Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2003-01-06
2004-12-28
Tsang, Cecilia J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S039000, C560S043000, C560S047000, C560S048000, C562S459000, C562S472000
Reexamination Certificate
active
06835848
ABSTRACT:
FIELD OF THE INVENTION
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-propenoates in which R represents methyl or ethyl, which are valuable intermediates for the production of highly active antibacterial quinolone medicaments.
BACKGROUND OF THE INVENTION
A previously known general method for the synthesis of intermediate, alkyl 3-cyclopropyl amino-2-[2,4-dibromo-3-(difluoromethoxy) benzoyl]-2-propenoate of the following formula:
has been reported in U.S. Pat. No. 5,935,952 assigned to Toyama Chemical Company Ltd. The general method described in this patent includes, reaction of the compound of the following formula:
with a halogenating agent such as thionyl chloride to obtain acid chloride of the following formula:
which on reaction with metal salt of malonic ester of the following formula:
Na/KOOCCH
2
COOR FORMULA IV
wherein R is the same as defined above, in the presence of magnesium chloride at a temperature of about 45° C. Decarboxylation of Formula IV affords a compound of the following formula:
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 the following formula:
wherein R
1
is methyl or ethyl, 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.
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.
SUMMARY OF THE INVENTION
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 of the present invention there is provided a one-pot process for the preparation of alkyl 3-cyclopropylamino-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoate of Formula I. 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 preparationofalkyl3-cyclopropylamino-2-[2,4-dibromo-3-dfluoromethoxy) benzoyl]-2-propenoate of Formula I, wherein R is methyl or ethyl comprising reacting 2,4-dibromo-3-(difluoromethoxy)benzoic acid of Formula II, 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 the following formula:
wherein R
1
is methyl or ethyl, in a suitable solvent in the presence of an organic base to give alkyl-3,3-dialkylamino2[2,4-dibromo-3-difluoromethoxy) benzoyl]-2-ropenoate of Formula VI wherein R and R
1
are methyl or ethyl which on treatment with cyclopropylamine affords the product of Formula I, 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 R
1
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 ester solvents and mixture(s) thereof. Preferably, the solvents are selected from the group comprising benzene, toluene, xylenes, chloroform, dichloroethane, dichloromethane methyl acetate, butyl acetate, ethyl acetate 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 organic layer contains the compound of Formula VI wherein R
1
is methyl or ethyl 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-cyclopropylamino-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.
REFERENCES:
patent: 5935952 (1999-08-01), Todo et al.
patent: 1132375 (2001-09-01), None
patent: 06-016642 (1994-01-01), None
patent: WO 99/21849 (1999-05-01), None
Cecchetti, V. et al., “Potent 6-Desfluoro-8-methylqunolones as New Lead Compounds in Antibacterial Chemotherapy,”J. Med. Chem.1996: 39; 4952-4957.
Bose Prosenjit
Kiyoto Taro
Kumar Naresh
Deshmukh, E Jayadeep R.
Oh Taylor V.
Ranbaxy Laboratories Limited
Tsang Cecilia J.
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