NO179450B - Analogous process for the preparation of 4-substituted 2-aminoalk-3-eno acids - Google Patents

Abstract

Substituted 2-aminoalk-3-enoic acid derivatives of the formula I <IMAGE> process for the preparation of unsaturated amino carboxylic acid derivatives of the formula I <IMAGE> in which R1 is an aliphatic or via a C atom bonded oxacycloaliphatic or optionally aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical which is substituted by optionally acylated or aliphatically or araliphatically etherified hydroxyl, by halogen, by optionally acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxacycloaliphatic radical, and R2 is free or esterified carboxyl, and their salts have a pronounced and selective antagonistic action on N-methyl-D-aspartic acid-sensitive (NMDA-sensitive) excitatory amino-acid receptors. They are prepared, for example, by, in a compound of the formula II <IMAGE> in which Z1, Z2 are optionally protected hydroxyl, Z3 is an aliphatic or via a C atom bonded oxacycloaliphatic or optionally protected or aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical which is substituted by optionally protected or acylated or aliphatically or araliphatically etherified hydroxyl, by halogen, by optionally protected or acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxacycloaliphatic radical, and Z4 is protected amino, converting protected amino Z4 and, where present, as component of Z3 into amino and, where present, protected hydroxyl Z1, Z2 and/or as component of Z3 into hydroxyl, and, where present, liberating a protected azacycloaliphatic hydrocarbon radical Z3 and, if required, converting a resulting compound into another compound of the formula I, fractionating a mixture of isomers obtainable according to the process into the components, and separating off the isomer which is preferred in each case, and/or converting a free compound obtainable according to the process into a salt or a salt obtainable according to the process into the corresponding free compound.

Description

The invention relates to an analogous method for the production of therapeutically active, substituted 2-aminoalk-3-enoic acid derivatives of formula I

where R^ stands for hydroxy-C₁-Cy-alkyl, C₁-C₁-alkyl-C-L-Cy-alkyl, amino-C₁-Cy-alkyl or halogen-C₁-Cy-alkyl, whereby halogen means chlorine or fluorine and R 2 means carboxy or C±-C 4 ~ alkoxycarbonyl and salts thereof.

Hydroxy C 1 -C 7 alkyl is, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl.

C1-C4-Alkoxy-C1-C7-alkyl means, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl or 6-methoxyhexyl.

Halogen-C1-C7-alkyl is, for example, halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, whereby halogen means chlorine or especially fluorine.

Amino-C4-Cy-alkyl is, for example, 4-aminobutyl, 5-aminopentyl or 6-aminohexyl.

C1~C4-Alkoxycarbonyl is, for example, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl.

The compounds with formula I exist because their amphoteric character in the form of internal salts and can form acid addition salts as well as salts with bases.

Acid addition salts of compounds of formula I are, for example, the pharmaceutically usable salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, e.g. hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, e.g. methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfaminates (cycla-mates).

Salts of compounds of formula I with bases are, for example, their salts with pharmaceutically usable bases, such as non-toxic metal salts derived from metals from groups Ia, Ib, Ila and Ilb, e.g. alkali metal, especially sodium or potassium salts, alkaline earth metal, especially calcium or magnesium salts, further ammonium salts with ammonia or organic amines or quaternary ammonium bases, such as optionally C-hydroxylated aliphatic amines, especially mono-, di- or tri-lower alkylamines, e.g. methyl, ethyl, diethyl or triethylamine, mono-, di- or tri-(hydroxylower alkyl)amines, such as ethanol, diethanol or triethanolamine, tris-(hydroxymethyl)methylamine or 2-hydroxytertiary-butylamine, or N -(hydroxylower alkyl)-N,N-dilower alkyl amines or N-(polyhydroxylower alkyl)-N-lower alkylamines, such as 2-(dimethylamino)ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, e.g. tetrabutylammonium hydroxide.

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

The compounds of formula I exhibit valuable pharmacological properties. In particular, they have a pronounced and selective antagonistic action against N-methyl-D-aspartic acid-sensitive (NMDA-sensitive) excitatory amino acid receptors in warm-blooded animals. This can be determined in vitro, for example, by the test device according to G. Fagg and Å. Matus, Proe. Nat. Acad. Sci., USA, 81, 6876-80 (1984). This determines the extent to which the binding of L-^H-glutamic acid to NMDA-sensitive receptors is inhibited. However, the NMDA-antagonistic properties of the new compounds can also be demonstrated in vivo, e.g. in mice, based on the inhibitory effect on NMDA-induced convulsions.

Because of these properties, the compounds of formula I and their pharmaceutically usable salts are eminently suitable for the treatment of pathological conditions which show a response to a blockade of NMDA-sensitive receptors, for example ischemic disease states, such as cerebral ischemia and of ischemic disease states of the eye, of tissue - and muscle spasms, as well as from migraines or from local or general spasticity, and especially from convulsions such as epilepsy.

The anticonvulsant properties of the compounds according to the invention can, for example, be determined on mice on the basis of their pronounced protective effect against electroshock-triggered or audiogenically induced convulsions, whereby e.g. can use the established electroshock mouse model or the test device according to Chapman et al., Arzneimittel-Forsch. 34» 1261 (1984). The compounds produced according to the invention are thereby distinguished, especially in the electro-shock mouse model, by an effect that is improved compared to structurally related compounds.

The antispastic properties which justify the suitability of the compounds produced according to the invention for the treatment of migraine can, for example, be shown in rats on the basis of the depression-inhibiting effect in the frontal cortex according to the experimental device described by R. Marannes et al., Brain Res. 457, 226 (1988). In this model, the compounds produced by the invention reduce the dose range from approx. 3 to 30 mg/kg ip. , the threshold value for "spreading depression" and shortens its duration.

In the NO applications no. 870577 and no. 883444, as well as in Br. J. Pharmacol. 99, 791-797 (1990) describes compounds of formula I with NMDA-antagonistic properties, which instead of R 1 L have an alkyl residue. Compared to the structurally closest compounds mentioned in the aforementioned publications by name, the compounds of formula I produced according to the invention have the advantage of increased anti-epileptic activity. Accordingly, comparative experiments in the electroshock model on mice, Chapman et al., Arzneimittel-Forsch. 34, 1261 (1984) the ED50 values given below:

Compounds according to patent application no. 870577

The invention primarily relates to compounds of formula I, in which Ri means 2-hydroxyethyl, 3-hydroxypropyl, hydroxymethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 4-aminobutyl, 6-aminohexyl or 2-fluoroethyl, and Rg means carboxy or C ^-C4-Alkoxycarbonyl and their salts.

The invention relates in particular to the compounds of formula I indicated in the examples and their salts, in particular their pharmaceutically usable salts.

The method for producing the compound according to the invention is characterized by the fact that

in a compound of formula II

where Z^, Z2 stands for optionally protected hydroxy, Z3 stands for an optionally protected residue R^ and Z4 means protected amino, transfers protected amino Z4 and, if present, as a component of Z3 to amino and, if present, transfers protected hydroxy Z ^, 1% and/or as a component of Z3 to hydroxy and, if present, a protected 5- to 7-membered azacycloalkyl residue Z3 is set free and, if

desired, a compound obtained is transferred to another compound of formula I, an isomer mixture obtained by the method is divided into its components and the isomer preferred in any case is separated and/or a free compound obtained by the method is transferred to a salt or a salt obtained by the method to the corresponding free compound.

In starting substances of formula II, protected hydroxy Z± and/or Z2 means, for example, etherified, especially aliphatic or aromatic etherified hydroxy, protected hydroxy as a component of Z3, for example acylated or silylated hydroxy, and protected amino Z4 and, if present, as a component of Z3 for example acylated amino.

Aliphatic etherified hydroxy is, for example, lower alkoxy, such as methoxy, ethoxy or especially isopropyloxy. Aromatic etherified hydroxy is, for example, phenoxy optionally substituted with lower alkyl, lower alkoxy, halogen, cyano and/or nitro.

Acylated hydroxy shows as an acyl group, for example, the acyl residue of an araliphatic carboxylic acid or a half-ester of a carboxylic acid and means, for example, lower alkanoyloxy, or a phenyl-lower alkanoyloxy or phenyl lower alkanoyloxy group optionally substituted in the phenyl part with lower alkyl, lower alkoxy, halogen, cyano and/or trifluoromethyl, e.g. benzyloxycarbonyloxy.

Silylated hydroxy is, for example, trilower alkylsilyloxy, e.g. trimethyl or tributylsilyloxy.

Acylated amino exhibits as acyl group, for example, from a suitable organic acid, such as formic acid or an araliphatic or aromatic half-ester of carboxylic acid-derived acyl. Acylated amino therefore means, for example, formylamino, lower alkoxycarbonylamino, such as methoxy, ethoxy or tertiary butyloxycarbonylamino, optionally in the phenyl part with lower alkyl, lower alkoxy, halogen, cyano and/or nitro substituted phenyl lower oxycarbonylamino, such as benzyloxycarbonylamino, or with lower alkyl, lower alkoxy, halogen , cyano and/or nitro substituted phenoxycarbonylamino.

