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CN-122003413-A - Crystalline polymorph form a of JAK inhibitor and process for preparing the same

CN122003413ACN 122003413 ACN122003413 ACN 122003413ACN-122003413-A

Abstract

The present application relates to a process for the preparation of ethyl (R) -4- ((1- (2-cyanoacetyl) piperidin-3-yl) amino) -1H-pyrrolo [2,3-b ] pyridine-5-carboxylate (compound 1). The process involves the addition of an ethyl formate (ethyl carboxylate) group, the displacement of a halogen with a chiral amine, deprotection of a chiral cyclic amine, and subsequent coupling reaction with cyanoacetic acid. The displacement may be performed in an autoclave at elevated pressure.

Inventors

  • G. Dresenzo
  • J. Springer
  • LAWSON JON P.
  • J. A. Schotten
  • SCHMIDT MONICA S.

Assignees

  • 阿克拉瑞斯治疗股份有限公司

Dates

Publication Date
20260508
Application Date
20240816
Priority Date
20230816

Claims (20)

  1. 1. A process for preparing compound 1 having the structure: (Compound 1) The method comprises the following steps: (a) Allowing the compound to react And a compound Contacting in the presence of a base to form a compound (B) contacting said compound STG-01 with ethyl chloroformate in the presence of a base to form a compound (C) contacting said compound STG-02 with an alcoholic solution of HCl to form a compound And (C) sum (D) STG-03 was converted to Compound 1.
  2. 2. The method of claim 1, further comprising contacting the compound STG-03 with a base to form a compound 。
  3. 3. The method of claim 2, further comprising reacting the compound STG-04 with Contacting in the presence of an amine base to form a compound 。
  4. 4. The method of claim 3, wherein the contacting is performed in an autoclave at elevated pressure.
  5. 5. The method of claim 3, further comprising contacting the compound STG-05 with an alcoholic solution of HCl to form a compound 。
  6. 6. The method of claim 5, further comprising reacting the compound STG-06 with In methylene chloride in the presence of a coupling reagent and an amine base, and thereby form compound 1.
  7. 7. The method of claim 5, further comprising reacting the compound STG-06 with In THF and ethanol in the presence of a coupling reagent and an amine base, and thereby compound 1 is formed.
  8. 8. The method of claim 5, further comprising reacting the compound STG-06 with In THF in the presence of a coupling reagent and an amine base, and thereby compound 1 was formed.
  9. 9. The method of claim 1, wherein the method results in an improved purity profile.
  10. 10. A process for preparing compound 1 according to the route shown in scheme 2.
  11. 11. The process of claim 10, wherein the process of preparing compound 1 according to the pathway shown in scheme 2 results in an improved purity profile.
  12. 12. A process for preparing compound 1 having the structure: (Compound 1) The method comprises the following steps: (a) Allowing the compound to react With an alcoholic solution of HCl to form a compound And (C) sum (B) STG-03 was converted to Compound 1.
  13. 13. The method of claim 12, further comprising contacting the compound STG-03 with a base to form a compound 。
  14. 14. The method of claim 13, further comprising reacting the compound STG-04 with Contacting in the presence of an amine base to form a compound 。
  15. 15. The method of claim 14, wherein the contacting is performed in an autoclave at an elevated pressure.
  16. 16. The method of claim 14, further comprising contacting the compound STG-05 with an alcoholic solution of HCl to form a compound 。
  17. 17. The method of claim 16, further comprising reacting the compound STG-06 with In methylene chloride in the presence of a coupling reagent and an amine base, and thereby form compound 1.
  18. 18. The method of claim 16, further comprising reacting the compound STG-06 with In THF and ethanol in the presence of a coupling reagent and an amine base, and thereby compound 1 is formed.
  19. 19. The method of claim 16, further comprising reacting the compound STG-06 with In THF in the presence of a coupling reagent and an amine base, and thereby compound 1 was formed.
  20. 20. The method of claim 12, wherein the method results in an improved purity profile.

Description

Crystalline polymorph form a of JAK inhibitor and process for preparing the same Cross Reference to Related Applications The application claims the benefit of U.S. provisional application No. 63/533,050, filed on 8 months 16 of 2023, and U.S. provisional application No. 63/606,795, filed on 12 months 6 of 2023, each of which is incorporated herein by reference in its entirety. Disclosure of Invention In one aspect, the present disclosure provides a novel process for preparing compound 1 having the structure: (Compound 1), the method comprising the steps of (a) reacting a compound And a compoundContacting in the presence of a base to form a compound(B) contacting said compound STG-01 with ethyl chloroformate in the presence of a base to form a compound(C) contacting said compound STG-02 with an alcoholic solution of HCl to form a compoundAnd (d) converting STG-03 to compound 1. Drawings For a fuller understanding of the nature and advantages of the present invention, reference should be made to the following detailed description taken together with the accompanying figures, in which: Fig. 1A provides an image of crystalline compound 1 under an optical microscope. Fig. 1B and 1C provide images of a single crystal for a single crystal measurement used to simulate the PXRD pattern of compound 1. Fig. 2 is a representative PXRD pattern collected from a sample of compound 1 polymorph form a. Fig. 3 is a PXRD pattern simulated from measurements of individual crystals of polymorph form a of compound 1. Figure 4 is a thermogravimetric analysis (TGA) curve and a Differential Scanning Calorimetry (DSC) curve of compound 1. Fig. 5 is a dynamic vapor adsorption (DVS) isotherm of compound 1. Fig. 6 is an FT-raman spectrum of compound 1. FIG. 7 is a schematic diagram of a plug flow reactor. Detailed Description Before describing the compositions and methods of the present invention, it is to be understood that the scope of the present invention is not limited to the specific processes, compositions, or methods described as such specific processes, compositions, or methods may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference in their entirety with respect to the aspects identified as being described. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Compound 1, shown below as formula I, is disclosed in U.S. patent application publication number 20190135808A1 (example 117), which is hereby incorporated by reference in relation to its disclosure of compound 1 and the methods of synthesizing the same. Compound 1 in its free base form has the formula C 18H21N5O3 and a molecular weight of 355.40 g/mol. As used herein, "compound 1" refers to ethyl (R) -4- ((1- (2-cyanoacetyl) piperidin-3-yl) amino) -1H-pyrrolo [2,3-b ] pyridine-5-carboxylate. Definition of the definition It must also be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a JAK inhibitor" is a reference to one or more JAK inhibitors and equivalents thereof known to those skilled in the art, and so forth. As used herein, the term "about" means ± 10% of the numerical value of the number used. Thus, about 50% means in the range of 45% to 55%. When used to describe a temperature, "about" refers to the identified temperature ± 5 degrees. The term "about" when used in describing the PXRD peaks refers to the identified 2Peak ± 0.2 degrees. In any embodiment, the methods and compositions disclosed herein can comprise the recited steps and components. As used herein, "comprising" is an open language that is used to describe steps or components included in a described method or composition, but that indicates that other elements may also be included, even if the elements are not explicitly described. In any embodiment, the methods and compositions disclosed herein can consist essentially of the recited steps and components. As used herein, "consisting essentially of" is used to describe steps or components included in the recited methods or compositions and to indicate that other elements may also be included, but that the other elements will not have a substantial effect on the