Title of Invention

"A PROCESS FOR THE PREPARATION OF ALKYL 3-CYCLOPROPYLAMINO-2-[2,4-DIBROMO-3-(DIFLUOROMETHOXY) BENZOYL]-2-PROPENOATE"

Abstract The present invention relates to a new and industrially advantageous one-pot process for the preparation of alkyl 3-cyclopropyl amino-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoate, which are valuable intermediates for the production of highly active antibacterial quinolone medicaments.
Full Text The present invention relates to a new and industrially advantageous one-pot process for the preparation of alkyl 3-cyclopropyl amino-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoate of Formula I in which R represents methyl or ethyl, as shown in the accompanied drawings and are valuable intermediates for the production of highly active antibacterial quinolone medicaments.
A previously known general method for the synthesis of intermediate, alkyl 3-cyclopropyl amino-2-[2,4-dibromo-3-(difluoromethoxy) benzoyl]-2-propenoate of Formula I, has been reported in US Patent No. 5,935,952 assigned to Toyama Chemical Company Ltd. The general method described in this patent includes reaction of the compound of Formula II, as shown in the accompanied drawings, with a halogenating agent such as thionyl chloride to obtain acid chloride of Formula III which on reaction with metal salt of malonic ester of Formula IV, as shown in the a.ccompanied drawings wherein R is the same as defined above, in the presence of magnesium chloride at a temperature of (to 45°C Decarboxylation affords a compound of Formula V, as shown in the accompanied drawings, in which R is as defined above. Reaction of the compound of Formula V with an acetal such as N, N-dimethylformamide dimethyl acetal, N, N-dimethylformamide diethyl acetal to give a compound of Formula VI wherein Ri is methyl or ethyl, as shown in the accompanied drawings, which on reaction with cyclopropylamine gives the intermediate, methyl/ethyl 3-cyclopropyl amino-2-[2,4-dibromo-3-(difluoromethoxy) benzoyl]-2-propenoate, of Formula I, as shown in the accompanied drawings.
The above mentioned method described in the prior art for the manufacture of the compound of Formula I suffers from the-following limitations and for various reasons stated below are not suitable for commercial purposes.
The process is lengthy involving six steps.
The process generates a lot of effluent waste and hence is not eco-friendly.
It is an object of the present invention to solve the problems associated with the prior art and to provide an efficient method. According to one aspect, the present invention provides a one-pot process for the preparation of alkyl 3-cyclopropyl amino-2-[2,4-dibromo-3-

(difluoromethoxy) benzoyl]-2-propenoate of Formula I (as shown in the accompanied drawings). The process provides obvious benefits with respect to economics and convenience to operate at a commercial scale.
More particularly, the present invention relates to a process for the preparation of alkyl 3-cyclopropylamino-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoate of Formula I (as shown in the accompanied drawings), wherein R is methyl or ethyl comprising reacting 2,4-dibromo-3-(difluoromethoxy)benzoic acid of Formula II, as shown in the accompanied drawings, with a halogenating agent to get a corresponding acid chloride of Formula III, which on reaction with ester of 3,3-dialkyl amino acrylate of Formula VII, wherein RI is methyl or ethyl as shown in the accompanied drawings, in a suitable solvent in the presence of an organic base to give alkyl-3,3-dialkylamino-2[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoate of Formula VI as shown in the accompanied drawings wherein R and RI are methyl or ethyl which on treatment with cyclopropylamine affords the product of Formula I, as shown in the accompanied drawings and R is the same as defined above. More particularly, the compound of Formula II is reacted with thionyl chloride to provide an acid chloride of Formula III following a process known in the prior art. The acid chloride is then reacted with methyl/ethyl ester of 3,3-dimethyl/diethylamino acrylate of Formula VI (R and RI are methyl or ethyl) in a suitable solvent in the presence of an organic base at a selected temperature within the range of 40-80°C, preferably, 50-70°C during a period of one to several hours. The suitable solvent is selected from the group comprising of aromatic solvents, chlorinated solvents or a mixture(s) thereof. Preferably, the solvents are selected from the group comprising benzene, toluene, xylenes, chloroform, dichloroethane, dichloromethane or mixture(s) thereof. The suitable organic base is selected from the group comprising triethylamine, trimethyl amine, picolines, pyridine and pyridine derivatives. The reaction mixture is then cooled and poured into water. The oganic layer contains the compound of Formula VI wherein RI is methyl or ethyl (as shown in the accompanied drawings) and is taken as such for reaction with cyclopropylamine at a selected temperature within the range of 0-30°C, preferably 5-10°C for 0.5 to several hours. The desired compound methyl/ethyl 3-cyclopropyl amino-2-[2,4-dibromo-3-(difluoromethoxy) benzoyl]-2-propenoate of Formula I is isolated by conventional methods.
In the following section a preferred embodiment is described by way of an example to illustrate the process of this invention. However, this is not intended in any way to limit the scope of the present invention-.
EXAMPLE
Preparation of Ethyl-3-cyclopropylamino-2-(2,4-dibromo-3-difluoromethoxy) benzoyl]-2-propenoate.
To a mixture of 2,4-dibromo-3-(difluoromethoxy) benzoic acid (10g) and thionyl chloride (4.38gm) was added a mixture of toluene (15ml) and N,N-dimethyl formamide (0.2ml). The reaction mixture was heated slowly to reflux and stirred at reflux for about 2.5 hours. The reaction mixture was then, cooled to 35°C and added a solution of ethyl 3,3-dimethylaminoacrylate (4.13gm), and triethylamine (3.79gm) in toluene (20ml) drop-wise during a period of about 1 hour maintaining a temperature of 35-40°C. After the addition was over, the reaction temperature was slowly increased to 60-65°C and stirred the reaction mixture for about 24 hours. Cooled the reaction mixture to 30°C, added water (20ml) and stirred for about 10 minutes. The organic layer was separated, cooled to about 5°C and cyclopropylamine (1.82gm) was added to it drop-wise maintaining temperature at 8-10°C during a period of about 10 minutes. Stirred the reaction mixture for about 2 hours, solvent was removed under vacuum (~ 80% of the original amount) and cooled the reaction mixture to about 20°C. The solid separated was filtered and dried to afford ethyl 3-cyclopropylamino-2-[2, 4-dibromo-3-(difluoromethoxy) benzoyl]-2-propenoate (10gm).





