further comprises hydrogen gas, and the hydrogen gas in the reaction mixture is maintained at about 0.75 MPa to about 1.25 MPa.

[0288] In some embodiments, the method of preparing compound 1 includes preparing intermediate I-9 by providing a mixture comprising intermediate I-6, a solvent, and an acid to provide intermediate I-9. [ka]

[0289] In some embodiments, the method of preparing compound 1 comprises: [ka] (a) combining racemic intermediate I-5 and an additive with a solvent to prepare a first reaction mixture; (b) heating the first reaction mixture at reflux to prepare a first solution, and subsequently cooling the first solution to a temperature of about 50° C. to about 100° C., preferably about 65° C. to about 75° C.; (c) combining (R)-proline and water to prepare a second solution, wherein the molar ratio of the total amount of (R)-proline used in the process to the total amount of intermediate I-5 used in the process is from about 0.40:1 to about 1.00:1; (d) adding about 1% to less than about 50% by volume, preferably about 5% to about 25% by volume, of the second solution to the first solution to prepare a second reaction mixture; (e) adding a first amount of a nucleation-inducing agent to the second reaction mixture to form a third reaction mixture; (f) adding from about 1% to less than about 50% by volume, preferably from about 5% to about 25% by volume, of the second solution to the third reaction mixture to prepare a fourth reaction mixture; (g) adding a second amount of a nucleation inducing agent to the fourth reaction mixture to form a fifth reaction mixture; (h) adding the remainder of the second solution to the fifth reaction mixture to prepare a sixth reaction mixture comprising intermediate I-6, thereby preparing intermediate I-6.

[0290] In some embodiments, the method of preparing compound 1 includes preparing intermediate I-8 by providing a mixture comprising intermediate I-4, camphorsulfonic acid, and a solvent to provide intermediate I-8. [ka]

[0291] In some embodiments, the camphorsulfonic acid is racemic camphorsulfonic acid.

[0292] In some embodiments, the camphorsulfonic acid is (+)-camphorsulfonic acid.

[0293] In some embodiments, the camphorsulfonic acid is (-)-camphorsulfonic acid.

[0294] In some embodiments, the method of preparing intermediate I-8 includes adding camphorsulfonic acid in a ratio of about 0:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:0 of ​​(+)-camphorsulfonic acid:(-)-camphorsulfonic acid.

[0295] In some embodiments, the method of preparing compound 1 includes preparing intermediate I-4, comprising providing a mixture comprising intermediate I-3, intermediate I-3A, and a solvent, to which a reducing agent is added under reaction conditions to provide intermediate I-4. [ka]

[0296] In some embodiments, the method of preparing compound 1 includes preparing intermediate I-3 by heating a mixture of intermediate I-2, a reducing agent, and a solvent to provide intermediate I-3. [ka]

[0297] In some embodiments, a method of preparing compound 1 includes preparing intermediate I-3A by providing a mixture of intermediate I-2A, a solvent, and a hydrogen source under conditions that effect hydrogenolysis of intermediate I-2A to provide intermediate I-3A. [ka]

[0298] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used herein is intended to describe particular embodiments only and is not intended to be limiting of the disclosure.

[0299] Where a range of values ​​is disclosed herein, the disclosure is understood to encompass each intervening value from the upper limit to the lower limit, to the nearest tenth of the lower limit (such as in the case of groups including the number of carbon atoms, in such cases an integer falling within the range is provided), and any other stated or intervening value in that stated range, unless the context clearly indicates otherwise. As a non-limiting example, the range of 1 to 10 includes each of 1.0, 1.1, 1.2, 1.3, etc. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges, which are also subject to any specifically excluded limit of the stated range and are also included within the disclosure. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0300] The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term is given its art-recognized meaning by those of ordinary skill in the art who apply the term in the context of its use in describing this disclosure.

[0301] As used herein, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0302] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "both, or either" of the elements so conjoined. That is, in some cases the elements are conjointly present and in other cases they are non-conjoined. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements are so conjoined. Other elements other than the elements specifically identified by the "and / or" clause may optionally be present, whether related or not to those specifically identified elements. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," may refer in one embodiment to only A (optionally including elements other than B), in another embodiment to only B (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), etc.

[0303] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as inclusive, i.e., including at least one of a number or list of elements, but optionally including more than one, and optionally including additional items not listed. Only terms that clearly suggest the contrary, such as "only one of," or "exactly one of," or, when used in the claims, "consisting of," refer to the inclusion of exactly one element of a number or list of elements. In general, as used herein, the term "or" should be interpreted to indicate exclusive alternatives (i.e., "one or the other, but not both") only when preceded by an exclusive term, such as, for example, "either," "one of," "only one of," or "exactly one of."

[0304] In the claims, as well as in the above specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are to be understood to be open-ended, i.e., inclusive but not exclusive. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the U.S. Patent and Trademark Office's Patent Examining Handbook, Ninth Edition, Revised October 2019, Section 2111.03.

[0305] As used herein, in the specification and claims, the phrase "at least one" in reference to a list of one or more elements means at least one element selected from any one or more of the list of elements, but does not necessarily include at least one of all elements specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. Furthermore, this definition allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether or not related to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one, optionally, two or more A, and no B (and optionally including elements other than B); in another embodiment to at least one, optionally, two or more B, and no A (and optionally including elements other than A); and in yet another embodiment to at least one, optionally, two or more A, and at least one, optionally, two or more B (and optionally including other elements).

[0306] In certain methods described herein that include two or more steps or actions, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited, unless otherwise indicated by context.

[0307] As used herein, the term "hydrogenolysis" refers to a chemical reaction in which a carbon-carbon or carbon-heteroatom single bond is broken or undergoes dissolution (destruction) by hydrogen. The heteroatom can vary, but is usually oxygen, nitrogen, or sulfur. A related reaction is hydrogenation, in which hydrogen is added to a molecule without breaking the bond. Hydrogenation is a chemical reaction between molecular hydrogen and an element or compound, usually in the presence of a catalyst. The reaction may be one in which hydrogen simply adds a double or triple bond connecting two atoms in the structure of the molecule, or one in which the addition of hydrogen results in the dissociation (decomposition) of the molecule (called hydrolysis or destructive hydrogenation). The most commonly used catalysts for hydrogenation reactions are the metals nickel, platinum, and palladium, and their oxides. For high pressure hydrogenation, copper and nickel chromate supported on diatomaceous earth (loose or porous diatomaceous earth) can be used.

[0308] As used herein, the term "mixture" or "reaction mixture" means a combination of two or more compounds, usually in a solvent, that is about to undergo, is in the process of undergoing, or has undergone a chemical reaction.

[0309] As used herein, the term "reaction" refers to a process that leads to the chemical conversion of one set of chemicals to another set. As used herein, the term "react" refers to the bringing together of chemicals to result in a chemical reaction.

[0310] As used herein, the terms "cooling" or "cooled" or "cooling" mean either passively allowing by heat dissipation or actively acting by using water or a heat sink (ice, dry ice, etc.) to reduce the temperature of an object, mixture, reaction mixture, concentrate, etc.

[0311] As used herein, the term "reducing agent" refers to a compound that loses (or "donates") electrons to an electron acceptor (oxidant) in a redox chemical reaction. Reducing agents include those generally known in the art, including, for example, sodium hypophosphite (NaH2PO2), formaldehyde (CHO) and other aldehydes, formic acid (HCOOH), salts of formic acid, salts of borohydrides (e.g., sodium borohydride (NaBH4)), salts of substituted borohydrides (e.g., sodium triacetoxyborohydride (Na(CH3CO2)3BH)), sodium alkoxides, lithium aluminum hydride (LiAlH4), diisobutylaluminum hydride (DIBAH), hydrazine (H2NNH2), and ammonia. Catalytic hydrogenation is also used for reduction.

[0312] As used herein, the term "camphorsulfonic acid" refers to camphorsulfonic acid, pure (+)-camphorsulfonic acid, pure (-)-camphorsulfonic acid, or a racemic mixture of various ratios of (+)-camphorsulfonic acid:(-)-camphorsulfonic acid, depending on the context.

[0313] As used herein, the term "nucleation inducing agent" refers to any object, substance, or action that results in primary or secondary nucleation. Primary nucleation is the initial formation of crystals in the absence of other crystals or that does not have any effect on the crystallization process if any crystals are present in the system. It can occur in two conditions. The first condition is homogeneous nucleation, which is nucleation that is not affected in any way by solids. These solids include the walls of the crystallization vessel and any foreign material. The second category is heterogeneous nucleation, which occurs when solid particles of foreign material (e.g., any material that is physically or chemically different from the crystals being formed) cause an increase in the nucleation rate that would not otherwise occur without the presence of these foreign materials. Homogeneous nucleation occurs rarely in practice due to the high energy required to initiate nucleation without a solid surface to catalyze nucleation. Secondary nucleation is when crystal growth is initiated upon contact with other pre-existing crystals or "seeds". The first type of known secondary crystallization is due to fluid shear. The second type results from collisions between already existing crystals, either with the solid surface of the crystallizer or with other crystals themselves. Other agents that induce nucleation include devices such as DTB crystallizers, evaporative crystallizers, or cooling crystallizers (e.g., Swenson-Walker crystallizers).

[0314] As used herein, the term "crystallization promoter" refers to an agent or material that can promote the solidification of a compound from a solution. In some embodiments, "crystallization promoter" refers to a seed crystal. In some embodiments, a crystallization promoter can be obtained by scratching against a glass surface to provide a surface area for crystallization. In some embodiments, sonication can promote the crystallization of a compound in a solution. In some embodiments, evaporation or solvent transfer crystallization can be used. Solvent layering can promote crystallization at the interface, which in turn promotes the crystallization of the compound of interest. Vapor diffusion (such as the hanging drop method and the sitting drop method), and batch methods of crystallization, for example, can be used. Seed crystals can be small pieces of single or polycrystalline material from which typically larger crystals of the same material grow. When used to replicate materials, the use of seed crystals to promote crystal growth avoids the otherwise slow randomness of natural crystal growth and allows for manufacturing on a scale suitable for industry. Other agents that promote crystallization include devices such as DTB crystallizers, evaporative crystallizers, or cooling crystallizers (e.g., Swenson-Walker crystallizers).

[0315] As used herein, the term "hydrogen source" refers to a catalyst capable of directly carrying out a hydrogenation reaction with the required input of H2 gas. Specifically, transfer hydrogenation is the addition of hydrogen (H2; dihydrogen in inorganic and organometallic chemistry) to a molecule from a source other than gaseous H2. It is applied in industry and organic synthesis, in part due to the inconvenience and expense of using gaseous H2. Hydrogen transfer catalysts have been developed based on ruthenium and rhodium complexes, often with diamine and phosphine ligands. Representative catalyst precursors are derived from (cymene)ruthenium dichloride dimer and tosylated diphenylethylenediamine. These catalysts are primarily used for the reduction of ketones and imines to alcohols and amines, respectively. The hydrogen donor (transfer agent) can be isopropanol, which is converted to acetone upon donation of hydrogen. Transfer hydrogenation can proceed with high enantioselectivity when the starting material is pristine.

[0316] As used herein, the term "antioxidant" refers to a compound that can neutralize free radicals by accepting or donating electrons to remove unpaired radicals that may be formed during a chemical reaction. Antioxidant molecules react directly with reactive radicals to destroy them, while they may become new free radicals that are less active, longer-lived, and less dangerous than the radicals they neutralize. They may be neutralized by other antioxidants or other mechanisms to terminate their radical state. For example, many antioxidants have aromatic ring structures and can delocalize the unpaired electron. Many antioxidants may react directly with any free ROS and / or free radical intermediates induced by liberated reactive oxygen species (ROS), terminating the chain reaction and thereby stopping the ROS-induced damage that may occur in a chemical reaction.

[0317] As used herein, the term "radical scavenger" refers to a compound that reacts with free radicals. Free radicals can cause auto-oxidation in the reaction mixture. Radical scavengers overlap with antioxidants and include naturally occurring tocopherols (vitamin E derivatives) as well as synthetic compounds such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and tertiary butyl hydroquinone (TBHQ), among others. Radical scavengers also include 1,2,2,6,6-pentamethylpiperidinyl methacrylate, 2,2,6,6-tetramethylpiperidinyl methacrylate, bis(2,2,6,6-tetramethyl-4-piperidine) sebacate, polymers of dimethyl succinate and 4-hydroxy-2,2,6,6,-tetramethyl-1-piperidineethanol, N,N',N",N"'-tetrakis-(4,6-bis-(butyl-(N-methyl))-propanol, and 1,2,2,6,6-tetrakis-(4,6-bis-(butyl-(N-methyl))-propanol. (ethyl-2,2,6,6-tetramethylpiperidin-4-yl)amino)-triazin-2-yl)-4,7-diazadecane-1,10-diamine, decanedioic acid bis(2,2,6,6-tetramethyl-1-(octyloxy)-4-piperidinyl) ester, bis(1,2,2,6,6-pentamethyl-4-piperidinyl)[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]butylmalonate, The reaction product of cyclohexane and the reaction product between peroxide N-butyl-2,2,6,6-tetramethyl-4-piperidinamine-2,4,6-trichloro-1,3,5-triazine and 2-aminoethanol (e.g., TINUVIN 152 manufactured by BASF Japan Ltd.), bis(1,2,2,6,6-pentamethyl-4-piperidinyl) sebacate, methyl-1,2,2,6,6-pentamethyl-4-piperidinyl Lysyl sebacate, tetrakis(1,2,2,6,6-pentamethyl-4-piperidine)-1,2,3,4-butanetetracarboxylate, 2-t-butyl-4-methoxyphenol, 3-t-butyl-4-methoxyphenol, 2,6-di-t-butyl-4-ethylphenol, 2,2'-methylene-bis(4-methyl-6-t-butylphenol), 4,4'-thiobis-(3-methyl-6-t-butylphenol), 4,4'-butylidenebis(3-methyl-6-t-butylphenol), 1,1,3-tris(2-methyl-4-hydroxy-5-t-butylphenyl)butane, 1,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)benzene, tetrakis[methylene-3-(3',5'-di-t-butyl-4'-hydroxyphenyl)propionate]methane, triphenyl phosphite, diphenyl isodecyl phosphite, phenyl diisodecyl phosphite, 4,4'-butylidene-bis(3-methyl-6-t-butylphenyl ditridecyl)phosphite, cyclic deneopentane tetrayl bis(nonylphenyl)phospha cyclic deneopentanetetraylbis(dinonylphenyl)phosphite, cyclic deneopentanetetrayltris(nonylphenyl)phosphite, cyclic deneopentanetetrayltris(dinonylphenyl)phosphite, 10-(2,5-dihydroxyphenyl)-10H-9-oxa-10-phosphaphenanthrene-10-oxide, diisodecyl pentaerythritol diphosphite, and one or more of tris(2,4-di-t-butylphenyl)phosphite, dilauryl 3,3'-thiodipropionate, distearyl 3,3'-thiodipropionate, N-cyclohexylthiophthalimide, and Nn-butylbenzenesulfonamide.

[0318] As used herein, the term "remainder," when used to refer to a solution or mixture, refers to what remains of the solution or mixture after any previous steps involving the solution or mixture have been performed. As a non-limiting example, a process may involve the addition of a solution in portions, where a first amount of the solution is administered first and the remaining solution is administered later. The remainder of the solution or mixture may include 0% to 100% of the original volume or solution or mixture. If a step of a process refers to the remainder of a solution or mixture and a previous step has consumed the entirety of the solution or mixture, then the "remainder" is 0% and none of the solution or mixture is used in that step.

[0319] As used herein, the term "oxygen scavenger" refers to a material that can combine with oxygen to reduce or completely remove the oxygen content in a reaction mixture or fluid. By limiting the amount of oxygen present, oxygen scavengers can reduce the number of decomposition reactions that can result in reduced yields, reduced % conversion, and / or reduced purity of a particular reaction.

[0320] As used herein, the term "metal chelator" refers to a compound capable of binding to a metal ion. Typically, metal chelation involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple-binding) ligand and a single central atom. Metal chelators include cyclic or acyclic polyaminocarboxylic acids such as DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), DTPA-bismethylamide, DTPA-bismorpholinamide, DO3A N-[[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetyl], HP-DO3A, DO3A-monoamide, and derivatives thereof. Other chelating agents known in the art include, but are not limited to, HYNIC, DTPA, EDTA, TETA, and bisaminobisthiol (BAT) chelating agents (see also U.S. Patent No. 5,720,934).For example, macrocyclic chelating agents, particularly N4 chelating agents, are described in U.S. Patent Nos. 4,885,363, 5,846,519, 5,474,756, 6,143,274, 6,093,382, 5,608,110, 5,665,329, 5,656,254, and 5,688,487, the disclosures of which are incorporated herein by reference in their entirety. Certain N3S chelators are described in PCT / CA94 / 00395, PCT / CA94 / 00479, PCT / CA95 / 00249, and U.S. Patent Nos. 5,662,885, 5,976,495, and 5,780,006, the disclosures of which are incorporated herein by reference in their entireties. Chelators can also include the N3S-containing chelating ligand mercapto-acetyl-glycyl-glycyl-glycine (MAG3), and derivatives of the N2S2 series, such as MAMA (monoamide monoamine dithiol), DADS (N2S diamine dithiol), etc.

[0321] As used herein, the term "protic solvent" refers to a solvent that contains a hydrogen atom bonded to an electronegative element. Examples of these are alcohols, amines (amines being understood to mean aliphatic and cycloaliphatic amines), acid amides, and carboxylic acids, in addition to water. These may in particular be lower alcohols, such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and / or 2-methyl-2-propanol. Protic solvents also include glycols, amines, acid amides and carboxylic acids, preferably glycols such as monoethylene glycol, diethylene glycol, mono-1,2-propylene glycol, di-1,2-propylene glycol, 1,2-butylene glycol, 2,3-butylene glycol and / or glycerol, and amines such as methylamine, ethylamine, n-propylamine, i-propylamine, n-butylamine, dimethylamine, diethylamine, di-n-propylamine, di-n-butylamine, pyrrolidine, piperidine, piperazine, N-methyl-piperazine, N-ethylpiperazine, morpholine, ethylenediamine, 1,2-propylenediamine, 1,3-propylenediamine, di-(2-cyanoethyl)amine, di-(2-amino-ethyl)amine, tri-(2-aminoethyl)amine, ethanolamine, diethanolamine, triethanolamine, propanolamine, dipropanolamine and / or tripropanolamine. The protic solvents can be used as a mixture or individually, this applies in particular to the mixture of water in the case of alcohols.

