Process for the preparation of 3-amino-2-hydroxypropylphosphinic acid derivatives

1. A process for the preparation of a compound of the formula I:

including its enantiomers or diastereomers, which comprises:

(a) reacting a compound of the formula II:

with hexamethyldisilazane to form a compound of formula III:

(b) reacting the compound of formula III with epihalohydrin and subsequent hydrolysis of the resulting adduct to form a compound of formula V:

(c) reacting compound of formula V with ammonia and subsequent hydrolysis of the ethyl phosphinate moiety to the compound of formula I, and optionally

(d) converting the compound of formula I into a pharmaceutically acceptable salt,

wherein R is benzyl or cyclohexylmethyl, and X is halogen.

2. The process as set forth in claim 1 , wherein the reaction of the compound of formula II with hexamethyldisilazane is carried out in the presence of a catalyst.

3. The process as set forth in claim 2 wherein said catalyst is an ammonium salt.

4. The process as set forth in claim 1 wherein said epihalohydrin is (S)- or (R)-epifluorohydrin, (S)- or (R)-epichlorohydrin, (S)- or (R)-epibromohydrin or (S)- or (R)-epiiodohydrin.

5. The process as set forth in claim 1 wherein said epihalohydrin is (S)- or (R)-epichlorohydrin.

6. The process as set forth in claim 5 wherein said reaction of the compound of formula III with (S)- or (R)-epichlorohydrin is carried out in the presence of a catalyst.

7. The process as set forth in claim 6 wherein a Lewis acid is used as the catalyst.

8. The process as set forth in claim 1 wherein the hydrolysis of the ethyl phosphinate moiety is carried out under acidic conditions.

9. The process as set forth in claim 8 wherein hydrochloric acid is used for the hydrolysis of the ethyl phosphinate moiety.

10. The process as set forth in claim 1 wherein a salt of the compound of formula I obtained in the hydrolysis is converted into the compound of formula I.

11. The process as set forth in claim 10 wherein an acid addition salt of the compound of formula I obtained in the hydrolysis is converted into the compound of formula I by treatment with an amine.

12. The process as set forth in claim 11 wherein said amine is triethylamine.

13. The process as set forth in claim 1 wherein R is cyclohexylmethyl.

14. The process as set forth in claim 1 wherein the compound of formula I having R configuration at the chiral carbon atom is prepared.

15. The process as set forth in claim 1 wherein (3-amino-(2R)-hydroxypropyl)-(cyclohexylmethyl)phosphinic acid of formula Ic is prepared

16. The process as set forth in claim 1 wherein (3-amino-(2R)-hydroxypropyl)-(benzyl)phosphinic acid of formula Id is prepared

17. The process as set forth in claim 1 wherein the compound of formula I having S configuration at the chiral carbon atom is prepared.

18. The process as set forth in claim 1 in which (3-amino-(2S)-hydroxypropyl)-(cyclohexylmethyl)phosphinic acid of formula Ie is prepared

19. The process as set forth in claim 1 in which (3-amino-(2S)-hydroxypropyl)-(benzyl)phosphinic acid of formula If is prepared

20. A process for the preparation of a compound of the formula Ic:

which comprises:

(b) reacting a compound of the formula IIc:

with hexamethyldisilazane to form a compound of formula IIIc:

(b) reacting the compound of formula III with (S)-(+)-epichlorohydrin and subsequent hydrolysis of the resulting adduct to form a compound of formula Vc:

(c) reacting compound of formula Vc with ammonia and subsequent hydrolysis of the ethyl phosphinate moiety to form compound of formula Ic as its hydrochloride; and

(d) treating the hydrochloride of compound of formula Ic with an amine to form the compound of formula Ic.