SI8811501A - Process for the preparation of new unsaturated amino acide compounds - Google Patents

Abstract

The invention relates to a process for preparation unsaturated amino acid compounds of formula (I) provided that A represents unsubstituted or substituted alpha, omega-alkylene with 1 to 3 carbon atoms if stands for B for a direct bond in which in the compound of formula (II) Sl 8811501 wherein R1 is hydrogen, alkyl or hydroxy, R2 is hydrogen, alkyl, halogenoalkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, arylalkylalkyl, lower alkenyl, halogen or aryl, R3 hydrogen, alkyl or aryl, R 4 is hydrogen or alkyl, R 5 is given case esterified or amidated carboxy, Re unsubstituted or a substituted amino group, A unsubstituted or substituted alpha, omega-alkylene with 1 to 3 carbon atoms or a direct bond and B methylene or a bond, sub in which Z1 means protected hydroxy optionally, Z2 group R1 or protected hydroxy, Z5 group R5 or carboxy protected, R6 protected group is released protected groups Ze and, optionally, Z1, Z2 and / or Z5 by treatment with trinylalkylhalogensilane.

Description

A process for the preparation of novel unsaturated amino acid compounds

FIELD OF THE INVENTION

The invention is in the field of organic chemical synthesis and relates to a process for the preparation of unsaturated amino acid compounds with a f ormula

in which _R1 represents hydrogen, alkyl or hydroxy, R is hydrogen, alkyl, halogennižjialkil, Hydroxy, lower alkoksinižjialkil, arilnižjialkil, lower alkenyl, halogen or aryl, denotes R ^ is hydrogen, alkyl or aryl, R R is hydrogen or alkyl, R ^ is optionally esterified or amidated carboxy, R ^ is unsubstituted or lower alkyl or arylalkyl substituted amino group, A represents unsubstituted or alkyl substituted d, uralkylene of 1 to 3 carbon atoms (C atoms) or a direct bond and B is methylene or a bond, provided that A represents unsubstituted or alkyl substituted J1, W-alkylene of 1 to 3 carbon atoms, if B is a direct bond, and their salts as well as ethyl ester (2R) - E-2-amino-4-methyl-5-phosphono3-pentenoic acid per se.

Compounds of formula I contain at least ¹ one chiral center and may be enantiomers or enantiomeric mixtures, such as racemates, and if they have more than one chiral center, the diastereo mers or diastereomeric mixtures. The carbon-carbon double bond of the compounds of the invention is, according to R _p and R 2, respectively. with respect to A and B trans-configured, i.e., compounds of formula I are E-type compounds.

Compounds of formula I in which R1 is hydrogen are phosphonic acids, such as wherein R1 is alkyl are phosphinic acids, such as wherein R4 is hydroxy are phosphonic acids. As prefixes for the designation of compounds of formula I to be considered as substituted carboxylic acids, phosphino (R @ 4 is hydrogen), phosphonyl "(R. @ 1 alkyl) and phosphono" (R @ 4 hydroxy) are used.

The esterified carboxy is e.g. with an aliphatic or araliphatic alcohol, as optionally substituted lower alkanol or phenylglycanol, esterified carboxy, as appropriate, lower alkoxy or phenylglycoxycarbonyl. Preferably, it is a pharmaceutically acceptable ester carboxy such as e.g. esterified carboxy, which under physiological conditions can be converted to carboxy. These esters of formula I may also be referred to as prodrug esters.

In a pharmaceutically acceptable manner, esterified carboxy means e.g. lower alkoxycarbonyl; in a position higher than PC position, amino, mono- or di-dialkylamino or hydroxy substituted lower alkoxycarbonyl; carboxy substituted lower alkoxycarbonyl, e.g. 4-carboxy substituted lower alkoxycarbonyl; lower alkoxycarbonyl substituted lower alkoxycarbonyl, e.g. JJ-N isyalkoxycarbonyl-substituted lower alkoxycarbonyl aryl jialkoxycarbonyl, e.g. and unsubstituted or substituted benzyloxycarbonyl or pyridylmethoxycarbonyl; lower alkanoyloxy-substituted methoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl; lower alkanoyloxy or lower alkoxy substituted lower alkoxymethoxycarbonyl; bicyclo (2.2.1) heptyloxycarbonyl-substituted methoxycarbonyl, such as bornyloxycarbonylmethoxycarbonyl; 3-phthalidoxycarbonyl; lower alkyl, lower alkoxy or halogen substituted 3-phthalidoxycarbonyl; or lower alkoxycarbonyloxy-loweralkoxycarbonyl, e.g. 1- (methoxy- or ethoxycarbonyloxy) -ethoxycarbonyl.

Particularly preferred prodrug esters are e.g. lower alkyl esters with up to 4 carbon atoms, such as e.g. butyl or ethyl ester, lower alkanoyloxymethyl esters such as e.g. pivaloyloxymethyl ester, in a higher position, with the lower alkylamino substituted lower alky wood and with 2 to 4 carbon atoms in each lower alkyl group, such as e.g. 2-diethylaminoethylester, as well as pyridylmethylester, such as 3-pyridylmethylester.

In amidated carboxy, an amino group means e.g.

optionally with hydroxy monosubstituted or aliphatic residues mono- or disubstituted amino, such as amino, hydroxy, mono- or di-dialkylamino or lower alkyleneamino with 5 to 7 ring members. Preferably, it is a pharmaceutically acceptable amidated carboxy such as e.g. amidated carboxy, which can be converted to carboxy under physiological conditions.

Preferred pharmaceutically acceptable amides are compounds of formula I wherein carbamoyl is lower alkylcarbamoyl, e.g. ethylcarbamoyl, dinylalkylcarbamoyl, e.g. diethylcarbamoyl, or N- (di-dialkylamino) lower alkylcarbamoyl, e.g. N- (2-diethylaminoethyl) carbamoyl or N- (3-diethylainopropyl) carbamoyl.

Alkyl means, in the context of the present invention, a saturated aliphatic hydrocarbon residue with e.g. up to 12 carbon atoms, especially up to 8 carbon atoms, the latter region being also referred to as lower alkyl.

Jj, UU-alkylene of 1 to 3 carbon atoms is methylene,

1,2-ethylene or 1,3-propylene. The alkyl substituted tC alkylene is substituted in any position. Thus, by means of alkyl substituted methylene e.g. 1,1-ethylene, 1,1-butylene or 1,1-octylene, alkyl-substituted 1,2-ethylene e.g.

1,2-propylene, 1,2-butylene, 2,3-butylene, 1,2-pentylene or

1,2-nonylene, and alkyl-substituted 1,2-propylene e.g.

1,3-butylene, 1,3-pentylene or 1,3-decylene.

With lower alkyl or arylalkylalkyl substituted amino is mono- or di-alkylalkylamino or arylalkylalkylamino.

Aryl is also, in definitions, such as aroyl or arylalkylalkoxycarbonyl, for aromatic hydrocarbon residues which are unsubstituted or substituted by lower alkyl, hydroxy, protected hydroxy, lower alkoxy, halogen, amino, halogenatedalkyl, aminoxynylalkyl and aminoalkylalkyl, aminoalkyl or alkyl. unsubstituted or appropriately substituted 1- or 2-naphthyl, preferably unsubstituted or suitably substituted phenyl, such as phenyl, lower alkylphenyl, e.g. methylphenyl, hydroxyphenyl, halogenphenyl, e.g. 4-halophenyl, such as 4-chlorophenyl, benzyloxyphenyl, lower alkoxyphenyl, e.g. methoxyphenyl, hydroxymethylphenyl, aminomethylphenyl or nitrophenyl.

The general terms used so far and until now have the following meanings, unless otherwise defined:

The term lower means that they contain suitably defined groups or compounds of up to and 8, preferably up to and 4, carbon atoms.

Lower alkyl means e.g. C1-C4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, but may also mean C1-C8-alkyl, such as n-pentyl, n-hexyl, n -heptyl or n-octyl, preferably methyl.

Arylalkylalkyl means, even in the definitions, arylalkylalkylamino, e.g. aryl-C 1 -C 4 -alkyl, wherein the aryl of yarns has the foregoing meanings and stands in the first C 1 -C 4 -alkyl for unsubstituted phenyl-C 1 -C 4 -alkyl, such as benzyl or 1- or 2-phenylethyl.

The lower alkenyl preferably contains up to 6 carbon atoms and is bonded via the sp ³ -'nibrized carbon atom and means e.g. 2-Propenyl, 2- or 3-butenyl or 3-pentenyl may also be vinyl.

Lower alkoxy is primarily for C 1 -C 4 -alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.

Halogen preferably has an atomic number of up to 35 and is especially chlorine, further fluorine or bromine, but may also be iodine.

Halogenylalkyl is e.g. halogen-C 1 -C 4 -alkyl such as fluoromethyl, trifluoromethyl or 1- or 2-chloroethyl.

The hydroxy-lower alkyl is e.g. mono- or dihydroxy-C1-C6 alkyl, carries a hydroxy group (s) in particular in a position higher than the position "b. and means e.g. hydroxymethyl or in particular dihydroxy-C2-Cy-alkyl monoals, such as 2-hydroxyethyl, 3-hydroxyali 2,3-dihydroxy-propyl, 4-hydroxy or 2,4-dihydroxybutyl 5-hydroxy, 2,5-dihydroxy- or 3,5-dihydroxy-pentyl.

The lower alkoxy lower alkyl is e.g. mono- or di-C 1 -C 4 alkoxy-C 1 -C 4 -alkyl, carries a lower alkoxy group (s) e.g. especially in a position higher than the position, and is especially C 1 -C 4 alkoxy-C 1 -C 4 -alkyl, e.g. 2-methoxy-, 2-ethoxy-, 2-propoxyally 2-isopropoxy-ethyl, 3-methoxy- or 3-ethoxy-propyl or

3,3-dimethoxy-, 3> 3-diethoxy-, 2,3-dimethoxy- or 2,3-diethoxy-propyl- or 4,4-dimethoxy-butyl, but may also be methoxy-, ethoxy-, dimethoxy- or propoxy or isopropoxymethyl.

Mono- or di-dialkylamino is e.g. N-C 1 -C 4 -alkyls N, N-di-C 1 -C 6 -alkylamino, such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino or butylamino.

The salts of the compounds of the invention are primarily pharmaceutically useful non-toxic salts of the compounds of formula I. Such salts form e.g. in the compounds of formula I, a carboxy group is present and are primarily metal or ammonium salts, such as alkali and alkaline earth metals, e.g. sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines such as lower alkylamines, e.g. methylamine, diethylamine, or triethylamine, with hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine, tris- (hydroxymethyl) methylamine or tris- (2-hydroxyethyl) -amine, with basic aliphatic carboxylic acid esters, e.g. such as 4-aminobenzoic acid 2-diethylaminoethyl ester, with lower alkyleneamines, e.g. 1-ethylpiperidine, lower alkylenediamines, e.g. ethylenediaminers, cycloalkylamines, e.g. dicyclohexylamine, or benzylamines, e.g. N, N'-Dibenzylethylenediamine, benzyltrimethylammonium hydroxide, dibenzylamine or N-benzyl-phenylethylamine. Compounds of formula I with a primary or secondary amino group may also form acid addition salts, e.g. with preferably pharmaceutically acceptable inorganic acids, such as hydrohalic acids, e.g. hydrochloric acid, hydrochloric acid, sulfuric acid, hydrochloric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. acetic, propionic, amber, glycol, milk, fumar, maleic, wine, oxal, citron, pyrogroup, benzoic almond, apple, ascorbic, cotton, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzolsulfonic, 4-naphthalenesulfonyl, 4 or toluenesulfonyl

Pharmaceutically acceptable salts may also be used to isolate or purify. Only pharmaceutically useful, non-toxic salts which are preferred for this purpose are suitable for therapeutic use.

According to the invention, the 'prepared' compounds have valuable pharmacological properties. Thus, for example, active selective N-methyl-D-aspartic acid (NMDA) antagonists of mammalian amino acid excitatory receptors. Therefore, they are suitable for treating diseases that respond to blocking NMDA-sensitive receptors, such as e.g. cerebral ischemia, muscle spasms (spasticity), convulsions (epilepsy) anxiety states or manic conditions.

These beneficial effects can be demonstrated in in vitro or in vivo assay assays. Preferred mammals, e.g. mice, rats or monkeys, or tissues or enzymatic preparations of such mammals. The compounds may be administered enterally or parenterally, preferably orally; or subcutaneously, intravenously or intraperitoneally, e.g. in gelatin capsules or in the form of aqueous suspensions or solutions. The in vivo dose to be administered may range from 0.1 to 600 mg / kg, preferably from 1 to 300 mg / kg. Compounds in the form of aqueous solutions can be used in vitro, with -M -8 concentrations ranging between 10 m olar and 10 molar solutions.

on

The inhibitory effect / NMDA-sensitive excitatory amino acid receptors can be determined in vitro by

G. Faggu and A. Matus, Off. Nat. Acad. Sci., USA, 81,

6876-80 (1984), we measure the extent to which L- ^ H-glutamic acid binding at NMDA-sensitive receptors is inhibited.

In vivo, the inhibitory effect on NMDA-sensitive amino acid excitatory receptors can be shown to be inhibited by NMDA-induced convulsions in mice.

The anticonvulsant properties of the compounds of the invention can be further demonstrated by their effectiveness in preventing audiogenically induced seizures in ¹ DBA / 2 mice (Chapman et al., Arzneimittel-Forsch. 34, 1261, 1984).

The anticonvulsant properties can be further demonstrated by the potency of the compounds of the invention as electro-shock antagonists in mice or rats.

The anxiolytic activity of the compounds of the present invention is indicated by their good performance in the Cook / Davidson conflict model (Psychopharmacologia 15, 159-168 (1968).

The good performance of the compounds of formula I depends to a large extent on the double bond configuration. That's how the racemate from Agric turned out. Biol. Chem. 41,

573-579 (1979), B. K. Park et al., Known D-2-amino-5-phosphono 3-cis-pentenoic acids e.g. in its ability to bind to the NMDA-sensitive receptor as significantly inferior to the racemate of the invention prepared 2-aminophosphono-3-trans-pentanoic acid (in these cases, denote these compounds as E-type compounds). Compounds of formula I in which the carbon atom bearing the Rg group has the R configuration are particularly effective.

Preference is given to the preparation of compounds of formula I wherein it is hydrogen, alkyl or aryl.

The invention relates primarily to a process for the preparation of compounds of formula I, wherein A is R is hydrogen, alkyl having up to 12 carbon atoms, or hydroxy, R ₂ is hydrogen, lower alkyl, halogennižjialkil, Hydroxy, nižjialkoksinižjialkil unsubstituted or in the phenyl moiety substituted phenylalkylalkyl, lower alkenyl, halogen or unsubstituted or substituted phenyl, Rg stands for hydrogen, lower alkyl or unsubstituted or substituted phenyl, Rg stands for hydrogen or lower alkyl, Rg stands for free or pharmaceutically acceptable ester or amidated carboxy, Rg stands for amino, mono - or di-dialkylamino, A means unsubstituted or lower alkyl substituted "b, uu-alkylene with 1 to 3 carbon atoms or a bond, and 3 means methylene or a bond, provided" that A is different from the bond, If B is a bond, where the phenyl substituents are selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halogen, amino, halogenoalkylamino, hydroxybenzylalkyl, aminobenzylalkyl and nitro and have lower residues of up to and 8 carbon atoms as well as their pharmaceutically acceptable salts.

It is preferable to use a process for the preparation of compounds of formula I, wherein R1 to R4, A and B are as defined above and, by one side, Rg is lower alkoxycarbonyl or amino, mono- or di-dialkylamino, hydroxy or lower alkanoyloxy substituted lower alkoxycarbonyl and Rg stands for amino or lower alkylamino, or on the other hand Rg stands for carboxy and Rg amino, especially their (relative to the amino group bearing atom) R-enantiomers as well as their pharmaceutically acceptable salts.

It is also preferred to use a process for the preparation of compounds of formula I wherein R 2, R 4 to R 8 as well as A and B are as defined above directly and where R ₂ and · independently of one another are hydrogen, lower alkyl, phenyl or with lower alkyl, hydroxy, lower alkoxy, halogen, amino, halogenoalkyl, hydroxybenzylalkyl, aminobenzylalkyl or nitrosubstituted phenyl, in particular their relative to the amino group bearing the R-enantiomers, and their pharmaceutically acceptable salts.

The invention relates in particular to a process for the preparation of compounds of formula I, wherein R stands ^ is hydrogen, alkyl having up to 12 carbon atoms, or hydroxy, R ₂ is hydrogen, lower alkyl, phenyl, halophenyl or fenilnižjialkil, represent R and R, hydrogen or lower alkyl and, on the one hand, Rg stands for alkoxycarbonyl or hydroxy-lower alkoxycarbonyl, and Rg stands for amino or mono-lower alkylamino, or on the other hand stands for Rg carboxy and Rg amino, in each case A being unsubstituted or lower alkyl substituted with, UL1-alkylene with 1 to 3 carbon atoms or bond and B represents methylene or bond, provided that A is different from the bond if B represents a bond, especially their (relative to the amino group bearing atom) R-enantiomers, and their pharmaceutically acceptable salts .

The invention relates in particular to a process for the preparation of compounds of formula I wherein R 1 is hydrogen, alkyl of up to and 12 carbon atoms or hydroxy, R ₂ is hydrogen, lower alkyl or halogenphenyl, R 2 is hydrogen or halogenphenyl,

R 1 represents hydrogen and, on the one hand, R 8 represents lower alkoxycarbonyl. or hydroxy-lower-alkoxycarbonyl and Rg amino or mono-lower-alkylamino, and on the other hand Rg stands for carboxy and Rg amino, with A each being O, CJ-alkylene having 1 to 3 carbon atoms or bond and B being methylene or bond, provided that A different from the bond if B is a bond, especially their (relative to the amino-bearing atom) R-enantiomers and their pharmaceutically acceptable salts.

The invention relates in particular to a process for the preparation of compounds of formula I wherein R 1 is hydrogen, lower alkyl or hydroxy, R ₂ is hydrogen or lower alkyl, R ₂ and R 4 are hydrogen and, on the one hand, R 8 is lower alkoxycarbonyl or, on the other hand, for carboxy and Rg is amino, each being A for, UJ-alkylene having 1 to 3 carbon atoms, B being a bond, especially their (relative to the amino-bearing atom) R-enantiomers as well as their pharmaceutically acceptable salts.

The invention relates first and foremost to a process for the preparation of compounds of formula I wherein R 1 is hydroxy,

R ₂ for hydrogen or lower alkyl, are standing R ^ and R ^ for hydrogen ter Rg represents lower alkoxycarbonyl or carboxy, stands Rg for amino, A means methylene and B ties, especially theirs (regarding on

-13 atom bearing the amino group) of the R-enantiomers as well as their pharmaceutically acceptable salts.

The invention relates in particular to the preparation of the compounds mentioned in the examples and their pharmaceutically acceptable salts.

*

A technical problem

There was a need to prepare novel unsaturated amino acid compounds with excellent pharmaceutical effect after a technologically advantageous treatment.

The state of the art

The compounds of formula I are novel, and therefore the methods for their preparation are not known.

Description of solution to a technical problem with implementation examples

The process of the invention is carried out in the compound of formula

in which, when appropriate, means protected hydroxy, Z ₂ group R ₁ or protected hydroxy, Z ^ group R ^ or protected carboxy, Zg represents a protected group Rg and Rp R ₂ , R ^ _R A and B have the meanings given above; of the Zg group and, optionally, Zp Z ₂ and / or Z _r - by treatment with trinylalkylhalogensilane and optionally the compound obtained is converted to another compound of formula I, the resulting mixture of optical isomers is separated into components and the desired isomer is selected and / or the free compound obtained converted to salt or the resulting salt converted to the free compound or to another salt.

The protected hydroxy Z ^ and / or Z ₂ in intermediates ia .._ of formula II is e.g. with aliphatic alcohol ethene hydroxy. As is the case with halogen or in a position higher than position L, with hydroxy, oxo, lower alkoxy, lower alkanoyloxy and / or mono- or di-dialkylamino substituted lower alkanol, lower alkenol or lower alkynol, ethero hydroxy and means e.g. lower alkoxy, halogen lower alkoxy or the corresponding hydroxy, oxo, lower alkoxy, lower alkanoyloxy or mono- or dichloalkylaminone lower alkoxy. Compounds of formula II in which and / or Z ₂ are ester hydroxy are esters of an phosphorus-containing acid group and, with respect to the meaning of R _1, are phosphonic, phosphinic or phosphonic acid esters. Preferred esters are, respectively, lower alkyl esters and hydroxinyl dialkyl esters.

The Z ^ groups in the intermediates of formula II are e.g. with an acyl substituted group Κθ, i.e. optionally lower alkyl or aryl lower alkyl H-substituted acylaminoacyl, wherein the / acyl residue of an organic acid with e.g. up to 18 carbon atoms, in the particular case of e.g. with halogen, amines or phenyl, substituted alkanecarboxylic acids, or in - ^primeru Ρ ^Γ · as the case may be / with halogen. lower alkoxy or nitro substituted benzoic acid or carbonic acid polyester. Such acyl groups are e.g. lower alkanoyl, such as forrayl, acetyl or propionyl, halogenatedalkanoyl, such as 2-halogenacetyl, in particular 2-flor-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl, aroyl, as optionally substituted benzoyl, e.g. benzoyl, halogenbenzoyl, such as 4-chlorobenzoyl, lower alkoxybenzoyl, such as 4-methoxybenzoyl, or nitro-benzoyl, such as 4-nitrobenzoyl. Lower alkenyloxycarbonyl, e.g. allyloxycarbonyl, or in the case at position 1 or 2, optionally substituted lower alkoxycarbonyl, in particular lower alkoxycarbonyl, e.g. tert-butoxy-, further methoxy- or ethoxycarbonyl, further optionally substituted benzyloxycarbonyl, e.g. benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, or aroylmethoxycarbonyl, where the aroyl group represents, as appropriate, e.g. with halogen, such as bromine, substituted benzoyl, e.g. phenacyloxy carbonyl, bromophenacyloxycarbonyl.

Further, in the corresponding acylamino group 7 b

acyl stands for amino and / or phenyl, carbamoyl, carboxy imidazolyl, lower alkylthio, tetrahydropyrrolyl, hydroxy indolylor, or hydroxyphenyl substituted alkanoylamino, such as meant e.g. acyl residues of amino acids e.g. natural amino acids such as alanyl, asparaginyl aspartyl, glycyl, his.tidyl, isoleucyl, leucyl, lysyl methionyl, phenylalanil, prolyl, seryl, threonyl, - tryptophil tyrosyl or valyl; also acyl residues of oligopeptides, e.g. di- or tripeptides, such as alanine, aspartic or aspartic acid oligopeptides

Furthermore, the protected amino Zg may represent a diacylamine group. In this, diacyl means e.g. two acyl residues as defined above, or diacyl e.g. an acyl residue of an organic dicarboxylic acid with e.g. up to 12 carbon atoms, in particular the corresponding aromatic dicarboxylic acid, in the phthalic acid angle. Such a group is the first phthalimido.

In addition, protected amino Zg may also be substituted by lower alkoxycarbonyl substituted amino, such as by 2-halogenated alkoxycarbonyl, e.g. 2,2,2-trichloro16 ethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) ethoxycarbonyl, such as 2-trifluoromethylsilylethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or 2- (di-n-butylmethylsilyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl such as 2-triphenylsilylethoxycarbonyl _; substituted amino or ethereal mercaptoamino or silylamino, or may be in the form of an enamino, nitro or azido group. The ethereal mercaptoamino group is preferably a lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine or bromine, and / or a nitro-substituted phenylthioamino group or a pyridylthioamino group. Relevant groups are e.g. 2- or 4-nitrophenylthioamino or 2-pyridylthioamino. The silylamino group is primarily an organic silylamino group. In these, the silicon atom preferably has lower alkyl, e.g. methyl, ethyl, n-butyl or tert-butyl, further aryl, e.g. phenyl as substituents. Suitable silyl groups are primarily trinylalkylsilyl, in particular trimethylsilyl or dimethyl-tert. butylsilyl. The enamino groups contain on a double bond in the 2substituted position that attracts electrons, e.g. carbonyl group. Protective groups of this type are e.g. 1-acyl-lower-1-en-2-yl residues wherein acyl, e.g. a corresponding lower alkanecarboxylic acid residue, e.g. acetic acids, as appropriate, e.g. with lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chloro.in/ or nitro, substituted benzoic acids, or in particular a carbonic acid polyester, e.g. as a lower alkylpolyester of carbonic acid, e.g.

- 17 methylpolesters or ethylpolesters, and loweralkyl-1-ene means especially 1-propene.

Suitable protecting groups are primarily 1-lower alkanoyl-prop-1-en-2yl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-loweralkoxycarbonylprop-1-en-2-yl, e.g. 1-ethoxycarbonyl-prop-1-en-2-yl.

The protected carboxy is typically protected in ester form, the ester group being cleavable under reductive, as hydrolytic, or solvolytic, as acidolytic or hydrolytic, as acidic, basic, or neutral hydrolytic conditions. The protected carboxy group may further, under physiological conditions, be transmissible, or readily translatable, to another functionally modified carboxy group, such as to another esterified carboxy group. Such esterified carboxy groups contain as esterifying groups primarily silyl groups, in particular trinylalkylsilyl groups, further in position 1 or 2 of the optionally substituted lower alkyl groups. Preferred carboxy groups in the ester form are, among others, trinylalkylsilyloxycarbonyl, e.g. triraethylsilyloxycarbonyl, (hetero-) arylmethoxycarbonyl having from 1 to 3 aryl radicals or with a monocyclic heteroaryl radical, wherein in this case the mono-polysubstituted e.g. with lower alkyl, such as tert.-lower alkyl, e.g. bybutyl, halogen, e.g. chlorine and / or nitro. Examples of such groups are, for example, e.g. as mentioned above, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, optionally e.g. as mentioned above, substituted diphenylmethoxycarbonyl, e.g. diphenylraethoxycarbonyl, or triphenylmethoxycarbonyl, or to a specified extent, e.g. as mentioned above, substituted picolyloxycarbonyl, e.g. 4-picolyloxycarbonyl, or furfuryloxycarbonyl, as

2-furfuryloxycarbonyl.

In particular, hydroxy Z ^ and / or Z ^ lower alkoxy, such as methoxy, ethoxy or isopropyloxy, protected carboxy trifluoroalkylsilyloxycarbonyl, such as trimethylsilyloxycarbonyl, and protected, optionally, lower alkyl or arylalkylalkyl substituted aminoamino lower amino, aminoalkyl formylaminoamino-lower alkylamino-formylamino-aminoalkyl-formylaminoamino-lower alkylamino-formylamino-aminoalkyl substituted - lower-alkanoyl-N-lower-alkylamino, especially Nformyl-N-lower-alkyl-amino, e.g. N-formyl-N-methyl-amino, or lower alkoxycarbonylamino, preferably tert-butyloxycarbonylamino.

Trinylalkylhalogensilanes are e.g. trichloroalkylsilanes, or in particular trichloalkylbromosilanes, preferably those in which lower alkyl _; the groups represent identical C 1 -C 6 alkyl radicals. Trimethylbromsilane, 'trimethylsiloxane', is preferred.

The release of the protected groups, i.e. hydroxy from the protected hydroxy groups of Z ₁ and / or Z £, the carboxy of the protected carboxy groups of Zg and / or optionally with lower alkyl or phenylalkylalkyl substituted amino of the protected amino groups of Zg by treatment with trinylalkylhalogensilane, e.g. . in an inert solvent, such as a halogenated, preferably, or fatty hydrocarbon, e.g. in dichlorinethane or other tri-or tetrachloromethane, trichloroethane or tetrachloroethane, in the temperature range from about -25 ° C to +50 ° C, preferably from about 0 ° C to about 30 ° C, e.g. at temperatures in the range of room temperature, ie at about 15 ° C to about 25 ° C, preferably under predominantly anhydrous conditions and under inert gas, e.g. under argon or nitrogen.

We treat in the usual way, with two cleaning operations being particularly advantageous. Either the crude product can be converted into a readily soluble derivative, e.g. from silyl, and as such distillatively obtained, then desilylated. Alternatively, the crude product may be mixed with an excess acid reactant such as hydrochloric acid to remove it.

For example, e.g. compounds to which the corresponding acid can be added, e.g. lower alkylene oxides (epoxides) than propylene oxide.

If the compounds of formula I in which R1 is esterified or amidated carboxy, such as lower alkoxycarbonyl or carbamoyl are to be obtained as the final substances, the starting materials of formula II and the conditions of the process can be chosen by releasing otherwise Zp Z ^ and Zg, however, that Z ^, which stands for the desired group Rg, remains unchanged at this stage of the process.

A particularly preferred embodiment is therefore directed to the preparation of compounds of formula I wherein R 1 -C 1 -alkoxycarbonyl and R 8 are amino. According to this embodiment, it is preferable to proceed from the compounds of formula II, wherein Z ₂ and Z _{2 represent} lower alkoxy or in a position higher than the position JL ·, with halogen, such as chlorine, substituted lower alkoxy, Z 2 represents C 1 - C1-6alkoxycarbonyl and Zg is lower alkanoylamino, such as forynylamino, or lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino. When starting from such compounds of formula II, the release of the protected groups in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at room temperature range, with a reagent such as trimethylbromsilane, followed by treatment with lower alkanol, such as ethanol, and a hydrogen halide receiver, such as an aliphatic epoxide, in particular epoxysilane, e.g. propylene oxide, so controlled to give directly the compounds of formula I, wherein R1 stands for hydroxy, R4 for C ₁ -C 4 -alkoxycarbonyl, R 8 stands for amino and the variables R 4, R 4 and R 4 for the formula I have the meanings given.

This process is particularly preferred for the preparation of compounds of formula I in which A is methylene or 1,3-propylene and B is a bond, R4 and R4 are hydrogen and R4 is alkyl with up to 4 carbon atoms such as methyl.

Another, also preferred, embodiment refers to a process for the preparation of compounds of formula I wherein R1 is carboxy. In this case, it is preferable to proceed from the compounds of formula II, wherein Z1 and lower alkoxy, or in a higher position, with halogen, such as chlorine, substituted lower alkoxy, are optionally protected, e.g. by treatment with N, O-bis-trimethylsilylacetamide silylated, carboxy and Zg represents a lower N-alkoxycarbonylamino, especially a 0 (-branched lower alkoxycarbonylamino, such as a tert-butyloxycarbonylamino. In this case, the carboxy group is preferably, but not necessary, protected in the interim by treatment with a silylating agent, such as an N, O-silylcycloalkanoic acid amide, for example, with yl, O-triethylsilylacetamide, The intermediates of formula II are preferably prepared by treating a compound of formula

(III), where R ₂ , R 4, R 4, A and B are defined as for formula I, Zg has the meaning of Rg or stands for protected carboxy, Zg stands for the protected group Rg and X for reactions capable of ester hydroxy, metabolised with a compound of formula (IV) wherein Z ₁ is hydroxy protected as appropriate, Z _{2 is} R ₂ or stands for protected hydroxy and R is a tetrahydro group and can be used without isolation or special purification.

The compounds of formula III can be prepared e.g. such that the N-protected ester of aminolonic acid of formula

hz ₅ where Z _q and Z 1 represent the same or different esterified carboxy groups, e.g. a lower alkoxycarbonyl group, is itself known to be metabolised by compounds of formula r

J-B-X '(VI) where X and X are, independently of one another, a reaction capable of esterified hydroxy such as halogen'. The compounds of formula (VII) thus obtained

B-W-Z;

h

X-AR2 can be converted to compounds of formula III, wherein R1 represents hydrogen such that e.g. under hydrolytic conditions, such as acid hydrolysis conditions, e.g. with halogenated acids such as hydrochloric acid, preferably when heated, soaped and decarboxylated or, without pre-saponification, dealkoxycarbonylated by heating in an aqueous aprotic solvent such as diraethylsulfoxide in the presence of alkali halide, such as sodium chloride

This variant is suitably particularly suitable for the preparation of compounds III, wherein R1 represents hydrogen, Zg free or ester carboxy and Zg protected amino, such as lower jialalkanoylamino.

Intermediates III, where A, optionally methyl, substituted methylene, B bond, X halogen and Zg form lamino, can be further prepared by treating the compound of formula

D = C / Rz = 0 3 '(VIII), where D stands for optionally substituted methylidene, such as the corresponding "L", ft-unsaturated aldehyde, e.g. acrolein or methacrolein, is reacted with an oti-isocyanic acetic kissin derivative, such as the lower alkyl ester of Jj-isocyanacetic acid. With suitable catalysis, such as with lower-valence metal salts, metals

i.e. derived from / groups I and II of the periodic table of the elements, e.g. with suitable metal oxides or metal halides, such as zinc chloride, cadmium chloride, silver oxide or preferably copper oxide, or gold (I) tetrafluoroborate complexes with aliphatic or cycloaliphatic isocyanides such as e.g. bis- (cyclohexylisocyanide) gold (I) tetrafluoroborate, the 5vinyl-2-oxazoline-4-carboxylic acid derivatives are thus obtained in a known manner, e.g. esters of formula ^D ' ¹ / ^s

M which can be converted to the compounds of formula

Open chain K2, where D stands for optionally substituted methylidene. These compounds can again be converted to compounds of formula III by selective halogenation, such as bromination or chlorination, preferably upon cooling, and by displacement of the double bond in terms of allyl displacement.

- 24 Another process for the preparation of compounds II, wherein R1 is hydrogen, A is methylene or 1,3-propylene and hydroxy, is based on the principle that a compound of formula

(XI) in which R ^ and R is hydrogen or preferably lower alkyl, such as methyl, and R stands for ^ amino-protecting group, is condensed with an ester of 2-R ₂ ~ acetic acid, or first with a R ^ -etenkovinsko compound, for example. with isopropenylmagnesium bromide, and then with acetic acid ester, in the resulting compound of formula ί ¹ / S

Ra

CtJzCHz-ZS

A, o ^z '\ \ / \ (XIIa) bzw.

° \ / \

A, (XIIb) wherein the ester is carboxy, e.g. lower alkoxycarbonyl, this group is reduced, e.g. with diisobutylaluminum hydride, to a hydroxymethyl, hydroxymethyl group is halogenated, e.g. brominated with tetrabromomethane / triphenylphosphine, the resulting compound with the f ormula

(XIII), where A is methylene or. 1,3-propylene, X halogen, e.g. bromine, further reacted with the compound of formula IV, cleaving the oxazolidine ring, e.g. with an ion exchanger such as Amberlyst 15θ and in the resulting compound of formula

Zi-P-CH ₂

ch ₂ oh • 6 (XIV) wherein Zg represents a protected amino group of the formula Rg-NH- (II '). oxidize the hydroxymethyl group in the usual way in carboxy.

The procedures described above for the preparation of intermediate products III and their subsequent transformation into intermediate products II need not be carried out in order to isolate all intermediate steps. Thus, in particular, the translation of compounds X into compounds III as well as their further metabolism by compounds IV into intermediates II can advantageously be carried out in situ.

A preferred embodiment of the process of the invention therefore lies in the fact that a compound of formula f ³ f ^u b - £ - with ₅ (m), wherein F 1, R 2, R 4, A and B are defined as for formula I, Z $ has the meaning R ^ or stands for protected carboxy, Zg stands for protected group Rg, e.g. protected amino, and X for the reaction-capable ester hydroxy is reacted with a compound of formula

(IV), where Z ^ stands for the protected hydroxy, Z _{2 has the} meaning R ^ or stands for the protected hydroxy, and represents the R group which is etched, the protected groups Zg, and optionally Zp and / or Z $ is released by treatment with trinylalkylhalogensilane, e.g. with trimethylbromsilane, and optionally the resulting compound of formula I is converted to another compound of formula I and / or optionally the resulting compound of formula I is converted to a salt or the resulting salt is converted to another salt or to a free compound of formula I and / or a given the optical isomer is isolated from a mixture of stereoisomeric forms of the resulting compound of formula I or a salt thereof.

Reactions A capable esterified hydroxy group such as X is a strong organic acid esterified hydroxy group, e.g. with aliphatic or aromatic sulfonic acid (such as lower alkanesulfonic acid, in particular methanesulfonic acid, trifluoromethanesulfonic acid, in particular benzolsulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid and p-nitrobenzenesulfonic acid), or with strong halogen or hydrochloric acid, hydrochloric acid, hydrochloric acid hydrochloric acid or most preferably hydrochloric acid or hydrobromic acid, a esterified hydroxy group.

In this connection, it should be noted that the surprising finding is that the preparation of intermediates II and their subsequent metabolism of the invention to the final substances I can be conducted stereoselectively. I.e. nor in the reaction sequence III + IV—> 11 oz. Ha—> 1, not even in the reaction sequences X

III and XI—> XII—> XIII—> XIV-911 no reverse configuration or notable racemization occurs. The process of the invention is therefore admirably suitable for the direct preparation of compounds of formula I with a preferred R-configuration on a carbon atom bearing the amino group Rg. The preparation of sterically uniform compounds of formula I as well as sterically uniform intermediates of formulas II, III, X, XI, XII, XIII and / or XIV is a further object of the present invention.

In another preferred embodiment, the compound of formula is subjected

selective halogenation, e.g. with thionyl chloride, to the corresponding intermediate III and metabolised in situ. i.e. without isolation, with component IV.

As mentioned above, the compounds obtained according to the invention can be converted to other compounds of formula I. In particular, the free amino group Rg can be substituted, e.g. is converted to the alkylamino group which is optionally phenylated, the free carboxy Rg is esterified or. esterified or amidated carboxy Rg is converted to free carboxy and / or free or esterified carboxy Rg is converted to amidated carboxy.

For the conversion of an amino group to an alkyl group which is phenylated optionally, the amino group may be alkylated by substituting e.g. with reactive esterified, optionally phenylated alkanolones, such as alkyl halide, or reductively, such as with an aldehyde or ketone,. as well as catalytically activated hydrogen, or, in the case of formaldehyde, advantageously with formic acid as a reducing agent.

The free carboxylic acids of formula I or their salts may, with known alcohols or their corresponding derivatives, be converted into the corresponding esters by known methods

i.e., with Formula I, e.g. lower alkyl esters, arylalkylalkyl esters, lower alkanoyloxymethyl esters or lower alkoxycarbonylalkylalkyl esters.

For esterification, the carboxylic acid can be reacted directly with diazoalkane, in particular diazomethane, or · with an appropriate alcohol in the presence of a strongly acid catalyst (eg, hydrohalic, sulfuric or organic sulfonic acid) and / or a dehydrating agent (eg dicyclohexylcarbodiimide). Alternatively, the carboxylic acid can be converted into a reaction-capable derivative, such as into a reaction-capable ester, or into a mixed anhydride, e.g. with an acid halide (e.g., acid chloride in particular) and the activated intermediate is reacted with the desired alcohol.

Compounds of formula I wherein Rg stands for esterified carboxy, such as in particular lower alkoxycarbonyl, e.g. ethoxycarbonyl can be converted to compounds of formula I wherein R8 is carboxy, e.g. by hydrolysis, in particular in the presence of inorganic acids, such as hydrohalic acids or sulfuric acid, or in another type of aqueous alkali such as alkali hydroxides, e.g. lithium or sodium hydroxide. In this connection, it should be noted that the release of carboxy from esterified carboxy can also be managed in such a way that no noteworthy racemization occurs. This can be achieved in particular by treating from about 0.2 to about 4-normal; e.g. about 1-normal, i.e. about 0.5 to about 2-normal aqueous mineral acid, if necessary when heatedUjnpr. at about 60 ° C to about boiling point, ie about 100 ° C. Surprisingly, slandering is taking place e.g. lower alkyl esters of phosphonic acid, a carboxylic acid of formula I, also without the addition of acidic or basic reagents _in high yield. A preferred process for the preparation of the carboxylic acids of formula I from the corresponding lower alkyl esters than the corresponding ethyl esters, therefore, exists in acid hydrolysis by treatment with about 0.2 to about 4-normal aqueous mineral acid, e.g. hydrochloric, sulfuric, phosphoric acid and the like. as well as in - preferably autocatalytic - saponification in water, preferably at elevated temperatures, as under reflux.

The above reactions are carried out by standard methods in the presence or absence of diluents, preferably those which are inert to the reagents and represent solvents for them, catalysts, condensing agents, or other agents and / or in an inert atmosphere, at low temperatures, at room temperature or at elevated temperatures, preferably at the boiling point of the solvents used, at atmospheric alinadatospheric pressure.

The invention further encompasses a large variant of the present process in which an intermediate obtained at any stage of this process is used as the starting material and the remaining steps are carried out, or the process is interrupted at any stage or the starting materials are formed under the reaction conditions or using the reaction conditions .components in the form of their salts or optically pure antipodes. In these reactions, mainly those starting materials should be used,

leading to the formation of compounds, of the above above as special precious. The invention also relates to new ones output substances and on the process for preparing them. It depends on the choice output substances and methods are

may be novel compounds in the form of one of the possible optical isomers or mixtures thereof, e.g. depending on the number of asymmetric carbon atoms in the form of pure optical isomers, 'as antipodes, or mixtures of optical isomers such as racemates, or mixtures of diastereoisomers from which the antipode can be isolated if desired.

The resulting mixtures of diastreoisomers and mixtures of racemates can, in a known manner, be separated into pure isomers, diastreoisores or racemates due to physicochemical differences, e.g. by chromatography or fractional crystallization.

The resulting racemates (racemic diastereoisomers) can be further separated into optical antipodes by known methods, e.g. by recrystallization from an optically active solvent, using microorganisms or enzyme catalysts in free or immobilized form or by metabolizing an acidic end product with an optically active base which forms salts with racemic acid and separating the salts thus obtained, e.g. based on their various solubilities, into diastreoisomers from which antipodes can be released by the action of suitable agents.

Basic racemic products- can also be separated into antipodes, e.g. by separating their diastereoisomeric salts, e.g. by fractionation crystallization of their d- or l-.tartrates. Any racemic intermediates or starting materials can be separated in a similar way.

Finally, the compounds of the invention are obtained either in free form or in the form of their salts. Any base obtained can be converted to a suitable acid addition salt, preferably using a pharmaceutically acceptable acid or anion-exchange preparation, or the resulting salts can be converted into suitable free bases, e.g. using a stronger base such as a metal or ammonium hydroxide or base salt, e.g. alkali hydroxide or carbonate, or a cation exchange composition. The compound of formula I may also be converted to the corresponding metal or ammonium salts. These or other salts, e.g. picrates can also be used to clean the resulting bases. The bases are converted into salts, the salts separated and the bases released. In view of the close relationship between the free compounds and the compounds in the form of their salts, the corresponding salt of that compound is included whenever appropriate in the present application, provided that it is possible or reasonable under the given conditions.

The compounds and their salts may also be obtained in the form of their hydrates or may contain other solvents used for crystallization.

The pharmaceutical compositions of the invention are those suitable for enteral, oral or rectal administration and parenteral administration to mammals, including humans, for the treatment and prevention of disorders that respond to NMDA receptor blocking, such as e.g. cerebral ischemia, muscle spasms (spasticity), convulsions (epilepsy), anxiety states or manic conditions. They comprise an effective amount of a pharmacologically active compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention may be used in the preparation of pharmaceutical compositions comprising an effective amount of the compound alone or in association or admixture with excipients or carriers suitable for enteral or parenteral use. Preferred · are tablets or gelatin capsules containing the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, b) glidants, e.g. silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol, for tablets also with c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or pv. ipyrrolidone, optionally d) with decomposable or. disintegrating agents, e.g. starches, agars, alginic acid or its sodium salt, or sparkling mixtures and / or e) with absorbents, colorants, flavoring agents and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. These compositions may be sterilized and / or contain adjuvants, such as preservative, stabilizing, wetting or emulsifying agents, dissolution enhancers, osmotic pressure regulating salts and / or buffers. They may additionally contain other therapeutically valuable substances. These preparations are prepared by conventional methods of mixing, granulating or milling. coatings and containing about 0.1 to 100%, preferably about 1 to 50%, of the active ingredient. A unit dose for a mammal of 50 to 70 kg may contain between about 1 and 500 mg, preferably between about 10 and 500 mg, of the active ingredient.

The following examples illustrate the invention and are not intended to be limiting. Temperatures are given in degrees Celsius and all parts are given in mass. parts. Unless otherwise stated, all evaporations under reduced pressure, preferably between about 2 and 13 kPa, are performed.

- 34 EXAMPLE 1 E-2-Amino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester

a) 5- (2-Propenyl) -oxazoline-4-carboxylic acid ethyl ester ()

1.6 g of red copper (I) oxide are presented in 200 ml of benzene. With vigorous stirring, a solution of 140 g of isocyanacetic acid ethyl ester and 105 g of freshly distilled methacrolein in 200 ml of benzene was added to this suspension for 10 minutes. The reaction temperature is maintained by ice cooling between 30 and 32 °. After the addition is complete, hold the nozzle until the exotherm is stopped at 30 to 32 ° and then stir for 1 hour at room temperature. After filtration of excess copper (I) oxide, the filtrate was evaporated in vacuo at 30 °. 600 ml of ether are added to the residue, filtered through celite and evaporated to dryness in vacuo. This gave 5- (2-propenyl) ethyl ester

2-Oxazoline-4-carboxylic acid as a colorless oil with boiling water. 110 to 130 ° (5.3 Pa).

b) E-2-Formylamino-3-hydroxy-4-methyl-4-pentanoic acid ethyl ester (R).

139 g of 5- (2-propenyl) -2-oxazoline-4-carboxylic acid ethyl ester was dissolved in 70 ml of tetrahydrofuran and added

27.4 g of water and 3.5 g of triethylamine. The reaction mixture was stirred for 62 hours at 65 to 70 ° and after cooling into 200 ml of dichloromethane. The solution was dried over 200 g of magnesium sulfate, filtered and evaporated in vacuo. Purification of the remaining viscous oil by column chromatography (silica gel; hexane / acetone 3: 2) afforded 2-formyl 35 amino-3-hydroxy-4-methyl-4-pentanoic acid ethyl ester as a diastereomeric mixture with m.p. 67 °.

c) E-2-Formylamino-4-methyl-5-diisopropylphosphono-3-pentanoic acid ethyl ester (_3)

To a solution of 40.20 g of crude ethyl ester of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid in 60Q ml of 1,2-dichloroethane was added dropwise 5 minutes at 20 ° with argon 18.6 ml of thionyl bromide (weakly cooled). After stirring at room temperature for 2 hours, 400 ml of water are added, slowly adding the first 50 ml. Mixture - Stir well for another 15 minutes. We decide the organic phase and

Wash 3 times with ice water and once with ice / saturated potassium bicarbonate solution (pH about 7.5). After drying over sodium sulfate and distilling off 1,2-dichloroethane at 35 ° in vacuo, crude bromide is obtained as an intermediate, which is mixed at room temperature with 160 ml of triisopropyl phosphite and then stirred at 75 ° for 17 hours (bath temperature {) at partial vacuum (about 13 kPa). The excess triisopropyl phosphite and other volatile by-products are then distilled off under high vacuum (bath temperature 90 °). Chromatography of the residue on a 10-fold mass of quartz gel (grain size of 0.04 to 0.06 mm) using ethyl acetate as eluant afforded E-2-formylamino-4-methyl-5-diisopropyiphosphonic-3-pentanoic acid ethyl ester yellow honey, IR (CH ₂ Cl ₂ ): 3410 (NH); 1740 (CO-ester); 1690 (CO-amide); 1235, (P = 0); 980-1015 (POC).

d) E-2-Amino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester (4)

- 36 To a solution of 25.42 g of E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentanoic acid ethyl ester and, 102 'ml of dry dichloromethane are added dropwise at 20 ° under argon for 15 minutes.

56.7 ml of trimethylbromosilane. After stirring at room temperature for 20 hours, 102 ml of ethanol are added dropwise over 15 minutes and the whole is stirred for another 20 hours. The clear reaction solution was then completely evaporated in vacuo. The residue was evaporated 3 more times under the addition of 100 ml of toluene each time. The oily residue was dissolved in 102 ml of ethanol and a solution of 102 ml of propylene oxide in 102 ml of ethanol was added dropwise. The crystalline product was filtered off after 2 hours (room temperature) and washed with ethanol and ether. After drying (80 [deg.] C. for 4 hours) under high vacuum, analytical grade ethyl ester of E-2-amino-4methyl-5-phosphono-3-pentanoic acid is obtained, m.p. 21 2 ° (dec.).

EXAMPLE 2 E-2-Amino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester

a) E-2-Forraylamino-4-methyl-5-dimethylphosphono-3-pentanoic acid ethyl ester (J_)

100.5 g of 2-formylamino-3-hydroxy-4-methyl-pentenoic acid ethyl ester was dissolved in 1.5 l of dichloroethane, 47 ml of thionyl bromide was added dropwise at 20 to 25 ° C and the product was stirred for 1 hour at room temperature. 750 ml of water were added to the reaction mixture and stirred vigorously for 10 minutes. The organic phase was determined, extracted with 1 l of ice water, 1 1 1 N potassium bidrogencarbon solution and n 1 1 more ice water, dried over magnesium sulfate and evaporated. The thus obtained E-5-bromo-2-formyl amino-4-methyl-3-pentenic acid ethyl ester, yellow oil, was mixed directly with 50 ml of trimethyl phosphite and stirred for 15 hours at a bath temperature of 70 ° and about 15 kPa. The reaction mixture was degassed for 30 minutes in a water jet vacuum and for 1 hour in a high vacuum at 40 to 50 °. The resulting product was taken up in 600 ml of water and extracted 3 times with 500 ml of acetone each. The combined organic phases are washed twice with 300 ml of water each. All the aqueous phases are combined, saturated with sodium chloride and extracted 3 times with 500 ml of dichloromethane each. The combined organic phases were dried over magnesium sulfate and evaporated. The product was chromatographed over a crunchy gel (ocetester / isopropanol 7: 2). E-2-Formylamino-4-methyl-5-dimethylphosphono-3-pentanoic acid ethyl ester is thus obtained as a yellow oil, 1 H-NMR (DMSO):

1.82 (d, 3H, 4-CH ₃ ), 2.69 (d, 2H), 5.03 (m, 1H), 5.32 (m,

1H).

b) E-2-Amino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester (2)

16.9 g of E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenic acid ethyl ester was dissolved in 80 ml of dichloromethane under a nitrogen atmosphere and 30 ml of trimethylbromsilane was added dropwise at about 25 ° for 30 minutes. The mixture was stirred for 20 hours at room temperature, then 80 ml of ethanol was added dropwise at about 25 ° C for 30 minutes, then stirred again for 22 hours at room temperature and then evaporated. The residue was dissolved in 80 ml of ethanol and, under gentle cooling, 80 ml of propylene oxide in 80 ml of ethanol were added dropwise. The mixture was stirred for 1 hour at room temperature, filtered and washed with ethanol and ether. E-2 ~ amino-4-methyl-5-phosphono-38 3-pentenoic acid ethyl ester is thus obtained, m.p. 215 to 217 ° (dec.).

EXAMPLE 3 E-2-Amino-4-methyl-5-phosphon-3-pentenoic acid ethyl ester

a) E-2-Formylamino-4-methyl-5-di (2-chloroethyl) phosphoin-3-pentenoic acid ethyl ester (/)

8.2 g of E-5-bromo-2-formylamino-4-methyl-3pentenoic acid ethyl ester and 19 ml of tris- (2-chloroethyl) phosphite were stirred for 20 hours at a bath temperature of 70 °. The resulting mixture was chromatographed on silica gel, eluting with acetone and acetone / isopropanol (7: 1), and the product was crystallized from acetone / diethyl ether. Thus, ethyl ester of E-2-formylamino-4-methyl-5-di (2-chloroethyl) -phosphono-3-pentanoic acid is obtained, m.p. 47 to 49 °.

b) E-2-Amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (2.)

Using 3 g of E-2-formylamino-4-methyl-5di (chloroethyl) phosphono-3-pentenoic acid ethyl ester yields the analogous method of Example 2 to E-2-amino-4-methyl-5-phosphono-3- pentenic acids, m.p. 215 ° (dec.).

EXAMPLE 4 E-2-Amino-4-phosphonomethyl-3,6-heptadenoic acid

a) 2-methylene-4-pentenaldehyde (_l)

A mixture of 14.7 S piperazine, 20.5 g of ice and 21.28 g of water are mixed s 24.5 g of 37% aqueous solution ine formaldehyde and mix 10 minutes at room temperature. Ob continued stirring was added to 25.35 g of 4-pentenaldehyde and the reaction mixture is heated · 3 hours at 75 °. After cooling on

room temperature the organic phase is decided and the aqueous phase

Extract 3 times with 50 ml of diethyl ether each. The combined organic phases are washed 3 times with 50 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. Fractionated distillation of the residue gave 2-methylene-4-pentenaldehyde as a colorless oil, boiling. 65 ° / 6.6 kPa.

f b j 5- / 2- (1,4-Pentadienyl) / 2-oxazoline-4-carboxylic acid methyl ester (j2)

By reacting isocyanacetic acid methyl ester with 2-raethylene-4-pentenaldehyde in toluene in an analogous manner as described in Example 1 _? and further purification by column chromatography (silica gel, acetone / hexane 1: 4) gave 5- (2- (1,4-pentadienyl)) -2-oxazoline-4-carboxylic acid methyl ester as a colorless oil, 1 H-NMR ( CDCl 4): 2.80 (d, 2H, CH ₂ ); 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 was dissolved in 20 ml of tetrahydrofuran and 10 ml of water was added. The reaction mixture was stirred for 1.5 hours at 75 ° and evaporated after cooling in vacuo. Crystallization of the isopropanol / hexane residue obtained gave 2-formylamino-3-hydroxy-4-methylene-6-heptenic acid methyl ester as a diastereomeric mixture, m.p. 75 to 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-heptenic acid methyl ester in 200 ml of dry tetrahydrofuran is cooled to -78 ° and 20 ml of 1,5-hexadiene is added. Slowly drop 9 ml of thionyl bromide so that the reaction temperature does not exceed -50 °. After the addition is complete, the reaction is heated to 0 ° C for about 3 hours and stirred at this temperature for 3 hours. The solution was then poured onto 300 ml of cold (5 to 10 °) saturated sodium bicarbonate solution and extracted with diethyl ether. The organic extracts were washed with saturated brine, dried over magnesium sulfate and evaporated in vacuo. Purification by column chromatography (silica gel, acetone / hexane 1: 1) gave E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl as a colorless oil, ¹ H-NMR (CDCl ₃ ): 3.20 ( d, 2H, C (5) -H); 4.00 (s, 2H, CH ₂ Br).

d) E-2-Formylamino-4-diethylphosphonomethyl-3,6-heptadienoic acid methyl ester Q)

3.7 g of E-2-formyl-amino-4-bromomethyl-3,6-heptadienoic acid methyl ester were dissolved in 37 ml of triethyl phosphite and heated at 75 ° C for 8 hours. The excess triethyl phosphite is then distilled off under high vacuum. Purification by column chromatography (silica gel, methanol / acetic ester 1:10) gave E-2-formilaraino-4-diethylphosphonomethyl 1-6,6-heptadienoic acid methyl as a colorless oil, ¹ H-HMR (CDCl 2): 2.54 ( d, 2H, -CH ₂ ); 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 was dissolved in 12 ml of dichloromethane and 0.7 ml of trimethylodsilane was added dropwise. After stirring at room temperature for 4 hours, as much as 1 N sodium thiosulphate is added until the reaction solution is clear. The reaction mixture was then mixed with 10 ml of 4.5 N hydrochloric acid solution and stirred at room temperature for 30 minutes. The aqueous phase was decided, washed twice with 20 ml of dichloromethane each and evaporated in vacuo. The residue was dissolved in 10 ml of 4.5 N hydrochloric acid, stirred at room temperature for 16 hours and then evaporated in vacuo. The residue thus obtained is taken up in 40 ml of ethanol, the filter is clear and 10 m propylene oxide / ethanol (1: 1) is added dropwise. The resulting white precipitate was filtered off and purified by column chromatography (Dowex 50 x 8 / H ₂ O). Evaporation gave E-2-amino-4-phosphonomethyl-3,6-heptadienoic acid as a white crystallite, m.p. 154 to 157 °, ¹ H-NMR (D 2 O): 2.64 (d, 2H, P-CH ₂ ); 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-pentanoic acid

a) (L) -N-tert. butoxycarbonyl-serine-N-methoxy-N-methylamide

d)

To a solution of 1 kg (L) -N-tert.butoxycarbonyl-serine

Q in 1 L of tetrahydrofuran is added for 27 minutes at -20 to -25

541.6 ml of N-methylmorpholine. After stirring for 15 minutes, 699.6 ml of hydrochloric acid isobutyl ester and 445.8 ml of N-methoxy-N-methylamine are added for 42 minutes at the same temperature. Let it warm to room temperature and evaporate the solvent on a rotary evaporator. The residue was dissolved in 3 l of ethyl acetate, the solution was extracted with 3.5 l of 2 n hydrochloric acid and 3 l of saturated NallCO 4 solution.

The aqueous phases are extracted 3 times with 1 L of ethyl acetate each time, the organic phases are washed with 2 L of saturated NaCl solution, dried with MgSO 4 and evaporated at 50 ° C in vacuo. The residue was stirred for 2 hours under ice-cooling with 3.5 l of hexane. The white suspension of the filtrate was washed with 1 l of hexane on the filter. Drying at 40 ° in vacuo gave 781 g _1_, m.p. 116 to 117 °. ^C i0 ⁿ 20 ^N 2 ° 5 ' ^Calcd - ^{: c 48} »38%, H 8.12%, M 11.28%; found:

C 48.28%, H 8.02%, N 11.32%.

b) N-methoxy-N-methylamide (L) -3-tert-butoxycarbonyl-2,2-dimethyl oxazolidine-4-carboxylic acid (2)

A mixture of 781 g of 3.3 l acetondimethylacetal and 42 g of pyridinium (toluene-4-sulfonate) was heated to 72 ° and then boiled under reflux for 17 hours. After addition of 20 g of pyridinium tosylate, boil for 9 hours, distilling off about 750 ml of solvent and replacing with 700 ml of acetone-dimethylacetal. The solvent was evaporated and the residue was dissolved in 2 l of diethyl ether.

The organic phase is extracted twice with 1 n hydrochloric acid (1 L,

0.5 1) and once with saturated NaHCO3 solution. NaCl (0.3 l each). The aqueous phases are extracted twice with 0.5 l of diethyl ether each. The residue of the organic phase was dried with MgSO 4, hot dissolved in 350 ml of hexane / diethyl = 9: 1. After addition of 600 ml of hexane and 50 ml of diethyl ether, cool and dilute with 1.1 l of hexane during crystallization. The suspension is filtered. The filter residue is washed with hexane. Drying at 40 ° in vacuo gave 640 g 2 melt. 67 to 68 °. ^c -i3 ^H 24 ^N 2 ⁰ 5 ^{; calculated} - ^{: c} 54.15%, Π 8.39%, N 9.72%, found: C 53.96%, H 8.37%, N 9.91%.

- 43 c) (4S) -2,2-dimethyl-4-formyl-3-oxazolidine-carboxylic acid tert-butyl ester (3.) c, a) Reduction with LiAlH ^

To a solution of 28.8 g 2 in 350 ml of dry diethyl ether, 2.53 g of LiAlH 2 was added under ice-cooling; internal temperature 5 to 15 ° C. After stirring at 5 ° for 1.5 hours, a solution of 5.77 g of KHSO 4 in 60 ml of water was added dropwise so that the temperature did not exceed 15 ° (40 min). The suspensions were filtered and the filter residue was washed with ether. With the addition of ice, the filtrate was washed twice with 200 ml of 1 n hydrochloric acid, twice with 150 ml of 5% NaHCO3 solution each time and with saturated NaCl solution. The aqueous phases were extracted once with diethyl ether, the organic extracts were dried with zH 2 SO 2 and evaporated. Distillation of the residue at 0.4 mbar yields 17.78 g 3 (boiling point 85-90 ° C), / Jb / p = -93 ° (C = 1, CHC1 ₃ ); C ₁₁ H _ig IJO _ll ; calculated: C 57.63% ', H 8.35%,' I 6.11%,

27.91%; found: C 57.59%, H 8.54%, N 6.17%, 0 27.74%.

c, b) Reduction with diisobutylaluminum hydride

To a solution of 10 g 2 in 120 ml of dry diethyl ether was added dropwise 66 ml of a solution of diisobutylaluminium hydride in hexane under ice-cooling. The mixture was stirred for 10 minutes at room temperature, cooled again to 0 and a solution of 38 g KHSOjj in 160 ml water (temp. 0-15 °) was added. Stirred for 30 minutes at room temperature and filtered. The filter residue was washed with diethyl ether and water, the organic phase of the filtrate was washed by ice-cooling 2 times with 100 ml of 1 n hydrochloric acid, twice with 100 ml of a 10% solution of NallCO2 and twice with

100 acre of saturated NaCl solution. The organic extracts were dried with Na ₂ S0 ^ and evaporated. Distillation of the residue at 0.2 mbar yields 5.83 g of 3 (ref. 78 ° C).

d) Ethyl ester 3 - ((4′R) -N-tert.butyloxycarbonyl-2 ′, 2′-dimethyl4′-oxazolidinyl) -2-methyl-propenoic acid (£)

A solution of 39.5 g of tert-butyl ester (4S) -2,2-dimethyl-4-formyl-oxazolidine-3-carboxylic acid 3 in 200 ml of dichloromethane was added dropwise to a solution of 68.7 g of 1-ethoxycarbonylethylidene-triphenylphosphorane in 900 ml of dichloromethane for 2 hours. After stirring at room temperature for 6 hours, it was cooled to 10 ° and 530 ml of 10% aqueous sodium hydrogen phosphate was added dropwise over 15 minutes. After stirring at 15 ° for 15 minutes, the organic phase is separated and the aqueous phase is extracted with 250 ml of dichloromethane. The organic phases were dried over magnesium sulfate and evaporated. The residue was mixed with 70 ml of etr. The suspension was filtered and the residue on the filter was washed with ether. The filtrate was evaporated and the residue was separated by chromatography on silica gel. Elution with hexane / ethyl acetate = 9: 1 yields in addition to 2.32 g of the cis isomer and 2.21 g of the mixed fraction (cis / trans = 38:62)

45.4 g _4. b'-NMR (60 MHz, CDCl2, trans-isoraer): among others

4.7 ppm (m, HC (4 ')); 6.7 ppm (d, J = 9, HC (3)) · ¹ HN ”R (60 MHz, CDClp cis isomer): 5.2 ppm (m, HC (4 '));

6.08 ppm (d, J = 7, H-C (3)).

e) Tert.butyl ester (4R) -2,2-dimethyl-4- (3'-hydroxy-2'-methylprop-1 '-enyl) -oxazolidine-3-carboxylic acid (5 ^)

To a solution of 48.7 g in 1 l of dry diethyl ether, cooled to 3 °, was added for 15 minutes

389 ml of 1 molar solution of diisobutylaluminum hydride in hexane. Allow to warm to 11 ° and add 100 ml of ethyl acetate under ice-cooling and then 50 ml of 2 n sodium hydroxide solution. Allow to cool to 28 ° C without cooling and add 7 ml of 2 n sodium hydroxide solution. Allow to stir for 15 hours at room temperature, add sodium sulfate and filter. Evaporation of the filtrate afforded 42.1 g of crude 5. The sample (0.97 g) was purified by chromatography on 40 g of silica gel. Elution with hexane / ethyl acetate: 3: 1 yields 0.74 g of 2. ^] H-NMR (300 MHz, DMSO-dg): among others

3.52 (dxd, J = 9 and 3) and 4.02 (dxd, J = 9 and 6) (2H-C (5)); 3.78 (m, 2H-C (3 ')); 4,54 (m, H-C (4)); 4.81 (t, J = 6, OH); 5.33 (d, J = 9, H-C (1 ')).

f) Tert.butyl ester (4R) -2,2-diraethyl-4- (3′-bromo-2′-methyl-prop1′-enyl) -oxazolidine-3-carboxylic acid (6).

To a solution of 41.0 g of _5 and 60.2 g of tetrabromomethane in 1 l of dry diethyl ether was added at 0 ° 47.6 g of triphenylphosphine.

After 30 minutes, remove the cooling bath and stir for 17 hours at room temperature. 20 g of tetrabromomethane and 15.9 g of triphenylphosphine were added and stirred for 2 hours at room temperature. The white suspension was filtered and the filter residue was washed with ether. The evaporation residue of the filtrate is chromatographed on 0.9 kg of silica gel. Elution with hexane / ethyl acetate = 9: 1 yields 30.59 g 6, m.p. 62-65 ° C, 'il-IIMR (300 MHz, DMSO-dg): among others 3.55 (dxd, J = 9 and 2) and 4.04 (dxd, J = S and 6) (2H-C (5)); 4.15 (m, 2H-C (3 ')); 4.49 (m, H-C (4)); 5.65 (d, J-9, H-C (1 ')).

- 46 g) (4R) -2,2-dimethyl-4- (3'-dimethylphosphono-2'methyl-prop-1'-enyl) -oxazolidine-3-carboxylic acid tert-butyl ester (7).

A solution of 13.4 g 6. was stirred for 15 hours at 80 ° C in 70 ml of trimethyl phosphite. The excess phosphite was evaporated at 24 mbar.

Drying the residue under high vacuum afforded 14.3 S crude 7. ¹ H-NMR (300 MHz, DMSO-dg): among others 2.63 (d, J = 23, 2Hr.C (3 ')); 3.59 (d, J = 11, (CH ₃ O) ₂ P0).

h) N - (((2R) 5-dimethylphosphono-1-hydroxy-4-methyl3-penten-2-yl) carbamic acid tert-butyl ester (Sl)

To a solution of 14.0 g j_ in 250 ml methanol was added 7 g

Z

R '4Amberlyst -a 15 (H -form 20-50 mesh). The mixture was stirred for 17 hours at room temperature, filtered and the filtrate was evaporated. Chromatography of the residue on 0.33 kg silica gel with ethyl acetate / methanol = 10: 1 as eluent afforded 10.6 g (3. Sl-NMR (300 MHz, DMSO-dg): among others 4.60 (t, J = 6, OH); 6.67 (d, J = 7, NH).

i) (2R) -2-tert-Butoxycarbonylamino-5-dimethyphosphono-4methyl-3-pentanoic acid (j)).

and, a) Oxidation with chromic sulfuric acid

To a solution of 0.323 g of S. in 10 ml of acetone is added 0.77 ml of a solution which is 3.25 aolar with chromium trioxide and 5.29 molar with sulfuric acid. It is stirred for 40 minutes at room temperature, 2 ml of isopropanol is added, then 50 ml of ethyl acetate and the mixture is mixed with 0.1 g of activated carbon. After 10 minutes, it was filtered and washed with 50 ml of ethyl acetate. The filtrate was extracted 3 times with 50 ml of 10% sodium hydrogen carbonate solution each. The aqueous phase is extracted twice with 40 ml of ethyl acetate each, acidified with 2 n hydrochloric acid at pH 1 and

- 47 Extracted with 70 ml of ethyl acetate 3 times each. The organic extracts were washed with saturated brine, dried over magnesium sulfate and evaporated. Chromatography on 8 g of silica gel with chloroform / methanol / acetic acid = 18: 1: 1 as eluent gave 65 mg _9. 1 H-NMR (300 MHz, DMSO-d 6) 1.37 (s, (CH ₃ ) ₃ CO); 1.82 (d, J = 2, CH ₃ -C (4)); 2 "_; 63 (d, J = 22, 2H-C (5)); 3.61 (d, J = 11, (CH ₃ O) ₂ PO); 4.62 (t, J = 8, HC (2)); 5.25 (m, HC (3)) and 7.18 (d, J = 8, NH); 11.7-12.5 (C0 ₂ H).

and, b) Oxidation by 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 dioxane was added a platinum suspension prepared by hydrogenating 313 mg of platinum oxide in 50 ml of water. In the cylindrical apparatus, oxygen is introduced from the bottom up with vigorous stirring at 55 ° using a glass fryer. It is filtered, washed with water and the filtrate extracted 5 times with 100 to 150 ml of ethyl acetate. Evaporation of the extracts gave 220 mg of educt 5. The aqueous phases were added 1 g / imberlyst ^ 15 (strongly acidic), filtered and evaporated in vacuo at 40 °. 3 Purification as f, a) gave 156 mg @ 1 H-NMR (300 MHz, CDCl 3): 1.43 (s, (CH ^ C); 1.96 (d, J = 3,

CH ₃ -C (4)); 2.55 and 2.71 (2 dxd, J = 22 and 15, 2H-C (5)); 3.75 and 3.76 (2 d, J = 11, 2 OCi ^); 4.97 (ra, HC (2)); 5.25-5.45 (ra, NH and 11-0 (3)) j) (2R) -2 _r amino-4-methyl-5'phosphono-3-pentenoic acid (10).

To a solution of 123 mg 9 in 3 ml of dichloromethane is added at

0 ° 0.71 ml trimethylsilyl bromide. After stirring for 4 hours at 0 °, 20 ml of water was added. After 30 minutes, the d-chloromethane phase was decided and washed 3 times with 15 ml of water each. The aqueous phases are extracted 3 times with 20 ml of dichloromethane each and evaporated in vacuo. The residue was dissolved in 10 ml of 5 n hydrochloric acid and stirred for 48 hours, diluted with 20 ml of water and extracted 3 times with 20 ml of dichloromethane each. The aqueous phase was evaporated in vacuo, the residue was dried in high vacuum, dissolved in 3 ml of ethanol and about 1 ml of propylene oxide was added dropwise. The suspension is filtered. Washing the residue on the filter with ethanol and drying in high vacuum at room temperature gave 62 mg 10, m.p. 165 ° C (dec).

The sample for the analysis of the enantiomer unity is converted by the chloride of (R) - (+) - methoxy-trifluoromethyl-phenylacetic acid to the amide derivative. ¹ H-NMR analysis (3Q0 MHz) with the integration of OCHg signals gave 95% (2R) -isomer (3.44 ppm) and <5% (2S) -isomer (3.37 ppm).

EXAMPLE 6 Ethyl (2R) -2-amino-4-methyl-5-phosphono-3-pentanoic acid

a) Tert.butyl ester (4R) -2,2-dimethyl-4- (3′-diisopyropylphosphono2′-methyl-prop-1′-enyl) -oxazolidine-3-carboxylic acid (O.

A solution of 6.68 g of bromide (Example 5f) in 14.8 ml of dry triisopropyl phosphite is heated for 17 hours at a pressure of 100 mbar at 70 ° C. The mixture was evaporated at 0.4 mbar / 70 °. Chromatography on 350 g of silica gel (eluent hexane / ethyl acetate = 1: 1) gave 8.28 g of 1, Rf-0.077.

- 49 b) N - ((2R) -5-Diisopropylphosphono-1-hydroxy-4methyl-3-penten-2-yl) carbamic acid tert-butyl ester (g)

To a solution of 4.49 g of phosphoric acid ester _1_ po

a) 2.25 g of Amberlyst ® 15 (H ⁺ form, 20 to 50 inesh) was added in 100 ml of methanol. The mixture was stirred at room temperature for 2 days, filtered and the filtrate was evaporated. Chromatography of the residue on 125 g of silica gel (eluent ethyl acetate / methanol = '20: i) yields 2.44 g 2.

c) (2R) -2-tert.butoxycarbonylamino-5-diisopropylphosphono-4methyl-3-pentanoic acid (_3)

To a solution of 1.6 g of alcohol 2 by b) in 60 ml of acetone is given at 0 to 5 ° 3.3 ml of a solution which is 3.25 molar with chromium (VI) oxide and 5.29 molar with sulfuric acid. Stirred for 6 hours at 0 ° and for 12 hours at room temperature. After addition of 5 ml of isopropanol and 40 al 20 ^- '% aqueous solution of sodium salt is stirred for 10 minutes, then for 15 hours continuously extracted with metilacetatom on Kutscher-Steudelovi apparatus. The organic phase was dried over sodium sulfate, evaporated and the residue chromatographed on 75 g of hexane / ethyl acetate / acetic acid = 16: 10: 1. From this, 0.92 g of 3 is obtained, / ώ / D = -94.5 ° (c = 1.2, CHC1,). ¹ H -1 NMR (300 MHz, CDCl 3; 1.2-1.3 (4d, (2-propO) 2);

1.4 (s, (CH ₃ ) ₃ CO). 1.95 (d, J = 3, CH ₃ -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,

HC (2)); 5.30 (m, HC (3); 5.42 (d, J = 7, UH), 9.0-10.0 (broad, C0 ₂ II)).

d) (2R) -2-tert.butoxycarbonylamino-5-diisopropylphosphono-4-methyl-3-pentanoic acid ethyl ester (4.)

To a solution of 0.2 g of acid 3 after c) in 15 ml of dry dichloromethane was added at 0 to 5 ° 0.09 g of 1-amino-1-chloro-N, N, 2-trimethylpropene. After stirring at 0 ° for 30 minutes, 0.4 g of pyridine in 5 ml of ethanol was added. The mixture is stirred at 0 ° C for 90 minutes and at room temperature for 15 hours, diluted with 20 ml of dichloromethane and washed twice with 20 ml of water each. The organic phase was dried with sodium sulfate, evaporated and chromatographed on 25 g of silica gel. Elution with ethyl acetate / methanol = 10: 1 yields 0.12 g.

&Lt; 1 &gt; H-NMR (300 MHz, CDCl3): 1.2-1.4 (m, 2 (CH2CHCHO, CfbCH2O); 1.45 (s, (CH2HCO); 1.98 (d, J ^e 3, .CH3 ~ C (4)); 2.55 (d, J "23, 2H-C (5)); 4.2 (m, CH3CH2O); 4.69 (m, 2 (CH3) 2CHO); 5.0 (m, HC (2)); 5.16 (m, HC (3),

NH).

e) (2R) -2-Amino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester (5)

To a solution of 0.1 g of ester 4. after d), 0.11 ml of trimethylsilyl bromide are added in 10 ml of dichloromethane. Stirred for 4 hours at 0 ° and for 15 hours at room temperature. Add 20 ml of water, stir for 15 minutes, decide the aqueous phase and evaporate the water in vacuo. The residue was dissolved twice in 5 ml of ethanol, evaporated and redissolved in 5 ml of ethanol. 0.5 ml of propylene oxide was added, the precipitate was filtered off, washed with ethanol and dried under high vacuum for 15 hours (15 hours; 48 mg 5, / ob / _β = -75 ° (c = 0.5, H ₂ 0).

The sample for the analysis of the enantiomeric purity was converted with the chloride of (R) - (+) -methoxy-trifluoromethyl-phenylacetic acid, then with diazomethane into an amide-dimethyl ester derivative. 1 H-NMR analysis (300 MHz) by integration of the OCH ^ signals of the daY_97% (2R) -isomer (3.5 ppm) and the <f 3% (2S) -isomer (3.37 ppm).

EXAMPLE 7: (2R) -2-Amino-4-methyl-7-phosphono-3-hept ^and acetic acid

a) Tert-Butyl ester (4r) -2,2-dimethyl- ¹ 1- (1 '-hydroxy-2'-methylprop-2' -enyl) -oxazolidine-3-carboxylic acid (_1_)

To a solution of 6.9 g of tert-butyl ester (4S) -2,2-dimethyl4-formyl-oxazolidine-3-carboxylic acid (according to Example 5c) in 60 ml of dry tetrahydrofuran was added dropwise at 0 to 5 ° 45 ml for 25 minutes. 1.1 molar solution of isopropenylmagnesium bromide. Stirred for 45 minutes at 0 °, allowed to warm to room temperature, cooled again to 10 ° and added 90 ml of buffer solution (1 m, phosphate, PH-7). It was filtered and the filtrate was extracted twice with 100 ml of ethyl acetate each. The organic phase is washed twice with 50 ml of water each and with saturated brine, dried with sodium sulfate.

Evaporation of the solvent gave 3 g of a _1_, diastereomeric mixture. It can be separated by chromatography on a hexane / ethyl acetate = 4: 1 crystalline gel to give the crystalline (1'S) -treo-epimer (value R ^: 0,2) and (1 'R) -erythro-epimer (value R _f : 0 , l6) in a ratio of about 1: 2.

b) Tert.butylester (4R) -4- (1′-aeethoxy-2′-methyl-prop-2′-enyl) 2,2-dimethyl-oxazolidine-3-carboxylic acid (s)

To a solution of 15.6 g of the epimeric mixture of a), 0 to 60 ml of acetic anhydride was added dropwise in 60 ml of pyridine for 10 minutes. The mixture was stirred for 15 hours at room temperature, diluted with 0.5 l diethyl ether and 200 acre of 2 n hydrochloric acid was added while cooling with ice. The organic phase is washed with 250 ml of 2 n hydrochloric acid and twice with 200 ml of 10% sodium carbonate solution each time. Drying over sodium sulfate and evaporation of the solvent gave 15.4 g 2.

c) Tert.butyl ester (4R) -4- (4'-carboxy-2'-methyl-butenyl) -2,2 'dimethyl-oxazolidine-3-carboxylic acid (.3)

To a solution of 5.25 g of diisopropylamine in 200 ml of dry tetrahydrofuran was added at 0 ° 34.5 ml of a 1.6 molar solution of butyllithium in hexane. Cool to -75 ° C and drop a solution of 15 g'acetate 2 after b) in 100 ml of tetrahydrofuran for 10 minutes and then a solution of 8 g of tert-butyldimethylsilyl chloride in 30 ml of 1,3-dimethyl-3,4,5,6 is added after 5 minutes -tetrahydro-2- (1H) -pyrimidinone. Allow to warm to room temperature, heat to reflux for 2 hours, cool to room temperature, add 230 ml of 45% ammonium fluoride solution, stir for 20 hours at room temperature and evaporate. To the oily evaporation residue of the organic phase was added 150 ml of n-sodium hydroxide while ice-cooling and the mixture was extracted twice with 200 ml of dichloromethane each time. The aqueous phase was acidified with 300 ml of 20; i citric acid solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are washed with 20% sodium chloride solution, dried over sodium sulfate and evaporated. Chromatography of the residue on 50 g of silica gel with hexane / ethyl acetate 1: 1 as eluent gave 11 g of solid 353 d) Tert.butyl ester (4R) -4- (4'-carb-ethoxy-2'-methyl-butenyl) 2, 2-Dimethyl-oxazolidine-3-carboxylic acid (4J d, a) From acid 3.

To a solution of 7.8 g of carboxylic acid 3 after c) in 100 ml of dry dichloromethane, cooled subsequently, 3.9 ml of 1-amino-1-chloro-N, N-2-trimethylpropene was added dropwise for 10 minutes. After 30 minutes at 0 °, a solution of 2.2 g of pyridine in 80 ml of ethanol was added for 20 minutes. After stirring for 12 hours at room temperature, dilute with 1Ό0 ml of dichloromethane and wash twice with 100 ml of water each. The organic phase was dried over sodium sulfate and evaporated.

Chromatography of the residue on silica gel with hexane / ethyl acetate 10: 1 gave 6.5 g of ester, / cu / p = + 6.17 ° (c = 1, chci ₃ ).

C _1Q H ₃₁ NO ₅ , calcd: C 63.32%, H 9.15%, N 4.10%; found: C

63.4%, H 9.2%, N 4.5%.

d, b) From epimeric mixture 2

A solution of 8 g of alcohol 2 P ° ^a ) 0 »05 ml of propionic acid in 10.5 ml of orthoacetic acid triethyl ester is heated for 14 hours with slow distillation of ethanol to 135 to 140 °. Evaporate under high vacuum at 40 °. Chromatography of the residue on silica gel with hexane / ethyl acetate 10: 1 yields 8 g 4.

e) Tert.butyl ester (4R) -2,2-dimethyl-4- (5'-hydroxy-2'-methylpent-1'-enyl) -oxazolidine-3-carboxylic acid (jj)

To a solution of 14.5 g lg (d) in 250 ml absolute diethyl ether, 0.61 g lithium aluminum hydride is added at 0 ° in portions. The mixture was stirred at 0-2 ° C for 18 hours and a solution of 5 g of potassium hydrogen sulphate in 60 ml of water was added while cooling with acetone / dry ice. It is filtered and washed 4 times with 200 ml of diethyl ether each. The organic phase is washed 3 times with 80 ml n hydrochloric acid, 3 times with 80 ml of saturated sodium bicarbonate solution and twice with 200 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated.

By silica gel chromatography with hexanones / ethyl acetate =

C

1.1 gives 11.3 g of 5, C ^ H ^ NO ^, calcd: C 64.19%, H 9.77%, N 4.68%; found: C 63.6%, H 9.8%, N 4.7%.

f) Tert.butyl ester (4R) -4- (5′-bromo-2′-methyl-pent-1 * -enyl) -2,2-dimethyl-oxazolidine-3-carboxylic acid (6)

At 0-2 ° C, 4.87 g of tetrabromomethane, 3.85 g of triphenylphosphine and 0.6 ml of pyridine are added to a solution of 4.4 g of alcohol according to e) in 200 ml of dichloromethane. After 12 hours at 0 to 2 °, 1 g of tetrabromomethane and triphenylphosphine are added further and stirred at 0 ° for 6 hours. It is evaporated, taken up in ethyl acetate, filtered and evaporated. Chromatography on silica gel with hexane / ethyl acetate = 10: 1 yields 4.5 g 6, C ₁₆ H _{2 g} NO ₃ Br: calculated: C 53.0%, H 7.79%, N 3.87%. Nr 22.06%; found: C

53.1%, H 7.7%, N 3.9%, Br 21.6%.

g) Tert.butyl ester (4R) -2,2-dimethyl-4- (2′-methyl-5′-diisopropylphosphono-pent-1′-one 1) -oxazolidine-3-carboxylic acid (7)

A solution of 10.9 g of bromide 6 in 22 ml of triisopropyl phosphite was heated for 24 hours at 100 mbar at 135 to 140 °. The excess reagent was evaporated at 0.1 mbar / 60 °. Chromatography of the residue on silica gel with hexane / ethyl acetate = 1: 1 yields

10.7 g 7.

h) N- (2R) -1-Hydroxy-4-methyl-7-diisopropylphosphono-hept-3-en-2-yl) -carbamic acid tert-butyl ester (.8).

To a solution of 3 g (7 g) in 100 ml of ethanol was added 3 g of Amberlyst®. _a 15 (H ⁺ -form). The mixture was stirred for 20 hours at room temperature, filtered, evaporated and chromatographed on 50 g silica gel. Elution with ethyl acetate / methanol = '10: 1 gave 2.3 g of 8, / ob- / _D = -5.9 ° (c = 1, CHCl 2).

C19K38NO6P; Calc'd: 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-heptenic acid (9.) i, a) Oxidation with chromic acid

At 0 to 5 °, 0.84 ml of the solution, which is

3.25-molar with chromium trioxide and 5.29-molar with sulfuric acid, to a solution of 0.5 ·. g of alcohol 8-by h) in 15 ml of acetone.

Stirred for 30 minutes at 0 and 35 minutes at room temperature, added 4 ml of isopropanol, 80 ml of ethyl acetate and 30 ml of 20% sodium chloride solution and filtered. Water phase

Extract 3 times with 20 ml of ethyl acetate each. The organic phase was dried over sodium sulfate and evaporated. Chromatography on 20 g of silica gel with hexane / ethyl acetate / acetic acid = 16: 10: 1 yields 0.34 g of 9, t "l _D " -35.25 ° (c «l, 39,

CHCl 3) ¹³ C-NMR (75 MHz, CDCl3): 173.8 (CO _Z H); 155.0 (OCON); 140.4 _χ (C (4)); 121.1 (C (3)); 79.5 (OC (CH ₃ ) ₃ ); 70.3 (OCH); 52.1 (C (2)); 39.7 (d, J = 18, C (5)); 28.3 ((CH ₃ ) ₃ C); 25.7 (d, J = 142, C (7)); 24.0 ((CH ₃ ) ₂ CH); 20.2 (d, J = 5, C (6)).

and, b) Oxidation with platinum oxygen

- 56 To a solution of 3 g of alcohol (8 h) in 105 ml of dioxane, a platinum suspension in 45 ml of water is prepared at 55 °, prepared by hydrogenation and degassing of 1 g of platinum oxide in 45 ml of water. At 55 to 60 ° with vigorous stirring (about 1900 rpm) (R), oxygen is translated. It was filtered through Celite, washed twice with 80 ml of water each, and the filtrate was evaporated at 40 ° C under high vacuum. Dissolve in 200 ml of water, add 1 g of sodium bicarbonate and 50 ml of 20% sodium chloride solution and extract 3 times with 100 ml of ethyl acetate. The organic phases are dried over sodium sulfate. Filtration and evaporation afforded 1.8 g of 8 ^ educt.

The aqueous phase was acidified with about 20 ml of n sulfuric acid and 5 times with 120 ml of ethyl acetate each. Drying over sodium sulfate, evaporation and chromatography of the residue according to i, a) gave 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 (i) and 2.6 g of N, O-bis-3-trimethylsilylacetamide was stirred for 1 hour at argon at room temperature. After 4.4 g of trimethylbromosilane were added, it was stirred for 24 hours. The reaction mixture was added dropwise at 0 ° to 400 ml of water and stirred for 30 minutes. The organic phase was decided and washed 3 times with 50 ml of water each. The aqueous phases are extracted 3 times with 30 ml of dichloromethane each and evaporated at 40 ° under high vacuum to 10 ml.

Chromatography on 20 ml of Dowex 50 Wx8 with water as eluent and lyophilization of the eluate afforded 0.4 g of 10 as an amorphous white powder from the ground. 252 ° (decay); [α] _β -86.5 ° ( _c -l, H ₂ 0);

0 ₈ 6ι ₆ Ν0 ₅ Ρ · 1 H ₂ 0; Calc .: C 37.05%, H 6.9%, N 5.5%, Found:

C 36.3%, H 6.5%, N 5.6%.

The sample for the analysis of the purity of the enantiomers is converted with the chloride (R) - (+) - methoxy-trifluoromethyl-phenylacetic acid • j into the amide derivative. H-NMR analysis (300 MHz) with the integration of OCH1-signals yields 94% (2R) -isomer (3.24 ppm) and 6% (2S) -isomer (3.17 ppm).

r

EXAMPLE 8: (2R) -2-Amino-7-pheno-3-heptenic acid

a) Tert.butyl ester (4R) -2,2-dimethyl-4- (1′-hydroxy-prop-2′-enyl) oxazolidine-3-carboxylic acid (_1_)

To a solution of 25 g of tert-butyl ester (4S) -2,2-dimethyl4-formyl-oxazolidine-3-carboxylic acid (according to example 5c) in 300 ml of dry tetrahydrofuran is added 30 minutes at 0 to 5 ° 60 ml of a 2.4 M solution of vinylmagnesium bromide in tetrahydrofuran. Stirred for 1 hour at 0, allowed to warm to room temperature and stirred for another hour at room temperature.

Upon cooling to 10 °, 300 ml of buffer solution (1 molar,

2 times phosphate, pH-7). It is filtered after 10 minutes, / is extracted with 150 ml of ethyl acetate and washed twice with 100 ml of water each. The aqueous phase was extracted twice with 100 ml of ethyl acetate each. The organic extracts were dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel with hexane / ethyl acetate = 4: 1 afforded 24.2 g of epimeric mixture 1; C ₁₃ H ₂₃ NO _U ·, Calc .: c 60.68%, H 9.01%, N 5.44%;

C 60.7%, H 9.1%, N 5.6%.

found :

b) (4R) -4- (4'-Ethoxycarbonylbutenyl) -2,2-dimethyl oxazolidine-3-carboxylic acid tert-butyl ester (2)

A solution of 22.5 g of alcohol _1_ after a) and 0.3 ml of propionic acid in 3θ, 5 acre of triethyl ester of orthoformic acid was heated for 4 hours with slow distillation of ethanol to 135 to 140 ° C. Evaporate in high vacuum at 50 ⁰ and chromatograph on 300 g silica gel. Cellulose with hexane / ethyl acetate = 4: 1 is obtained. 23.9 g 2, (o) _{D 1} -10.0 ° (c 1, 5, CHCl 3); C17H29NOS; Calc'd: G 62.36%, H 8.93%, N 4.28%;

H, C 62.2%, H 8.9%, N 4.4%.

(c) (4R) -2,2-dimethyl-4- (5'-hydroxy-pentenyl) oxazolidine-3-carboxylic acid tert-butyl ester (^)

At 0 to 2 °, 23.5 g 2 after b) v is added to the solution

550 ml absolute diethyl ether, 2.7 g portions of lithium aluminum hydride. Pb for 3 hours stirring at 0 to 2 °, while cooling, a solution of 25 g of potassium hydrogen sulphate in 250 (r) acre of water. Filter through Celite ^into and rinse well with diethyl ether. The organic phase is washed twice with po. 200 ml n hydrochloric acid and twice with 250 ml 10% sodium bicarbonate solution each. The aqueous phases are extracted twice with 100 ml of ether each. Wash the washed organic phase with 20% sodium chloride solution over sodium sulfate and evaporate.

Chromatography on silica gel with hexane / ethyl acetate as eluant afforded 18.6 g 3, Ια] _β “-10.1 ° (c = 1.4,

CHCI3); C ₁₅ H ₂₇ NOi; Calc'd: C 63.13%, H 9.54%, N 4.91%; found:

C 63.0%, H 9.5%, N 5.0%.

d) (4R) -4- (5'-Bromo-pentenyl) -2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (Ji)

To a solution of 18.5 g of alcohol (P ° C), 28.2 g of tetrabromomethane and 22.3 g of triphenylphosphine in 600 ml of dichloromethane are added dropwise at 0 ° 7 ml of pyridine. The mixture was stirred for 12 hours at 0-2 ° C, evaporated, taken up in 150 ml of ethyl acetate, filtered, evaporated to 50 ml and chromatographed on 200 g of silica gel. Elution with hexane / ethyl acetate 10: 1 is obtained

19.9 g of Tranid 4, [αίθ - -18.9 ° (c - 1, CHCl3); Ci ₅ H ₂ 6NO ₃ Br;

Calc'd: 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- (5'-di-2-propylphosphonopentenyl) -oxazolidine-3-carboxylic acid tert-butyl ester (jj)

A solution of 19.9 g of bromide ¹ 4'fto d) in 60 ml triizopropilfosfita heated for 20 hours under 100 mbar at 130 to 135 °. The excess reagent was distilled off at 60 ° / 0.1 mbar and the residue chromatographed on 250 g silica gel. Elution with hexane / ethyl acetate = 1: 1 yields 20.6 g of phosphonic acid ester 5, 1 l _n · ^{_ 8 6} (c-0.8, CHCl3); ΟίΐΗι, οΝΟβΡ; Calc .: 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%.

f) N - ((2R) -1-Hydroxy-7- (diisopropylphosphonohept-3-en-2-yl) -carbamic acid tert-butyl ester (j5)

A solution of 20.6 g 5 by e) in 800 acre methanol was stirred ₊ hours with 30 g Amberlyst 15 (H-form) at room temperature

It was filtered, washed with methanol, evaporated and chromatographed on 100 g of silica gel. Elution with ethyl acetate gave 14.8 g of 6,

U! _o = 3.6 ”

- 60 (c-1.5, CHCl ₃ ); Ci ₈ H ₃ 6NO ₆ P;

calculated: C 54.95%, H 9.22%, N 3.56%,

C 53.6%, H 9.0%,

N, 3.4%, P, 9.0%.

g) (2R) -2-tert.butoxycarbonylamino-7-diisopropylphosphono-3-heptenic acid (7.)

To a solution of 73 g of alcohol 6 (f) in 300 ml of acetone is added dropwise at 0 to 2 ° C for 20 minutes 15 ml of a solution which is 3.25 molar with crora trioxide and 5.29 molar with sulfuric acid. It is stirred for 2 hours at 0-2 ° C, for 4 hours at room temperature and then 30 ml of isopropanol, 300 ml of ethyl acetate and 200 ml of 20% sodium chloride solution are added. The aqueous phase was extracted 3 times with 250 ml of ethyl acetate each time, the organic phases were dried over sodium sulfate and evaporated.

Chromatography on 200 g of silica gel with hexane / ethyl acetate / acetic acid = 16: 10: 1 yields 4.55 g of acid 7_, / _D = -24.9 ° (c = 0.8, CHCl3).

h) (2R) -2-Amino-7-phosphono-3-heptenoic acid (S)

A solution of 3.1 g of acid 7 and 3 sl of N, O-bis-trimethylsilylacetamide in 200 ml of dry dichloromethane was stirred for 1 hour at room temperature. Add 3.5 ml trimethylbromosilane and stir for 30 hours at room temperature. The volatiles were evaporated, the residue was taken up in 50 ml of dichloromethane and 250 ml of water was added at 0 to 2 °. The aqueous phase was decanted and evaporated in an isotropic vacuum to 10 ml. Chromatography on 20 ml of Dowex® 50 Wx8 with water as eluent and lyophilis ¹ -'- 'as amorphous powder, l “] _D - -65,2'

D ₂ O): 172.8 (CO ₂ H); 140.3 (C (4));

J - 17, C (5)), 27.3 (d, J - 134, C (7)); 22.6 (d, J = 4, C (6)) J

- 61 The sample for the analysis of the purity of the enantiomers is converted with the chloride of (R) - (+) - methoxytrifluoromethyl-phenylacetic acid and then with diazomethane to an arnid-trimethyl ester derivative. H-NMR analysis (300 MHz) with the integration of OCH ^ signals at the ^ _95% (2R) -isomer (3.54 ppm) and <ζ5% (2S) -isomer (3.37 ppm).

EXAMPLE 9: (2R) -2-Amino-4-fluoro-5-phosphono-3-pentanoic acid (7)

a) Tert.butyl ester (4R) -4- (2'-carbomethoxy-2'-fluoro-vinyl) 2,2-dimethyl-oxazolidine-3-carboxylic acid O)

To a suspension of 13 S of zinc powder and 2 g of copper (I) chloride in a solution of 8.2 g of tert.butyl ester (4S) -2,2-dimethyl-4-formyl-oxazolidine-3-carboxylic acid (according to example 5c) in 200 ml of dry tetrahydrofuran and 4.1 g of acetic anhydride were added while stirring and heating 8.1 g of dichlorofluoroacetic acid methyl ester (argon atmosphere). Boil for 2 hours under reflux, allow to cool, dilute with diethyl ether, filter through Celite ® and evaporate the filtrate.

Chromatography of the residue on silica gel with hexane / ethyl acetate = 19.1 as eluent gave 5.7 g of mass spectrum (field desorption): 303 (M ⁺ ); ^{* 1} U-NMR (60 MHz, CDCl 3: among others 5.93 (dxd, J = 31 and 8.5, HC (1 ')).

b) (4R) -2,2-dircetyl-4- (2'-fluoro-3'-hydroxypropenyl) -oxazolidine-3-carboxylic acid tert-butyl ester (2R)

To a solution of 4.9 g of ester _1_ according to a), dropwise at 0 to 5 °, 39 ml of 1M solution of diisobutylaluminium hydride in hexane is added to 160 ml of absolute diethyl ether. Stirred for 1 hour at

O to 5 °, 80 ml of ethyl acetate are added, followed by 25 ml, 2 N sodium hydroxide solution, keeping the temperature below 25 °. Allow to stir for 30 minutes at room temperature, add 50 g of sodium sulfate, filter and wash with ethyl acetate. By drying the filtrate with sodium sulfate, evaporation and chromatography on · 100 g silica gel with hexane / ethyl acetate = 3: 1 ³ ' ⁷ e 2' («1 _D - +2,5 (c« 2,5, CHCl3); C ₁₃ C _2Z NO., F;

C 56.72 X, H 8.06 X, N 5.09 X; found: C 56.2 X, H 8.2 X, N 5.1 X.

we get

c) Tert.butyl ester (4R) -4- (3′-bromo-2′-fluoro-propenyl) -2,2-di · methyl-oxazolidine-3-carboxylic acid (3.)

To a solution of 3.7 g of alcohol 2 by b), in 200 ml of dry dichloromethane, 6.63 g of tetrabromomethane and 5.24 g of triphenylphosphine are administered at 0-2 ° C for 10 minutes. After stirring for 15 hours at 0-2 ° C, it was evaporated, taken up in 80 ml of ethyl acetate, filtered and the filtrate evaporated. Chromatography of the residue on 50 g of silica gel with hexane / ethyl acetate = 4: 1 gives 3.7 g of bromide 3, l «°] _D + ¹² » ⁷ ( ^whole »

CHCl3); Cl3H2iNBrFOj; Calc'd: C 46.17 X, H 6.26 X, N 4.14 X; found : C 46.4 X, H 6.3 X, N 4.2 X.

d) Tert.butyl ester (4R) -2,2-dimethyl-4- (2′-fluoro-3′-di-2-pro pilphosphono-propenyl) -oxazolidine-3-carboxylic acid (4)

A solution of 3.7 g of bromide 3 after c) in 30 ml of tri-2-propylphosphite was heated for 7 hours at 100 mbar at 130 to 135 °.

- 63 The excess reagent was evaporated at 9 ° C, 1 mbar. Chromatography of the residue on 100 g of silica gel with hexane / ethyl acetate = 3: 1

2.8 g of phosphonate 4; [<x] _D = -8.6 ° (c = 3, CHCl ₃ ); Ci ₉ H3 ₅ NFO ₆ P; calc .:

C 53.89%, H 8.33%, N 3.31%; . Found: C 53.7%, H 8.4%, N 3.4%.

we get

e) N- (2R) -4-Fluoro-1-hydroxy-5-di-2-propyl • phosphono-pent-3-en-2-yl) -carbamic acid tert-butyl ester (j>)

A solution of 2.3 g of phosphonate 4 after d) in 250 ml of methanol was stirred with 5 g of Araberlyst 15 (H ⁺ form) for 20 hours at room temperature. Filter, evaporate and chromatograph on 80 g of silica gel. Elution with ethyl acetate gave 1.31 g of alcohol 5, [αίθ - -21.1 ° (c = 1, CHC1 ₃ );

C13H31NFO5P; Calc .: C 52.31%, H 8.51%, N 3.81 4, found.

C 50.2 H 8.2%, N 3.7%.

f) (2R) -2-tert-Butoxycarbonylamino-4-fluoro-5-di-2-propylphosphono-3-pentanoic acid (_6)

To a solution of 1.3 g of alcohol 5 by e) in 80 ml of acetone is added at 0 to 2 ° 2.5 ml of a solution which is 3.25 M with chromium trioxide and 5.29 M with sulfuric acid. Stirred at 2 ° C for 2 hours and allowed to warm to room temperature for 4 hours. After the addition of 10 ml of 2-propanol, 100 ml of ethyl acetate and 50 ml of a 20% solution of NaCl, the aqueous phase was decided and extracted 4 times with 100 ml of ethyl acetate each time. Drying the organic phase with sodium sulfate, evaporation and chromatography on 70 g silica gel with hexane / ethyl acetate / acetic acid = 10: 16: 1 yielded 0.87 g of acid J5, /. OV / = -72.9 as the eluent ° (c = 0.8, CHCl ₃ ).

g) (2R) -2-amino-4-fluoro-5-phosphono-3-pentenoic acid (7)

A solution of 0.8 g 6. according to f) and 0.84 ml of N, O-bis-triraethylsilyl

of acetamide in 80 ml of dry dichloromethane was stirred for 1 hour at room temperature.

After the addition of 0.98 ml of trimethylbromosilane, it was stirred for 30 hours at room temperature. Evaporate the volatiles, dissolve the residue in 50 ml of dichloromethane and add 200 ml of water at 0 to 5 °. The organic phase was decided and washed twice with 50 ml of water each.

Evaporate the aqueous phases under high vacuum to 10 ml. Chromatography on 30 ml of Dowex 50 Wx8 with water as eluent and lyophilization of the eluate afforded 0.22 g [α] -44.8 ° (c = 0.5, H; 0); JBass spectrum (fast-atom bombardment):

214, (M + H) < ⁺ &gt;. ¹³ C-NMR (75 MHz, D ₂ O): 172.7 <CO ₂ H); 161.5 (dxd, J «263 & 12, C (4)); 100.9 (t, J ca. 11, C (3)); 49.5 (C (2)); 33.5 (dxd,

J-128 and 26, C (5)).

The sample for the analysis of the purity of the enantiomers is converted with the chloride of (R) - (+) - methoxy-trifluoromethylphenylacetic acid into an amide derivative. H-NMR analysis (300 MHz) with the integration of OCH ₃ signals gave 90% (2R) -isomer (3.49 ppm) and έ 10% (2S) -isomer (3.38 ppm).

EXAMPLE 10 Ethyl (2R) -2-aryano-4-methyl-5-phosphono-3-pentanoic acid

a) (2R, 3S) -2-Formylamino-3-hydroxy-4-methyl-4-pentene ethyl ester

- 65 acids (J_) aa) From ethyl ester of 1,1,3,3-tetramethyl-1,3-disyl-2-azolidin-Nacetic acid

To a solution of 2.26 ml of N-cyclohexyl-N-isopropylamine in 60 ml of absolute tetrahydrofuran was added to -20 ° 7.6 ml of a 1.6 molar solution of butyllithium in hexane. After 20 minutes, they were cooled to -78 ° C and a solution of 3 g of 1,1,3,3tetra-ethyl-1,3-disyl-2-azolidin-N-acetic acid ethyl ester in 60 ml of tetrahydrofuran was added dropwise. It is stirred for 1 hour at -78 ° and then 142 ml of about 0.035-molar solution of cyclopentadienyl-bis-O-1,2 is added:

5,6-Diisopropylidene-D-glucofuranosyl-titanium (IV) chloride in ether and stirred for 17 hours at -78 °. The reaction solution was converted by means of an argon-pressed steel cannula into a vessel with a solution of 1.1 ml methacrolein in 15 ml tetrahydrofuran ^ cooled to -78 °. Slowly allow to warm to room temperature,

The mixture was stirred for 2 hours, 1.5 ml of water was added and filtered. The filtrate is diluted with 250 ml of diethyl ether ^ washed 3 times with 250 ml each of about 10% sodium chloride solution and 250 ml of saturated sodium chloride solution. The aqueous phases are extracted twice with 250 ml of diethyl ether each. The organic phases are dried over sodium sulfate, evaporated and hot dissolved in 150 ml of cyclohexane. On cooling, 1,2: 5,6-di-O-isopropylidene-D-gluco furanose crystallizes. The mother liquor was evaporated, the residue was taken up in 120 ml of tetrahydrofuran, 24 ml of water and 4.5 ml of acetic acid and stirred at room temperature for 2 hours. Evaporation under high vacuum at room temperature afforded 10.6 g of a residue containing (2R, 3S) -2-amino-3-hydroxy-4-methyl-4obenzoic acid ethyl ester. The sample (5 mg) was transferred to a derivative with 0.2 ml of trifluoroacetic anhydride in 0.3 ml of dichlorometh per hour for 2 hours. By capillary gas chromatography (ChirasiL-k-L-Val, 90

- 18 ° (2 ° per minute), 99.25% (2R, 3S) -enantiomer (retention time T _five = 10.28 minutes) and 0.75% (2S, 3R) -enter ratio (retention time T. = 11.48 minutes). Then we heat and L ·

5.5 hours in 80 ml formic acid formic acid to reflux.

Evaporation and chromatography on silica gel with hexane / ethyl acetate = 1.1 yielded 1.64 g of formamide

Sample analysis (5 mg) as acetate by gas chromatography (Chirasil®-L-Val, 160 - 180 °, 1 ° per minute): 99.2% (2R, 3S) of the enantiomer (T = ”13.64 minutes), 0.8% (2S, 3R) -enantiomer (T _five = 13.94 minutes).

a, b) From isocyanacetic acid ethyl ester

To a solution of 24.88 g of isocyanacetic acid ethyl ester and 18.51 g of methacrolein in 220 ml of 1,2-dichloromethane was added at 50 ° 1.65 g of (S) -N-methyl-N / 2- (dimethylamino) -ethyl / - 1 / (R) -1 ', 2-bis (diphenylphosphino) - ferrocenyl / -ethylamine and 1.105 g of bis (cyclohexylisocyanide) -gold (I) tetrafluoroborate. It was stirred for 5 hours at 50 ° under argon, evaporated, taken up in 400 ml diethyl ether, filtered and the filtrate evaporated. Distillation of the evaporation residue under high vacuum (0.04 mbar) afforded 33.62 g of a stereoisomeric mixture of 5- (2-propenyl) -oxazoline-4-carboxylic acid ethyl ester from boiling. 42 to 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 to reflux for 3 hours. Evaporation in vacuo afforded 36.1 g of a mixture of stereoisomeric ethyl esters of 2-formylamino

3-Hydroxy-4-methyl-4-pentanoic acid 2. The sample (35 mg) was converted to 2 ml of dichloromethane with 0.05 ml of N, O-bis-trimethylsilylacetamide in the derivative and analyzed by capillary gas chromatography (Chirasi ^ - L-Wave, 150 · °) 89.1% (2R, 3S) -isomer (T. = 22.1 minutes), 5.8% (2S, 3R) -isomer

L c L »(T _ret = 23.1 minutes), 2.8% (2R, 3R) -isomer (T _ret = ²ⁱ / 3 minutes),

2.3% (2S, 3S) -isomer (1 / .= 25.4 minutes).

p e L c

To a solution of 20.2 g 2, 16.83 ml of triethylamine and

0.62 g of 4-dimethylamino-pyridine in 300 ml of dichloromethane was added dropwise at 0 to 3 ° a solution of 11.42 ml of acetic anhydride in 50 ml of dichloromethane for 25 minutes. After 30 minutes, rinse

2 times with ice-cold 2 n hydrochloric acid and 2 times with 10% sodium chloride solution. The aqueous phases are extracted with 100 m dichloromethane. The evaporation residue was dissolved hot in sodium sulfate dried organic phases in hexane / ethyl acetate = 4: l. On slow cooling to about 30 ° it crystallizes

1.82 g of (2R ^x , 2S ^x ) -2-formylamino-3-acetoxy-4-methyl-4-pentamic acid racemic ethyl esters, m.p. 98 to 106 °. The mother liquor was slowly cooled to -12 ° C and held at this temperature for 1 hour. Filtration gave 15.04 g of acetate 3, m.p. 73-75, [[alpha]] -75.6 (c = 1, CHCI3), gas chromatographic analysis (Chiraail®-L-Val, 160-180 °, l ° _per minute):

(2R, 3S) -isomer93.5% (T ^ - 14.5 Minutes) (2S, 3R) -isomer 2.2% < ^T ret IM time), ·, (2R, 3R) -isomer2.2% (t = 16.8 minutes),

IVU ret (2S, 3S) -isoraer2, 1% (T = 17.1 minutes).

To a solution of (2R, 3S) -2-formylamino-3-acetoxy-4-methyl-4-pentenoic acid (3) ethyl ester in 400 ml of absolute ethanol was added at -16 ° 20.64 g of anhydrous potassium carbonate.

After stirring for 4 hours at -18 ° to -11 ° C, 500 ml of buffer solution (1 molar, phosphate, pH = 7) was added dropwise. The mixture was stirred at room temperature for 3.0 minutes and the 3-kphate extracted with 350 ml of dichloroethane each. Chromatography of the evaporated residue over sodium sulfate of the dried organic phases per 1 kg of silica gel with hexane / ethyl acetate = 1: 2 as eluent gives% δ g of alcohol

K

b) (2R) -2-Formylamino-4-methyl-5-diisopropylphosphono-3-pentanoic acid ethyl ester (4.)

To a solution of 14.19 g (a) in 210 ml of 1,2-dichloroethane, 6.57 ml of thionyl bromide are added at 18 to 20 ° and 135 ml of water are stirred after 2 hours. After 15 minutes, we decide the organic phase

Wash 3 times with 150 ml of ice water each and once with 100 ml of ice-cold saturated sodium hydrogen carbonate solution. The evaporation residue with the sodium sulfate of the dried organic phase was stirred dissolved in 60 ml of triisopropyl phosphite for 17 hours at 75 ° / 100 ° rars. The excess reagent was distilled off at 90 ° under high vacuum. Chromatography of the residue on 650 g of silica gel with ethyl acetate / methanol = 20: 1 yields 10.88 g of phosphonic acid ester _4, / OC / ^ = - 123,5 ° (c = 1.

CHCl ^). 1 H-NMR analysis (300 MHz) with the addition of (1R) -1- (9'-anthracenyl) -2,2,2-trifluoroethanol showed an enantiomeric purity of 90%.

c) Ethyl (2R) -2-aryano-4-methyl-5-phosphono-3-pentenic acid (jj)

To a solution of 10.3 g _4 according to b), 42 ml of dichloromethane are added dropwise at room temperature for 15 minutes at 23 ml of trimethylbromosilane. After 21.5 hours, 42 acres of ethanol were added under ice-cooling and stirred for another 20 hours. Evaporate, dissolve the residue 3 times each time

- 69 70 ml of toluene and evaporate again. The residue was dissolved in 42 ml of ethanol and 42 ml of propylene oxide were added. Filter by

1.5 hours. Drying the filter residue in a vacuum desiccator over P2O ₅ / KOH (3 ' _hours - / 80 °) yields 6.17 g 5;

[a] _D ⁼ “78 ° (c 0.6, H2O); tal-. 194-197 ° (dec.) CeHieNOsP; calcd.

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%.

The sample for the analysis of the enantiomeric purity was transformed with (R) - (+) - methoxytrifluoromethyl-phenylacetic acid chloride and diazomethane into an amide-dimethylphosphonate derivative and analyzed by 1 H-NMR (300 MHz) by integration of OCH1-signals: (2R) -isors - 93% (3.51 ppm), (2S) -isomer £ 7% (3.37 ppm).

EXAMPLE 11 (2R) -2-Amino-4-methyl-5-phosphono-3-pentanoic acid

A solution of 100'mg (2R) -2-amino-4-methyl-5phosphono-3-pentenoic acid ethyl ester according to example 10 in 3 rolls of hydrochloric acid is heated for 4.5 hours in a 100 ° C bath. Evaporate and dry the residue for 30 minutes in a high vacuum at 60 °. Dissolve the residue in 15 ml of ethanol and add 4 ml of propylene oxide. Filtration and drying of the residue on the filter in a vacuum desiccator over P ^^ / KOH afforded 62 mg of acid.

The sample to determine the purity of the enantiomers was converted with the chloride of (R) - (+) - methoxy-trifluoromethyl-phenylacetic acid into an amide derivative and analyzed with b-UMB (300 MHz), integration of OCH1-signals: 95% (2R) -enantiomer ( 3.25 ppm) and 5% (2S) -enantiomer (3.1.8 ppm).

EXAMPLE 12 E-2-Amino-4-ethyl-5-phosphono-3-pentanoic acid (1) g of E-2-amino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester was stirred in 70 ml of water 19 hours under reflux. The reaction mixture was slowly cooled to room temperature, stirred for 1 hour in an ice bath, filtered and washed with cold water. E-2-amino-4-methyl-5-phosphono-3-pentenic acid is thus obtained as a monohydrate, m.p. 163 ° (dec.).

EXAMPLE 13 E-2-Dimethylamino-4-methyl-5-phosphono-3-pentanoic acid

A mixture of 3.56 g of E-2-amino-4-methyl-5-phosphono3-pentenoic acid ethyl ester, 45 ml of 98% formic acid and 30 ml of 37% aqueous formaldehyde was stirred for 30 minutes at a bath temperature of L105 °. , Evaporate the NATO vacuum to dryness. The residue is taken up in a little water and evaporated again in vacuo. We repeat this mode twice more. The solid residue was mixed with 80 ml of water. After 1 hour, the solution was dissolved through a hard filter and then washed with water. Evaporate the filtrate and wash water in vacuo to dryness. The residue was suspended in 100 ml of water and allowed to stand after the addition of 30 ml of 1 L sodium hydroxide solution for 2 days at room temperature. The reaction mixture was evaporated to a residual volume of about 25 ml in vacuo and purified by ion exchange chromatography (Dowex 50 W x 8 i ^ O). The fractions containing the desired product were combined, evaporated in vacuo and recrystallized from water / ethanol. This gives the E-2-dimethylamino-4-methyl-5-phosphono-3-pen71 acetic acid, m.p. 235 ° (dec.).

EXAMPLE 14 E-2-Dimethylamino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester

1.19 g of E-2-dimethylamino-4-methyl-5-phosphono-3-pentenoic acid are mixed with 30 ml of 8 n ethanol hydrochloric solution and stirred for 24 hours at 40 °. The reaction mixture was evaporated to dryness in vacuo. Evaporation after addition of 30 ml of pure ethanol gave 1.90 g of a reddish oil which was dissolved in hot isopropanol. Upon cooling, crystalline ethyl ester hydrochloride of E-2-dimethylamino-4-methyl-5-phosphono-3-pentanoic acid was obtained, m.p. 203 ° (dec.).

EXAMPLE 15 E-2-Benzylamino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester

A solution of 5.69 from E-2-amino-4-raethyl-5-phosphono-3-pentenoic acid ethyl ester in 48 ml of water and 48 ml of ethanol was mixed with 16 ml of glacial acetic acid, 5.90 g of sodium acetate (anhydrous) and 12. 2 ml of benzaldehyde. Under intense ice and salt cooling for 1 hour in about 70 portions, 15.70 g of sodium boron hydride is added, with 4 ml of benzaldehyde added after half an hour of addition. The temperature of the reaction mixture was maintained between 0 and 10 °. After complete addition, the mixture was stirred for 1 hour at 0 ° C and then 1 N hydrochloric acid was added dropwise to the Congo acid reaction. The undissolved salts are filtered off and subsequently washed with water. The filtrate was evaporated to dryness in vacuo and the residue was further evaporated twice after the addition of ethanol. The residue is now mixed with 150 ml of ethanol, filtered off and then washed with ethanol. 25 ml of propylene oxide was added to the filtrate and stirred for 2 hours. The crystallized material (mainly the educt) is filtered off. Evaporate the mother liquor to dryness and mix with 350 ml of ethyl acetate. After crystallization, the crude product obtained was crystallized from ethanol. E-2-benzylamino-4-methyl5-phosphono-3-pentanoic acid ethyl ester is thus obtained, m.p. 192 ° (dec;).

EXAMPLE 16 E-2-Benzylamino-4-methyl-5-phosphono3-pentanoic acid ethyl ester

A solution of 1.00 g of E-2-benzylamino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester in 6 ml of water was stirred for 20 hours under reflux. The reaction mixture was evaporated to dryness in vacuo. Ethanol was added to the residue and evaporated again. We repeat this procedure twice more. The residue was dissolved in boiling ethanol. Upon cooling, crystalline E-2-benzylamino-4-methyl-5phosphono-3-pentanoic acid was obtained, m.p. 150 ° (dec.).

EXAMPLE 17 E-2-Isopropylamino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester

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 is mixed with 6.64 g of sodium acetate (anhydrous) and 13 m of acetone. With intense ice / salt cooling, 17.67 g of sodium boron hydride was added in about 70 portions in about 70 minutes, with 18 ml of acetone added after 20 minutes and 50 minutes each time. After completion of the addition, the dense white suspension was stirred for 30 minutes at 0 ° and then 1 N hydrochloric acid was added dropwise to the Congo-acid reaction. The clear solution was evaporated in vacuo and the residue was further evaporated twice after the addition of ethanol. The residue was mixed with 200 ml of ethanol at room temperature, filtered undissolved and washed with ethanol. The filtrate was evaporated in vacuo and the residue was recrystallized from isopropanol. E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester hydrochloride is thus obtained, m.p. 203 to 205 ° (dec.)

EXAMPLE 18 E-2-Isopropylamino-4-methyl-5-phosphono-3-pentanoic acid

A solution of 1.20 g ethyl ether hydrochloride Ε-2-isopropylamino-4-methyl-5-phosphono-3-pentanoic acid in 7 ml of water was stirred for 20 hours under reflux. The reaction mixture was evaporated to dryness in vacuo. Ethanol was added to the residue and evaporated again.

We repeat this procedure twice more. The residue was dissolved in 25 ml of ethanol, a total of 5 acres of propylene oxide was added dropwise and evaporated to dryness. Dissolve the residue in a little water and mix with ethanol until complete.

With stirring at room temperature for 4 hours, slow crystallization takes place. The product was filtered off, washed with ethanol and diethyl ether and dried at 100 ° C under high vacuum.

There is thus obtained E-Z-isopropylamino-M-inethyl-S-phosphono-S-pentanoic acid, m.p. 225 to 227 ° (dec.).

EXAMPLE 19 E-2-Methylamino-4-methyl-5-phenyl-3-pentanoic acid

a) 2- (N-Methyl-yl-formyl-amino) -3-hydroxy-4-methyl-4-pentanoic acid ethyl ester (J_)

20.60 g of 5- (2-propenyl) -2-oxazoline-4-carboxylic acid ethyl ester prepared as an example; 1, dissolved in 200 ml of dry dichloromethane under argon. A suspension of 16.60 g of trimethyloxonium tetrafluoro borate in 200 ml of dry dichloromethane is now added dropwise at 15 °. The reaction mixture was stirred at room temperature for 17 hours and then 150 ml of water and 45 acre of saturated potassium bicarbonate solution were slowly added to give a pH of 7. The washed organic phase was washed twice with water and once with saturated sodium chloride solution and dried over sodium sulfate. . After distillation of dichloromethane, distillate the oily residue in a ball tube, boil. 120 to 13O ° / 13 Pa. 2- (H-Methyl-formylamino) 3-hydroxy-4-methyl-4-pentenoic acid ethyl ester is obtained as a light yellow □ ed, IR (CH ₂ C1 ₂ ): 3550 (HO); 1740 (CO-ester); 1675 (CO-amide).

b) E-2 - (? -Rethyl-N-formyl-amino) -4-methyl-5-diisopropylphosphono-3-pentanoic acid ethyl ester (2j

To a solution of 17.80 g of 2- (N-methylformylamino) 3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester in 248 ml of 1,2-dichloroethane was added dropwise at 20 ° under argon of 7.70 ml of thionibromide. The mixture was stirred for 2 hours at room temperature. Then, under weak cooling (20 °), 150 ml of water are added. The two-phase mixture was stirred well for another 20 minutes. The organic phase is determined and washed three times with water / ice, once with ice / saturated potassium bicarbonate solution and once with saturated sodium chloride solution. The intermediate product obtained after drying over sodium sulfate and distilling off 1,2-dichloroethane at 35 ° in vacuo, is mixed at room temperature with 66 ml of triisopropyl phosphite and then stirred at 75 ° for 17 hours under reduced pressure (about 13 kPa). The excess triisopropyl phosphite and other volatile by-products are then distilled off under high vacuum. Column chromatographic purification (quartz gel, acetone) (

E-2- (N-methyl-phenylamino) -4-methyl-5-diisopropylphosphono-3-pentanoic acid ethyl ester is obtained as a yellowish honey; IR (C ^ Cl2

1740 (CO-ester); 1670 (CO-amide); 1235 (P = 0), 980-1010 (P-O-C). The compound is a mixture of two rotamers according to the H-NMR spectrum.

c) E-2-Rethylamino-4-methyl-5-phosphono-3-pentanoic acid (_3)

A solution of 9.50 g of E-2- (N-methyl-formylamino) -4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester was added dropwise at 20 ° under argon 20 ml of trimethylbromosilane for 40 minutes in dry argon. Pc was stirred for 20 hours at room temperature for 15 minutes 37 ml of ethanol and stirred again for 20 hours. The clear reaction solution was then evaporated to dryness in vacuo. The residue was evaporated twice more after the addition of 30 ml of toluene each time. The resulting oil was mixed with 128 acre of 2 N hydrochloric acid and stirred for 16 hours at a bath temperature of 85 °. The reaction mixture was evaporated in vacuo. Evaporation twice with the addition of ethanol / toluene 1: 1 gave an oily residue which was dissolved in 51 ml of ethanol and added dropwise to a solution of 51 ml of propylene oxide in 51 ml of ethanol. The crystalline product was filtered off after 2 hours and recrystallized from water / ethanol. There is thus obtained E-2-raethylamino-4-methyl-5-phospho-76 phono-3-pentenoic acid, m.p. 239 (diff)

EXAMPLE 20:

In the analogous manner as described in Examples 1 to 3 or 6 and 9, the following can be further prepared: E-2-amino-5-phosphino-3-pentenic acid ethyl ester, m.p. 172 to 173 °.

E-2-amino-5-phosphino-3-pentenoic acid butyl ester, m.p. I60 to 161 °.

E-2-amino-5-phosphono-3-pentenoic acid ethyl ester, m.p. 167 to 168 °.

E-2-amino-5-phosphono-3-pentenoic acid butyl ester, m.p.

160 to 161 ° E-2-anino-5-phosphono-3-pentenoic acid octyl ester, m.p.

161 to 162 ° E-2-Amino-5-phosphono-3-pentenoic acid propyl ester, m.p. 161 to 162 ° E-2-amino-5-phosphono-3-pentenoic acid pentyl ester, m.p. 160 to 161 ° E-2 ~ amino-5-phosphono-3-pentenoic acid isobutyl ester, m.p. 163 to 164 ° sec E-2-amino-5-phosphono-3-pentenoic acid butyl ester, m.p. 169 to 170 ° E-2-amino-4-methyl-5 ~ phosphono-3-pentenoic acid methyl ester, m.p. 193 to 194 ° (water / acetone (9: 1));

E-E-amino / 1-methyl-S-phosphono-S-pentenic acid propyl ester,. m.p. 184 to 135 ° (water);

E-2-Araino-4-methyl-5-phosphono-3-pentenoic acid n-butyl ester. 186 to 187 ° (water / acetone (2: 1));

E-2-Amino-4-methyl-5-phosphono-3-pentenoic acid isobutyl ester, m.p. 181 to 182 ° (water / acetone (9: 1)); E-2-amino-4-methyl-5-phosphono-3-pentenoic acid pentyl ester, m.p. 207 to 208 ° E-2-Amino-4-methyl-5-phosphono-3-pentetic acid hexyl ester,

m.p. 207 do 208 ° butyl ester 186 ° E-2-amino-7-phosphono-4-heptene acids, m.p. methylcster 219 to 220 0 E-2-amino-5-phosphono-4-pentene acids, m.p. ethyl ester 234 ° E-2-amino-5-phosphono-4-pentene acids, m.p. butyl ester 235 ° Ε-2-aminc-5-phosphono-4-pentene acids, m.p. oktiiester E-2-anino-5-fluoro-4-pentene acids, m.p.

236 °

E-2-Amino-5-phosphono-4-pentenoic acid 2-hydroxyethylester m.p. 197 °

EXAMPLE 21 In the analogous manner as in Examples 4, 12, 13, 18, and 19 or 5, 7, 8, 9 and 11, the following can be prepared: E-2-amino-5-phosphono-4-pentenoic acid, m.p. 219 to 220 ° E-2-amino-5-methylphosphonyl-4-pentenoic acid, m.p. 222 ° E-2-Araino-5-butylphosphonyl-4-pentenoic acid, m.p. 232 do

- 78 E-2-Amino-5-octylphosphonyl-4-pentenoic acid, m.p. 221 to 223 °

E-2-amino-5-dodecylphosphonyl-4-pentenoic acid, m.p. 211 ° E-2-amino-6-phosphono-4-hexanoic acid, m.p. 244 to 246 ° E-2-amino-6-methylphosphonyl-4-hexanoic acid, m.p. 145 to 150 °

E-2-amino-6-butylphosphonyl-4-hexanoic acid, m.p. 216 ° E-2-amino-6-octylphosphonyl-4-hexanoic acid, m.p. 209 to 210 °

E-2-amino-6-dodecylphosphonyl-4-hexanoic acid, m.p. 197 to 200 °

E-2-amino-7-phosphono-4-heptenoic acid, m.p. 125 ° (dec.)

E-2-amino-5-phosphono-3-pentanoic acid, white amorphous powder, (D, O): 2.39 (dd, 2H, C (5) -H); 9.27 (d, 1H, C (2) -H); 5.53 (a, 1H, C (3) -H);

5.87 (», ih, c (4) -h), m.p. after recrystallization from ethanol / water 191-192 °:

«» * 44 l

E-2-amino-4-methyl-5-phosphono-3-pentensko acid, ¹ H-NMR (D, 0): 1.73 (β, 3H CHZ) |

E-2-aryano-5-methylphosphonyl-3-pentanoic acid, amorphous tel powder, 1 H-NMR (D 2 O): 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-amino-5-phosphino-3 ~ pentenoic acid, m.p. 139 to 14o ^J E-2-amino-4-methyl-5-f'osfino-3-pentensko acid, mp. 176 dc 177 ° (2S) -E-2-anino -> - 4-methyl-5-phenyl-3-pentanoic acid, m.p. 196 ° [a] 2 ° - + 97, 1 ± 1, 9 ° (c = 0.5; water);

E-2-amino ~ 4-methyl-5-methylphosphonyl-3-pentanoic acid, ¹ h-NMR (D ₂ O): 1,2 <

(d, 3H, CH3-P); 1.75 (d, 3H, CH ₃ ); 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 to 226 ° (from water);

E-2-aryano-3-methyl-5-phosphono-3-pentanoic acid ^ white powder, m.p. 1 68 ° ¹ H-NMR (D ₂ O): 1.50 (d, 3H, CH ₃ ); 2.4 (m, 2H, CH ₂ ); 4.30 ^f (s, 1H, C (2) -H);

5.60 (m, 1H, C (4) -H);

E-2-amino-5-methyl-5-phosphono-3 ~ pentanoic acid, white amorphous solid and _{H @ 1 NMR (θ2θ); 1> θ5 <dd> 3H} , _{CHj); 2A5 1H} , _{C (5) _H ); 4> 33 (d} ,

2H, C (2) -H); 5.5 and 5.9 (2ro, 2H, C (3) -H and C (4) -H);

E-2-amino-4-ethyl-5-phosphono-3-pentenoic acid, m.p. 176 ° E-2-anino-4-propyl-5-phosphono-3-pentenoic acid, m.p. 193 ° S -2-amino-4-butyl-5-phosphono-3-pentenoic acid, m.p. 186 to 187 °

E-2-Amino-4-isopropyl-5-phosphono-3-pentenoic acid, m.p. 201 E-2-Arano-4-tert-butyl-5-phosphono-3-pentanoic acid, m.p.

252 to? ^c '' ° j

0.95 (s, 9H, <CH2) ₃ C);

Z-2-amino-4-tert-butyl-5-phosphono-3-pentenoic acid, (D ₂ O) · Ι, θ (3 ^,; 9H, (CH 2) C); 2.45 (ro, 2H, CH ₂ ); 4.95 (d, 1H, C (2) -H>; 5.20 (ro, 1H,

C (3) -H).

E-2-amino-4-benzyl-5-phosphono-3-pentenoic acid, colorless needles, m.p. 196 dc 198 °

E-2-amino-4-phenyl-5-phosphono-3-pentenoic acid, color needles, m.p. 230 to 233 °;

E-2-Araino-4-methyl-5-methylphosphono-3-pentenoic acid as a by-product, m.p. 149 to 150 °.

EXAMPLE 22: E-2-Methylamino-4-methyl-3-pentene acid ethyl ester

1.20 g of E-2-methylaminin-4-methyl-5-phosphono-3-pentenoic acid are mixed with 50 ml of 8 N ethanol hydrochloric solution and stirred at 40 ° for 25 hours. The reaction mixture was evaporated to dryness in vacuo. Evaporation twice with ethanol / toluene 1: 1 gave an oily residue which was dissolved in 5 ml of ethanol and a solution of 5 ml of propylene oxide in 5 ml of ethanol was added dropwise. The crystalline product was filtered off after 2 hours and washed with ethanol and ether. After drying (80 °, 4 hours), ethyl acetate of E-2-methylamino-4-methyl5-phosphono-3-pentanoic acid was obtained under high vacuum. m.p. 235 to 240 ° (dec.).

EXAMPLE 23 Preparation of 1000 capsules each containing 10 mg of the active substance of Example 6 with the following composition:

E-2-amino-6-phosphono-4-hexanoic acid 10.0 g milk sugar 207.0 g modified starch 80.0 g magnesium stearate 3.0 g

Procedure: Sift all dusty ingredients with a sieve with a loop width of 0.6 mm. The active substance is then placed in a suitable blender and mixed until homogeneous, first with magnesium stearate, then with milk sugar and starch. Gelatin capsules no. 2 is filled with 300 mg of this mixture using a capsule filling machine.

In an analogous manner, capsules containing up to 200 mg of one of the other compounds described and in examples 1 to 21 are prepared.

EXAMPLE 24:

Preparation of 10,000 tablets containing 10 mg of the active substance of Example 6 with the following composition:

E-2-Amino-6-phosphono-4-hexanoic acid 100.00 g milk sugar 2.535.00 g corn starch 125.00 g polyethylene glycol 6000 150.00 g magnesium stearate 40.00 g purified water q.s.

Process:

All dusty components are sieved with a sieve width of 0.6 mm. The active substance is then mixed with milk sugar, magnesium stearate and half a starch in a suitable blender. The other half of the starch is suspended in 65 ml of water and the suspension is added to a boiling solution of polyethylene glycol in 260 ml of water. The paste obtained is added to the powders and, if appropriate, granulated with the addition of a further amount of water. Dry the granulate overnight at 35 °, slurry through a sieve with a width of 1.2 mm loops and compress into tablets having a breakage groove.

Tablets containing 10 to 200 mg of one of the other compounds described and examples 1 to 21 are prepared in an analogous manner.

Claims (10)

A process for the preparation of unsaturated - amino acid compounds of formula HO- (D, in which R _{1 is} hydrogen, alkyl or hydroxy, R _{2 is} hydrogen, alkyl, halogenationalkyl, hydroxybenzylalkyl, lower alkoxybenzylalkyl, arylalkylalkyl, lower alkenyl, halogen or aryl, R 1 represents hydrogen, alkyl or aryl, R ^ hydrogen or alkyl, Rg being optionally esterified or amidated carboxy, Rg is unsubstituted or lower alkyl or arylalkyl substituted amino group, A represents unsubstituted or alkyl substituted d ^ alkylene of 1 to 3 carbon atoms (C-atoms) or -direct bond, and B is methylene or bond, provided that A represents an unsubstituted or alkyl-substituted alkylene of 1 to 3 carbon atoms, if B is a direct bond, and their salts, characterized in that in compound with formula: —- Zs (II), - 83 in which Z ^ represents a protected hydroxy, Z ₂ group R ₁ or a protected hydroxy, Zg group Rg or a protected carboxy, Zg represents a protected group Rg and Rp is R ₂ , Rg, R4 .- Rg, Rg, A and B of the above meanings, the protected Zg groups are liberated and optionally Z ^, Z ₂ and / or Zg by treatment with trinylalkyl halogensilane and optionally converted to the second compound of formula I, the resulting mixture of optical isomers is separated into components and desired the isomer is selected and / or the resulting free compound is converted into a salt or the resulting salt is converted to the free compound or to another salt. A process according to claim 1, characterized in that the compound of formula f 'J, lin, L where R ₂ , Rg, R ^, A and B are defined as for formula I, Zg is Rg or stands for protected carboxy, Zg is a protected group Rg and X is for reaction capable of ester hydroxy, reacted with a compound of formula ' R Zi - (IV), where hydroxy is protected, optionally Z ₂ is protected hydroxy, and R is a tetrahydroxy group in the intermediate obtained with the formula Zg and, in the case of Z ^, Z ₂ and / or Zg is released by treatment with trinylalkylLogensilane i _n optionally in a compound obtained in the context of a process wherein Rg is a carboxy ester, the ester carboxy group is converted to a carboxy or a compound obtained according to the invention, where Rg is a carboxy, carboxy group in the esterified carboxy group and / or optionally converted compound of formula I into a salt or salt obtained into another salt or to a free compound of formula I and / or optically optical Isomer is isolated from a mixture of stereoisomeric forms of the resulting compound of formula I or a salt thereof. A process according to claim 1 for the preparation of compounds of formula I, wherein Rp has R ₂ , R ₂ , R 4, R 8, A and B in claim 1 have the meanings indicated and R 8 represents esterified or amidated carboxy, and salts thereof, , to give a compound of formula X - A - z ₅ * 6 (III) - 85 where R ₂ , R 4, R 4, A and B are defined for formula I, Zg has the meaning of Rg, Zg stands for protected amino and X is esterified hydroxy for reaction, reacted with a compound of formula IV where Z ₁ stands for the hydroxy protected in the given case, Z _{2 has the} meaning R ₂ or stands for protected hydroxy and represents the R group which etches', in the obtained intermediate product, the protected groups Zg are released and, in the case in question, Zp Z ₂ and / or Zg to give the group Rg is treated with trimethylbromsilane and optionally converted the compound of formula I into a salt or salt obtained into another salt or into a free compound of formula I and / or optionally an isomer is isolated from a mixture of stereoisomeric forms of the compound obtained of formula I or a salt thereof. A process according to claim 1 for the preparation of compounds of formula I, wherein Rp has R ₂ , R ₂ , R 4, R 8, A and B have the meanings indicated in claim 1 and R 8 is carboxy, and their salts, characterized in that a compound of formula II, wherein, as the case may be, a protected hydroxy, Z ₂ group R ₁ or a protected hydroxy, Zg carboxy or ester, amidated or protected carboxy and Zg protected group Rg and have R ₁ , R ₂ , R ₄ , R p R 8, A and B of the above meanings, the protected Zg groups are liberated and optionally Zp Z ₂ and / or Zg by treatment with trinylalkylhalogensilane and in a compound obtained in the sense of a process where Rg is esterified or amidated carboxy, esterified - 86 or an amidated carboxy group in carboxy and / or optionally converted compound of formula I into a salt or salt obtained into another salt or into a free compound of formula I and / or optionally isolates an optical isomer from a mixture of stereoisomeric forms of the resulting compound of formula And but its salts. Process according to one of Claims 1 to 4, characterized in that they come from a group of formulas II or IV, wherein the protected hydroxy Z ₁ and / or Z ₂ represents aliphatic alcohol with tetrahydroxy, as in the case of halogen or a position higher than the alpha position, with hydroxy, oxo, lower alkoxy, lower alkanoyloxy and / or mono- or di-dialkylamino substituted lower alkanol, lower alkenol or lower alkynol ether hydroxy. Process according to claim 3, characterized in that it is derived from a compound of formulas II or IV, wherein the protected hydroxy Z ₁ and / or Z ₂ 'represents aliphatic alcohol with tetrahydroxy, as in the case of halogen or higher as the alpha position, with hydroxy, oxo, lower alkoxy, lower alkanoyloxy and / or mono- or di-dialkylamino substituted lower alkanol, lower alkenol or lower alkynol ether hydroxy. A process according to any one of claims 1 to 4, characterized in that it is derived from a compound of formulas II or IV, wherein the protected hydroxy Z 1 and / or Z _{2 represents} lower alkoxy. A process according to claim 3, characterized in that it is derived from a compound of formulas II or IV, wherein the protected hydroxy Z 1 and / or Z _{2 represents} lower alkoxy. 87. The process according to any one of claims 1 to 8, characterized in that it is derived from a compound of formulas II or III and IV, wherein the protected group Zg, optionally with lower alkyl or arylalkyl, is an N-substituted acylamino group. A process according to any one of claims 3, 6 and 8, characterized in that it is derived from a compound of formulas II or III, wherein the protected group Zg represents an acylamino group. A process according to any one of claims 1 to 9, characterized in that it is derived from a compound of formulas II or III and IV, wherein the protected group Zg, optionally with lower alkyl or arylalkylalkyl, is an N-substituted acylamino group, where acyl is acyl carbonic acid polyester group. A process according to any one of claims 1 to 9, characterized in that it is derived from a compound of formulas II or III and IV, wherein the protected group Zg, optionally in position 1 or 2, is substituted by a lower alkoxycarbonylamino group, e.g. tert.butyloxycarbonylamino. A process according to any one of claims 1 to 9, characterized in that it is derived from a compound of formulas II or III and IV, wherein the protected group Zg is optionally lower alkyl or arylalkyl N-substituted lower alkanoylamino group, e.g. formylamino. A process according to any one of claims 3, 6 and 8, characterized in that it is derived from a compound of formulas II or III, wherein the protected amino Zg represents a lower alkanoylamino group, e.g. formylamino. - 88 - ' Process according to one of Claims 1 to 14, characterized in that it is used as trinylalkylhalogensilane trinylalkyl chlorosilane, trinylalkylcydosilane or trinylalkylbromosilane. Process according to one of Claims 1 to 14, characterized in that trinylalkylhalogensilane is used as trinylalkylbromosilane. Process according to any one of claims 3, 6,8 and 10, characterized in that trimethylbromosilane is used as trinylalkylhalogensilane. Process according to one of Claims 1 to 14, characterized in that trimethylbromosilane is used as trinylalkylhalogensilane. A process according to any one of claims 1 to 18, characterized in that the protected groups Zp Z ₂ and / or Zg are liberated in the halogenated hydrocarbon. Process according to one of claims 3, 6, 8, 10, 14 and 17, characterized in that the protected groups Zp are released Z ₂ , Zj. and / or Zg in a halogenated hydrocarbon. Process according to one of Claims 1 to 20, characterized in that the protected groups Zp Z ₂ and / or Zg are released in the halogenated aliphatic hydrocarbon. Process according to one of Claims 1 to 19, characterized in that it is operated in dichloromethane as a solvent or diluent. A method according to any one of claims 3, 6, 8, 10, 14, 17 and 20, characterized in that we work in dichloromethane as a solvent or diluent. - 89 24. A process according to any one of claims 1 to 22, characterized in that a halogen hydrogen acceptor is added. Process according to one of claims 3, 6, 8, 10, 14, 17, 20 and 23, characterized in that a hydrogen bromide acceptor is added. 26. A process according to any one of claims 1 to 25, characterized in that epoxybenzene is added in admixture with lower alkanol as a hydrogen halide acceptor. Process according to one of Claims 1 to 26, characterized in that propylene oxide is added in admixture with ethanol as a hydrogen halide acceptor. Process according to one of claims 3, 6, θ, 10, 14, 17, 20, 23 and 25, characterized in that propylene oxide is added in admixture with ethanol as a hydrogen bromide acceptor. A process according to any one of claims 1 to 27 for the preparation of unsaturated amino acid compounds of formula (D. wherein R _{1 is} hydrogen, alkyl or hydroxy, R _{2 is} hydrogen, alkyl, haloalkylalkyl, hydroxybenzylalkyl, lower alkoxybenzylalkyl, arylbenzylalkyl, lower alkenyl, halogen or aryl, R 2 is hydrogen, alkyl or aryl, R 4 is hydrogen or alkyl, stands R ^ for optionally esterified or amidated carboxy represents R ^ unsubstituted or lower alkyl or arylalkyl substituted amino group, A represents 90 unsubstituted or alkyl substituted (X, alk-alkylene of 1 to 3 carbon atoms or a direct bond and B represents methylene or a bond, provided that A represents unsubstituted or alkyl substituted fr, to) -alkylene of 1 to 3 atoms carbon, if B is a direct bond, in the form of those enantiomers in which the carbon atom bearing the amino group Rg, R configuration, and salts thereof, is derived from a compound of formula II or. from compounds of formulas III and IV, wherein the carbon atom bearing the Zg group has the R configuration. Process according to one of Claims 1 to 29, characterized in that hydrolysis of a compound of formula I is obtainable by process (Ib), wherein Rp R ₂ , Rg, R4 and Rg have the meaning given in claim 1 and means the Rg esterified carboxy group, without the addition of acid or base in water to acid. A process according to any one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that the compound of formula I, wherein R 1, R ₂ , R 8, R 4 and R 8 the meaning given in claim 1 and Rg represents the lower alkoxycarbonyl group which can be obtained by the process is hydrolyzed to the acid. A process according to any one of claims 1 to 31, characterized in that compounds of formula I are prepared, wherein R 1 is hydrogen, alkyl of up to and 12 carbon atoms or hydroxy, R _{2 is} hydrogen, lower alkyl, halogenated alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl , unsubstituted or phenyl-substituted phenylalkyl, lower alkenyl, halogen or unsubstituted or substituted phenyl, represents hydrogen, lower alkyl or unsubstituted or substituted phenyl, R ^ stands for hydrogen or lower alkyl, R ^ stands for free or pharmaceutically acceptable ester or amidated carbocyclic or amidated , Rg stands for amino, mono- or di-dialkylamino, A stands for unsubstituted or lower alkyl substituted b, t-alkylene having 1 to 3 carbon atoms or a bond, and B · stands for methylene or a bond, provided that A is different from bonds, if B is a bond, wherein the phenyl substituents are selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, or a pharmaceutically acceptable salt thereof. - 92 halogen, amino, halogen lower alkylamino, hydroxy lower alkyl, aminone lower alkyl and nitro or a pharmaceutically acceptable salt thereof. 33- Process according to one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that compounds of formula I are prepared, where hydrogen, alkyl with up to and 12 carbon atoms or hydroxy, R ₂ hydrogen, lower alkyl, halogenylalkyl, hydroxybenzylalkyl, lower alkoxybenzylalkyl, unsubstituted or phenyl substituted phenylbenzyl, lower alkenyl, halogen or unsubstituted or substituted phenyl, R 2 or hydrogen substituted R ^ is hydrogen or lower alkyl, R ^ is a pharmaceutically acceptable esterified or amidated carboxy, Rg is amino, rano- or di-dialkylamino, A is unsubstituted or lower alkyl substituted t-alkyne with 1 to 3 carbon atoms or a bond and B represents methylene or a bond, provided that A is different from a bond, if B means a bond wherein the phenyl substituents are selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halogen, amino, halogenylalkyl, hydroxynitalkyl, aminobenzylalkyl and nitro, or a pharmaceutically acceptable salt thereof. The process of claim 33, wherein the compounds of formula I are prepared, wherein R 1 to R 4, A and B have the meanings indicated in claim 31, R 1 is lower alkoxycarbo93 nyl or with amino, mono- or di-dialkylamino, hydroxy or lower alkanoyloxy substituted lower alkoxycarbonyl, and Rg stands for amino or mono-lower alkylamino, or a pharmaceutically useful salt thereof. A process according to any one of claims 1 to 31, characterized in that compounds of formula I are prepared wherein hydrogen, alkyl of up to and 12 carbon atoms or hydroxy, for hydrogen, lower alkyl, phenyl, halogenphenyl or phenylalkyl, are R4 and R4 are hydrogen or lower alkyl, R8 is carboxy and R8 is amino, wherein A is unsubstituted or lower alkyl substituted x-alkylene with 1 to 3 carbon atoms or bond and B is methylene or bond, provided that that A is different from the bond when B is a bond or a pharmaceutically acceptable salt thereof. 36. The method according to one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that compounds of formula I are prepared wherein R _{1 is} hydrogen, alkyl of up to and 12 carbon atoms or hydroxy, R _{2 is} hydrogen, lower alkyl, phenyl , halogenphenyl or phenylalkylalkyl, mean Rg and R4 are hydrogen or lower alkyl, Rg stands for alkoxycarbonyl or hydroxy-lower-alkoxycarbonyl, and Rg stands for amino or mono-loweralkylamino, wherein A is unsubstituted or lower alkyl substituted with 1, 3-alkylene by 1 to 3 alkylene with 1, or a bond and B represents methylene or a bond, provided that A is different from the bond if B represents a bond or a pharmaceutically acceptable salt thereof. - 94 37. A process according to any one of claims 1 to 31 "characterized in that, to prepare compounds of formula I, wherein R stands ^ is hydrogen, alkyl having up to 12 carbon atoms, or hydroxy, R ₂ represents hydrogen, lower alkyl or halophenyl , Rg stands for hydrogen or halogenphenyl, R ^ stands for hydrogen, Rg stands for carboxy, and Rg stands for amino, A stands for, ^ - alkylene of 1 to 3 carbon atoms or a bond and B stands for methylene or a bond, provided that A is different from the bond if B is a bond or a pharmaceutically acceptable salt thereof. 38. The process according to one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that compounds of formula I are prepared wherein R _{1 is} hydrogen, alkyl of up to and 12 carbon atoms or hydroxy, R _{2 is} hydrogen, lower alkyl or halogenphenyl, Rg stands for hydrogen or halogenphenyl, stands for R ^ hydrogen, Rg is lower alkoxycarbonyl or hydroxy-lower alkoxycarbonyl and Rg is amino or mono-lower alkylamino, A stands for o, U.-alkylene with 1 to 3 carbon atoms or bond and B stands for methylene or bond, provided that A is different from the bond when B is a bond or a pharmaceutically acceptable salt thereof. 39- Method according to one of claims 1 to 29, characterized in that, to prepare compounds of formula I, wherein R stands ^ are hydrogen, lower alkyl or hydroxy, R ₂ represents hydrogen or lower alkyl, and R stand for hydrogen, R for carboxy or lower alkoxycarbonyl, and Rg is amino, where A is N, N-alkylene of 1 to 3 carbon atoms, B is a bond, or a pharmaceutically useful salt thereof. 95. The method of any one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that compounds of formula I are prepared wherein R ₁ stands for hydrogen, 'lower alkyl or hydroxy, R _{2 represents} hydrogen or lower alkyl, Rg and Rjj are hydrogen , R4 is lower alkoxycarbonyl and R8 is amino, wherein A is O, R4-alkylene of 1 to 3 carbon atoms, represents a B bond, or a pharmaceutically useful salt thereof. A process according to any one of claims 1 to 31 »characterized in that compounds of formula I are prepared wherein R 1 is hydroxy, R _{2 is} hydrogen or lower alkyl, and R ₁ is hydrogen, R 4 is lower alkoxycarbonyl or carboxy , stands R? for amino, A is methylene and B is a bond, or a pharmaceutically useful salt thereof. 42. The method according to one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25, 28'and 31, characterized in that compounds of formula I are prepared wherein R _{1 is} hydroxy, R _{2 is} hydrogen or lower alkyl, R ₁ and R ₂ are hydrogen, stands for R4 lower alkoxycarbonyl or carboxy, stands R? for amino, A is methylene and B is a bond, or a pharmaceutically useful salt thereof. A process according to any one of claims 1, 2, 4, 5, 7, 9, 11 to 13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that the ethyl ester E- 2-amino-4-methyl-5-phosphono3-pentenoic acid or a pharmaceutically acceptable salt thereof. 44. The process according to one of claims 3, 6, 8, 10, 14, 17, 20 ,. 23, 25 and 28, characterized in that we prepare 96 E-2-Amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester or a pharmaceutically acceptable salt thereof. Process according to one of claims 1, 2, 4, 5, 7, 9, 11 to 13, 15, 16, 18, 19, 21, 22, 24, 26, 27 and 30, characterized in that E -2-amino-4-methyl-5-phosphono-3pentenoic acid or a pharmaceutically acceptable salt thereof. A process according to claim 31, characterized by the tern for preparing E-2-amino-4-methyl-5-phosphono-3-pentanoic acid or a pharmaceutically useful salt thereof. Process according to one of claims 1, 2, 4, 5, 7, 9, 11 to 13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that the methyl ester E- 2-amino-4-methyl-5-phosphono3-pentenoic acid or a pharmaceutically acceptable salt thereof. Process according to one of Claims 1, 2, 4, 5, 7, 9, 11 to 13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that 'n- E-2-amino-4-methyl-5-phosphono-3-pentenoic acid propyl ester or a pharmaceutically acceptable salt thereof. Process according to one of the claims 1, 2, 4, 5, 7, 9, 11 to 13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that n-butyl ester is prepared E-2-amino-4-methyl-5-phosphoin-3-pentenoic acid or a pharmaceutically acceptable salt thereof. Process according to one of the claims 1, 2, 4, 5, 7, 9, 11 to 13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that the isobutyl ester E- 2-amino-4-methyl-5-phospho-3-pentenoic acid or a pharmaceutically acceptable salt thereof. 97. The method of any one of claims 1, 2, 4, 5, 7, 9, 11 to 13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that the n-pentyl ester of E-2-amino-4-methyl-5-phosphono-3-pentene is prepared acid or a pharmaceutically acceptable salt thereof. 52. The method of any one of claims 1, 2, 4, 5, 7, 9, 11 to 13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that the n-hexyl ester of E-2-amino-4-methyl-5-phosphoηο-3-pentene is prepared acid or a pharmaceutically acceptable salt thereof. 53. The method according to one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that E-2-amino-4-methyl-5-phosphono-3-pentanoic acid methyl ester or a pharmaceutically acceptable salt thereof is prepared. 54. The process according to one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that the N-propyl ester of E-2-amino-4-methyl-5-phosphono-3-pentanoic acid or a pharmaceutically useful salt thereof is prepared. 55. The method of any one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that the N-butyl ester of E-2-amino-4-methyl-5-phosphono-3-pentanoic acid or a pharmaceutically useful salt thereof is prepared. 56. The method of any one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that E-2-amino-4-raethyl-5-phosphono-3-pentenoic acid isobutyl ester or a pharmaceutically acceptable salt thereof is prepared. - 38 57. The process according to one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that the N-pentyl ester of E-2-aryano-4-methyl-5-phosphoxy-3-pentanoic acid or a pharmaceutically acceptable salt thereof is prepared. 58. The method according to one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that the N-hexyl ester of E-2-aryano-4-methyl-5-phosphono-3-pentanoic acid or a pharmaceutically acceptable salt thereof is prepared. 59. The process of claim 1 for the preparation of E-2-amino-4 phosphonomethyl-3,6-heptadienoic acid and its pharmaceutically useful salts, wherein the methyl ester is E-2-formylamino 4-Diethylphosphonomethyl-3,6-heptadienoic acid is reacted in dichloromethane with trimethylsodilane and the primary product is treated with hydrochloric acid. 60. The process according to any one of claims 1 to 59, characterized in that the enantiomer is prepared in which the carbon atom bearing the amino group Rg has the R configuration. A method according to any one of claims 1, 2, 4, 5, 7, 9, 11 to 13, 15, 16, 18, 19, 21, 22, 24, 26, 27 and 29 to 31, characterized in that (2R) -E-2-amino-4-methyl-5-sulfon-3-pentenoic acid or a pharmaceutically acceptable salt thereof is prepared. 62. The process of claim 31, wherein (2R) -E-2-amino-4-methyl-5-phosphono-3-pentanoic acid or a pharmaceutically useful salt thereof is prepared. 99. A method according to any one of claims 1, 2, 4, 5, 7, 9, 11 to 13, 15, 16, 18, 19, 21, 2-2, 24, 26, 27 and 29, characterized in to prepare (2R) -E-2-amino-4-ethyl ethyl ester 5-phosphono-3-pentenoic acid or its. a pharmaceutically useful salt. 64. The method of any one of claims 3, 6, 8, 10, i 14, 17, 20, 23, 25 and 28, characterized in that (2R) - E-2-amino-4-methyl-5-phosphono-3-pentanoic acid ethyl ester or a pharmaceutically acceptable salt thereof is prepared. 65. The method according to one of claims 1, 2, 4, 5, 7, 9, 11 to 13, 15, 16, 18, 19, 21, 22, 24, 26, 27 and 29 to 31, characterized in that (2R) -E-2-amino-4-methyl-7-phosphono-3-heptenoic acid or a pharmaceutically acceptable salt thereof is prepared.