[0322] As used herein, the term "azeotropic removal" or "azeotropic distillation" refers to techniques that exploit interactions between components of a solution to create unique properties in the solution, since most processes involve non-ideal mixtures where Raoult's law does not hold. Such interactions can result in constant-boiling azeotropes, which behave as if they were pure compounds (i.e., boiling at a single temperature instead of a range). As an azeotrope, the solution contains the given components in the same proportions as the vapor, such that evaporation does not change the purity and distillation does not result in separation. For example, ethyl alcohol and water form a 95.6% azeotrope at 78.1°C. When an azeotrope is not considered pure enough for use, there are several techniques to break the azeotrope and obtain a pure distillate. This set of techniques is known as azeotropic distillation. Some techniques achieve this by "jumping" on the azeotropic composition (by adding another component to create a new azeotrope or by changing the pressure). Others work by chemically or physically removing or sequestering the impurities. For example, to purify ethanol to greater than 95%, a drying agent (or a drying agent such as potassium carbonate) can be added to convert soluble water to insoluble water of crystallization. Molecular sieves are often used for this purpose. Immiscible liquids such as water and toluene readily form azeotropes. Generally, these azeotropes are referred to as low-boiling azeotropes because the boiling point of the azeotrope is lower than the boiling point of either pure component. The temperature and composition of the azeotrope are easily predicted from the vapor pressures of the pure components without using Raoult's law. Azeotropes are easily broken in a distillation setup by using a liquid-liquid separator (decanter) to separate the two liquid layers, one of which is the condensed overhead. Only one of the two liquid layers is refluxed to the distillation setup. High-boiling azeotropes also exist, such as a 20 weight percent mixture of hydrochloric acid in water. As the name suggests, the boiling point of an azeotrope is higher than the boiling point of either pure component.

[0323] As used herein, the term "supercritical fluid chromatography" or "SFC" refers to a form of normal phase chromatography that uses a supercritical fluid, such as carbon dioxide, as the mobile phase. It is used for the analysis and purification of low to medium molecular weight thermolabile molecules and may also be used for the separation of chiral compounds. The principle is similar to that of high performance liquid chromatography (HPLC); however, SFC typically utilizes carbon dioxide as the mobile phase and therefore the entire chromatographic flow path must be pressurized. Because the supercritical phase represents a state where the properties of the liquid and gas converge, supercritical fluid chromatography is sometimes referred to as convergent chromatography. SFC with CO2 utilizes a carbon dioxide pump that requires the incoming CO2 and the pump head to be kept cold and at a temperature and pressure that maintains the carbon dioxide in a liquid state that can be effectively metered at some specified flow rate. The CO2 then becomes supercritical in the column oven after the injector and the temperature and pressure to which it is subjected are raised above the critical point of the liquid and the supercritical state is achieved. SFC as a chromatographic process is compared to processes that have the combined properties of the force of a liquid to dissolve the matrix, chromatographic interactions and the dynamics of a gas. The result is a large mass per injection while maintaining high chromatographic efficiency. Typically, gradient elution is used in analytical SFC using a polar co-solvent such as methanol, and perhaps a low concentration of weak acid or base, around 1%. Effective plate counts per analysis can be observed to be in excess of 500K plates per meter for 5 μm material on a routine basis. The operator uses the software to set the mobile phase flow rate, co-solvent composition, system back pressure, and column oven temperature, which must exceed 40°C to achieve supercritical conditions with CO2. In addition, SFC provides an additional control parameter, namely pressure, by using an automatic back pressure regulator. From an operational standpoint, SFC is as simple and robust as HPLC, but fraction collection is more convenient as the primary mobile phase evaporates leaving only the analyte and a small amount of polar co-solvent.If the outlet CO2 is captured, it can be recompressed and recycled, allowing reuse of >90% of the CO2. Like HPLC, SFC uses a variety of detection methods including UV / VIS, mass spectrometry, FID (different from HPLC), and evaporative light scattering.

[0324] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present disclosure are apparent from different examples. The examples provided show different components and methods useful for implementing the present disclosure. The examples do not limit the disclosure claimed. Based on the present disclosure, a person skilled in the art can identify and adopt other components and methods useful for implementing the present disclosure.

[0325] All publications and patent documents cited in this specification are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, and does not constitute any admission as to their contents or date. Although the invention has been described by the description set forth herein, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the following foregoing description and examples are for illustrative purposes only and are not limiting of the scope of the following claims. EXAMPLES

[0326] The process of the present invention will be better understood by reference to the following examples, which are intended as illustrative and not limiting the scope of the present application.

[0327] Example 1. Synthesis of intermediate I-4 [ka]

[0328] Scheme for the preparation of intermediate I-4. Step 1. Preparation of intermediate I-1 [ka] Copper(I) cyanide (55.0 kg) was charged into a 3000 L glass-lined reactor, then N,N-dimethylformamide (456.0 kg) was added to the mixture at 15-30 °C. Nitrogen was bubbled through the bottom port every 5-10 min and stirred for 30 min. The mixture was heated to 70-80 °C.

[0329] Methyl 2-bromo-4-fluorobenzoate (120.0 kg) was added to the mixture at a rate of 70-120 kg / hr at 70-80° C. and nitrogen was bubbled through the bottom port every 1-2 hr.

[0330] The mixture was reacted at 75-85°C and sampled for HPLC analysis every 2-6 hours until methyl 2-bromo-4-fluorobenzoate was ≦2% or the difference between two consecutive samples was ≦1%. Sampling method: Take approximately 5 mL of the mixture and add 3 drops to 20 mL of acetonitrile.

[0331] The mixture was cooled to 15-25°C while nitrogen was bubbled through the bottom port every 1-2 hours.

[0332] Purified water (1440.0 kg) was added to the mixture at a rate of 100-400 kg / hr at 15-25° C. and nitrogen was bubbled in through the bottom port every 1-2 hr. After addition, the mixture was stirred for 4 hr and then sampled for HPLC analysis every 1-3 hr until the weight percent of intermediate I-1 was ≦0.5% or the difference between two consecutive samples was ≦0.5 wt%.

[0333] Sampling method: Take approximately 5 ml of the mixture and add 3 drops to 20 ml of acetonitrile.

[0334] The mixture was filtered in two portions through a stainless steel Nutsche filter. The filter cake was rinsed with purified water (240.0 kg x 2) for each portion. The filter cake was then rinsed with acetonitrile (663.8 kg) until the filter cake was essentially dissolved. The filtrate was then transferred to a 5000 L glass-lined reactor.

[0335] Reduce the pressure (P≦-0.08MPa) until 180L to 300L (1.5 to 2.5V) remains. 内部 ≦40℃(T ジャケット <50° C.) the mixture was concentrated.

[0336] Ethyl acetate (2160.0 kg) was added to the mixture at 15-30° C., and then the mixture was stirred for more than 3 hours.

[0337] The organic phase was washed with ammonium chloride solution (825.0 kg + 825.0 kg + 825.6 kg) at 15-30 °C, stirred for 1-2 h, and allowed to settle until the mixture became layered before separation. Note: Ammonium chloride solution was prepared with ammonium chloride (675.6 kg) and purified water (1800.0 kg).

[0338] The organic phase was washed with sodium carbonate solution (930.0 kg + 930.0 kg) at 15-30°C, stirred for 2-3 hours, and then allowed to settle until the mixture was layered before separation. Note: The sodium carbonate solution was prepared with sodium carbonate (60.0 kg) and purified water (1800.0 kg).

[0339] The organic phase was washed with sodium chloride solution (816.0 kg) at 15-30°C, stirred for 1-2 hours, and then allowed to settle until the mixture formed layers before separation. Note: The sodium chloride solution was prepared with sodium chloride (216.0 kg) and purified water (600.0 kg).

[0340] Reduce the pressure (P≦-0.08MPa) until 180L to 300L (1.5 to 2.5V) remains. 内部 ≦40℃(T ジャケットThe mixture was concentrated at 15-45°C (P ≦-0.08 MPa). Heptane (160.0 kg) was added to the mixture at 15-45°C. The mixture was concentrated under reduced pressure (P ≦-0.08 MPa) until 100-150 L remained. 内部 = ≦ 40℃ (T ジャケット =≦50° C. Heptane (163.0 kg) was added to the mixture at 15-45° C. The mixture was sampled for HPLC analysis until ethyl acetate remained ≦5%.

[0341] Sampling Method: Take approximately 5 ml of supernatant liquid for ethyl acetate residue analysis.

[0342] The mixture was heated to 60-70° C. while nitrogen was bubbled through the bottom port every 1-2 hours and maintained for more than 4 hours.

[0343] The mixture was cooled to 15-25°C at a rate of 10-15°C / hr while nitrogen was bubbled through the bottom port every 1-2 hr and maintained for 2 hr.

[0344] The mixture was filtered in portions through a stainless steel Nutsche filter, and the filter cake was sampled for intermediate I-1 purity analysis until the purity of intermediate I-1 was ≧98%.