The release of the protected groups from compounds of formula II, i.e. of hydroxy from protected hydroxy groups Zi, Z2 and/or protected hydroxy groups as a component of Z3 or of amino from protected amino groups Z4 and, if present, of protected amino groups as a component of Z3, takes place for example by treatment with an acidic agent, for example with a trilower alkylhalosilane, such as trimethylbromosilane, tributylbromosilane or trimethyliodosilane. Thereby, one preferably works in an inert solvent such as a halogenated aliphatic hydrocarbon, e.g. in dichloromethane or in other tri- or tetrachloromethane, trichloroethane or tetrachloroethane, for example in a temperature range from approx. -25° to approx. +50°C, preferably from approx. 0° to 30°C, e.g. at room temperature, i.e. at approx. 15" to 25°C, advantageously under substantially anhydrous conditions and under inert gas, such as argon or nitrogen. The work-up advantageously takes place with the addition of a hydrogen halide scavenger, in particular an aliphatic epoxy compound, such as an epoxy lower alkane, e.g. of propylene oxide or in a lower alkanol, such as ethanol.

In a preferred embodiment, one starts, for example, from compounds of formula II, where Z 1 and Z 2 mean lower alkoxy, e.g. isopropyloxy, and Z4 means lower alkanoylamino, such as formylamino, and treating these in an aliphatic hydrogen hydrocarbon, such as dichloromethane, at 15" to 25°C with a trilower alkyl bromosilane, such as trimethylbromosilane or tributylbromosilane, allowing this to react for some time, e.g. 2 to 30 hours, then add an ethanolic solution of propylene oxide and filter the product.

Starting substances with formula II are prepared, for example, by reacting an α,<g->unsaturated aldehyde with formula IIa

with an α-isocyanoacetic acid ester of formula Hb in a manner known per se, for example in the presence of a copper or gold catalyst, e.g. of copper I-oxide or bis(cyclohexyl isocyanide)gold I-tetrafluoroborate, to the corresponding 5-substituted 2-oxazoline-4-carboxylic acid ester of formula lic this is transferred by hydrolysis, e.g. in aqueous tetrahydrofuran, to the corresponding open-chain ester of formula Ild, this is converted by treatment with thionyl bromide in a manner known per se to the corresponding u-bromo ester of formula Ile and this is further reacted in a manner known per se with a phosphoric acid triester of formula P(Za)()(Zc), where Za, Z^ and Zc stand for the same or different hydroxy groups protected in an ether form, such as a tri-lower alkyl phosphite, e.g. with triisopropyl phosphite, to corresponding compounds of formula II'

Compounds obtained by the method can be transferred in the usual way to other compounds of formula I.

Consequently, free and esterified carboxy groups R2 can be transferred to each other in the usual way. In particular, esterified carboxy R2 can be transferred by hydrolysis to carboxy or free carboxy R2 by reaction with an alcohol in esterified carboxy. Furthermore, esterified carboxy R2 can be transesterified to another esterified carboxy group. This is done in the usual way under hydrolytic, alcoholytic or reesterifying conditions.

The hydrolysis of carboxylic acid esters (I; R 2 = C 1 -C 4 -alkoxycarbonyl) takes place in the usual way, if necessary in the presence of an acidic or basic agent, such as a mineral acid, e.g. of hydrogen chloride or sulfuric acid, or a base, such as an alkali metal hydroxide, e.g. sodium hydroxide.

In the transesterification of esters (I; R2 = C1-C4~alkoxycarbonyl) with alcohols, one usually works under acid or base catalytic conditions, for example in the presence of a catalytic amount of a mineral acid, such as hydrogen chloride or sulfuric acid, or a metal base , such as from sodium hydroxide, or by using the alcohol component in the form of a metal alcoholate, e.g. an alkali metal alcoholate.

Furthermore, in aliphatic etherified hydroxy substituted aliphatic hydrocarbon residues, such as α-phenyl lower alkyl lower alkyl residues, R-^ in the α-phenyl lower alkyl group can be reductively transferred, e.g. by treatment with hydrogen in the presence of a hydrogenation catalyst, such as palladium on carbon or Raney nickel, to hydroxy.

Obtained salts can be converted in a manner known per se to the free compounds, e.g. by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or ammonia, or another initially mentioned salt-forming base or with an acid, such as a mineral acid, e.g. with hydrogen chloride, or another initially mentioned salt-forming acid.

Obtained salts can be transferred in a manner known per se to other salts, acid addition salts, e.g. by treatment with a suitable metal salt such as a sodium, barium or silver salt, or other acid in a suitable solvent, in which an inorganic salt that is formed is insoluble and is thus separated at reaction equilibrium, and base salts by release of the free acid and renewed salt formation .

The compounds of formula I, including their salts, can also be obtained in the form of hydrates, or contain the solvent used for crystallization.

Due to the close relationship between the new compounds in free form and in the form of their salts, above and in the following, free compound and their salts are understood, where appropriate, also the corresponding salts or the free connections.

Obtained diastereomer mixtures and racemate mixtures can be divided on the basis of physico-chemical differences for the components, in a known manner into the pure diastereomers or the racemates, for example by chromatography and/or fractional crystallization.

