Process for the synthesis of anti-neoplasia agent VNP40101M
View Patent ↗The present invention relates to simple, safe, high-yield methods of synthesizing VNP40101M, 1,2-bis(methylsulfonyl)-2-(2-chloroethyl)-2-(methylaminocarbonyl)hydrazine, an anti-neoplasia agent. One particularly preferred method uses methyl chloroformamide in a one-pot reaction at elevated temperatures to provide VNP40101M in high yield.
1. A method for producing a compound of the formula:
comprising subjecting a compound of the formula:
to a chloroformylating reaction to produce a reactive intermediate of the formula
which is subjected to a methylaminylating reaction to produce VNP40101M, said method optionally further purifying VNP40101M to a purity higher than 97% by subjecting said VNP40101M produced to at least one round of ethanol solubilization and crystallization.
2. The method according to claim 1 where the chloroformylating agent is phosgene.
3. The method according to claim 1 where the chloroformylating agent is trichloromethylchloroformate (triphosgene).
4. The method according to claim 1 where the chloroformylating agent is bistrichloromethylcarbonate (diphosgene).
5. The method according to claim 1 for producing a compound of the formula:
at a purity higher than 97% by subjecting said compound produced according to the method of claim 1 to one or more than one ethanol rounds of solubilization and crystallization steps.
6. A method for producing a compound of the formula:
comprising subjecting a compound of the formula:
to a reaction with ClCONHMe to produce VNP40101M, said method optionally further purifying VNP40101M to a purity higher than 97% by subjecting said VNP40101M produced to at least one round of ethanol solubilization and crystallization.
7. The method according to claim 6 wherein VNP40101M is produced at a purity higher than 97% by subjecting said VNP40101M to at least one round of ethanol solubilization and crystallization.
8. A method for producing a compound of the formula:
comprising subjecting a compound of the formula:
to a reaction with ClC(O)OR to produce a carbamate of the formula:
which is subjected to a methylaminylating reaction containing methylamine and a Lewis acid to produce VNP40101M, said method optionally further purifying VNP40101M to a purity higher than 97% by subjecting said VNP40101M produced to at least one round of ethanol solubilization and crystallization.
9. The method according to claim 8 where the R in ClC(O)OR is an alkyl.
10. The method according to claim 8 where the R in ClC(O)OR is an aryl.
11. The method according to claim 8 for producing a compound of the formula:
at a purity higher than 97% by using one more than one rounds of ethanol solubilization and crystallization steps.