Methods of manufacturing a bifunctional compound

Abstract

This disclosure pertains to the preparation of bifunctional compounds (e.g., Compound 1), intermediates in the preparation of such compounds, and preparation of such intermediates.

Description

METHODS OF MANUFACTURING A BIFUNCTIONAL COMPOUNDCROSS REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of U.S. Provisional Application Number 63 / 649,795, filed on May 20, 2024, and U.S. Provisional Application Number 63 / 673,395, filed on July 19, 2024, each of which is incorporated herein by reference in its entirety.BACKGROUND

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

[0003] The present disclosure relates to a process for preparing (S)-3-(5-(4-((l-(4-((lR,25)-6- hydroxy-2-phenyl- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)phenyl)piperidin-4-yl)methyl)piperazin- 1 - yl)-l -oxoiso indolin-2-yl)piperidine-2, 6-dione or (3<S)-3-[l,3-dihydro-l-oxo-5-[4-[[l-[4-[(lR,2S)- 1,2, 3, 4-tetrahydro-6-hydroxy-2 -phenyl- l-naphthalenylphenyl]-4-piperidinyl]methyl]-l - piperazinyl]-2 / / -isoindol-2-yl]-2,6-piperidinedione (referred to herein as “Compound 1”) which has the molecular formula of C45H49N5O4 and the following structure:

[0004] Compound 1 is in clinical development as a PROTAC® protein degrader that targets estrogen receptor (ER) for the potential treatment of breast cancer and has been shown to be a useful modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway. Compound 1 is in phase 3 clinical trials for the treatment of patients with estrogen receptor positive / human epidermal growth factor receptor 2 negative (ER+ / HER2-) metastatic breast cancer.

[0005] Compound 1 and its synthesis have been described in the PCT international patent applications published as WO 2018 / 102725 and WO 2023 / 009521, the contents of which are incorporated herein by reference in their entirety. Crystalline forms of Compound 1 are also described in the PCT international patent application published as WO 2022 / 056368, the content of which is incorporated herein by reference in its entirety.

[0006] There is a need in the art to provide improved processes for manufacturing such bifunctional compounds.SUMMARY

[0007] 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., Intermediates 2, 3, 4, 5, 6, 7, 8, 9, and 10), and (iii) processes for preparing such intermediates.

[0008] In some embodiments, disclosed herein is a method, comprising(IV) reacting Intermediate 7:and a hydrogen source and, optionally, a catalyst, in a solvent to provide Intermediate 8:

[0009] In some embodiments, disclosed herein is a method, comprising(V)(a) heating a mixture comprising Intermediate 8:and a solvent, to provide a first solution;(b) combining (R)-proline, isopropyl alcohol, and water to prepare a second solution;(c) adding about 1% to less than about 50% by volume of the second solution to the first solution to prepare a first reaction mixture;(d) adding an agent that induces nucleation to the first reaction mixture to prepare a second reaction mixture, followed by adjusting the second reaction mixture to a temperature of about 60 °C to about 70 °C (e.g., about 70 °C);(e) adding the remainder of the second solution to the second reaction mixture to prepare a third reaction mixture to provide Intermediate 9:

[0010] In some embodiments, step (IV) is conducted in the presence of a catalyst.

[0011] In some embodiments, the catalyst in step (IV) comprises Pd / C.

[0012] In some embodiments, the hydrogen source in step (IV) comprises hydrogen gas.

[0013] In some embodiments, the solvent in step (IV) comprises tetrahydrofuran.

[0014] In some embodiments, the method does not comprise purification of Intermediate 8 using chromatography or crystallization.|0015] In some embodiments, Intermediate 8 used in step (V) is provided as a solution comprising Intermediate 8 and tetrahydrofuran.

[0016] In some embodiments, Intermediate 8 used in step (V) is provided as a crude composition comprising Intermediate 8.

[0017] In some embodiments, the solvent in the mixture in step (V-a) comprises isopropyl alcohol, tetrahydrofuran, or a combination thereof.

[0018] In some embodiments, the agent in step (V-d) is a seed crystal comprising Intermediate 9.

[0019] In some embodiments, disclosed herein is a method, comprising(VI) reacting Intermediate 9:with an acid, in a first solvent to provide a first solution comprising crude Intermediate 10:a base, and a reducing agent in a solvent to provide Compound 1:

[0020] In some embodiments, the acid in step (VI) comprises sulfuric acid.

[0021] In some embodiments, the solvent in step (VI) comprises tetrahydrofuran.

[0022] In some embodiments, the method does not comprise purification of Intermediate 10 using chromatography or crystallization.

[0023] In some embodiments, Intermediate 10 used in step (VII) is provided as a solution comprising Intermediate 10 and dimethylacetamide.

[0024] In some embodiments, Intermediate 10 used in step (VII) is provided as a crude composition comprising Intermediate 10.

[0025] In some embodiments, the base in step (VII) comprises N-methyl -morpholine.

[0026] In some embodiments, the solvent in step (VII) comprises dimethylacetamide.

[0027] In some embodiments, disclosed herein is a method, comprising(III) reacting Intermediate 5:wherein the solvent comprises sulfolane.

[0028] In some aspects, disclosed herein is a method, comprising:(Ill) reacting Intermediate 5:and (+)-camphorsulfonic acid in a solvent to provide Intermediate 6:and a hydrogen source and, optionally, a catalyst, in a solvent to provide Intermediate 8:(a) heating a mixture comprising Intermediate 8:and a solvent, to provide a first solution;(b) combining (R)-proline, isopropyl alcohol, and water to prepare a second solution;(c) adding about 1% to less than about 50% by volume of the second solution to the first solution to prepare a first reaction mixture;(d) adding an agent that induces nucleation to the first reaction mixture to prepare a second reaction mixture, followed by adjusting the second reaction mixture to a temperature of about 60 °C to about 70 °C (e.g., about 70 °C);(e) adding the remainder of the second solution to the second reaction mixture to prepare a third reaction mixture to provide Intermediate 9:with an acid, in a solvent to provide a first solution comprising crude Intermediate 10:a base, and a reducing agent in a solvent to provide Compound 1:

[0029] In some embodiments, disclosed herein is Compound 1 manufactured by the methods as disclosed herein (e.g., step I, II, III, IV, V, VI, and / or VII).DETAILED DESCRIPTION

[0030] The synthetic steps of the disclosure present several advantages compared to previously known synthetic routes for preparing Compound 1. The process includes an efficient convergent synthetic strategy through the final reductive amination of two advanced chiralintermediates, as well as several highly efficient telescoped processes and robust crystallization for purity control. This convergent, robust, and scalable process for preparing Compound 1 allows for a rapid and efficient synthesis of key intermediates and the final active pharmaceutical ingredient (API), Compound 1.INTERMEDIATE 3

[0031] In some embodiments, disclosed herein are methods for preparing Intermediate 3, comprising(I) reacting Intermediate 2, a hydrogen source and, optionally, a catalyst, in a first solvent to provide Intermediate 3:

[0032] In some embodiments, step (I) is conducted in the presence of a catalyst.

[0033] In some embodiments, the catalyst in step (I) comprises Pd(OH)2 / C.

[0034] In some embodiments, the catalyst in step (I) is Pd(OH)2 / C.

[0035] In some embodiments, the hydrogen source in step (I) comprises hydrogen gas.

[0036] In some embodiments, the hydrogen source in step (I) is hydrogen gas.

[0037] In some embodiments, the first solvent in step (I) comprises methanol.

[0038] In some embodiments, the first solvent in step (I) is methanol.

[0039] In some embodiments, step (I) further comprises(I-a) filtering and rinsing with a second solvent to provide a solution of Intermediate 3.

[0040] In some embodiments, the second solvent in step (I-a) comprises methanol.

[0041] In some embodiments, the second solvent in step (I-a) is methanol.

[0042] In some embodiments, the solution of Intermediate 3 comprises methanol.

[0043] In some embodiments, step (I) does not comprise further purification of Intermediate3.

[0044] In some embodiments, step (I) does not comprise purification of Intermediate 3 using chromatography or crystallization.

[0045] In some embodiments, the solution of Intermediate 3 in step (I-a) is used in a subsequent step without further purification.

[0046] In some embodiments, the solution of Intermediate 3 in step (I-a) is used in a subsequent step without further concentration.INTERMEDIATE 5

[0047] In some embodiments, disclosed herein are methods for preparing Intermediate 5 comprising(II) reacting Intermediate 4 and Intermediate 3 in a solvent in the presence of a reducing agent to provide Intermediate 5:

[0048] In some embodiments, disclosed herein are methods for preparing Intermediate 5 comprising(I) reacting Intermediate 2, a hydrogen source and, optionally, a catalyst, in a solvent to provide Intermediate 3;(II) reacting Intermediate 4 and Intermediate 3 in a solvent in the presence of a reducing agent to provide Intermediate 5:

[0049] In some embodiments, Intermediate 3 used in step (II) is provided as a crude composition comprising Intermediate 3.

[0050] In some embodiments, Intermediate 3 used in step (II) is provided as a solution comprising Intermediate 3 and methanol.

[0051] In some embodiments, the solution of Intermediate 3 in step (I-a) is used in step (II) without further purification.

[0052] In some embodiments, the solution of Intermediate 3 in step (I-a) is used in step (II) without further concentration.

[0053] In some embodiments, Intermediate 3 used in step (II) is provided as the solution afforded from step (I-a).

[0054] In some embodiments, the solution of Intermediate 3 afforded from step (I-a) comprises methanol.

[0055] In some embodiments, the solvent in step (II) comprises methanol.

[0056] In some embodiments, the solvent in step (II) is methanol.

[0057] In some embodiments, the solvent in step (II) further comprises an acid.

[0058] In some embodiments, the solvent in step (II) further comprises acetic acid.

[0059] In some embodiments, the reducing agent in step (II) is added to the reaction mixture as a solution in methanol.

[0060] In some embodiments, the reducing agent in step (II) is sodium cyanoborohydride.INTERMEDIATE 6[00611 In some embodiments, disclosed herein are methods for preparing Intermediate 6, comprising(III) reacting Intermediate 5 and (+)-camphorsulfonic acid in a solvent to provide Intermediate 6, wherein the solvent comprises sulfolane:

[0062] In some embodiments, the molar ratio of (+)-camphorsulfonic acid to Intermediate 5 in the reaction mixture is about 1 : 1 to about 5: 1, about 1 : 1 to about 4: 1, about 1 : 1 to about 3 : 1 , or about 1 : 1 to about 2: 1.[0063 In some embodiments, the molar ratio of (+)-camphorsulfonic acid to Intermediate 5 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.[ 00641 In some embodiments, the molar ratio of (+)-camphorsulfonic acid to Intermediate 5 in the reaction mixture is about 1.5: 1.

[0065] In some embodiments, the solvent further comprises acetonitrile.

[0066] In some embodiments, the solvent comprises a mixture of acetonitrile and sulfolane.

[0067] In some embodiments, the solvent comprises acetonitrile, sulfolane, or a mixture thereof.

[0068] In some embodiments, the solvent comprises acetonitrile and sulfolane 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), about 1 : 10 (v / v).

[0069] In some embodiments, the solvent comprises acetonitrile and sulfolane in a ratio of about 4: 1 (v / v).

[0070] In some embodiments, step (III) is conducted at a temperature of about 70°C to about 100°C.INTERMEDIATE 8

[0071] In some embodiments, disclosed herein are methods for preparing Intermediate 8, wherein the methods comprise(IV) reacting Intermediate 7 and a hydrogen source and, optionally, a catalyst, in a solvent to provide Intermediate 8:

[0072] In some embodiments, step (IV) is conducted in the presence of a catalyst.

[0073] In some embodiments, the catalyst in step (IV) comprises Pd / C.

[0074] In some embodiments, the catalyst in step (IV) is Pd / C.

[0075] In some embodiments, the hydrogen source in step (IV) comprises hydrogen gas.

[0076] In some embodiments, the hydrogen source in step (IV) is hydrogen gas.

[0077] In some embodiments, the solvent in step (IV) comprises an ethereal solvent.

[0078] In some embodiments, the solvent in step (IV) comprises tetrahydrofuran.

[0079] In some embodiments, the solvent in step (IV) is tetrahydrofuran.

[0080] In some embodiments, the solvent in step (IV) comprises 2 -methyltetrahydrofuran.

[0081] In some embodiments, the solvent in step (IV) is 2-methyltetrahydrofuran.

[0082] In some embodiments, step (IV) further comprises filtering and rinsing with a rinsing solvent to provide a solution of Intermediate 8.

[0083] In some embodiments, the rinsing solvent comprises an ethereal solvent.

[0084] In some embodiments, the rinsing solvent comprises tetrahydrofuran.

[0085] In some embodiments, the rinsing solvent is tetrahydrofuran.

[0086] In some embodiments, the rinsing solvent comprises 2-methyltetrahydrofuran.

[0087] In some embodiments, the rinsing solvent is 2-mehthyltetrahydrofuran.

[0088] In some embodiments, the solution of Intermediate 8 in step (IV) comprises tetrahydrofuran.

[0089] In some embodiments, the solution of Intermediate 8 in step (IV) comprises 2- methyltetrahydrofuran.

[0090] In some embodiments, step (IV) does not comprise purification of Intermediate 8 using chromatography or crystallization.

[0091] In some embodiments, Intermediate 8 used in step (V) is provided as a solution comprising Intermediate 8 and tetrahydrofuran.

[0092] In some embodiments, Intermediate 8 used in step (V) is provided as a solution comprising Intermediate 8 and 2-methyltetrahydrofuran.

[0093] In some embodiments, Intermediate 8 used in step (V) is provided as a solution comprising Intermediate 8 and tetrahydrofuran, wherein the solution is concentrated to reach a water content target.

[0094] In some embodiments, Intermediate 8 used in step (V) is provided as a solution comprising Intermediate 8 and 2-methyltetrahydrofuran, wherein the solution is concentrated to reach a water content target.

[0095] In some embodiments, Intermediate 8 used in step (V) is provided as a solution comprising Intermediate 8 and tetrahydrofuran, wherein the solution is concentrated to reach a water content target, wherein the water content is less than about 10%, about 5%, about 2%, or about 1%.

[0096] In some embodiments, Intermediate 8 used in step (V) is provided as a solution comprising Intermediate 8 and 2-methyltetrahydrofuran, wherein the solution is concentrated to reach a water content target, wherein the water content is less than about 10%, about 5%, about 2%, or about 1%.

[0097] In some embodiments, step (IV) does not comprise further purification ofIntermediate 8.

[0098] In some embodiments, the solution of Intermediate 8 in step (IV) is used in a subsequent step without further purification.

[0099] In some embodiments, the solution of Intermediate 8 in step (IV) is used in a subsequent step without further concentration.

[0100] In some embodiments, Intermediate 8 afforded from step (IV) is a mixture of 8a and8b:

[0101] In some embodiments, the molar ratio of 8a and 8b is 1: 1 (i.e., a racemic mixture).

