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EP-4735435-A1 - NEW PREPARATION METHOD OF COMPOUND AND NEW CRYSTALLINE FORM

EP4735435A1EP 4735435 A1EP4735435 A1EP 4735435A1EP-4735435-A1

Abstract

The present invention relates to a novel method for preparing N-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholin-4-carboxamide 1,1-dioxide and a novel synthetic pathway for a main intermediate used in the method, and a novel crystalline form of the compound and the method thereof.

Inventors

  • EOM, Dahan
  • PARK, Janghyun
  • KIM, DONG WOAN
  • KIM, KYUNGHWAN

Assignees

  • Chong Kun Dang Pharmaceutical Corp.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. Claims 1. A method for preparing a compound represented by Chemical Formula 1 below, the method comprising: in-situ preparing a compound represented by Chemical Formula 1 below from a compound represented by Chemical Formula 6 below: [Chemical Formula 1] .
  2. 2. The method according to claim 1, wherein the preparing of the compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 6 is performed in the presence of a base.
  3. 3. The method according to claim 2, wherein the base comprises imidazole.
  4. 4. The method according to claim 1, wherein the compound represented by Chemical Formula 1 is prepared by using at least one selected from a compound represented by [Chemical Formula A] below and a compound represented by [Chemical Formula B], and the compound represented by Chemical Formula 6 as a reaction material: [Chemical Formula A] [Chemical Formula B] wherein, in above Chemical formula B, X 1 is F, Cl, Br or I.
  5. 5. The method according to claim 1, wherein the preparing of the compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 6 comprises: a) preparing a reaction part 1 including a compound represented by Chemical Formula A or B below and a base; and b) mixing the reaction part 1 with a reaction part 2 including the compound represented by Chemical Formula 6 to prepare the compound represented by Chemical Formula 1: [Chemical Formula A] [Chemical Formula B] in above Chemical Formula B, X 1 is F, Cl, Br or I.
  6. 6. The method according to claim 5, wherein Step a) is performed by mixing a mixture comprising a base and a solvent with the compound represented by Chemical Formula A or B.
  7. 7. The method according to claim 5, wherein Step a) comprises: preparing the mixture including the base and the solvent; and adding the compound represented by Chemical Formula A or Chemical Formula B to the mixture.
  8. 8. The method according to claim 7, the method further comprises: cooling the mixture into 0-10°C after preparing the mixture including the base and the solvent.
  9. 9. The method according to claim 5, further comprising: stirring after adding the compound represented by Chemical Formula A or Chemical Formula B to the mixture.
  10. 10. The method according to claim 5, wherein the reaction part 2 in Step b) comprises the compound represented by Chemical Formula 6 and the solvent.
  11. 11. The method according to claim 5, wherein mixing the reaction part 2 and the reaction part 1 in the Step b) is performed by adding the reaction part 1 to the reaction part 2.
  12. 12. The method according to claim 11, wherein adding the reaction part 1 to the reaction part 2 is performed at -15℃ to 5℃.
  13. 13. The method according to claim 12, further comprising: heating to a temperature of 20 to 45℃ after completely mixing in Step b).
  14. 14. A method for preparing a compound represented by Chemical Formula 6 below, the method comprising: preparing a compound represented by Chemical Formula 6 below from hydrazine(N 2 H 4 ) or a hydrate thereof and a compound represented by Chemical Formula 5 below in the presence of a solvent including a C1 to C6 linear or branched alcohol or a mixture of a C1 to C6 linear or branched alcohol and water: [Chemical Formula 5] in above Chemical Formula 5, R is C1-C6 linear or branched alkyl or benzyl.
  15. 15. The method according to claim 14, wherein the solvent is methanol or a mixture of methanol and water.
  16. 16. The method according to claim 14, wherein a volume ratio of the alcohol and the water is 10:1 to 1:1.
  17. 17. The method according to claim 14, wherein R is methyl.
  18. 18. A method for preparing a compound represented by Chemical Formula 5, the method comprising: reacting a compound represented by Chemical Formula 3 below with a compound represented by Chemical Formula 4 in the presence of a base to prepare a compound represented by Chemical Formula 5: [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] in above Chemical Formulas 3 and 5, R is C1-C6 linear or branched alkyl or benzyl, and in above Chemical Formula 4, X is F, Cl, Br or I.
  19. 19. The method according to claim 18, wherein R is methyl and X is Cl.
  20. 20. The method according to claim 18, wherein the base is triethylamine, N,N- diisopropylethylamine, imidazole, pyridine, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, or a mixture thereof.

