Synthesis of brensocatib((2S)-n-((1S)-1-cyano-2-(4-(3-methyl-2-OXO-2,3 -dihydrobenzo[d]oxazol-5-YL)phenyl)ethyl)-1,4-oxazepane-2-carboxamide)

Abstract

The present invention relates to: 1. A method of synthesizing Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein the method comprises: step 1 A: in a reactor, reacting Compound A with Compound B in a solution in the presence of a metal catalyst, to provide a solution comprising Compound C; and step 1B: treating the solution comprising Compound C with a metal scavenger, wherein Compound C is converted to Compound 1 in two or more additional steps. 57. A method of synthesizing Compound E having the structure (Compound E), according to the steps as shown below: 59. Compound 1, or a pharmaceutically acceptable salt or hydrate thereof prepared by the method of any one of claims 1-56. wherein Compound 1 or a pharmaceutically acceptable salt or hydrate thereof, has a purity greater than 98.1%.

Description

SYNTHESIS OF (2S)-N-((lS)-l-CYANO-2-(4-(3-METHYL-2-OXO-2,3- DIHYDROBENZO[D]OXAZOL-5-YL)PHENYL)ETHYL)-l,4-OXAZEPANE-2- CARBOXAMIDECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to European Patent Application No. 24383243.3, filed on November 15, 2024, the content of which is hereby incorporated by reference in its entirety for all purposes.BACKGROUND

[0002] (2S)-N-((lS)-l-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-l,4-oxazepane-2-carboxamide (Compound 1, also known as brensocatib, CAS number 1802148-05-5) has demonstrated inhibitory activity for DPP1 and is being investigated in clinical trials. Brensocatib is a promising candidate for treating various diseases associated with DPP1 and neutrophil elastase.

[0003] U.S. Pat. No. 9,522,894 discloses syntheses of brensocatib at the scale of up to about 1.3 kilogram. However, large scale synthesis (e.g., tens and hundreds of kilograms) of brensocatib with high purity and low palladium content is not reported.SUMMARY

[0004] Aspects of the present disclosure relate to synthetic methods of Compound 1(Compound 1, or “brensocatib”), or a pharmaceutically acceptable salt or hydrate thereof. In one embodiment, synthesis of brensocatib monohydrate is provided.

[0005] In some embodiments, the method comprises:step 1 A: reacting Compound A with Compound B in solution, in the presence of a metal catalyst to provide Compound C; andstep IB: treating the solution comprising Compound C with a metal scavenger.

[0006] In some embodiments, the metal scavenger is N-acetyl cysteine.

[0007] Compound C is then converted to Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, in additional steps, e.g., two, three, four, five or six additional steps.

[0008] In some embodiments, the metal catalyst in step 1A is Pd(dppf)C12, Pd(Oac)2, PdCh, Pd(PPh3)2Ch, Pd(PPh3)4, Pd2(dba)3, Pd(PhCN)2Cl2, PEPPSI-iPr, PdCl2[P(Cy)3]2, NiCh, NiCh-diglyme or Ni(COD)2.

[0009] In one embodiment, the metal catalyst in step 1 A is a catalytic palladium compound. In a further embodiment, the metal catalyst is Pd(dppf)C12, Pd(Oac)2, PdCh, Pd(PPh3)2Ch, Pd(PPh3)4, Pd2(dba)3, Pd(PhCN)2C12 or PdCh[P(Cy)3]2. In a further embodiment, the metal catalyst is Pd(dppf)C12.

[0010] In some embodiments, step 1A of the method comprises adding a base to a mixture comprising Compound A, Compound B and the metal catalyst. In a further embodiment, the base is K2CO3, K3PO4, K2HPO4, KHCO3, CS2CO3, Na2CO3, NaHCO3, K2CO3, KF, NaOAc or KO Ac. In a further embodiment, the base is K2CO3. The mixture can then be heated and stirred.

[0011] In some embodiments, step 1A of the method further comprises the use of a solvent, wherein the solvent comprises acetonitrile and water. For example, in one embodiment, acetonitrile is added to the solution subsequent to the addition of Compound A, Compound B and the metal catalyst. In another embodiment, acetonitrile is added to the solution subsequent to the addition of Compound A, Compound B and the metal catalyst, and prior to the base addition.

[0012] In some embodiments, step 1 A of the method is performed at a temperature in the range from about 40 °C to about 80 °C. In a further embodiment, step 1 A of the method is performed at a temperature of about 70 °C.

[0013] In some embodiments, Compound A and Compound B of step 1 A are reacted in a weight ratio of from 1:2 to 2:1. In some embodiments, Compound A and Compound B of step 1A are reacted in a weight ratio of about 1:1. In some embodiments, Compound A and Compound B of step 1A are reacted in a molar ratio of from 1:2 to 2:1. In some embodiments, Compound A and Compound B of step 1 A are reacted in a molar ratio of about 1 : 1

[0014] In some embodiments, step IB of the method further comprises addition of a solvent to the reaction mixture, wherein the solvent comprises isopropyl acetate (AcOiPr).

[0015] In some embodiments, Compound C obtained in step IB is taken to step 2 without isolating Compound C from step IB.

[0016] In some embodiments, the method further comprises:step 2: deprotecting Compound C via acid treatment, to provide Compound D:step 2

[0017] In one embodiment, the acid is formic acid. In a further embodiment, upon addition of formic acid to the reaction, the reaction is concentrated, e.g., via distillation under vacuum.

[0018] In some embodiments, a solvent, e.g., a solvent comprising isopropyl acetate is added after concentrating.

[0019] Compound D, in one embodiment, is a solid product and is collected by filtration.

[0020] In some embodiments, the method affords Compound D with a palladium content lower than 60 ppm. In some embodiments, the method affords Compound D with a palladium content lower than 30 ppm. In some embodiments, the method affords Compound D with a palladium content lower than 10 ppm.

[0021] In embodiments described herein, the method further comprises:step 3 : reacting Compound D with Compound E to provide Compound F

[0022] In some embodiments, the reaction between the carboxylic acid of compound E and the primary amine of compound D is mediated by acid activation, e.g., via propylphosphonic anhydride (T3P), e.g., in the presence of N,N-diisopropylethylamine (DIPEA).

[0023] In a further embodiment, step 3 is performed in a solvent comprising acetonitrile. For example, T3P may be provided as a 50% solution in acetonitrile.

[0024] Compound F, in one embodiment, is not isolated prior to subjecting it to a subsequent dehydration reaction.

[0025] In some embodiments, the method further comprises:step 4: dehydrating Compound F to form Compound G

[0026] In some embodiments, Compound F is not isolated from reaction step 3 before being reacted in step 4. In such embodiments, steps 3 and 4 are combined as step 3’ (provided as Scheme 3 herein).

[0027] Step 3’: reacting Compound D with Compound E to provide Compound G (through intermediate Compound F).Scheme 3 - Step 3’ comprising step 3 and step 4

[0028] In some embodiments, the method affords Compound G, or a pharmaceutically acceptable salt or hydrate thereof, with a palladium content lower than 40 ppm. In some embodiments, the method affords Compound G, or a pharmaceutically acceptable salt or hydrate thereof, with a palladium content lower than 30 ppm. In some embodiments, the method affords Compound G, or a pharmaceutically acceptable salt or hydrate thereof, with a palladium content lower than 10 ppm.

[0029] In some embodiments, the method further comprises:step 5: reacting Compound G to provide Compound 1, or a pharmaceutically acceptable salt or hydrate thereof:

[0030] In some embodiments, step 5 of the method (deprotection) is performed in the presence of formic acid. For example, formic acid and Compound G, in one embodiment, are stirred in a reactor. The mixture can be heated while stirred, followed by cooling. In a further embodiment, step 5 further includes the addition of a solvent after addition of the formic acid. The solvent, in one embodiment, comprises water, isopropyl acetate, ethanol or a combination thereof.

[0031] In some embodiments, Compound 1 prepared by step 5 is a hydrate.

[0032] Compound 1 prepared by step 5, in embodiments provided herein, is a crude solid product.

[0033] In some embodiments, the method further comprises recrystallizing the crude solid of Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, from a solvent. In some embodiments, the solvent comprises ethanol and water. For example, in one embodiment, the crude product is mixed with water and ethanol and heated until dissolved into solution. The solution can be filtered, cooled and seeded with Compound 1 seeds while stirring. Solid can be collected on a filter and washed with a mixture of water and ethanol.

[0034] In some embodiments, the method provided herein is performed on a scale greater than 1.5 kilograms. In some embodiments, the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, at a scale greater than 5 kilograms. In some embodiments, the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, at a scale greater than 10 kilograms.

[0035] In some embodiments, the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, with a purity greater than 98.1%. In some embodiments, the method affords Compound 1 or a pharmaceutically acceptable salt or hydrate thereof, with a purity greater than 98.5%. In some embodiments, the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, with a purity greater than 99.0%.

[0036] In some embodiments, the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof with a palladium content lower than 50 ppm. In some embodiments, the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof with a palladium content lower than 25 ppm. In some embodiments, the method affords Compound 1 with a palladium content lower than 5 ppm. In some embodiments, the method affords Compound1, or a pharmaceutically acceptable salt or hydrate thereof with a palladium content lower than 3 ppm.

[0037] In some embodiments, Compound 1 prepared by any of the methods disclosed herein is a hydrate. In some embodiments, Compound 1 prepared by any of the methods disclosed herein is a monohydrate.

[0038] In one aspect, the present disclosure provides a method of synthesizing Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, according to FIG. 1.

[0039] In one aspect, the present disclosure provides a method of synthesizing Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, according to FIG. 3.

[0040] In one aspect, the present disclosure provides a method of synthesizing Compound E,(Compound E), according to the steps as shown below in Scheme 2.Scheme 2: Synthesis of Compound EStep a Step b

[0041] In one embodiment, a method is provided for the synthesis of compound E. In a further embodiment, the method for the synthesis of compound E is the method provided at FIG. 2.

[0042] In one embodiment, the present disclosure provides a method of synthesizing Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, according to FIG. 1 or FIG. 3, wherein Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, has a purity greater than 98.1%.

[0043] In one aspect, the present disclosure provides Compound 1,(Compound 1), or a pharmaceutically acceptable salt or hydrate thereof, prepared by any of the methods provided herein. In embodiments, Compound 1 or a pharmaceutically acceptable salt or hydrate thereof, prepared by any of the methods provided herein, has a purity of at least 98.1%. In embodiments, Compound 1 or a pharmaceutically acceptable salt or hydrate thereof, prepared by any of the methods provided herein, has a purity of at least 99%. In embodiments, Compound 1 or a pharmaceutically acceptable salt or hydrate thereof, prepared by any of the methods provided herein, contains less than 3 ppm metal. In embodiments, Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, provided herein is a hydrate of Compound 1. In embodiments, Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, provided herein is a monohydrate of Compound 1.BRIEF DESCRIPTION OF THE DRAWINGS

[0044] FIG. 1 shows one embodiment of a synthesis scheme for Compound 1.

[0045] FIG. 2 shows one embodiment of a synthesis scheme for Compound E. (Cmpd: compound).