[0102] In some embodiments, the molar ratio of 8a and 8b is about 1 : 1.INTERMEDIATE 9

[0103] In some embodiments, disclosed herein are methods for preparing Intermediate 9, wherein the methods comprise(V)(a) heating a mixture comprising Intermediate 8 and a solvent, to provide a first solution; wherein the solvent comprises tetrahydrofuran;(b) combining (R)-proline, isopropyl alcohol, and water to prepare a second solution;(c) adding about 1% to less than about 50% by volume of the second solution to the first solution to prepare a first reaction mixture;(d) adding an agent that induces nucleation to the first reaction mixture to prepare a second reaction mixture, followed by adjusting the second reaction mixture to a temperature of about 70 °C;(e) adding the remainder of the second solution to the second reaction mixture to prepare a third reaction mixture to provide Intermediate 9:

[0104] In some embodiments, disclosed herein are methods for preparing Intermediate 9, wherein the methods comprise:(IV) reacting Intermediate 7 and a hydrogen source and, optionally, a catalyst, in a solvent to provide Intermediate 8;(V)(a) heating a mixture comprising Intermediate 8 and a solvent, to provide a first solution;(b) combining (R)-proline, isopropyl alcohol, and water to prepare a second solution;(c) adding about 1% to less than about 50% by volume of the second solution to the first solution to prepare a first reaction mixture;(d) adding an agent that induces nucleation to the first reaction mixture to prepare a second reaction mixture, followed by adjusting the second reaction mixture to a temperature of about 70 °C;(e) adding the remainder of the second solution to the second reaction mixture to prepare a third reaction mixture to provide Intermediate 9:

[0105] In some embodiments, disclosed herein are methods for preparing Intermediate 9, wherein the methods comprise(V)(a) heating a mixture comprising Intermediate 8 and a solvent, to provide a first solution; wherein the solvent comprises tetrahydrofuran;(b) combining (R)-proline, isopropyl alcohol, and water to prepare a second solution;(c) adding about 1% to less than about 50% by volume of the second solution to the first solution to prepare a first reaction mixture;(d) adding an agent that induces nucleation to the first reaction mixture to prepare a second reaction mixture, followed by adjusting the second reaction mixture to a temperature of about 60 °C to about 70 °C;(e) adding the remainder of the second solution to the second reaction mixture to prepare a third reaction mixture to provide Intermediate 9:

[0106] In some embodiments, disclosed herein are methods for preparing Intermediate 9, wherein the methods comprise:(IV) reacting Intermediate 7 and a hydrogen source and, optionally, a catalyst, in a solvent to provide Intermediate 8;(V)(a) heating a mixture comprising Intermediate 8 and a solvent, to provide a first solution;(b) combining (R)-proline, isopropyl alcohol, and water to prepare a second solution;(c) adding about 1% to less than about 50% by volume of the second solution to the first solution to prepare a first reaction mixture;(d) adding an agent that induces nucleation to the first reaction mixture to prepare a second reaction mixture, followed by adjusting the second reaction mixture to a temperature of about 60 °C to about 70 °C;(e) adding the remainder of the second solution to the second reaction mixture to prepare a third reaction mixture to provide Intermediate 9:

[0107] In some embodiments, Intermediate 8 used in step (V) is provided as a crude composition comprising Intermediate 8.

[0108] In some embodiments, the solution of Intermediate 8 in step (IV) is used in step (V) without further purification.

[0109] In some embodiments, the solution of Intermediate 8 in step (IV) is used in step (V) without further concentration.

[0110] In some embodiments, Intermediate 8 used in step (V) is provided as the solution afforded from step VI.

[0111] In some embodiments, the solution of Intermediate 8 afforded from step (IV) comprises an ethereal solvent.

[0112] In some embodiments, the solution of Intermediate 8 afforded from step (IV) comprises 2-methyltetrahydrofuran.

[0113] In some embodiments, the solution of Intermediate 8 afforded from step (IV) comprises tetrahydrofuran.

[0114] In some embodiments, the solvent in the mixture in step (V-a) comprises isopropyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.

[0115] In some embodiments, the solvent in the mixture in step (V-a) comprises isopropyl alcohol, tetrahydrofuran, or a combination thereof.

[0116] In some embodiments, the mixture in step (V-a) is heated to provide the first solution.

[0117] 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 is selected from any range between any two of the preceding values.

[0118] In some embodiments, the first solution is cooled to a temperature of about 65 °C to about 75°C.

[0119] In some embodiments, step (V-c) 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 first reaction mixture.

[0120] In some embodiments, step (V-c) comprises adding about 5% to about 25% by volume of the second solution to the first solution to prepare a first reaction mixture.

[0121] In some embodiments, the agent in step (V-d) is a seed crystal comprising Intermediate 9.

[0122] In some embodiments, the first solution in step (V-a) comprises isopropyl alcohol, tetrahydrofuran, or a combination thereof.

[0123] In some embodiments, the second reaction mixture is adjusted to a temperature of about 60 °C.INTERMEDIATE 10

[0124] In some embodiments, disclosed herein are methods for preparing Intermediate 10.

[0125] In some embodiments, the methods for preparing Intermediate 10, comprise(VI) reacting Intermediate 9 with an acid, in a first solvent to provide a first solution comprising Intermediate 10.

[0126] In some embodiments, the first solvent in step (VI) comprises tetrahydrofuran.

[0127] In some embodiments, the first solvent in step (VI) is tetrahydrofuran.

[0128] In some embodiments, the first solvent in step (VI) comprises 2- methyltetrahydrofuran.

[0129] In some embodiments, the first solvent in step (VI) is 2 -methyltetrahydrofuran.

[0130] In some embodiments, the acid in step (VI) comprises sulfuric acid.

[0131] In some embodiments, the acid in step (VI) is sulfuric acid.

[0132] In some embodiments, the acid in step (VI) comprises phosphoric acid.

[0133] In some embodiments, the acid in step (VI) is phosphoric acid.

[0134] In some embodiments, the acid in step (VI) comprises hydrochloric acid.

[0135] In some embodiments, the acid in step (VI) is hydrochloric acid.

[0136] In some embodiments, step (VI) further comprises an additive that is an antioxidant, radical scavenger, oxygen scavenger, or metal chelator.

[0137] In some embodiments, step (VI) further comprises further comprises an additive that is 2,6-di-te / 7-butyl-4-methylphenol.

[0138] In some embodiments, step (VI) is conducted at a temperature of about 20°C to about 40°C.

[0139] In some embodiments, step (VI) is conducted at a temperature of about 20°C, about 25°C, about 30°C, about 35°C, or about 40, or any ranges between any two of the aforementioned temperatures.

[0140] In some embodiments, step (VI) is conducted at a temperature of about 30°C.

[0141] In some embodiments, step (VI) farther comprises step (Vl-a)(i) adjusting pH of the first solution upon reaching an Intermediate 9 content target in the first solution;(ii) optionally removing water from the first solution of crude Intermediate 10 to provide a second solution of Intermediate 10;(iii) optionally concentrating the second solution with additional first solvent to provide a third solution of Intermediate 10; and(iv) optionally concentrating the third solution of crude Intermediate 10 with a second solvent to provide a fourth solution of Intermediate 10.

[0142] In some embodiments, the first solution in step (Vl-a) comprises tetrahydrofuran.

[0143] In some embodiments, the Intermediate 9 content target in the first solution of step(Vl-a) is less than about 10%, about 5%, about 2%, or about 1%.

[0144] In some embodiments, the Intermediate 9 content target in the first solution of step (Vl-a) is less than about 2%.

[0145] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted to about 4 to about 7.

[0146] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted to about 4 to about 5.

[0147] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted with an aqueous solution of trisodium citrate, sodium hydroxide, potassium hydroxide, potassium phosphate, or potassium carbonate.

