Micro-electrolysis reactor for ultra fast, oxidant free, C—C coupling reaction and synthesis of daclatasvir analogs thereof

Patent metadata

Field	Value
Publication number	US-11344858-B2
Application number	US-202016837070-A
Country	US
Kind code	B2
Filing date	Apr 1, 2020
Priority date	May 2, 2019
Publication date	May 31, 2022
Grant date	May 31, 2022

Abstract

The present invention relates to a continuous micro-electro-flow reactor system for ultra-fast, oxidant free, C—C coupling reaction for making symmetrical biaryls and analogs thereof. This invention further relates to the said process for preparation of antiviral drug, daclatasvir of general formula I.

First claim

We claim:

1. A continuous flow process for preparation of daclatasvir of Formula I, comprising the steps of:

a) introducing a solution of a haloarene of Formula 1 and a Ni catalyst of Formula 2 in an aprotic solvent to a continuous micro-electro-flow reactor and maintaining a reaction mixture in the reactor for about 1-200 minutes at a temperature of about 25-80° C. and at a pressure of about 0-5 bar to obtain compounds of Formula 3a-3h;

wherein compounds of Formula 1 are independently selected from the group: bromobenzene (1a); chlorobenzene (1a′); 1-bromo-4-methylbenzene (1b); 1-chloro-4-methylbenzene (1b′); 1-bromo-3-methylbenzene (1c); 1-chloro-3-methylbenzene (1c′); 1-bromonaphthalene (1d); 1-chloronaphthalene (1d′); 2-bromonaphthalene (1e); 2-chloronaphthalene (1e′); 4-bromo-1,1′-biphenyl (1f); 4-chloro-1,1′-biphenyl (1f′); 2-(4-bromophenyl)-2-methyl-1,3-dioxolane (1g); 1-(4-bromophenyl) ethanone (1h);

b) continuous flow bromination of the compound of Formula 3h obtained in step a) by reacting with a brominating agent in an aprotic solvent while maintaining a reaction mixture in the reactor for about 10-200 minutes at a temperature of about 30-50° C. and at a pressure of about 1-10 bar to obtain a compound of Formula 4;

c) reaction of the compound of formula 4 obtained in step b) with N-protected-L-proline in an aprotic solvent while maintaining a reaction mixture in the reactor for about 1-5 minutes at a temperature of about 30-80° C. and at a pressure of about 1-10 bar to obtain a compound of formula 5;

d) reaction of the compound of formula 5 obtained in step c) with a regent while maintaining a reaction mixture in the reactor for about 1-5 minutes at a temperature of about 130-180° C. and at a pressure of about 10-30 bar to obtain a compound of formula 6;

e) deprotection of the compound of formula 6 obtained in step d) by reacting it with aqueous HCl in a protic solvent while maintaining a reaction mixture in the reactor for about 1-5 minutes at a temperature of about 20-40° C. and at a pressure of about 1-10 bar to obtain a compound of formula 7;

f) coupling of the compound of formula 7 or its pharmaceutically acceptable salt obtained in step e) with N-Moc-L-valine while maintaining a reaction mixture in the reactor for about 20-100 minutes at a temperature of about 20-40° C. and at a pressure of about 1-10 bar to obtain daclatasvir of formula I.

2. The process as claimed in claim 1 , wherein the continuous micro-electro-flow reactor comprising of a copper plate anode support micro-patterned with inorganic nanoparticles; wherein, the inorganic nanoparticles comprise nickel nanoparticles, platinum nanoparticles or a combination thereof, wherein, the inorganic nanoparticles (Ni, Pt@Ni) have an average size in the range of 10-100 nm and a electroplated thickness of 4-100 μM.

3. The process as claimed in claim 1 , wherein in step a) a reacting compound of formula 1 reacts with a compound of formula 2 in presence of various combinations of electrodes, wherein, the electrode is selected from the group consisting of Ni@Cu, Pt@Ni@Cu, Graphite, and Cu.

4. The process as claimed in claim 1 , wherein in bromination step b) the compound of formula 3h reacts with brominating agent in presence of a Lewis acid and solvent, wherein, the brominating agent is selected from the group consisting of bromine, boron tribromide, phosphorus tribromide, carbon tetrabromide, N-bromoacetamide, N-bromophthalimide, N-bromosuccinimide, bromotrichloromethane, pyridinium tribromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethyl ammoniumtribromide, bromodimethylsulfonium bromide, 1-butyl-3-methylimidazolium tribromide, 1, 2-dibromo-1, 1, 2, 2-tetrachloroethane, 4-dimethylaminopyridinium bromide, 2, 4, 4, 6-tetrabromo-2, 5-cyclohexadienone, and mixtures thereof; and the Lewis acid is selected from the group consisting of BF 3 , MgBr 2 , SnCl 4 , TiCl 4 , FeCl 3 , AlCl 3 , MeAlCl 2 , Me 2 AlCl, LiClO 4 , and mixtures thereof.

5. The process as claimed in claim 1 , wherein in steps a), b) and c) the solvent is a polar aprotic solvent selected from the group consisting of acetonitrile, dichloromethane, dicholoroethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-Methylpyrrolidone, and mixtures thereof.

6. The process as claimed in claim 1 , wherein in the step c) reaction of the compound of formula 4 with N-Protected-L-proline is performed in presence of a base and a solvent, wherein, the base is selected from the group consisting of trimethylamine, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and mixtures thereof.

7. The process as claimed in claim 1 , wherein in step d) reaction of the compound of formula 5 with the reagent occurs in presence of a base and a solvent, wherein, the reagent is selected from the group consisting of ammonium acetate, ammonium formate, ammonium sulfamate, ammonium phosphate, ammonium citrate, ammonium carbamate, ammonia, and mixtures thereof.

8. The process as claimed in claim 1 , wherein in deprotection step e) reaction of the compound of formula 6 is carried out using a deprotecting agent in presence of a solvent, wherein, the deprotecting agent is selected from the group consisting of HCl, H 2 SO 4 , HNO 3 , trimethylsilyl iodide, and mixtures thereof and the solvent is selected from the group consisting of alcohol, ester, and mixtures thereof.

9. The process as claimed in claim 1 , wherein, in coupling step f) the compound of formula 7 is reacted with N-Moc-L-valine in presence of a coupling agent, a base, and a solvent, wherein, the coupling agent is selected from the group consisting of 1,1′-carbonyldiimidazole, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole hydrate, 3-hydroxyl-2, 3-benzotriazin-4(3H)-one, 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride, 4-nitrophenol, pentafluorophenol, 2-hydroxypyridine, N-hydroxysuccinimide, N-hydroxyphthalamide, 2-mercaptobenzoxazole, trimethylacetyl chloride, isobutylchloroformate, chlorodimethoxytriazole, oxalyl chloride, 2-hydroxypyridine-N-oxide, 5-nitro-2-hydroxypyridine, Boc-L-valine anhydride, and mixtures thereof.

10. The process as claimed in claim 1 , wherein, the continuous flow process system is employed for bulk scale preparation of daclatasvir (formula I).

Assignees

• Council Scient Ind Res

Inventors

• Singh Ajay Kumar
• Pabbaraja Srihari
• Ghosh Subhash
• Bhushan Mahajan
• Mujawar Taufiqueahmed

Classifications

• B01J2219/00858

  Aspects relating to the size of the reactor · CPC title

• B01J2219/00961

  Temperature · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• B01J2219/00162

  controlling the pressure · CPC title

• C25D3/50

  of platinum group metals · CPC title