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US-20260125385-A1 - PROCESS FOR THE PREPARATION OF REMIMAZOLAM

US20260125385A1US 20260125385 A1US20260125385 A1US 20260125385A1US-20260125385-A1

Abstract

The invention provides a compound of formula I and a process for preparing a compound of formula I, wherein R is H (Formula Ia) or CH 2 COCH 3 (Formula Ib). The compound of formula I may be used in the synthesis of a compound of formula V,

Inventors

  • Sandeep DHAVARIA
  • Anil Shamraj BHOYAR
  • Rohit Kumar
  • Chandan Kumar Gupta
  • Hemant Kumar Singh
  • Nitin Gupta
  • Govind Singh
  • Walter Cabri

Assignees

  • FRESENIUS KABI ONCOLOGY LIMITED

Dates

Publication Date
20260507
Application Date
20260105
Priority Date
20220408

Claims (20)

  1. 1 . A compound of formula I, wherein R is H or CH 2 COCH 3 .
  2. 2 . The compound according to claim 1 , wherein formula I is formula Ia, wherein R of formula 1 is H.
  3. 3 . The compound according to claim 1 , wherein formula I is formula Ib, wherein R of formula 1 is CH 2 COCH 3 .
  4. 4 . A compound of formula Ia, prepared by a process comprising reacting a compound of formula IV, with a carbonyl group activating agent and adding an amination agent to obtain the compound of formula Ia.
  5. 5 . The compound according to claim 4 , wherein the carbonyl group activating agent comprises triflic anhydride, methanesulphonic anhydride, p-toluenesulfonic anhydride, benzenesulphonic anhydride, methanesulfonyl chloride, or p-toluenesulphonyl chloride.
  6. 6 . The compound according to claim 5 , where the carbonyl group activating agent is triflic anhydride.
  7. 7 . The compound according to claim 4 , wherein the amination agent comprises ammonia, ammonium hydroxide, ammonium chloride, ammonium bromide, ammonium iodide, or ammonium carbonate.
  8. 8 . The compound according to claim 7 , wherein the amination agent is ammonia.
  9. 9 . The compound according to claim 4 , wherein the reaction of the compound of formula IV with the carbonyl group activating agent is done in the presence of a base comprising pyridine, 2-bromopyridine, 2-chloropyridine, 2,6-dibromopyridine, 2,6-dichloropyridine, or a mixture thereof.
  10. 10 . The compound according to claim 9 , where the base is 2-bromopyridine or 2-chloropyridine.
  11. 11 . The compound according to claim 4 , wherein the reaction of the compound of formula IV with the carbonyl group activating agent is carried out in the presence of a solvent comprising dichloromethane, chloroform, acetonitrile, toluene, tetrahydrofuran, or a mixture thereof.
  12. 12 . The compound according to claim 11 , where the solvent is dichloromethane.
  13. 13 . The compound according to claim 4 , wherein addition of the amination agent is provided in a solvent comprising methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane, or a mixture thereof.
  14. 14 . The compound according to claim 13 , wherein the solvent is isopropyl alcohol.
  15. 15 . The compound according to claim 4 , wherein the compound of formula Ia has an HPLC purity of greater than 98%.
  16. 16 . A compound of formula Ib, prepared by a process comprising reacting a compound of formula Ia, with a compound of formula III, wherein X═Cl, Br, I, or OH to obtain a compound of formula Ib.
  17. 17 . The compound according to claim 16 , wherein the reaction of the compound of formula Ia with the compound of formula III is carried out in the presence of a solvent comprising dimethylformamide, acetone, dimethyl sulfoxide, methyl ethyl ketone, acetonitrile, ethyl acetate, methyl acetate, propyl acetate, or a mixture thereof.
  18. 18 . The compound according to claim 17 , wherein the reaction of the compound of formula Ia with the compound of formula III is carried out in the presence of a base comprising potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, triethyl amine, diisopropylethylamine, 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU), or a mixture thereof.
  19. 19 . The compound according to claim 16 , wherein the reaction is carried out in the presence of a catalyst.
  20. 20 . The compound according to claim 19 , wherein the catalyst is potassium iodide.

