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CN-121986098-A - Synthesis of lanuno intermediates

CN121986098ACN 121986098 ACN121986098 ACN 121986098ACN-121986098-A

Abstract

The present disclosure relates to a process for preparing a compound of formula (I) comprising a palladium-free coupling reaction between N- (4-chloro-2-iodo-phenyl) -1, 3-benzothiazole-6-sulfonamide and methyl 5-hexynoate in the presence of a copper catalyst. (I)

Inventors

  • Benazar Bubia
  • JEROME GONZALEZ
  • FREDERIC BELL

Assignees

  • 伊文蒂瓦公司

Dates

Publication Date
20260505
Application Date
20240829
Priority Date
20230831

Claims (14)

  1. 1. A process for preparing a compound of formula (I): (I), The process comprises coupling N- (4-chloro-2-iodo-phenyl) -1, 3-benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of a copper catalyst, wherein the coupling reaction is performed in the absence of a palladium catalyst.
  2. 2. The method of claim 1, wherein the copper catalyst is a copper (I) catalyst or a copper (II) catalyst.
  3. 3. The process according to claim 1 or 2, wherein the copper (I) catalyst is selected from copper (I) bromide, copper (I) chloride, copper (I) iodide, copper (I) acetate, copper (I) oxide, copper (I) tetra acetonitrile triflate, copper (I) bis (triphenylphosphine) borohydride, and mixtures thereof.
  4. 4. The process according to claim 1 or 2, wherein the copper (II) catalyst is selected from copper (II) sulfate, copper (II) triflate, copper (II) oxide, copper (II) bromide, copper (II) chloride, copper (II) iodide, copper (II) acetate, copper acetylacetonate, and mixtures thereof.
  5. 5. The process according to any of the preceding claims, wherein the coupling reaction is carried out in the presence of 0.1 to 2.0 equivalents of copper catalyst.
  6. 6. A process according to any one of the preceding claims, wherein the coupling reaction is carried out in the presence of a base.
  7. 7. The process of claim 6 wherein the base is selected from cesium carbonate, sodium carbonate, potassium carbonate, sodium t-butoxide, potassium t-butoxide, sodium acetate, diisopropylamine, triethylamine, trans-diaminocyclohexane, 1, 8-diazabicyclo [5.4.0] undec-7-ene, pyridine and 4- (dimethylamino) pyridine.
  8. 8. The method of any one of claims 1 to 5, wherein the coupling reaction is performed in the absence of a base.
  9. 9. The method of any of the preceding claims, wherein the coupling reaction is performed at a temperature ranging from about 70 ℃ to about 120 ℃.
  10. 10. A process according to any one of the preceding claims, wherein the coupling reaction is carried out in the presence of a solvent.
  11. 11. The process according to claim 10, wherein the solvent is selected from the group consisting of water, methanol, ethyl acetate, acetonitrile, ethers, toluene, pyridine, dimethyl sulfoxide, dimethylformamide, and mixtures thereof, such as methyltetrahydrofuran or dioxane.
  12. 12. A method according to any one of the preceding claims, wherein the coupling reaction is carried out in the presence of a ligand.
  13. 13. The method of claim 12, wherein the ligand is selected from the group consisting of phenanthroline, N '-dimethylethylenediamine, N', N "-trimethyldiethylenetriamine, 2- (2-pyridyl) pyridine, bis (2-picolyl) amine, and glyoxalbis (2-hydroxyaniline).
  14. 14. A process for preparing lanuno, the process comprising: a) A compound of formula (I) prepared by a process as claimed in any one of claims 1 to 13, and B) Deprotection of the ester group of the compound of formula (I).