[0148] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted with an aqueous solution comprising trisodium citrate, sodium hydroxide, potassium hydroxide, potassium phosphate, potassium carbonate, or mixtures thereof.

[0149] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted with an aqueous solution of trisodium citrate.

[0150] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted with an aqueous solution comprising trisodium citrate.

[0151] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted to about 4 to about 7 with an aqueous solution of trisodium citrate.

[0152] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted to about 4 to about 7 with an aqueous solution comprising trisodium citrate.

[0153] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted to about 4 to about 5 with an aqueous solution of trisodium citrate.

[0154] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted to about 4 to about 5 with an aqueous solution comprising trisodium citrate.

[0155] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted to about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or about 7.

[0156] In some embodiments, the pH of the first solution in step (Vl-a) is adjusted to about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, or about 5.

[0157] In some embodiments, upon concentrating the second solution with additional first solvent, a water content in the third solution of Intermediate 10 is less than about 10%, about 5%, about 2%, or about 1%.

[0158] In some embodiments, upon concentrating the second solution with additional first solvent, a water content in the third solution of Intermediate 10 is less than about 1%.

[0159] In some embodiments, the second solution in step (Vl-a) comprises tetrahydrofuran.

[0160] In some embodiments, the third solution in step (Vl-a) comprises tetrahydrofuran.

[0161] In some embodiments, the second solvent in step (Vl-a) comprising dimethylacetamide.

[0162] In some embodiments, the second solvent in step (Vl-a) is dimethylacetamide.

[0163] In some embodiments, the fourth solution in step (Vl-a) comprising dimethylacetamide and tetrahydrofuran.

[0164] In some embodiments, upon concentrating the third solution of Intermediate 10, a content of the first solvent in the fourth solution is less than about 20%, about 15%, about 10%, about 5%, or about 2%.

[0165] In some embodiments, upon concentrating the third solution of Intermediate 10, a content of the first solvent in the fourth solution is less than about 10%.

[0166] In some embodiments, step (Vl-a) does not comprise fiirther purification of Intermediate 10.

[0167] In some embodiments, the fourth solution of Intermediate 10 in step (VI -a) is used in a subsequent step without further purification.

[0168] In some embodiments, the fourth solution of Intermediate 10 in step (Vl-a) is used in a subsequent step without further concentration.

[0169] In some embodiments, step (Vl-a) does not comprise further purification of Intermediate 10.

[0170] In some embodiments, step (Vl-a) does not comprise purification of Intermediate 10 using chromatography or crystallization.COMPOUND 1

[0171] In some embodiments, the present disclosure is directed to methods for preparingCompound 1, wherein the methods comprise(VII) reacting Intermediate 10 with Intermediate 6, a base, and a reducing agent in a solvent to provide Compound 1:

[0172] In some embodiments, the present disclosure is directed to methods for preparing Compound 1, wherein the methods comprise(VI) reacting Intermediate 9 with an acid, in a first solvent to provide a first solution comprising Intermediate 10; and(VII) reacting Intermediate 10 with Intermediate 6, a base, and a reducing agent in a first solvent to provide Compound 1:

[0173] In some embodiments, the present disclosure is directed to Compound 1 manufactured by the methods described herein (e.g., step I, II, III, IV, V, VI, or VII).

[0174] In some embodiments, Intermediate 10 used in step (VII) is provided as a crude composition comprising Intermediate 10.

[0175] In some embodiments, the fourth solution of Intermediate 10 in step (Vl-a) is used in step (VII) without further purification.

[0176] In some embodiments, the fourth solution of Intermediate 10 in step (VI -a) is used in step (VII) without further concentration.

[0177] In some embodiments, Intermediate 10 used in step (VII) is provided as a solution comprising Intermediate 10 and dimethylacetamide

[0178] In some embodiments, Intermediate 10 used in step (VII) is provided as the solution afforded from step (Vl-a).

[0179] In some embodiments, the solution of Intermediate 10 afforded from step (Vl-a) comprises dimethylacetamide, tetrahydrofuran, or a combination thereof.

[0180] In some embodiments, the base in step (VII) comprises N-methyl-morpholine.

[0181] In some embodiments, the base in step (VII) is N-methyl-morpholine.

[0182] In some embodiments, the molar ratio of the base to Intermediate 6 in step (VII) is about 1 : 1 to about 3: 1.

[0183] In some embodiments, the molar ratio of the base to Intermediate 6 in step (VII) is about 2.1: 1.

[0184] In some embodiments, the reducing agent in step (VII) comprising sodium triacetoxyborohydride.

[0185] In some embodiments, the reducing agent in step (VII) is sodium triacetoxyborohydride.

[0186] In some embodiments, the molar ratio of the reducing agent to Intermediate 6 in step (VII) is about 1: 1 to about 3: 1.

[0187] In some embodiments, the molar ratio of reducing agent to Intermediate 6 in the reaction mixture is about 1.2: 1.

[0188] In some embodiments, the first solvent in step (VII) comprising dimethylacetamide.

[0189] In some embodiments, the first solvent in step (VII) is dimethylacetamide.

[0190] In some embodiments, step (VII) is conducted at a temperature of about -10°C to about 10°C.

[0191] In some embodiments, step (VII) is conducted at a temperature of about 0°C.

[0192] In some embodiments, step (VII) further comprises step Vll-a(i) quenching with water to form a first solution comprising Compound 1;(ii) optionally preparing a second solvent in a separate vessel;(iii) optionally adding the first solution comprising Compound 1 to the second solvent to provide a precipitate comprising Compound 1;(iv) optionally filtering the precipitate comprising Compound 1 to provide a cake comprising Compound 1; and(v) optionally washing the cake comprising Compound 1 with a third solvent, and then followed by a fourth solvent.

[0193] In some embodiments, the second solvent in step (Vll-a) comprising ethanol or water.

[0194] In some embodiments, the second solvent in step (Vll-a) comprising ethanol and water.

[0195] In some embodiments, the second solvent in step (Vll-a) is ethanol or water.

[0196] In some embodiments, the second solvent in step (Vll-a) is ethanol and water.

[0197] In some embodiments, the second solvent of ethanol and water has an ethanokwater ratio of about 1: 1 (v / v).

[0198] In some embodiments, step (Vll-a) further comprises adding seed crystals into the second solvent.

[0199] In some embodiments, the seed crystals comprise seed crystals of Compound 1.

[0200] In some embodiments, the seed crystals are seed crystals of Compound 1.

[0201] In some embodiments, the second solution is heated to about 50°C to about 70°C.

[0202] In some embodiments, step (VH-a) further comprises cooling the precipitate of Compound 1.

[0203] In some embodiments, cooling the precipitate of Compound 1 is at a temperature of 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.

[0204] In some embodiments, cooling the precipitate of Compound 1 is at a temperature of about 40°C.

[0205] In some embodiments, the precipitate of Compound 1 is filtered.

[0206] In some embodiments, the cake of Compound 1 is washed.

[0207] In some embodiments, the third solvent comprises water or ethanol.

[0208] In some embodiments, the third solvent comprises water and ethanol.

[0209] In some embodiments, the third solvent is water or ethanol.

[0210] In some embodiments, the ethanokwater ratio in the third solvent is the same as the ethanol: water ratio in the second solvent.

[0211] In some embodiments, the ethanol water ratio in the third solvent 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).

[0212] In some embodiments, the fourth solvent comprises ethanol.

[0213] In some embodiments, the fourth solvent is ethanol.

[0214] In some embodiments, the methods for preparing Compound 1 further comprises purifying Compound 1.