[0046] FIG. 3 shows one embodiment of a synthesis scheme for Compound 1. (Cmpd: compound).DETAILED DESCRIPTION

[0047] The present disclosure relates a method of synthesizing Compound 1,(Compound 1), or a pharmaceutically acceptable salt or hydrate thereof.

[0048] Compound 1, (2S)-N-((lS)-l-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-l,4-oxazepane-2-carboxamide (also known as brensocatib, CAS No. 1802148-05-5), including synthetic methods and uses, is disclosed in U.S. Pat. 9,522,894, which is incorporated by reference in its entirety for all purposes. All publications, patents and patent applications, including any drawings and appendices therein are incorporated by reference in theirentirety for all purposes to the same extent as if each individual publication, patent or patent application, drawing, or appendix was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.Definitions

[0049] The following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[0050] Compound 1 is (2S)-N-((lS)-l-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-l,4-oxazepane-2-carboxamide having the structure> (Compound 1). In some embodiments, Compound 1 prepared by any of the methods disclosed herein is a polymorph. In some embodiments, Compound 1 is a monohydrate (MH), i.e., brensocatib MH, having the CAS registry number 2923839-30-7).

[0051] Throughout the present specification, the terms “about” and / or “approximately” may be used in conjunction with numerical values and / or ranges. The term “about” is understood to mean those values near to a recited value. Furthermore, the phrases “less than about [a value]” or “greater than about [a value]” should be understood in view of the definition of the term “about” provided herein. The terms “about” and “approximately” may be used interchangeably.

[0052] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).

[0053] The term “a” or “an” refers to one or more of that entity; for example, “a metal catalyst” refers to one or more metal catalysts or at least one metal catalyst. As such, the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein. In addition, reference to “an acid” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the acids is present, unless the context clearly requires that there is one and only one of the acids.

[0054] As used herein, the verb “comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present invention may suitably “comprise”, “consist of’, or “consist essentially of’, the steps, elements, and / or reagents described in the claims.

[0055] The term “pharmaceutically acceptable salt” includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0056] The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art.

[0057] The present disclosure relates to a method of synthesizing Compound 1,(Compound 1), or a pharmaceutically acceptable salt or hydrate thereof. In a further embodiment, the present disclosure relates to a method of synthesizing the monohydrate of Compound 1, i.e., brensocatib MH, having the CAS registry number 2923839-30-7.

[0058] In one embodiment, the synthesis method comprises Step 1, which comprises Steps 1A and Step IB.step 1

[0059] Step 1A, in one embodiment, comprises reacting Compound A, or a pharmaceutically acceptable salt thereof, with Compound B, or a pharmaceutically acceptable salt thereof, in the presence of a metal catalyst in solution, to provide a solution comprising Compound C, or a pharmaceutically acceptable salt.

[0060] Step IB, in one embodiment, comprises treating a solution comprising Compound C, or a pharmaceutically acceptable salt thereof, with a metal scavenger. The metal scavenger, in embodiments described herein, is isopropyl acetate. The solution comprising Compound C, in one embodiment, is a filtered through a filter prior to the addition of the metal scavenger.

[0061] In a preferred embodiment, the metal catalyst is Pd(dppf)C12 and the metal scavenger is N-acetyl cysteine.

[0062] In some embodiments, the metal catalyst in step 1A is Pd(dppf)C12, Pd(Oac)2, PdCh, Pd(PPh3)2Ch, Pd(PPh3)4, Pd2(dba)3, Pd(PhCN)2Cl2, PEPPSI-iPr, PdCl2[P(Cy)3]2, NiCh, NiCh-diglyme or Ni(COD)2. In one embodiment, the metal catalyst in step 1A is a catalytic palladium compound. In a further embodiment, the metal catalyst is Pd(dppf)C12, Pd(Oac)2, PdCh, Pd(PPh3)2Ch, Pd(PPh3)4, Pd2(dba)3, Pd(PhCN)2Cl2or PdCl2[P(Cy)3]2. In a further embodiment, the metal catalyst is Pd(dppf)C12.

[0063] In embodiments, step IB comprises introducing the metal scavenger into the solution comprising Compound C. In a further embodiment, the metal is palladium. The solution comprising Compound C, in one embodiment, is a filtered solution.

[0064] In some embodiments, the solution comprising Compound C comprises water and Compound C. In some embodiments, the solution comprising Compound C comprises acetonitrile, water and Compound C. In some embodiments, the solution comprising Compound C comprises isopropyl acetate, acetonitrile, water and Compound C. Removing metals such as palladium and / or nickel can be accomplished via the methods described in U.S. Patent No.6,239,301, the disclosure of which is incorporated by reference in its entirety.

[0065] The metal scavenger of step IB, in one embodiment, comprises cysteine, N-acetyl cysteine, l,2-bis(diphenylphosphino)ethane, 1,2-diaminopropane, propylamine, diaminoethane, A7-(2-aminoethyl)ethane-l,2-diamine, trithiocyanuric acid, ethanedithiol, thiophenol, diethylthiourea, triphenylphosphine oxide, 2-mercaptonicotinic acid or any combination thereof. In embodiments, the metal scavenger of step IB is N-acetyl cysteine.

[0066] In embodiments, the metal catalyst loading in step 1A is in the range of about 20 / 1 (substrate / metal catalyst = S / C) to about 2,000 / 1, including all values and ranges therebetween is used. In embodiments, the catalyst loading (S / C) is in the range of from about 25 / 1 to about1,000 / 1. In embodiments, the catalyst loading (S / C) is in the range of about 200 / 1 to about 1,000 / 1. In embodiments, the catalyst loading (S / C) is about 25 / 1, about 50 / 1, about 100 / 1, about 150 / 1, about 200 / 1, about 250 / 1, about 300 / 1, about 350 / 1, about 400 / 1, about 450 / 1, about 500 / 1, about 550 / 1, about 600 / 1, about 650 / 1, about 700 / 1, about 750 / 1, about 800 / 1, about 850 / 1, about 900 / 1, about 950 / 1, about 1,000 / 1, about 1,100 / 1, about 1,200 / 1, about 1,300 / 1, about 1,400 / 1, about 1,500 / 1, about 1,600 / 1, about 1,700 / 1, about 1,800 / 1, about 1,900 / 1, or about 2,000 / 1. In embodiments, the catalyst loading (S / C) is in the range of about 100 / 1 to about 400 / 1, including all values and ranges therebetween. In embodiments, the catalyst loading (S / C) is in the range of about 10 / 1 to about 300 / 1. In embodiments, the catalyst loading (S / C) is in the range of about 150 / 1 to about 250 / 1, including all values and ranges therebetween. In embodiments, the catalyst loading (S / C) is in the range of about 180 / 1 to about 220 / 1. In embodiments, the catalyst loading (S / C) is about 200 / 1. In embodiments, the catalyst loading is based on molar equivalence.

[0067] In embodiments, step 1 A further comprises the use of a base, wherein the base is selected from K2CO3, K3PO4, K2HPO4, KHCO3, CS2CO3, Na2CO3, NaHCCh, K2CO3, KF, NaOAc or KO Ac. In embodiments, the base used in step 1 A is K2CO3. In one embodiment, the metal catalyst, e.g., palladium catalyst, is added to a reactor comprising compound A and compound B, followed by addition of the base. In a further embodiment, the base is K2CO3. The subsequent mixture can then be heated and stirred, and subsequently cooled. The cooled mixture can then be transferred to another reactor through a filter, prior to the addition of a metal scavenger in step IB.

[0068] In one embodiment, step 1 A further comprises the use of a solvent. In embodiments, the solvent used in step 1 A is an organic solvent. In embodiments, the solvent used in step 1 A is an aqueous solvent. In embodiments, the solvent used in step 1 A is a mixture of organic and aqueous solvents. In embodiments, the solvent used in step 1 A comprises acetonitrile. In embodiments, the solvent used in step 1 A comprises water. In embodiments, step 1 A further comprises the use of a solvent, wherein the solvent comprises acetonitrile and water. In one embodiment, the metal catalyst, e.g., palladium catalyst, is added to a reactor comprising Compound A and Compound B, followed by addition of the solvent, followed by addition of the base. In a further embodiment, the solvent comprises acetonitrile. In even a further embodiment, the base is K2CO3. Components in the reactor, in one embodiment, are heated and stirred. In a further embodiment, the mixture is heated and stirred for about 2 hours to about 4 hours.

[0069] As provided above, metal catalyst is removed via the use of a metal scavenger in step IB. In embodiments, step IB further comprises the use of a solvent. The solvent, in one embodiment, comprises an organic solvent. In another embodiment, the solvent used in step IB comprises an aqueous solvent. In embodiments, the solvent used in step IB comprises water. In embodiments,the solvent used in step IB comprises an ester solvent. In yet another embodiment, the solvent comprises isopropyl acetate. In embodiments, step IB further comprises the use of a solvent, wherein the solvent comprises water and isopropyl acetate. The solvent, in one embodiment, is added to the reaction mixture prior to the addition of the metal scavenger. In one embodiment, once solvent and metal scavenger are added, the reaction is agitated. In a further embodiment, the metal scavenger comprises N-acetyl cysteine.

[0070] In embodiments, step 1A and step IB are performed in sequence. In embodiments, step IB is performed after step 1 A is completed.

[0071] In one embodiment of Step 1 (comprising steps 1 A and IB), Compound A, Compound B and a palladium catalyst, are charged into a reactor followed by addition of solvent. A solution of base in water, in a further embodiment, is transferred to the reactor. The mixture, in a further embodiment, is heated and stirred. The mixture, in a further embodiment, is cooled and transferred to another reactor through a filter. In a further embodiment, solvent is charged to the mixture and is heated. Water and a metal scavenger, in a further embodiment, are charged into the reactor and stirred. The agitation is stopped, in one embodiment, to allow for phase separation. Water and sodium chloride solution, in a further embodiment, is charged to the reactor with the organic phase and stirred and the solution is allowed to separate. The organic phase is filtered. Isopropyl acetate is then charged into a reactor and is distilled under vacuum.

[0072] In another embodiment of Step 1 (comprising steps 1 A and IB), Compound A, Compound B and Pd(dppf)C12 are charged into a reactor followed by addition of acetonitrile. A solution of potassium carbonate in water, in a further embodiment, is transferred to the reactor. The mixture, in a further embodiment, is heated and stirred. The mixture, in a further embodiment, is cooled and transferred to another reactor through a filter. In a further embodiment, isopropyl acetate is charged to the mixture and is heated. Water and Wacetyl cysteine, in a further embodiment, are charged into the reactor and stirred. The agitation is stopped, in one embodiment, to allow for phase separation. Water and sodium chloride solution, in a further embodiment, is charged to the reactor with the organic phase and stirred and the solution is allowed to separate. The organic phase is filtered. Isopropyl acetate is then charged into a reactor and is distilled under vacuum.