Description

CROSS REFERENCE TO RELATED PATENT APPLICATION(S) This patent application is a divisional of U.S. patent application Ser. No. 18/855,229, filed on Oct. 8, 2024, which is the U.S. national phase of International Application No. PCT/IB2023/053516, filed on Apr. 6, 2023, which claims the benefit of Indian Patent Application No. 202211021182, filed on Apr. 8, 2022, which are incorporated by reference herein in their entireties. FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of a compound of formula V or a salt thereof, The present invention also provides a process for the preparation of a compound of formula I, used in the synthesis of the compound of formula V. wherein Formula I is Formula Ia, when R is Hwherein Formula I is Formula Ib, when R is CH2COCH3 BACKGROUND OF THE INVENTION Remimazolam, a benzodiazepine drug, is represented by Formula V. Remimazolam besylate (marketed under the trade name BYFAVO®, PAION) is indicated in adults for procedural sedation. Remimazolam besylate is represented by Formula VI, Remimazolam is disclosed in WO 2000/69836 that also provides a process for the preparation of Remimazolam. The process disclosed in WO2000/69836 requires hazardous and expensive reagents and some steps of the process operate at extremely low temperature (−78° C.). This makes the process less suitable for commercial purposes. Moreover, column chromatography and a high number of purification steps, result in low overall yield and insufficient optical purity of Remimazolam. WO2014/136730 discloses the synthesis of Remimazolam comprising oxidation reaction in presence of 2-azaadamantane-N-oxyl or 2-azaadamantan-2-ol as oxidation catalyst. WO2011/032692 and WO2019/020790 disclose a synthesis of Remimazolam comprising oxidizing intermediate compounds with Dess-Martin periodinane oxidizing agent. However, the use of costly oxidation catalysts, their potential explosive nature and oxidation reaction makes these processes unfavourable for industrial application. CN 108264499 also describes a process where unstable, moisture sensitive & non-commercial reagents are used in the synthesis. WO2018/148361 discloses the preparation of Remimazolam involving an intermediate compound of formula III/IIIa. The process uses non-commercial and costly raw materials such as 2,2-Dimethoxypropan-1-amine. On top, the ketal intermediates formed in the described process are not stable. From the foregoing, it is apparent that there are various prior arts disclosing different processes of Remimazolam synthesis. They either involve complex oxidation reactions conditions, or expensive or pyrophoric reagents that are unsuitable for commercial aspects. In some cases, the intermediates formed in the prior art processes are isolated by cumbersome work-up procedures using numerous reagents and various steps. Thus, there remains a need to provide an efficient, simple and industrially viable synthetic process which can overcome the drawbacks of the prior art. OBJECT OF THE INVENTION The objective of the present invention is to provide an improved and commercially viable process for the synthesis of Remimazolam. SUMMARY OF THE INVENTION In a first aspect, the present invention relates to a process for the preparation of a compound of formula V or a salt thereof, comprising the steps ofa. reacting a compound of formula IV, with a carbonyl group activating agent and adding an amination agent to obtain a compound of formula Ia, b. converting the compound of formula Ia to the compound of formula V or a salt thereof. In another aspect, the present invention relates to a process for preparation of a compound of formula Ia, comprising reacting a compound of formula IV, with a carbonyl group activating agent and adding an amination agent to obtain a compound of formula Ia. Another aspect of the invention is to provide a process for the preparation of a compound of formula Ib, comprising reacting a compound of formula Ia, with a compound of formula III, wherein X═Cl, Br, I, or OH. In another aspect, the present invention provides a compound of formula I, wherein Formula I is Formula Ia, when R is Hwherein Formula I is Formula Ib, when R is CH2COCH3. Another aspect of the invention is to provide a process for the preparation of a compound of formula V or a salt thereof, comprising the steps ofa. reacting a compound of formula IV, with triflic anhydride and ammonia to obtain a compound of formula Ia, b. reacting the compound of formula Ia, with a compound of formula III, wherein X═Cl, Br, I, or OHin the presence of a base to obtain a compound of formula Ib, c. treating the compound of formula Ib with trimethyl silyl chloride in methanol to obtain the compound of formula V or a salt thereof. Definitions The following definitions are used in connection with the present application unless the context indicates otherwise. The term “carbonyl group activating agent” refers to a chemical compound or a reagent that a