NO170938B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE PHOSPHONOSUBSTITUTED AMINOALKY ACIDS - Google Patents

Abstract

Phosphorus-contg. unsaturated amino acids of formula (I) and their salts are new: R1 = hydroxy or etherified hydroxy; R2 = H, alkyl, hydroxy or etherified hydroxy; R3 = H, alkyl, haloalkyl, hydroxyalkyl, lower alkoxyalkyl, arylalkyl, lower alkenyl, halogen or aryl; R4 = H, alkyl or arl; R5 = H or alkyl; R6 = carboxy or esterified or amidated carboxy; R7 0 amino opt. substd. by alkyl or aryl; A = opt. alkyl-substd. 1-3C alpha, omega-alkylene or a direct bond; B = methyleue or direct bond; provided that A and B are both direct bonds. Specifically claimed are 9 cpds. including E-2-amino-5- phosphono-3-pentenoic acid, E-2-amino-4-methyl-5-phosphono -3-pentenoic acid, and E-2-amino-4-methyl -5-phosphono-3-pentenoic acid ethyl ester.

Description

The invention relates to the production of new therapeutically effective phosphonosubstituted aminoalkenic acids with the formula:

there

R<*> means hydroxy,

R<2> means hydrogen, C₁-C₆ alkyl or hydroxy,

R<3> means hydrogen, C1-C8-alkyl, phenyl-C1-C4-alkyl or phenyl,

R<4> means hydrogen or C^-C4~alkyl,

R<5> means hydrogen or C^-C^alkyl,

R<6> means carboxy or C 1 -C 6 -alkoxycarbonyl,

R<7> means amino or with C 1 -C 8 -alkanoyl-substituted amino,

Å means unsubstituted or with C^-C4-alkyl substituted C^-C3-0: ,co-alkylene with 1 to 3 carbon atoms, and

B means a bond, whereby R<3> and R<4> respectively A and B can be trans in relation to each other, as well as salts thereof.

The compounds of formula I contain at least one chiral center and can exist as enantiomers or as enantiomer mixtures, as racemates, if they have more than one chiral center, also as diastereomers or as diastereomer mixtures.

The carbon-carbon double bond of the compound according to the invention is with respect to R<3> and ^ respectively with respect to A and B transconfigured, i.e. the compounds of formula I are about the compounds of the E series.

Compounds of formula I, in which R<2> means hydrogen, are phosphonic acids, those in which R<2> means C 1 -C 8 alkyl, are phosphinic acids and those in which R<2> means hydroxy are phosphonic acids. As prefixes in the designation of the compounds of formula I, which are to be considered substituted carboxylic acids, "phosphino" is used

(R<2> means hydrogen), "phosphonyl" (R<2> means C1-C8 alkyl) and "phosphono" (R<2> means hydroxy).

With C1-C4-alkyl substituted C1-C3-CX, the u-alkylene is substituted at a desired position, and means, for example, methylene, 1,2-ethylene, 1,1-ethylene, 1,1-butylene, 1,1 -octylene, 1,2-propylene, 1,2-butylene, 2,3-butylene, 1,2-pentylene or 1,2-nonylene, 1,3-propylene, for example 1,3-butylene, 1,3-pentylene or 1 ,3-decylene.

Salts of compounds of formula I are primarily pharmaceutically acceptable, non-toxic salts of compounds of formula I. Such salts are formed, for example, by the carboxy group present in the compounds of formula I and are primarily metal or ammonium salts, such as alkali metal - and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, such as lower alkyl amines, e.g. methylamine, diethylamine or triethylamine, hydroxyl lower alkylamines, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tris-(hydroxymethyl)methylamine or tris-(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid-2-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethylpiperidine, lower alkylenediamines, e.g. ethylenediamine, cycloalkylamines, e.g. dicyclohexylamine, or benzylamines, e.g. N,N'-dibenzyl-ethylenediamine, benzyltrimethylammonium hydroxy, dibenzylamine or N-benzyl-P-phenylethylamine. Compounds of formula I with a primary or secondary amino group can also form acid addition salts, e.g. with preferably pharmaceutically acceptable inorganic acids, such as hydrohalic acids, e.g. hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, citric acid, pyruvic acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid or naphthalenesulfonic acid.

Pharmaceutically unsuitable salts can also be used for isolation or purification. For therapeutic use only the pharmaceutically acceptable non-toxic salts, which are therefore preferred.

The above and hereinafter stated general terms have, if they are differently defined, the following meanings: C 1 -C 8 -alkyl means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl, further n-pentyl, n-hexyl, n-heptyl or n-octyl, preferably methyl. Phenyl-C 1 -C 4 -alkyl is, for example, benzyl or 1- or 2-phenylethyl.

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

C1-C4-Alkoxycarbonyl is e.g. methoxycarbonyl or ethoxycarbonyl.

From Ågric. Biol. Chem. 40, 1905-6 (1976), Agric. Biol. Chem. 41, 573-9 (1977) and JP-A1-78/87, 314 (Vergl. Chem. Abstr. 89: 195402a (1978) were Z-(D)-2-amino-5-phonono-3-pentenoic acid and its carboxamide already known as the peptide building block in the antibiotic tripeptides Plumbemycin A and B respectively. Furthermore, it was known, for example, from TJS 4,483,853 and GB 2,104,079 that aliphatic 2-amino-o)-phosphonocarboxylic acids antagonize N-methyl-D -aspartic acid (NMDA) on NMDA-sensitive excitatory amino acid receptors. In particular, 2-amino-7-phosphono-4-heptenoic acid was known from GB 2,104,079.

The invention is based on the fact that it has been determined that the compounds of formula I are active and selective antagonists of N-methyl-D-aspartic acid (NMDA) on NMDA-sensitive excitatory amino acid receptors in mammals. They are therefore suitable for the treatment of diseases that respond to a blockade of NMDA-sensitive receptors, such as e.g. cerebral ischaemia, muscle spasms (spasticity), convulsions (epilepsy), anxiety states or manic states.

These beneficial effects can be demonstrated in in vitro or in vivo test devices. Thereby, mammals are preferably used, e.g. mice, rats or monkeys, or tissues or enzyme preparations of such mammals. The compounds can 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 applicable in vivo dose may range between 0.1 and 600 mg/kg, preferably between 1 and 300 mg/kg. In vitro, the compounds can be used in the form of aqueous solutions, as the concentrations can vary between

10~4 molar and 10~8 molar solutions.