[0073] In embodiments, step 1A is performed at a temperature in the range from about 40 °C to about 90 °C, including all values and ranges therebetween. In embodiments, step 1 A is performed at a temperature in the range from about 40 °C to about 85 °C, including all values and ranges therebetween. In embodiments, step 1 A is performed at a temperature in the range from about 40 °C to about 80 °C, including all values and ranges therebetween. In embodiments, step 1A is performed at a temperature in the range from about 50 °C to about 80 °C, including all values andranges therebetween. In embodiments, step 1A is performed at a temperature in the range from about 60 °C to about 80 °C, including all values and ranges therebetween. In embodiments, step 1A is performed at a temperature in the range from about 65 °C to about 75 °C, including all values and ranges therebetween. In embodiments, step 1A is performed at a temperature in the range from about 65 °C to about 73 °C, including all values and ranges therebetween. In embodiments, step 1 A is performed at a temperature of about 70 °C.

[0074] In embodiments, Compound A and Compound B of step 1 A are reacted in a weight ratio of from 1:2 to 2:1 (A:B to A:B), including all values and ranges therebetween. In embodiments, Compound A and Compound B of step 1A are reacted in a weight ratio of from 1:1.5 to 1.5:1. In embodiments, Compound A and Compound B of step 1A are reacted in a weight ratio of from 1 : 1.4 to 1.4: 1. In embodiments, Compound A and Compound B of step 1 A are reacted in a weight ratio of from 1:1.3 to 1.3:1. In embodiments, Compound A and Compound B of step 1A are reacted in a weight ratio of from 1 : 1.2 to 1.2: 1. In embodiments, Compound A and Compound B of step 1 A are reacted in a weight ratio of from 1 : 1.1 to 1.1 : 1. In embodiments, Compound A and Compound B of step 1 A are reacted in a weight ratio of about 1 : 1. In embodiments, Compound A and Compound B of step 1 A are reacted in a weight ratio of about 1.1:1.

[0075] In embodiments, Compound A and Compound B of step 1 A are reacted in a molar ratio of from 1:2 to 2:1 (A:B to A:B), including all values and ranges therebetween. In embodiments, Compound A and Compound B of step 1A are reacted in a molar ratio of from 1:1.5 to 1.5:1. In embodiments, Compound A and Compound B of step 1 A are reacted in a molar ratio of from 1:1.4 to 1.4:1. In embodiments, Compound A and Compound B of step 1A are reacted in a molar ratio of from 1 : 1.3 to 1.3 : 1. In embodiments, Compound A and Compound B of step 1 A are reacted in a molar ratio of from 1:1.2 to 1.2:1. In embodiments, Compound A and Compound B of step 1A are reacted in a molar ratio of from 1 : 1.1 to 1.1 : 1. In embodiments, Compound A and Compound B of step 1A are reacted in a molar ratio of about 1:1. In embodiments, Compound A and Compound B of step 1 A are reacted in a molar ratio of about 1.1:1.

[0076] In embodiments, the synthesis method the method further comprises:step 2: deprotecting Compound C, or a pharmaceutically acceptable salt thereof, to provide Compound D, or a pharmaceutically acceptable salt thereof.

[0077] In embodiments, Compound C from step IB is not isolated, prior to subjecting it to step 2 of the process. In embodiments, Compound C from step IB is not purified, prior to subjecting it to step 2 of the process. In embodiments, Compound C from step IB is not isolated or purified, prior to subjecting it to step 2 of the process.

[0078] In embodiments provided herein, step 2 deprotection is performed in the presence of an acid selected from HC1, formic acid, H3PO4, CH3COOH, CF3COOH or any combination thereof. In a further embodiment, step 2 is performed in the presence of formic acid.

[0079] In embodiments, step 2 further comprises the use of a solvent. In embodiments, the solvent used in step 2 comprises an organic solvent. In embodiments, the solvent used in step 2 comprises an aqueous solvent. In embodiments, the solvent used in step 2 comprises water. In embodiments, the solvent used in step IB comprises an ester solvent. In embodiments, step 2 is performed in a solvent comprising isopropyl acetate. In embodiments, step 2 is performed in a solvent comprising isopropyl acetate and water. In some embodiments, step 2 is performed in a solvent comprising ethanol. In a further embodiment, step 2 is performed in a solvent comprising isopropyl acetate and ethanol.

[0080] In one embodiment, formic acid is charged into a reactor comprising a solution of Compound C, and the solution is concentrated, e.g., by distillation under vacuum. In a further embodiment, water is charged into the reactor, and the mixture is cooled. Isopropyl acetate, in a further embodiment, is added and stirred, agitation is stopped, and the aqueous phase is transferred to a reactor. In a further embodiment, water and ethanol are charged, and the temperature is adjusted, e.g., to from about 15 °C to about 25 °C. The pH is adjusted to about 7.0. The reactor, in a further embodiment, is seeded with Compound D and stirred. The pH is adjusted further to a target of about 9.0. The solid (Compound D) is collected by filtration. The solid (Compound D), in one embodiment, is suspended in water and stirred. The solid (Compound D) is collected on a filter, the wet cake is washed with water, and then dried. In one embodiment, the yield of Compound D is from about 60% to about 90%.

[0081] In a preferred embodiment, Compound C obtained in step IB is taken to step 2 without isolating Compound C from the step IB mixture (see Scheme 1).Scheme 1

[0082] In embodiments, the synthesis method further comprises:step 3: reacting Compound D, or a pharmaceutically acceptable salt thereof, with Compound E, or a pharmaceutically acceptable salt thereof, to provide Compound F, or a pharmaceutically acceptable salt thereof:

[0083] In embodiments described herein, step 3 comprises a convergent amidation reaction between the carboxylic acid of Compound E and the primary amine of Compound D, and the reaction is mediated by acid activation, e.g., via an acid anhydride. In embodiments, step 3 is performed in the presence of an acid anhydride selected from carboxylic anhydride, maleic anhydride, acetic anhydride, phosphonic acid anhydride or any combination thereof. In embodiments, step 3 is performed in the presence of a phosphonic acid anhydride. In embodiments, step 3 is performed in the presence of propylphosphonic anhydride (T3P). The acid anhydride, in one embodiment, is a 50% solution in solvent. In a further embodiment, the acid anhydride is a 50% solution in acetonitrile. In even a further embodiment, the acid anhydride is T3P and is a 50% solution in acetonitrile.

[0084] In one embodiment, Compound D and Compound E are charged into a reactor, and stirred. In a further embodiment, a base is added to the reactor in parallel, or after stirring the Compound D and E mixture. The base, in one embodiment, is selected from diethyl amine, trimethyl amine,triethyl amine, triisopropylamine, N,N-diisopropylethylamine (DIPEA), tributylamine or any combination thereof. In a further embodiment, the base is N,N-diisopropylethylamine (DIPEA).

[0085] In one embodiment, the acid anhydride is added to the reactor after the base is added. The acid anhydride, in a further embodiment, is T3P. In even a further embodiment, the base is N,N-diisopropylethylamine (DIPEA).

[0086] In embodiments, step 3 is performed in a solvent. For example, in one embodiment, Compound D and Compound E are charged into a reactor together with the solvent, and stirred. The solvent, in one embodiment, is an organic solvent. In another embodiment, the solvent is an aqueous solvent. In one embodiment, in the solvent comprises isopropyl acetate. In another embodiment, the solvent comprises acetonitrile. In even another embodiment, the solvent comprises isopropyl acetate and acetonitrile.

[0087] In embodiments, the synthesis method further comprises:step 4: dehydrating Compound F, or a pharmaceutically acceptable salt thereof, to form Compound G, or a pharmaceutically acceptable salt thereof.

[0088] In one embodiment, a solution comprising Compound F is concentrated and a solvent is added and the mixture is stirred. The solvent, in one embodiment, is an organic solvent. In another embodiment, the solvent is an aqueous solvent. In yet another embodiment, the solvent comprises a mixture of organic solvent and aqueous solvent.

[0089] Sodium chloride solution, in one embodiment, is added to the mixture comprising Compound F and solvent (e.g., isopropyl acetate). The mixture can be agitated and heated. The resulting aqueous phase can then be transferred to waste and the organic phase filtered, followed by addition of additional solvent to the organic phase. The additional solvent, in one embodiment, is isopropyl acetate. The solution comprising the organic phase can then be concentrated, for example, by distillation under vacuum, followed by cooling of the solution. Solvent, for example, an alkane solvent, can then be added. The alkane solvent, in one embodiment, is n-heptane.

[0090] The resulting mixture, in one embodiment, is centrifuged and the wet cake is then washed. Washing of the wet cake (Compound G), in one embodiment, comprises washing with a mixture of isopropyl acetate and n-heptane. The mixture of isopropyl acetate and n-heptane, in oneembodiment, is cooled, e.g., to about 5 °C prior to washing the wet cake product (Compound G). The wet cake solid (Compound G) is then dried. Drying, in one embodiment, is under vacuum.

[0091] In embodiments, Compound F is not isolated from reaction step 3 before being subjected to step 4. In embodiments, Compound F is not purified or isolated from reaction step 3 before being reacted in step 4. This is shown in the reaction Scheme 3, herein. Convergent amidation reaction between the carboxylic acid of Compound E and the primary amine of Compound D is mediated by acid activation, e.g., by T3P. Without wishing to be bound by theory, in the presence of excess T3P, the unreacted primary amide of the Compound F intermediate undergoes dehydration to convert to the nitrile group of Compound G.Scheme 3 - Step 3’ comprising step 3 and step 4

[0092] In one aspect of the disclosure, methods for synthesizing compound E are provided. According to some embodiments provided herein, compound E4 is oxidized to provide compound E (step d).

[0093] In embodiments, step d is performed in the presence of (2,2,6,6-tetramethylpiperidin-l-yljoxyl (TEMPO), NaBr and trichloroisocyanuric acid (TCCA).

[0094] In one embodiment, a protecting group is added to compound E3 to provide compound E4, shown as step c below.step c: protecting Compound E3 to provide Compound E4

[0095] In one embodiment, Step c is performed in the presence of di-tertbutyl dicarbonate (BOC2O) and K2CO3.

[0096] In one embodiment, compound E3 is provided by deprotecting compound E2, shown as Step b.

[0097] step b: deprotecting Compound E2 to provide Compound E3

[0098] In one embodiment, Step b is performed in the presence of H2 and Pd / C. In embodiments, the H2 pressure used in step b is about 2.0-5.0 bar, about 3.0-4.0 bar, about 3.2-3.7 bar, including any values and ranges therebetween. In embodiments, the H2 pressure used in step b is about 3.5 bar.

[0099] Compound E2 is provided in embodiments, by freebasing compound El, shown as Step a.

[0100] Step a: freebasing Compound El to provide Compound E2;

[0101] In embodiments, Step a is performed in the presence of a base. In embodiments, step a is performed in the presence of a base selected from NaOH, KOH, Na2COs, K2CO3 or a combination thereof. In embodiments, step a is performed in the presence of NaOH.

[0102] Compound E, in some embodiments, is synthesized according to the following steps: step a: freebasing Compound El to provide Compound E2,step b: deprotecting Compound E2 to provide Compound E3step c: protecting Compound E3 to provide Compound E4step d: oxidizing Compound E4 to provide Compound E,

[0103] The synthesis of Compound E according to some embodiments described herein, is summarized in Scheme 2.

