Process for preparing N.sup.G -monoalkyl-L-arginine and related

Details Process for preparing N.sup.G -monoalkyl-L-arginine and related Process for preparing N.sup.G -monoalkyl-L-arginine and related

1995-02-22

1998-11-24

Geist, Gary

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

562104, 562118, 562553, 562555, 562561, 562575, 564240, C07C24902, C07C27700, C07C27912

Patent

active

058409726

DESCRIPTION:

BRIEF SUMMARY
This is a 35 USC 371 of application PCT/GB94/00966 filed May 5, 1994.
The present invention relates to a process for the preparation of N.sup.G -monoalkyl-L-arginine and related compounds and in particular N.sup.G -monomethyl-L-arginine hydrochloride (L-NMMA hydrochloride).
The most widely used method for preparing guanidines in the laboratory is the reaction of amines with an S-alkyl isothiouronium salt; a method which commonly utilizes S-methylisothiouronium salts, for example the process reported by Ferrario et al. (Synth. Commun. 1991, 21, 99-105). A byproduct of this reaction is the noxious gas methyl mercaptan, which has a threshold of detection by humans of about 1ppb. Provision therefore needs to be made to convert the methyl mercaptan into an environmentally acceptable byproduct. A further disadvantage of the above process is the need to handle methyl iodide, a highly toxic substance, for the preparation of the S-methylisothiouronium salt. Whilst handling of the toxic compounds is possible on a small scale, the quantities of toxic compounds needed to be handled on a larger scale would be unacceptable.
Maryanoff et al (J. Org. Chem., 1986, 51, 1882-1884) propose a synthetic method which utilizes the intermediate aminoiminomethane sulphonic acid by the reaction of a thiourea with hydrogen peroxide. Attempts by Maryanoff et al. to repeat the oxidation procedures of Walter et al. (Liebigs Ann. Chem., 1969, 722, 98) using freshly prepared peracetic acid in methanol were unsuccessful. In addition, in order to achieve the required process using hydrogen peroxide, it was necessary to employ a catalyst, namely sodium molybdate dihydrate. The process described using hydrogen peroxide had not been used for the preparation of N.sup.G -monoalkyl-L-arginine or derivatives thereof.
It has now been found that it is possible to utilize the guanylating agent N-alkylaminoiminomethane sulphonic acid, to prepare guanidine derivatives, e.g. arginine derivatives without the hazards or possibility of contamination of the catalyst in the final product associated with earlier methods.
It is the object of the present invention to provide a hazard-free process for the pure preparation of guanidine derivatives of formula (I) ##STR2## pharmaceutically acceptable salt or ester thereof wherein R.sup.1 is C.sub.1-6 alkyl and n is 3 to 5, without the problems of contamination in the final product.
Accordingly, the present invention provides a process for the preparation of a compound of formula (I) as hereinbefore defined which comprises reacting a guanylating agent of formula (II) ##STR3## wherein R.sup.1 is as hereinbefore defined, with a compound of formula (III) ##STR4## or a pharmaceutically acceptable salt or ester thereof wherein n is as hereinbefore defined.
The reaction may be carried out by the addition of an inorganic base to an aqueous solution containing compounds of formula (II) and (III), at a non-extreme temperature of from -20.degree. C. to 100.degree. C., for example -5.degree. C. to 50.degree. C. and conveniently 5.degree. C. to room temperature. The reaction mixture is preferably at the pH of 9 to 10.
Suitably the inorganic base is potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide or calcium hydroxide.
Preferably the inorganic base is calcium hydroxide, potassium carbonate or sodium hydroxide; most preferably sodium hydroxide.
Compounds of formula (II) may be prepared by the oxidation of a compound of formula (IV) ##STR5## wherein R.sup.1 is as hereinbefore defined.
Suitably the oxidation is effected by the reaction of a compound of formula (IV) as hereinbefore defined with peracetic acid in a polar solvent. Such solvents include water, C.sub.1-6 alcohol or SVM (ethanol plus 2% methanol). Preferred solvents are water, methanol or SVM and most preferred is water. The reaction is preferably carried out at a non-extreme temperature of -20.degree. C. to 100.degree. C., for example -5.degree. C. to 50.degree. C. and conveniently between 0.degree. C. to 20.degree.

REFERENCES:
patent: 4656291 (1987-04-01), Maryanoff et al.
Ferrario et al., "Multigram ... Characterization", Synthetic Communications, vol. 21(1), pp. 99-105, 1991.
Maryanoff et al., A Conventional Synthesis ... Thioureas, J. Org. Chem. vol. 51, pp. 1882-1884, 1986.
Cho et al., Preparation of NG-Monoethyl-L-arginine, Anal. Biochem., vol. 139, No. 2, pp. 377-382, Jun. 1984.
Justus Liebigs Ann Chemie 722, 98-109 (1969).
546C88 for Septic Shock--Study termination Apr. 24, 1998 London Scrip Display Apr. 27, 1998 Glaxo Wellcome hits problems in sepsis.

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