The inhibitory effect on NMDA sensitive excitatory amino acid receptors can be determined in vitro, and according to G. Fagg and A. Matus, Proe. Nat. Acad. Sei., USA, 1981, 6876-80

(1984), measurements are made to determine the extent to which the binding of l-<3>H-glutamic acid to NMDA-sensitive receptors is inhibited. The inhibitory effect on NMDA-sensitive excitatory amino acid receptors can be illustrated in vivo, as NMD-induced convulsions are inhibited in mice.

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

The anticonvulsant properties can also be demonstrated by the action of the compounds of formula I as electroshock antagonists on mice or rats.

Thus, comparison experiments with the amino-7-phosphono-4-heptenoic acid known from GB 2,104,079 and US 4,483,853 (comparison) in the electroshock mouse model yielded the following EDsø values for the protective effect against shock convulsions: E-2-amino-5 -phosphono-3-pentenoic acid: 107; E-2-amino-4-methyl-5-phosphono-3-pentenoic acid; 13; E-2-amino-5-phosphono-3-pentenoic acid butyl ester: 95; E-2-amino-5-phosphono-3-pentenoic acid propyl ester: 128; E-2-amino-5-phosphono-3-pentenoic acid pentyl ester: 81; E-2-amino-5-phosphono-3-pentenoic acid isobutyl ester: 36; E-2-amino-4 methyl-5-phosphono-3-pentenoic acid ethyl ester: 4; E-2-amino-4-methyl-5-phosphono-3-pentenoic acid methyl ester: 4; E-2-amino-4-methyl-5-phosphono-3-pentenoic acid butyl ester: 2; E-2-amino-4-methyl-5-phosphono-3-pentenoic acid hexyl ester: 4; E-2-amino-4-ethyl-5-phosphono-3-pentenoic acid: 14; E-2-amino-7-phosphono-4-heptenoic acid (comparison): no protective effect at 20 and at 100 mg kg/p.o.

A reference to the anxiolytic activity of the compounds of formula I gives their good effect in the conflict model according to Cook/Davidson (Phychopharmacologia 15, 159-168 (1968)).

The good effect of the compounds of formula I depends to a surprisingly high degree on the configuration of the double bond. Thus shows the racemate of it from Agric. Biol. Chem. 41, 573-579 (1979), B.K. Park et al. known D-2-amino-5-phosphono-3-cis-pentenoic acid, e.g. in its ability to bind to NMDA-sensitive receptors, far inferior to the acemate of the 2-amino-5-phosphono-3-trans-pentenoic acids produced according to the invention (in the example section these compounds are referred to as compounds from the "E series").

Preferred are compounds of formula I, in which R<3> means hydrogen, alkyl or phenyl.

Preferred are compounds of formula I, in which R<1> and R<2 >mean hydroxy, R<3> means hydrogen or C₁-C₆ alkyl, R<4> and R<5>mean hydrogen, R₂ means carboxy .

The new compounds of formula I are prepared according to the present invention by reacting a compound of the formula: where R<3>, R<4>, R<5>, A and B are as indicated above, Z<6> means with C ^-C^-alkyl protected carboxy, Z<7> means with C^-C alkanoyl-protected amino and X means halogen, with a compound of formula III

where Z<1> means with C1-C8-alkyl protected hydroxy, Z<2> means C1-C8-alkyl, with a,a,-di-C1-C4-alkoxy-C1-C4-alkyl protected hydrogen or with C ^-C 8 alkyl protected hydroxy, and R means C 1 -C 8 alkyl, and then sets the protected groups free hydrolytically and optionally, in an obtained compound of formula I, where R^ is carboxy, esterifies the carboxy group to lower alkoxycarbonyl, in an obtained compound where R 7 is

amino, acylate the amino group to lower alkanoylamino, if desired transfer an obtained compound of formula I to a salt or transfer an obtained salt to another salt or to a free compound of formula I and if desired isolate an optical isomer from a mixture of stereoisomeric forms of an obtained compound of formula I or isolates a salt thereof.

In the above method, protected hydroxy stands for e.g. for C₁-C₆-alkoxy and protected amino for C₁-C₆-alkanoylamino. Protected carboxy is usually protected with C-1-C 12 alkyl * esterified form.

With a, a-di-Ci-C4-Alkoxy-C1-C4-alkyl protected hydrogen Z<1> is protected in a manner known per se, as for example described in EP-Å-0 009 348. In the case of corresponding protecting groups, it is preferably groups with the formula -CiC^-^-alkyl)(0R<a>)0R<b>, preferably of groups with -CH(0R<a>)0RlD, in which Ra and R<b> respectively mean C 4-4-alkyl. Particularly suitable is the group -CHfOC^Hs^-

Halogen X is a hydroxy group esterified with a strong organic acid, e.g. one with an aliphatic or aromatic sulfonic acid (such as a lower alkanesulfonic acid, especially methanesulfonic acid, trifluoromethanesulfonic acid, especially benzenesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid and p-nitrobenzenesulfonic acid) or with a strong inorganic acid, such as especially sulfuric acid, or a halohydrogen acid, such as hydrochloric acid or most preferably hydroiodic acid or hydrobromic acid, esterified hydroxy group.

The conversion is carried out in a manner known per se, especially under the known conditions of the Michaelis-Arbuzov reaction.

In this method, if of the groups Z-*-, Z<2>, Z^ and T? more means protected groups, these are advantageously chosen so that they can be released in a single step. The relevant conditions, under which the protected groups are released, are preferably hydrolytic conditions, such as an acid hydrolysis, e.g. with hydrohalic acids, such as with hydrochloric acid, preferably under heating.

Processing takes place in a manner known per se, as two cleaning operations in particular prove to be advantageous. Either the raw product can be transferred in a volatile derivative, e.g. by silylation, and is distilled as such, then desilylated. Or the raw product can be mixed with an agent that reacts with excess acids, such as hydrohalic acid, thus removing it. For example, there will be compounds, to which the corresponding acid can add, e.g. lower alkylene oxides (epoxides), such as propylene oxide.

The compounds of formula II can be prepared, e.g. in that N-protected aminomalonic acid esters are reacted with compounds of formula VII

in a manner known per se, wherein X and X' independently of each other mean reactive esterified hydroxy. The thus formed compounds II' can be transferred to compounds of formula II, as they are decarboxylated.