[0104] In yet another embodiment, synthesis of Compound E is carried out according to the steps set forth in FIG. 2.Scheme 2: Synthesis of Compound EStep a Step bE4 E

[0105] According to the synthesis methods provided herein, Compound G is deprotected to provide Compound 1 (crude), as shown below in step 5.

[0106] Step 5: deprotecting Compound G, or a pharmaceutically acceptable salt or hydrate thereof, to provide Compound 1 or a pharmaceutically acceptable salt or hydrate thereof

[0107] In step 5, the carbamate protecting group of Compound G is removed via acid treatment, to provide the crude Compound 1. The acid, in one embodiment, is selected from HC1, formic acid, H3PO4, CH3COOH, CF3COOH or any combination thereof. In one embodiment, the acid is formic acid.

[0108] In one embodiment, water and acid are mixed in a reactor, followed by addition of Compound G to provide a mixture. The mixture, in one embodiment, is stirred and heated. After heating for a predetermined time, for example, from about 2 hours to about 4 hours, the mixture is cooled. Once deprotection is carried out, a workup procedure is initiated to isolate Compound 1 as a crude product.

[0109] In embodiments, the acid, e.g., formic acid of step 5 is used in an amount ranging from about 2.5 to about 3.5 kg per 1 kg of Compound G. In embodiments, formic acid of in step 5 is used in an amount ranging from about 2.9 kg to about 3.2 kg per 1 kg of Compound G. In embodiments, formic acid of in step 5 is used in an amount ranging from about 2.95 kg to about 3.15 kg per 1 kg of Compound G. In embodiments, formic acid of in step 5 is used in an amount ranging from about 2.99 kg to about 3.11 kg per 1 kg of Compound G.

[0110] In embodiments, following deprotection, the workup procedure comprises the addition of a solvent to the mixture. The solvent, in one embodiment, is an organic solvent. In another embodiment, the solvent is an aqueous solvent. In yet another embodiment, the solvent is an organic solvent comprising an ester solvent. In a preferred embodiment, the solvent comprises isopropyl acetate. The solvent, in another embodiment, comprises isopropyl acetate and ethanol.

[0111] In embodiments, Compound 1 prepared by step 5 is a hydrate. In embodiment, Compound 1 prepared by step 5 is a monohydrate.

[0112] In embodiments, the synthesis method comprises step 6: recrystallizing Compound 1 or a pharmaceutically acceptable salt or hydrate thereof from a solvent. In embodiments, step 6 comprises recrystallizing Compound 1 or a pharmaceutically acceptable salt or hydrate thereof from a solvent comprising ethanol and water. In embodiments, step 6 comprises Compound 1from a solvent to form a hydrate of Compound 1. In embodiments, step 6 comprises recrystallizing Compound 1 from a solvent to form a monohydrate of Compound 1. In embodiments, step 6 comprises recrystallizing Compound 1 from a solvent comprising ethanol and water to form a hydrate. In embodiments, step 6 comprises recrystallizing Compound 1, or a pharmaceutically acceptable salt or solvate thereof, from a solvent comprising ethanol and water to form a monohydrate of Compound 1.

[0113] In some embodiments, the product of step 5, i.e., crude Compound 1, is recrystallized. As such, in one embodiment, step 6 of a method provided herein comprises recrystallizing Compound 1, or a pharmaceutically acceptable salt or solvate thereof, through a cooling recrystallization process. In some embodiments, the cooling recrystallization process comprises lowering the temperature of the solution comprising Compound 1, or a pharmaceutically acceptable salt or solvate thereof, to reduce solubility of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and induce crystallization of Compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, step 6 comprises dissolving Compound 1, or a pharmaceutically acceptable salt or solvate thereof, in a solvent at an elevated temperature and slowly cooling the temperature to initiate recrystallize Compound 1 or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, once recrystallization is initiated, an anti-solvent is added. In embodiments, the anti-solvent is water.

[0114] In embodiments, the synthesis method comprises:step 1 A: reacting Compound A with Compound B in the presence of a metal catalyst to provide Compound Cstep IB: treating a solution comprising Compound C with a metal scavenger, e.g., N-acetyl cysteine;step 2: deprotecting Compound C to provide Compound Dstep 3 : reacting Compound D with Compound E to provide Compound Fstep 4: dehydrating Compound F to form Compound Gstep 5: reacting Compound G to provide Compound 1 or a pharmaceutically acceptable salt or hydrate thereof

[0115] In some embodiments, the method comprises isolating Compound 1, or pharmaceutically acceptable salt or hydrate thereof. In some embodiments, Compound 1, or pharmaceutically acceptable salt or hydrate thereof, is isolated as a solid. In some embodiments, Compound 1, or pharmaceutically acceptable salt or hydrate thereof, is crystalized as a solid. In some embodiments, the method comprises crystallizing or recrystallizing Compound 1, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the method comprises crystallizing or recrystallizing Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, by an anti-solvent addition process. In some embodiments, the method comprisescrystallizing or recrystallizing Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, by a solvent addition process, wherein the solvent comprises ethanol and water.

[0116] In embodiments, an anti-solvent is a solvent in which a Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, is not soluble in or has a low solubility in. In embodiments, the addition of an anti-solvent during crystallization or recrystallization reduces the solubility of Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, and induces or facilitates crystallization of Compound 1, or a pharmaceutically acceptable salt or hydrate thereof. In embodiments, the anti-solvent is water. In embodiments, the anti-solvent is added after crystal seed of Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, is added. In embodiments, the anti-solvent is added after an initiation of crystallization of Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, is observed.

[0117] In embodiments, the synthesis method comprises:step 1 A: reacting Compound A with Compound B in the presence of a metal catalyst in solution, to provide Compound C,step 1A Hstep IB: treating the solution comprising Compound C with a metal scavenger, e.g., N-acetyl cysteine;step 2: deprotecting Compound C to provide Compound Dstep 3’ : reacting Compound D with Compound E to provide Compound Gstep 5: deprotecting Compound G to provide Compound 1 or a pharmaceutically acceptable salt or hydrate thereof.

[0118] In embodiments, Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, prepared by any of the methods disclosed herein is a hydrate. In embodiments, the hydrate of Compound l is a monohydrate.

[0119] In another embodiment, a method for synthesizing Compound 1 is provided and the method proceeds according to the steps set forth in FIG. 1. In another embodiment, a method for synthesizing Compound 1 is provided and the method proceeds according to the steps set forth in FIG. 3.

[0120] In embodiments, the method is performed on a scale greater than 0.5 kg, 1.0 kg, 1.1 kg, 1.2 kg, 1.3 kg, 1.4 kg, 1.5 kg, 1.6 kg, 1.7 kg, 1.8 kg, 1.9 kg, 2kg, 3kg, 4kg, 5 kg, 6 kg, 7 kg, 8 kg, 9 kg, 10 kg, 11 kg, 12 kg, 13 kg, 14 kg, 15 kg, 16 kg, 17 kg, 18 kg, 19 kg, 20 kg, 25 kg, 30 kg, 35 kg, 40 kg, 45 kg, 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, 75 kg, 80 kg, 85 kg, 90 kg, 95 kg, 100 kg, 105 kg, 110 kg, 115 kg, 120 kg, 125 kg, 130 kg, 135 kg, 140 kg or 150 kg, including all values and ranges therebetween. In embodiments, the method is performed on a scale greater than 1.4 kg, 1.5 kg, 1.6 kg, 1.7 kg, 1.8 kg, 1.9 kg, 2kg, 3kg, 4kg, 5 kg, 6 kg, 7 kg, 8 kg, 9 kg, 10 kg, 11 kg, 12 kg, 13 kg, 14 kg, 15 kg, 16 kg, 17 kg, 18 kg, 19 kg, 20 kg, 25 kg, 30 kg, 35 kg, 40 kg, 45 kg, 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, 75 kg, 80 kg, 85 kg, 90 kg, 95 kg, 100 kg, 105 kg, 110 kg, 115 kg, 120kg, 125 kg, 130 kg, 135 kg, 140 kg or 150 kg, including all values and ranges therebetween. In embodiments, the method is performed on a scale of from about 0.5 kg to about 300 kg, about 1.0 kg to about 300 kg, from about 1.3 kg to about 300 kg, from about 1.4 kg to about 300 kg, from about 2.0 kg to about 300 kg, from about 3.0 kg to about 300 kg, from about 5.0 kg to about 300 kg, from about 5.0 kg to about 300 kg, from about 10 kg to about 300 kg, from about 20 kg to about 300 kg, from about 20 kg to about 200 kg, from about 20 kg to about 180 kg, from about 20 kg to about 170 kg, from about 20 kg to about 160 kg, or from about 20 kg to about 150 kg, including all values and ranges therebetween. In embodiments, the scale is determined by the weight of Compound 1, or a pharmaceutically acceptable or hydrate thereof, prepared by the method. In embodiments, the scale is determined by the weight of Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, prepared by the disclosed method where Step 5 is performed in a single reaction (i.e., the weight of Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, is not based on combined amount of Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, from different reactions performed separately). In embodiments, the scale is determined by the weight of the hydrate of Compound 1 prepared by the method.

[0121] In embodiments, the method affords Compound 1 with a purity greater than 95.0%, 95.5%, 96.0%, 96.5%, 97.0%, 97.5%, 97.6%. 97.8%, 97.9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%, including all values and ranges therebetween. In embodiments, the method affords Compound 1 with a purity greater than 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%, including all values and ranges therebetween. In embodiments, the method affords Compound 1 with a purity of from about 95.0% to about 99.9%, from about 95.5% to about 99.9%, from about 96.0% to about 99.9%, from about 96.5% to about 99.9%, from about 97.0% to about 99.9%, from about 97.5% to about 99.9%, from about 98.0% to about 99.9%, from about 98.1% to about 99.9%, from about 98.2% to about 99.9%, or from about 98.3% to about 99.9%, including all values and ranges therebetween. In embodiments, the purity is by weight (%w / w). In some embodiments, the purity is determined by high-performance liquid chromatography (HPLC). In some embodiments, the purity is determined by ultra-performance liquid chromatography (UPLC). In some embodiments, the purity is determined by quantitatively determining all impurities in Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, and subtracting the total % of those impurities from 100.

[0122] In embodiments, the method affords Compound 1 with (a) a purity greater than 95.0% and (b) a palladium content lower than 50 ppm. In embodiments, the method affords Compound 1 with (a) a purity greater than 95.0% and (b) a palladium content lower than 25 ppm. In embodiments, the method affords Compound 1 with (a) a purity greater than 95.0% and (b) a palladium content lower than 10 ppm. In embodiments, the method affords Compound 1 with (a) a purity greater than 95.0% and (b) a palladium content lower than 5 ppm. In embodiments, the method affords Compound 1 with (a) a purity greater than 95.0% and (b) a palladium content lower than 3 ppm.

[0123] In embodiments, the method affords Compound 1 with (a) a purity greater than 98.0% and b) a palladium content lower than 50 ppm. In embodiments, the method affords Compound 1 with (a) a purity greater than 98.0% and (b) a palladium content lower than 25 ppm. In embodiments, the method affords Compound 1 with (a) a purity greater than 98.0% and (b) a palladium content lower than 10 ppm. In embodiments, the method affords Compound 1 with (a) a purity greater than 98.0% and (b) a palladium content lower than 5 ppm. In embodiments, the method affords Compound 1 with (a) a purity greater than 98.0% and (b) a palladium content lower than 3 ppm.

