Generated: April 25, 2017
|Title:||2-Halomethyl derivatives of 2-amino acids|
|Abstract:||2-(Fluoromethyl or chloromethyl)-2,5-diaminopentanoic acid, 2-(fluoromethyl or chloromethyl)-2,6-diaminohexanoic acid, and 2-fluoromethyl-2-amino-5-guanidinopentanoic acid, and certain derivatives thereof, are inhibitors of ornithine decarboxylase. Methods of preparing the compounds and derivatives are also described.|
|Inventor(s):||Bey; Philippe (Strasbourg, FR), Jung; Michel (Illkirch-Graffenstaden, FR)|
|Assignee:||Merrell Dow France et Cie (Strasbourg, FR)|
|Filing Date:||Jan 27, 1988|
|Claims:||1. A method for preparing a compound of the formula: ##STR17## wherein n is 3 or 4; Y is --CH.sub.2 F or --CH.sub.2 Cl; which comprises: (a) treating a compound of the formula ##STR18## wherein n is as defined above, R' is (C.sub.1 -C.sub.8)alkoxy, R.sub.3 is hydrogen, phenyl, (C.sub.1 -C.sub.4)alkyl, methoxy or ethoxy, R.sub.4 is phenyl or (C.sub.1 -C.sub.4)alkyl, or R.sub.3 and R.sub.4 taken together form --CH.sub.2 --(CH.sub.2).sub.m --CH.sub.2 -- wherein m is an integer of from 3 to 5, and R.sub.2 is a group of the formula ##STR19## wherein R.sub.6 is phenyl, benzyl or (C.sub.1 -C.sub.4)alkyl and R.sub.3 and R.sub.4 are as defined above, |
with a strong base to form the corresponding carbanion;
(b) reacting the carbanion with an alkylating agent of the formula X.sub.1 CH.sub.2 X, wherein X.sub.1 is fluorine or chlorine and X is chlorine, bromine or iodine, in an aprotic solvent in the presence of hexamethylphosphoramide at a temperature of about -120.degree. C. to 120.degree. C. and a reaction time of about 1/2 hour to 48 hours; and
(c) hydrolyzing the alkylated product.
2. A method as defined in claim 1 for preparing 2-fluoromethyl-2,5-diaminopentanoic acid wherein the protected 2,5-diaminopentanoic acid employed in Step (a) is a (C.sub.1 -C.sub.8)alkyl ester of 2,5-bis(benzylideneamino)pentanoate, and the alkylating agent employed in Step (b) is chlorofluoromethane, bromofluoromethane, or iodofluoromethane.
3. A method as defined in claim 2 wherein the (C.sub.1 -C.sub.8)alkyl ester is the methyl ester.
4. A method as defined in claim 2 or 3 wherein the strong acid employed in Step (a) is sodium tert-butoxide and the alkylating agent employed in Step (b) is chlorofluoromethane.