[0215] In some embodiments, the methods for preparing Compound 1 further comprises crystallizing Compound 1.

[0216] In some embodiments, purifying Compound 1 comprises(VII-R)(i) adding Compound 1 in a first solvent to provide a first solution of Compound 1;(ii) optionally polish filtering the first solution of Compound 1 to provide a second solution of Compound 1;(iii) optionally concentrating the second solution of Compound 1 to provide a third solution of Compound 1;(iv) optionally adding a second solvent to the third solution of Compound 1 to provide a fourth solution of Compound 1;(v) optionally concentrating the fourth solution of Compound 1 to provide a fifth solution of Compound 1 until a target internal temperature of the fifth solution of Compound 1 reached;(vi) optionally adding a second solvent to the fifth solution of Compound 1 to provide a sixth solution of Compound 1;(vii) optionally cooling the sixth solution to provide a precipitate comprising Compound 1;(viii) optionally filtering the precipitate comprising Compound 1 to provide a cake comprising Compound 1; and(ix) optionally washing the cake comprising Compound 1 with a third solvent.

[0217] In some embodiments, the first solvent in step (VII-R) comprises dichloromethane or methanol.

[0218] In some embodiments, the first solvent in step (VII-R) comprises dichloromethane and methanol.

[0219] In some embodiments, the first solvent in step (VII-R) is dichloromethane or methanol.

[0220] In some embodiments, the first solvent in step (VII-R) is dichloromethane and methanol.

[0221] In some embodiments, the ratio of dichloromethane to methanol in the first solution in step (VII-R) is about 6: 1 (v / v) to about 10: 1 (v / v) or about 7.6: 1 (v / v).

[0222] In some embodiments, step (VII-R) further comprises adding 2,6-di-tert-butyl-4- methylphenol to the first solution of Compound 1.

[0223] In some embodiments, the first solution of Compound 1 in step (VII-R) is polish filtered.

[0224] In some embodiments, the second solution of Compound 1 in step (VII-R) comprises dichloromethane and methanol.

[0225] In some embodiments, the third solution of Compound 1 in step (VII-R) comprises dichloromethane and methanol.

[0226] In some embodiments, the second solvent in step (VII-R) comprises 1-BuOH.

[0227] In some embodiments, the second solvent in step (VII-R) is 1 -BuOH.

[0228] In some embodiments, the fourth solution of Compound 1 in step (VII-R) comprises dichloromethane, methanol, and 1 -BuOH.

[0229] In some embodiments, the fourth solution of Compound 1 in step (VII-R) further comprises seed crystals of Compound 1.

[0230] In some embodiments, the target internal temperature of the fifth solution of Compound 1 is about 40 °C to about 70 °C.

[0231] In some embodiments, the target internal temperature of the fifth solution of Compound 1 is about 60 °C.

[0232] In some embodiments, the fifth solution of Compound 1 in step (VII-R) comprises dichloromethane, methanol, and 1-BuOH.

[0233] In some embodiments, the sixth solution of Compound 1 in step (VII-R) comprises dichloromethane, methanol, and 1-BuOH.

[0234] In some embodiments, the sixth solution of Compound 1 is adjusted to about 50°C, about 60°C, or about 70°C.

[0235] In some embodiments, the sixth solution of Compound 1 is further cooled to a temperature of 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.

[0236] In some embodiments, the sixth solution of Compound 1 is further cooled to a temperature of about 20°C.

[0237] In some embodiments, the precipitate of Compound 1 is filtered.

[0238] In some embodiments, the cake of Compound 1 is washed.

[0239] In some embodiments, the third solvent comprises 1-BuOH or methyl tert-butyl ether(MTBE).

[0240] In some embodiments, the third solvent comprises 1 -BuOH and methyl tert-butyl ether (MTBE).

[0241] In some embodiments, the third solvent is 1-BuOH or methyl tert-butyl ether (MTBE).Definitions

[0242] 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 in this description is intended to describe particular embodiments only and is not intended to limit the disclosure.

[0243] Where a range of values is disclosed herein, it is understood that the present disclosure encompasses each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise (such as in the case of a group containing a number of carbon atoms; in such cases, each integer falling within the range is provided), from the upper to the lower limit ofthat range, and any other stated or intervening value in that stated range. As a non-limiting example, the range of 1-10 encompasses each of 1.0, 1.1. 1.2, 1.3, etc. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and these are also encompassed within the present disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0244] The following terms are used to describe the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure.

[0245] The articles “a” and “an” as used herein and in the appended claims 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.

[0246] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “both or either” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0247] As used herein in the specification and in the 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 being inclusive, i.e., the inclusion of at least one, but also optionally including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.”

[0248] In the claims, as well as in the specification above, 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., to include but not be limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Ninth Edition, Revision 10.2019, Section 2111.03.

[0249] As used herein in the specification and in the 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 elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting 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 including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0250] It should also be understood that, in certain methods described herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited unless the context indicates otherwise

[0251] As used herein, the term “crude composition” refers to the material produced in the performance of a chemical reaction procedure which has not been subjected to additional purification steps, e.g., separate post-reaction procedure steps, such as chromatography or recrystallization steps. In the preparation of a crude composition, the material can be subjected to simple steps, e.g., such as aqueous washes, solvent extractions and / or filtrations, which are considered an integral part of the reaction procedure, because such steps are commonly used to terminate a chemical reaction and / or to “work-up” a reaction product. Such reaction workup steps are not considered to be additional purification steps, as described above, but are merely part of the preparation of a crude composition.

[0252] As used herein, the term “mixture” or “reaction mixture” means a combination of more than one compound, usually within a solvent, that is about to undergo a chemical reaction, is in the process of undergoing a chemical reaction, or has undergone a chemical reaction.

[0253] As used herein, the term “reaction” means a process that leads to the chemical transformation of one set of chemical substances to another. As used herein, the term “to react” means to introduce chemical substances together to result in a chemical reaction.

[0254] As used herein, the term “cool” or “cooled” or “to cool” means to either passively allow by means of heat dissipation or act by using water or a heat sink (ice, dry ice, etc.) to actively decrease the temperature of an object, mixture, reaction mixture, concentrate, etc.

[0255] As used herein, the term “reducing agent” means a compound that loses (or "donates") an electron to an electron recipient (oxidizing agent) in a redox chemical reaction. Reducing agents include those generally known in the art including, for example, sodium hypophosphite (Nal PCh), formaldehyde (CH2O) and other aldehydes, formic acid (HCOOH), salts of formic acid, salts of borohydride (e.g., sodium borohydride (NaBH4)), salts of substituted borohydrides (e.g., sodium triacetoxyborohydride (Na(CH3CO2)3BH)), sodium alkoxides, lithium aluminum hydride ( Li Al H ), diisobutyl aluminum hydride (DIBAH), hydrazine (H2NNH2), and ammonia. Also used for reduction is catalytic hydrogenation.

[0256] As used herein, the term “camphorsulphonic acid” refers to a racemic mixture of camphorsulphonic acid, the pure (+)-camphorsulphonic acid, the pure (-)-camphorsulphonic acid or various ratios of (+)-camphorsulphonic acid: (-)-camphorsulphonic acid, depending on the context.