Description

Specification Title New preparation method of Compound and New Crystalline Form Technical Field The present disclosure relates to a novel method for preparing N-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholin-4-carboxamide 1,1-dioxide, a novel method for preparing intermediates used in synthesis of the compound, and a novel crystalline form of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4- carboxamide 1,1-dioxide. Background N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine- 4-carboxamide 1,1-dioxide represented by the following Chemical Formula 1 is a material having an effect of preventing or treating histone deacetylase 6 activity-related diseases. A method for preparing a compound represented by Chemical Formula 1 below is disclosed in Korean Registered Patent No. 10-1799010. [Chemical Formula 1] In the conventional preparation method which is disclosed in the above patent, as shown in the following [Reaction Formula 1], a compound of Chemical Formula 10 obtained by reacting aniline with a thiomorpholine derivative in the presence of triphosgene is subjected into N-alkylation reaction with a compound of Chemical Formula 8b to prepare a compound of Chemical Formula 5a. A compound of Chemical Formula 6 obtained by reacting the synthesized compound of Chemical Formula 5a with a hydrazine hydrate is reacted with a difluoroacetic anhydride to prepare a compound of Chemical Formula 9, and a compound represented by Chemical Formula 1 is prepared by using 1-methoxy-N- triethylammoniosulfonyl-methaneimidate (Burgess reagent). [Reaction Formula 1] However, the synthesis method through the path of the reaction formula 1 has a number of problems during the preparation process. The triphosgene used when preparing the compound of Chemical Formula 10 has very high reactivity, and thus has low stability, is easily decomposed when coming into contact with moisture, and releases toxic gas, which is vulnerable to work safety, thus causing a big problem in mass production. In addition, a long reaction time of 16 hours and a low reaction yield of 20% or less are problematic for preparation efficiency and commercial potential. Furthermore, the base used when preparing the compound of Chemical Formula 5a from the compound of Chemical Formula 10 is sodium hydride, which is an inflammable material, and the reaction yield is also low. Moreover, according to the conventional method, when preparing the compound represented by Chemical Formula 6 and the compound represented by Chemical Formula 1, there is a problem in that the reaction is performed under a high temperature condition of 100℃ or more using microwaves, and a reagent which is not generally used well and expensive, such as a Burgess reagent, should be used. Besides, column chromatography needs to be used for purification at all stages of reaction, and thus industrial mass production is impossible. In other words, according to the conventional method, the preparation of the compound of Chemical Formula 1, which is a target material, has a total yield of only about 1.5% through a total of five steps, and equipment and reagents used in the reaction are expensive and has a long reaction time, and the use of inflammable materials or reagents having low safety is required, and thus industrial mass production is almost impossible with very low economic efficiency. In the above patent, the compound represented by Chemical Formula 1 is only prepared in an oil state. However, a compound in an oil state is not suitable for development as a medicament, and has a disadvantage in that it is difficult to remove the residual solvent and that the compound is not easy to industrially handle. Therefore, there is a need for developing a compound in a solid form, which is pharmaceutically useful, easy to handle during preparation, and capable of stable production, and a preparation method thereof. Prior Art Reference Patent Document (Patent Document 0001) Korean Registered Patent No. KR 1799010 B1 (Patent Document 0002) International Patent Publication WO 2015/082616 A1 (Patent Document 0003) International Patent Publication WO 2021/246781 A1 (Patent Document 0004) International Patent Publication WO 2000/060044 A1 (Patent Document 0005) International Patent Publication WO 2001/055115 A1 (Patent Document 0006) International Patent Publication WO 2019/182938 A1 (Patent Document 0007) International Patent Publication WO 2002/000626 A1 (Patent Document 0008) Chinese Patent Publication CN 103265479 A Description of the Invention Technical Problem To solve the problems of the existing preparation method, the present disclosure may provide a novel method for preparing N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N- phenylthiomorpholin-4-carboxamide 1,1-dioxide, which is a compound represented by Chemical Formula 1, or a pharmaceuticall