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CN-122003412-A - Process for preparing raniranol

CN122003412ACN 122003412 ACN122003412 ACN 122003412ACN-122003412-A

Abstract

The present disclosure relates to a process for preparing ranilanno comprising reacting N- (4-chloro-2-iodophenyl) -1, 3-benzothiazole-6-sulfonamide with 5-hexynoic acid in the presence of a palladium catalyst and a copper salt.

Inventors

  • FREDERIC BELL
  • Cecil Broso
  • victoria. zubar

Assignees

  • 伊文蒂瓦公司

Dates

Publication Date
20260508
Application Date
20240920
Priority Date
20230922

Claims (20)

  1. 1. A process for the preparation of lanuno comprising reacting N- (4-chloro-2-iodophenyl) -1, 3-benzothiazole-6-sulfonamide with 5-hexynoic acid in the presence of Pd/C and a copper salt.
  2. 2. The method of claim 1, wherein the copper salt is selected from the group consisting of copper chloride, copper acetate, copper carbonate, copper sulfate, copper bromide, copper trifluoroacetate, copper nitrate, copper hydroxide, copper oxide, copper iodide, and mixtures thereof.
  3. 3. The method of claim 2, wherein the copper salt is copper iodide.
  4. 4. The process of any of the preceding claims, wherein the copper salt is used in an amount of about 0.01 to about 0.15 equivalents based on the amount of starting N- (4-chloro-2-iodophenyl) -1, 3-benzothiazole-6-sulfonamide.
  5. 5. The process according to any one of the preceding claims, wherein 5-hexynoic acid is used in an amount of about 1.0 to about 2.0 equivalents based on the amount of starting N- (4-chloro-2-iodophenyl) -1, 3-benzothiazole-6-sulfonamide.
  6. 6. The process according to any of the preceding claims, wherein the reaction is carried out in a solvent, in particular selected from dichloromethane, chloroform, pyridine, 4-dimethylaminopyridine, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, water, ethyl acetate, toluene, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, methyl butyl ketone, and mixtures thereof.
  7. 7. The process according to any of the preceding claims, wherein the reaction is carried out in the presence of a base, in particular selected from trimethylamine, triethylamine, pyridine, imidazole, 4-dimethylaminopyridine, 2, 6-dimethylpyridine, 1, 4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, N-dimethylaniline, and mixtures thereof.
  8. 8. The process of claim 7, wherein the base is used in an amount of about 1.0 to about 20.0 equivalents based on the amount of starting N- (4-chloro-2-iodophenyl) -1, 3-benzothiazole-6-sulfonamide.
  9. 9. The process of any of the preceding claims, wherein the reaction is carried out at a temperature of about 35 ℃ to about 200 ℃.
  10. 10. A process for preparing crystalline form β of lanuno, the process comprising: a) Preparing a hot slurry of ranitidine in a suitable solvent for ranitidine; b) Optionally, filtering the warm slurry of lanuno; c) Cooling the slurry of ranilanno to a temperature of about 15 ℃ to about 95 ℃, and D) The slurry of ranitidine is maintained at a temperature of about 15 ℃ to about 95 ℃ for about 15 minutes to about 72 h.
  11. 11. The process according to claim 10, wherein the suitable solvent for lanunox is selected from the group consisting of water, dimethyl sulfoxide, alcoholic solvents, halogenated hydrocarbon solvents, ether solvents, ketone solvents, ester solvents, hydrocarbon solvents, nitrile solvents, amide solvents, and mixtures thereof.
  12. 12. The process according to claim 11, wherein the suitable solvent for lanunox is selected from toluene, tetrahydrofuran, acetic acid, and mixtures thereof.
  13. 13. The process according to claim 10 or 12, wherein the slurry of lanunox is heated in step a) to a temperature of about 70 ℃ to about 120 ℃, such as about 70 ℃ to about 110 ℃, about 80 ℃ to about 105 ℃, or about 85 ℃ to about 100 ℃.
  14. 14. The process of any one of claims 10 to 13, wherein the slurry of lanunox is cooled in step C) to a temperature of about 15 ℃ to 95 ℃, about 20 ℃ to 95 ℃, about 25 ℃ to 95 ℃, about 30 ℃ to 95 ℃, about 35 ℃ to 95 ℃, about 40 ℃ to 95 ℃, about 45 ℃ to 95 ℃, about 50 ℃ to about 95 ℃, about 55 ℃ to about 95 ℃, about 60 ℃ to 95 ℃, about 65 ℃ to 95 ℃, about 70 ℃ to 95 ℃, about 75 ℃ to 95 ℃, about 80 ℃ to 95 ℃, about 85 ℃ to 95 ℃, or about 90 ℃ to 95 ℃.
  15. 15. The process of any one of claims 10 to 14, wherein the slurry of lanunox is maintained in step d) at a temperature of about 15 to 95 ℃, about 20 to 95 ℃, about 25 to 95 ℃, about 30 to 95 ℃, about 35 to 95 ℃, about 40 to 95 ℃, about 45 to 95 ℃, about 50 to about 95 ℃, about 55 to about 95 ℃, about 60 to 95 ℃, about 65 to 95 ℃, about 70 to 95 ℃, about 75 to 95 ℃, about 80 to 95 ℃, about 85 to 95 ℃, or about 90 to 95 ℃.
  16. 16. The method according to any one of claims 10 to 15, wherein step d) is performed over a period of about 15 minutes to about 72 hours, such as about 30 minutes to about 48 hours, about 1 hour to about 30 hours, about 1 hour to 25 hours, about 1 hour to 20 hours, about 1 hour to 15 hours.
  17. 17. The method according to any one of claims 10 to 16, wherein the temperature in step d) is the same as the temperature in step c).
  18. 18. The process according to any one of claims 10 to 17, wherein no seeding of crystalline form β of lanunox is added during the reaction.
  19. 19. The process according to any one of claims 10 to 17, wherein a seed crystal of crystalline form β of lanunox is added during step c) and/or step d).
  20. 20. The method according to any one of claims 10 to 19, wherein steps c) and d) are repeated 1 to 10 times.