Obtained racemates can further be decomposed into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the help of microorganisms or by reacting the obtained diastereomer mixture, e.g. the racemate with an optically active auxiliary compound, e.g. corresponding to the acidic, basic or functionally derived groups contained in the compounds of formula I with an optically active acid, base or an optically active alcohol, in mixtures of diastereomeric salts or functional derivatives, such as esters, splitting these into the diastereomers, from which the enantiomer desired in any case can be set free in the usual way. For this purpose suitable bases, acids or alcohols are, for example, amino acids, especially D- or L-lysine, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine, 3-pipecoline, ephedrine, amphetamine and similar synthetically available bases, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid, or D- or L-camphorsulfonic acid, respectively optically active alcohols, such as borneol or D- or L-(1-phenyl)ethanol.

The new compounds of formula I can e.g. find use in the form of pharmaceutical preparations containing a therapeutically effective amount of the active substance, possibly together with inorganic or organic, solid or liquid, pharmaceutically usable carriers, which are suitable for enteral administration, e.g. oral or parenteral administration. Consequently, tablets or gelatin capsules are used which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets may also contain binders, e.g. magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired, explosives, e.g. starches, agar, alginic acids or a salt thereof, e.g. sodium alginate, and/or fizzy mixes or absorbents, colourants, flavorings and sweeteners. Furthermore, the new compounds of formula I can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonically aqueous solutions or suspensions, whereby these e.g. in the case of lyophilized preparations containing the active substance alone or together with a carrier material, e.g. mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preserving, stabilizing, wetting and/or emulsifying agents, solubility mediators, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which if desired may contain further pharmacologically active substances, are produced in a manner known per se, e.g. by means of conventional mixing, granulating, coating, dissolving or lyophilizing methods and containing from 0.1% to 100%, especially from 1% to 50%, lyophilisates up to 100 1o of the active substance.

The dosage may depend on various factors, such as method of administration, species, age and/or individual condition. The daily doses that are administered are for oral administration between 0.25 and 10 mg/kg and for warm-blooded animals with a body weight of 70 kg preferably between 20 mg and 500 mg.

The following examples serve to illustrate the invention.

Example 1

3.57 g (8.5 mmol) of 6-acetoxy-4-diisopropylphosphonomethyl-2-formylaminohex-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane and mixed at room temperature dropwise with 4.4 ml (34 mmol) of trimethylbromosilane. The mixture is allowed to stand at room temperature for 22 hours, 22 ml of ethanol is added dropwise, the mixture is again allowed to stand for 22 hours, it is evaporated on a rotary evaporator, the residue is dissolved in 22 ml of ethanol and a mixture of 22 ml of propylene oxide and 22 ml of ethanol is added dropwise. A suspension is formed which is stirred for a further 90 minutes and then sucked off. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is obtained with m.p. 195"C (decomposition).

The starting material can e.g. is prepared as follows: 13.0 g (100 mmol) acetic acid-(4-oxo)butyl ester, 92.0 g (112.6 mmol) dimethylammonium chloride and 10.8 ml (117 mmol) 37% formaldehyde solution are heated with stirring for 1 hour to 100°C. The mixture is allowed to cool and extracted 3 times, each time with 30 ml of diethyl ether. The organic phases are collected, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. Acetic acid (3-formyl)but-3-enyl ester is obtained as a colorless oil, which can be reacted further without further purification.

13.5 g (95 mmol) of acetic acid (3-formyl)but-3-enyl ester and 10.4 g (95 mmol) of isocyanoacetic acid ethyl ester are added dropwise to a suspension of 0.38 g of copper I oxide in 50 ml of benzene. After completion of the exothermic reaction, it is stirred for a further 45 minutes at room temperature, filtered over "Hyflo" and evaporated to dryness. The residue is taken up in 75 ml of tetrahydrofuran, mixed with 25 ml of water and heated with stirring for 4 hours to reflux. It is evaporated to dryness and chromatographed on silica gel with toluene/isopropanol (9:1) as eluent. 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester is obtained as a brownish oil.

9.19 g (35.9 mmol) of 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 100 ml of dichloromethane and mixed at room temperature dropwise with 3.34 ml (43.1 mmol) of thionyl bromide. After 1 hour, 10 ml of water is added and stirred intensively for 10 minutes. The organic phase is separated, washed step by step with water, saturated potassium hydrogen carbonate solution and once again with water, dried over magnesium sulfate, filtered and evaporated. 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a brownish oil.

8.7 g (25 mmol) of 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 21 ml (75 mmol) of triisopropylphosphite (90%) are heated to 80 to 90°C and stirred under a pressure of about. 100 mbar for 19 hours. The excess triisopropyl phosphite is distilled off and the evaporation residue is chromatographed on 150 g of silica gel with first ethyl acetate and then ethyl acetate/ethanol (9:1) as eluent. 6-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a yellowish oil.