The starting compounds of formula III are preferably trialkyl phosphite (Z<1>= alkoxy, Z<2>=alkyl,, R=alkyl) or alkylphosphorus acid dialkyl ester (Z<1>= alkoxy, Z<2>=alkyl, R= alkyl). They are known or can be produced in an analogous manner to known methods.

Compounds of formula II, in which A means methylene optionally substituted with alkyl, B means a bond, X means halogen and tP means formylamino, can be e.g. prepare, wherein an ot,p-unsaturated aldehyde, e.g. acrolein or methacrolein, is reacted with an α-isocyanoacetic acid derivative, such as e.g. an α-isocyanacetic acid lower alkyl ester. Under suitable catalysis, such as with low-value metal salts, e.g. metal oxides or metal halides, such as zinc chloride, cadmium chloride, silver oxide or preferably copper oxide, 5-vinyl-2-oxazoline-4-carboxylic acid derivatives, e.g. esters, which can be transferred in the open chain compounds of formula IX

wherein D means methyl idene optionally substituted with alkyl. These compounds in turn can be transferred to compounds of formula II by selective halogenation, such as bromination or chlorination, preferably during cooling, and during rearrangement of the double bond in the form of an allyl rearrangement.

For the transfer of a formed compound of formula I to another compound of formula I, the conversion can be carried out as follows: An amino group can be released from its esterified form by hydrolysis or hydrogenolysis, become acylated and/or free carboxy can be esterified.

For esterification, a carboxylic acid can be directly reacted with a diazoalkane, especially diazomethane, or with a corresponding alcohol in the presence of a strongly acidic catalyst (e.g. a hydrohalic acid, sulfuric acid or an organic sulphonic acid) and/or a dehydrating agent (e.g. .dicyclohexylcarbodiimide). Alternatively, the carboxylic acid can be transferred in a reactive derivative, such as a reactive ester to a mixed anhydride, e.g. with an acid halide (e.g. especially an acid chloride), and this activated intermediate is reacted with the desired alcohol. Esterifications of hydroxy bound to phosphorus can take place as above or in another manner known per se.

Compounds of formula I, in which R<7> means amino, can be converted to compounds in which R<7> means acylamino, e.g. using a corresponding acid anhydride or halide, or vice versa, by methods which belong to the state of the art, and are described here in connection with protecting groups.

The above-mentioned reactions are carried out according to standard methods in the presence or absence of the diluent, preferably those which are inert to the reagents and form their solvent, of catalysts, condensation agents or the other agents and/or in an inert atmosphere at lower temperatures, room temperature or elevated temperatures, preferably at the boiling point of the solvent used, at atmospheric or superatmospheric pressure.

Depending on the choice of starting materials and methods, the new compounds can exist in the form of one of the possible optical isomers or of their mixtures, for example depending on the number of asymmetric carbon atoms, as pure optical isomers, as antipodes or as mixtures of optical isomers, which as racemates or as mixtures of diastereoisomers, from which the antipodes can, if desired, be isolated.

Formed mixtures of diastereisomers and mixtures of the racemates can, due to the physico-chemical differences of the components, be separated in a known manner into the pure isomers, diastereoisomers or racemates, e.g. by chromatography and/or fractional crystallization.

The formed racemates (racemic diastereoisomers) can be further divided into the optical antipodes according to methods known per se, for example by recrystallization from an optically active solvent, with the help of microorganisms or by reacting an acidic end product with an optically active hase that forms salts with the racemic acid and dividing the salts formed in this way, for example on the basis of their different solubilities, into the diastereomers from which the antipodes can be released by the action of suitable agents. Basic racemic products can likewise be cleaved in the antipodes, e.g. by cleavage of their diastereomeric salts, e.g. by fractional crystallization of their d- or 1-tartrates. Any racemic intermediates or starting materials can be separated in a similar way.

Finally, the compounds of formula I are obtained either in free form or in the form of their salts. One or other base formed can be transferred to a corresponding acid addition salt, preferably using a pharmaceutically acceptable acid or an anion exchange preparation or salts formed can be transferred to the corresponding free bases, for example using a stronger base, such as a metal or ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchange preparation. A compound of formula I can also be transferred in the corresponding metal or ammonium salts. These or other salts, for example the picrates, can also be used for purification of the formed bases. The bases are transferred to the salts, the salts are separated and the bases are released from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is mentioned here, corresponding salts of these compounds are also included, provided that this is possible or appropriate under the given circumstances.

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

The invention will be explained by some examples. All parts are stated in terms of parts by weight. When nothing else is mentioned, all evaporations are carried out under reduced pressure, preferably between approx. 2 and 13 kilopascals (kPa).

Example 1

8.22 g of E-2-formylamino-5-diethylphosphono-3-pentenoic acid ethyl ester are dissolved in 170 ml of 6N hydrochloric acid and heated for 22 hours under reflux. After evaporation in a vacuum, the oily residue is taken up in a little ethanol and the mixture is evaporated again in a vacuum. This is repeated two more times. The residue thus formed is dissolved in 15 ml of ethanol and mixed dropwise with 20 ml of ethanol/propylene oxide (1:1). The brown precipitate formed is filtered off and purified by ion exchange chromatography ("Dowex" 50W x 8/E<2>q). After evaporation and lyophilization, E-2-amino-5-phosphono-3-pentenoic acid is obtained as white amorphous powder, <1->H-NMR (D20): 2.39 (dd, 2H, C(5)-H), 4.27 (d, 1H, C(2)-H), 5.53 (m, 1E, C(3)-E), 5.87 (m, 1H, C(4)-E), m.p. after recrystallization from ethanol/water 191-192°C.

The starting material is produced as follows:

1.6 g of red copper(I) iron oxide is dissolved in 200 ml of benzene. With intense stirring, a solution of 140 g of isocyanoacetic acid ethyl ester and 84 g of freshly distilled acrolein in 200 ml of benzene is dripped into this suspension over the course of 10 minutes. The reaction temperature is thereby kept by ice cooling between 300 and 32°C. After the addition is finished, the mixture is kept at 30-32°C until the end of the exotherm, and is then stirred for 1 hour at room temperature. After filtering off excess copper (I) oxide, the filtrate is evaporated in a vacuum at 30°C. The residue is mixed with 600 ml of ether, filtered over "Celite" and evaporated in vacuo to dryness. 5-Vinyl-2-oxazoline-4-carboxylic acid ethyl ester is thus obtained as pale yellow oil, boiling point 100-110°C (5.3 Pa).

128 g of the 5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester are dissolved in 70 ml of tetrahydrofuran and mixed with 27.4 g of water and 3.5 g of triethylamine. The reaction mixture is stirred for 62 hours at 65-70°C and, after cooling, taken up in 200 ml of dichloromethane. The solution is dried over 200 g of magnesium sulphate, filtered and evaporated in vacuo. Purification of the remaining viscous oil by column chromatography (silica gel, hexane/acetic ester 3:2) gives 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester as a diastereomeric mixture, melting point 50-51°C.

2.0 g of 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester in 80 ml of dry tetrahydrofuran is cooled to -78°C. 2.5 ml of thionyl bromide is slowly added dropwise, so that the reaction temperature does not exceed -75°C. After the addition is complete, the reaction solution is heated for approx. 3 hours at 0°C and stirred for 2.5 hours at this temperature. The orange-yellow solution is then poured into 300 ml of a cold (5-10°C) saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic extracts are dried over magnesium sulfate and evaporated at room temperature in a vacuum. The remaining oil is dissolved in 20 ml of triethyl phosphite and heated for 2 hours in vacuum (10 kPa) under reflux (55°C). Excess triethyl phosphite is then distilled off in high vacuum. Column chromatographic purification (silica gel, ethyl acetate/hexane (2:1), then ethyl acetate) gives E-2-formylamino-5-diethylphosphono-3-pentenoic acid ethyl ester as a pale yellow oil, ^H-NMR(CDC13):2.62 (m , 2E, C(5)-E), 5.19 (m, 1E, C(2)-E), 5.75 (m, 2E, C(3)-E and C(4)-E).

Example 2

By hydrolysis of E-2-formylamino-4-methyl-5-diethylphospheno-3-pentenoic acid ethyl ester in an analogous manner as described in example 1, E-2-amino-4-methyl-5-phosphono-3-pentenoic acid is obtained, ^E- NMR (D 2 O): 1.73, (s, 3E, CE 3 ), 4.55, (s, 1E, C(2)-E).

The starting material is produced as follows:

By reacting isocyanoacetic acid ethyl ester with methacrolein in an analogous manner as described in example 1 and after subsequent fractional distillation, 5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester is obtained as a colorless oil, boiling point 110-130°C (5.3 Pa ).

By hydrolysis of 5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester in an analogous manner as discussed in example 1, 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester is obtained, melting point 67°C.

By reaction of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in an analogous manner as described in example 1, E-2-formyl-4-methyl-5-diethylphosphono- 3-pentenoic acid ethyl ester as a pale yellow oil.

Example 3

By hydrolysis of E-2-formylamino-5-(0-ethyl-methylphosphonyl)-3-pentenoic acid ethyl ester in an analogous manner to that described in example 1, E-2-amino-5-methylphosphonyl-3-pentenoic acid is obtained after precipitation with propylene oxide as amorphous white powder, ^-H-NMR (D2O): 2.55 (dd, 2H, C(5)-H), 4.38 (d, 1H, C(2)-H), 5.64 ( m, 1H, C(3)-E), 5.91 (m, 1H, C(4)-H).

The starting material is produced as follows:

By reacting E-2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with methylphosphoric acid diethyl ester instead of triethyl phosphite in an analogous manner as discussed in example 1, E-2-formylamino-5-(0-ethyl- methylphosphonyl)-3-pentenoic acid ethyl ester as colorless oil, 1H-NMR (CDCl 3 ): 2.63 (dd, 2H, C(5)-H), 5.1 (m, 1H, C(2)-E), 5 .75 (m, 2H, C(3)-H and C(4)-H).

Example 4

25 g of E-2-formylamino-5-O-ethyl-diethoxymethylphosphonyl-3-pentenoic acid ethyl ester are stirred with 500 ml of 6N hydrochloric acid for 1 16 hours under reflux and then evaporated at 70°C in vacuum. The residue is suspended in 100 ml of 95% ethanol/water, mixed with 20 ml of propylene oxide, and the product is filtered off. After recrystallization, E-2-amino-5-phosphino-3-pentenoic acid is obtained, melting point 139-140°C.

The starting material is produced as follows:

10 g of 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester in 50 ml of dry tetrahydrofuran are cooled to -78°C. 12.7 g of thionyl chloride are added dropwise so that the reaction temperature does not exceed -75°C. The reaction solution is then heated to -20°C over the course of 3 hours and stirred for 3 hours at this temperature.

The yellow solution is then poured onto 300 ml of a cold (5°C) saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic extracts are dried over sodium sulphate and evaporated at 30°C in a vacuum. The residue is purified by column chromatography (silica gel, ethyl acetate), the remaining pale yellow oil is dissolved in 10 ml of tetrahydrofuran. After adding 17.0 g of diethoxymethylphosphoric acid ethyl trimethylsilyl ester, the mixture is stirred for 24 hours at 35°C. The dark yellow solution is then poured onto 100 ml of a cold (5°C) saturated sodium bicarbonate solution and extracted with dichloromethane. The organic extracts are dried over sodium sulphate and evaporated at 30°C in a vacuum. After purification of the residue by column chromatography (silica gel, ethyl acetate/methanol), E-2-formylamino-5-0-ethyl-diethoxymethylphosphonyl-3-pentenoic acid ethyl ester is obtained as a pale yellow oil, <*>H-NMR (CDCl3):2.70 ( m, 2H, C(5)-H), 4.68 (q, 1E, C(2)-H), 5.20 (m, 1H, (C-P)-H), 5.80 (m, 2H , C(3)-H and C(4)-H

Example 5

a) 1.0 g of E-2-amino-5-phosphino-3-pentenoic acid is suspended in 20 ml of ethanol and saturated with chlorine hydrogen gas for 2 hours at

65°C. After evaporation, the residue is dissolved in 10 ml of ethanol, mixed with 10 ml of propylene oxide and the precipitate filtered off. After recrystallization from water/acetone 1:1, E-2-amino-5-phosphino-3-pentenoic acid ethyl ester is obtained, melting point 172-173°C.

b) 1.0 gE-2-amino-5-phosphino-3-pentenoic acid is suspended in 20 ml of n-butanol and saturated with chlorine hydrogen gas for 3 hours at

60°C. After evaporation, the residue is dissolved in 15 ml of n-butanol, mixed with 10 ml of propylene oxide and the precipitate filtered off. After recrystallization from water/acetone 1:1, E-2-amino-5-phosphino-3-pentenoic acid butyl ester is obtained, melting point 160-161°C.

