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EP-4739693-A2 - IMPROVED MANUFACTURING PROCESS AND INTERMEDIATES FOR A PYRROLO[2,3-D]PYRIMIDINE COMPOUND AND USE THEREOF

EP4739693A2EP 4739693 A2EP4739693 A2EP 4739693A2EP-4739693-A2

Abstract

The present invention relates to an improved manufacturing process and intermediates for preparing N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1- sulfonamide.

Inventors

  • CUSACK, Declan Thomas Patrick
  • DEFOREST, Jacob Cole
  • DUBBAKA, SRINIVAS REDDY
  • O'NEILL, PADRAIG MARY

Assignees

  • Pfizer Ireland Pharmaceuticals Unlimited Company

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. 1 . A process for preparing a compound having the structure: which comprises (a) preparing a sulfonamide or salt thereof having the structure: where said salt selected from the group consisting of the hydrochloric acid salt, acetic acid salt, phosphoric acid salt, (1S)-(+)-10-camphor sulfonic acid salt, 1 ,2-ethanedisulfonic acid salt, dibenzoyl-L-tartaric acid salt, dibenzoyl-D-tartaric acid salt, citric acid salt, succinic acid salt, fumaric acid salt, maleic acid salt, oxalic acid salt, p-toluenesulfonic acid salt, L-(+)-tartaric acid salt, D-(-)-tartaric acid salt, hydrobromic acid salt, acid salt, mesylate salt and malonic acid salt; and, (b) reacting said sulfonamide or salt thereof under suitable conditions with a compound having the structure: where X is selected from the group consisting of chloride, bromide and iodide, and thereby form the compound having the structure:
  2. 2. The process of claim 1 , wherein the sulfonamide salt is a tosic acid or acetic acid salt.
  3. 3. The process of claim 1 , wherein X is chloride.
  4. 4. The process of claim 1 , wherein the reaction of step (b) is carried out in the presence of an organic or inorganic base selected from the group consisting of diisopropylethyl amine, potassium carbonate, potassium hydroxide, diethylmethyl amine, triethylamine, 1 , 1 ,3,3- tetramethylguanidine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene and N-methylpiperidine.
  5. 5. The process of claim 1 , wherein the reaction of step (b) is carried out in the presence of an inorganic base which is potassium carbonate in an aqueous solvent.
  6. 6. A process for preparing a compound having the structure: which comprises (a) preparing the acetic acid salt of a sulfonamide having the structure: and, (b) reacting said salt in the presence of an organic or inorganic base selected from the group consisting of diisopropylethyl amine, potassium carbonate, diethylmethyl amine, triethylamine, 1 ,1 ,3,3-tetramethylguanidine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene and N-methylpiperidine, under suitable conditions, with a compound having the structure: and thereby form the compound having the structure:
  7. 7. The process of claim 6, wherein step (b) is carried out in the presence of an inorganic base which is potassium carbonate in an aqueous solvent.
  8. 8. A process for preparing a salt of a sulfonamide having the structure: where said salt is selected from the group consisting of the hydrochloric acid salt, acetic acid salt, phosphoric acid salt, (1S)-(+)-10-camphor sulfonic acid salt, 1 ,2-ethanedisulfonic acid salt, dibenzoyl-L-tartaric acid salt, dibenzoyl-D-tartaric acid salt, citric acid salt, succinic acid salt, fumaric acid salt, maleic acid salt, oxalic acid salt, p-toluenesulfonic acid salt, L-(+)-tartaric acid salt, D-(-)-tartaric acid salt, hydrobromic acid salt, acid salt, mesylate salt and malonic acid salt, said process comprising (a) reacting an acyl halide having the structure: where Y is chloride or bromide, with a vinyl ester having the structure: where Ri, R2 and R3 are independently selected from hydrogen, (Ci-C3)alkyl, substituted or unsubstituted phenyl, and (Ci-C 3 )alkyloxy In the presence of a metal selected from the group consisting of zinc and magnesium, and a suitable inert solvent selected from a group consisting of dioxane and tetra hydrofuran; (b) adding an acid selected from a group consisting of acetic acid, propionic acid and hydrochloric acid; (c) adding a sulfonamide having the structure: where R 4 and R 5 are independently selected from the group consisting of phenyl, (Cr C 3 )alkylphenyl, di(Ci-C 3 )alkylphenyl, and tri(Ci-C 3 )alkylphenyl, said phenyl being optionally further substituted by halide and (Ci-C 3 )alkoxy, under suitable basic conditions followed by dehalogenation conditions to provide an intermediate having the structure: and, (d) reductively aminating the intermediate formed in step (c) with N-methylbenzylamine or N- methylamine under suitable conditions to provide the salt of the sulfonamide having the structure:
  9. 9. The process of claim 8, wherein Y is chloride.
  10. 10. The process of claim 8, wherein step (a) is performed in the presence of an acid selected from the group consisting of acetic acid and hydrochloric acid, and wherein the metal is zinc.
  11. 11 . The process of claim 8, wherein step (b) is performed in the presence of a reagent selected from the group consisting of DBU, potassium-butoxide, sodium hydride, sodium ethoxide, and sodium methoxide.
  12. 12 The process of claim 8, wherein step (b) is performed in the presence of an acid selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, (1S/R )-(+/-)-10- camphor sulfonic acid, 1 ,2-ethanedisulfonic acid, dibenzoyl-L-tartaric acid, dibenzoyl-D-tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, oxalic acid, p-toluenesulfonic acid, L- (+)-tartaric acid, D-(-)-tartaric acid, hydrobromic acid, mesylate and malonic acid and lactic acid.
  13. 13. The process of claim 8, wherein the acid in step (b) is acetic acid or p-toluenesulfonic acid.
  14. 14. The process of claim 8, wherein the reductive amination in step (b) is performed using hydrogen gas in the presence of suitable catalyst selected from the group consisting of Pd, Pd/C, Pt, and Pt/C, or using a hydrogenation reagent selected from the group consisting of STAB, sodium borohydride, and lithium borohydride.
  15. 15. The process of claim 8, wherein R 4 and R 5 are both phenyl.
  16. 16. A process for preparing the acetic acid salt of a sulfonamide having the structure: said process comprising (a) reacting an acyl halide having the structure: with a vinyl ester having the structure: In the presence of zinc, acetic acid and optionally chlorotrimethylsilane; (b) adding a sulfonamide having the structure: where and R 4 and R 5 are independently selected from the group consisting of phenyl, (Cr C 3 )alkylphenyl, di(Ci-C 3 )alkylphenyl, and tri(Ci-C 3 )alkylphenyl, said phenyl being optionally further substituted by halide and (Ci-C 3 )alkoxy, in the presence of DBU under suitable conditions to provide an intermediate having the structure: and, (c) reductively aminating the intermediate formed in step (b) using hydrogen gas in the presence of Pd and acetic acid under suitable conditions to provide the acetic acid salt of the sulfonamide.
  17. 17. The process of claim 16, where R 4 and R 5 are both phenyl.
  18. 18. A process for preparing an acid salt of a sulfonamide having the structure: where said acid HA salt is selected from the group consisting of the hydrochloric acid salt, acetic acid salt, phosphoric acid salt, (1 S)-(+)-10-camphor sulfonic acid salt, 1 ,2- ethanedisulfonic acid salt, dibenzoyl-L-tartaric acid salt, dibenzoyl-D-tartaric acid salt, citric acid salt, succinic acid salt, fumaric acid salt, maleic acid salt, oxalic acid salt, p-toluenesulfonic acid salt, L-(+)-tartaric acid salt, D-(-)-tartaric acid salt, hydrobromic acid salt, acid salt, mesylate salt and malonic acid salt, said process comprising (a) reductively aminating a cyclobutanone having the structure: where Rs is selected from the group consisting of t-Boc and FMOC, under suitable conditions to provide an aminocyclobutane having the structure: (b) treating said aminocyclobutane with an acid HA corresponding to the salt of said sulfonamide under suitable conditions to provide an acid salt having the structure: (c) treating said acid salt formed in step (b) with n-propyl sulfonyl halide under suitable conditions to provide the protected sulfonamide having the structure: ; and, (d) deprotecting the protected sulfonamide with a hydride reducing agent selected from the group consisting of LiAIH 4 and NaBH 4 , followed by an acid quench with the acid HA under suitable conditions to provide the acid salt of the sulfonamide.
  19. 19. The process of claim 18, wherein the acid HA is acetic acid or p-toluenesulfonic acid.
  20. 20. The process of claim 18, wherein the reductive amination in step (a) is performed using the enzyme ATA-251 .