WE CLAIM:
1. A process for the preparation of alkyl 3-cyclopropylamino-2-[2-4-dibromo-3-
(difluoromethoxy)benzoyl]-2-propenoate of Formula I, as shown in the accompanied
drawings wherein R is methyl or ethyl, comprising reacting 2,4-dibromo-3-
(difluoromethoxy) benzoic acid of Formula II, as shown in the accompanied drawings,
with a halogenating agent to get a corresponding acid chloride of Formula III, which on
reaction with alkyl ester of 3,3-dialkyl amino acrylate of Formula VII, wherein RI is
methyl or ethyl as shown in the accompanied drawings, in a suitable solvent in the
presence of an organic base, to give alkyl 3, 3-dialkylamino-2-[2,4-dibromo-3-
(difluoromethoxy) benzoyl]-2-propenoate of Formula VI, wherein R and R! are methyl
or ethyl as shown in the accompanied drawings wherein R and RI are the same as
defined above, which on treatment with cyclopropylamine affords the product of
Formula I.
2. The process as claimed in claim 1 wherein the halogenating agent is thionyl chloride.
3. The process as claimed in claim 1 wherein the alkyl ester of 3,3-dialkylaminoacrylate
is methyl ester of 3,3-dimethylaminoacrylate.
4. The process as claimed in claim 1 wherein the alkyl ester of 3,3-dialkylamino acrylate
is ethyl ester of 3,3-diethylamino acrylate.
5. The process as claimed in claim 1 wherein the solvent is selected from a group
comprising aromatic solvents, chlorinated solvents or a mixture(s) thereof.
6. The process as claimed in claim 5 wherein a solvent is selected from the group
comprising benzene, toluene, xylenes, chloroform, dichloromethane, dichloroethane or
mixture(s) thereof.
7. The process as claimed in claim 1 wherein the organic base is selected from the group
comprising triethylamine, trimethylamine, picoline(s), pyridine and pyridine derivatives.
8. The process as claimed in claim 1 wherein the reaction temperature is in the range of
40-80°C.
9. The process as claimed in claim 8 wherein the reaction temperature is in the range of
50-70°C.
10. The process as claimed in claim 1, further comprising preparation of quinolone
medicaments from the compound of Formula I obtained.
11. The process for the preparation of methyl/ethyl 3-cyclopropylamino-2-[2,4-dibromo-3-
(difluoromethoxy)benzoyl]-2-propenoate of Formula I, as shown in the accompanied
drawings, as herein described and illustrated by the example, herein.

Documents:

196-del-2000-abstract.pdf

196-del-2000-claims.pdf

196-del-2000-correspondence-others.pdf

196-del-2000-correspondence-po.pdf

196-del-2000-description (complete).pdf

196-del-2000-drawings.pdf

196-del-2000-form-1.pdf

196-del-2000-form-2.pdf

196-del-2000-form-3.pdf

196-del-2000-form-4.pdf

196-del-2000-pct-210.pdf

196-del-2000-petition-138.pdf


Patent Number 212058
Indian Patent Application Number 196/DEL/2000
PG Journal Number 47/2007
Publication Date 23-Nov-2007
Grant Date 14-Nov-2007
Date of Filing 07-Mar-2000
Name of Patentee RANBAXY LABORATORIES LIMITED
Applicant Address 19, NEHRU PLACE, NEW DELHI - 110 019, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 PROSENJIT BOSE RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001 (HARYANA), INDIA.
2 TORO KIYOTO TOYAMA CHEMICAL CO., LIMITED, 4-1, SHIMOOKUI 2-CHOME, TOYAMA, 930-8508, JAPAN.
3 NARESH KUMAR RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001 (HARYANA), INDIA.
PCT International Classification Number A61K 31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA