NZ225649A

NZ225649A - Preparation of unsaturated amino acid compounds, and pharmaceutical compositions

Info

Publication number: NZ225649A
Application number: NZ225649A
Authority: NZ
Inventors: Hans Allgeier; Christof Angst; Guido Bold; Rudolf Duthaler; Roland Heckendorn; Antonio Togni
Original assignee: Ciba Geigy Ag
Priority date: 1987-08-04
Filing date: 1988-08-02
Publication date: 1991-05-28
Also published as: KR890003786A; KR970011164B1; NO883444D0; DD282016A5; FI94415B; EP0302826A2; NO172495B; JPH0248586A; FI94415C; ZA885653B; DK434788D0; EP0302826A3; HU202242B; PH27591A; FI883589A; AU605340B2; JPH1053597A; IL87246A0; NO172495C; HUT47947A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £25649 m 2256 HQ DRAWINGS Priority Date(s): .. X-K Complete Specification Filed: Clmw? I ^»„"diLZ^'MW.'.".'. P.O. Journal, No: Patents Form No. 5 NEW ZEALAND PATENTS ACT 195 3 COMPLETE SPECIFICATION A PROCESS FOR THE MANUFACTURE OF V UNSATURATED AMINO ACID COMPOUNDS C \ o ^We, CIBA-GEIGY AG of Klybeckstrasse 141/ 4002 Basle, Switzerland/ a Swiss Corporation/ hereby declare the invention, for which ^J^we pray that a patent may be granted to ip^/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by page la) p^' setttwtr- la 4-16618/+ A process for the manufacture of unsaturated amino acid compounds Abstract The invention relates to a process for the manufacture of unsaturated amino acid compounds of formula in which Ri is hydrogen, alkyl or hydroxy, R2 is hydrogen, alkyl, halo-alkyl, hydroxyalkyl, lower alkoxyalkyl, aryl-lower alkyl, lower alkenyl, halogen or aryl, R3 is hydrogen, alkyl or aryl, Rt is hydrogen or alkyl, R5 is unsubstituted carboxy or esterified or amidated carboxy, R6 is an amino group that is unsubstituted or substituted by alkyl or by arylated alkyl, A is unsubstituted or alkyl-substituted a.w-alkylene having from 1 to 3 carbon atoms (C-atoms) or is a direct bond, and B is methylene or a bond, with the proviso that A is unsubstituted or alkyl-substituted oc,io-alkylene having from 1 to 3 C-atoms when B is a direct bond, and the salts thereof, characterised in that in a compound of formula in which Zi is free or protected hydroxy, Z2 is an Rj group or p hydroxy, Z5 is an R, group or protected carboxy, Ze is a protected group Zg, and Ra, R2 , R3 , R<», R5, Rs, A and B are as defined hereinbefore, the protected groups Zs and, when applicable, Zi, Z2 and/or Z% are freed by treatment with a tri-lower alkylhalosilane and, if desired, the resulting compound is converted into a different compound of formula I, a resulting mixture of optical isomers is resolved into the components and the (I), (II), (followed by page 2) - 2 - 225649 Compounds of formula I in which Rj is hydrogen are phosphonous acids, those in which Ri is alkyl are phosphinic acids, and those in which Ri is hydroxy are phosphonic acids. In the names of the compounds of formula I that are to be regarded as substituted carboxylic acids, the prefixes "phosphino" (Ri is hydrogen), "phosphonyl" (Ri is alkyl) and "phosphono" (Ri is hydroxy) are used. Esterified carboxy is, for example, carboxy esterified by an aliphatic or araliphatic alcohol, such as an unsubstituted or substituted lower alkanol or phenyl-lower alkanol, such as corresponding lower alkoxy- or phenyl-lower alkoxy-carbonyl. Esterified carboxy is preferably pharma-ceutically acceptable esterified carboxy, such as, for example, esterified carboxy that can be converted into carboxy under physiological conditions. These esters of formula I may also be called prodrug esters. Carboxy esterified in a pharmaceutically acceptable manner is, for example, lower alkoxycarbonyl; lower alkoxycarbonyl substituted in a position higher than the a-position by amino, by mono- or di-lower alkyl-amino or by hydroxy; lower alkoxycarbonyl substituted by carboxy, for example a-carboxy-substituted lower alkoxycarbonyl; lower alkoxycarbonyl substituted by lower alkoxycarbonyl, for example a-lower alkoxycarbonyl-substituted lower alkoxycarbonyl, aryl-lower alkoxycarbonyl, for example unsubstituted or substituted benzyloxycarbonyl, or pyridylmethoxycar-bonyl; lower alkanoyloxy-substituted methoxycarbonyl, for example pivaloyloxymethoxycarbonyl; lower alkoxymethoxycarbonyl substituted by lower alkanoyloxy or by lower alkoxy; bicyclo(2.2.1]heptyloxycarbonyl substituted methoxycarbonyl, such as bornyloxycarbonylmethoxycarbonyl; 3-phthalidoxycarbonyl; 3-phthalidoxycarbonyl substituted by lower alkyl, lower alkoxy or by halogen; or lower alkoxycarbonyloxy-lower alkoxycarbonyl, for example l-(methoxy- or ethoxy-carbonyloxy)-ethoxycarbonyl. Especially preferred prodrug esters are, for example, lower alkyl esters having up to four carbon atoms, such as, for example, butyl or ethyl esters, lower alkanoyloxymethyl esters, such as, for example, pivaloyl-oxymethyl ester, lower alkyl esters that have from two to four carbon atoms in each lower alkyl group and are substituted in a position higher w o VltCI1.9 uautjiKj - 3 - than the a-position by di-lower alkylamino, such as, for example, 2-di-ethylaminoethyl ester, and also pyridylmethyl esters, such as 3-pyridyl-methyl ester. In amidated carboxy the amino group is, for example, amino that is unsubstituted, monosubstituted by hydroxy, or mono-or di-substituted by aliphatic radicals, such as amino, hydroxyamino, mono- or di-lower alkylamino or lower alkyleneamino having from 5 to 7 ring members. Preferably, amidated carboxy is pharmaceutical^ acceptable amidated carboxy, such as, for example, amidated carboxy that can be converted into carboxy under physiological conditions. Preferred pharmaceutical^ acceptable amides are compounds of formula I in which Rs is carbamoyl, lower alkylcarbamoyl, for example ethylcarba-moyl, di-lower alkylcarbamoyl, for example diethylcarbamoyl, or in the form of N-(di-lower alkylamino)-lower alkylcarbamoyl, for example N-(2-diethylaminoethyl)carbamoyl or (3-diethylaminopropyl)carbamoyl. Within the scope of this invention, alkyl is a saturated aliphatic hydrocarbon radical having, for example, up to 12 carbon atoms, but especially having up to 8 carbon atoms, the latter range also being represented by the term lower alkyl. a, co-Alkylene having from 1 to 3 carbon atoms is methylene, 1,2-ethylene or 1,3-propylene. a,to-Alkylene substituted by alkyl is substituted at any position. Thus, methylene substituted by alkyl is, for example, 1.1-ethylene, 1,1-butylene or 1,1-octylene, 1,2-ethylene substituted by alkyl is, for example, 1,2-propylene, 1,2-butylene, 2,3-butylene, 1.2-pentylene or 1,2-nonylene, and 1,3-propylene substituted by alkyl is, for example, 1,3-butylene, 1,3-pentylene or 1,3-decylene. Amino monosubstituted by lower alkyl or by aryl-lower alkyl is mono-lower alkylamino or aryl-lower alkylamino. - 4 - 22 5 6 4 9 Aryl, also In definitions such as aroyl or aryl-lower alkoxycarbonyl, represents aromatic hydrocarbon radicals that are unsubstituted or substituted by lower alkyl, hydroxy, protected hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl or by nitro, and is, for example, unsubstituted or correspondingly substituted 1- or 2-naphthyl, but preferably unsubstituted or correspondingly substituted phenyl, such as phenyl, lower alkylphenyl, for example tnethylphenyl, hydroxyphenyl, halophenyl, for example 4-halophenyl, such as 4-chlorophenyl, benzyloxyphenyl, lower alkoxyphenyl, for example methoxyphenyl, hydroxymethylphenyl, aminomethylphenyl or nitrophenyl. The general terms used hereinbefore and hereinafter, unless defined otherwise, have the following meanings: The term "lower" indicates that groups or compounds so defined contain up to and including 8, preferably up to and including 4, carbon atoms. Lower alkyl is, for example, Ci-Ci,alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl, but can also be Cs-Csalkyl, such as n-pentyl, n-hexyl, n-heptyl or n-octyl, and is preferably methyl. Aryl-lower alkyl, also in definitions such as aryl-lower alkylamino, is, for example, aryl-Ci-Ct,alkyl in which aryl has the meanings given above, and is especially, for example, unsubstituted phenyl-Ci-Ci,alkyl, such as benzyl or 1- or 2-phenylethyl. Lower alkenyl contains preferably up to 6 carbon atoms and is bonded by way of an spd-hybridised carbon atom and is, for example, 2-propenyl, 2-or 3-butenyl or 3-pentenyl but can also be vinyl. Lower alkoxy is especially Ci-Ci,alkoxy, such as methoxy, ethoxy, n-prop-oxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy. Halogen preferably has an atomic number of up to 35 and is especially chlorine, or also fluorine or bromine, but can also be iodine. - 5 - 22 5 6 4 9 Halo-lower alkyl is, for example, halo-Ci-Cr, alkyl, such as fluoromethyl, trifluoromethyl or 1- or 2-chloroethyl. Hydroxy-lower alkyl is, for example, mono- or di-hydroxy-Ci-C7alkyl, carries the hydroxy group(s) especially in a position higher than the a-position and is, for example, hydroxymethyl or especially mono- or di-hydroxy-C2-C7~alkyl, such as 2-hydroxyethyl, 3-hydroxy- or 2,3-di-hydroxy-propyl, 4-hydroxy- or 2,4-dihydroxy-butyl, or 5-hydroxy-, 2,5-di~ hydroxy- or 3,5-dihydroxy-pentyl. Lower alkoxy-lower alkyl is, for example, mono- or di-Ci-Cgalkoxy-Ci-C7-alkyl, carries the lower alkoxy group(s), for example, especially in a position higher than the a-position and is especially Ci-Ci»-alkoxy-C2-Ci(-alkyl, for example, 2-methoxy-, 2-ethoxy-, 2-propoxy- or 2-iso-propoxy-ethyl, 3-methoxy- or 3-ethoxy-propyl or 3,3-dimethoxy-, 3,3-di-ethoxy-, 2,3-dimethoxy- or 2,3-diethoxy-propyl or 4,4-dimethoxybutyl, but may also be methoxy-, ethoxy-, dimethoxy-, propoxy- or isopropoxy-methyl. Mono- or di-lower alkylamino is, for example, N-Ci-Ci,alkylamino or N,N-di-Ci-Ci)alkylamino, such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino or butylamino. Salts of compounds according to the invention are especially pharma-ceutically acceptable non-toxic salts of compounds of formula I. Such salts are formed, for example, from the carboxy group present in compounds of formula I, and are especially metal or ammonium salts, such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, and also ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, for example methylamine, diethylamine or triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine, tris-(hydroxymethyl)-methylamine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, for example l-ethyl-piperidine, lower alkylenediamines, for example ethylenediamine, cyclo- - 6 - 225649 alkylamines, for example dicyclohexylamine, or benzylamines, for example N,N'-dibenzylethylenediamine, benzyltrimethylamrnoniuni hydroxide, dibenzylamine or N-benzyl-fi-phenylethylamine. Compounds of formula I having a primary or secondary amino group may also form acid addition salts, for example with preferably pharmaceutically acceptable inorganic acids, such as hydrohalic acids, for example hydrochloric acid or hydro-bromic acid, sulphuric acid, nitric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, for example acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, citric acid, pyruvic acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, pamoa acid, nicotinic acid, methanesulphonic acid, ethanesulphonic acid, hydroxy-ethanesulphonic acid, benzenesulphonic acid, 4-toluenesulphonic acid or naphthalenesulphonic acid. It is also possible to use pharmaceutically unsuitable salts for isolation or purification. Only the pharmaceutically acceptable non-toxic salts are used therapeutically, and these are therefore preferred. The compounds prepared in accordance with the invention have valuable pharmacological properties. They are, for example, active and selective antagonists of N-methyl-D-aspartic acid (NMDA)-sensitive excitatory amino acid receptors in mammals. They are therefore suitable for the treatment of diseases that respond to a blocking of NMDA-sensitive receptors, such as, for example, cerebral ischaeraia, muscular spasms (spasticity), convulsions (epilepsy), conditions of anxiety or manic conditions. These advantageous effects may be demonstrated in in vitro or in in vivo test arrangements. For these, preferably mammals are used, for example mice, rats or monkeys, or tissue or enzyme preparations from such mammals. The compounds may be administered enterally or parentally, preferably orally; or subcutaneously, intravenously or intraperitoneally, for example in gelatin capsules or in the form of aqueous suspensions or solutions. The dosage to be used in vivo may range from 0.1 to 600 mg/kg, - 7 - 22 5 6 preferably from 1 to 300 mg/kg. In vitro, the compounds may be used in the form of aqueous solutions, the concentrations ranging from 10 ^ to —8 10 molar solutions. The Inhibiting action on the NMDA-sensitive excitatory amino acid receptors may be determined in vitro by measuring, in accordance with G. Fagg and A. Matus, Proc. Nat. Acad. Sci., USA, 81^, 6876-80 (1984), to what extent the bonding of L-:'H-glutamic acid to NMDA-sensitive receptors is inhibited. In vivo, the inhibiting action on NMDA-sensitive excitatory amino acid receptors may be demonstrated by the inhibition of NMDA-induced convulsions in mice. The anti-convulsive properties of the compounds according to the invention may furthermore be shown by their effectiveness in preventing audiogenically induced attacks in DBA/2 mice (Chapman et al., Arznei-mittel-Forsch. 34, 1261, 1984). The anti-convulsive properties may furthermore be shown by the effectiveness of the compounds according to the invention as electric shock antagonists in mice or in rats. An indication of the anxiolytic activity of the compounds of the present invention is given by their pronounced effectiveness in the conflict model according to Cook/- Davidson (Psychopharmacologia 1_5, 159-168 (1968)). The pronounced effectiveness of the compounds of formula I depends to a surprisingly high extent on the configuration at the double bond. For example, the racemate of D-2-amino-5-phosphono-3-cis-pentenoic acid known from Agric. Biol. Chem. 41, 573-579 (1979), B. K. Park et al., proves, for example in its ability to bond to the NMDA-sensitive receptor, to be far inferior to the racemate of the 2-amino-5-phosphono-3-trans-pentenoic acid according to the invention (in the Examples these compounds are referred to as compounds of the "E-series"). Compounds of the formula I, wherein the carbon atom carrying the group R6 has R-configuration, have been found to be especially active. ZZ 5 6 - 8 - The manufacture of compounds of formula I in which R2 is hydrogen, alkyl or aryl is preferred. The invention relates especially to a process for the manufacture of compounds of formula I in which Ri is hydrogen, alkyl having up to and including 12 carbon atoms, or hydroxy, R2 is hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl that is unsubstituted or substituted in the phenyl moiety, lower alkenyl, halogen, or unsubstituted or substituted phenyl, R3 is hydrogen, lower alkyl or unsubstituted or substituted phenyl, Rt, is hydrogen or lower alkyl, R5 is free or pharmaceutically acceptable esterified or amidated carboxy, R6 is amino, or mono- or di-lower alkylamino, A is unsubstituted or lower alkyl-substituted a,w-alkylene having from 1 to 3 carbon atoms or is a bond, and B is methylene or a bond, with the proviso that A is other than a bond when B is a bond, the substituents of phenyl being selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and nitro, and wherein "lower" groups possess up to and including 8 carbon atoms, and also to pharmaceutically acceptable salts thereof. Preferred is the use of the process for the manufacture of compounds of formula I in which Ri to Rii, A and B are as defined hereinbefore and, on the one hand, R5 is lower alkoxycarbonyl, or lower alkoxycarbonyl substituted by amino, mono- or di-lower alkylamino, hydroxy or by lower alkanoyloxy and R6 is amino or lower alkylamino or, on the other hand, Rs is carboxy and Rg is amino, especially the R-enantiomers thereof in respect of the atom carrying the amino group, and pharmaceutically acceptable salts thereof. Also preferred is the use of the process for the manufacture of compounds of formula I in which Ri, Ri* to Rs and A and B are as defined directly hereinbefore and in which R2 and R3, independently of one another, each represents hydrogen, lower alkyl, phenyl or phenyl substituted by lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy- - 9 - 22 5 6 4 9 lower alkyl, amino-lower alkyl or by nltro, especially the R-enantiomers thereof in respect of the atom carrying the amino group, and pharmaceutically acceptable salts thereof. The invention relates especially to a process for the manufacture of compounds of formula I in which Ri is hydrogen, alkyl having up to and including 12 carbon atoms, or hydroxy, R2 is hydrogen, lower alkyl, phenyl, halophenyl or phenyl-lower alkyl, R3 and Ri, are hydrogen or lower alkyl and, on the one hand, R5 is alkoxycarbonyl or hydroxy-lower alkoxycarbonyl and R$ is amino or mono-lower alkylamino or, on the other hand, R5 is carboxy and Rs is amino, A in each case being unsubstituted or lower alkyl-substituted a,w-alkylene having from 1 to 3 carbon atoms or being a bond and B in each case being methylene or a bond, with the proviso that A is other than a bond when B is a bond, especially the R-enantiomers thereof in respect of the atom carrying the amino group, and pharmaceutically acceptable salts thereof. The invention relates especially to a process for the manufacture of compounds of formula I in which Ri is hydrogen, alkyl having up to and including 12 carbon atoms, or hydroxy, R2 is hydrogen, lower alkyl or halophenyl, R3 is hydrogen or halophenyl, Ri» is hydrogen and, on the one hand, R5 is lower alkoxycarbonyl or hydroxy-lower alkoxycarbonyl and Rs is amino or mono-lower alkylamino or, on the other hand, Rs is carboxy and Rg is amino, A in each case being a,w-alkylene having from 1 to 3 carbon atoms or being a bond and B in each case being methylene or a bond, with the proviso that A is other than a bond when B is a bond, especially the R-enantiomers thereof in respect of the atom carrying the amino group, and pharmaceutically acceptable salts thereof. The invention relates especially to a process for the manufacture of compounds of formula I in which Ri is hydrogen, lower alkyl or hydroxy, R2 is hydrogen or lower alkyl, R3 and Ri, are hydrogen and Rs is on the one hand lower alkoxycarbonyl or on the other hand carboxy, and Rs is amino, A in each case being a,w-alkylene having from 1 to 3 carbon atoms - 10 - 2 2 5 6 4 9 and B in each case being a bond, especially the R-enantiomers thereof in respect of the atom carrying the amino group, and pharmaceutically acceptable salts thereof. The invention relates most especially to a process for the manufacture of compounds of formula I in which Ri is hydroxy, R2 is hydrogen or lower alkyl, R3 and Ri# are hydrogen and Rs is lower alkoxycarbonyl or carboxy, R6 is amino, A is methylene and B is a bond, especially the R-enantiomers thereof in respect of the atom carrying the amino group, and pharmaceutically acceptable salts thereof. The invention relates to the manufacture of the compounds mentioned specifically in the Examples and to the pharmaceutically acceptable salts thereof. The process of the invention is characterised in that in a compound of formula in which Zi is free or protected hydroxy, Zz is an Ri group or protected hydroxy, Z5 is an Rs group or protected carboxy, Z& is a protected R6 group, and Ri, R2, R3, Rij, R5, R6, A and B are as defined hereinbefore, the protected groups and, where applicable, Zi, Z2 and/or Z& are freed by treatment with a tri-lower alkylhalosilane and, if desired, the resulting compound is converted into a different compound of formula I, a resulting mixture of optical isomers is resolved into the components and the desired isomer is separated off, and/or a resulting free compound is converted into a salt or a resulting salt is converted into the free compound or into a different salt. Protected hydroxy Zi and/or Z2 in intermediates of formula II is, for example, hydroxy etherified by an aliphatic alcohol, such as hydroxy etherified by a lower alkanol, lower alkenol or lower alkynol each of (II), - 11 - r 9 5 6 4 9 which is unsubstituted or substituted by halogen or, in a position higher than the a-position, by hydroxy, oxo, lower alkoxy, lower alkanoyloxy and/or by mono- or di-lower alkylamino, and is, for example, lower alkoxy, halo-lower alkoxy, or corresponding hydroxy-, oxo-, lower alkoxy-, lower alkanoyloxy- or mono- or di-lower alkylamino-lower alkoxy. Compounds of formula II in which Zi and/or Zg are etherified hydroxy are esters of the phosphorus-containing acid group and, depending on the meaning of Ri, are phosphonous acid esters, phosphinic acid esters or phosphonic acid esters. Preferred esters are the respective lower alkyl esters and hydroxy-lower alkyl esters. Groups Zg in intermediates of formula II are, for example, Rg groups substituted by acyl, that is to say acylamino that is unsubstituted or N-substituted by lower alkyl or by aryl-lower alkyl in which acyl is the acyl radical of an organic acid having, for example, up to 18 carbon atoms, especially an alkanecarboxylic acid that is unsubstituted or substituted, for example, by halogen, amino or by phenyl, or benzoic acid that is unsubstituted or substituted, for example, by halogen, lower alkoxy or by nitro, or of a carbonic acid semiester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, especially 2-fluoro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, aroyl, such as unsubstituted or substituted benzoyl, for example benzoyl, halobenzoyl, such as 4-chlorobenzoyl, lower alkoxybenzoyl, such as 4-methoxybenzoyl, or nitrobenzoyl, such as 4-nitrobenzoyl. The following are also especially suitable: lower alkenyloxycarbonyl, for example allyloxycarbonyl, or especially lower alkoxycarbonyl that is unsubstituted or substituted in the 1- or 2-position, such as, especially, lower alkoxycarbonyl, for example tertiary butoxycarbonyl and also methoxy- or ethoxy-carbonyl, and also unsubstituted or substituted benzyloxycarbonyl, for example benzyloxycarbonyl or 4-nitrobenzyloxy-carbonyl, or aroylmethoxycarbonyl in which the aroyl group is benzoyl that is unsubstituted or substituted, for example, by halogen, such as bromine, for example phenacyloxycarbonyl or bromophenacyloxycarbonyl. - 12 - 225649 Furthermore, In a corresponding acylamino group Zs, acyl may be alkanoyl-amino substituted by amino and/or by phenyl, carbamoyl, carboxy, imidazolyl, lower alkylthio, tetrahydropyrrolyl, hydroxy, indolyl or by hydroxyphenyl, and thus includes, for example, the acyl radicals of amino acids, for example naturally occurring amino acids, such as alanyl, asparaginyl, aspartyl, glycyl, histidyl, isoleucyl, leucyl, lysyl, methionyl, phenylalanyl, prolyl, seryl, threonyl, tryptophyl, tyrosyl or valyl; also included are the acyl radicals of oligopeptides, for example di- or tri-peptides, such as oligopeptides of alanine, asparagine or aspartic acid. Furthermore, protected amino Zs may be a diacylamino group. In this group diacyl is, for example, two acyl radicals of the definitions given hereinbefore, or diacyl is, for example, the acyl radical of an organic dicarboxylic acid having, for example, up to 12 carbon atoms, especially a corresponding aromatic dicarboxylic acid, such as phthalic acid. Such a group is especially phthalimido. In addition, protected amino 2c, may also be amino substituted by substituted lower alkoxycarbonyl, such as amino substituted by 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-chloro-ethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or by 2-(tris-8ubstituted silyl)-ethoxycarbonyl, such as 2-tri-lower alkyl-silylethoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or by 2-triarylsilylethoxy-carbonyl, such as 2-triphenylsilylethoxycarbonyl, or etherified mercapto-amino or silylamino, or may be in the form of an enamino, nitro or azido group. An etherified mercaptoamino group is especially a phenylthioamino group that is unsubstituted or substituted by lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine or bromine, and/or by nitro, or a pyridylthioamino group. Corresponding groups are, for example, 2- or 4-nitrophenylthioamino or 2-pyridylthio-amino. A silylamino group is especially an organic silylamino group. In such groups the silicon atom contains as substituent(s) preferably lower alkyl, for example methyl, ethyl, n-butyl or tert.-butyl, also aryl, for example phenyl. Suitable silyl groups are especially tri-lower alkyl- 22 5 6 4 9 silyl, especially trimethylsilyl or dimethyl-tert.-butylsilyl. Enamino groups contain at the double bond in the 2-position an electron-attracting substituent, for example a carbonyl group. Protecting groups of this kind are, for example, 1-acyl-lower alk-l-en-2-yl radicals in which acyl is, for example, the corresponding radical of a lower alkane-carboxylic acid, for example acetic acid, of a benzoic acid that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, or especially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester, for example methyl semiester or ethyl semiester, and lower alk-l-ene is especially 1-propene. Corresponding protecting groups are especially 1-lower alkanoyl-prop-1-en-2-yl, for example l-acetyl-prop-l-en-2-yl, or 1-lower alkoxycarbonyl-prop-l-en-2-yl, for example l-ethoxycarbonyl-prop-l-en-2-yl. Protected carboxy Z5 is customarily protected in esterified form, it being possible for the ester group to be cleaved under reductive, such as hydrogenolytic, or solvolytic, such as acidolytic or hydrolytic, such as acid-hydrolytic, basic-hydrolytic or neutral-hydrolytic, conditions. A protected carboxy group may furthermore be an esterified carboxy group that can be cleaved under physiological conditions or that can readily be converted into a different functionally modified carboxy group, such as into a different esterified carboxy group. Such esterified carboxy groups contain as esterifying groups especially silyl groups, especially tri-lower alkylsilyl groups, or lower alkyl groups that are suitably substituted in the 1- or 2-position. Preferred carboxy groups in esterified form are, inter alia, tri-lower alkylsilyloxycarbonyl, for example tri-methylsilyloxycarbonyl, (hetero-)arylmethoxycarbonyl having from 1 to 3 aryl radicals or having one monocyclic heteroaryl radical, these being unsubstituted or mono- or poly-substituted, for example, by lower alkyl, such as tert.-lower alkyl, for example tert.-butyl, halogen, for example chlorine, and/or by nitro. Examples of such groups are benzyloxycarbonyl that is unsubstituted or substituted, for example in the manner mentioned above, for example 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or triphenylmethoxycarbonyl that is unsubstituted or substituted, for example in the manner mentioned above, for example diphenylmethoxycar- - 14 - 22 5 6 4 9 bonyl, or picolyloxycarbonyl, for example 4-picolyloxycarbonyl, or fur-furyloxycarbonyl, such as 2-furfuryloxycarbonyl that is unsubstituted or substituted, for example in the manner mentioned above. Protected hydroxy Z\ and/or Zz is especially lower alkoxy, such as methoxy, ethoxy or isopropoxy, protected carboxy is especially tri-lower alkylsilyloxycarbonyl, such as trimethylsilyloxycarbonyl, and protected amino 2$ unsubstituted or substituted by lower alkyl or by aryl-lower alkyl is especially lower alkanoylamino, especially formylamino, N-lower alkanoyl-N-lower alkylamino, especially N-formyl-N-lower alkylamino, for example N-fortnyl-N-methylamino, or lower alkoxycarbonylami.no, preferably tertiary butoxycarbonylamino. Tri-lower alkylhalosilanes are, for example, tri-lower alkyliodosilanes or, especially, tri-lower alkylbromosilanes, preferably those in which the lower alkyl groups are identical Ci-Ci,alkyl radicals. Trimethyl-bromosilane is preferred, with trimethyliodosilane as second choice. Freeing the protected groups, that is to say freeing hydroxy from protected hydroxy groups Zi and/or Zz, freeing carboxy from protected carboxy groups Z5 and/or freeing amino that is unsubstituted or substituted by lower alkyl or by phenyl-lower alkyl from protected amino groups Zg by treatment with a tri-lower alkylhalosilane is effected, for example, in an inert solvent, such as a halogenated, preferably aliphatic hydrocarbon, for example dichloromethane or, less preferably, tri- or tetra-chloromethane, trichloroethane or tetrachloroethane, in a temperature range of approximately from -25° to +50°C, preferably from approximately 0°C to approximately 30°C, for example at temperatures in the region of room temperature, that is to say at from approximately 15°C to approximately 25°C, advantageously under substantially anhydrous conditions and under an inert gas, for example under argon or nitrogen. Working up is carried out in a manner known per se, two purifying methods especially having proved advantageous. Either the crude product can be converted into a readily volatile derivative, for example by silylation, and recovered as such by distillation and then desilylated, or the crude - 15 - 22 5 6 product can be treated with an agent that reacts with excess acid, such as hydrohalic acid, thereby removing it. Suitable agents are, for example, compounds to which a corresponding acid can be added, for example lower alkylene oxides (epoxides), such as propylene oxide. If compounds of formula I in which Rs is esterified or amidated carboxy, such as lower alkoxycarbonyl or carbamoyl, are desired as end products, the starting materials of formula II and the process conditions can be so selected that although in the last step Zi, Z2 and Z6 are freed, Z5, which represents the desired R5 group, remains unaffected. An especially preferred process variant is accordingly directed to the manufacture of compounds of formula I in which R5 is Ci-(\alkoxycarbonyl and R6 is amino. In this process variant the starting materials used are preferably compounds of formula II in which Zi and Z2 are lower alkoxy or lower alkoxy substituted in a position higher than the a-position by halogen, such as chlorine, Z5 is Ci~Ci»alkoxycarbonyl and Zg is lower alkanoylamino, such as formylamino, or lower alkoxycarbonylamino, such as tert.-butoxycarbonylamino. Starting from such compounds of formula II the freeing of the protected groups can be so controlled by treatment in an inert solvent, such as a halogenated hydrocarbon, for example dichloro-methane, at temperatures in the region of room temperature, with a reagent such as trimethylbromosilane, and by subsequent treatment with a lower alkanol, such as ethanol, and a substance absorbing hydrogen halide, such as an aliphatic epoxide, especially an epoxy-lower alkane, for example propylene oxide, that compounds of formula I in which Rj is hydroxy, R5 is Ci-C^alkoxycarbonyl, R6 is amino and the variables R2, R3 and Ri( are as defined for formula I, are obtained directly. This process is especially preferred for the manufacture of compounds of formula I in which A is methylene or 1,3-propylene and B is a bond, R3 and Ri» are hydrogen and R2 is alkyl having up to 4 carbon atoms, such as methyl. - 16 - 225649 Another especially preferred process variant is the manufacture of compounds of formula I in which R5 is carboxy. In this case the starting materials used are preferably compounds of formula II in which Zi and Z2 are lower alkoxy or lower alkoxy substituted in a position higher than the a-position by halogen, such as chlorine, Z5 is optionally protected carboxy and Zf, is lower alkoxycarbonylamino, especially a-branched lower alkoxycarbonylamino, such as tert.-butoxycarbonylamino. In this case, the carboxy group is preferably, but not necessarily, intermediately protected, for example by treatment with a silylation agent, such as an N,0-silyl-lower alkanoic acid amide, for example with N,0-trimethylsilyl-acetamide. Intermediates of formula II are preferably manufactured by reacting a compound of formula (III), in which R2, R3, Ri,, A and B are as defined for formula I, Z5 has the meaning of R5 or is protected carboxy, Z& is a protected Re group and X is reactive esterified hydroxy, with a compound of formula (IV), in which Zi is free or protected hydroxy, Z2 has the meaning of Ri or is protected hydroxy and R is an etherifying group, and can be used without being isolated or specially purified. Compounds of formula III can be manufactured, for example, by reacting an N-protected aminomalonic acid ester of formula V ZJ-JH-Z5 (V) , - 17 - 225649 in which Z5 and Z£ are identical or different esterified carboxy groups, for example lower alkoxycarbonyl groups, in a manner known per se with a compound of formula in which X and X1, independently of one another., each represents reactive esterified hydroxy, such as halogen. The resulting compounds of formula J-H-t-ls (VII) X-A-T Zs can be converted into compounds of formula III in which m is hydrogen by hydrolysis, for example under hydrolytic conditions, such as the conditions of an acidic hydrolysis, for example with hydrohalic acids, such as hydrochloric acid, preferably with heating, and by decarboxylation, or by dealkoxycarbonylation, without previous hydrolysis, by heating in an aqueous aprotic solvent, auch as dimethyl sulphoxide, in the presence of an alkali metal halide, such as sodium chloride. This variant is accordingly especially suitable for producing compounds III in which Ri« is hydrogen, Z5 is free or esterified carboxy and Zg is protected amino, such as lower alkanoylamino. Intermediates III in which A is methylene that is unsubstituted or substituted by alkyl, B is a bond, X is halogen and Z6 is formylamino can furthermore be produced by reacting a compound of formula wherein D denotes optionally alkylated methylidene, such as a corresponding a,0-unsaturated aldehyde, for example acrolein or methacrolein, with an a-isocyanoacetic acid derivative, such as an a-isocyanoacetic acid lower alkyl ester. With suitable catalysis, such as with low valency T (VI) k (VIII) - 18 - 22 5 6 4 9 metal salts, that Is to say metal salts derived from metals of groups I and II of the Periodic Table of Elements, for example corresponding metal oxides or metal halides, such as zinc chloride, cadmium chloride, silver oxide or, preferably, copper oxide or complexes of gold-I-tetrafluoro-borate with aliphatic or cycloaliphatic isocyanides, for example bis-(cyclohexylisocyanide)gold-I-tetrafluoroborate, there are thus obtained in a manner known per se 5-vinyl-2-oxazoline-4-carboxylic acid derivatives, for example esters of formula which can be converted into the open-chained compounds of formula in which D is unsubstituted or alkyl-substituted methylidene. These compounds can in turn be converted by selective halogenation, such as bromination or chlorination, preferably with cooling and with displacement of the double bond in the manner of an allyl rearrangement, into compounds of formula III. Another process for the manufacture of compounds II in which Ri, is hydrogen, A is methylene or 1,3-propylene and R5 is carboxy, is based on the principle that a compound of formula H= ^5 (IX) (X) (XI) - 19 - 225649 In which R^ and Rg are hydrogen or preferably lower alkyl, such as methyl, and R^ is an amino-protecting group, is condensed with a 2-R2-acetic acid ester or condensed first with a 1-Rz-ethene-metal compound, for example with isopropenylmagnesium bromide, and subsequently with an acetic acid ester, in the resulting compound of formula /Zs f3 /HzCHa-Z* -/=L 2 (Xlla) or 0^ (Xllb) <\ * <\ ' <vX in which Z5 is esterified carboxy, for example lower alkoxycarbonyl, this group is reduced to hydroxymethyl, for example by means of diiso-butylaluminium hydride, the hydroxymethyl group is halogenated, for example brominated by means of tetrabromomethane/triphenylphosphine, the resulting compound of formula f3 /"°\ J—\ >rCxiii), X—A—? X/ V 1: Y in which A denotes methylene or 1,3-propylene and X is halogen, for example bromine, is further reacted with a compound of formula IV, the oxazolidine ring is cleaved, for example, by means of an ion exchanger, such as Amberlyst 15®, and, in the resulting compound of formula (XIV), in which Ze is a protected amino group of formula RC-NH-(II'), the hydroxymethyl group is oxidised to carboxy in customary manner. When carrying out the above-described processes for the manufacture of intermediates III and the further reaction of the same to form inter- * mediates II it is not necessary to isolate all of the intermediate 20 - 22 5 6 4 9 stages. For example, especially the conversion of compounds X into compounds III and the further reaction thereof with compounds IV to form intermediates II can advantageously be carried out in situ. A preferred variant of the process of the invention accordingly consists of the following: a compound of formula in which Rz, R3, Ri,, A and B are as defined for formula I, Z5 has the meaning of R5 or is protected carboxy, Zs is a protected R6 group, for example protected amino, and X is reactive esterified hydroxy, is reacted with a compound of formula in which Zi is free or protected hydroxy, Z2 has the meaning of Ri or is protected hydroxy and R is an etherifying group, the protected groups Z6 and, where applicable, Zj, Z2 and/or Z5 are freed by treatment with a tri-lower alkylhalosilane, for example with trimethylbromosilane, and, if desired, a resulting compound of formula I is converted into a different compound of formula I and/or, if desired, a resulting compound of formula I is converted into a salt or a resulting salt is converted into a different salt or into a free compound of formula I and/or, if desired, an optical isomer is isolated from a mixture of stereoisomeric forms of a resulting compound of formula I or of a salt thereof. A reactive esterified hydroxy group, such as X, is a hydroxy group esterified by a strong organic acid, for example a hydroxy group esterified by an aliphatic or aromatic sulphonic acid (such as a lower alkanesulphonic acid, especially methanesulphonic acid, trifluoromethane-sulphonic acid, especially benzenesulphonic acid, p-toluenesulphonic acid, p-bromobenzenesulphonic acid and p-nitrobenzenesulphonic acid) or .(III), <IV), - 21 22 5 6 4 9 by a strong inorganic acid, such a6, especially, sulphuric acid, or a hydrohalic acid, such as hydrochloric acid or, most preferably, hydriodic acid or hydrobromic acid. Attention is drawn in this connection to the surprising finding that the manufacture of the intermediates II and their further reaction according to the invention to form the end products I can be carried out stereo-selectively. That is, neither in the reaction sequence III + IV -> II or Ila -> I, nor in the reaction sequences X -> III and XI XII -> XIII XIV -> II is there reversal of configuration or significant racemisation. The process of the invention is therefore excellently suitable for the direct manufacture of compounds of formula I with the preferred R-con-figuration at the carbon atom carrying the amino group R6. The invention also relates to the manufacture of sterically homogeneous compounds of formula I and sterically homogeneous intermediates of formulae II, III, X, XI, XII, XIII and/or XIV. According to another preferred process variant, a compound of formula is subjected to selective halogenation, for example by means of thionyl chloride, to form the corresponding intermediate III, and this is reacted in situ, that is to say without being isolated, with component IV. As mentioned, compounds obtainable in accordance with the invention can be converted into different compounds of formula I. In particular, a free amino group Re may be substituted, for example converted into an unsubstituted or phenylated alkylamino group, free carboxy R5 may be esterified, or esterified or amidated carboxy R5 may be converted into free carboxy, and/or free or esterified carboxy Rs may be converted into amidated carboxy. (X) - 22 - 22 5 6 4 9 To convert an amino group into an unsubstituted or phenylated alkylamino group the amino group may be alkylated by substitution, for example with a reactive esterified optionally phenylated alkanol, such as an alkyl halide, or by reduction, such as with an aldehyde or ketone, and also with catalytically activated hydrogen or, in the case of formaldehyde, advantageously with formic acid as reducing agent. Free carboxylic acids of formula I or salts thereof may be converted according to known processes by suitable alcohols or corresponding derivatives thereof into the corresponding esters, that is to say into compounds of formula I that are, for example, in the form of lower alkyl esters, aryl-lower alkyl esters, lower alkanoyloxymethyl esters or lower alkoxycarbony1-lower alkyl esters. For the esterification, a carboxylic acid may be reacted directly with a diazoalkane, especially diazomethane, or with a corresponding alcohol in the presence of a strongly acidic catalyst (for example a hydrohalic acid, sulphuric acid or an organic sulphonic acid) and/or of a dehydrating agent (for example dicyclohexylcarbodiimide). Alternatively, the carboxylic acid may be converted into a reactive derivative, such as into a reactive ester, or into a mixed anhydride, for example with an acid halide (for example, especially an acid chloride), and this activated intermediate is reacted with the desired alcohol. Compounds of formula I in which R5 is esterified carboxy, such as, especially, lower alkoxycarbonyl, for example ethoxycarbonyl, can be converted into compounds of formula I in which R5 is carboxy, for example by hydrolysis especially in the presence of inorganic acids, such as hydrohalic acids or sulphuric acid or, less preferably, aqueous alkalis, such as alkali metal hydroxides, for example lithium or sodium hydroxide. In this connection attention is drawn to the fact that also carboxy can be freed from esterified carboxy in such a manner that no significant racemisation occurs. This can be achieved especially by treatment with from approximately 0.2N to approximately 4N, for example approximately IN, that is to say from approximately 0.5N to approximately 2N, aqueous mineral acid, if necessary while heating, for example at from approxi - 23 225649 mately 60°C to approximately boiling temperature, that is to say approximately 100°C. Surprisingly, the hydrolysis, for example, of phosphonic acid carboxylic acid lower alkyl esters of formula I, proceeds with a high yield even without the addition of acidic or basic reagents. A preferred process for the manufacture of carboxylic acids of formula I from the corresponding lower alkyl esters, such as the respective ethyl esters, therefore consists in acidic hydrolysis by treatment with from approximately 0.2N to approximately 4N aqueous mineral acid, for example hydrochloric acid, sulphuric acid, phosphoric acid or the like, and also in the - possibly autocatalytic - hydrolysis in water, preferably at elevated temperatures, such as with heating under reflux. The above reactions are carried out according to standard methods in the absence or presence of diluents, preferably those that are inert towards the reagents and are solvents therefor, in the presence of catalysts, condensation agents or the other agents and/or in an inert atmosphere, at low temperature, room temperature or elevated temperature, preferably at the boiling point of the solvents used, at atmospheric or superatmos-pheric pressure. The invention includes furthermore any variant of the present processes in which an intermediate obtainable at any stage of that process is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage, or in which the starting materials are formed under the reaction conditions or in which the reactants are used in the form of their salts or optically pure antipodes. There should especially be used in these reactions those starting materials that result in the formation of the compounds mentioned hereinbefore as being especially valuable. The invention relates also to novel starting materials and processes for their manufacture. Depending on the choice of starting materials and methods, the novel compounds may be in the form of one of the possible optical isomers or in the form of mixtures thereof, for example depending on the number of - 24 - 225649 asymmetric carbon atoms they may be in the form of pure optical isomers, such as antipodes, or mixtures of optical isomers, such aa racemates, or mixtures of dlastereoisomers from which one antipode, if desired, may be isolated. Resulting mixtures of dlastereoisomers and mixtures of racemates may be separated in known manner on the basis of the physico-chemical differences between the constituents into the pure isomers, dlastereoisomers or racemates, for example by chromatography and/or fractional crystallisation. The resulting racemates (racemic dlastereoisomers) may furthermore be separated into the optical antipodes according to methods known per se, for example by recrystallisation from an optically active solvent, with the aid of microorganisms or enzyme-catalyst in free or in an immobilised form or by reaction of an acidic end product with an optically active base that forms salts with the racemic acid, and separation of the salts obtained in this manner, for example on the basis of their different solubilities, into the dlastereoisomers, from which the antipodes can be freed by the action of suitable agents. Basic racemic products can also be separated into the antipodes, for example by separation of the dia-stereoisomeric salts thereof, for example by fractional crystallisation of the d- or 1-tartrates thereof. Any racemic intermediate or starting material can be separated in a similar manner. Finally, the compounds according to the invention are obtained either in free form or in the form of their salts. Any resulting base can be converted into a corresponding acid addition salt, preferably using a pharmaceutically acceptable acid or an anion-exchange preparation, or resulting salts can be converted into the corresponding free bases, for example using a stronger base, such as a metal or ammonium hydroxide or a basic salt, for example an alkali metal hydroxide or carbonate, or a cation-exchange preparation. A compound of formula I can also be converted into the corresponding metal or ammonium salts. These or other salts, for example the picrates, can also be used for the purification of resulting bases. The bases are converted into salts, the salts are - 25 - 22 5 6 4 9 separated and the bases are freed from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is mentioned in this Application, a corresponding salt of that compound is also included, provided that this is possible or appropriate under the given circumstances. The compounds, including their salts, can also be obtained in the form of their hydrates or contain other solvents used for the crystallisation. The pharmaceutical preparations according to the invention are those that are suitable for enteral, such as oral or rectal, and parenteral administration to mammals, including man, for the treatment or prevention of diseases that respond to the blocking of NMDA-receptors, such as, for example, cerebral ischaemia, muscular spasms (spasticity), convulsions (epilepsy), conditions of anxiety or manic conditions. They comprise an effective amount of a pharmacologically active compound of formula I or a pharmaceutically acceptable salt thereof, on its own or in combination with one or more pharmaceutically acceptable carriers. The pharmacologically active compounds of the invention can be used in the manufacture of pharmaceutical compositions that comprise an effective amount of the active compound on its own or in conjunction or admixture with excipients or carriers that are suitable for enteral or parenteral administration. Preferred are tablets and gelatin capsules that comprise the active constituent together with a) diluents, for example lactose, dextrose, sucrose, raannitol, sorbitol, cellulose and/or glycine, b) glidants, for example silicon dioxide, talc, stearic acid, the magnesium or calcium salt thereof and/or polyethylene glycol, for tablets also c) binders, for example magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired d) dispersing agents or disintegrators, for example starches, agar, alginic acid or the sodium salt thereof, or foaming mixtures and/or e) absorbents, colouring agents, flavourings and sweeteners. Injectable preparations are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously produced from fatty emulsions or suspensions. These compositions may be sterilised 22 5 6 and/or contain adjuvants, such as preservatives, stabilisers, wetting agents or etnulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. In addition they may also contain other therapeutically valuable substances. These preparations are manufactured according to conventional mixing, granulating or coating methods and contain approximately from 0.1 to 100 %, preferably approximately from 1 to 50 %, active constituent. A unit dose for a mammal weighing approximately from 50 to 70 kg may contain approximately from 1 to 500 rag, preferably approximately from 10 to 500 mg, of active constituent. The following Examples are intended to illustrate the invention and do not represent limitations. The temperatures are in degrees Celsius and all parts are quoted in the form of parts by weight. Unless stated otherwise, all evaporation is carried out under reduced pressure, preferably approximately from 2 to 13 Kilopascal (kPa). Example 1: E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester a) 5-(2-propenyl)-oxazoline-4-carboxylic acid ethyl ester (X) 1.6 g of red copper(I) oxide are introduced into 200 ml of benzene. A solution of 140 g of isocyanoacetic acid ethyl ester and 105 g of freshly distilled methacrolein in 200 ml of benzene is added dropwise to this suspension within a period of 10 minutes with vigorous stirring, during which time the reaction temperature is kept at between 30 and 32° by cooling with ice. When the addition is complete, the mixture is kept at 30-32° until the exothermic reaction subsides, and is then stirred at room temperature for one hour. After excess copper(I) oxide has been filtered off, the filtrate is concentrated by evaporation in vacuo at 30°. 600 ml of ether are added to the residue, which is then filtered over Celite and concentrated to dryness by evaporation in vacuo. In this manner, 5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester is obtained in the form of a colourless oil having a boiling point of 110-130° (5.3 Pa). 22 5 6 4 9 b) E-2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester (2) 139 g of 5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester are dissolved in 70 ml of tetrahydrofuran, and 27.4 g of water and 3.5 g of triethylamine are added thereto. The reaction mixture is stirred at 65-70° for 62 hours and, after cooling, is taken up in 200 ml of di-chloromethane. The solution is dried over 200 g of magnesium sulphate, filtered and concentrated by evaporation in vacuo. Purification of the viscous oil which remains by column chromatography (silica gel; hexane/ ethyl acetate 3:2) yields 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in the form of a diastereoisomeric mixture having a melting point of 67°. c) E-2-formylaniino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester (3) Under an argon atmosphere, 18.6 ml of thionyl bromide are added dropwise at 20°, within a period of 5 minutes, to a solution of 40.20 g of crude 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in 600 ml of 1,2-dichloroethane (slight cooling). After stirring for two hours at room temperature, 400 ml of water are added, the first 50 ml being slowly added dropwise. The mixture is stirred thoroughly for a further 15 minutes to complete the reaction. The organic phase is separated off and washed three times with ice-water and once with ice/saturated potassium bicarbonate solution (pH approximately 7.5). Drying over sodium sulphate and removal of the 1,2-dichloroethane by distillation in vacuo at 35° yields the crude bromide as intermediate, to which 160 ml of trilsopropyl phosphite are added at room temperature, and the mixture is then stirred at 75° (bath temperature) under a partial vacuum (approximately 13 kPa) for 17 hours. The excess trilsopropyl phosphite and other volatile by-products are then distilled off under a high vacuum (bath temperature 90°). Chromatography of the residue on ten times the amount by weight of silica gel (particle size 0.04-0.06 mm) using ethyl acetate as eluant yields E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester in the form of a light-yellow honey, IR (CH2C12): 3410 (NH); 1740 (CO ester); 1690 (CO amide); 1235 (P=0); 980-1015 (P-O-C).' - 28 - 22 5 6 4 d) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (4) 56.7 ml of trimethylbromosilane are added dropwise within a period of 15 minutes at 20° to a solution of 25.42 g of E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester in 102 ml of dry di~ chloromethane. After stirring at room temperature for 20 hours, 102 ml of ethanol are added dropwise within a period of 15 minutes, and the whole is stirred for a further 20 hours. The clear reaction solution is then completely concentrated by evaporation in vacuo. The residue is concentrated by evaporation a further three times in each case after the addition of 100 ml of toluene. The oily residue is dissolved in 102 ml of ethanol, and a solution of 102 nil of propylene oxide in 102 ml of ethanol is added dropwise thereto. The product, obtained in crystalline form, is filtered off after 2 hours (room temperature) and washed with ethanol and ether. After drying (80°, 4 hours) under a high vacuum, E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester is obtained in analytically pure form, m.p. 212° (decomp.). Example 2: E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester a) E-2-forjnylaraino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester Q) 100.5 g of 2-formylamino-3-hydroxy-4-methyl~4-pentenoic acid ethyl ester are dissolved in 1.5 litres of dichloroethane, and then 47 ml of thionyl bromide are added dropwise at 20-25° and the mixture is stirred at room temperature for one hour. 750 ml of water are added to the reaction mixture, which is then stirred vigorously for 10 minutes. The organic phase is separated off, extracted with 1 litre of ice-water, 1 litre of IN potassium hydrogen carbonate solution and a further 1 litre of ice-water, dried over magnesium sulphate and concentrated by evaporation. 50 ml of trimethyl phosphite are added directly to the resulting E-5-bromo-2-formylamino-4-methyl-3-pentenoic acid ethyl ester, a yellow oil, and the mixture is stirred at a bath temperature of 70° and approximately 15 kPa for 15 hours. The reaction mixture is degassed for 30 minutes under a water-jet vacuum and for one hour under a high vacuum at 40-50°. The resulting product is taken up in 600 ml of water and extracted three times with 500 ml of ethyl acetate each time. The - 29 - 22 5 6 4 9 combined organic phases are washed twice with 300 ml of water each time. All the aqueous phases are' combined, saturated with sodium chloride and extracted three times with 500 ml of dichloromethane each time. The combined organic phases are dried over magnesium sulphate and concentrated by evaporation. The product is chroraatographed over silica gel (ethyl acetate/isopropanol 7:2). In this^manner, E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester is obtained in the form of a yellow oil, 1H-NMR (DMSO): 1.82 (d, 3H, 4-CH3); 2.69 (d, 2H); 5.03 (m, 1H); 5.32 (m, 1H). b) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (2) 16.9 g of E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester are dissolved in 80 ml of dichloromethane under a nitrogen atmosphere, and 30 ml of trimethylbromosilane are added dropwise at approximately 25° within a period of 30 minutes. The mixture is stirred at room temperature for 20 hours, and then 80 ml of ethanol are added dropwise at approximately 25° within a period of 30 minutes. The mixture is then again stirred at room temperature for 22 hours and is then concentrated by evaporation. The residue is dissolved in 80 ml of ethanol, and 80 ml of propylene oxide in 80 ml of ethanol are added dropwise with slight cooling. The mixture is stirred at room temperature for one hour to complete the reaction, filtered and washed with ethanol and ether. In this manner there is obtained E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 215-217° (decomp.). Example 3: E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester a) E-2-formylamino-4-methyl-5-di(2-chloroethyl)phosphono-3- pentenoic acid ethyl ester (1_) 8.2 g of E-5-bromo-2-formylamino-4-methyl—3-pentenoic acid ethyl ester and 19 ml of tris-(2-chloroethyl)-phosphite are stirred at a bath temperature of 70° for 20 hours. The resulting mixture is chromatographed on silica gel using ethyl acetate and ethyl acetate/isopropanol (7:1) as eluant, and the product is crystallised from ethyl acetate/diethyl ether. In this manner there is obtained E-2-formylamino-4-methyl-5-di(2-chloro-ethyl)phosphono-3-pentenoic acid ethyl ester, m.p. 47-49°. - 30 - 225649 b) E-2-amino-4~methyl-5-phosphono-3-pentenoic acid ethyl ester (2) In a manner analogous to that described in Example 2, using 3 g of E-2-formylamino-4-methyl-5-di(chloroethyl)phosphono-3-pentenoic acid ethyl ester, there is also obtained E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 215° (decomp.). Example 4: E-2-aniino-4-phosphonoinethvl-3.6-heptadienoic acid a) 2-methylene-4-pentenealdehyde (].) 24.5 g of a 37 % aqueous formaldehyde solution are added to a mixture of 14.7 g of piperazine, 20.5 g of glacial acetic acid and 21.28 g of water, and the whole is stirred at room temperature for 10 minutes. While continuing stirring, 25.35 g of 4-pentenealdehyde are added, and the reaction mixture is heated at 75° for 3 hours. After cooling to room temperature, the organic phase is separated off and the aqueous phase is extracted three times with 50 ml of diethyl ether each time. The combined organic phases are washed three times with 50 ml of a saturated sodium bicarbonate solution each time, dried over magnesium sulphate and concentrated by evaporation in vacuo. Fractional distillation of the residue yields 2-methylene-4-pentenealdehyde in the form of a colourless oil, b.p. 65°/6.6 kPa. b) 5—[2—(1,4-pentadienyl)]-2-oxazoline-4-carboxylic acid methyl ester (2) By reaction of isocyanoacetic acid methyl ester with 2-methylene-4-pentenealdehyde in toluene in a manner analogous to that described in Example 1, and after subsequent purification by column chromatography (silica gel, ethyl acetate/hexane 1:4), 5-(2-(l,4-pentadienyl))-2-oxa-zoline-4-carboxylic acid methyl es£er is obtained in the form of a colourless oil, 1H-NMR (CDC13): 2.80 (d, 2H, CH2); 4.45 (dd, 1H, C(4)-H); 5.82 (m, 1H, C=CH-); 7.00 (d, 1H, C(2)-H). 8.1 g of 5—(2—(1,4-pentadienyl))-2-oxazoline-4-carboxylic acid methyl ester are dissolved in 20 ml of tetrahydrofuran, and 10 ml of water are added thereto. The reaction mixture is stirred at 75° for 1.5 hours and, after cooling, is concentrated by evaporation in vacuo. Crystallisation 22 5 6 ££ - 31 - of the resulting residue from isopropanol/hexane yields 2-formylamino-3-hydroxy-4-methylene-6-heptenoic acid methyl ester in the form of a diastereoisomeric mixture, m.p. 75-77°. c) E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl ester (3) 5.0 g of 2-formylamino-3-hydroxy-4-methylene-6-heptenoic acid methyl ester in 200 ml of dry tetrahydrofuran are cooled to -78°, and 20 ml of 1,5-hexadiene are added thereto. 9 ml of thionyl bromide are added slowly dropwise in such a manner that the reaction temperature does not exceed -50°. When the addition is complete, the reaction solution is heated to 0° within a period of approximately 3 hours and is stirred at that temperature for 3 hours. The solution is then poured onto 300 ml of a cold (5-10°) saturated sodium bicarbonate solution and extracted with diethyl ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation in vacuo. Purification by column chromatography (silica gel, ethyl acetate/hexane 1:1) yields E-2-formylamino-4-bromomethyl-3,6-hepta-dienoic acid methyl ester in the form of a colourless oil, 1H-NMR (CDC13): 3.20 (d, 2H, C(5)-H); 4.00 (s, 2H, CH2Br). d) E-2-formylamino-4~diethylphosphonomethyl-3,6-heptadienoic acid methyl eater (4) 3.7 g of E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl ester are dissolved in 37 ml of triethyl phosphite, and the mixture is heated at 75° for 8 hours. Excess triethyl phosphite is then distilled off under a high vacuum. Purification by column chromatography (silica gel, methanol/ethyl acetate 1:10) yields E-2-formylamino-4-diethylphosphono-methyl-3,6-heptadienoic acid methyl ester in the form of a colourless oil, 'H-NMR (CDCI3): 2.54 (d, 2H, P-CHZ); 3.10 (m, 2H, C(5)-H); 5.10 (m, 2H, C(7)-H); 5.37 (d, 1H, C(2)-H); 5.74 (m, 1H, C(6)-H). e) E-2-amino-4-phosphonomethyl-3,6-heptadienoic acid (5) 0.74 g of E-2-formylamino-4-diethylphosphonomethyl-3,6-heptadienoic acid methyl ester is dissolved in 12 ml of dichloromethane, and 0.7 ml of trimethyliodosilane is added dropwise thereto. After stirring at room temperature for 4 hours, IN sodium thiosulphate solution is added until - 32 - 22 5 6 4 9 the colour of the reaction solution becomes lighter. 10 ml of a 4.5N hydrochloric acid solution.are then added to the reaction mixture, which is then stirred at room temperature for 30 minutes. The aqueous phase is separated off, washed twice with 20 ml of dichloromethane each time, and concentrated by evaporation in vacuo. The residue is dissolved in 10 ml of 4.5N hydrochloric acid, stirred at room temperature for 16 hours, and then concentrated by evaporation in vacuo. The residue so obtained is taken up in 40 ml of ethanol and filtered until clear, and then 10 nil of propylene oxide/ethanol (1:1) are added dropwise. The resulting white precipitate is filtered off and purified by column chromatography (Dowex 50 x 8/H2O). Concentration yields E-2-amino-4-phosphonomethyl-3,6-hepta-dienoic acid in the form of a white crystallisate, m.p. 154-157°, 1H-NMR (D20): 2.64 (d, 2H, P-CH2); 3.15 (m, 2H, C(5)-H); 5.20 (m, 2H, C(7)-H); 5.50 (dd, 1H, C(3)-H); 5.90 <m, 1H, C(6)-H). Example 5; (2R)-2-amino-4-methyl-5-phosphono-3-pentenqic acid a) (L)-N-tert.butoxycarbonyl—serine-N-methoxy-N-methyl 541.6 ml of N-methylmorpholine are added within 27 minutes at -20° to -25° to ay solution of 1 kg of (L)-N-tert.butoxycarbonyl-serine in 1 litre of tetrahydrofurane. The reaction mixture is stirred for 15 minutes at this temperature. Then 699.6 ml of chloroformic acid iso-butyl ester and subsequently 445,8 ml of N-methoxy-N-methylamine are added within 42 and 40, resp. minutes. The reaction mixture is allowed to warm to room temperature and evaporated to dryness. The residue is dissolved in 3 litres of ethyl acetate. The solution is extracted with 3.5 litres of 2n-hydrochloric acid and subsequently with 3 1 of saturated aqueous sodium hydrogencarbonate solution. The water-layers are extracted with 3 1-litre ethyl acetate. All organic extracts are combined, washed with 2 litres of saturated sodium dichloride solution, dried over magnesium sulfate an evaporated at 50° to dryness. The residue is triturated with 3.5 litres of hexane with ice-cooling. The resulting white precipitate is filtrated off, washed with 1 1 of hexane and dried under reduced pressure to yield 781 g 2, m.p. 116-117°; calculated for C11H20N2O5 C 48.38 %, H 8.12 % N 11.28 %; found C 48.28 %, H 8.02 %, N 11.32 %. 22 5 6 A 9 b) (L)-3-tert.butoxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylic acid-N-methoxy-N-methyl-amide (2) A mixture of 781 g of 1_, 3.3 litres of acetone dimethylacetal and 42 g of pyridinium(toluol-4-sulfonate) are warmed to 72° and refluxed for 17 hours. After addition of additional 20 g of pyridinium(toluol-4-sulfonate) heating to boil is continued for additional 9 hours while gradually destilling of approximately 750 ml of solvent and adding 700 ml of acetone dimethylacetal. All volatile constituents we destilled off. The residue is dessolved in 2 litres of diethyl ether and extracted twice with 1 litre and 0.5 litre of n-hydrochloric acid, once with 0.3 litre of saturated sodium hydrogencarbonate solution and once with 0.3 litre of saturated sodium chloride solution. The aqueous extracts we re-extracted twice with 0.5 litre either time of diethyl ether. All organic extracts are combined, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved hot in a 9:l-mixture of hexane and diethyl ether. After addition of additional 600 ml of hexane and 50 ml of diethyl ether, the reaction mixture is cooled down while diluting a crystallisation with 1.1 litre of hexane. The precipitate formed is filtered off, washed with hexane and dried under reduced pressure at 40° yielding 640 g of 2; m.p. 67-68°; calculated for Ci3H2<,N205 C 54.15 %, H 8.39 %, N 9.72 %; found C 53.96 %, H 8.37 %, N 9.91 %. c) (4S)-2,2-dimethyl-4-formyl-3-oxazolidine-carboxylic acid tert.butyl ester (3) 2.53 g of lithium aluminium hydride are added with cooling to maintain a temperature of 5 to 15° to 28.8 g of 2, dissolved in 350 ml of diethyl ether. After stirring at 5° for 1.5 hours a solution of 5.77 g of sodium hydrogen sulfate is added slowly to keep the reaction temperature at 15° (40 minutes). The suspensions formed is filtered clear and the solid portion is washed with ether. The filtrate is washed, with cooling, twice with 200 ml each of n-hydrochloric acid, twice with 150 ml each of 5 % sodium hydrogencarbonate solution and dried with 100 ml of saturated sodium chloride solution. The aqueous extracts are re-extracted with ether and all organic extracts are combined, dried over sodium sulfate and evaporated. The residue is distilled at 0.4 ml yielding 17.78 g of 3; - 34 - 22 5 6 4 9 b.p. 85-90°, [a]D - -94 (c=l, CHC13); calculated for CnHigNOi, C 57.63 %, H 8.35 % N 6.11 %, 0 27.91%; found C 57.59 %, H 8.54 %, N 6.17 %, 0 27.74 %. d) 3-((4'R)-N-tert.-butoxycarbonyl-21,21-dimethyl-4'-oxazolidinyl)-2-methylpropenoic acid ethyl ester (4) A solution of 39.5 g of (4S)-2,2-dimethyl-4-formyl-3-oxazolidinecarbo-xylic acid tert.-butyl ester 3 in 200 ml of dichloromethane is added dropwise within a period of 2 hours to a solution of 68.7 g of 1-ethoxy-carbonylethylidenetriphenylphosphorane in 900 ml of dichloromethane. After stirring at room temperature for 6 hours, the mixture is cooled to 10° and there are then added dropwise within a period of 15 minutes 530 ml of a 10 % aqueous sodium hydrogen phosphate solution. After stirring at 15° for 30 minutes, the organic phase is separated off and the aqueous phase is extracted with 250 ml of dichloromethane. The organic phases are dried over magnesium sulphate and concentrated by evaporation. The residue is stirred with 70 ml of ether. The suspension is filtered and the filtration residue is washed with ether. The filtrate is concentrated by evaporation and the residue is separated by chromatography on silica gel. Elution with hexane/ethyl acetate 9:1 yields, in addition to 2.32 g of cis-isomer and 2.21 g of mixed fraction (cis/trans - 38:62), 45.4 g of 4. lH-NMR (60 MHz, CDC13, trans-isomer): inter alia 4.7 ppm (m, H-C(4')); 6.7 ppm (d, J=9, H-C(3)). XH-NMR (60 MHz, CDC13, cis-isomer): inter alia 5.2 ppm (m H-C(4')); 6.08 ppm (d, J=7, H~C(3)). e) (4R)-2,2-dimethyl-4-(3'-hydroxy-2'-methylprop-1'-enyl)-oxazolidine-3-carboxylic acid tert.-butyl ester (5) 389 ml of a 1 molar solution of diisobutylaluminium hydride in hexane are added within a period of 15 minutes to a solution, cooled to 3°, of 48.7 g of 4 in 1 litre of dry diethyl ether. The temperature of the mixture is allowed to rise to 11°, and there are then added thereto, while cooling with ice, 100 ml of ethyl acetate followed by 50 ml of 2N sodium hydroxide solution. The temperature of the mixture is allowed to rise to approximately 28°, without cooling, and then a further 7 ml of 2N sodium hydroxide solution are added. The mixture is stirred at room - 35 - 22 5 6 A 9 temperature for 15 hours, and then sodium sulphate is added and the whole is filtered. Concentration of the filtrate by evaporation yields 42.1 g of crude 2. A sample (0.97 g) is purified by chromatography on 40 g of silica gel. Elution with hexane/ethyl acetate 3:1 yields 0.74 g of 5. 1H-NMR (300 MHz, DMSO-d6): inter alia 3.52 (dxd, J=9 and 3) and 4.02 (dxd, J«=9 and 6) (2H-C(5)); 3.78 (ra, 2H-C(3')); 4.54 (m, H-C(4)); 4.81 (t, J=6, OH); 5.33 (d, J=9, H-C(l')). r f) (4R)-2,2-dirnethyl-4-(3'-broroo-2'-methylprop-1'-enyl)-oxazolidine-3-carboxylic acid tert.-butyl ester (6) 47.6 g of triphenylphosphine are added at 0° to a solution of 41.0 g of 5 and 60.2 g of tetrabromomethane in 1 litre of dry diethyl ether. After 30 minutes, the cooling bath is removed and the mixture is stirred at room temperature for 17 hours. 20 g of tetrabromomethane and 15.9 g of triphenylphosphine are added, and the mixture is stirred at room temperature for 2 hours. The white suspension is filtered and the filtration residue is washed with ether. The residue remaining after the filtrate has been concentrated by evaporation is chromatographed on 0.9 kg of silica gel. Elution with hexane/ethyl acetate 9:1 yields 30.59 g of 6, m.p. 62-65°C. 1H-NMR (300 MHz, DMSO-ds): inter alia 3.55 (dxd, J-9 and 2) and 4.04 (dxd, J=9 and 6) (2H-C(5)); 4.15 (m, 2H-C(3')); 4.49 (m, H-C(4)); 5.65 (d, J=9, H-C(l')). g) (4R)-2,2-dimethyl-4-(3'-dimethylphosphono-2'-methylprop-1'-enyl)-oxa-zolidine-3-carboxylic acid tert.-butyl ester (2) A solution of 13.4 g of 6 in 70 ml of trimethyl phosphite is stirred at 80° for 15 hours. The excess phosphite is evaporated off at 24 mbar. Drying of the residue under a high vacuum yields 14.3 g of crude 1_. 1H-NMR (300 MHz, DMSO-ds): inter alia 2.63 (d, J=23, 2H-C(3')); 3.59 (d, J=ll, (CH30)2PO). h) N-((2R)-5-dimethylphosphono-l-hydroxy-4-methyl-3-penten- 2-yl)-carbaraic acid tert.-butyl ester (8) 7 g of Amberlyst® 15 (H+ form, 20-50 mesh) are added to a solution of 14.0 g of T_ in 250 ml of methanol. The mixture is stirred at room temperature for 17 hours and filtered, and the filtrate is concentrated - 36 - 22 5 6 A 9 by evaporation. Chromatography of the residue on 0.33 kg of silica gel using ethyl acetate/methanol 10:1 as eluant yields 10.6 g of 8. 1H-NMR (300 MHz, DMSO-ds): inter alia 4.60 (t, J-6, OH); 6.67 (d, J=7, NH). i) (2R)-2-tert.-butoxycarbonylamino-5-dimethylphosphono-4- methyl-3-pentenoic acid (9) i,a) Oxidation with chromosulphuric acid To a solution of 0.323 g of 8 in 10 ml of acetone there is added 0.77 ml of a solution that is 3.25 molar in chromium trioxide and 5.29 molar in sulphuric acid. The mixture is stirred at room temperature for 40 minutes and then there are added 2 ml of isopropanol followed by 50 ml of ethyl acetate. 0.1 g of active carbon is then added to the mixture. After 10 minutes, the mixture is filtered and washed with 50 ml of ethyl acetate. The filtrate is extracted three times with 50 ml of 10 % sodium hydrogen carbonate solution each time. The aqueous phase is extracted twice with 40 ml of ethyl acetate each time, acidified to pH 1 using 2N hydrochloric acid, and then extracted three times with 70 ml of ethyl acetate each time. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. Chromatography on 8 g of silica gel using chloroform/ methanol/acetic acid 18:1:1 as eluant yields 65 mg of 9. 1H-NMR (300 MHz, DMSO-ds): 1.37 (s, (CH3)3C0); 1.82 (d, J-2, CH3-C(4)); 2.63 (d, J«22, 2H-C(5)); 3.61 (d, J-ll, (CH30)2P0); 4.62 (t, J=8, H-C(2)); 5.25 (m, H-C(3)); 7.18 (d, J-8, NH); 11.7-12.5 (C02H). i,b) Oxidation with oxygen/platinum To a solution of 0.66 g of 8 and 0.2 g of sodium hydrogen carbonate in 20 ml of water and 2 ml of dioxan there is added a suspension of platinum prepared by hydrogenation of 313 mg of platinum oxide in 50 ml of water. In a cylindrical apparatus, oxygen is passed through the mixture from bottom to top at 55° by means of a glass frit, with vigorous stirring. The mixture is filtered and washed with water, and the filtrate is extracted five times with 100-150 ml of ethyl acetate each time. Concentration of the extracts by evaporation yields 220 mg of educt 5. 1 g of Amberlyst® 15 (strongly acidic) is added to the aqueous phase, which is - 37 - 22 5 6 4 9 then filtered and concentrated by evaporation in vacuo at 40°. Purification as in f,a) yields 156 mg of 9. 'H-NMR (300 MHz, CDC13): 1.43 (b, (CH3)3C); 1.96 (d, J=3 Hz, CH3-C(4)); 2.55 and 2.71 (2 dxd, J=22 and 15, 2H-C( 5))', 3.75 and 3.76 (2 d, J-ll, 2 0CH3); 4.97 (m, H-C(2)); 5.25-5.45 (m, NH and H-C(3)). j) (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (10) 0.71 ml of trimethylsilyl bromide is added at 0° to a solution of 123 mg of 9 in 3 ml of dichloromethane. After stirring at 0° for 4 hours, 20 ml of water are added. After 30 minutes, the dichloromethane phase is separated off and washed three times with 15 ml of water each time. The aqueous phases are extracted three times with 20 ml of dichloromethane each time and concentrated by evaporation in vacuo. The residue is dissolved in 10 ml of 5N hydrochloric acid and is then stirred for 48 hours, diluted with 20 ml of water and extracted three times with 20 ml of dichloromethane each time. The aqueous phase is concentrated by evaporation in vacuo, and the residue is dried under a high vacuum and dissolved in 3 ml of ethanol, and then approximately 1 ml of propylene oxide is added dropwise thereto. The suspension is filtered. Washing of the filtration residue with ethanol and drying under a high vacuum at room temperature yields 62 mg of 10, m.p. 165°C (decomposition). In order to analyse the purity of the enantiomer, a sample is derivatised to the amide with (R)-(+)-raethoxytrifluoromethylphenylacetic acid chloride. lH-NMR analysis (300 MHz) by integration of the 0CH3 signals gives £95 % (2R)-isomer (3.44 ppm) and < 5 % (2S)-isomer (3.37 ppm). Example 6: (2R)-2-aniino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester a) (4R)-2,2-dimethyl-4-(3'-diisopropylphosphono-2,-methyl- prop-1'-enyl)- oxazolidine-3-carboxylic acid tert.-butyl ester O) A solution of 6.68 g of bromide according to Example 5f in 14.8 ml of dry triisopropyl phosphite is heated at 70°C for 17 hours under a pressure of - 38 - 22 5 6 100 mbar. The mixture is concentrated by evaporation at 0.4 mbar/70'. Chromatography on 350 g of silica gel (eluant hexane/ethyl acetate 1:1) yields 8.28 g of 1., value « 0.077. b) N-((2R)-5-diisopropylphosphono-l-hydroxy-4-methyl-3-penten-2-yl)-carbamic acid tert.-butyl ester (2) 2.25 g of Amberlyst® 15 (H+ form, 20-50 mesh) are added to a solution of 4.49 g of phosphonic acid ester 1_ according to a) in 100 ml of methanol. The mixture is stirred at room temperature for 2 days and is filtered, and the filtrate is concentrated by evaporation. Chromatography of the residue on 125 g of silica gel (eluant ethyl acetate/methanol 20:1) yields 2.44 g of 2. c) (2R)-2-tert.-butoxycarbonylamino-5-diisopropylphosphono-4-methyl-3-pentenoic acid (3) To a solution of 1.6 g of alcohol 2 according to b) in 60 ml of acetone there are added at 0-5° 3.3 ml of a solution that is 3.25 molar in chromium(VI) oxide and 5.29 molar in sulphuric acid. The mixture is stirred at 0° for 6 hours and at room temperature for 12 hours. After the addition of 5 ml of isopropanol and 40 ml of 20 % sodium chloride solution, the mixture is stirred for 10 minutes and is then extracted continuously with methyl acetate for 15 hours in a Kutscher-Steudel apparatus. The organic phase is dried over sodium sulphate and concentrated by evaporation, and the residue is chromatographed on 75 g of hexane/ethyl acetate/acetic acid 16:10:1. This yields 0.92 g of 3, [<x]q " -94.5° (c = 1.2, CHCls). 1H-NMR (300 MHz, CDC13): 1.2-1.3 (4d, (2-prop0)2); 1.4 (s, (CH3)3CO); 1.95 (d, J=3, CH3-C(4)); 3.5 and 3.62 (2 dxd, J-23 and 15, 2H-C(5)); 4.66 (m, (2-propO)2); 4.92 (m, H-C(2)); 5.30 (m, H-C(3)); 5.42 (d, J-7, NH); 9.0-10.0 (broad, C02H). d) (2R)-2-tert.-butoxycarbonylamino-5-diisopropylphosphono-4-methyl-3-pentenoic acid ethyl ester (4) 0.09 g of l-amino-l-chloro-N,N,2-trimethylpropene is added at 0-5° to a solution of 0.2 g of acid 3 according to c) in 15 ml of dry dichloromethane. After stirring for 30 minutes at 0°, 0.4 g of pyridine in 5 ml of ethanol is added. The mixture is stirred further at 0° for 90 minutes - 39 - 22 5 6 4 9 and at room temperature for 15 hours, and is then diluted with 20 ml of dichloromethane and washed twice with 20 ml of water each time. The organic phase is dried using sodium sulphate, concentrated by evaporation and chromatographed on 25 g of silica gel. Elution with ethyl acetate/ methanol 10:1 yields 0.12 g of 4. 1H-NMR (300 MHz, CDC13): 1.2-1.4 <m, 2 (CHi)2CH0, CHaCHaO): 1.45 (s, (CH3)3CO); 1.98 (d, J*3, CH3-C(4)); 2.55 (d, J=23, 2H-C(5)); 4.2 <m, CH3CH2Q); 4.69 (m, 2 (CH3)2CH0); 5.0 (m, H-C(2)); 5.16 (m, H-C(3), NH). e) (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (5) 0.11 ml of trimethylsilyl bromide is added at 0° to a solution of 0.1 g of ester 4 according to d) in 10 ml of dichloromethane. The mixture is stirred at 0° for 4 hours and at room temperature for 15 hours. 20 ml of water are added, the mixture is stirred for 15 minutes, and then the aqueous phase is separated off and the water is evaporated off under a high vacuum. The residue is dissolved twice in 5 ml of ethanol each time, concentrated by evaporation and again dissolved in 5 ml of ethanol. 0.5 ml of propylene oxide is added. The precipitate is filtered off, washed with ethanol and dried under a high vacuum for 15 hours; 48 mg of 5, [a)D - -75° (c-0.5, Ha0). In order to analyse the purity of the enantiomer, a sample is derivatised to the amide dimethyl ester with (R)-(+)-methoxytrifluoromethylphenyl-acetic acid chloride followed by diazomethane. 1H-NMR analysis (300 MHz) by integration of the OCH3 signals gives i 97 % (2R)-isomer (3.5 ppm) and £ 3 % (2S)-isomer (3.37 ppm). Example 7: (2R)-2-amino-4-methyl-7-phosphono-3-heptenoic acid (10) a) (4R)-2,2-dimethyl-4-(1'-hydroxy-2'-methylprop-2'-enyl)-oxazolidine- 3-carboxylic acid tert .-butyl ester (1_) 45 ml of a 1.1 molar solution of isopropenylmagnesium bromide are added dropwise at 0-5° within a period of 25 minutes to a solution of 6.9 g of (4S)-2,2-dimethyl-4-formyloxazolidine-3-carboxylic acid tert.-butyl ester (according to Example 5c)) in 60 ml of dry tetrahydrofuran. The mixture is stirred at 0° for 45 minutes, allowed to warm up to room temperature - AO 225649 and cooled again to 10°, and then 90 ml of buffer solution (1 molar, phosphate, pH 7) are added. The mixture is filtered and the filtrate is extracted twice with 100 ml of ethyl acetate each time. The organic phase is washed twice with 50 ml of water each time and with saturated sodium chloride solution, and is dried with sodium sulphate. Removal of the solvent by evaporation yields 8 g of 1, a diastereoisomeric mixture. Separation may be effected by chromatography on silica gel using hexane/ ethyl acetate 4:1 and yields crystalline (1'S)-threo-epimer (R^ value: 0.2) and (1'R)-erythro-epimer (R^ value: 0.16) in a ratio of approximately 1:2. b) (4R)-4-( 1'-acetoxy-21-methylprop-2'-enyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert.-butyl ester (2) 60 ml of acetic anhydride are added dropwise at 0-5° within a period of 10 minutes to a solution of 15.6 g of the epimer mixture according to a) in 60 ml of pyridine. The mixture is stirred at room temperature for 15 hours and diluted with 0.5 litre of diethyl ether, and then 200 ml of 2N hydrochloric acid are added while cooling with ice. The organic phase is washed with 250 ml of 2N hydrochloric acid and twice with 200 ml of 10 % sodium carbonate solution each time. Drying over sodium sulphate and removal of the solvent by evaporation yields 15.4 g of 2. c) (4R)-4-(4'-carboxy-2'-methylbutenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert.-butyl ester (3) 34.5 ml of a 1.6 molar solution of butyllithium in hexane are added at 0° to a solution of 5.25 g of diisopropylamine in 200 ml of dry tetrahydro-furan. The mixture is cooled to -75°C and a solution of 15 g of acetate 2 according to b) in 100 ml of tetrahydrofuran is added dropwise within a period of 10 minutes, and after 5 minutes a solution of 8 g of tert.-butyldimethylsilyl chloride in 30 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2-(lH)-pyrimidinone is added. The mixture is allowed to warm up to room temperature and is then heated under reflux for 2 hours and cooled to room temperature. 230 ml of 45 % ammonium fluoride solution are added, and the whole is stirred at room temperature for 20 hours and is then concentrated by evaporation. 150 ml of IN sodium hydroxide solution are added, while cooling with ice, to the oily residue which is obtained - 41 - 22 5 6 after concentration of the organic phase by evaporation, and the mixture is extracted twice with 200 ml of dichloromethane each time. The aqueous phase is acidified with 300 ml of 20 % citric acid solution and is extracted three times with 300 ml of dichloromethane each time. The organic phases are washed with 20 % sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. Chromatography of the residue on 50 g of silica gel using hexane/ethyl acetate 1:1 as eluant yields 11 g of solid 3. d) (4R)-4-(4'-carbaethoxy-2'-methylbutenyl)-2,2-dimethyl-oxazolidine-3-/ carboxylic acid tert.-butyl ester (4) d,a) Starting from the acid 3 3.9 ml of l-amino-l-chloro-N,N,2-trimethylpropene are added dropwise within a period of 10 minutes to an ice-cooled solution of 7.8 g of carboxylic acid 3 according to c) in 100 ml of dry dichloromethane. After 30 minutes at 0°, a solution of 2.2 g of pyridine in 80 ml of ethanol is added within a period of 20 minutes. After stirring at room temperature for 12 hours, the mixture is diluted with 100 ml of dichloromethane and washed twice with 100 ml of water each time. The organic phase is dried over sodium sulphate and concentrated by evaporation. Chromatography of the residue on silica gel using hexane/ethyl acetate 10:1 yields 6.5 g of ester 4, [«]jj ■ +6.17° (c=*l, CHCI3). C1BH31NO5, calculated: C 63.32 %, H 9.15 %, N 4.10 %; found: C 63.4 %, H 9.2 %, N 4.5 %. d,b) Starting from the epimer mixture 1 A solution of 8 g of alcohol 1^ according to a) and 0.05 ml of propionic acid in 10.5 ml of orthoacetic acid triethyl ester is heated at 135-140° for 14 hours, with ethanol slowly being distilled off. The whole is concentrated by evaporation at 40° under a high vacuum. Chromatography of the residue on silica gel using hexane/ethyl acetate 10:1 yields 8 g of 4. - 42 - 225649 e) (4R)-2,2—dimethyl-4-(5'-hydroxy-21-methylpent-1'-enyl)-oxazolidine-3-carboxylic acid tert.-butyl ester (5) 1.61 g of lithium aluminium hydride are added in portions at 0° to a solution of 14.5 g of 4 according to d) in 250 ml of absolute diethyl ether. The mixture is stirred at 0-2° for 18 hours, and a solution of 5 g of potassium hydrogen sulphate in 60 ml of water is added while cooling with acetone/dry ice. The mixture is filtered and washed four times with 200 ml of diethyl ether each time. The organic phase is washed three times with 80 ml of IN hydrochloric acid each time, three times with 80 ml of saturated sodium bicarbonate solution each time, and twice with 200 ml of saturated sodium chloride solution each time, and is then dried over sodium sulphate and concentrated by evaporation. Chromatography on silica gel using hexane/ethyl acetate 1:1 yields 11.3 g of 5, Ci6H29N0i), calculated: C 64.19 %, H 9.77 %, N 4.68 %; found: C 63.6 %, H 9.8 %, N 4.7 %. f) (4R)-4-(5'-bromo-2'-methylpent-1'-enyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert.-butyl ester (6) 4.87 g of tetrabromomethane, 3.85 g of triphenylphosphine and 0.6 ml of pyridine are added at 0-2° to a solution of 4.4 g of alcohol 5 according to e) in 200 ml of dichloromethane. After 12 hours at 0-2°, a further 1 g of tetrabromomethane and 1 g of triphenylphosphine are added and the mixture is stirred at 0° for 6 hours. The mixture is concentrated by evaporation, taken up in ethyl acetate, filtered and concentrated. Chromatography on silica gel using hexane/ethyl acetate 10:1 yields 4.5 g of 6, Ci6H28N03Br; calculated: C 53.04 %, H 7.79 %, N 3.87 %, Br 22.06 %; found: C 53.1 %, H 7.7 %, N 3.9 %, Br 21.6 %. g) (4R) -2,2-dimethyl-4-(21-methyl-5'-diisopropylphosphono-pent-1'-enyl)-oxazolidine-3-carboxylic acid tert.-butyl ester (7) A solution of 10.9 g of bromide 6 in 22 ml of trilsopropyl phosphite is heated at 135-140° for 24 hours at 100 mbar. The excess reagent is evaporated off at 0.1 mbar/60°. Chromatography of the residue on silica gel using hexane/ethyl acetate 1:1 yields 10.7 g of 22 5 6 4 - 43 - h) N-((2R)-l-hydroxy-4-methyl-7-diisopropylphosphonohept-3- en-2-yl)-carbamic acid tert.-butyl ester (8) 3 g of Amberlyst® 15 (H+ form) are added to a solution of 3 g of 1_ according to g) in 100 ml of ethanol. The mixture is stirred at room temperature for 20 hours, filtered, concentrated by evaporation and chromatographed on 50 g of silica gel. Elution with ethyl acetate/ methanol 10:1 yields 2.3 g of 8, * -5.9° (c=l, CHCI3). C19H38NO6P; calculated: C 56.0 %, H 9.4 %, N 3.44 %, P 7.6 %; found: C 55.4 %, H 9.3 %, N 3.4 %, P 7.3 %. i) (2R)-2-tert.-butoxycarbonylamino-4-methyl-7-diisopropylphosphono-3-heptenoic acid (9) i,a) Oxidation with chromic acid 0.84 ml of a solution which is 3.25 molar in chromium trioxide and 5.29 molar in sulphuric acid is added dropwise at 0-5° to a solution of 0.5 g of alcohol 8 according to h) in 15 ml of acetone. The mixture is stirred at 0° for 30 minutes and at room temperature for 35 minutes, and then 4 ml of isopropanol, 80 ml of ethyl acetate and 30 ml of 20 % sodium chloride solution are added thereto, and the mixture is filtered. The aqueous phase is extracted three times with 20 ml of ethyl acetate each time. The organic phase is dried over sodium sulphate and concentrated by evaporation. Chromatography on 20 g of silica gel using hexane/ethyl acetate/acetic acid 16:10:1 yields 0.34 g of 9, [aJp * -35.25° (c=1.39, CHCI3), 13C-NMR (75 MHz, CDC13): 173.8 <C02H); 155.0 (0C0N); 140.4 (C(4)); 121.1 (C(3)); 79.5 (OC(CH3)3); 70.3 (0CH); 52.1 (C(2)); 39.7 (d, J=18, C(5)); 28.3 ((CH3)3C); 25.7 (d, J=142, C(7)); 24.0 ((CH3)2CH); 20.2 (d, J»5, C(6)). 1,b) Oxidation with platinum/oxygen To a solution of 3 g of alcohol 8 according to h) in 105 ml of dioxan there is added at 55° a suspension of platinum in 45 ml of water prepared by hydrogenation and degassing of 1 g of platinum oxide in 45 ml of water. Oxygen is passed through the mixture at 55-60° with vigorous stirring (approximately 1900 rpm). The mixture is filtered through Celite® and washed twice with 80 ml of water each time, and the filtrate 225649 is concentrated by evaporation at 40° under a high vacuum. The resulting product is dissolved in 200 ml of water, and 1 g of sodium bicarbonate and 50 ml of 20 % sodium chloride solution are added and the mixture is extracted three times with 100 ml of ethyl acetate each time. The organic phases are dried over sodium sulphate. Filtration and concentration by evaporation yield 1.8 g of educt 8. The aqueous phase is acidified with approximately 20 ml of IN sulphuric acid and extracted five times with 120 ml of ethyl acetate each time. Drying over sodium sulphate, concentration by evaporation and chromatography of the residue according to i,a) yield 0.8 g of acid 9. j) (2R)-2-amino-4-methyl-7-phosphono-3-heptenoic acid (10) A solution of 3.3 g of acid 9 according to i) and 2.6 g of N,0-bis-tri-methylsilylacetamide is stirred at room temperature for one hour under argon. After the addition of 4.4 g of trimethylbromosilane, the mixture is stirred for 24 hours. The reaction mixture is added dropwise at 0° to 400 ml of water, and the whole is stirred for 30 minutes. The organic phase is separated off and washed three times with 50 ml of water each time. The aqueous phases are extracted three times with 30 ml of dichloromethane each time and concentrated to 10 ml at 40° under a high vacuum. Chromatography on 20 ml of Dowex® 50 Wx8 using water as eluant, and lyophilisation of the eluate yield 0.4 g of 10 in the form of an amorphous white powder having a melting point of 252° (decomposition); [ot]D « -86.5° (c»l, H20); C8Hi6N05P.1 H20; calculated: C 37.05 %, H 6.9 %, N 5.5 %; found: C 36.3 %, H 6.5 %, N 5.6 %. In order to analyse the purity of the enantiomer, a sample is derivatised to the amide with (R)-(+)-methoxytrifluoromethylphenylacetic acid chloride. 1H-NMR analysis (300 MHz) by integration of the OCH3 signals gives 2 94 % (2R)-isomer (3.24 ppm) and £ 6 % (2S)-isomer (3.17 ppm). - 45 - 22 5 6 4 9 Example 8: (2R)-2-amino-7-phos-phono-3-heptenoic acid a) (4R)-2,2-dimethyl-4-( 1 '-hydroxyprop-21 -enyl)-oxazol-idine-3-carboxylic acid tert.-butyl ester (1_) 60 ml of a 2.4M solution of vinylmagnesium bromide in tetrahydrofuran are added at 0-5° within a period of 30 minutes to a solution of 25 g of (4S)-2,2-dimethyl-4-formyloxazolidine-3-carboxylic acid tert.-butyl ester (according to Example 5c) in 300 ml of dry tetrahydrofuran. The mixture is stirred at 0° for one hour, allowed to warm up to room temperature and then stirred at room temperature for a further one hour. 300 ml of buffer solution (1 molar, phosphate, pH 7) are added while cooling to 10°. After 10 minutes, the mixture is filtered, extracted twice with 150 ml of ethyl acetate each time and washed twice with 100 ml of water each time. The aqueous phase is extracted twice with 100 ml of ethyl acetate each time. The organic extracts are dried over sodium sulphate and concentrated by evaporation. Chromatography of the residue on silica gel using hexane/ ethyl acetate 4:1 yields 24.2 g of epimer mixture _1; C13H23NO1,; calculated: C 60.68 %, H 9.01 %, N 5.44 %; found: C 60.7 %, H 9.1 %, N 5.6 %. b) (4R)-4-(4'-ethoxycarbonylbutenyl)-2,2-dimethyloxazol-idine-3-carboxylic acid tert.-butyl ester (2) A solution of 22.5 g of alcohol 1_ according to a) and 0.3 ml of propionic acid in 38.5 ml of orthoformic acid triethyl ester is heated at 135-140°C for 4 hours, with ethanol slowly being distilled off. The mixture is concentrated by evaporation at 50° under a high vacuum and chromato-graphed on 300 g of silica gel. Elution with hexane/ethyl acetate 4:1 yields 23.9 g of 2, [<*]q = -10.0° (c=1.5, CHCI3); C17H29NO5; calculated: C 62.36 %, H 8.93 %, N 4.28 %; found: C 62.2 %, H 8.9 %, N 4.4 %. c) (4R)-2,2-dimethyl-4-( 5'-hydroxypentenyl)-oxazolidine-3-carboxylic acid tert.-butyl ester (3) 2.7 g of lithium aluminium hydride are added in portions at 0-2° to a solution of 23.5 g of 2 according to b) in 550 ml of absolute diethyl ether. After stirring at 0-2° for 3 hours, a solution of 25 g of potassium hydrogen sulphate in 250 ml of water is added dropwise with - 46 - 225649 cooling. The mixture is filtered through Celite® and washed thoroughly with diethyl ether. The organic phase is washed twice with 200 ml of IN hydrochloric acid each time and twice with 250 ml of 10 % sodium bicarbonate solution each time. The aqueous phases are extracted twice with 100 ml of ether each time. The organic phases are washed with 20 % sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. Chromatography on silica gel using hexane/ethyl acetate as eluant yields 18.6 g of 3, [«Jq " -10.1° (c=1.4, CHCI3); CisI^NOi,; calculated: 63.13 %, H 9.54 %, N 4.91 %; found: C 63.0 %, H 9.5 %, N 5.0 %. d) (4R)-4-(5'-bromopentenyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert.-butyl ester (4) 7 ml of pyridine are added dropwise at 0° to a solution of 18.5 g of alcohol 3 according to c), 28.2 g of tetrabromomethane and 22.3 g of triphenylphosphine in 600 ml of dichloromethane. The mixture is stirred at 0-2° for 12 hours, concentrated by evaporation, taken up in 150 ml of ethyl acetate, filtered, concentrated to 50 ml and chromatographed on 200 g of silica gel. Elution with hexane/ethyl acetate 10:1 yields 19.9 g of bromide 4, («]jj = -18.9° (c=l, CHCI3); CisH26N03Br; calculated: C 51.73 %, H 7.53 %, N 4.02 %, Br 22.94 %; found: C 51.7 %, H 7.7 %, N 4.2 %, Br 23.0 %. e) (4R)-2,2-dimethyl-4-(51-di-2-propylphosphonopentenyl)-oxazolidine-3-carboxylic acid tert.-butyl ester (5) A solution of 19.9 g of bromide 4 according to d) in 60 ml of triiso-propyl phosphite is heated at 130-135° for 20 hours at 100 mbar. The excess reagent is distilled off at 60°/0.1 mbar, and the residue is chromatographed on 250 g of silica gel. Elution with hexane/ethyl acetate 1:1 yields 20.6 g of phosphonic acid ester 5, [ot}^ =« -8.6° (c=0.8, CHCI3); C21Hi,oN06P; calculated: C 58.18 %, H 9.30 %, N 3.23 %, P 7.15 %; found: C 57.4 %, H 9.3 %, N 3.2 %, P 7.5 %. - 47 - 22 5 6 4 9 f) N-((2R)-l-hydroxy-7-(diisopropylphosphonohept-3-en-2-yl)-carbamic acid tert.-butyl ester (6) A solution of 20.6 g of 5 according to e) in 800 ml of methanol is stirred at room temperature for 20 hours with 30 g of Amberlyst® 15 (H+ form). The mixture is filtered, washed with methanol, concentrated by evaporation and chromatographed on 100 g of silica gel. Elution with ethyl acetate yields 14.8 g of 6, [ct]p = -3.6° (c=1.5, CHCI3); Ci8H36K06P; calculated: C 54.95 %, H 9.22 %, N 3.56 %, P 7.87 %; found: C 53.6 %, H 9.0 %, N 3.4 %, P 9.0 %. g) (2R)-2-tert.-butoxycarbonylamino-7-diisopropylphosphono- 3-heptenoic acid (7) To a solution of 7.4 g of alcohol 6 according to f) in 300 ml of acetone there are added dropwise at 0-2°C, within a period of 20 minutes, 15 ml of a solution which is 3.25 molar in chromium trioxide and 5.29 molar in sulphuric acid. The mixture is stirred at 0-2° for 2 hours and at room temperature for 4 hours, and then 30 ml of isopropanol, 300 ml of ethyl acetate and 200 ml of 20 % sodium chloride solution are added. The aqueous phase is extracted three times with 250 ml of ethyl acetate each time, and the organic phases are dried over sodium sulphate and concentrated by evaporation. Chromatography on 200 g of silica gel using hexane/ethyl acetate/acetic acid 16:10:1 yields 4.55 g of acid [oe]^ « -24.9° (c=0.8, CHCls). h) (2R)-2-amino-7-phosphono-3-heptenoic acid (8) A solution of 3.1 g of acid J. and 3 ml of N,0-bis-trimethylsilylacetamide in 200 ml of dry dichloromethane is stirred at room temperature for one hour. 3.5 ml of trimethylbromosilane are added, and the mixture is stirred at room temperature for 30 hours. The volatile portions are evaporated off, the residue is taken up in 50 ml of dichloromethane, and 250 ml of water are added at 0-2°. The aqueous phase is separated off and concentrated to 10 ml under a high vacuum. Chromatography on 20 ml of Dowex® 50 Wx8 using water as eluant, and lyophilisation of the eluate - 48 - 22 5 6 4 S yield 1.04 g of 8 in the form of an amorphous powder, [alp = -65.2° (c=l, H20); 13C-NMR (75 MHz, D20): 172.8 (C02H); 140.3 (C(4)); 122.2 <C(3)); 56.4 (C(2)); 33.3 (d, J=17, C(5)); 27.3 (d, J=134, C(7>); 22.6 (d, J=4, C(6)). In order to analyse the purity of the enantiomer, a sample is derivatised to the amide trimethyl ester with (R)-(+)-methoxytrifluoro-methylphenylacetic acid chloride followed by diazomethane. 1 H-NMR analysis (300 MHz) by integration of the OCH3 signals gives £ 95 % (2R)-isomer (3.54 ppm) and £ 5 % (2S)-isomer (3.37 ppm). Example 9: (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester a) (2R,3S)-2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester (_1) aa) Starting from 1,1,3,3-tetramethyl-l,3-disilane-2-azolidine-N-acetic acid ethyl ester 7.6 ml of a 1.6 molar solution of butyllithium in hexane are added at -20° to a solution of 2.26 ml of N-cyclohexyl-N-isopropylamine in 60 ml of absolute tetrahydrofuran. After 20 minutes, the mixture is cooled to -78° and there is added dropwise a solution of 3 g of 1,1,3,3-tetramethyl-l ,3-disila-2-azolidine-N-acetic acid ethyl ester in 60 ml of tetrahydrofuran. The mixture is stirred at -78° for one hour, and then 142 ml of an approximately 0.035 molar solution of cyclopentadienyl-bis-0-l,2:5,6-diisopropylidene-D-glucofuranosyltitanium(IV) chloride in ether are added and the mixture is stirred at -78° for 17 hours. The reaction solution is transferred via a small steel tube, by argon pressure, into a vessel containing a solution, cooled to -78°, of 1.1 ml of methacrolein in 15 ml of tetrahydrofuran. The whole is allowed to warm up slowly to room temperature, and is then stirred for 2 hours. 1.5 ml of water are added, and the mixture is filtered. The filtrate is diluted with 250 ml of diethyl ether, and is then washed three times with 250 ml of approximately 10 % sodium chloride solution each time and with 250 ml of saturated sodium chloride solution. The aqueous phases are extracted twice with 250 ml of diethyl ether each time. The organic phases are dried over sodium sulphate, concentrated by evaporation, and dissolved hot in 150 ml of cyclohexane. On cooling, 1,2:5,6-di-O-isopropylidene-D- 22 5 6 4 9 glucofuranose crystallises. The mother liquor is concentrated by evaporation, the residue is taken-up in 120 ml of tetrahydrofuran, 24 ml of water and 4.5 ml of acetic acid, and the mixture is stirred at room temperature for 2 hours. Concentration by evaporation at room temperature under a high vacuum yields 10.6 g of residue, contamining (2R,3S)-2-amino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester. A sample (5 mg) is derivatised for 2 hours with 0.2 ml of trifluoroacetic acid anhydride in 0.3 ml of dichloromethane. Capillary gas chromatography (Chirasil®-L-Val, 90-180°/2° per minute) yields 99.25 % (2R,3S)-enantiomer (retention time TreJ_ = 10.28 minutes) and 0.75 % (2S,3R)-enantiomer (retention time T _ = 11.48 minutes). The main mixture is then heated under reflux for ret 5| hours in 80 ml of formic acid ethyl ester. Concentration by evaporation and chromatography on silica gel using hexane/ethyl acetate 1:1 yield 1.64 g of formamide _1. Analysis of a sample (5 mg) in the form of the acetate by gas chromatography (Chirasil®-L-Val, 160-180°, 1° per minute): 99.2 % (2R,3S)-enantiomer (T t = 13.64 minutes), 0.8 % (2S,3R)-enantiomer (T t = 13.94 minutes). a,b) Starting from isocyanoacetic acid ethyl ester 1.65 g of (S)-N-methyl-N-[2-(dimethylamino)-ethyl]-l-[(R)-l' ,2-bis-(di-phenylphosphino)-ferrocenyl]-ethylamine and 1.105 g of bis(cyclohexyl-isocyanide)gold(I) tetrafluoroborate are added at 50° to a solution of 24.88 g of isocyanoacetic acid ethyl ester and 18.51 g of methacrolein in 220 ml of 1,2-dichloromethane. The mixture is stirred at 50° for 5 hours under argon, concentrated by evaporation, taken up in 400 ml of diethyl ether and filtered, and the filtrate is concentrated by evaporation. Distillation of the residue under a high vacuum (0.04 mbar) yields 33.62 g of a stereoisomeric mixture of 5-(2-propenyl)-oxazoline-4-carboxylic acid ethyl ester having a boiling point of 42-52°; MS.: m/e ■ 183 (2 %, M +), 110 (80 %), 85 (100 %). A solution of 33 g of this mixture in 74 ml of water and 33 ml of tetrahydrofuran is heated under reflux for 3 hours. Concentration by evaporation in vacuo yields 36.1 g of a mixture of stereoisomeric 2-formamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester 2. A sample (35 mg) is derivatised in 2 ml of dichloromethane with 0.05 ml of N,0-bis-trimethylsilylacetamide and analysed by means of capillary gas chromatography (Chirasil®-L-Val, 150°): 89.1 % 22 5 6 4 (2R,3S)-isomer (T ■ 22.1 minutes), 5.8 % (2S,3R)-isomer (T ® 23.1 minutes), 2.8 % (2R,3R)-isomer (T t = 24.3 minutes), 2.3 % (2S,3S)- isomer (T ^ ° 25.4 minutes). ret A solution of 11.42 ml of acetic anhydride in 50 ml of dichloromethane is added dropwise at 0-3° within a period of 25 minutes to a solution of 20.2 g of 2, 16.83 ml of triethylamine and 0.62 g of 4-(dimethylamino)- pyridine in 300 ml of dichloromethane. After 30 minutes, the mixture is washed twice with ice-cold 2N hydrochloric acid and twice with 10 % sodium chloride solution. The aqueous phases are extracted with 100 ml of dichloromethane. The organic phases are dried over sodium sulphate and concentrated by evaporation, and the residue is dissolved hot in hexane/ ethyl acetate 4:1. On cooling slowly to approximately 30° there crystallise 1.82 g of racemic (2R*,2S*)-2-formamino-3-acetoxy-4-methyl-4- pentenoic acid ethyl ester having a melting point of 98-106®. The mother liqour is slowly cooled to -12°C and kept at that temperature for one hour. Filtration yields 15.04 g of acetate 3, m.p. 73-75°, [o]D = -75.6° (c«l, CHCI3), analysis by gas chromatography (Chirasil®-L-Val, 160-180®, 1° per minute): (2R,3S)-isomer 93.5 % (T t = 14.5 minutes), (2S,3R)- isomer 2.2 % (T . = 14.8 minutes), (2R,3R)-isomer 2.2 % (T _ = ret ret 16.8 minutes), (2S,3S)-isomer 2.1 X (T t = 17.1 minutes). 20.64 g of anhydrous potassium carbonate are added at -16° to a solution of (2R,3S)-2-formylamino-3-acetoxy-4-methyl-4-pentenoic acid ethyl ester (3) in 400 ml of absolute ethanol. After stirring at -18° to -11°C for 4 hours, 500 ml of buffer solution (1 molar, phosphate, pH=7) are added dropwise. The mixture is stirred at room temperature for 30 minutes and extracted three times with 350 ml of dichloromethane each time. The organic phases are dried over sodium sulphate and concentrated by evaporation, and the residue is chromatographed on 1 kg of silica gel using hexane/ethyl acetate 1:2 as eluant, yielding 9.8 g of alcohol K 22 5 t> b) (2R)-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester (4) To a solution of 14.19 g of 1 according to a) in 210 ml of 1,2-dichloroethane there are added at 18-20° 6.57 ml of thionyl bromide and, after stirring for 2 hours, 135 ml of water. After 15 minutes, the organic phase is separated off and washed three times with 150 ml of ice-water each time and once with 100 ml of ice-cooled saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and concentrated by evaporation, and the residue is dissolved in 60 ml of triisopropyl phosphite and stirred at 75°/100 mbar for 17 hours. The excess reagent is distilled off at 90° under a high vacuum. Chromatography of the residue on 650 g of silica gel using ethyl acetate/methanol 20:1 yields 10.88 g of phosphonic acid ester 4, [ct]p = -123.5° (c*l, CHCI3). 1 H-NMR analysis (300 MHz) with the addition of (lR)-l-(9'-anthra-cenyl)-2,2,2-trifluoroethanol shows an enantiomeric purity of > 90 %. c) (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (5) 23 ml of trimethylbromosilane are added dropwise at room temperature within a period of 15 minutes to a solution of 10.3 g of 4 according to b) in 42 ml of dichloromethane. After 21| hours, 42 ml of ethanol are added while cooling with ice, and the mixture is stirred for 20 hours. The whole is then concentrated by evaporation and the residue is dissolved three times in 70 ml of toluene each time and in each case is concentrated by evaporation again. The residue is dissolved in 42 ml of ethanol, and 42 ml of propylene oxide are added. After If hours, the mixture is filtered. Drying the filtration residue in a vacuum desiccator over P2O5/KOH (3 hours/800) yields 6.17 g of 5; [alp B -78° (c=0.6, H2O); m.p. 194-197° (decomp.), C8H16NO5P; calculated: C 40.51 %, H 6.80 %, N 5.91 %, P 13.06 %; found: C 39.4 %, H 7.09 %, N 5.73 %, P 12.98 %. In order to analyse the purity of the enantiomer, a sample is derivatised to the amide dimethyl phosphonate with (R)-(+)-methoxytrifluoromethyl-phenylacetic acid chloride and diazomethane and analysed by 1H-NMR (300 MHz) using the integration of the OCH3 signals: (2R)-isomer t 93 % (3.51 ppm), (2S)-isomer £ 7 % (3.37 ppm). - 52 - 22 5 6 4 9 Example 10: (2R)-2-amino-4-methvl-5-phosphono-3-pentenoic*8fcrtt A solution of 100 mg of (2R)-2-amino-4-niethyl-5-phosphono-3-pentenoic acid ethyl ester according to Example 6 in 3 ml of IN hydrochloric acid is heated in a bath at 100°C for 4f hours. The solution is concentrated by evaporation and the residue is dried at 60° under a high vacuum for 30 minutes. The residue is dissolved in 15 ml of ethanol, and 4 ml of propylene oxide are added thereto. Filtration and drying of the filtration residue in a vacuum desiccator over P2O5/KOH yield 62 mg of acid. In order to determine the purity of the enantiomer, a sample is derivatised to the amide with (R)-(+)-methoxytrifluoromethylphenyl acetic acid chloride and is analysed by 1H-NMR (300 MHz), integration of the OCH3 signals: £ 95 % (2R)-enantiomer (3.25 ppm) and £ 5 % (2S)-enantiomer (3.18 ppm). Example 11: E-2-amino-4-methvl-5-phosphono-3-pentenoic acid 12 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester are stirred under reflux in 70 ml of water for 19 hours. The reaction mixture is slowly cooled to room temperature, stirred in an ice bath for one hour, filtered and washed with cold water. In this manner there is obtained E-2-amino-4-methyl-5-phosphono-3-pentenoic acid in the form of the monohydrate, m.p. 163" (decomp.). Example 12: E-2-dimethvlamino-4-methvl-5-phosphono-3-pentenoic acid A mixture of 3.56 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, 45 ml of 98 % formic acid and 30 ml of 37 % aqueous formaldehyde solution is stirred at a bath temperature of 105° for 30 minutes. The mixture is then concentrated to dryness by evaporation in vacuo. The residue is taken up in a little water and the whole is again concentrated by evaporation in vacuo. This procedure is repeated twice more. The solid residue is stirred with 80 ml of water. After one hour, the undissolved material is separated off over a hard filter and washed with water. The filtrate and the washing water are concentrated to dryness by evaporation in vacuo. The residue is suspended in 100 ml of water and, after the addition of 30 ml of IN sodium hydroxide solution, - 53 - 22 5 6 49 is left to stand at room temperature for 2 days. The reaction mixture is concentrated to a residual volume of approximately 25 ml by evaporation in vacuo and purified by ion exchanger chromatography (Dowex 50 W x 8 H20). The fractions which contain the desired product are combined, concentrated by evaporation in vacuo and recrystallised from water/ ethanol. In this manner there is obtained E-2-dimethylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 239° (decomp.). Example 13: E-2-dimethylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 30 ml of 8N ethanolic hydrogen chloride solution are added to 1.19 g of E-2-dimethylamino-4-methyl-5-phosphono-3- pentenoic acid, and the mixture is stirred at 40° for 24 hours. The reaction mixture is concentrated to dryness by evaporation in vacuo. After the addition of 30 ml of pure ethanol, the mixture is again concentrated by evaporation, giving 1.90 g of reddish oil, which is dissolved in hot isopropanol. After cooling there is obtained crystalline E-2-dimethylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester hydrochloride, m.p. 203° (decomp.). Example 14: E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 16 ml of glacial acetic acid, 5.90 g of sodium acetate (anhydrous) and 12.2 ml of benzaldehyde are added to a solution of 5.69 g of E-2-amino-4-methyl-5-phosphono-3- pentenoic acid ethyl ester in 48 ml of water and 48 ml of ethanol. 15.70 g of sodium borohydride are added in approximately 70 portions within a period of one hour with intensive cooling with ice/sodium chloride, 4 ml of benzaldehyde being added after half the addition has taken place, after approximately 30 minutes. The temperature of the reaction mixture is kept at from 0 to 10°. When the addition is complete, the mixture is stirred at 0° for one hour to complete the reaction, and then IN hydrochloric acid is added dropwise until an acidic reaction to Congo red takes place. The undissolved salts are filtered off and washed with water. The filtrate is concentrated to dryness by evaporation in vacuo, and the residue is concentrated by evaporation twice - 54 - 22 5 6 more after the addition of ethanol. The residue is then stirred with 150 ml of ethanol, and the undissolved material is filtered off with suction and washed with ethanol. 25 ml of propylene oxide are added to the filtrate, and the mixture is then stirred for 2 hours. The material which crystallises out (mainly educt) is filtered off. The mother liquor is concentrated to dryness by evaporation and stirred with 350 ml of ethyl acetate. The crystalline crude product obtained after filtration with suction is recrystallised from ethanol. In this manner there is obtained E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 192° (decomp.). Example 15: E-2-benzvlamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester A solution of 1.00 g of E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester in 6 ml of water is stirred under reflux for 20 hours. The reaction mixture is concentrated to dryness by evaporation in vacuo. Ethanol is added to the residue, and the mixture is again concentrated by evaporation. This process is repeated twice more. The residue is dissolved in boiling methanol. After cooling there is obtained crystalline E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 150° (decomp.). Example 16: E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 6.64 g of sodium acetate (anhydrous) and 18 ml of acetone are added to a solution of 6.40 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester in 54 ml of water and 18 ml of glacial acetic acid. 17.67 g of sodium borohydride are added in approximately 70 portions within a period of 90 minutes with intensive cooling with ice/sodium chloride, 18 ml of acetone being added after 20 minutes and after 50 minutes. When the addition is complete, the thick white suspension is stirred at 0° for 30 minutes to complete the reaction, and then IN hydrochloric acid is added dropwise until an acidic reaction to Congo red takes place. The resulting clear solution is concentrated by evaporation in vacuo, and the residue is concentrated by evaporation twice more after the addition of ethanol. The residue is then stirred with 200 ml of ethanol at room - 55 - 22 5 6 k 9 temperature, and the undissolved material is filtered off and washed with ethanol. The filtrate is concentrated by evaporation in vacuo, and the residue is recrystallised from isopropanol. In this manner there is obtained E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester hydrochloride, m.p. 203-205° (decomp.). Example 17: E-2-isopropylan)ino-4-niethyl-5-phosphono-3-pentenoic acid A solution of 1.20 g of E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester hydrochloride in 7 ml of water is stirred under reflux for 20 hours. The reaction mixture is concentrated to dryness by evaporation in vacuo. Ethanol is added to the residue, and the mixture is again concentrated by evaporation. This process is repeated twice more. The residue is dissolved in 25 ml of ethanol, a total of 5 ml of propylene oxide is added dropwise thereto with stirring, and the whole is concentrated to dryness by evaporation. The residue is dissolved in a little water, and ethanol is added until the solution becomes cloudy. The solution is stirred at room temperature for 4 hours to complete the reaction, during which time crystallisation slowly takes place. The product is filtered off, washed with ethanol and diethyl ether and dried at 100° under a high vacuum. In this manner there is obtained E-2-iso-propylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 225-227° (decomp.). Example 18: E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid a) 2-(N-methyl-N-formylamino)-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester (X) 20.60 g of 5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester, prepared according to Example 1, are dissolved in 200 ml of dry dichloromethane under argon. A suspension of 16.60 g of trimethyloxonium tetra-fluoroborate in 200 ml of dry dichloromethane is then added dropwise at 15°. The reaction mixture is stirred at room temperature for 17 hours, and then 150 ml of water and 45 ml of saturated potassium bicarbonate solution are added slowly, so that a pH of 7 is produced. The organic phase is separated off and washed twice with water and once with saturated sodium chloride solution, and is then dried over sodium 225649 sulphate. After the dichloromethane has been distilled off, the oily residue is distilled in a bulb tube, b.p. 120-130°/13 Pa. In this manner there is obtained 2-(N-methylformylamino)-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in the form of a light-yellow honey, IR (CH2CI2)! 3550 (HO); 1740 (CO ester); 1675 (CO amide). b) E-2-(N-methyl-N-formylamino)-4-methyl-5-diisopropyl-phosphono-3-pentenoic acid ethyl ester (2) 7.70 ml of thionyl bromide are added dropwise at 20° under argon to a solution of 17.80 g of 2-(N-methylformylamino)-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in 248 ml of 1,2-dichloroethane. The mixture is stirred at room temperature for 2 hours. 150 ml of water are then added dropwise with slight cooling (20°). The two-phase mixture is stirred thoroughly for a further 20 minutes to complete the reaction. The organic phase is separated off and washed three times with water/ice, once with ice/saturated potassium bicarbonate solution and once with saturated sodium chloride solution. To the intermediate obtained after drying over sodium sulphate and removal of the 1,2-dichloroethane by distillation at 35° in vacuo there are added at room temperature 66 ml of trilsopropyl phosphite, and the mixture is then stirred at 75° under reduced pressure (approximately 13 kPa) for 17 hours. The excess trilsopropyl phosphite and other volatile by-products are then distilled off under a high vacuum. Purification by column chromatography (silica gel, ethyl acetate) yields E-2-(N-methylformylamino)-4-methyl-5-diisopropyl-phosphono-3-pentenoic acid ethyl ester in the form of a yellowish honey; IR (CH2Cla): 1740 (CO ester); 1670 (CO amide); 1235 (P-0); 980-1010 (P-0-C). According to the 1 H-NMR spectrum, the compound is in the form of a mixture of two retainers. c) E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid (3) 20 ml of trimethylbromosilane are added dropwise at 20° within a period of 10 minutes under argon to a solution of 9.50 g of E-2-(N-methylformyl-amino)-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester in 40 ml of dry dichloromethane. After stirring at room temperature for - 57 - 22 5 6 4 9 20 hours, 37 ml of ethanol are added dropwise within a period of 15 minutes, and the whole is stirred for a further 20 hours. The clear reaction solution is then concentrated to dryness by evaporation in vacuo. The residue is concentrated by evaporation twice more in each case after the addition of 30 ml of toluene. 128 ml of 2N hydrochloric acid are added to the resulting oil, and the mixture is stirred at a bath temperature of 85° for 16 hours. The reaction mixture is concentrated by evaporation in vacuo. Concentration by evaporation twice after the addition of ethanol/toluene 1:1 yields an oily residue, which is dissolved in 51 ml of ethanol and to which there is added dropwise a solution of 51 ml of propylene oxide in 51 ml of ethanol. The product obtained in crystalline form is filtered off after 2 hours and re-crystallised from water/ethanol. In this manner there is obtained E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 239° (decomp.). Example 19: The following can also be prepared in a manner analogous to that described in Examples 1-3 or 6 and 9: E-2-amino-5-phosphino-3-pentenoic acid ethyl ester, m.p. 172-173°; E-2-amino-5-phosphino-3-pentenoic acid butyl ester, m.p. 160-161°; E-2-amino-5-phosphono-3-pentenoic acid ethyl ester, m.p. 167-168°; E-2-amino-5-phosphono-3-pentenoic acid butyl ester, m.p. 160-161°; E-2-amino-5-phosphono-3-pentenoic acid octyl ester, m.p. 161-162°; E-2-amino-5-phosphono-3-pentenoic acid propyl ester, m.p. 161-162°; E-2-amino-5-phosphono-3-pentenoic acid pentyl ester, m.p. 160—161°; E-2-amino-5-phosphono-3-pentenoic acid isobutyl ester, m.p. 163-164°; E-2-amino-5-pho8phono-3-pentenoic acid sec.-butyl ester, m.p. 169-170°; E-2-amlno-4-methyl-5-phosphono-3-pentenoic acid methyl ester, m.p. 193-194°, [water/acetone (9:1)]; E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-propyl ester, m.p. 184-185°, (water); E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-butyl ester, m.p. 186-187°, [water/acetone (2:1)]; E-2-amino-4-methyl-5-phosphono-3-pentenoic acid isobutyl ester, m.p. 181-182°, [water/acetone (9:1)]; 22 5 6 - 58 - E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-pentyl ester, m.p. 207-208°; E-2-amino-4-methyl-5-phosphono-3-pertenoic acid n-hexyl ester, m.p. 207-208°; E-2-amino-7-phosphono-4-heptenoic acid butyl ester, m.p. 186°; E-2-amino-5-phosphono-4-pentenoic acid methyl ester, m.p. 219-220°; E-2~amino-5-phosphono-4-pentenoic acid ethyl ester, m.p. 234°; E-2-amino-5-phosphono-4-pentenoic acid butyl ester, m.p. 239°; E-2-amino-5-phosphono-4-pentenoic acid octyl ester, m.p. 236°; E-2-amino-5-phosphono-4-pentenoic acid 2-hydroxyethylester, m.p. 197°. Example 20: The following can also be prepared in a manner analogous to that described in Examples 4, 11, 12, 17 and 18 or 5, 7, 8, 9 and 10: E-2-amino-5-phosphono-4-pentenoic acid, m.p. 219-220°; E-2-amino-5-methylphosphonyl-4-pentenoic acid, m.p. 222°; E-2-amino-5-butylphosphonyl-4-pentenoic acid, m.p. 232-233°; E-2-amino-5-octylphosphonyl-4-pentenoic acid, m.p. 221-223°; E-2-amino-5-dodecylphosphonyl-4-pentenoic acid, m.p. 211°; E-2-amino-6-phosphono-4-hexenoic acid, m.p. 244-246°; E-2-amino-6-methylphosphonyl-4-hexenoic acid, m.p. 145-150°; E-2-amino-6-butylphosphonyl-4-hexenoic acid, m.p. 216°; E-2-amino-6-octylphosphonyl-4-hexenoic acid, m.p. 209-210°; E-2-amino-6-dodecylphosphonyl-4-hexenoic acid, m.p. 197-200°; E-2-amino-7-phosphono-4-heptenoic acid, m.p. 125° (decomposition); (2R)-E-2-amino-4-fluoro-5-phosphono-3-pentenoic acid, («1jj ■ -44.8° (c-0.5; H20); 13C-NMR-spectrum (75 MHz, D20): 172.7 (COOH); 161.5 (dxd, j-263+12: CO; 100.9 (t, J-ll: C3); 49.5 (C2); 33.5 (dxd, J-128+26: C5); E-2-amino-5-phosphono-3-pentenoic acid, white amorphous powder, 1H-NMR (D20): 2.39 (dd, 2H, C(5)-H); 4.27 (d, 1H, C(2)-H); 5.53 (m, 1H, C(3)-H); 5.87 (m, 1H, C(4)-H); m.p. after recrystallisation from ethanol/water 191-192°; E-2-amino-4-methyl-5-phosphono-3-pentenoic acid, 'H-NMR (D20): 1.73 (s, 3H, CH3); 4.55 (s, 1H, C(2)-H); - 59 - 22 5 6 4 9 E-2-amino-5-methylphosphonyl-3-pentenoic acid, amorphous white powder, 1H-NMR (D20): 2.55 (dd, 2H, C(5)-H); 4.38 (d, 1H, C(2)-H); 5.64 (m, 1H, C(3)-H); 5.91 (m, 1H, C(4)-H); E-2-aniino-5-phosphino-3-pentenoic acid, m.p. 139-140°; E-2-anilno-4-methyl-5-phosphino-3-pentenoic acid, m.p. 176-177°; (2S)-E-2-amino-4-methyl-5-phosphono-3~pentenoic acid, m.p. 196°, [a]^° = +97.1 ± 1.9° (c=0.5, water); (2R)-E-2-amitio-4-methyl-5-phosphono-3-pentenoic acid, m.p. 194°, C"* = (£=0.8, water); E-2-amino-4-inethyl-5-methylphosphonyl-3-pentenoic acid, 1H-NMR (D20): 1.20 (d, 3H, CH3-P); 1.75 (d, 3H, CH3); 2.45 (d, 2H, C(5)-H); 4.50 (d, 1H, C(2)-H); 5.15 (m, 1H, C(3)-H); E-2-amino-2-methyl-5-phosphono-3-pentenoic acid, m.p. 225-226° (from water); E-2-amino-3-methyl-5-phosphono-3-pentenoic acid, white powder, m.p. 168°, 1H-NMR (D20): 1.50 (d, 3H, CH3); 2.4 (m, 2H, CH2); 4.30 (s, 1H, C(2)-H); 5.60 (m, 1H, C(4)-H); E-2-amino-5-methyl-5-phosphono-3-pentenoic acid, white amorphous solid, 1H-NMR (D20): 1.05 (dd, 3H, CH3); 2.45 (m, 1H, C(5)-H); 4.33 (d, 2H, C(2)-H); 5.5 and 5.9 (2m, 2H, C(3)-H and C(4)-H); E-2-amino-4-ethyl-5-phosphono-3-pentenoic acid, m.p. 176°; E-2-amino-4-propyl-5-phosphono-3-pentenoic acid, m.p. 193°; ^ E-2-amino-4-butyl-5-phosphono-3-pentenoic acid, m.p. 186-187°; E-2-amino-4-isopropyl-5-phoaphono-3-pentenoic acid, m.p. 201°; E-2-amino-4-tert.-butyl-5-phosphono-3-pentenoic acid, m.p. 252-253°, 1H-NMR <D20): 0.95 (s, 9H, (CH3)3C); Z-2-amino-4-tert.-butyl-5-phosphono-3-pentenoic acid, 1H-NMR (D20): 1.08 (s, 9H, (CH3)3C); 2.45 (m, 2H, CH2); 4.95 (d, 1H, C(2)-H); 5.20 (m, 1H, W C(3)-H); E-2-amino-4-benzyl-5-phosphono-3-pentenoic acid, colourless needles, m.p. 196-198°; E-2-amino-4-phenyl-5-phosphono-3-pentenoic acid, colourless needles, m.p. 230-233°; E-2-amino-4-methyl-5-methylphosphono-3-pentenoic acid as by-product, m.p. 149-150°. - 60 - 225649 Example 21: E-2-methylamino-4-methvl-3-pentenoic acid ethyl e3ter 50 ml of 8N ethanolic hydrogen chloride solution are added to 1.20 g of E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid, and the mixture is stirred at 40° for 25 hours. The reaction mixture is concentrated to dryness by evaporation in vacuo. Concentration by evaporation twice after the addition of ethanol/toluene 1:1 yields an oily residue, which is dissolved in 5 ml of ethanol and to which there is added dropwise a solution of 5 ml of propylene oxide in 5 ml of ethanol. The product obtained in crystalline form is filtered off after 2 hours and washed with ethanol and ether. After drying (80°, 4 hours) under a high vacuum, there is obtained E-2-methyla!nino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 235-240° (with decomposition). Example 22: Preparation of 1000 capsules each containing 10 mg of the active ingredient of Example 6 and having the following composition: E-2-amino-6-phosphono-4-hexenoic acid 10.0 g lactose 207.0 g modified starch 80.0 g magnesium stearate 3.0 g Method: All the pulverulent constituents are sieved through a sieve having a mesh width of 0.6 mm. The active ingredient la then placed in a suitable mixer and mixed first with the magnesium stearate and then with the lactose and starch, until a homogeneous mixture is obtained. No. 2 gelatin capsules are each filled with 300 mg of this mixture, a capsule-filling machine being used. Capsules that contain from 10 to 200 mg of one of the other disclosed compounds mentioned in Examples 1-20 are prepared in analogous manner. Example 23: Preparation of 10,000 tablets each containing 10 mg of the active ingredient of Example 6 and having the following composition: E-2-amino-6-phosphono-4-hexenoic acid 100.00 g lactose 2535.00 g corn starch 125.00 g </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 61 - 22 5 6 4 9 polyethylene glycol 6000 magnesium stearate purified water 150.00 g 40.00 g q.s. Method: All the pulverulent constituents are sieved through a sieve having a mesh width of 0.6 mm. The active ingredient is then mixed in a suitable mixer with the lactose, the magnesium stearate and half of the starch. The other half of the starch is suspended in 65 ml of water, and the suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting paste is added to the powders and the mixture is granulated, if necessary with the addition of more water. The granulate is dried overnight at 35°, forced through a sieve having a mesh width of 1.2 mm, and compressed to form tablets which have a breaking groove. Tablets that contain from 10 to 200 mg of one of the other disclosed compounds mentioned in Examples 1-20 are prepared in analogous manner. - 62 - o G G WHAT WE CLAIMS ISi-

1. A process for the manufacture of unsaturated amino acid compounds of formula (I), in which Ri is hydrogen, alkyl or hydroxy, R2 is hydrogen, alkyl, halo-alkyl, hydroxyalkyl, lower alkoxyalkyl, aryl-lower alkyl, lower alkenyl, halogen or aryl, R3 is hydrogen, alkyl or aryl, Ri> is hydrogen or alkyl, R5 is unsubstituted carboxy or esterified or amidated carboxy, R6 is an amino group that is unsubstituted or monosubstituted by alkyl or by arylated alkyl, A is unsubstituted or alkyl-substituted a,w-alkylene having from 1 to 3 carbon atoms (C-atoms) or is a direct bond, and B is methylene or a bond, with the proviso that A is unsubstituted or alkyl-substituted a,io-alkylene having from 1 to 3 C-atoms when B is a direct bond, and to the salts thereof, characterised in that in a compound of formula (II), in which Zi is free or protected hydroxy, Zz is an Ri group or protected hydroxy, Z5 is an Rs group or protected carboxy, Z& is a protected group Rs, and Ri, R2, R3, Ru, Rs, R6, A and B are as defined above, the protected groups Zs and, when applicable, Zi, Zz and/or Z5 are freed by treatment with a tri-lower alkylhalosilane and, if desired, the resulting compound is converted into a different compound of formula I, a resulting mixture of optical isomers is resolved into the components and the desired isomer is separated off, and/or a resulting free compound is converted into a salt or a resulting salt is conve^t«|jfe■^J^Hlo^ the fteg-.-rrf; compound or into a different salt. i TTTzT) U 1 - 63 -

2. A process according to claim 1, characterised in that a compound of formula X—A- (III) , in which R2, R3 , Ri», A and B are as defined for formula I, Z5 has the meaning of R5 as defined in claim 1 or is protected carboxy, Z& is a protected amino group R.6 as defined in claim 1, and X is reactive esterified hydroxy, is reacted with a compound of formula (IV), in which Zi is free or protected hydroxy, Zz has the meaning of Ri as defined in claim 1 or is protected hydroxy and R is an etherifying group, in the resulting intermediate of formula (II), the protected groups Zs and, when applicable, Zi, Zz and/or Z5 are freed by treatment with a tri-lower alkylhalosilane and, if desired, in a compound obtainable according to the process in which R5 is esterified carboxy, the esterified carboxy group is converted into carboxy or, in a compound obtainable according to the process in which R5 is carboxy, the carboxy group is converted into an esterified carboxy group and/or, if desired, a resulting compound of formula I is converted into a salt or a resulting salt is converted into a different salt or into a free compound of formula I and/or, if desired, an optical isomer is isolated from a mixture of stereoisomeric forms of a resulting compound of formula I or of a salt thereof.

3. A process according to claim 1 for the manufacture of compounds of formula I in which Ri, R2, R3 , Ri<, R6, A and B are as de£S3ied' in--claim-1_,_ and Rs is esterified or amidated carboxy, and salts thereof, cbf ised in that a compound of formula X - 64 - .f/du o J±TJ zxrtfr4? (in) in which R2 , R3, Ri,, A and B are as defined for formula I, Z5 has the meaning of esterified or amidated carboxy Rs as defined in claim 1, Zi is protected amino, and X is reactive esterified hydroxy, is reacted with a compound of formula (IV), in which Zi is free or protected hydroxy, Z2 has the meaning of Ri as defined in claim 1 or is protected hydroxy and R is an etherifying group, in the resulting intermediate the protected groups Z$ and, when applicable, Zi and/or Zz are freed, whilst R; is retained, by treatment with trimethylbromosilane and, if desired, a resulting compound of formula I is converted into a salt or a resulting salt is converted into a different salt or into a free compound of formula I and/or, if desired, an optical isomer is isolated from a mixture of stereoisomeric forms of a resulting compound of formula I or of a salt thereof.

4. A process according to claim 1 for the manufacture of compounds of formula I in which Ri, R2, R3, Ri,, R$, A and B are as defined in claim 1 and R5 is carboxy, and the salts thereof, characterised in that in a compound of formula II in which Zi is free or protected hydroxy, Z2 is an Ri group or protected hydroxy, Z5 is free or protected carboxy and Z6 is protected group R6 and Ri, Rj, R3, R4, R6, A and B are as defined above, the protected groups Zs and, when applicable Zi, Z2 and/or Zs are freed by treatment with a tri-lower alkylhalosilane and, if desired, in a compound obtainable according to the process in which R5 is esterified carboxy, the esterified carboxy group is converted into carboxy and/or, if desired, a resulting compound of formula I is converted into a salt or a resulting salt is converted into a different salt or into a free compound of formula I and/or, if desired, an optical isomer is isolated from a mixture of stereoisomeric forms of a resufrfih|'Cfltnpu'uud uJi,-formula I or of a salt thereof. r r>

5. A process according to any one of claims 1, 2 and 4, characterised in that the starting material used is a compound of formulae II or IV in which protected hydroxy Zi and/or Zz is hydroxy etherified by a lower alkanol, lower alkenol or lower alkynol each of which is unsubstituted or substituted by halogen or, in a position higher than the a-position, by hydroxy, oxo, lower alkoxy, lower alkanoyloxy and/or by mono- or di-lower alkylamino.

6. A process according to claim 3, characterised in that the starting "* material used is a compound of formula IV in which protected hydroxy Zi and/or Zz is hydroxy etherified by a lower alkanol, lower alkenol or lower alkynol each of which is unsubstituted or substituted by halogen or, in a position higher than the a-position, by hydroxy, oxo, lower alkoxy, lower alkanoyloxy and/or by mono- or di-lower alkylamino.

7. A process according to any one of claims 1, 2 and 4, characterised in that the starting material used is a compound of formulae II or IV in which protected hydroxy Zi and/or Zz is lower alkoxy.

8. A process according to claim 3, characterised in that the starting material used is a compound of formula IV in which protected hydroxy Zi and/or Zz is lower alkoxy. O ■ V

9. A process according to any one of claims 1 to 8, characterised in that the starting material used is a compound of formulae II or III in which the protected group Z$ is an acylamino group, optionally N-substituted by lower alkyl or phenyl-lower alkyl. u ...

10. A process according to any one of claims 3, 6 and 8, characterised xn that the starting material used is a compound of formula III in which the protected group Zs is an acylamino group.

11. A process according to any one of claims 1 to 9, characterised in that the starting material used is a compound of formulae II or III in which the protected group Z$ is R6 protected by the acyl group of a carbonic acid semiester. o 1 i.z.rc^ - 66 -

12. A process according to any one of claims 1 to 9, characterised in that the starting material used is a compound of formulae II or III in which the protected group Zs is a lower alkoxycarbonylamino group that is unsubstituted or substituted in the 1- or 2-position.

13. A process according to any one of claims 1 to 8, characterised in that the starting material used is a compound of formulae II or III in which the protected group Zi is a lower alkanoylamino group, optionally N-substituted by lower alkyl or phenyl-lower alkyl.

14. A process according to any one of claims 3, 6, 8 and 10, characterised in that the starting material used is a compound of formula III in which the protected group Z& is a lower alkanoylamino group, for example formylamino.

15. A process according to any one of claims 1 to 14, characterised in that the tri-lower alkylhalosilane used is a tri-lower alkylchlorosilane, tri-lower alkyliodosilane or tri-lower alkylbromosilane.

16. A process according to any one of claims 1 to 14, characterised in that the tri-lower alkylhalosilane used is a tri-lower alkylbromosilane. G G

17. A process according to any one of claims 1, 2, 4, 5, 7, 9, 11 to 13, 15 and 16, characterised in that the tri-lower alkylhalosilane used is trimethylbromosilane.

18. A process according to any one of claims 3, 6, 10 and 14, characterised in that the tri-lower alkylhalosilane used is trimethylbromosilane.

19. A process according to any one of claims 1, 2, 4, 5, 7, 9, 11-13 and 15 to 17, characterised in that the protected groups Zi, Z2, Z5 and/or Z& are freed in a halogenated hydrocarbon.

20. A process according to any one of claims 3, 6, 8, ^0, 14 and 18, characterised in that the protected groups Zi, Z2 , Zs and/or Z6 are freed in a halogenated hydrocarbon. I \ / / / ju.r c^«r "'iMilifi 1 - 67 -

21. A process according to any one of claims 1 to 20, characterised in that the protected groups Zj., Z2 > Z5 and/or Z6 are freed in a halogenated aliphatic hydrocarbon. o

22. A process according to any one of claims 1, 2, 4, 5, 7, 9, 11-13, 15 to 17 and 19, characterised in that the reaction is carried out in dichloromethane as solvent or diluent. Cs

23. A process according to any one of claims 3, 6, 8, 10, 14, 18 and 20, $ characterised in that the reaction is carried out in dichloromethane as solvent or diluent.

24. A process according to any one of claims 1 to 23, characterised in that a substance absorbing hydrogen halide is added.

25. A process according to any one of claims 18, 20 and 23 characterised in that a substance absorbing hydrogen bromide is added.

26. A process according to any one of claims 1 to 25, characterised in that an epoxy-lower alkane in admixture with a lower alkanol is added as substance absorbing hydrogen halide.

27. A process according to any one of claims 1, 2, 4, 5, 7, 9, 11-13, 15-17, 19, 21, 22 and 24, characterised in that propylene oxide in admixture with ethanol is added as substance absorbing hydrogen halide.

28. A process according to any one of claims 18, 20, 23 and 25, characterised in that propylene oxide in admixture with ethanol is added as substance absorbing hydrogen bromide.

29. A process according to any one of claims 1 to 28 for the manufacture of unsaturated amino acid compounds of formula HO— "*V (I), iJL^C J/JOij !(■> - 68 - in which Ri is hydrogen, alkyl or hydroxy, R2 is hydrogen, alkyl, halo-alkyl, hydroxyalkyl, lower alkoxyalkyl, aryl-lower alkyl, lower alkenyl, halogen or aryl, R3 is hydrogen, alkyl or aryl, Ri» is hydrogen or alkyl, Rs is unsubstituted carboxy or esterified or amidated carboxy, R6 is an amino group that is unsubstituted or monosubstituted by alkyl or by arylated alkyl, A is unsubstituted or alkyl-substituted a,<o-alkylene having from 1 to 3 carbon atoms (C-atoms) or is a direct bond, and B is methylene or a bond, with the proviso that A is unsubstituted or alkyl-substituted oc,a)-alkylene having from 1 to 3 C-atoms when B is a direct bond, in the form of those enantiomers in which the C-atom carrying the amino group R6 is in the R-configuration, and the salts thereof, characterised in that the starting material used is a compound of formula IV or compounds of formulae II and III in which the C-atom carrying the group is in the R-configuration.

30. A process according to any one of claims 1 to 29, characterised in that a compound of formula I in which Ri is hydrogen, alkyl having up to and including 12 carbon atoms, or hydroxy, R2 is hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy—lower alkyl, phenyl-lower alkyl that is unsubstituted or substituted in the phenyl moiety, lower alkenyl, halogen, or unsubstituted or substituted phenyl, R3 is hydrogen, lower alkyl or unsubstituted or substituted phenyl, Ru is hydrogen or lower alkyl, R5 is free or pharmaceutically acceptable esterified or amidated carboxy, Rg is amino or mono—lower alkylamino, A is unsubstituted or lower alkyl-substituted a,w-alkylene having from 1 to 3 carbon atoms or is a bond, and B is methylene or a bond, with the_ proviso that A is other than a bond when B is a bond, the substituents of phenyl being selected from the group consisting of lower alkyl, hydr lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alky amino-lower alkyl and nitro, or a pharmaceutically acceptable sal thereof, is manufactured.

31. A process according to any one of claims 3, 6, 8, 10, 14, 18, 20, 25 and 28, characterised in that a compound of formula I in wHich.igi_ is hydrogen, alkyl having up to and including 12 carbon atoms, or hydroxy, R2 is hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower allcoxy-lower alkyl, phenyl-lower alkyl that is unsubstituted or substituted in the phenyl moiety, lower alkenyl, halogen, or unsubstituted or c r> 69 - substituted phenyl, R3 is hydrogen, lower alkyl or unsubstituted or substituted phenyl, Ri, is hydrogen or lower alkyl, Rs is pharmaceutically acceptable esterified or amidated carboxy, Rs is amino or mono-lower alkylamino, A is unsubstituted or lower alkyl-substituted a,w-alkylene having from 1 to 3 carbon atoms or is a bond, and B is methylene or a bond, with the proviso that A is other than a bond when B is a bond, the substituents of phenyl being selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and nitro, or a pharmaceutically acceptable salt thereof, is manufactured.

32. A process according to claim 31, characterised in that a compound of formula I in which Ri to Ru, A and B are as defined in claim 33, R5 is lower alkoxycarbonyl or lower alkoxycarbonyl substituted by amino, nono-or di-lower alkylamino, hydroxy or by lower alkanoyloxy and R6 is amino or mono-lower alkylamino, or a pharmaceutically acceptable salt thereof, is manufactured.

33. A process according to any one of claims 1 to 29, characterised in that a compound of formula I in which Ri is hydrogen, alkyl having up to and including 12 carbon atoms, or hydroxy, R2 is hydrogen, lower alkyl, phenyl, halophenyl or phenyl-lower alkyl, R3 and Ru are hydrogen or lower alkyl, Rs is carboxy and R6 is amino, A being unsubstituted or lower alkyl-substituted a,w-alkylene having from 1 to 3 carbon atoms or being a bond and B in each case being methylene or a bond, with the proviso that A is other than a bond when B is a bond, or a pharmaceutically acceptable salt thereof, is manufactured.

34. A process according to any one of claims 3, 6, 8, 10, 14, 18, 20, 23, 25 and 28, characterised in that a compound of formula I in which Ri is hydrogen, alkyl having up to and including 12 carbon atoms, or hydroxy, R2 is hydrogen, lower alkyl, phenyl, halophenyl or phenyl-lower alkyl, R3 and R<» are hydrogen or lower alkyl and, on the one hand, Rs is alkoxycarbonyl or hydroxy-lower alkoxycarbonyl and R6 is amino or mono-lower alkylamino, A representing unsubstituted or lower a^Ucjrl-substituted a,w-alkylene having from 1 to 3 carbon atoms or representing a~T>orfcr~and-;.^ representing methylene or a bond, with the proviso that A is other than a bond when B is a bond, or a pharmaceutically acceptable salt thereof, is manufactured.

35. A process according to any one of claims 1 to 29, characterised in that a compound of formula I in which Ri is hydrogen, alkyl having up to and including 12 carbon atoms, or hydroxy, R2 is hydrogen, lower alkyl or halophenyl, R3 is hydrogen or halophenyl, Ri, is hydrogen, Rs is carboxy and R& is amino, A being a,w-alkylene having from 1 to 3 carbon atoms or being a bond and B in each case being methylene or a bond, with the proviso that A is other than a bond when B is a bond, or a pharmaceutically acceptable salt thereof, is manufactured.

36. A process according to any one of claims 3, 6, 8, 10, 14, 18, 20, 23, 25 and 28, characterised in that a compound of formula I in which Ri is hydrogen, alkyl having up to and including 12 carbon atoms, or hydroxy, R2 is hydrogen, lower alkyl or halophenyl, R3 is hydrogen or halophenyl, Rtt is hydrogen, R5 is lower alkoxycarbonyl or hydroxy-lower alkoxycarbonyl and R6 is amino or mono-lower alkylamino, with the proviso that A is other than a bond when B is a bond, or a pharmaceutically acceptable salt thereof, is manufactured.

37. A process according to any one of claims 1 to 29, characterised in that a compound of formula I in which Ri is hydrogen, lower alkyl or hydroxy, R2 is hydrogen or lower alkyl, R3 and Ri, are hydrogen, R5 is lower alkoxycarbonyl and Rg is amino, A representing o,u>-alkylene having from 1 to 3 carbon atoms and B representing a bond, or a pharmaceutically acceptable salt thereof, is manufactured.

38. A process according to any one of claims 3, 6, 8, 10, 14, 18, 20, 23, 25 and 28, characterised in that a compound of formula I in which Ri is hydrogen, lower alkyl or hydroxy, R2 is hydrogen or lower alkyl, R3 and Ri» are hydrogen, R5 is lower alkoxycarbonyl and Rg is amino, A representing a,to-alkylene having from 1 to 3 carbon atoms and B representing a bond, or a pharmaceutically acceptable salt thereWf^ is manufactured."Wl r 71

39. A process according to any one of claims 1, 2 and 4 to 29, characterised in that a compound of formula I in which Ri is hydroxy, Rz is hydrogen or lower alkyl, R3 and Ru are hydrogen, Rs is lower alkoxycarbonyl or carboxy, Rg is amino, A is methylene and B is a bond, or a pharmaceutically acceptable salt thereof, is manufactured.

40. A process according to any one of claims 3, 6, 8, 10, 14, 18, 20, 23, 25 and 28, characterised in that a compound of formula I in which Ri is hydroxy, Rz is hydrogen or lower alkyl, R3 and Rt are hydrogen, R5 is lower alkoxycarbonyl or carboxy and Rg is amino, A is methylene and B is a bond, or a pharmaceutically acceptable salt thereof, is manufactured.

41. A process according to any one of claims 3, 6, 8, 10, 14, 18, 20, 23, 2 5 and 28, characterised in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester or a pharmaceutically acceptable salt thereof is manufactured.

42. A process according to any one of claims 1, 2 and 4 to 28, characterised in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof is manufactured.

43. A process according to claim 29, characterised in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof is manufactured.

44. A process according to claim,1 for the manufacture of E-2-amino-4-phosphonomethyl-3,6-heptadienoic acid and pharmaceutically acceptable salts thereof, characterised in that E-2-formylamino-4-diethylphosphono-methy1-3,6-heptadienoic acid methyl ester is reacted with trimethyl-iodosilane in dichloromethane and the primary product is treated with hydrochloric acid.

45. A process according to any one of claims 1 to 44, characterised in that that enantiomer is produced in which the CjpLtcjn_carrying the amino group Rg has the R-configuration. ' u i-i-STS^4} - 72 -

46. A process according to any one of claims 1 to 29, characterised in that (2R)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof is manufactured.

47. A process according to any one of claims 1 to 29, characterised in that (2R)-2-amino-4-methyl-7-phosphono-3-heptenoic acid or a pharmaceutically acceptable salt thereof is manufactured.

48. A process according to any one of claims 1 to 29, characterised in that (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester or a pharmaceutically acceptable salt thereof is manufactured.

49. A process according to any one of claims 1 to 29, characterised in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid methyl ester or a pharmaceutically acceptable salt thereof is manufactured.

50. A process according to any one of claims 1 to 29, characterised in that E-2-amino—4—methyl-5~phosphono-3-pentenoic acid n-propyl ester or a pharmaceutically acceptable salt thereof is manufactured.

51. A process according to any one of claims 1 to 29, characterised in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-butyl ester or a pharmaceutically acceptable salt thereof is manufactured.

52. A process according to any one of claims 1 to 29, characterised in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid isobutyl ester or a pharmaceutically acceptable salt thereof is manufactured.

53. A process according to any one of claims 1 to 29, characterised in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-pentyl ester or a pharmaceutically acceptable salt thereof is manufactured.

54. A process according to any one of claims 1 to 29, characterised in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-hexyl ester or a pharmaceutically acceptable salt thereof is manufactured.-- ■ rv c X3-C^<\ T i r i' fi' r~ .rTSTTTT*Tv7 73 -

55. A process according to any one of claims 3, 5, 6, 8, 12, 15, 16, 18, 20, 23, 26 and 28, characterised in that E-2-amino-4-methyl-5-phos-phono-3-pentenoic acid methyl ester or a pharmaceutically acceptable salt thereof is manufactured.

56. A process according to any one of claims 3, 5, 6, 8, 12, 15, 16, 18, 20, 23, 26 and 28, characterised in that E-2-amino-4-methyl-5-phos-phono-3-pentenoic acid ethyl ester or a pharmaceutically acceptable salt thereof is manufactured.

57. A process according to any one of claims 3, 5, 6, 8, 12, 15, 16, 18, 20, 23, 26 and 28, characterised in that E-2-amino-4-methyl-5-phos-phono-3-pentenoic acid n-propyl ester or a pharmaceutically acceptable salt thereof is manufactured.

58. A process according to any one of claims 3, 5, 6, 8, 12, 15, 16, 18, 20, 23, 26 and 28, characterised in that E-2-amino-4-methyl-5-phos-phono-3-pentenoic acid n-butyl ester or a pharmaceutically acceptable salt thereof is manufactured. o

59. A process according to any one of claims 3, 5, 6, 8, 12, 15, 16, 18, 20, 23, 26 and 28, characterised in that E-2-amino-4-methyl-5-phos-phono-3-pentenoic acid isobutyl ester or a pharmaceutically acceptable salt thereof is manufactured. o

60. A process according to any one of claims 3, 5, 6, 8, 12, 15, 16, 18, 20, 23, 26 and 28, characterised in that E-2-amino-4-methyl-5-phos— phono-3-pentenoic acid n-pentyl ester or a pharmaceutically acceptable salt thereof is manufactured.

61. A process according to any one of claims 3, 5, 6, 8, 12, 15, 16, 18, 20, 23, 26 and 28, characterised in that E-2-amino-4-methyl-5-phos-phono-3-pentenoic acid n-hexyl ester or a pharmaceutically acceptable salt thereof is manufactured. JL 225(340 74

62. A process according to any one of claims 3, 5, 6, 8, 12, 15, 16, 18, 20, 23, 26, 28 and 31, characterised in the (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof is manufactured.

63. (2R)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester or a pharmaceutically acceptable salt thereof.

64. Pharmaceutical composition containing (2R)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester or a pharmaceutically acceptable salt thereof and customary pharmaceutical carriers. </div>