Example 6

a) 2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are dissolved in 50 ml of ethanol and saturated with chlorine hydrogen gas for 2.5 hours at 50°C.

After evaporation, the residue is dissolved in 18 ml of ethanol, mixed with 18 ml of propylene oxide and the precipitate filtered off. After recrystallization from water/ethanol 1:3, 2-amino-5-phosphono-3-pentenoic acid ethyl ester is obtained, melting point 167-168°C. b) 2.0 g of E-2-amino-5-phosphino-3-pentenoic acid are suspended in 40 ml of n-butanol and saturated for 3 hours at 40° C with chlorine hydrogen gas. After evaporation, the residue is dissolved in 30 ml of n-butanol, mixed with 15 ml of propylene oxide and the precipitate filtered off. After recrystallization from water/acetone 1:1, E-2-amino-5-phosphono-3-pentenoic acid butyl ester is obtained, melting point 160-161°C. c) 2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of n-octanol and saturated with chlorine hydrogen gas for 4 hours vec

70°C. The mixture is concentrated in vacuo at 70°C to half the volume, mixed with 50 ml of diethyl ether and 15 ml of propylene oxide and filtered. After recrystallization from water/acetone 1:1, E-2-amino-5-phosphono-3-pentenoic acid octyl ester is obtained, melting point 161-162°C.

d) 2.0 g of 2-amino-5-phosphono-3-pentenoic acid are suspended in 15 ml of 1-dodecanol and 25 ml of tetrahydrofuran and saturated with

chlorine hydrogen gas 4 hours at 50°C. The mixture is freed from tetrahydrofuran in vacuum at 50°C, mixed with 40 ml of acetone and 20 ml of propylene oxide and filtered. After stirring with water/acetone 1:1, E-2-amino-5-phosphono-3-pentenoic acid dodecyl ester is obtained, melting point 158-159°C.

e) 1.5 g of E-2-amino-5-phosphono-3-pentenoic acid is suspended in 30 ml of n-propanol and saturated with chlorine hydrogen gas for 2.5 hours at

50°C. After evaporation, the residue is dissolved in 15 ml of n-propanol, mixed with 15 ml of propylene oxide and the precipitate is filtered off. After recrystallization from water/acetone 1:3, E-2-amino-5-phosphono-3-pentenoic acid propyl ester is obtained, melting point 4 161-162°C.

f) 1.5 g of 2-amino-5-phosphono-3-pentenoic acid is suspended in 30 ml of n-pentanol and saturated with chlorine hydrogen gas for 3 hours at

50°C. After evaporation, the residue is dissolved in 15 ml of n-pentanol, mixed with 15 ml of propylene oxide and the precipitate filtered off. After recrystallization from water/acetone 1:1, E-2-amino-5-phosphono-3-pentenoic acid pentyl ester is obtained, melting point 160-161°C.

g) 1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of iso-butanol and saturated with chlorine hydrogen gas for 3.5 hours

at 70°C. After evaporation, the residue is dissolved in 10 ml of iso-butanol, mixed with 10 ml of propylene oxide and the precipitate filtered off. After recrystallization from water/acetone 1:1, E-2-amino-5-phosphono-3-pentenoic acid isobutyl ester is obtained, melting point 163-164°C.

h) 1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 m 1 sec.-butanol and saturated with chlorine hydrogen gas for 4 hours

at 75°C. After evaporation, the residue is dissolved in 10 ml of 2-butanol, mixed with 10 ml of propylene oxide and the precipitate filtered off. After recrystallization from water/acetone 1:1, E-2-amino-5-phosphono-3-pentenoic acid sec-butyl ester is obtained, melting point 169-170°C.

Example 7

By hydrolysis of E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester in an analogous manner to that described in example 1, E-2-amino-4-methyl-5-phosphono-3-pentenoic acid is obtained. ^H-NMR see example 2. In preliminary fractions, E-2-amino-4-methyl-5-methylphosphono-3-pentenoic acid is obtained as a by-product, melting point 149-150°C.

The starting material is produced as follows:

By reacting 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethylphosphite in an analogous manner as described in example 1, E-2-formylamino-4-methyl-5-dimethylphosphono- 3-pentenoic acid ethyl ester as pale yellow oil.

Example 8

2.0 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid are dissolved in 50 ml of ethanol and saturated with chlorine hydrogen gas for 2.5 hours at 50°C. After evaporation, the residue is dissolved in 20 ml of ethanol, mixed with 20 ml of propylene oxide and the precipitate filtered off. After recrystallization from water/ethanol (1:3), E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester is obtained, melting point 193-194°C.

In an analogous way, the following esters are obtained:

b) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid methyl ester, melting point 193-194°C, [water/acetone (9:1)],

c ) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-propyl ester,

melting point 184-185°C (water),

d) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid-n-butyl ester, melting point 186-187°C, [water/acetone (2:1)], e) E-2-amino- 4-methyl-5-phosphono-3-pentenoic acid iso-butyl ester, melting point 181-182°C, [water/acetone (9:1)], f) E-2-amino-4-methyl-5-phosphono- 3-pentenoic acid-n-pentyl ester, melting point 207-208°C, g) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid-n-hexyl ester, melting point 207-208°C.

Example 9

21 g of E-2-formylamino-4-methyl-5-0-ethyl-diethoxymethylphosphonyl-3-pentenoic acid ethyl ester is stirred with 400 ml of 4.35N hydrochloric acid for 16 hours at 80° C. and then evaporated at 45° C. in vacuum. The residue is dissolved in 100 ml of ethanol and mixed with 30 ml of propylene oxide, the product is filtered off. After recrystallization from water, E-2-amino-4-methyl-5-phosphino-3-pentenoic acid is obtained, melting point 176-177°C.

The starting material is produced as follows:

50 g of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in 500 ml of dry tetrahydrofuran is cooled to -78°C. 89 g of thionyl chloride are added dropwise so that the reaction temperature does not exceed -70°C. The reaction solution is then heated over the course of 3 hours to -10°C and stirred for 3 hours at this temperature and then evaporated under high vacuum at 20°C.