[0345] Weight: 65.6 kg, corrected 63.5 kg. Weight %: 96.82%. Yield: 71.1%. Purity: 100%. Physical state: off-white solid

[0346] Step 2. Preparation of intermediate I-2 [ka] A clean, dry 500 L glass-lined reactor 1 was verified to have an oxygen content of ≦1.0%.

[0347] N,N-Dimethylacetamide (177.4 kg) was charged to glass-lined reactor 1 at 15-30° C. Mix for KF analysis until KF≦0.05%.

[0348] Intermediate I-1 (65.0 kg) and tert-butyl 1-piperazinecarboxylate (99.0 kg) were added to the mixture through a solid addition funnel and then stirred for 0.5 h, potassium carbonate (400 mesh) (75.0 kg) was added to the mixture through a solid addition funnel, and the mixture was bubbled with nitrogen through the bottom valve every 0.5 to 1 h.

[0349] The mixture was heated to 50-60° C. Nitrogen was bubbled through the mixture through the bottom valve every 0.5-1 hour.

[0350] The mixture was allowed to react at 50-60° C. After 6 h, the mixture was sampled every 2-6 h for HPLC analysis until the area % of the raw material was ≦1 area % or the difference between two consecutive samples was ≦0.5%.

[0351] Sampling Method: Approximately 5 ml of the mixture is taken and submitted for analytical testing.

[0352] The mixture was cooled to 20-40°C.

[0353] The mixture in glass-lined reactor 1 was filtered through a 1000 L stainless steel Nutsche filter. The filtrate was added to receiving tank 1 for temporary storage. N,N-Dimethylacetamide (60.0 kg) was added to glass-lined reactor 1 and the filter cake was added to the mixture through a solid addition funnel, then stirred for 0.5-1 h, and the mixture was bubbled with nitrogen through the bottom valve every 20-30 min. The mixture was filtered through a stainless steel Nutsche filter. The filtrate was added to receiving tank 1 for temporary storage.

[0354] Purified water (754.0 kg) was added to glass-lined reactor 2 at 20-30° C. The mixture from receiving tank 1 was added to glass-lined reactor 2 at 20-30° C. at a nominal rate of 40-60 Kg / hr.

[0355] The mixture was stirred at 20-30° C. for crystallization. After 2 h, the mixture was sampled every 2-6 h for mother liquor wt % analysis until either ≦0.2 wt % or the difference between two consecutive samples was ≦0.5%.

[0356] The mixture in glass-lined reactor 1 was filtered through a 1000 L stainless steel centrifuge at 20-30°C. Purified water (283.0 kg) was added to glass-lined reactor 2. The cake was then added to reactor 2 through the funnel while stirring. The solid addition funnel was rinsed with purified water (5.0 kg) to remove residual solids. The mixture was stirred for 2-3 hours and bubbled with N2 every 0.5-1 hour. The mixture in glass-lined reactor 2 was filtered through a stainless steel centrifuge.

[0357] The solids were dried in a rotary conical dryer at T ≤ 45 °C and P ≤ 0.06 MPa, the mixture was exchanged with nitrogen every 1-2 hours, and after 8 hours the solids were sampled for Karl Fischer (KF) analysis every 4-8 hours until KF ≤ 5%. After drying, the mixture was cooled to 20-30 °C.

[0358] Weight: 99.6 kg, corrected 94.6 kg. Yield: 78.0%. Purity: 100%. Physical state: white solid.

[0359] Step 3. Preparation of intermediate I-3 [ka] A clean, dry 3000 L glass-lined reactor 1 was checked for oxygen content ≦1.0%. Purified water (630.8 kg) was charged into the glass-lined reactor 1 at 20-30°C.

[0360] Acetic acid (510.6 kg) was added to the mixture, and then pyridine (45.8 kg) was slowly added to the mixture at 20-30°C.

[0361] Intermediate I-2 (63.2 kg) was added to the above glass-lined reactor 1 through a solid addition funnel. Nickel TK-630 (35.4 kg) was added to the mixture through the solid addition funnel, the solid addition funnel was rinsed with purified water (16.0 kg), and the mixture was bubbled with nitrogen through the bottom valve every 0.5-1 hour. The mixture was heated to 50-60°C.

[0362] The mixture was allowed to react at 50-60° C. After 1 h, the mixture was sampled every 1-3 h for HPLC analysis until the area % of intermediate I-2 was ≦20% and the area % of intermediate I-3 was ≧70%, or the difference between two consecutive samples was ≦2%.

[0363] Sampling method: Approximately 0.5 ml of the mixture is taken up in 10 ml of ACN, filtered, and the filtrate is collected and submitted for analytical testing.

[0364] The mixture was rapidly cooled to 20-30° C., and simultaneously, isopropyl acetate (329.4 kg) was added to the mixture while cooling, and the mixture was stirred for 0.5-1 hour.

[0365] The mixture was filtered through a 1000 L stainless steel Nutsche filter. Isopropyl acetate (218.0 kg) was added to glass-lined reactor 1, and the rinse was then transferred to the stainless steel Nutsche filter to rinse the filter cake. The filtrate was transferred to a 3000 L glass-lined reactor 2 for temporary storage.

[0366] The mixture was stirred at 20-30°C for 0.5 h and then allowed to settle until the mixture was stratified before separation. The lower aqueous phase was transferred to glass-lined reactor 1 for temporary storage. The upper organic phase was left in glass-lined reactor 2 for temporary storage. The lower aqueous phase was transferred to glass-lined reactor 1 for temporary storage.

[0367] The aqueous phase in glass-lined reactor 1 was extracted with IPAC (437.4 kg) at 20-30°C, the mixture was stirred for >0.5 h, and the mixture was allowed to settle until it became layered before separation. The upper organic phase was left in glass-lined reactor 2 for temporary storage.

[0368] Sodium carbonate solution (900.0 kg) was added to glass-lined reactor 2 at a base rate of 100-150 Kg / hr and the mixture was stirred for ≥0.5 h and allowed to settle until the mixture was stratified before separation. The upper organic phase was left in glass-lined reactor 2 for temporary storage. Note: Sodium carbonate solution was prepared with sodium carbonate (300.0 kg) and purified water (1500.0 kg).

[0369] Sodium carbonate solution (579.8 kg) was added to glass-lined reactor 2 at 10-20°C and the pH of the mixture was adjusted to 8-9 at a reference rate of 100-150 Kg / hr (test aqueous phase), the mixture was stirred for ≥0.5 h and allowed to settle until the mixture was stratified before separation. The upper organic phase was left in glass-lined reactor 2 for temporary storage.

[0370] Citric acid monohydrate solution (900.6 kg) was added to glass-lined reactor 2 at 10-20 °C and the mixture was stirred for ≥ 0.5 h and allowed to settle until the mixture was stratified before separation. The upper organic phase was left in glass-lined reactor 2 for temporary storage. NOTE: Citric acid monohydrate solution was prepared with citric acid monohydrate (275.0 kg) and purified water (1536.0 kg).

[0371] Citric acid monohydrate solution (724.6 kg) was added to glass-lined reactor 2 and the pH of the mixture was adjusted to 1-2 (test aqueous phase), then stirred for >0.5 h and allowed to settle until the mixture was stratified before separation. The upper organic phase was left in glass-lined reactor 2 for temporary storage.

[0372] Sodium bicarbonate solution (320.0 kg) was added to the glass-lined reactor through a liquid materials filter at 10-20 °C and the mixture was stirred for ≥ 0.5 h and allowed to settle until the mixture stratified before separating the aqueous phase for pH analysis until pH ≥ 7. The upper organic phase was left in glass-lined reactor 2 for temporary storage. Note: Sodium bicarbonate solution was prepared with sodium bicarbonate (21.0 kg) and purified water (300.0 kg).

[0373] Sodium chloride solution (750.2 kg) was added to glass-lined reactor 2, then stirred for ≥ 0.5 h and allowed to settle until the mixture was stratified at 20-30 °C before separation. The upper organic phase was left in glass-lined reactor 2 for temporary storage. The aqueous phase was sampled for pH analysis until pH ≥ 7. Note: Sodium chloride solution was prepared with sodium chloride (150.2 kg) and purified water (605.0 kg).

[0374] The mixture was concentrated under reduced pressure (P≦-0.08 MPa) at T≦40° C. until 1-1.5 volumes remained. The mixture, less in the later stages of concentration, was transferred to a 200 L glass-lined reactor 3 to continue concentration. The mixture was adjusted to T≦30° C. DCM (78.0 kg) was added to the mixture at T≦30° C. and the mixture was stirred until homogenous.

[0375] Silica gel (270.0 kg) (200-300 mesh) was added to a chromatography column, then sodium chloride (40.0 kg) (5-15 cm) was added to the silica gel, and then a layer of filter cloth and a glass plate were packed over the sodium chloride under vacuum for 4-6 hours.

[0376] The addition of NaCl was performed by repeatedly squeezing n-heptane (814.8 kg) into the column and packing a layer of filter cloth on top of the sodium chloride to retain 40-80 Kg of n-heptane on the top layer of the column, and then adding the latter concentrated mixture to the column.

[0377] The silica gel column was eluted with the washings, and the eluate was monitored by TLC each time until no traces of intermediate I-3 remained when 100-400 L of eluate had been received. Note: The washings were prepared with isopropyl acetate (1349.4 kg + 361.6 kg) and n-heptane (3727.0 kg + 2701.0 kg).