[0124] In embodiments, the method affords Compound 1 with (a) a purity in the range of 95.0% to 100% and (b) a palladium content om the range of 0 ppm to 50 ppm. In embodiments, the method affords Compound 1 with (a) a purity in the range of 95.0% to 100% and (b) a palladium content om the range of 0 ppm to 25 ppm. In embodiments, the method affords Compound 1 with (a) a purity in the range of 95.0% to 100% and (b) a palladium content in the range of 0 ppm to 10 ppm. In embodiments, the method affords Compound 1 with (a) a purity in the range of 95.0% to 100% and b) a palladium content om the range of 0 ppm to 5 ppm. In embodiments, the method affords Compound 1 with (a) a purity in the range of 95.0% to 100% and (b) a palladium content om the range of 0 ppm to 3 ppm. In embodiments, the method affords Compound 1 with (a) a purity in the range of 95.0% to 99.99% and (b) a palladium content om the range of 0 ppm to 10 ppm. In embodiments, the method affords Compound 1 with (a) a purity in the range of 95.0% to 99.99% and (b) a palladium content om the range of 0 ppm to 5 ppm. In embodiments, the method affords Compound 1 with (a) a purity in the range of 95.0% to 99.99% and (b) a palladium content om the range of 0 ppm to 3 ppm. In embodiments, the method affords Compound 1 with an assay greater than 95.0%, 95.5%, 96.0%, 96.5%, 97.0%, 97.5%, 97.6%. 97.8%, 97.9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%, including all values and ranges therebetween. In embodiments, the method affords Compound 1 with an assay of from about 95.0% to about 99.9%, from about 95.5% to about 99.9%, from about 96.0% to about 99.9%, from about 96.5% to about99.9%, from about 97.0% to about 99.9%, from about 97.5% to about 99.9%, from about 98.0% to about 99.9%, from about 98.1% to about 99.9%, from about 98.2% to about 99.9%, or from about 98.3% to about 99.9%, including all values and ranges therebetween. In embodiments, the assay is by weight (%w / w) of Compound 1 on anhydrous and solvent-free basis. In some embodiments, the assay is determined by high-performance liquid chromatography (HPLC). In some embodiments, the assay is determined by ultra-performance liquid chromatography (UPLC). In some embodiments, the assay is performed against a reference standard of Compound 1 of known purity and concentration.

[0125] In embodiments, the method affords Compound 1 with a palladium content lower than 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75ppm, 70 ppm , 65 ppm, 60 ppm, 59 ppm, 58 ppm, 57 ppm, 56 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, 4 ppm or 3 ppm, including all values and ranges therebetween. In embodiments, the method affords Compound 1 with a palladium content lower than 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, 4 ppm or 3 ppm, including all values and ranges therebetween. In embodiments, the method affords Compound 1 with a palladium content lower than 10 ppm. In embodiments, the method affords Compound 1 with a palladium content lower than 5 ppm. In embodiments, the method affords Compound 1 with a palladium content lower than 3 ppm. In embodiments, the method affords Compound 1 with a palladium content in the range of 0 ppm and about 50 ppm. In embodiments, the method affords Compound 1 with a palladium content in the range of 0 ppm and about 25 ppm. In embodiments, the method affords Compound 1 with a palladium content in the range of 0 ppm and about 10 ppm. In embodiments, the method affords Compound 1 with a palladium content in the range of 0 ppm and about 5 ppm. In embodiments, the method affords Compound 1 with a palladium content in the range of 0 ppm and about 3 ppm.

[0126] In embodiments, the method affords Compound D with a palladium content lower than 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75ppm, 70 ppm , 65 ppm, 64 ppm, 63 ppm, 62 ppm, 61 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm or 10 ppm, including all values and ranges therebetween. In embodiments, the method affords Compound D with a palladium content lower than 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm or 10 ppm, including all values and ranges therebetween.

[0127] In embodiments, the method affords Compound G with a palladium content lower than 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75ppm, 70 ppm , 65 ppm, 64 ppm, 63 ppm, 62 ppm, 61 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm or 10 ppm, including all values and ranges therebetween. In embodiments, the method affordsCompound G with a palladium content lower than 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm or 10 ppm, including all values and ranges therebetween.

[0128] Aspects of the present disclosure relate to Compound 1, or a pharmaceutically acceptable salt or hydrate thereof prepared by any of the methods disclosed herein. In embodiments, the present disclosure relates to Compound 1 hydrate prepared by any of the methods disclosed herein. In embodiments, the present disclosure relates to Compound 1 monohydrate prepared by any of the methods disclosed herein. In embodiments, Compound 1 or a pharmaceutically acceptable salt or hydrate thereof, prepared by any of the methods provided herein, has a purity of at least 98.1%. In embodiments, Compound 1 or a pharmaceutically acceptable salt or hydrate thereof, prepared by any of the methods provided herein, has a purity of at least 99%. In embodiments, Compound 1 or a pharmaceutically acceptable salt or hydrate thereof, prepared by any of the methods provided herein, contains less than 3 ppm metal. In embodiments, Compound 1 or a pharmaceutically acceptable salt or hydrate thereof, prepared by any of the methods provided herein, contains less than 3 ppm palladium.

[0129] Examples

[0130] The present invention is further illustrated by reference to the following Examples. However, it should be noted that these Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the invention in any way.

[0131] Example 1 - Synthesis of Compound 1Scheme 4

[0132] Rection conditions: step 1: (a) Pd(dppf)C12, K2CO3, AcOiPr / CHsCN / ftO; (b) N-acetyl cysteine; step 2: (a) HCOOH, (b) NH3 (aq ), AcOiPr / CHsCN / ftO; step 3: N,N-Diisopropylethylamine (DIPEA), Propanephosphonic acid anhydride (T3P), Acetonitrile; step 4:AcOiPr, H2O, NaCl, n-heptane; step 5: (a) HCOOH, b) NH3 (aq.), AcOiPr / CHaCN / IfcO; and (c) recyclization in ethanol and water; step a: NaOH, Toluene / BfcO; step b: H2, Pd / C; step c: (a) HCOOH, b) NH3 (aq.), AcOiPr / CHsCN / ftO; step d: (a) (2,2,6,6-tetramethylpiperidin-l-yl)oxyl (TEMPO) / NaBr / trichloroisocyanuric acid (TCCA), NHCO3 / H2O; (b) Na2CO3 / IPA / AcOEt / H2O / n-hepatne / HCl.

[0133] Compound 1 (Brensocatib) was prepared through eight chemical transformations and five solid isolations according to Scheme 4. Each reaction step of Scheme 4 is described in detail in Examples 2-5. Intermediate Compound E was prepared from fumarate salt of (S)-4-benzyl-2-((benzyloxy)methyl)-l,4-oxazepane (Compound El) and intermediate Compound D was prepared from Compound A and Compound B via Suzuki coupling reaction with Pd catalyst followed by deprotection. Compound D and Compound E were then coupled, reduced, and deprotected to afford crude Compound 1. The crude Compound 1 was recrystallized from ethanol / water to produce highly pure monohydrate of Compound 1 with Pd content of less than 3 ppm.

[0134] Table 1 shows that Compound 1 was successfully synthesized in accordance with Scheme 4 in multiple batches at a scale ranging from 18.5 kg to 150.0 kg.

[0135] Table 2 shows the analysis of Compound 1 from batch numbers 7-10 from Table 1.< < < <

[0136] Table 3 shows that Compound D, Compound G and Compound 1 prepared according to Scheme 1 in different batches have palladium content less than 20 ppm, 10 ppm and 3 ppm, respectively. The batch number in Table 3 correspond to the batch number in Table 1.< < << < << < << < << < << << << << < <Example 2 - Process for the manufacture of Compound D from Compound A (step 1 and

[0137] Step 1

[0138] Reactor A (4000 L) was charged with Compound A (224.64 kg, 1.10 molar eqiuv.), Compound B (288 kg, 1 molar equiv.) and Pd(dppf)C12 (2.707 kg, 0.005 molar equiv.) with acetonitrile (1440 L). Reactor A was purged with vacuum and nitrogen. K2CO3 (126.72 kg, 1.24 molar equiv.) was added to Reactor B (1500 L) with water (691.2 L) was and stirred to dissolve K2CO3.

[0139] The mixture in Reactor B was transferred to Reactor A. The combined mixture in Reactor A was heated to about 70 °C (normal operating range (NOR): 68-73 °C) and stirred for about 3 hours. After stirring for 3 hours at about 70 °C, the mixture in Reactor A was cooled to about 60 °C (NOR: 55-63 °C) and filtered at about 60 °C (NOR: 55-63 °C) through a K100 filter. Isopropyl acetate (3167.7 L) was added to Reactor A (for rinsing), heated to about 60 °C, then filtered. The combined filtrate was collected and transferred to Reactor C (8000 L).

[0140] N-acetyl cysteine (NAC) wash: To a cleaned Reactor B, a first potion of water (1152.0 L) and N-acetyl cysteine (4.9 kg) was charged and stirred. Once N-acetyl cysteine was dissolved, the content of Reactor B was transferred to Reactor C. Reactor B and transfer line was rinsed with water (144 L) and the rinse was also transferred to Reactor C. The mixture in Reactor C was heated to about 70 °C (NOR: 65-73 °C) and stirred at about 70 °C (NOR: 65-73 °C) for 3 hours. The stirring was stopped and the aqueous layer was decanted and discarded. Repeat the NAC wash step once.

[0141] In a similar manner to the NAC wash, the contents of Reactor C was washed with sodium chloride (40.32 kg in 1152.0 L water) which was heated to about 70 °C before transferring to Reactor C (Reactor B was also rinsed with 144L water at about 70 °C). Once heated sodium chloride solution was transferred to Reactor C, the mixture was stirred at about 70 °C (NOR: 65-73 °C) for NLT 30 min. The stirring was stopped and the aqueous layer was decanted and discarded. The sodium chloride wash was repeated.

[0142] The remaining mixture in Reactor C was filtered through carbon cartridge AKS2 (200-250 L / m2h) at about 70 °C (NOR: 65-73 °C). The filtrate was transferred to Reactor D (10000 L). Isopropyl acetate (2017.0 L) was added to Reactor C and heated to about 70 °C and used to rinse the filter and filtration line. The isopropyl acetate rinse was transferred to Reactor D.

[0143] The mixture in Reactor D was distilled under vacuum at an internal temperature (TP) <70 °C until the volume the mixture in Reactor D reached about 2300 L (about 8 volumes). Isopropyl acetate (2304.7 L) was added to Reactor D and distilled under vacuum at TP<70 °C until the volume of the mixture in Reactor D reached about 2880 L (about 10 volumes). Isopropyl acetate (1729.3 L) was added to Reactor D and distilled under vacuum at TP<70 °C until the volume ofthe mixture in Reactor D reached about 1730 L (about 6 volumes). Reactor D was cooled down to about 25 °C.

[0144] Step 2.