The residue is taken up in 400 ml of dichloromethane and neutralized with saturated aqueous sodium bicarbonate solution. The organic extracts are dried over sodium sulphate and evaporated at 30°C in a vacuum. The residue is purified by column chromatography (silica gel, ethyl acetate), the remaining pale yellow oil is dissolved in 30 ml of toluene. After adding 94 g of diethoxymethylphosphoric acid ethyltrimethylsilyl ester, the mixture is stirred for 16 hours at 90°C. The dark yellow solution is poured onto ice/water, neutralized with sodium bicarbonate and extracted with dichloromethane. The organic extracts are dried over sodium sulfate and evaporated at 30 °C in a vacuum. After purification of the residue by column chromatography (silica gel, ethyl acetate, then ethyl acetate/methanol 9:1), E-2-formylamino-4-methyl-5-O-ethyl-diethyl phosphonyl-3-pentenoic acid ethyl ester is obtained as a pale yellow oil , ^E-NMR(CDCl 3 ): 2.64 (dd, 2H, C(5)-H), 4.60 (d, 1H, P-CH), 5.26 (m, 2E, C(2) -H and C(3)-H).

Example 10

Racemate resolution of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid.

209 mg of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid 1 21 ml of 2N caustic soda are mixed under vigorous stirring during 20 minutes at 20°C with a solution of 1.5 ml of phenylacetyl chloride in 25 ml 1 ,4-dioxane and stirred for 4 hours at room temperature. The reaction solution is poured into 250 ml of water and extracted several times with dichloromethane. The aqueous phase is concentrated in vacuo at 40° C. to 20 ml, prepurified by ion exchange chromatography ("Dowex 50" Wx8/water/1,4-dioxane 3:1) and evaporated in vacuo at 40° C. The E-2-phenylacetylamino-4-methyl-5-phosphono-3-pentenoic acid thus formed is adjusted in 150 ml of water with 2N caustic soda to pH 7.5 and stirred with 250 mg of "EUPERGIT-ACYLASE" for 16 hours at 37°C. After filtration in vacuo at 40° C, the mixture is concentrated to 10 ml and separated by ion exchange chromatography ("Dowex 50" Wx8/water) into (D)-E-2-phenylacetylamino-4-methyl-5-phosphono-3-pentenoic acid and into (L)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid.

a) The water phase of (L)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid is evaporated in a vacuum and the residue is purified by

recrystallization from water, melting point 96°C, [a]<2>oD +97.1+-1.9° (c=0.5, water).

b) The water phase of (D)-E-2-phenylacetylamino-4-methyl-5-phosphono-3-pentenoic acid is evaporated in vacuo, the residue is stirred with 25 ml of 4.35 N hydrochloric acid for 3.5 hours at 85 °C and then extracted several times with dichloromethane. After evaporation of the water phases in vacuum and purification of the residue by ion exchange chromatography in (D)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid is obtained, melting point 194° C, [oc]<2>0D = -96.7+-l .2248C (c=0.8, water).

Example 11

2.5 g of E-2-formylamino-5-(0-ethyl-methylphosphonyl)-4-methyl-3-pentenoic acid ethyl ester are heated in 200 ml of 4.35N hydrochloric acid for 26 hours under nitrogen at 80°C. Evaporate in vacuum and dissolve the residue each time 2 times in each time 200 ml of water, tetrahydrofuran and ethanol, the solution respectively being evaporated in vacuum. Dissolution in 150 ml of ethanol, addition of 5 ml of propylene oxide in 100 ml of tetrahydrofuran/ethanol (1:1) at 0°C during 20 minutes, filtration of the precipitate and drying for 12 hours at 50°C in vacuum gives the crude E- 2-amino-4-methyl-5-methylphosphonyl-3-pentenoic acid, which is purified by chromatography on 20 g "Dowex 50" Wx8 (E2) (amorphous white powder), <1>E-NMR(D20):1.20 (d, 3H, CH3-P), 1.75 (d, 3E, CH3), 2.45 (d, 2E, C(5)-H), 4.50 (d, 1H, C(2)- H, 5.15 (m, 1H, C(3)-H).

The starting material is prepared by reacting 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester with thionyl bromide as in example 18 and subsequent treatment with methyl phosphoric acid diethyl ester instead of triethyl phosphite.

Example 12

14.5 g of E-2-formylamino-2-methyl-5-diethylphosphono-3-pentenoic acid methyl ester are heated in 500 ml of 4.35N hydrochloric acid for 32 hours under nitrogen at 100-105°C. The work-up as in example 11 gives E-2-amino-2-methyl-5-phosphono-3-pentenoic acid, melting point 2225-226°C (from water).

The starting material is produced as follows:

To a solution of 17 g of anhydrous zinc chloride in 75 ml of tetrahydrofuran, a solution of 14.1 g of 2-isocyanopropionic acid methyl ester and 8.5 g of freshly distilled acrolein in 50 ml of tetrahydrofuran is added at 0-5°C under nitrogen over the course of 20 minutes. it is allowed to stir for 45 hours at 0-5°C. Pour into 500 ml of 10% sodium hydrogen carbonate solution and extract with 200 ml of dichloromethane. The organic phase is dried over sodium sulfate and evaporated. Filtration of the residue over silica gel (acetic ester as eluent) gives 4-methyl-5-vinyl-2-oxazoline-4-carboxylic acid methyl ester. By hydrolysis of 4-methyl-5-vinyl-2-oxazolyl-4-carboxylic acid methyl ester in an analogous manner as in example 1, 2-formylamino-2-methyl-3-hydroxy-4-pentenoic acid methyl residues are obtained. By reacting 2-formylamino-3-hydroxy-2-methyl-4-pentenoic acid methyl ester with thionyl bromide and subsequent treatment with triethylphosphite as described in example 17, E-2-formylamino-2-methyl-5-diethylphosphono-3-pentenoic acid is obtained -methyl ester as yellow oil:

Calculated: C 46.91% H 7.22% N 4.56% P 10.08%

Found: C 46.1% H 7.3% N 4.1% P 10.6%

Example 13

6.3 g of E-2-formylamino-3-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester are heated in 400 ml of 4.35N hydrochloric acid during 30 hours under nitrogen at 100-105°C. The work-up which in example 11 gives E-2-amino-3-methyl-5-phosphono-3-pentenoic acid as white powder, melting point 168°C, ^-E-NMR (D2O )1.50, (d, 3H, CH3 ), 2.4 (m, 2H, CH2), 4.30 (s, 1H, C(2)-E), 5.60 (m, 1H, C(4)-H).

