Process for preparing phosphinyloxy propanaminium inner salt derivatives

A process for preparing a compound of the formula:

• ##STR18## where X.sub.1 and X.sub.2 are independently O or S, and
• R.sub.1 is R.sub.5 --Y--R.sub.6 or R.sub.7 --Z--R.sub.8,
• where
• Y is --O--, --S--, --CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C--, --N(R.sub.10)--CO--, or --CO--N(R.sub.10)--,
• Z is --O--, --S-- or --CH.sub.2 --,
• R.sub.5 is straight or branched chain (C.sub.1-17)alkyl or .omega.-triflouro-(C.sub.1-8)alkyl, and
• R.sub.6 is straight chained (C.sub.2-18)alkylene,
• and the total number of carbons in R.sub.5 --Y--R.sub.6 is from 7 to 19,
• R.sub.7 is unsubstituted phenyl, phenoxyphenyl, biphenyl, naphthyl or naphthoxyphenyl, or phenyl, phenoxyphenyl, biphenyl, naphthyl or naphthoxyphenyl mono-, di-, or tri-substituted with halogen, NO.sub.2, NH.sub.2, CN, (C.sub.1-8)alkyl, (C.sub.1-8)alkoxy, triflouromethyl, triflouromethoxy, or acetyl,
• R.sub.8 is straight chained (C.sub.3-15)alkylene, --(CH.sub.2).sub.m --N(R.sub.10)--CO--(CH.sub.2).sub.n --, --(CH.sub.2).sub.m --CO--N(R.sub.10)--(CH.sub.2).sub.n --, or --CH.sub.2 --R.sub.11 --O--R.sub.12 --,
• m is 1 to 7,
• n is 1 to 7,
• R.sub.10 is hydrogen, methyl, or ethyl,
• R.sub.11 is straight or branched chain alkyl of 1 to 7 carbon atoms,
• R.sub.12 is straight chained (C.sub.2-7)alkylene,
• and the total number of carbons in the aryl substituents of R.sub.7 and the carbon atoms in R.sub.8 is from 3 to 15,
• R.sub.2, R.sub.3, and R.sub.4 are each independently straight or branched chain (C.sub.1-4)alkyl,
• and pharmaceutically acceptable salts, physiological hydrolysable esters, and pro-drug forms thereof, comprising the steps of
• A) reacting a compound of the formula
• R.sub.1 --O--P--Q.sub.2 (II)
• with a compound of the formula ##STR19## in an inert solvent;
• Bi) oxidizing and hydrolysing the product obtained with an oxidizing agent of the formula
• NaQ'O.sub.4
• where R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as defined above and Q and Q' are independently chlorine, bromine, or iodine, in water to obtain a compound of formula (I) in which X.sub.1 and X.sub.2 are oxygen, or
• Bii) thiolating and hydrolysing the product obtained in step A with sulfur and water to obtain a compound of formula (I) in which one of X.sub.1 and X.sub.2 is sulfur and the other is oxygen, or
• Biii) sulfating and sulfolysing the product obtained in step A with sulfur and hydrogen sulfide to obtain a compound of formula (I) in which both X.sub.1 and X.sub.2 are sulfur;
• and
• C) isolating and purifying the compound of formula (I) by chromatography over reverse phase silica gel (C-8) or AMBERLITE XAD-4 nonionic polymeric adsorbent.