[0257] As used herein, the term “agent that induces nucleation” refers to any object, material or action that results in primary or secondary nucleation. Primary nucleation is the initial formation of a crystal where there are no other crystals present or where, if there are crystals present in the system, they do not have any influence on the crystallization process. This can occur in two conditions. The first is homogeneous nucleation, which is nucleation that is not influenced in any way by solids. These solids include the walls of the crystallizer vessel and particles of any foreign substance. The second category is heterogeneous nucleation, which occurs when solid particles of foreign substances (e.g., any substance that is physically or chemically distinct from the crystals to be formed) cause an increase in the rate of nucleation that would otherwise not occur without the presence of these foreign substances. Homogeneous nucleation rarely occurs in practice due to the high energy necessary to begin nucleation without a solid surface on which to catalyze the nucleation. Secondary nucleation is when crystal growth is initiated with contact of other existing crystals or "seeds". The first type of known secondary crystallization is attributableto fluid shear. The second type is due to collisions between already existing crystals with either a solid surface of the crystallizer or with other crystals themselves. Other agents that induce nucleation include devices, such as a DTB crystallizer, an evaporative crystallizer, or cooling crystallizers (e.g., a Swenson-Walker crystallizer).

[0258] As used herein, the term “antioxidant” refers to compounds that can neutralize free radicals by accepting or donating electron(s) to eliminate unpaired radicals that may form during a chemical reaction. The antioxidant molecules may directly react with the reactive radicals and destroy them, while they may become new free radicals which are less active, longer-lived and less dangerous than those radicals they have neutralized. They may be neutralized by other antioxidants or other mechanisms to terminate their radical status. For example, many antioxidants have aromatic ring structures and are able to delocalize the unpaired electron. Many antioxidants may directly react with any free reactive oxygen species (ROS) and / or free radical intermediates induced by ROS and terminate the chain reaction, thereby stopping the ROS-induced damage that may occur in a chemical reaction.

[0259] As used herein, the term “radical scavenger” refers to compounds that react with free radicals. Free radicals can cause autoxidation in a reaction mixture. Radical scavengers overlap with antioxidants and include the naturally occurring tocopherols (vitamin E derivatives) but also synthetic compounds such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and tertiary butylhydroquinone (TBHQ), among others. Radical scavengers also include one or more of 1,2,2,6,6-pentamethylpiperidinyl methacrylate, 2,2,6,6-tetramethylpiperidinyl methacrylate, bis(2,2,6,6-tetramethyl-4-piperidine)sebacate, a polymer of dimethyl succinate and 4-hydroxy-2,2,6,6,-tetramethyl-l -piperidineethanol, N,N',N",N'"-tetrakis-(4,6-bis-(butyl-(N- methyl-2,2,6,6-tetramethylpiperidine-4-yl) amino)-triazine-2-yl)-4,7-diazadecane-l,10-diamine, decanedioic acid bis(2,2,6,6-tetramethyl-l-(octyloxy)-4-piperidinyl)ester, bis( 1,2, 2,6,6- pentamethyl-4-piperidinyl) [[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]methyl]butylmalonate, a reaction product between a reaction product of cyclohexane and a peroxide N-butyl-2,2,6,6-tetramethyl-4-piperidineamine-2,4,6-trichloro-l,3,5- triazine and 2 -aminoethanol (for example, TINUVIN 152 manufactured by BASF Japan Ltd.), bis(l,2,2,6,6-pentamethyl-4-piperidinyl)sebacate, methyl- 1,2, 2,6, 6-pentamethyl -4- piperidylsebacate, tetrakis(l,2,2,6,6-pentamethyl-4-piperidine)-l,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'- butylidene bis(3-methyl-6-t-butylphenol), 1 , 1 ,3-tris(2-methyl-4-hydroxy-5-t-butylphenyl)butane, l,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, cyclicneopentane tetrayl bis(nonylphenyl)phosphite, cyclicneopentane tetrayl bis(dinonylphenyl)phosphite, cyclicneopentane tetrayl tris(nonylphenyl)phosphite, cyclicneopentane tetrayl tris(dinonylphenyl)phosphite, 10-(2,5-dihydroxyphenyl)- 10H-9-oxa- 10- phosphaphcnanthrene-10-oxide, diisodecyl pentaerythritol diphosphite, and tris(2,4-di-t- butylphenyl)phosphite, dilauryl 3,3'-thiodipropionate, distearyl 3,3'-thiodipropionate, N- cyclohexylthio phthalimide, N-n-butylbenzene sulfonamide.

[0260] As used herein, the term “remainder,” when used to refer to a solution or mixture, refers to whatever is left of the solution or mixture after any prior steps involving the solution or mixture have been carried out. As a non-limiting example, a process may involve the addition of a solution by portions, with a first amount of the solution being administered first, and the remainder of the solution being administered later. The remainder of a solution or mixture may comprise from between 0% to 100% of the original volume or the solution or mixture. If a step in a process refers to the remainder of a solution or mixture, and previous steps have consumed the entirety of the solution or mixture, the “remainder” is 0%, and none of the solution or mixture is used in that step.

[0261] As used herein, the term “oxygen scavenger” refers to a material which can combine with oxygen to reduce or completely remove oxygen content in a reaction mixture or fluid. By limiting the amount of oxygen present, the oxygen scavenger can reduce the number of deteriorative reactions that can lead to reduced yield, reduced conversion %, and / or reduced purity of a particular reaction.

[0262] As used herein, the term “metal chelator” refers to compounds that are capable of binding to metal ions. Usually, the metal chelation involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) 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 -bismorpholineamide, DO3A N-[[4,7,10- Tris(carboxymethyl)-l,4,7,10-tetraazacyclododec-l-yl]acetyl], HP-DO3A, DO3A-monoamide and derivatives thereof. Other chelators known in the art include, but are not limited to, HYNIC, DTPA, EDTA, TETA, and bisamino bisthiol (BAT) chelators (see also U.S. Pat. No. 5,720,934). For example, macrocyclic chelators, and in particular N4 chelators are described in U.S. Pat. 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 by reference herein in their entirety. CertainN3S chelators are described in PCT / CA94 / 00395, PCT / CA94 / 00479, PCT / CA95 / 00249 and in U.S. Pat. Nos. 5,662,885; 5,976,495; and 5,780,006, the disclosures of which are incorporated by reference herein in their entirety. The chelator may also include derivatives of the chelating ligand mercapto-acetyl-glycyl-glycyl-glycine (MAG3), which contains an N3S, and N2S2 systems such as MAMA (monoamidemonoaminedithiols), DADS (N2S diaminedithiols).

[0263] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0264] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were 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, nor does it constitute any admission as to the contents or date of the same. The disclosure having now been described by way of written description, those of skill in the art will recognize that the disclosure can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.EXAMPLESExample 1: Synthesis of Intermediate 3 (Step 1)2 3

[0265] Note: All numbers in this procedure are based on limiting reagent Intermediate 2.

[0266] A stainless steel pressure reactor was charged with a solution consisting ofIntermediate 2 (288.6 kg, 1.0 equiv) and methanol (1732 L, 6.0 L / kg). 20% Pd(OH)2 on carbon (8.6 kg, 3.0 wt%) was charged. The vessel was purged with nitrogen (3x), and then hydrogen (3x) at 10-30 °C, pressurized to 10 barg of hydrogen and stirred at 10-20°C for at least 6 h, at which time hydrogen uptake was complete. The vessel was depressurized and purged with nitrogen, and an aliquot was analyzed for reaction completion (<1.0% of Intermediate 2 remaining). The reaction mixture was fdtered through a glass fiber filter, rinsed with methanol (2 x 288 L, 2 x 1.0L / kg) to give a light-yellow solution of Intermediate 3, which was used without further purification in Step 2 (yield >99%, purity >99%).Example 2: Synthesis of Intermediate 5 (Step 2)

[0267] Note: All numbers in this procedure are based on limiting reagent Intermediate 4 after the potency correction.