The starting material is produced as follows:

By reacting isocyanoacetic acid ethyl ester with methyl vinyl ketone analogously to that described in example 12, 5-methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester is obtained, boiling point 65-75°C (13 Pa). By hydrolysis of 5-methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester analogously to that described in example 1, 2-formylamino-3-hydroxy-3-methyl-4-pentenoic acid ethyl ester is obtained. Reaction of 2-formylamino-3-hydroxy-3-methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite analogously to that described in example 1 gives E-2-formylamino-3-methyl-5-diethyl phosphorus o-3-pentenoic acid is reported as a colorless liquid.

Example 14

E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl ester is hydrolyzed as described in Example 11 with 4.35N hydrochloric acid. E-2-amino-5-methyl-5-phosphono-3-pentenoic acid is isolated as a white amorphous solid. <3->H-NMR (D2O): 1.05 (dd, CH3), 2.45 (m, 1H, C(5)-H), 4.33 (d, 2H, C(2)-H ), 5.5 and 5.9 (2m, 2H, C(3)-E and C(4)-H).

The starting materials are produced as follows:

Reaction of crotonaldehyde with isocyanoacetic acid ethyl ester analogous to example 17 gives 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester analogously to example 1, 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester is obtained. Reaction of 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite analogously to example 1 (12 hours) gives E-2-formylamino-5-diethylphosphoni-5-methyl-3-pentenoic acid ethyl ester.

Example 15

Hydrolysis of E-2-formylamino-4-ethyl-5-dimethylphosphono-3-pentenoic acid ethyl ester analogously to that described in example 11 gives E-2-amino-4-ethyl-phosphono-3-pentenoic acid, melting point 176°C, (H20) .

The starting material is produced as follows:

Reaction of 2-methylene-butyraldehyde with isocyanoacetic acid ethyl ester analogous to example 1 gives 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. A solution of 16 g of 5-(buten-2-yl)-2-oxazolin-4-carboxylic acid ethyl ester in 100 ml of ethanol/water (1:1) is heated to boiling for 15 hours under reflux. Evaporation in vacuo, absorption of the residue in 200 ml of dichloromethane, drying over sodium sulphate, filtration and evaporation of the filtrate gives 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester.

Reaction of 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethylphosphite analogously to that indicated in example 1 gives E-2-formylamino-4-ethyl-5-dimethylphosphono-3-pentenoic acid ethyl ester .

Example 16

Hydrolysis of E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester analogous to example 11 gives E-2-amino-4-propyl-5-phosphono-3-pentenoic acid, melting point 193°C (H2O).

The starting material is produced as follows:

Reaction of 2-methylene-pentanal with isocyanoacetic acid ethyl ester analogous to example 1 gives 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester analogously to example 15, 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester is obtained. Reaction of 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethylphosphite analogously to example 1 gives E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.

Example 17

Hydrolysis of E-2-formylamino-4-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester analogously to that in example 11 gives E-2-amino-4-butyl-5-phosphono-3-pentenoic acid, melting point 186-187"C, (H2O).

The starting material is produced as follows:

Reaction of 2-methylene-hexanal with isocyanoacetic acid ethyl ester analogous to example 11 gives 5-(hexen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which analogously to example 33 is hydrolyzed to 2-formyl-3-hydroxy-4-butyl-4 -pentenoic acid ethyl ester. Reaction of 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethylphosphite analogous to example 1 gives E-2-formylamino-4-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.

Example 18

Hydrolysis of E-2-formylamino-4-isopropyl-5-dimethylphosphono-3-pentenoic acid ethyl ester analogous to example 11 gives E-2-amino-4-isopropyl-5-phosphono-3-pentenoic acid, melting point 201°C (H2O).

The starting material is produced as follows:

Reaction of 3-methyl-2-methylene-butanal with isocyanoacetic acid ethyl ester analogous to example 1 gives 5-(3-methyl-buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which analogously to example 15 is hydrolyzed to 2-formylamino-3 -hydroxy-4-isopropyl-4-pentenoic acid ethyl ester. Subsequent treatment with thionyl bromide followed by reaction with trimethylphosphite analogously to example 1 gives E-2-formylamino-4-isopropyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.

Example 19

3.9 g of E-2-formylamino-4-tert.-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester are hydrolyzed analogously to example 11. Cleavage by ion exchange chromatograph ("Dowex W 50", H2O) yields 1.8 g of E-2 -amino-4-tert-butyl-5-phosphono-3-pentenoic acid and 0.075 g of Z-2-amino-4-tert-butyl-5-phosphono-3-pentenoic acid.

E- isomer: Melting point 252-253"C (H2O), 3H-NMR (D2O): 0.95 (s, 9H, (CH3)3C), 2.65 (m, 2H, CH2), ca.4 .7 (d, 1H, C(2)-H), 5.333 (m, 1H, C(3)-H).

The starting material is produced as follows:

Reaction of 3,3-dimethyl-2-methylene-butanol with isocyanoacetic acid ethyl ester analogous to example 1 gives 5-(3,3-dimethyl-buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, analogous to example 33 hydrolysis style 2- formylamino-3-hydroxy-4-tert-butyl-4-pentenoic acid ethyl ester. Subsequent reaction with thionyl bromide followed by treatment with trimethylphosphite analogous to example 1 gives E-2-formylamino-43-tert-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.

Example 20

0.44 g of E-2-formylamino-4-benzyl-5-diethylphosphono-3-pentenoic acid ethyl ester is dissolved in 8 ml of 4.4N hydrochloric acid and heated for 48 hours at 85°C. After evaporation in a vacuum, the residue is dissolved in a little ethanol and mixed dropwise with 1 ml of ethanol/propylene oxide (1:1). The white precipitate formed is filtered off, after recrystallization from water E-2-amino-4-benzyl-5-phosphono-3-pentenoic acid is obtained as colorless needles, melting point 196-198°C.

The starting material is produced as follows:

By reaction of isocyanoacetic acid ethyl ester with 2-benzyl-propenal analogous to example 1 and after purification by column chromatography (silica gel, dichloromethane/acetic ester, 98:2) 5-(3-phenyl-propen-2-yl)-2-oxazolin- 4-carboxylic acid ethyl ester as colorless oil, %-NMR (CDCl3): 3.33 (s, 2H, CH2), 4.37 (dd, 1H, C(4)-H), 4.87 (s, 1H, 5 .07 (dd, 1H, C(5)-H), 5.16 (s, 1H).