Description

Process for preparing raniranol Technical Field The present disclosure relates to a process for preparing lanuno (lanifibranor). In particular, the present disclosure relates to methods of obtaining a desired compound in high yield and purity, which can then be incorporated into pharmaceutical compositions. Background Lanunox or 1- (6-benzothiazolylsulfonyl) -5-chloro-1H-indole-2-butyric acid is a pan-PPAR agonist, currently in clinical development for the treatment of non-alcoholic steatohepatitis (NASH) patients, and no approved therapeutic methods are currently available. Processes for preparing ranitidine have been reported (J. Med. Chem. 2018,61,6,2246-2265; WO 2007/026097). However, these methods are laboratory scale methods, are not suitable for industrial preparation, and may result in the formation of byproducts and/or impurities that are not present in the pharmaceutical form intended for administration to the patient. In addition, these methods use a catalyst which is not recyclable, and the reaction takes a long time to complete (16 to 30 hours). There remains a need for a process for preparing ranitidine which can be scaled up, is economical and environmentally friendly in terms of the raw materials used, and gives the desired product in high yields and purity. Disclosure of Invention In one aspect, the present disclosure relates to a process for preparing ranilanno comprising reacting N- (4-chloro-2-iodophenyl) -1, 3-benzothiazole-6-sulfonamide with 5-hexynoic acid in the presence of Pd/C and a copper salt. In another aspect, the present disclosure relates to a process for preparing crystalline form β of ranitidine comprising preparing a hot slurry of ranitidine in a suitable solvent for ranitidine and cooling and maintaining the slurry at a temperature of about 20 ℃ to about 85 ℃ for a period of time. Drawings Fig. 1 shows a PXRD pattern of crystalline form β of lanuno. Figure 2 shows the DSC profile of crystalline form β of ranilanno. Fig. 3 shows the TGA profile of crystalline form β of ranilanno. Fig. 4 shows a DVS isotherm plot of crystalline form β of lanuno. Fig. 5A and 5B show the IR spectrum of crystalline form β of lanunox and the index of the absorption band for IR analysis. Fig. 6 and 7 show the overlap of PXRD patterns for crystalline forms of ranilanno. Fig. 8 shows 1 H NMR spectra of crystalline form β of ranilanno of example 18. Fig. 9 shows 13 C NMR spectra of crystalline form β of ranilanno of example 18. Fig. 10 shows the raman spectrum of crystalline form β of lanuno. Detailed Description As used herein, the term "raniranol" is understood to mean the free acid of raniranol, i.e. a compound of the formula: 。 As used herein, "crystalline form β of ranilanno" refers to a crystalline form having the characteristics shown in fig. 1-10 and table 1 below. As used herein, "deuterated form of lanuno" refers to a compound of the formula: Wherein at least one of the groups R 1 to R 7 is a deuterium (D) atom and the other groups R 1 to R 7 are hydrogen (H) atoms. In some embodiments, at least the group R 1 is D. In some embodiments, at least one of the groups R 2 to R 7 is D, in particular at least one of the groups R 2 and R 3 and/or at least one of the groups R 4 and R 5 and/or at least one of the groups R 6 and R 7 is D. In some embodiments, each of R 2、R3、R4、R5、R6 and R 7 is D. In some embodiments, the deuterated form of lanunox is 4- (1- (2-deutero-1, 3-benzothiazol-6-yl) sulfonyl) -5-chloro-1H-indol-2-yl) butyric acid or 4- [1- (1, 3-benzothiazol-6-ylsulfonyl) -5-chloro-indol-2-yl ] -2, 3, 4-hexadeuterated butyric acid. As used herein, the range "a to B" includes endpoints a and B. As used herein, all values disclosed herein are approximate, whether the term "about" or "approximately" is used, and each value may differ by ± 1%, ± 2%, or ± 5% based on the disclosed value. As used herein, "room temperature" or "ambient temperature", commonly abbreviated as "RT", refers to a temperature of an object that is close to or equal to the temperature of the space (e.g., room or fume hood) in which the object is located. Typically, room temperature is about 20 ℃ plus or minus 5 ℃. The term "suitable solvent for ranitidine" may be a single solvent or a mixture of solvents, meaning that the solubility of ranitidine in the single solvent or mixture of solvents at room temperature, as determined by methods well known in the art, is greater than 0.1/L, or greater than 0.2/L, or greater than 0.3/L, or greater than 0.4/L, or greater than 0.5/L, or greater than 0.6/L, or greater than 0.7/L, or greater than 0.8/L, or greater than 0.9/L, or greater than 1/L, or greater than 1.1/L, or greater than 1.2/L, or greater than 1.3/L, or greater than 1.4/L, or greater than 1.5/L, or greater than 1.6/L, or greater than 1.7/L, or greater than 1.8/L, or greater than 1.9/L, or greater than 2/L, or greater than 3/L, or greater than 4/L, or greater than 5/L, or greater than 6/L, or greater than 7/L, or greater than