Example 2

0.415 g (1.55 mmol) of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated in 3 ml of water for 24 hours to reflux. The reaction mixture is evaporated, purified chromatographically on 10 g of silica gel with ethanol/water (1:1) as eluent and crystallized from ethanol. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid is obtained with m.p. >300°C.

Example 3

0.5 g (1.0 mmol) of 8-(N-benzyloxycarbonylamino)-4-diethyl-phosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is heated in 5.0 ml of 6n-hydrochloric acid for 6 hours to reflux. Evaporation to dryness gives 2,8-diamino-4-phosphonomethyl-oct-3-enoic acid dihydrochloride as a gummy solid which is recrystallized from acetonitrile; m.p. 128°C (decomposition).

The starting material can be produced in the following way:

To a solution of 5.52 g (47 mmol) 6-aminohexan-1-ol and 3.95 g (47 mmol) sodium bicarbonate in 100 ml acetone and 50 ml water, 7.06 ml (47 mmol) chlorine formic acid benzyl ester. It is stirred for 18 hours at room temperature, evaporated to approx. 70 ml, the white precipitate is filtered off, this is washed with 20 ml of water, taken up in 250 ml of methylene chloride, dried over magnesium sulphate, this is filtered off and the residue is evaporated to dryness. 6-(N-benzyloxycarbonylamino)hexan-1-ol is obtained in the form of white crystals with m.p. 58-60°C.

To a solution of 0.19 ml (2.20 mmol) of oxalyl chloride in 10 ml of methylene chloride stirred at -50° C., 0.32 ml (4.40 mmol) of dimethylsulfoxide is added dropwise under nitrogen. It is stirred for 15 minutes and then 0.5 g (2 mmol) of 6-(N-benzyloxycarbonylamino)hexan-1-ol is added. It is stirred for 25 minutes at -50°C, 1.78 ml (10 mmol) of N-ethyl-N,N-diisopropylamine are added dropwise and poured into 10 ml of ice water. The organic phase is separated, and the aqueous phase is extracted with 10 ml of methylene chloride. The organic phases are combined, washed twice, each time with 5 ml of n-hydrochloric acid and once with 10 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The oil obtained is purified chromatographically on silica gel with hexane/acetic acid ethyl ester (1:1) as eluent. 6-(N-benzyloxycarbonylamino)-hexanal is obtained.

To a solution of 1.5 g (17 mmol) anhydrous piperazine and 2.03 g (34 mmol) acetic acid in 18.7 ml water is added 2.44 g (30 mmol) 37 # aqueous formaldehyde solution. It is stirred for 15 minutes at 25°C and then 7.48 g (30 mmol) of 6-(N-benzyloxycarbonylamino)hexanal are added. The reaction mixture is heated to reflux for 2 hours, then cooled with ice water and extracted twice, each time with 50 ml of methylene chloride. "The extracts are combined, washed twice, each time with 25 ml of saturated sodium bicarbonate solution and with 25 ml of saturated sodium bicarbonate solution, dried and evaporated to dryness. 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal is obtained as a yellowish liquid.

4.0 g (15.3 mmol) 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal and 1.62 ml (16.8 mmol) isocyanoacetic acid methyl ester are dissolved in 50 ml toluene and added at 40°C dropwise to a suspension of 0.12 g of 96.4% copper I oxide in 50 ml of toluene. It is stirred for 2.5 hours at room temperature, filtered, poured onto a column filled with 60 g of silica gel and extracted first with hexane/ethyl acetate (1:1) and then with ethyl acetate. 5-[6-(N-benzyloxycarbonylamino)hex-1-en-2-yl]-oxazoline-4-carboxylic acid methyl ester is obtained; oil.

9.4 g (26.1 mmol) of 5-[6-(N-benzyloxycarbonylamino)hex-l-en-2-yl]-oxazoline-4-carboxylic acid methyl ester are dissolved in 40 ml of tetrahydrofuran and 20 ml of water, mixed with a few drops of triethylamine and heated for 18 hours to reflux. The solvent is removed under reduced pressure and the remaining oil is taken up in a total of 125 ml of methylene chloride, dried over magnesium sulphate and evaporated to dryness. 8-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester is obtained.

2.46 g (6.5 mmol) of 8-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester in 25 ml of tetrahydrofuran are mixed with 5.5 ml (46 mmol) of hexa-1,5 -diene and then at -50°C dropwise with 2.6 ml (32.5 mmol) of thionyl bromide. It is stirred for 2 hours at 0 to 5°C, poured into 25 ml of ice-cold saturated sodium bicarbonate solution and extracted twice, each time with 20 ml of methylene chloride. The organic phase is washed with 10 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The oil obtained is purified chromatographically on silica gel with hexane/ethyl acetate (3:1). 8-(N-benzyl-oxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.