[0145] Reactor D from step 1 containing crude Compound C in isopropyl acetate was charged with formic acid (1152.0 L) and purged with vacuum and nitrogen. The mixture in Reactor D was distilled under vacuum with Tint max (maximum internal temperature) of about 30 °C (preferably 25-33 °C, no more than (NMT) 33 °C) until the volume of the mixture of Reactor D reached about 1150 L (about 4 volumes). Formic acid addition and distillation was repeated 3 or more times until acceptable conversion to Compound D is determined by UPLC (as indicated by no more than 1.5% Compound C remaining).

[0146] Reactor D was charged water (1103.0 L), adjusted to about 10 °C (NOR: 5-13 °C), and purged with vacuum and nitrogen. The mixture of the Reactor D was filtered at about 10 °C (NOR: 5-13 °C) through a K100 filter, and the filtrate was collected and transferred into a clean Reactor C. Reactor D, the filter and the transfer line were rinsed with water (316.8 L) at about 10 °C and the rinse was collected and transferred to Reactor C.

[0147] The temperature of the mixture in Reactor C was adjusted at about 10 °C (NOR: 5-13 °C) then charged with water (950.4 L) and isopropyl acetate (1269.7 L). The mixture was stirred at about 10 °C (NOR: 5-13 °C) for less than 10 minutes. The stirring and agitation of Reactor C was stopped and the aqueous phase containing Compound D was transferred to clean Reactor D and the organic phase was discarded. The isopropyl acetate (1269.7 L) addition and stirring at about 10 °C (NOR: 5-13 °C) for no less than 10 min was repeated. The stirring and agitation of Reactor D was stopped and the aqueous phase containing Compound D was transferred to clean Reactor C which was purged with vacuum and nitrogen and was charged with water (316.8 L). The organic phase was discarded.

[0148] Reactor C was charged with water (316.8 L) and the temperature of Reactor C’s mixture was adjusted to about 5 °C (NOR: 0-10 °C). Then, ethanol (721.8 L) was charged to Reactor C and the temperature of Reactor C’s mixture was adjusted to about 17 °C (NOR: 12-22 °C). The solution of Reactor C was transferred to Reactor D.

[0149] Reactor E (10000 L) was purged with vacuum and nitrogen. The solution of Reactor D was transferred to Reactor E. The pH of the solution in Reactor E was adjusted to 7.0-7.5 by dropwise addition of 25% ammonium hydroxide aqueous solution (about 1289.6L) with Tp of about 17 °C (12-22 °C). After the addition of ammonium hydroxide, the temperature of the solution in reactor E was adjusted to about 17 °C and stirred for 10 min. The pH of the solution was retested and readjusted to 7.0-7.5 if necessary.

[0150] To Reactor E at Tp of about 17 °C was added Compound D seeds (0.288 kg) and the solution was stirred for no less than 2 hours at about 17 °C. The pH of the solution in Reactor E was adjusted to greater than 9.0 by dropwise addition of ammonium hydroxide (about 163. 2 L) with Tp of about 25 °C (20-30 °C). After the addition of ammonium hydroxide, the solution was stirred for 10 min and the pH of the solution was retested and readjusted to >9 if necessary. The solution’s temperature was adjusted to about 25 °C (NOR: 20-30 °C) and stirred for no less than 18 hours.

[0151] The solution of Reactor E was filtered and the solid was collected as a wet cake of compound D (277.38 kg of wet Compound D). The wet cake was washed twice with water (316.8 L each ). Suspend the wet solid in water (2304 L) for 1 to 3h at about 25 °C (20-30 °C). The solids were filtered and washed twice with water (316.8 L each). The wet solid cake was dried under vacuum for no less than 8 hours with the drying jacket temperature of about 45 °C (NMT 50 °C) until the amount of water is no more than 1.0% by Karl Fischer titration. 173.49 kg of dry Compound D was obtained (75.5 % yield).

[0152] Without bound to any theory, N-Acetyl-cysteine (NAC) can bind to palladium and increase palladium water solubility. Through increasing palladium’s water solubility, NAC can be used to remove residual palladium from Compound C and / or Compound D.

[0153] Normal operating ranges (NOR), proven acceptable ranges (PAR) for the manufacture process for Compound D (step 1 and step 2) are summarized in Table 4.Example 3 - Process for the manufacture of Compound G from Compound D and Compound E (step 3 and step 4)

[0154] Steps 3 and 4

[0155] Reactor A (3000 L) was charged with Compound D (86.74 kg, 1 molar equiv), Compound E (68.53 kg, 1 molar equiv), acetonitrile (520.7 L). The mixture in Reactor A was stirred and the temperature of the mixture was adjusted to about 15 °C (NOR: 10-25 °C). N,N-Diisopropylethylamine (DIPEA) (215.99 kg, 6 molar equiv.) was charged to Reactor A with static vacuum while maintaining Tp at about 20 °C (NOR: 10-25 °C). Reactor A was purged with vacuum and nitrogen and the temperature of the mixture in Reactor A was adjusted to about 15 °C (NOR: 10-25 °C). Propanephsophonic acid anhydride (T3P) 50% in acetonitrile (4 equiv, 783.29 kg, 824.5 L) was added to Reactor A while the internal temperature of the mixture was maintained at about 20 °C (NOR: 10-25 °C). Acetonitrile (43.2 L) was used to rinse the system used to add T3P and the rinse was added to Reactor A.

[0156] Reactor A was purged with vacuum and nitrogen. The mixture in Reactor A was heated to about 50 °C (NOR: 45-55 °C) and stirred for 3 hours at about 50 °C (NOR: 45-55 °C). A sampleof the mixture in Reactor A was collected and analyzed using UPLC. If the content of Compound F in the sample is more than 1%, then continue to stir mixture of Reactor A at 50 °C for 60 mins.

[0157] Once the content of Compound F is determined to be no more than 1%, the mixture in the Reactor A was distilled under vacuum at a jacket temperature (Tj) <65 °C until the volume of the mixture reached about 10 volume (about 867 L, NOR: 9.5-10.5 volume). The temperature of mixture in Reactor A was adjusted to about 20 °C (NOR: 15-25 °C). Isopropyl acetate (694.1 L) was added to Reactor A and the resulting mixture was stirred for 10 mins.

[0158] NaCl wash: A clean Reactor B was charged with sodium chloride (26.02 kg) and water (867.4 L). The temperature of the mixture in Reactor B was adjusted to about 20 °C (NOR: 15-25 °C) and the mixture was stirred to dissolve NaCl. The mixture from Reactor A was added to Reactor B. Reactor A and addition line was rinsed with isopropyl acetate (173.3 L) and the rinse was added to Reactor B. The combined mixture of Reactor B was heated to about 40 °C (NOR: 25 / 60 °C). If precipitation was observed, the mixture of reactor B was heated to about 50 °C and stirred for no less than 20 min. The stirring was stopped and the aqueous layer was separated and discarded. Repeat the NaCl wash twice. The organic layer in Reactor B resulting from the NaCl wash was filtered through a K100 filter. Isopropyl acetate (867.4 L) was added to Reactor B (for rinsing). The filtrate and rinse were collected and transferred to Reactor A.

[0159] The resulting solution (containing Compound G) of Reactor A was distilled under vacuum at a jacket temperature (Tj) of <65 °C until the volume of the solution in Reactor A reached about 7 volumes (about 607 L, NOR: 6.5-7.5 volumes). Isopropyl acetate (995.9 L) was added to Reactor A, and the resulting solution in Reactor A was distilled under vacuum at a Tj of <65 °C until the volume of the solution in Reactor A reached about 7 volumes (607L, NOR: 6.5-7.5 volumes). The internal temperature (TP) of Reactor A’s solution was adjusted to about 50°C (NOR 45-55 °C) and then cooled to about 5°C (NOR: 0-10 °C) in no less than 8 h while slow stirring was maintained. The solution in Reactor A was stirred at 5 °C for no less than 2 hours. n-Heptane (260.0 L) was added to Reactor A at about 5°C (NOR: 0-10 °C). The resulting solution in Reactor A was stirred at about 5 °C for no less than 8 hours.

[0160] The resulting solution in Reactor A was filtered and the solid (containing Compound G) was collected as a wet cake. The wet cake was washed sequentially with isopropyl acetate (259.9 L) and n-heptane (260.0 L) at about 5 °C (NOR: 0-10 °C), and then washed with n-heptane (520.0 L) at about 20 °C (NOR: 15-25 °C). The wet cake (184.95 kg) was dried under vacuum at Tj of about 55 °C (NMT 60 °C) for no less than 6 h. Dried Compound G (116.32 kg, 80.2 % yield) was obtained.

[0161] Normal operating ranges (NOR), proven acceptable ranges (PAR) for the manufacture process for Compound G from Compound D and compound E (steps 3 and 4) are included in Table 5.Example 4 - Process for the manufacture of Compound 1 monohydrate from Compound G (step 5)

[0162] Step 5

[0163] Reactor B (4000 L) was charged with water (60.5 L) and formic acid (581.6 L, 709.55 kg, 34.5 molar equiv.). The mixture in Reactor B was stirred with its temperature maintained at about 20 °C (NOR: 15-25 °C). Reactor B was purged with vacuum and nitrogen.

[0164] Reactor A (3000 L) was charged with Compound G (232.64 kg, 1 molar equiv.) and then purged with vacuum and nitrogen. The solution from Reactor B was transferred to Reactor A. The resulting solution in Reactor A was stirred with its temperature maintained at about 20 °C (NOR: 10-30) °C under vacuum (about -0.3 bar; NOR: -0.2 to -0.4 bar) for no less than 30 min. The solution in Reactor A was heated to about 40 °C (NOR: 37-43 °C, preferably 38-42 °C) in no less than 30 minutes and stirred at about 40 °C (NOR: 37-43 °C) under vacuum (about -0.3 bar; NOR: -0.2 to -0.4 bar) for no less than 3 h and no more than 4 h. The resulting solution in Reactor A was cooled to about 10 °C (NOR: 5-25 °C) and the vacuum was stopped. A sample of the solution was collected and analyzedusing UPLC for Compound G. If the amount of Compound G in the sample is more than 4% (area %), then continue to stir the solution of Reactor A at about 40 °C for about 60 mins.

[0165] Once the amount of Compound G is determined by UPLC to be no more than 3% (area %), Reactor A was opened to atmospheric pressure with nitrogen. The temperature of the solution in Reactor A was adjusted to about 10 °C (NOR: 5-15 °C). Reactor A was charged with water (1209.7 L) and isopropyl acetate (929.5 L). The temperature of the solution in Reactor A was adjusted to about 10 °C (NOR: 5-15 °C) and the solution was stirred for no less than 30 min. The stirring was stopped, top organic layer was discarded, and the bottom aqueous layer containing Compound 1 was transferred to a cleaned Reactor B.

[0166] Reactor B was charged with isopropyl acetate (929.5 L). The temperature of the solution in Reactor B was adjusted to about 10 °C (NOR: 5-15 °C) and the solution was stirred for no less than 30 min. The stirring was stopped, top organic layer was discarded, and the bottom aqueous layer containing Compound 1 was transferred to a cleaned Reactor A.