By hydrolysis of 5-(3-phenyl-propen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester analogously to example 1, 2-formylamino-3-hydroxy-4-benzyl-4-pentenoic acid ethyl ester is obtained, melting point 87-89°C .

By reacting 2-formylamino-3-hydroxy-4-benzyl-3-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite at 100°C in an analogous manner to example 1 and after chromatography (silica gel, ethyl acetate) E-2 is obtained -formylamino-4-benzenyl-5-diethylphosphono-3-pentenoic acid ethyl ester as colorless oil, 3-H-NMR (CDCl3): 2.45 (d, 2H, C(5)-H), 3.80 (s, 1H, CH2), 5.51 (m, 1H, C(3)-H).

Example 21

0.15 g of E-2-formylamino-4-phenyl-5-diethylphosphono-3-pentenoic acid methyl ester is dissolved in 10 ml of 4.5N hydrochloric acid and heated for 192 hours to 75°C. After evaporation in a vacuum, the foamy residue is dissolved in a little ethanol and mixed dropwise with 1 ml of ethanol/propylene oxide (1:1). It formed a white precipitate

filtered off and recrystallized from water/acetone (1:2). E-2-amino-4-phenyl-5-phosphono-3-pentenoic acid is thus obtained as colorless needles, melting point 230-233°C.

The starting material is produced as follows:

By reaction of isocyanoacetic acid methyl ester with 2-phenylacrolein analogously to example 1 and after purification by column chromatography (silica gel, dichloromethane/methanol 97.5:2.5) 5-(1-phenyl-vinyl)-2-oxazoline-4 is obtained -carboxylic acid methyl ester as pale yellow oil. 1 H NMR (CDCl 3 ): 3.80 (s, 3H, CE 3 ), 4.45 (dd, 1H, C(4)-E), 5.76 (d, 1H, C(5)-H).

By hydrolysis of 5-(1-phenyl-vinyl)-2-oxazoline-4-carboxylic acid methyl ester in an analogous manner to that discussed in example 1, 2-formylamino-3-hydroxy-4-phenyl-4-pentenoic acid methyl ester is obtained, melting point 173 -174°C.

By reaction of 2-formylamino-3-hydroxy-4-phenyl-4-pentenoic acid methyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in an analogous manner as in example 1 and after chromatography (silica gel, ethyl acetate/hexane 4:1) is obtained E-2-formylamino-4-phenyl-5-diethyl phosphono-3-pentenoic acid methyl ester as a colorless oil, 3-H-NMR (CDCl 3 ): 2.98 (d, 2H, C(5)-H ), 5.03 (dd, 1H, C(2)-H, 5.77 (dd, 1H, C(3)-H).

Example 22

To a solution of 100 mg E-2-amino-5-phosphono-3-pentenoic acid 1 6 ml dioxane/water (1:1) you have at 0°C 170 mg sodium hydrogen carbonate and within 5 minutes 50 microliters of acetic anhydride. Stir for 30 minutes at 0°C, add approx. 2 ml "Dowex 50 H<+>" and filter. The filtrate is evaporated and purified by ion exchange chromatography ("Dowex 50 H<+>"). Lyophilization of the pure fractions yields 110 mg of E-2-acetamino-5-phosphono-3-pentenoic acid, melting point 155°C.

Claims (6)

1. Analogous process for the preparation of therapeutically active compounds of formula I, there R<1> means hydroxy, R<2> means hydrogen, C--C8-alkyl or hydroxy, R<3> means hydrogen, C1-C8-alkyl, phenyl-C1-C1-alkyl or phenyl, R<4> means hydrogen or C₁-C₄ alkyl, R<5> means hydrogen or C₁-C₄ alkyl, r<6> means carboxy or C 1 -C 14 alkoxycarbonyl, R<7> means amino or with C 1 -C 8 -alkanoyl-substituted amino, A means unsubstituted or C 1 -C 4 -alkyl substituted C 1 -C 8 -c ,co -alkylene with 1 to 3 carbon atoms, and B means a bond, whereby R<3> and R<4> respectively A and B can be trans in relation to each other, as well as salts thereof, characterized by converting a compound of formula II where R<3>, R<4>, R^, A and B are as indicated above, Z^ means with C1-C12-alkyl protected carboxy, Z<7> means with C^-C alkanoyl-protected amino and X means halogen, with a compound of formula III where Z<1> means with C^-Cg-alkyl protected hydroxy, Z<2> means Ci-Cg-alkyl, with a,a,-di-<C>^-C4-alkoc<sy->C^- C 4 -alkyl protected hydrogen or with C 1 -C 8 alkyl protected hydroxy, and R means C 1 -C 8 alkyl, and then sets the protected groups free hydrolytically and optionally, in an obtained compound of formula I, where R 1 is carboxy, esterifies the carboxy group to lower alkoxycarbonyl, in an obtained compound where R7 is amino, acylate the amino group to lower alkanoylamino, if desired transfer an obtained compound of formula I to a salt or transfer an obtained salt to another salt or to a free compound of formula I and if desired isolate an optical isomer from a mixture of stereoisomeric forms of an obtained compound of formula I or isolates a salt thereof. 2. Process according to claim 1, for the production of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid, as well as pharmaceutically acceptable salts thereof, characterized in that one starts from suitable compounds with the formulas II and III. 3. Analogous method according to claim 1, for the production of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, as well as pharmaceutically acceptable salts thereof, characterized in that one starts from suitable compounds with the formulas II and III. 4. Analogous method according to claim 1, for the production of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid methyl ester, as well as pharmaceutically acceptable salts thereof, characterized in that one starts from suitable compounds with the formulas II and III. 5. Analogous process according to claim 1, for the production of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid-n-butyl ester, as well as pharmaceutically acceptable salts thereof, characterized in that one starts from suitable compounds with the formulas II and III . 6. Analogous method according to claim 1, for the preparation of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid-n-pentyl ester or E-2-amino-4-methyl-5-phosphono-3-pentenoic acid-n- hexyl ester, as well as pharmaceutically acceptable salts thereof, characterized by starting from suitable compounds with the formulas II and III.