1.45 g (3.3 mmol) of 8-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester are mixed with 5 ml of triethyl phosphite and heated with stirring for 8 hours at 75° C. The excess triethyl phosphite is distilled off under reduced pressure and gives an oily residue. This is purified chromatographically on a silica gel column with first acetic acid ethyl ester and then acetic acid ethyl ester/methanol (9:1). 8-(N-benzyloxycarbonylamino)-4-diethyl-phosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.

Example 4

1.77 g (4.5 mmol) of 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester are dissolved in 12 ml of dichloromethane and mixed at room temperature dropwise with 2.32 ml (18.0 mmol) of trimethylbromosilane. It is allowed to stand for 22 hours at room temperature, 12 ml of ethanol is added dropwise, it is left to stand again for 24 hours, evaporated on a rotary evaporator, the residue is dissolved in 10 ml of ethanol and a mixture of 2 ml of propylene oxide and 2 ml of ethanol is added. A suspension is formed which is stirred for a further 2 hours at room temperature and 2 hours under ice cooling and then suctioned off. 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is obtained with m.p. 242°C (decomposition).

The starting material can e.g. produced as follows:

19.7 g (193 mmol) of 4-methoxybutanal, 17.7 g (217 mmol) of dimethylammonium chloride and 17.0 ml (226 mmol) of 37 # formaldehyde solution are heated with stirring for 3 hours at 100°C. This is allowed to cool and extracted 3 times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and evaporated to dryness. 4-Methoxy-2-methylenebutanal is obtained as a yellowish oil, which is further reacted without further purification.

16.5 g (144.5 mmol) of 4-methoxy-2-methylene-butanal and 15.8 ml (144.5 mmol) of isocyanoacetic acid ethyl ester are dissolved in 145 ml of toluene and mixed with 400 mg of copper I oxide. After completion of the exothermic reaction, it is stirred for a further 2 hours, filtered over "Hyflo" and evaporated to dryness. The residue is taken up in 145 ml of tetrahydrofuran, mixed with 33 ml of water and heated with stirring for 2 hours to reflux. Evaporate to dryness, mix with toluene and evaporate again. Chromatography on silica gel with toluene/ethanol (95:5) as eluent gives 2-formylamino-3-hydroxy-6-methoxy-4-methylene-hexanoic acid ethyl ester as a red-brown oil.

19.0 g (77.5 mmol) of 2-formylamino-3-hydroxy-6-methoxy-4-methylene-hexanoic acid ethyl ester are dissolved in 190 ml of 1,2-dichloroethane and mixed at room temperature dropwise with 7.20 ml (93.0 mmol) thionyl bromide. After 45 minutes, 100 ml of water is added and stirred intensively for 10 minutes. The organic phase is separated, washed step by step with water, 1 N potassium hydrogen carbonate solution and once again with water, dried over sodium sulphate, filtered and evaporated. 4-Bromo-methyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained as a reddish-brown oil.

3.38 g (11.0 mmol) 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester and 12.0 ml (44 mmol) triisopropyl phosphite

(96%) is heated to 80°C and stirred under a pressure of approx. 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified chromatographically on silica gel with acetic acid ethyl ester. 4-Diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained as a yellowish oil.

Example 5

0.98 g (3.5 mmol) of 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated in 7 ml of water for 17 hours to reflux. The reaction mixture is evaporated and crystallized from a mixture of water and ethanol. 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid is obtained with m.p. 214°C (decomposition).

Example 6

0.52 g (1.36 mmol) of 4-diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is dissolved in 3.5 ml of dichloromethane, and mixed at room temperature dropwise with 0.7 ml (5.45 mmol ) trimethylbromosilane. This is allowed to stand for 24 hours at room temperature, 3.5 ml of ethanol is added dropwise, the mixture is again allowed to stand for 24 hours, evaporated on a rotary evaporator, the residue is dissolved in 2.4 ml of ethanol and a mixture of 0.6 ml of propylene oxide and 0.6 ml of ethanol. A suspension is formed which is stirred for a further 2 hours at room temperature and 2 hours under ice cooling, and then suctioned off. 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester is obtained with m.p. 222°C (decomposition).

The starting material can e.g. is prepared as follows: 2.4 g (26.6 mmol) 4-fluorobutanal, 2.44 g (30.0 mmol) dimethylammonium chloride and 2.34 ml (31.1 mmol) 37% formaldehyde solution are heated with stirring in 2 hours at 100°C. The mixture is allowed to cool and extracted 3 times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and evaporated to dryness. 4-fluoro-2-methylene-butanal is obtained as a yellowish oil, which can be reacted further without further purification.