[0268] A methanolic solution of Intermediate 3 (assay 189.4 kg, 1.1 equiv) from Step 1 was charged to a reaction vessel and the temperature was adjusted to 5 °C. Intermediate 4 (296.3 kg, 1.0 equiv) was added followed by acetic acid (56.4 kg, 1.1 equiv). The temperature was adjusted to 25 °C and stirred for 8 h. A solution of sodium cyanoborohydride (39.2 kg, 0.7 equiv) in methanol (1.0 L / kg) was added slowly to the reaction mixture at 0-25 °C. The mixture was warmed to 25 °C and was allowed to react until less than 2.0 A% of Intermediate 4 remaining. The temperature was adjusted to 40 °C, and the mixture was stirred for 10 h. Upon reaction completion (less than 1.0% of Intermediate tert-butyl (S)-4-(3-(((l-amino-5-(tert-butoxy)-l,5- dioxopentan-2-yl)amino)niethyl)-4-(methoxycarbonyl)phenyl)piperazine-l -carboxylate), water (592.6 L, 2.0 L / kg) was added, and the mixture was stirred for 30 minutes. The mixture was then concentrated under reduced pressure while adding ethyl acetate until methanol content was less than 1.0% and the final volume was at 6.0 L / kg. The mixture was then washed with aqueous NaCl solution (23 wt%, 7.0 L / kg). The organic phase was stirred with sulfhydryl silica gel (59.4 kg, 20 wt%), and the mixture was filtered through a celite plug. The solvent was switched to toluene with vacuum distillation at 40-50 °C with the final volume of 10.0 L / kg. Temperature was adjusted to 25 °C and n-heptane (1482 L, 5.0 L / kg) was added. The slurry was then cooled to 5 °C for 2 h and filtered. After washing with a mixture of toluene and heptane (3:2, 888 L, 3.0 L / kg) and heptane (741 L, 2.5 L / kg), the solid was dissolved with ethyl acetate (4740 L, 16.0 L / kg) and was filtered. The filtrate was concentrated under reduced pressure with temperature at less than 40 °C until the final volume at 3.0 to 4.0 L / kg. The temperature was adjusted to 25 °C and n-heptane (1778 L, 6.0L / kg) was added. The slurry was filtered, washed with n-heptane (593 L, 2.0 L / kg), and dried to yield Intermediate 5 as white solid (364.4 kg, 85.3% yield, 99.9% purity).Example 3: Synthesis of Intermediate 6 (Step 3)

[0269] Note: All numbers in this procedure are based on limiting reagent Intermediate 5.

[0270] To a glass-lined reactor was charged acetonitrile (760 L, 8.0 L / kg), sulfolane (190 L, 2.0 L / kg), and (1 £)-(+)- 10-camphorsulfonic acid (65.9 kg, 1.5 equiv). The water content of the mixture was tested to be less than 0.1% (azeotropic distillation with additional acetonitrile could be performed in case of water content was above 0.1%). Intermediate 5 (95 kg, 1.0 equiv) was added, and the mixture was heated to reflux and was allowed to react for 24 h. Upon reaction completion (less than 2.0% of Intermediate (S)-5-amino-5-oxo-4-(l-oxo-5-(piperazin-l- yl)isoindolin-2-yl)pentanoic acid), the temperature was adjusted to 20 °C. The slurry was filtered, washed with acetonitrile (3 x 195 L, 2.0 L / kg), and dried to give Intermediate 6 as white solid (95.3 kg, 90.0% yield, >97% achiral purity, >98.5 chiral purity).Example 4: Synthesis of Intermediate 8 (Step 4)

[0271] Note: All numbers in this procedure are based on limiting reagent Intermediate 7.

[0272] A pressure reactor was charged with 5% Pd / C (EvonikNoblyst®P1095, 10 wt %, 26.5 kg). A solution of Intermediate 7 (265 kg, 1.0 eq) in THF (3445 L, 13.0 L / kg) was then added at 15 °C. The vessel was purged with nitrogen (3x), and then hydrogen (3x), pressurized to 3.8 barg of hydrogen. The mixture was warmed to 43 °C and held at 43 °C for 12.5 h. The temperature was then increased to 60 °C, and the mixture was held at 60 °C for at least 10 h. The vessel was depressurized and purged with nitrogen, and an aliquot was analyzed for reaction completion(<0.5% of 7, <0.3% of Intermediate 5-(4-(4-(dimethoxymethyl)piperidin- 1 -yl)phenyl)-6-phenyl- 7,8-dihydronaphthalen-2-ol, and <0.9% of Intermediate l -(4-(( l / ?,2S)-6-(benzyloxy)-2-phenyl- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)phenyl)-4-(dimethoxymethyl)piperidine remaining). The reaction mixture was filtered through a glass fiber filter, rinsed with THF (795 L, 3.0 L / kg) to give a light-yellow solution of Intermediate 8, which was used without further purification in Step 5.Example 5: Synthesis of Intermediate 9 (Step 5)

[0273] Note: All numbers in this procedure are based on limiting reagent Intermediate 7 in Step 4.

[0274] The THF solution of Intermediate 8 from Step 4 was concentrated under atmospheric pressure to final volume of 6.0 L / kg and water content was tested to be <1 % (azeotropic distillation with additional THF could be performed in case of water content was above 1%). To the mixture was charged isopropyl alcohol (2756 L, 10.4 L / kg), and the temperature was adjusted to 75 °C to give a clear solution. In a separate vessel, a D-Proline solution was prepared by combining isopropyl alcohol (424 L, 1.6 L / kg), water (66.3 L, 0.25 L / kg) and D-Proline (34.1 kg, 0.61 eq.). The temperature of the solution of Intermediate 8 in THF / IPA was adjusted to 70 °C and 15% of the D-Proline solution was added. The temperature was then adjusted to 60 °C, and seed crystals of Intermediate 9 (1.06 kg, 0.4 wt%) were added. The temperature of the mixture was adjusted to 70 °C and the remaining 85% D-Proline solution was added. After 2.5 h at 70 °C, the slurry was cooled to 25 °C and filtered. The cake was washed with isopropyl alcohol (3 x 663 L, 3 x 2.5 L / kg), and dried at 70 °C to give Intermediate 9 as white solid (111.2 kg, 40% overall yield of Steps 4 and 5).Example 6: Synthesis of Intermediate 10 (Step 6)

[0275] Note: All numbers in this procedure are based on limiting reagent Intermediate 9.

[0276] To a glass-lined reactor was charged Intermediate 9 (29.2 kg, 1.0 eq), 2,6-di-to7- butyl-4-methylphenol (0.56 kg, 0.05 equiv), and tetrahydrofuran (146 L, 5.0 L / kg). Sulfuric acid (20 wt% in water, 87.7 L, 4.0 equiv) was charged. The mixture was wanned to 30 °C and held for 8 h. Upon reaction completion (less than 1.7% of Intermediate 9 remaining), an aqueous solution of trisodium citrate (34 wt% in water, 204 L, 7.0 L / kg) was added and the aqueous layer was removed. The organic layer was concentrated under atmospheric pressure with additional tetrahydrofuran (2 x 175 L, 2 x 6.0 L / kg) to reach the water content target of <1.0%. Dimethylacetamide (58.4 L, 2.0 L / kg) was charged, and the mixture was concentrated under reduced pressure with temperature <55 °C until the content of tetrahydrofuran was <10%. The solution of Intermediate 10 in DMAc was used without further purification in Step 7.Example 7: Synthesis of Compound 1 (Step 7)

[0277] Note: All numbers in this procedure are based on limiting reagent 9 in Step 6.