[0378] The mixture was transferred to a 2000 L glass-lined reactor 4.

[0379] The mixture was concentrated under reduced pressure (P≦-0.08 MPa) at T≦4180 L°C until 120 L-180 L (4V-5V) remained. n-Heptane (208.0 kg + 208.4 kg) was added to the mixture at a nominal rate of 40-60 Kg / hr at T≦40°C. The mixture was sampled for isopropyl acetate residual analysis, which showed isopropyl acetate residual≦1%. The mixture was cooled to 0-10°C.

[0380] The mixture was stirred at 0-10° C. for crystallization. After 4 h, the mixture was sampled every 2-6 h for mother liquor wt % analysis until it was ≦0.2 wt % or the difference between two consecutive samples was ≦0.5%.

[0381] The mixture was filtered through a 500 L stainless steel Nutsche filter. The filter cake was retained in the stainless steel Nutsche filter.

[0382] The solid was dried under reduced pressure (P≦-0.06 MPa) at T≦40°C and after 10 h the solid was sampled for analysis every 4-8 h until n-heptane remaining≦0.5% and isopropyl acetate remaining≦0.5%, KF≦0.5%. After drying, the mixture was cooled to 20-30°C.

[0383] Weight: 36.0 kg, corrected 35.5 kg. Yield: 58.4%. Purity: 99%. Assay: 98.61%. Physical State: Yellow solid.

[0384] The method for preparing intermediate I-3 was also accomplished following the same process as above, but using 2,6-lutidine and propionic acid as described below. [Table 1]

[0385] Step 4A: Preparation of Intermediate I-2A [ka] A clean, dry 3000 L glass-lined reactor 1 was verified to have an oxygen content of ≦1.0%.

[0386] 1,4-dioxane (679.8 kg) was charged to glass-lined reactor 1 at 15-25° C. The mixture was sampled for KF and purity analysis until KF≦0.1%. KF was 0.36% and additional 1,4-dioxane (679.8 kg) was added to the mixture and then sampled until KF≦0.1%.

[0387] N-(carbobenzyloxy)-L-glutamic acid (110.1 kg) was added portionwise to the mixture at 15-25° C. in 5-10 minute intervals through a solid addition funnel, after which nitrogen was bubbled through the mixture through the bottom valve for 2-3 minutes and then stirred for 20-30 minutes until the mixture was essentially clear.

[0388] Pyridine (6.6 kg) was added via pump to the mixture at 15-25° C. Ammonium bicarbonate (34.0 kg) was added to the mixture through a solid addition funnel and the mixture was bubbled with nitrogen through the bottom valve every 0.5-1 hour.

[0389] Di-tert-butyl dicarbonate (92.4 kg) was slowly added to the mixture at 15-25° C. at a base rate of 15-25 Kg / hr and the mixture was bubbled with nitrogen through the bottom valve every 0.5-1 hr.

[0390] The mixture was allowed to react at 15-25° C. After 10 h, the mixture was sampled every 2-6 h for HPLC analysis until the area % of N-(carbobenzyloxy)-L-glutamic acid was ≦1 area %.

[0391] Sampling Method: Approximately 5 ml of the mixture is taken and submitted for analytical testing.

[0392] Purified water (440.0 kg) and ethyl acetate (581.2 kg) were added to the mixture at 15-25°C.

[0393] The mixture was stirred at 15-25°C for ≥0.5 h and then allowed to settle until the mixture was layered before separation. The aqueous phase was transferred to glass-lined reactor 2.

[0394] The aqueous phase in glass-lined reactor 2 was extracted with ethyl acetate (297.2 kg) at 15-25° C., then stirred for ≥0.5 h and allowed to settle until the mixture was stratified before separation. The organic phase was combined with the organic phase and transferred to glass-lined reactor 2 for temporary storage.

[0395] The mixture was stirred for 0.5 hours or more and allowed to settle until the mixture became layered before separation. The upper organic phase was left in the glass-lined reactor for temporary storage.

[0396] The potassium bicarbonate solution was added to the glass-lined reactor, washed at 15-25 °C, stirred for 1-1.5 h, and allowed to settle until the mixture was stratified before separation. The upper organic phase was left in glass-lined reactor 2 for temporary storage. Note: Potassium bicarbonate solution was prepared with potassium bicarbonate (11.0 kg) and purified water (100.0 kg).

[0397] The citric acid monohydrate solution was added to glass-lined reactor 2 at 15-25 °C, stirred for at least 1 h, and allowed to settle until the mixture became stratified before separation. The upper organic phase was left in glass-lined reactor 2 for temporary storage. Note: The citric acid monohydrate solution was prepared with citric acid monohydrate (27.5 kg) and purified water (275.0 kg).

[0398] Sodium chloride solution was added to glass-lined reactor 2 at 15-25°C, then stirred for ≥0.5 h and allowed to settle until the mixture was stratified before separation. The aqueous phase was sampled for pH analysis until pH=6-8. The organic phase, pH=5, was washed with sodium chloride solution until the pH of the aqueous phase was 6-8. Note: Sodium chloride solution was prepared with sodium chloride (83.0 kg x 3 + 84.0 kg) and purified water (250.0 kg x 3 + 252.0 kg).

[0399] The mixture was concentrated under reduced pressure (P≦-0.08 MPa) at T≦30°C until 495.5-605.6 L (4.5V-5.5V) remained. n-Heptane (752.4 kg + 546.4 kg) was added to the mixture at a base rate of 150-200 Kg / hr and the mixture was stirred until clear. The mixture was sampled for ethyl acetate residual analysis until ethyl acetate residual was ≦1%.

[0400] The mixture was adjusted to 40-45°C and held for 0.5-1 hour, the mixture was slowly cooled to 0-10°C at a baseline rate of 5-15°C / hour and held for 2 hours, and the mixture was sampled every 2-6 hours for mother liquor wt% analysis until ≤0.3 wt% or the difference between two consecutive samples was ≤0.3%.

[0401] The mixture was filtered through a Φ1250 stainless steel centrifuge. After filtration, if there was a lot of solid residue in the reactor, the reactor was first rinsed with mother liquor.

[0402] The solid was dried in a rotary conical dryer at T≦40°C and P≦0.06 MPa, and after 10 hours the solid was sampled for KF and solvent residual analysis every 4-8 hours until n-heptane residual, ethyl acetate residual, and KF≦0.5% were obtained. After drying, the solid was cooled to 20-30°C.

[0403] Weight: 100.1 kg. Yield: 91.3%. Purity: 100.0%. Physical state: white solid.

[0404] Step 4B: Preparation of Intermediate I-3A [ka] A clean, dry 300 L autoclave reactor 1 was verified to have an oxygen content of ≦1.0%.

[0405] Methanol (118.6 kg) was added to autoclave reactor 1. The mixture was sampled for KF analysis until KF≦0.1%.

[0406] Intermediate I-2A (50.2 kg) was added to autoclave reactor 1 through a solid addition funnel at 10-30° C. and then stirred for at least 0.5 hours.

[0407] The autoclave reactor 1 was purged with nitrogen through a subsurface pipe to 0.10-0.20 MPa and then vented to 0.02-0.05 MPa. This was repeated three times. After replacement, the oxygen content was monitored until it was ≦1.0%.

[0408] 10% Pd(OH)2 (2.56 kg) was added to autoclave reactor 1 at 10-30 °C.

[0409] The autoclave reactor 1 was purged with nitrogen through a subsurface pipe to 0.10-0.20 MPa and then vented to 0.02-0.05 MPa. This was repeated three times. After replacement, the oxygen content was monitored until it was ≦1.0%.

[0410] The mixture was adjusted to 5-15°C.

[0411] The autoclave reactor 1 was purged with hydrogen through a subsurface pipe to 0.15-0.30 MPa and then vented to 0.03-0.04 MPa. This was repeated five times. In the final exchange, the pressure was increased to 0.9-1.1 MPa with hydrogen.

[0412] The mixture was reacted at 5-15°C. The pressure was maintained with hydrogen at 0.9-1.1 MPa (target: 1.0 MPa). (Every 6-10 hours, the mixture was vented to 0.03-0.04 MPa, the mixture was purged with hydrogen through a subsurface pipe to 0.9-1.1 MPa, then vented to 0.03-0.04 MPa). After 6 hours, the mixture was sampled every 2-6 hours for intermediate I-2A assay analysis until the assay for intermediate I-2A was ≦1.0%.

[0413] Sampling method: Take 5 ml of the mixture, filter the mixture and submit the filtrate for analytical testing.

[0414] The autoclave reactor 1 was vented with nitrogen through a subsurface pipe to 0.02-0.05 MPa and then purged to 0.2-0.3 MPa. This was repeated eight times. After each exchange, the mixture was monitored until the oxygen content was ≦1.0% and the hydrogen content was ≦1.0%.

[0415] The mixture was filtered through a DN500 stainless steel Nutsche filter. Methanol (3.96 kg) was added to autoclave reactor 1, which was then pre-cooled to T≦15° C., and the filter cake was then soaked.

[0416] The intermediate was transferred to a 1000 L glass-lined reactor 2 and the mixture was cooled to −10 to 10° C. for temporary storage.

[0417] Weight: 160.0 kg, corrected 28.5 kg. Yield: 94.4%. Assay: 17.81%. Purity: 99.2%. Physical State: Colorless liquid.

[0418] Step 4: Preparation of intermediate I-4 [ka] A solution of intermediate I-3A in methanol (79.2 kg, corrected to 76.8 kg) was charged to a 1000 L glass-lined reactor 1 and the mixture was adjusted to 0-10°C.

[0419] Intermediate I-3 (79.2 kg) was added to the mixture through a solid addition funnel at 0-10° C. Acetic acid (15.2 kg) was added to the mixture through a pump at 0-10° C.

[0420] The mixture was heated to 20-30° C. The mixture was reacted at 20-30° C. The mixture was stirred for 8 hours.

[0421] Methanol (63.0 kg) was added to the 200 L glass reactor 2. The mixture was sampled for KF analysis until KF≦0.1%.

[0422] Sodium cyanoborohydride (10.4 kg) was added through a solid addition funnel to glass-lined reactor 2. The mixture was stirred until clear and stored for later use.

[0423] The mixture was cooled to 5-10° C. A solution of sodium cyanoborohydride in methanol was added to the glass-lined reactor 1 at a nominal rate of 5-25 Kg / hr and then stirred for not less than 1 hour.

[0424] The mixture in glass-lined reactor 1 was heated to 20-30° C. The mixture was allowed to react at 20-30° C. After 3 hours, the mixture was sampled every 1-3 hours for HPLC analysis until the area % of intermediate I-3 was ≦2%.

[0425] Sampling method: Take approximately 5 ml of the mixture, dilute with 20 ml of acetonitrile, filter, and submit the filtrate for analytical testing.

[0426] The mixture was heated to 35-40° C. The mixture was allowed to react at 35-40° C. After 10 hours, the mixture was sampled every 2-6 hours for HPLC analysis until the area % of intermediate 1 of the second stage was ≦3% or the difference between two consecutive samples was ≦0.5%.

[0427] Sampling method: Take approximately 5 ml of the mixture, dilute with 20 ml of acetonitrile, filter, and submit the filtrate for analytical testing.

[0428] Purified water (160.0 kg) was added to glass-lined reactor 1, the mixture was stirred for 30 min, and the mixture was degassed for 2-4 h by bubbling nitrogen through the bottom valve and detected until the hydrogen content was ≦1000 ppm.

[0429] Reduce the pressure (P≦-0.08MPa) until 2 to 3V remains. 内部 ≦40℃(T ジャケット At T≦40° C., the mixture was concentrated. Ethyl acetate in the mixture (286.2 kg+285.2 kg+427.4 kg) at T≦40° C.

[0430] The mixture was transferred to the 5000 L glass-lined reactor 2 at T≦40° C. Ethyl acetate (751.6 kg) was added to the glass-lined reactor 1 at T≦40° C., the mixture was stirred for 10 minutes, and the mixture was transferred to the glass-lined reactor 2.

[0431] The mixture was stirred at 15-30°C for at least 1 hour.

[0432] The mixture was filtered through a 1000 L plastic-lined Nutsche filter backed by a plastic-lined liquid material filter. Ethyl acetate (142.6 kg) was added to the glass-lined reactor 2, and the rinse was then transferred to the plastic-lined Nutsche filter to rinse the filter cake.

[0433] The filtered mixture was transferred to a 5000 L glass-lined reactor 3 at 20-30 °C. The mixture was allowed to settle until layered before separation. The upper organic phase was left in the glass-lined reactor 3 for temporary storage.

[0434] Sodium chloride solution (618.0 kg x 2) was added to the glass-lined reactor 3 at 15-30°C, then stirred for ≥ 0.5 h and allowed to settle until the mixture was stratified before separation. The upper organic phase was left in the glass-lined reactor 3 for temporary storage. Purified water (396.0 kg) was added to the reactor 3, then stirred for ≥ 0.5 h and allowed to settle until the mixture was stratified before separation.

[0435] The top organic phase was left in Reactor 3. Note: Sodium chloride solution was prepared with sodium chloride (474.2 kg) and purified water (1582.0 kg).

[0436] Sulfhydryl silica gel (16.0 kg) was added to the mixture. The mixture was stirred for at least 2 hours.

[0437] Celite (10.0 kg) was added to a 1000 L plastic-lined Nutsche filter (2 cm). Ethyl acetate (144.0 kg) was added to the glass-lined reactor 3, and the rinse was then transferred to the plastic-lined Nutsche filter to rinse the filter cake. The filtrate was transferred to the 3000 L glass-lined reactor 4.

[0438] Under reduced pressure (P≦-0.08MPa) until (4V~6V) remains, T 内部 ≦40℃(T ジャケット The mixture was adjusted to 40-50°C and toluene (688.8 kg + 689.2 kg + 689.8 kg) was added to the mixture through a liquid material filter at a base rate of 50-100 Kg / hr. The mixture was sampled for ethyl acetate residual analysis.

[0439] The mixture was adjusted to 20-30° C. n-Heptane (542.0 kg) was added to the mixture at 20-30° C. through a liquid materials filter.

[0440] The mixture was adjusted to 20-30° C. The mixture was stirred at 20-30° C. for crystallization. After 6 hours, the mixture was sampled every 1-3 hours for intermediate I-4 mother liquor wt % analysis until it was ≦1 wt % or the difference between two consecutive samples was ≦0.5%.

[0441] The mixture was filtered through a 1000L stainless steel Nutsche filter. Toluene (52.0kg+135.0kg) and n-heptane (122.0kg+135.0kg) were added to the 3000L glass-lined reactor 4 through a liquid material filter (1V:3V), and then the rinse was transferred through the liquid material filter to the stainless steel Nutsche filter to rinse the filter cake.

[0442] n-Heptane (134.6 kg) is added to the 3000 L glass-lined reactor 4 through the liquid material filter, and the rinse is then transferred through the liquid material filter to the stainless steel Nutsche filter, rinsing the filter cake twice.

[0443] Ethyl acetate (640.6 kg) was added to the glass-lined reactor 4 through a liquid material filter. The filter cake was then added to the mixture, and the mixture was bubbled with nitrogen through the bottom valve every 0.5 to 2 hours and stirred at 30 to 40 °C for 4 to 8 hours.

[0444] Reduce the pressure (P≦-0.08MPa) until 158.4 to 316.8L (2V to 4V) remains. 内部 ≦40℃(T ジャケット The mixture was cooled to 30°C (≦50°C). Ethyl acetate (640.8 kg) was added to the mixture at 30-40°C. The mixture was cooled under reduced pressure (P≦-0.08 MPa) until 237.6-396 L (3V-5V) remained. 内部 ≦40℃(T ジャケット ≦50°C).

[0445] At 20-30°C, n-heptane (484.8 kg) was added to the mixture through a liquid material filter at a base rate of 50-100 Kg / hr.

[0446] The mixture was stirred at 20-30° C. for crystallization. After 4 hours, the mixture was sampled every 1-3 hours for intermediate I-4 mother liquor wt % analysis until it was ≦1 wt % or the difference between two consecutive samples was ≦0.5%.

[0447] The mixture was filtered through a 1000 L stainless steel Nutsche filter. The filter cake was rinsed with n-heptane (79.2 kg). The filter cake was sampled for purity and toluene remaining.

[0448] The solid is ジャケット The mixture was dried at ≦40°C and the solids were sampled for analysis every 4-8 hours until after 10 hours, the contents of methanol remaining were ≦0.4%, ethyl acetate remaining were ≦0.4%, toluene remaining were ≦0.4%, and n-heptane remaining were ≦0.4%. After drying, the mixture was cooled to 20-30°C.

[0449] Weight: 83.3 kg. Yield: 72.9%. Purity: 99.8%. Physical state: off-white solid.

[0450] Example 2. Synthesis of intermediate I-6 [ka] A vessel was charged with 2-propanol (74 L) at 25° C. and intermediate I-5 (4.903 kg) and 2,6-di-tert-butyl-4-methylphenol (BHT) (23.9 g) were added with stirring followed by 2-methyl-THF (37 L).

[0451] The suspension was heated to reflux (IT=80° C.) within 74 min with the jacket temperature set at 105° C.

[0452] After 6 min at reflux, a clear solution was obtained and the internal temperature was reduced to 77 °C within 32 min (min jacket temperature 65 °C). NOTE: It is important that no solids are present anymore, as they can act as seed crystals for the racemate.

[0453] A solution of D-proline (706 g) in water (1.4 L) was prepared and 10% of this proline solution was added to the intermediate I-5 solution over 1 minute.

[0454] Seeding crystals (Intermediate I-6, 9.21 g) were then added to the solution. The seeds dissolved within about 1-2 minutes. A second portion of 10% of the proline solution was added to the Intermediate I-5 solution over a period of 2 minutes. A second portion of seeding crystals (Intermediate I-6, 9.30 g) was then added to the brown solution, instantly giving a slightly cloudy suspension.

[0455] After 7 min, the remaining amount of the D-proline solution was added over a period of 7 min.

[0456] The flask with the proline solution was flushed with 2-propanol (0.8 L) and this was added to the vessel. The brown suspension was aged for 25 min at an internal temperature of 75° C. The suspension was cooled to 27° C. over 75 min. Once an internal temperature of 27° C. was reached, the suspension was filtered. The filtration time (without washing) was 45 min (filter diameter 30 cm). The filter cake was washed three times with 2-PrOH (5.0 L each time) and pre-dried on the filter for approximately 32 min.

[0457] The crude was continuously dried under vacuum (<10 mbar) at 45° C. 2.564 kg (42%) of an off-white solid was obtained.

[0458] Example 3. Synthesis of intermediate I-8 [ka] A vessel was charged with acetonitrile (50.0 L) at 25° C. and intermediate I-4 (7.053 kg) was added with stirring. DMF (14.0 L) was added, followed by CSA (7.350 kg). Acetonitrile (7.0 L) was added once more.

[0459] The clear solution was heated to reflux for 68 minutes with the jacket temperature set at 100° C. Slight bubbling was observed during heating.

[0460] 37.5 L of solvent was distilled over 4 h 53 min (IT: 85-86 °C). During this time, acetonitrile (5 x 7.5 L) was added in five portions to keep the reaction concentration approximately constant. IPC1 showed 69% conversion.

[0461] The jacket temperature was reduced to 78° C. over 40 min to ensure safe stirring overnight (12 h). IPC2 showed 96.9% conversion. Conversion criteria were already met (≧93%).

[0462] The internal temperature was allowed to decrease from 77° C. to 26° C. over 75 minutes. The white suspension was stirred at 26°-25° C. for an additional hour.

[0463] The product was filtered within 43 minutes using a 30 cm filter. No lumps or crusts were observed on the vessel walls. The product was dried in two portions on a rotary evaporator at 50° C. and <10 mbar. 7.259 kg of white product (92% yield) was obtained with an HPLC purity of 98.6% a / a and a chiral purity of 98.4% a / a.

[0464] Example 4. Synthesis of Compound 1 - First Synthesis [ka] The vessel was charged with water (18.5 L) at 25° C. 32% HCl (5.55 L) was added portionwise with stirring. The addition tank was rinsed with water (0.6 L).

[0465] 2-Methyltetrahydrofuran (12 L) was added to the vessel.

[0466] Intermediate I-6 (6.104 kg) was added at 25° C., followed by BHT (14 g) to the vessel. 2-Methyltetrahydrofuran (0.60 L) was added.

[0467] The reaction mixture was stirred at 25° C. for 2.5 h.

[0468] IPC1 showed 98.7% conversion.

[0469] A solution of K3PO4 (14.712 kg) in water (16.0 L) was prepared to give a total volume of 19 L.

[0470] 9.0 L of K3PO4 solution was added to the reaction mixture to reach pH 7.

[0471] The brown emulsion was stirred for 5 minutes and then the layers were separated (fast phase separation).

[0472] The aqueous layer was extracted once more with 2-methyl-tetrahydrofuran (12.0 L).

[0473] The combined organic layers were concentrated at 45° C. to give an oil over 230 min. DMAc (6.0 L) was added and the brown solution was stirred on a rotary evaporator at 45° C. and maximum vacuum capacity (start: 40 mbar, end: 17 mbar) for 80 min. IPC2 by NMR showed a residual content of 0.14 equivalents of 2-methyltetrahydrofuran compared to intermediate I-9.

[0474] The solution of the aldehyde in DMAc was transferred to a vessel. DMAc (25.5 L) was added and the brown solution was cooled to an internal temperature of 0° C. with stirring and stored as such overnight.

[0475] The next morning, intermediate I-8 (5.796 kg) was added in one portion (no exotherm), followed by N-methylmorpholine (2.265 kg) over 3 minutes (slightly exothermic).

[0476] The addition vessel was rinsed with DMAc (3.0 L) and the reaction mixture was stirred at an internal temperature of +1 to +2 °C for 37 min.

[0477] NaBH(OAc)3 (1.357 kg, 1.348 kg, and 1.351 kg) was added in three portions at internal temperatures of -1°C to +1°C, waiting 21 minutes and 20 minutes between additions.

[0478] 23 min after the last addition, IPC3 was sampled and HPLC showed a ratio of compound 1 to intermediate I-9 of 97:3.

[0479] Water (4.0 L) was added to the reaction mixture at −1 to 8° C. as a pre-quench over a period of 14 min (exothermic reaction).

[0480] The reaction mixture was warmed to 10° C. over 22 min and transferred to a mixing vessel. The reaction mixture was stirred at room temperature for 101 min and degassed.

[0481] Meanwhile, the vessel was charged with water (40 L) and ethanol (40 L). The solvent mixture was heated to an internal temperature of 73°C.

[0482] The temperature control was switched to external temperature control and a jacket temperature of 80°C was set.

[0483] To precipitate the crude product, 4.5 L of the DMAc solution from the mixing vessel was added to the water / EtOH mixture over 21 min at 73-75° C. Seeds (5.3 g) were added and a fine white suspension formed within 10 min.

[0484] The remaining DMAc solution was added at 76-71°C over a period of 32 min.

[0485] The resulting suspension was stirred at elevated temperature for a further 11 minutes and then cooled to 25° C. over 84 minutes. The suspension was stirred at an internal temperature of 25° C. overnight.

[0486] The crude product was filtered (32 min) and washed with water (2×6.0 L) and ethanol (2×6.0 L).

[0487] After drying in a 20 L rotary evaporator in two portions for 23 hours at 70° C., 5.858 kg (78.3%) of a white crude product was obtained with an HPLC purity of 98.6% area (achiral) and a chiral purity of 97.6 / 97.5% area.

[0488] A stirred vessel was charged with DCM (33.0 L).

[0489] The crude product (5.850 kg) was added, followed by BHT (17.7 g).

[0490] Methanol (3.5 L) was added and the mixture was stirred until all solids had dissolved.

[0491] Hyflo (0.57 kg) was added and the suspension was stirred for 24 minutes.

[0492] The dark brown suspension was filtered through a deep filter plate (fast filtration) followed by a 3 μm in-line filter. The stirred vessel and filter were rinsed with a mixture of dichloromethane (5.5 L) and methanol (0.6 L).

[0493] The filtered crude product solution (45 L) was transferred to a vessel. The jacket temperature was increased to 55° C. and 19 L of solvent was distilled at atmospheric pressure within 50 min.

[0494] The vessel was switched to reflux. In-line filtered n-butanol (6.0 L) was added over 10 min, causing the internal temperature to rise from 38° C. to 40° C.

[0495] Seed crystals (5.7 g) were added to the brown solution, which was still clear 5 minutes after addition.

[0496] The vessel was switched to distillation. Over a period of 16 minutes, 5.8 L of solvent mixture was distilled at a jacket temperature of 55-80° C. The internal temperature rose to 42° C.

[0497] The vessel was switched to reflux. In-line filtered n-butanol (6.0 L) was added over 8 minutes, causing the internal temperature to rise from 43° C. to 45° C.

[0498] Seed crystals (5.7 g) were again added to the brown solution. Five minutes after addition, small particles were observed and a light brown suspension formed.

[0499] The vessel was switched to distillation. 6.0 L of solvent mixture was distilled over 10 minutes. The internal temperature rose to 50°C.

[0500] The vessel was switched to reflux. In-line filtered n-butanol (6.0 L) was added over and the internal temperature rose to 51°C.

[0501] The vessel was switched back to distillation. After 5.0 L had been distilled, an internal temperature of 60° C. was reached and the system was switched to reflux.

[0502] In-line filtered n-butanol (6.0 L) was added and the brown suspension was stirred for 2 h at a jacket temperature of 80 °C (IT: 61-69 °C).

[0503] The jacket temperature was decreased to 25° C. over 60 min and the brown suspension was stirred at 25° C. overnight.

[0504] The crude was filtered the next morning (filtration time: 55 min including rinsing the vessel with mother liquor). The filter cake was washed with in-line filtered n-BuOH (2×6.0 L) and in-line filtered TBME (2×6.0 L).

[0505] After drying at 70° C. for 22 h, 5.556 kg (74% yield, 95%) of a white solid was obtained with an achiral purity of 99.2% and a chiral purity of 98.1%. NMR showed a residual n-BuOH content of 0.058 equiv.

[0506] Example 5. Synthesis of Compound 1 - Second Synthesis The reaction up to the isolation of crude compound 1 was carried out in two separate batches similar to the reaction previously described above, the only difference being the performance of the Hyflo treatment of a solution of intermediate I-9 in 2-methyltetrahydrofuran due to foreign particles of the starting intermediate I-6.

[0507] Both crude products were collected on the same 50 L glass nutsch. Up to the isolation of the crude products, all three reactions can be summarized as follows: [Table 2]

[0508] The crude wet cake of both reactions was dissolved on a Nutsche in a mixture of dichloromethane (65 L) and methanol (7.5 L) (1.5 h).

[0509] The resulting solution was transferred to a stirred vessel charged with Hyflo (1.13 kg) and BHT (35 g).

[0510] The resulting suspension was stirred for 9 minutes and then filtered through a Celite deep filter plate followed by a 3 μm in-line filter into a vessel. The stirred vessel and filter cake were rinsed with a mixture of dichloromethane (10.0 L) and methanol (1.0 L).

[0511] The volume of the product solution was determined to be approximately 94 L. By LOD, the product content of 12.5 kg was estimated with an HPLC achiral purity of 98.7% and chiral purity of 97.4%.

[0512] The jacket temperature of the vessel containing the in-line filtered product solution was increased to 57° C. and 43 L of solvent was distilled at atmospheric pressure within 103 minutes.