[0167] Reactor C which was purged with vacuum and nitrogen, charged with ethanol (1464.7 L) and ammonium hydroxide (25%, 1269.2 L), and cooled to about 5 °C (0-15 °C).

[0168] Reactor A was purged with vacuum and nitrogen. The temperature of the solution in Reactor A was adjusted to adjusted to about 5 °C (NOR: 2-15 °C) and the solution was filtered through a KI 00 filter then added to Reactor C with ethanol and ammonium hydroxide. Reactor A and the filter was rinsed with water (395.5 L) and the rinse was collected and transferred to Reactor C.

[0169] The temperature of the mixture in Reactor C was adjusted to about 25 °C (20-30 °C) and stirred for 30 min. The pH of the mixture of Reactor C was tested. If pH < 9.0, the pH was readjusted with extra addition of ammonium hydroxide (25%, 5L). Once pH is confirmed to be > 9.0, the mixture in Reactor C was stirred at about 25 °C (NOR: 20-30 °C) for no less than 2 h.

[0170] The temperature of the mixture in Reactor C was cool to about 10 °C (NOR: 5-15 °C) and the solution was stirred at about 10 °C (NOR: 5-15 °C) for no less than 2 h. The resulting mixture in Reactor C was filtered and the solid (containing Compound 1) was obtained as a wet cake. The wet cake was washed with water (697.9 L x 2). The wet cake and water (2791.7 L) were added back to Reactor C. The resulting mixture in Reactor C was cooled to about 10 °C (NOR: 5-15 °C) and stirred at about 10 °C (NOR: 5-15 °C) for about 1 to 2 hours. The resulting mixture in Reactor C was filtered and the solid was obtained as a wet cake. The wet cake was washed with water (1046.9 L x 2). The wet cake (179.78 kg) was dried under vacuum at Tj of about 45 °C (NMT 50 °C) for no less than 9 h. 143.83 kg (73.4 % yield) dried Compound 1 monohydrate was obtained.

[0171] Normal operating ranges (NOR), proven acceptable ranges (PAR) for the manufacture of hydrate of Compound 1 from Compound G (step 5) are included in Table 6.Example 5 - Process for the crystallization of Compound 1 monohydrate (step 6)

[0172] Reactor A (10000 L) was purged with vacuum and nitrogen. Reactor A was charged with purified water (80.0 L) and ethanol (722.4 L). The water-ethanol mixture was heated to reflux and filtered through AKS2 (carbon cartridge) and polish filters and recirculated back to Reactor A.

[0173] To Reactor B (10000 L) was charged crude Compound 1 (143.83 kg). Reactor B was purged with vacuum and nitrogen. A first portion of purified water (287.7 L) and ethanol (2588.5 L) was added to Reactor B. The solution in Reactor B was stirred and heated to about 65 °C (NOR: 60-70 °C) in no less than 30 min. The temperature was maintained at about 65 °C to assure complete dissolution of Compound 1 (NLT 10 min). The solution was filtered through AKS2 (carbon cartridge) and polish filters at 200-250 L / m2h at about 65 °C (NOR: 60-70 °C) and the filtrate was collected into Reactor A with water-ethanol mixture.

[0174] To Reactor B was charged a second portion of purified water (43.1 L) and ethanol (388.3 L) for rinsing Reactor B. The water-ethanol mixture in Reactor B was stirred and heated to about 65 °C (NOR: 60-70 °C), filtered through the same AKS2 (carbon cartridge) and polish filters, and collected into Reactor A.

[0175] The resulting mixture in Reactor A was stirred and heated to about 65 °C (NOR: 60-70 °C) until complete dissolution of Compound 1. The solution in Reactor A was cooled to about 55 °C (NOR: 53-57 °C). Compound 1 seeds (0.719 kg) were added to Reactor A. The resulting mixture was stirred for about 30 min at about 55 °C (NOR: 53-57 °C) and checked for presence of solid. If no solid was observed, additional Compound 1 seeds (0.0025 - 0.005 kg / kg of crude Compound 1) was added. If solid was observed in the mixture of Reactor A, then the mixture wascooled to about 40 °C (NOR: 35-45 °C) in no less than 3 hours (approximate cooling rate: -5 °C per hour). The resulting mixture is then heated to about 50 °C (NOR: 45-55 °C) in no less than 1 hour, and then cooled to about 35 °C (NOR: 30-40 °C) in no less than 3 hours (approximate cooling rate: -5 °C per hour), and then heated to about 45 °C (NOR: 40-50 °C) in no less than 1 hour, and then cooled to about 12 °C (NOR: 7-17 °C) in no less than 6 hours (approximate cooling rate -5 °C per hour).

[0176] Reactor C was charged with purified water (287.7 L) in no less than 1 hour at about 12 °C (NOR: 7-17 °C), and the resulting mixture in Reactor C was stirred at about 12 °C (NOR: 7-17 °C) for no less than 3 hours. The mixture in Reactor C was filtered and the solid containing Compound 1 was collected. The solid was washed three times with purified water-ethanol mixture (each wash: 57.5 L water + ethanol 230.1 L) that was cooled to about 10 °C (NMT 15 °C). The solid was then dried under vacuum at about 25 °C (NOR: 20-30 °C) (Tj: NMT 30 °C) for no less than 2 h. 120.0 kg (83.4%) dried Compound 1 monohydrate was obtained.Example 6 - Process for the manufacturing of Compound E

[0177] Reaction conditions: step a: NaOH, Toluene / TbO; step b: H2, Pd / C; step c: a) HCOOH, b) NH3 (aq.), AcOiPr / CHsCN / TbO; step d: a) (2,2,6,6-tetramethylpiperidin-l-yl)oxyl (TEMPO) / NaBr / trichloroisocyanuric acid (TCCA), NHCO3 / H2O; b) Na2CO3 / IPA / AcOEt / H2O / n-hepatne / HCl.

[0178] Step a

[0179] Reactor 1 was purged with vacuum and nitrogen. Reactor 1 was charged with Compound El (115.8 kg, 1 molar equiv.), water (1205.1 L) and toluene (642.7 L). The resulting mixture in Reactor 1 was stirred and adjusted to pH of about 9 (NOR: 8-9; PAR: 7-10) by adding NaOH 30% aqueous solution (63.2 L). The resulting solution in Reactor 1 was stirred at about 22 °C (NOR: 20-25 °C). Stirring of the mixture was stopped and the aqueous phase was transferred to Reactor 2 and the organic phase was transferred to Reactor 3.

[0180] Reactor 2 was charged with toluene (642.7 L) and the mixture in Reactor 2 was stirred for no less than 30 min at about 22 °C (NOR: 20-25 °C). Stirring of the mixture was stopped and the aqueous phase was discarded and the organic phase was transferred to Reactor 3.

[0181] The resulting solution of Reactor 3 was distilled under vacuum at Tj < 50°C until the volume of the solution reached about 1.7 volume (NOR: 1.3-2.0 volume; 1 volume = 57.9 L). Reactor 3 was charged with ethanol (561.9 L) and the resulting mixture of Reactor 3 was transferred a H2 Reactor. The transferred line was rinsed with ethanol (9357.9.7 L) and the rinse was transferred to the H2 Reactor.

[0182] Step b

[0183] Reactor 3 was charged with concentrated HC1 (42.1 L) and water (186.4 L). The resulting solution in Reactor 3 was stirred for no less than 15 min and transferred to the H2 Reactor.

[0184] The H2 Reactor was charged with 10% P / C (9.4 kg) and pressurized with H2 to about 1.0 bar. The temperature of the mixture in H2 Reactor was adjusted to about 45 °C (NOR: 40-50 °C). The H2 Reactor was pressurized with H2 to about 3.5 bar (NOR / PAR: 3.0-4.0 bar). The mixture in the H2 Reactor was stirred at about 45 °C for NLT 4.5 h, cooled to about 22 °C (NOR: 20-25 °C) and then filtered. The filtrate (containing Compound E3) was transferred to Reactor 1.

[0185] Step c

[0186] Reactor 1 was charged with potassium carbonate (50.1 kg) and water (252.0 L). If the pH of the solution in Reactor 1 was < 8.5, then additional potassium carbonate was added to adjust it pH to be 8.5-9. Reactor 1 was charged with 70% DiBoc / toluene solution (124.7 L). The resulting mixture in Reactor 1 was stirred for no less than 1 hour at about 22°C (NOR: 20-25 °C). The resulting mixture was distilled at Tj <50°C until the volume of the solution reached about 4.3 volumes (NOR: 4.1 - 4.6 volume). Water (252.2 L) was added to Reactor 1 and the resulting mixture was distilled to at Tj <50°C until the volume of the solution reached 4.3 volumes (NOR: 4.1 - 4.6 volume). Such water addition and continued distillation was repeated twice.

[0187] Methyl tertbutyl ether (MTBE) extraction: MTBE (504.0 L) was added to Reactor 1 and the resulting mixture was stirred for no less than 30 min at 20-25°C. The stirring and agitation was stopped and the aqueous phase added to Reactor 2 and the organic was added to Reactor 3. The mixture in Reactor 2 was extracted twice with MTBE (504.0 L x 2) and the organic phase from these two extractions are added to Reactor 3.

[0188] The resulting mixture in Reactor 3 was distilled at Tj < 50 °C until the volume of the mixture reached 1.3 volumes (NOR: 1.1-1.6 volumes). Ketone (403.2 L) was added to Reactor 3 and the resulting mixture was distilled at Tj < 50°C until the volume of the mixture reached 1.3 volumes (NOR: 1.1 - 1.6 volume). Such addition of ketone and continued distillation was repeated twice using 403.2 L and 756.1 L ketone. After distillation, the resulting mixture in Reactor 4 (containing Compound E4) was transferred to Reactor 2.

[0189] Step d

[0190] Reactor 2 was charged with solution containing NaHCCh (51.4 kg) and water (521.8 L). The resulting mixture in Rector 2 was stirred and cooled to about 5 °C (NOR: 0-10 °C). Reactor 2 was further charged with 2,2,6,6-Tetramethylpiperidine 1-oxyl, 2,2,6,6-Tetramethyl-l-piperidinyloxy (TEMPO) (2.5 kg) and NaBr (6.4 kg) and the resulting mixture in Reactor 2 was stirred for NLT 15 min at 5 °C (NOR: 0-10 °C). Solution containing acetone (276.6 L) and trichloroisocyanuric acid (TCCA) (83.9kg) was slowly added to Reactor B with the temperature being controlled at NMT 10 °C. The resulting mixture was stirred for NLT 6 min at about 5 °C (NOR: 0-10 °C). Isopropanol (159.9 L) and lMNa2CO3 solution (containing 38.2 kgNa2COs and 347.6 L water) were added to Reactor 2. The resulting mixture in Reactor 2 was stirred for 6 hours with its pH maintained at 2-3 and temperature maintained at 0-10 °C. After stirring is finished, additional Na2COs solution (containing 44.2 kg Na2COs and 395.5 L water) was added to Reactor 2 to adjust pH to 7.5-8.0 (NOR: 7.5-8.5) with the temperature maintained at NMT 10 °C.

