PROCESS FOR PREPARATION OF CARMUSTINE

Abstract

The present invention relates to an improved process for preparation of carmustine (I). The present invention also relates to preparation of 1,3-bis(2-chloroethyl)urea (II) an intermediate used in preparation of carmustine.

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Claims

1. A process for preparation of carmustine (I) ##STR00010## comprising a step of: a) converting 2-chloroethylamine (III) to 1,3-bis(2-chloroethyl)urea (II) ##STR00011## in absence of phosgene.

2. A process for preparation of carmustine (I) ##STR00012## comprising steps of: a) converting 2-chloroethylamine (III) to 1,3-bis(2-chloroethyl)urea (II) ##STR00013## in absence of phosgene. b) converting urea of formula (II) to carmustine (I).

3. The process according to claim 1, wherein step (a) is carried out in presence of a reagent selected from group consisting of 1,1-carbonyldiimidazole, triphosgene and phenyl chloroformate.

4. The process according to claim 2, wherein step (b) is carried out in presence of nirosating reagent.

5. The process according to claim 4, wherein nitrosating reagent is selected from group consisting of di-nitrogen trioxide, sodium nitrite and acid.

6. The process according to claim 5, wherein acid is selected from hydrochloric acid, sulphuric acid, formic acid and acetic acid.

7. The process according to claim 4, wherein nitrosating reagent is sodium nitrite and sulphuric acid.

8. A process for preparation of carmustine (I) comprising steps of: a) reacting 2-chloroethyl amine (III) or its salt with a reagent selected from 1,1-carbonyldiimidazole, triphosgene and phenyl chloroformate in presence of base to obtain 1,3-bis (2-chloroethyl) urea (II); b) reacting 1,3-bis(2-chloroethyl)urea with nitrosating reagent in presence of solvent to obtain carmustine; wherein step (a) is carried out in absence of phosgene.

9. The process according to claim 8, wherein base used in step (a) is triethylamine.

10. The process according to claim 8, wherein solvent used in step (b) is dichloromethane and water.

11. The process according to claim 2, wherein step (a) is carried out in presence of a reagent selected from group consisting of 1,1-carbonyldiimidazole, triphosgene and phenyl chloroformate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0042] The main embodiment of the present invention is to provide a process for preparation of carmustine (I).

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[0043] In another embodiment, the present invention provides a process wherein 2-chloroethylamine or its salts are converted to 1,3-bis(2-chloroethyl)urea (II) in absence of phosgene.

[0044] Processes known in the art generally uses phosgene for above conversion. Phosgene is very hazardous chemical and need to be avoided on large scale preparation. Present invention provides a process for preparation of carmustine wherein the step of preparing intermediate (II) entirely avoids use of phosgene, and thus make the overall process simple yet efficient and environment friendly.

[0045] In another embodiment the present invention provides a process to prepare carmustine as depicted by following scheme:

##STR00009##

[0046] Conversion of 2-chloroethyl amine of formula (III) to an intermediate of formula (II) can be carried out in presence of a reagent selected from 1,1-carbonyldiimidazole, triphosgene or phenyl chloroformate.

[0047] This reaction can be carried out in presence of base and solvent. Base for the purpose of above conversion can be selected from any suitable organic or inorganic base. Preferably the reaction to prepare urea intermediate is carried out in presence of triethylamine.

[0048] Solvent can be selected from any organic solvent or mixture of solvents suitable for the reaction. This reaction is generally carried out at temperature in the range from 550 C.

[0049] In next step of the process intermediate of formula (II) is subjected to nitrosation.

[0050] Carmustine is nitroso-urea compound so the synthesis involves first step of obtaining urea intermediate i.e. intermediate of formula (II) and then converting urea intermediate to carmustine by nitrosation.

[0051] The nitrosation reaction can be carried out in presence of sulphuric acid and sodium nitrite. The reaction is carried out in presence of solvent. The reaction can be carried out in presence of single solvent, mixture of solvents or in two phase solvent system. Preferably the nitrosation reaction is carried out in presence of dichloromethane and water. Nitrosation is generally carried out at a temperature in range of 5 C. to 10 C.

[0052] The nitrosation reaction can be carried out by using suitable nitrosating agent selected from dinitrogen trioxide, sodium nitrite and aq. HCl, sodium nitrite and H.sub.2SO.sub.4, sodium nitrite and HCOOH and sodium nitrite and CH.sub.3COOH.

[0053] The final product i.e. carmustine can be isolated by removal of solvent from reaction mixture or separating the layers and isolating the product from organic layer.

[0054] In an embodiment the product can be isolated by removing the solvent from the reaction mixture, followed by addition of suitable solvent to the residue to isolate the product.

[0055] In another embodiment carmustine can be isolated by removing solvent from organic layer, adding suitable solvent to the residue to dissolve carmustine, followed by addition of anti-solvent to isolate carmustine. Solvents used to dissolve residue (i.e. carmustine) can be selected form group consisting of ether such as diethyl ether, methyl tert-butyl ether, alkyl acetate such as ethyl acetate, aromatic hydrocarbon such as toluene and alkanol such as ethanol, isopropanol. Anti-solvent used to isolate carmustine can be selected from group consisting of alkanes such as heptane, hexane, or pentane, cycloalkanes such as cyclohexane and water.

[0056] In general the solvents used for the purpose of present invention i.e. used for conducting the reaction or isolating the product can be selected form any suitable solvent such as alkanol, ketone, ether, hydrocarbon, chlorinated solvents, water, aprotic solvents, alkanes or mixture thereof.

[0057] The process of the present invention uses non-hazardous and easily available reagents for preparation of carmustine, thus, makes the process commercially viable.

[0058] Following examples are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES

Example 1: Preparation of 1,3-(bis(2-chloroethyl)urea (II)

[0059] 2-chloroethyl amine hydrochloride (20 g) and triethylamine (90 ml) were added to a round bottom flask. The resultant reaction mixture was cooled to 10-20 C., to this 15 g of 1,1-carbonyldiimidazole (CDI) was added, the reaction mixture was stirred for 2 hrs at 35-40 C. After completion of reaction the reaction mixture was cooled to 20-25 C., solvent was distilled of to obtain residue. 100 ml water was added to the residue and the mixture was filtered, the solid thus obtained was dried to give 13 g of title compound.

Example 2: Preparation of Carmustine (I)

[0060] Water (80 ml) was taken in a round bottom flask, cooled to 0-5 C., to this sulphuric acid (38 g) was added. This was followed by addition of 80 ml of methylene dichloride and 10 g of 1,3-bis(2-chloroethyl)urea (II). The reaction mixture was stirred while maintaining the temperature at about 0-5 C., to this sodium nitrite solution (24 g sodium nitrite in 120 ml water) was added. The reaction mixture was stirred at the same temperature for 2 hrs, after completion of reaction, layers separated, organic layer was washed with sodium sulfate, and the solvent was distilled off. To the residue a mixture of n-heptane and methyl tertiary butyl ether was added. Reaction mixture was stirred for 1 hr, filtered and the solid thus obtained was dried to give 12 g of title compound.