Description

Synthesis of lanuno intermediates Technical Field The present invention relates to a process for the preparation of a compound useful for the synthesis of lanunox (lanifibranor), and to a process for the preparation of lanunox from said compound. 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. Ranitino is described in example 117 of WO 2007/026097 and has the following structure: Its synthesis is described in WO 2007/026907 and J Med Chem 2018,61 (6), 2246-2265. In the latter document, the synthesis of ranilanno comprises (i) reacting 4-chloro-2-iodoaniline with 1, 3-benzothiazole-6-sulfonyl chloride to give N- (4-chloro-2-iodoaniline) -1, 3-benzothiazole-6-sulfonamide, (ii) reacting the compound obtained in step (i) with methyl hex-5-ynoate to give methyl 4- [1- (1, 3-benzothiazol-6-ylsulfonyl) -5-chloro-indol-2-yl ] -butyrate, and (iii) deprotecting the ester group of the compound obtained in step (ii). The reagent and the condition in the step (ii) are alkyne, pd (PPh 3)2Cl2, cuI, diethylamine, DMF and microwave at 130 ℃. It is understood that the use of a microwave heat source for chemical reactions is not suitable for large-scale production of Active Pharmaceutical Ingredients (APIs). It should also be appreciated that the high demand and limited supply of palladium has led to a serious shortage of this metal over the last few years. In addition, the process that palladium must undergo from its ore to round bottom flask is accompanied by environmental consequences that tend to be underestimated, the low concentration of palladium in the ore (< 10 g/ton), and the presence of other first-row transition metals and platinum group metals, meaning that palladium refining is an energy-consuming process, also dependent on hazardous chemicals. Thus, in synthesizing APIs, it is desirable to find less toxic and sustainable alternatives to palladium-based catalysts. The present invention has been made in view of the above-described problems. Disclosure of Invention In one aspect, the present disclosure relates to a process for preparing a compound of formula (I): (I), The process comprises coupling N- (4-chloro-2-iodo-phenyl) -1, 3-benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of a copper catalyst, wherein the coupling reaction is performed in the absence of a palladium catalyst. In some embodiments, the copper catalyst is a copper (I) catalyst. In some embodiments, the copper catalyst is a copper (II) catalyst. In some embodiments, the coupling reaction is performed in the presence of a base. In some embodiments, the coupling reaction is performed in the presence of a solvent. In another aspect, the present disclosure relates to a process for preparing lanuno, the process comprising: a) The compounds of formula (I) are prepared by the process described above, and B) Deprotection of the ester group of the compound of formula (I). Detailed Description In one aspect, the present disclosure relates to a process for preparing a compound of formula (I): (I), The process comprises coupling N- (4-chloro-2-iodo-phenyl) -1, 3-benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of a copper catalyst, wherein the coupling reaction is performed in the absence of a palladium catalyst. In the context of the present invention, the expression "no palladium catalyst" means that the coupling reaction is carried out without using a palladium catalyst. Preferably, the coupling reaction is carried out under palladium-free conditions. In some embodiments, wherein the copper catalyst is a copper (I) catalyst or a copper (II) catalyst. In some embodiments, the copper catalyst is a copper (I) catalyst. Suitable copper (I) catalysts include copper (I) bromide, copper (I) chloride, copper (I) iodide, copper (I) acetate, copper (I) oxide, copper (I) tetraacetonitrile triflate, copper (I) bis (triphenylphosphine) borohydride, and mixtures thereof. In some embodiments, the copper catalyst is a copper (II) catalyst. Suitable copper (II) catalysts include copper (II) sulfate, copper (II) triflate, copper (II) oxide, copper (II) bromide, copper (II) chloride, copper (II) iodide, copper (II) acetate, copper acetylacetonate, and mixtures thereof. In some embodiments, the coupling reaction is performed in the presence of about 0.1 to about 2.0 equivalents of copper catalyst. In some embodiments, the coupling reaction is performed in the presence of 0.1 equivalent of copper catalyst. In some embodiments, the coupling reaction is performed in the presence of 0.2 equivalent of copper catalyst. In some embodiments, the coupling reaction is performed in the presence of 0.3 equivalent of copper catalyst. In some embodiments, the coupling reaction is performed in the presence of 0.4 equivalent of co