[0278] To a glass-lined reactor was charged Intermediate 6 (28.6 kg , 1.0 equiv), sodium triacetoxyborohydride (13.0 kg, 1.2 equiv), A-methylmorpholine (11.8 L, 2.1 equiv), and dimethylacetamide (73 L, 2.5 L / kg). The mixture was cooled to 0 °C, and the solution of Intermediate 10 in DMAc from Step 6 was added over 2 h. The reaction mixture was held at 0 °C for 2 h, and an aliquot was analyzed for reaction completion (<1.75% of Intermediate 10 remaining). Water (14.6 L, 0.5 L / kg) was charged, and the mixture was warmed to 15 °C for 5 h. To a separate vessel were charged ethanol (234 L, 8.0 L / kg), water (234 L, 8.0 L / kg), and seed crystals of Compound 1 (0.29 kg, 1.0 wt%). The EtOH / water mixture was heated to 58 °C, and the above reaction mixture was added into EtOH / water mixture over 1 h. The mixture was held at 58 °C for 1 h, and cooled to 40 °C and filtered. The cake was washed with a 1 : 1 mixture of ethanol and water (2 x 73 L, 2 x 2.5 L / kg) followed by ethanol (73 L, 2.5 L / kg), and dried at 60 °C to yield crude Compound 1 as white solid (29.5 kg, 80%).Example 8: Crystallization of Compound 1

[0279] Note: All numbers in this procedure are based on limiting reagent Compound 1.

[0280] The crude Compound 1 (24.4 kg, 1.0 equiv) and 2,6-di-tert-butyl-4-methylphenol (0.027 kg, 0.004 equiv) were charged to a reaction vessel and dissolved in DCM (149 L, 6. 1 L / kg) and MeOH (19.5 L, 0.8 L / kg). The solution was polish filtered into the crystallization vessel and concentrated under atmospheric pressure to a final volume of about 3.2 L / kg. 1-BuOH (54 L, 2.2 L / kg) was charged at 33-39 °C, and seed crystals of Compound 1 (0.049 kg, 0.2 wt%) were added. The mixture was concentrated under atmospheric pressure until internal temperature reached 60 °C. 1 -BuOH (51 L, 2. 1 L / kg) was charged with internal temperature above 50 °C. The temperature was adjusted to 60 °C and the mixture was held for 2 h. The mixture was then cooled to 20 °C, held for 14 h, and filtered. The cake was washed with 1-BuOH (73 L, 3.0 L / kg) and MTBE (73 L, 3.0 L / kg), and dried at 70 °C to yield Compound 1 as white solid (22.4 kg, 92%).EQUIVALENTS

[0281] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

[0282] The methods of the disclosure have been described herein by reference to certain preferred embodiments. However, as particular variations thereon will become apparent to those skilled in the art, based on the disclosure set forth herein, the disclosure is not to be considered as limited thereto.

[0283] 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. In the specification and claims, the singular forms also include the plural unless the context clearly dictates otherwise.

[0284] It is to be understood that at least some of the descriptions of the disclosure have been simplified to focus on elements that are relevant for a clear understanding of the disclosure, while eliminating, for purposes of clarity, other elements that those of ordinaiy skill in the art will appreciate may also comprise a portion of the disclosure. However, because such elements are well known in the art, and because they do not necessarily facilitate a better understanding of the disclosure, a description of such elements is not provided herein.

[0285] Further, to the extent that a method does not rely on the particular order of steps set forth herein, the particular order of the steps recited in a claim should not be construed as a limitation on that claim.

[0286] All patents, patent applications, references and publications cited herein are fully and completely incorporated by reference as if set forth in their entirety. Such documents are not admitted to be prior art to the present disclosure.

Claims

CLAIMS1. A method, comprising(IV) reacting Intermediate 7:and a hydrogen source and, optionally, a catalyst, in a solvent to provide Intermediate8:

2. A method, comprising(V)(a) heating a mixture comprising Intermediate 8:and a solvent, to provide a first solution;(b) combining (R)-proline, isopropyl alcohol, and water to prepare a second solution;(c) adding about 1% to less than about 50% by volume of the second solution to the first solution to prepare a first reaction mixture;(d) adding an agent that induces nucleation to the first reaction mixture to prepare a second reaction mixture, followed by adjusting the second reaction mixture to a temperature of about 60 °C to about 70 °C;(e) adding the remainder of the second solution to the second reaction mixture to prepare a third reaction mixture to provide Intermediate 9:

3. The method of claim 2, wherein Intermediate 8 is prepared according to the method of claim 1.

4. The method of claim 1 or 3, wherein the catalyst in step (IV) comprises Pd / C.

5. The method of any one of claims 1 and 3-4, wherein the hydrogen source in step (IV) comprises hydrogen gas.

6. The method of any one of claims 1 and 3-5, wherein the solvent in step (IV) comprises tetrahydrofuran.

7. The method of claim 3, wherein the method does not comprise purification of Intermediate 8 using chromatography or crystallization.

8. The method of claim 7, wherein Intermediate 8 used in step (V) is provided as a solution comprising Intermediate 8 and tetrahydrofuran.

9. The method of any one of claims 2-8. wherein the solvent in the mixture in step (V -a) comprises isopropyl alcohol, tetrahydrofuran. or a combination thereof.

10. The method of any one of claims 2-9, wherein the agent in step (V-d) is a seed cry stal comprising Intermediate 9.

11. A method, comprising(VI) reacting Intermediate 9:with an acid, in a first solvent to provide a first solution comprising Intermediate 10:(VII) reacting Intermediate 10:with Intermediate 6:a base, and a reducing agent in a solvent to provide Compound 1:

12. The method of claim 11, wherein the acid in step (VI) comprises sulfuric acid.

13. The method of claim 11 or 12, wherein the solvent in step (VI) comprises tetrahydrofuran.

14. The method of any one of claims 11-13, wherein the method does not comprise purification of Intermediate 10 using chromatography or crystallization.

15. The method of any one of claim 1 1-14, wherein Intermediate 10 used in step (VII) is provided as a solution comprising Intermediate 10 and dimethylacetamide.

16. The method of any one of claims 11-15, wherein the base in step (VII) comprises N- methyl-morpholine.

17. The method of any one of claims 11-16, wherein the solvent in step (VII) comprises dimethylacetamide.

18. A method, comprising(III) reacting Intermediate 5:and (+)-camphorsulfonic acid in a solvent to provide Intermediate 6:wherein the solvent comprises sulfolane.

19. The method of claim 11, wherein Intermediate 9 is prepared according to the method of claim 2.

20. The method of claim 11, wherein Intermediate 6 is prepared according to the method of claim 18.

21. A method, comprising:(III) reacting Intermediate 5:and (+)-camphorsulfonic acid in a solvent to provide Intermediate 6:wherein the solvent comprises sulfolane;(IV) reacting Intermediate 7:and a hydrogen source and, optionally, a catalyst, in a solvent to provide Intermediate 8:(V)(a) heating a mixture comprising Intermediate 8:and a solvent, to provide a first solution;(b) combining (R)-proline, isopropyl alcohol, and water to prepare a second solution;(c) adding about 1% to less than about 50% by volume of the second solution to the first solution to prepare a first reaction mixture;(d) adding an agent that induces nucleation to the first reaction mixture to prepare a second reaction mixture, followed by adjusting the second reaction mixture to a temperature of about 60°C to about 70 °C:(e) adding the remainder of the second solution to the second reaction mixture to prepare a third reaction mixture to provide Intermediate 9:(VI) reacting Intermediate 9:with an acid, in a first solvent to provide a first solution comprising crude Intermediate10:(VII) reacting Intermediate 10:with Intermediate 6:a base, and a reducing agent in a solvent to provide Compound 1:

22. Compound 1 manufactured by the method of any one of claims 11-17 and 19-21.

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