1.43 g (14.0 mmol) of 4-fluoro-2-methylene-butanal and 1.53 ml (14.0 mmol) of isocyanoacetic acid ethyl ester are dissolved in 14 ml of toluene and mixed with 40 mg of copper I oxide. After completion of the exothermic reaction, it is stirred for a further 2 hours, filtered over "Hyflo" and evaporated to dryness. The residue is taken up in 14 ml of tetrahydrofuran, mixed with 3.1 ml of water and heated with stirring for 2 hours to reflux. Evaporate to dryness, mix with toluene and evaporate again. Chromatography on silica gel with toluene/acetic acid ethyl ester (1:1) as eluent gives 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester as a dark yellow oil.

1.40 g (6.0 mmol) of 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester is dissolved in 14 ml of 1,2-dichloroethane and mixed at room temperature dropwise with 0.56 ml (7.2 mmol) thionyl bromide. After 45 minutes, add 12 ml of water and stir vigorously for 15 minutes. The organic phase is separated, washed step by step with water, 1 N potassium hydrogen carbonate solution and once again with water, dried over sodium sulphate, filtered and evaporated. 4-bromo-methyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a brown-yellow oil.

1.43 g (4.82 mmol) of 4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester and 5.3 ml (19 mmol) of triisopropyl phosphite (96 $>) are heated to 80°C and stirred under a pressure of approx. 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified chromatographically on silica gel with acetic acid ethyl ester. 4-Diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a yellowish oil.

Example 7

0.5 g (1.86 mmol) of 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated in 4 ml of water for 17 hours to reflux. The reaction mixture is evaporated and partitioned on strongly acidic ion exchanger ("Dowex 50Wx8"; H<®->form) with water. 2-amino-6-fluoro-4-phosphonomethylhex-3-enoic acid is obtained with m.p. 160-162°C (decomposition).

Example 8

In a similar manner as described in example 3, starting from 8-aminooctan-1-ol, 2,10-diamino-4-phosphono-methyl-dec-3-enoic acid dihydrochloride is obtained, m.p. 126°C.

Example 9

8.63 g (15.2 mmol) of 10-(N-benzyloxycarbonylamino)-4-diiso-propylphosphonomethyl-2-formyl amino-dec-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane, and mixed at room temperature dropwise with 9.82 ml (75.9 mmol) of trimethylbromosilane. It is stirred for 22 hours at room temperature, then 22 ml of absolute ethanol is added dropwise, it is stirred for a further 22 hours and evaporated on a rotary evaporator. The residue is poured over with 20 ml of toluene and evaporated in vacuo. This process is repeated 3 times. The clear yellow foam obtained is dissolved in 150 ml of absolute ethanol and mixed dropwise over 90 minutes with a solution of 7.5 ml of propylene oxide in 7.5 ml of ethanol. A crystal suspension is formed which is stirred overnight at room temperature. The product is filtered off and washed with ethanol and ether. After drying in high vacuum at room temperature, 4.70 g of crude product is obtained as bright yellow crystals. For further purification, it is stirred with 46 ml of water. After filtering off some undissolved material (0.33 g), the clear yellow filtrate is completely evaporated in vacuo. The residue is mixed with 20 ml of ethanol and 20 ml of toluene and evaporated again to dryness. This process is repeated a further 2 times with toluene. After drying in a high vacuum, the residue is suspended in 150 ml of absolute ethanol and mixed with stirring dropwise with a 5 N solution of hydrogen chloride gas in ethanol, until the mixture reacts congo acid. It formed

the clear solution is mixed dropwise over the course of 1 hour with a mixture of 7.4 ml of propylene oxide in 7.4 ml of ethanol. A crystal suspension forms which is stirred for a further 15 hours and then suctioned off. After washing with ethanol and ether, the product is dried for 48 hours in a high vacuum at 50°C. In this way, 2.86 g of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester is obtained, which begins to sinter at 157°C and melts at 194°C during decomposition.

This product contains as contaminants approx. 5-10 wt-# of the corresponding, in the 10-position N-benzylated and N-(2-hydroxy)propylated, compound.

The starting material is produced as follows:

In a similar way as in example 3, starting from 8-aminooctan-l-ol via 8-(N-benzyloxycarbonylamino)-octan-l-ol and 8-(N-benzyloxycarbonylamino)octanal, 8-(N-benzyloxycarbonylamino) -2-methylene-octanal.

15.30 g (52.9 mmol) of 8-(N-benzyloxycarbonylamino)-2-methylene-octanal and 7.37 ml (67.4 mmol) of isocyanoacetic acid ethyl ester are dissolved in 78 ml of toluene and added dropwise to a suspension of 0.30 g of copper I oxide in 76 ml of toluene under argon during 75 minutes. It is stirred for 90 minutes at 30° C, cooled to room temperature, filtered and the bright bright red filtrate is poured onto a column filled with 250 g of silica gel (grain size 0.04 - 0.063 mm) and eluted with hexane/ethyl acetate (2:1). After evaporation of the suitable fractions, 8.15 g of 5-[8-(N-benzyloxycarbonylamino)oct-1-en-2-yl]oxazoline-4-carboxylic acid ethyl ester are obtained as colorless honey.