[0191] The resulting mixture in Reactor 2 was heated to about 30°C (NOR: 25-35 °C) and distilled at Tp < 45°C and Tj <55°C until the volume of the mixture reached aboutl0.8 volume (NOR: 10.5 -11.0 volumes). A first portion of ethyl acetate (595.9 L) was added to Reactor 2 and the resulting mixture was distilled at Tp < 45°C and Tj <55°C until the volume of the mixture reached 10.8 volume (NOR: 10.5 -11.0 volumes). A second portion of ethyl acetate (595.9 L) and water (348.0 L) was added to Reactor 2 and the resulting mixture was distilled at Tp < 45°C and Tj <55°C until the volume of the mixture reached 10.8 volume (NOR: 10.5 -11.0 volumes). The pH of the solution in Reactor 2 was tested. If the pH was < 8.0, then sodium carbonate solution (prepared using 44.2 kg Na2COs and 395.5 L water) was added to adjust pH to be 8.0-8.5 (NOR: 8.0-9.0).

[0192] The resulting mixture of Reactor 2 was stirred for NLT 30 min at about 30°C (NOR: 25-35 °C) and then centrifuged. The mother liquid (ML1) was transferred to Reactor 1. Water (139.1 L) was added to Reactor 2. The resulting mixture was centrifuged and the mother liquid (ML2) was transferred to Reactor 1. Water (139.1 L) was added to Reactor 2. The resulting mixture was centrifuged and the mother liquid (ML3) was transferred to Reactor 1.

[0193] The resulting solution in Reactor 1 was stirred for NLT 30 min at about 30°C (NOR: 25-35 °C). The stirring and agitation were stopped and the aqueous phase transferred to Reactor 2 the organic phase was discarded.

[0194] To Reactor 2 was added ethyl acetate (695.5 L) and the resulting mixture was cooled to about 5°C (NOR: 0-10 °C). The resulting solution in Reactor 2 was stirred for NLT 30 min at about 30°C (NOR: 25-35 °C). The stirring and agitation were stopped and the aqueous phase was transferred to Reactor 1 and the organic phase was discarded.

[0195] Workup with ethyl acetate and HC1: To Reactor 1 was added ethyl acetate (695.5 L) and the resulting mixture was cooled to 5°C (NOR: 0-10 °C). The pH of the mixture in Reactor 1 was adjusted to 2.0-3.0 using 2M HC1 solution. The pH-adjusted solution was stirred for NLT 30 min at about 5°C (NOR: 0-10 °C). The stirring and agitation were stopped the aqueous phase was transferred to Reactor 2 and the organic phase was transferred to Reactor 4. Such a workup process on the resulting aqueous phase in Reactor 2 using ethyl acetate and HC1 was repeated twice. The resulting organic phase (containing Compound E) from the repeated workup was collected and transferred to Reactor 4.

[0196] The mixture in Reactor 4 was distilled at Tj< 50°C until the volume of the mixture reached about 2.2 volumes (NOR: 2.0-2.4 volumes). The remaining mixture in Reactor 4 was heated to about 45°C (NOR: 40-50 °C) and the mixture was transferred to Reactor 2 through a polish filter. Reactor 4 and the transfer pipes were rinsed with ethyl acetate (172 L) and the rinse was transferred to Reactor 2.

[0197] To Reactor 2 was slowly charged n-heptane (695.4 L) with the temperature of the mixture maintained at 40-50 °C. The resulting mixture was cooled to about 2°C (NOR: 0-5 °C) and centrifuged. Compound E was collected as the solid through the centrifugation. The crude Compound E was dried with vacuum at NMT 45 °C. 58.5 kg (76.0 yield) dry Compound E was obtained.

[0198] Normal operating ranges (NOR), proven acceptable ranges (PAR) for the manufacturing of Compound E are included in Table 7.

Claims

CLAIMS:

1. A method of synthesizing Compound 1(Compound 1), or a pharmaceutically acceptable salt or hydrate thereof,wherein the method comprises:step 1 A: in a reactor, reacting Compound A with Compound B in a solution in the presence of a metal catalyst, to provide a solution comprising Compound C; andstep IB: treating the solution comprising Compound C with a metal scavenger, wherein Compound C is converted to Compound 1 in two or more additional steps.

2. The method of claim 1, where the metal scavenger is N-acetyl cysteine.

3. The method of claim 1 or 2, wherein the metal catalyst is selected from Pd(dppf)C12, Pd(OAc)2, PdCl2, Pd(PPh3)2C12, Pd(PPh3)4, Pd2(dba)3, Pd(PhCN)2Cl2, PEPPSI-iPr, PdCl2[P(Cy)3]2, NiCh, NiCh-diglyme or Ni(C0D)2.

4. The method of any one of claims 1-3, wherein the metal catalyst in step 1 A is Pd(dppf)C12.

5. The method of any one of claims 1-4, wherein step 1A further comprises adding a base to the reactor, wherein the base is selected from K2CO3, K3PO4, K2HPO4, KHCO3, Cs2CO3, Na2CO3, NaHCO3, K2CO3, KF, NaOAc or KO Ac.

6. The method of claim 5, wherein the base is K2CO3.

7. The method of any one of claims 1-6, wherein step 1A further comprises adding a solvent to the reactor comprising Compound A, Compound B and the metal catalyst, wherein the solvent comprises acetonitrile.

8. The method of any one of claims 1-7, wherein step 1A is performed at a temperature in the range of from about 40 °C to about 80 °C.

9. The method of any one of claims 1-8, wherein step 1A is performed at a temperature of about 70 °C.

10. The method of any one of claims 1-9, wherein Compound A and Compound B are reacted at a ratio of from 1 :2 to 2: 1.

11. The method of any one of claims 1-10, wherein Compound A and Compound B are reacted at a ratio of about 1:1.

12. The method of any one of claims 1-11, wherein step IB further comprises adding a solvent to the solution comprising Compound C, wherein the solvent comprises isopropyl acetate (AcOiPr).

13. The method of any one of claims 1-12, wherein Compound C is not isolated.

14. The method of any one of claims 1-13, wherein the method further comprises:step 2: deprotecting Compound C to provide Compound D:

15. The method of claim 14, wherein step 2 is performed in the presence of an acid.

16. The method of claim 15, wherein of the acid is formic acid.

17. The method of any one of claims 14-16, wherein step 2 is performed in a solvent comprising isopropyl acetate.

18. The method of any one of claims 14-17, wherein Compound C obtained in step IB is taken to step 2 without isolating Compound C from step IB.

19. The method of any one of claims 1-18, wherein the method further comprisesstep 3 : reacting Compound D with Compound E in a reactor to provide Compound F20. The method of claim 19, wherein step 3 is performed in the presence of an acid anhydride.

21. The method of claim 20, wherein the acid anhydride is propylphosphonic anhydride (T3P).

22. The method of claim 20 or 21, wherein step 3 further comprises adding a solvent to the reactor.

23. The method of any one of claims 19-22, wherein step 3 comprises adding a base to the reactor.

24. The method of claim 23, wherein the base is diethyl amine, trimethyl amine, triethyl amine, triisopropylamine, N,N-diisopropylethylamine (DIPEA), tributylamine or any combination thereof.

25. The method of claim 24, wherein the base is N,N-diisopropylethylamine (DIPEA).

26. The method of any one of claims 1-25, wherein the method further comprisesstep 4: dehydrating Compound F to form Compound G27. The method of any one of claims 19-26, wherein Compound F is not isolated from step 3 prior to subjecting it to step 4.

28. The method of any one of claims 1-27, wherein the method comprisesstep 5: in a reactor, reacting Compound Gto provide Compound 1, or a pharmaceutically acceptable salt or hydrate thereof:

29. The method of claim 28, wherein step 5 is performed in the presence of an acid selected from HC1, formic acid, H3PO4, CH3COOH, CF3COOH or any combination thereof.

30. The method of claim 29, wherein the acid is formic acid.

31. The method of claim 29 or 30, wherein the acid is added to the reactor prior to adding Compound G to the reactor.

32. The method of any one of claims 28-30, wherein Compound 1 is a crude product.

33. The method of any one of claims 28-32, further comprising adding a solvent to the reactor subsequent to the adding of the acid.

34. The method of claim 33, wherein the solvent comprises isopropyl acetate.

35. The method of claim 34, wherein the solvent further comprises ethanol.

36. The method of any one of claims 1-35, wherein the method comprises recrystallizing Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, from a solvent.

37. The method of claim 36, wherein the solvent comprises ethanol and water.

38. The method of any one of claims 1-37, wherein the method is performed on a scale greater than 1.5 kilogram.

39. The method of any one of claims 1-38, wherein the method is performed on a scale greater than 5 kilograms.

40. The method of any one of claims 1-39, wherein the method a is performed on a scale greater than 10 kilograms.

41. The method of any one of claims 1-40, wherein the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof with a purity greater than 98.1%.

42. The method of any one of claims 1-40, wherein the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof with a purity greater than 98.5%.

43. The method of any one of claims 1-40, wherein the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof with a purity greater than 99.0%.

44. The method of any one of claims 14-43, wherein the method affords Compound D with a palladium content lower than 60 ppm.

45. The method of any one of claims 14-43, wherein the method affords Compound D with a palladium content lower than 30 ppm.

46. The method of any one of claims 14-43, wherein the method affords Compound D with a palladium content lower than 10 ppm.

47. The method of any one of claims 26-46, wherein the method affords Compound G, or a pharmaceutically acceptable salt or hydrate thereof with a palladium content lower than 40 ppm.

48. The method of any one of claims 26-46, wherein the method affords Compound G, or a pharmaceutically acceptable salt or hydrate thereof with a palladium content lower than 30 ppm.

49. The method of any one of claims 26-46, wherein the method affords Compound G, or a pharmaceutically acceptable salt or hydrate thereof with a palladium content lower than 10 ppm.

50. The method of any one of claims 1-49, wherein the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof with a palladium content lower than 50 ppm.

51. The method of any one of claims 1-49, wherein the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof with a palladium content lower than 25 ppm.

52. The method of any one of claims 1-49, wherein the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof with a palladium content lower than 5 ppm.

53. The method of any one of claims 1-49, wherein the method affords Compound 1, or a pharmaceutically acceptable salt or hydrate thereof with a palladium content lower than 3 ppm.

54. The method of any one of claims 1-53, wherein Compound 1, or a pharmaceutically acceptable salt or hydrate thereof is a monohydrate.

55. A method of synthesizing Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, according to FIG. 1.

56. A method of synthesizing Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, according to FIG. 3.

57. A method of synthesizing Compound E having the structure(Compound E), according to the steps as shown below:Step a Step b58. A method of synthesizing Compound E, or a pharmaceutically acceptable salt or hydrate thereof, according to FIG. 2.

59. Compound 1(Compound 1), or a pharmaceutically acceptable salt or hydrate thereof, prepared by the method of any one of claims 1-56, wherein Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, has a purity greater than 98.1%.

60. The compound of claim 59, wherein the compound is a hydrate.

61. The compound of claim 59 or 60, wherein the compound is a monohydrate.

62. The compound of any one of claims 59-61, or a pharmaceutically acceptable salt or hydrate thereof, wherein the compound has purity of at least 99%.

63. The compound of any one of claims 59-62, wherein the compound contains less than 3 ppm metal.

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