[0513] The vessel was switched to reflux. In-line filtered n-butanol (11.5 L) was added over 16 minutes and the internal temperature rose to 38° C. to 39° C. Seed crystals (11.0 g) were added as a slurry in n-butanol (35 ml). Five minutes after addition the brown solution was still clear.

[0514] The vessel was switched to distillation. Over 43 minutes, 12 L of solvent mixture was distilled at a jacket temperature of 57° C. The internal temperature rose to 44° C.

[0515] The vessel was switched to reflux. In-line filtered n-butanol (11.5 L) was added over 13 minutes, causing the internal temperature to rise from 44° C. to 45° C. Seed crystals (11.0 g) were again added as a slurry in n-butanol (35 ml). Five minutes after addition, small particles were observed and a light brown suspension had formed.

[0516] The vessel was switched to distillation. 12 L of solvent mixture was distilled over 43 minutes. The internal temperature rose to 53°C.

[0517] The vessel was switched to reflux. In-line filtered n-butanol (11.6 L) was added and the internal temperature rose to 54°C.

[0518] The vessel was switched back to distillation. After 4.0 L had been distilled, an internal temperature of 60° C. was reached and the system was switched to reflux.

[0519] In-line filtered n-butanol (11.4 L) was added and the brown suspension was stirred for 2 h at a jacket temperature of 80 °C (IT: 61-67 °C).

[0520] The jacket temperature was decreased to 25° C. over 60 min and the brown suspension was stirred at 25° C. overnight.

[0521] The next morning the crude was filtered (filtration time: 21 min). The filter cake was washed with in-line filtered n-BuOH (11.3 L and 11.5 L) and in-line filtered TBME (2×11.5 L).

[0522] The resulting product was dried in two portions at 70° C. for 24 hours. A total of 10.187 kg (68% yield) of white solid was obtained with 99.3% achiral purity and 97.9% chiral purity. NMR showed a residual n-BuOH content of 0.055 / 0.053 equiv.

[0523] Equivalent It is to be understood that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects as illustrative rather than limiting the invention described herein. The scope of the present invention is therefore indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. reducing aminating intermediate I-9 【Chemical 1】 in the presence of intermediate I-8, [Chemical Formula 2] a base, and a reducing agent in a solvent to provide Compound 1, a method for preparing Compound 1. [Chemical Formula 3]

2. The method according to claim 1, wherein the base is N-methyl-morpholine, the reducing agent is sodium triacetoxyborohydride, and the solvent is dimethylacetamide.

3. The molar ratio of N-methyl-morpholine to intermediate I-8 is about 1.00:1, about 1.05:1, about 1.10:1, about 1.15:1, about 1.20:1, about 1.25:1, about 1.30:1, about 1.35:1, about 1.40:1, about 1.45:1, about 1.50:1, about 1.55:1, about 1.60:1, about 1.65:1, about 1.70:1, about 1.75:1, about 1.80:1, about 1.85:1, about 1.90:1, about 1.95:1, about 2.00:1, about 2.05:1, about 2.10:1, about 2.15:1, about 2.20:1, about 2.25:1, about 2.30:1, about 2.35:1, about 2.40:1, or about 2.45:1, the method according to claim 2.

4. The molar ratio of sodium triacetoxyborohydride to intermediate I-8 is about 1.00:1, about 1.05:1, about 1.10:1, about 1.15:1, about 1.20:1, about 1.25:1, about 1.30:1, about 1.35:1, about 1.40:1, about 1.45:1, about 1.50:1, about 1.55:1, about 1.60:1, about 1.65:1, about 1.70:1, about 1.75:1, about 1.80:1, about 1.85:1, about 1.90:1, about 1.95:1, about 2.00:1, about 2.05:1, or about 2.10:1, the method according to claim 2.

5. The method according to claim 1, wherein the method is carried out at a temperature of about -30 °C to about 30 °C.

6. The method according to claim 1, wherein the method is carried out at a temperature of 0 °C, about 5 °C, about 10 °C, about 15 °C, or about 20 °C.

7. The method according to claim 1, further comprising quenching with water, alcohol, or a combination thereof to form a first solution.

8. The method according to claim 7, further comprising forming a precipitate comprising Compound 1, wherein the first solution is added to a second solution of alcohol and water to form a precipitate comprising Compound 1.

9. The method according to claim 8, wherein the alcohol is ethanol.

10. The method according to claim 8, wherein when the solution of alcohol and water is combined with the quenched reaction mixture, the temperature of the solution of alcohol and water is from about 50 °C to about 90 °C, preferably from about 60 °C to about 80 °C.

11. The method according to claim 8, wherein the alcohol: water ratio in the second solution is about 1:1 (v / v).

12. The method according to claim 8, further comprising adding an agent for inducing nucleation to the mixture of the first solution and the second solution.

13. The method according to claim 12, wherein the agent for inducing nucleation is a crystallization promoter.

14. The method according to claim 13, wherein the crystallization promoter is a seed crystal of Compound 1.

15. The method according to claim 8, further comprising cooling and filtering the precipitate to provide a filtrate, and further comprising washing the filtrate with water and alcohol.

16. The method according to claim 15, wherein the filtrate is washed with water and ethanol.

17. The method according to any one of claims 8 to 16, further comprising purifying Compound 〗.

18. The method according to claim 17, wherein purifying Compound 1 comprises dissolving Compound 1 in a dichloromethane / methanol solution.

19. Intermediate I-6 is 【Chemical Formula 4】 reacted with an acid and optionally an additive in a solvent to provide Intermediate I-9. 【Chemical Formula 5】

20. Intermediate I-4 【Chemical Formula 6】 and camphorsulfonic acid are reacted in a solvent to provide Intermediate I-8 【Chemical 7】 A method comprising:

21. Intermediate I-3 is [Chemical Formula 8] reacted with Intermediate I-3A in a solvent in the presence of a reducing agent to 【Chemical Formula 9】 provide Intermediate I-4 【Chemical Formula 10】 A method comprising:

22. Intermediate I-2A, 【Chemical 11】 a hydrogen source, and optionally a catalyst are reacted in a solvent to provide Intermediate I-3A 【Chemical 12】 A method comprising:

23. Intermediate I-9 is prepared by a method comprising mixing Intermediate I-6, 【Chemical 13】 and an acid in a solvent to provide Intermediate I-9, according to the method of claim 1. 【Chemical 14】

24. Intermediate I-8 is prepared by a method comprising reacting Intermediate I-4, 【Chemical Formula 15】 and camphorsulfonic acid in a solvent to provide Intermediate I-8, according to the method of claim 1.

25. Intermediate I-4 is prepared by a method comprising reacting Intermediate I-3 【Chemical 16】 with Intermediate I-3A in a solvent in the presence of a reducing agent to 【Chemical 17】 provide Intermediate I-4, according to the method of claim 24.

26. The method according to claim 25, wherein the reducing agent is sodium cyanoborohydride.

27. The intermediate I-3A is prepared by a method comprising reacting intermediate I-2A, 【Chemical 18】 a hydrogen source, and optionally a catalyst in a solvent to provide intermediate I-3A 【Chemical Formula 19】 The method according to claim 25.

28. A method for preparing Compound 1, comprising: (a) reacting intermediate I-2A, 【Chemical 20】 a hydrogen source, and optionally a catalyst in a solvent to provide intermediate I-3A; 【Chemical 21】 (b) reacting intermediate I-3 with 【Chemical 22】 intermediate I-3A in a solvent in the presence of a reducing agent to 【Chemical 23】 provide intermediate I-4; 【Chemical formula 24】 (c) reacting intermediate I-4, 【Chemical Formula 25】 and camphorsulfonic acid in a solvent to provide intermediate I-8, 【Chemical 26】 ; (d) reacting intermediate I-6 with 【Chemical 27】 an acid to provide intermediate I-9; 【Chemical Formula 28】 (e) contacting intermediate I-9 with 【Chemical Formula 29】 intermediate I-8 in the presence of a base and a reducing agent to 【Chemical 30】 provide Compound 1. 【Chemical 31】

29. (a) reacting intermediate I-6 with 【Chemical 32】 an acid to provide intermediate I-9; 【Chemical 33】 (b) contacting intermediate I-9 with 【Chemical Formula 34】 intermediate I-8 in the presence of a base and a reducing agent to 【Chemical 35】 provide Compound 1. A method for preparing a compound of formula 1 comprising: 【Chemical 36】

30. (a) reacting intermediate I-4 with 【Chemical 37】 camphorsulfonic acid to provide intermediate I-8; 【Chemical Formula 38】 (b) contacting intermediate I-9 with 【Chemical Formula 39】 intermediate I-8 in the presence of a base and a reducing agent to 【Chemical 40】 provide Compound 1. A method for preparing a compound of formula 1 comprising: 【Chemical Formula 41】

31. (a) reacting intermediate I-4 with 【Chemical 42】 camphorsulfonic acid to provide intermediate I-8; 【Chemical Formula 43】 (b) reacting intermediate I-6 with 【Chemical 44】 an acid to provide intermediate I-9; 【Chemical 45】 (c) contacting intermediate I-9 with 【Chemical 46】 intermediate I-8 in the presence of a base and a reducing agent to 【Chemical 47】 provide Compound 1. A method for preparing a compound of formula 1 comprising: 【Chemical 48】

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