Description

IMPROVED MANUFACTURING PROCESS AND INTERMEDIATES FOR A PYRROLO[2,3- D]PYRIMIDINE COMPOUND AND USE THEREOF FIELD OF THE INVENTION The present invention relates to an improved manufacturing process and intermediates for preparing N-((1 S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1 - sulfonamide. The invention also relates to compounds and salts prepared by said processes. BACKGROUND OF THE INVENTION N-((1 S,3S)-3-(Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)prop-ane-1- sulfonamide, also known as abrocitinib and CIBINQO®, has the chemical formula C14H21N5O2S and the following structural formula: A preparative synthesis of N-((1 S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclobutyl)propane-1 -sulfonamide is described in commonly assigned US9,035,074, the contents of which are incorporated herein by reference in their entirety. The compound N- ((1 S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1 -sulfonamide is useful as an inhibitor of protein kinases, such as the enzyme Janus Kinase (JAK), and as such is useful therapeutically as an immunosuppressive agent for organ transplants, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other indications where immunosuppression would be desirable. The present invention relates to an improved manufacturing process and intermediates for preparing N-((1 S,3S)-3-(methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)cyclobutyl)propane-1 -sulfonamide. SUMMARY OF THE INVENTION The present invention is directed to a process for preparing a compound having the structure: which comprises (a) preparing a sulfonamide or salt thereof having the structure: where said salt selected from the group consisting of the hydrochloric acid salt, acetic acid salt, phosphoric acid salt, (1S)-(+)-10-camphor sulfonic acid salt, 1 ,2-ethanedisulfonic acid salt, dibenzoyl-L-tartaric acid salt, dibenzoyl-D-tartaric acid salt, citric acid salt, succinic acid salt, fumaric acid salt, maleic acid salt, oxalic acid salt, p-toluenesulfonic acid salt, L-(+)-tartaric acid salt, D-(-)-tartaric acid salt, hydrobromic acid salt, acid salt, mesylate salt and malonic acid salt; and, (b) reacting said sulfonamide or salt thereof under suitable conditions with a compound having the structure: where X is selected from the group consisting of chloride, bromide and iodide, and thereby form the compound having the structure: The term "alkyl," as used herein, means a straight or branched chain monovalent hydrocarbon group of formula -CnH(2n+i). Non-limiting examples include methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1 ,1 -dimethylethyl, pentyl and hexyl. The term "alkoxy," as used herein, means an alkyl substituent attached through an oxygen atom. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexyloxy. The term “benzyl,” as used herein, means a phenylmethyl group. The term "aryl,” as used herein, means a 6 to 8-membered monocyclic or 6 to 12- membered bicyclic carbocycle which is aromatic or partially unsaturated, said carbocycle being optionally substituted by one or more groups R. Examples include phenyl or naphthalenyl. The term “halogen,” or “halo,” as used herein, refers to fluoride, chloride, bromide, or iodide. The term “amino,” as used herein, refers to -NH2. Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art. If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s). DETAILED DESCRIPTION OF THE INVENTION The present invention is related to preparative processes which are useful in the manufacture of compounds which are selective JAK1 modulators useful for the treatment of diseases and conditions associated with dysregulation of the JAK1. In a first embodiment (E1) the invention provides a process for preparing a compound having the structure: which comprises (a) preparing a sulfonamide or salt thereof having the structure: where said salt selected from the group consisting of the hydrochloric acid salt, acetic acid salt, phosphoric acid salt, (1S)-(+)-10-camphor sulfonic acid salt, 1 ,2-ethanedisulfonic acid salt, dibenzoyl-L-tartaric acid salt, dibenzoyl-D-tartaric acid salt, citric acid salt, succinic acid salt, fumaric acid salt, maleic acid salt, oxalic acid salt, p-toluenesulfonic acid salt, L-(+)-tartaric acid salt, D-(-)-tartaric acid salt, hydrobromic acid salt, acid salt, mesylate salt and malonic acid salt; and, (b) reacting said sulfonamide or salt thereof