8.15 g (20.25 mmol) of 5-[8-(N-benzyloxycarbonylamino)oct-1-en-2-yl]oxazoline-4-carboxylic acid ethyl ester is heated in 40 ml of tetrahydrofuran and 20 ml of water with stirring for 4 hours more backflow. The reaction mixture is evaporated in vacuo at 55° C to dryness, and the honey-like residue is further evaporated

more than 2 times after toluene addition. The crude product is dissolved in dichloromethane, dried with sodium sulphate, filtered and evaporated. After drying in high vacuum at room temperature, 9.03 g of 10-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester are obtained as yellowish honey.

13.70 g (32.60 mmol) of crude 10-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in 137 ml of tetrahydrofuran are mixed under argon with 18.5 ml (156.4 mmol) hexa-1,5-diene and then at 10° C dropwise over 15 minutes with 6.1 ml (78.2 mmol) of thionyl bromide. It is then stirred for 1 hour at 10°C and 2 hours at room temperature, poured into 200 ml of ice-cold, saturated sodium bicarbonate solution, the organic phase is separated and extracted once with dichloromethane. The organic phase is washed with ice-cold 0.5 N sodium bicarbonate solution and then saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness at 40° C. in vacuum. 3-monoacid ethyl ester (27 g, yellow honey) is immediately mixed with 64 ml (260 mmol) of triisopropyl phosphite (96 $ >) and stirred under a pressure of about 100 mbar for 17 hours at 80°C, whereby the formed isopropyl bromide is collected in a cooling trap (COg). The excess triisopropyl phosphite is then distilled off under reduced pressure and the evaporation residue (23 g) is purified chromatographically on a column with 650 g of silica gel (0.04 - 0.063 mm) with ethyl acetate/methanol (95:5). 8.73 is obtained g 10-(N-benzyloxycarbonylamino)-4-diisopro pylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester as yellowish honey.

Example 10

2.25 g (6.98 mmol) of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester are dissolved under argon in 45 ml of 2 N hydrochloric acid and stirred for 17 hours at a bath temperature of 120°C. The clear, light brown solution is evaporated on a rotary evaporator. The residue is dissolved in 20 ml of ethanol and evaporated after adding 30 ml of toluene in vacuum. This process is repeated further

more than 3 times. The resulting beige foam is dissolved in 75 ml of absolute ethanol and mixed dropwise over the course of 35 minutes with a solution of 15 ml of propylene oxide in 15 ml of ethanol. The formed crystal suspension, which exhibits a pH value of 3, is filtered off after stirring for 1.5 hours and washed well with ethanol and ether. After drying in vacuum, 1.65 g of beige crude product is obtained, which is dissolved in the minimal amount of water (approx. 2 ml), and chromatographed on a column filled with 67 g of reversed-phase silica gel ("Opti-Up C^g"» grain size 40 pm), with pure water as eluent at slight excess pressure (0.2 bar). One obtains a pure fraction, Rf value on silica gel = 0.37 with n-propanol/water/pyridine/acetic acid (15:12:10:3) as eluent, and several mixed fractions with a by-product of Rf value = 0, 48. Re-chromatography of this mixed fraction and pooling of the pure fractions followed by lyophilization from water gives 2,10-diamino-4-phosphono-methyl-dec-3-enoic acid hemihydrochloride hydrate as an amorphous glass, which from 134°C slowly sinters and which decomposes at 149°C during foaming.

Example 11

4.3 g (9.9 mmol) of 7-acetoxy-4-diisopropylphosphonomethyl-2-formylaminohept-3-enoic acid ethyl ester are dissolved in 25 ml of dichloromethane and mixed at room temperature dropwise with 5.1 ml (39.5 mmol) of trimethylbromosilane. It is allowed to stand for 24 hours at room temperature, 25 ml of ethanol is added dropwise and the whole is allowed to stand for a further 24 hours, evaporated, the residue is dissolved in 25 ml of ethanol and a mixture of 25 ml of propylene oxide and 25 ml of ethanol is added dropwise. A suspension is formed which is stirred for 1 hour at room temperature and 1 hour in an ice bath and then suctioned off. After drying, 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester is obtained with m.p. 210°C (decomposition).

The starting material can e.g. is prepared as follows: 10 g (69.4 mmol) of 5-acetoxypentanal, 6.37 g (78.2 mmol) of dimethylammonium chloride and 6.1 ml (81.2 mmol) of 37 # formaldehyde solution are kept under stirring for 1, 5 hours at reflux (bath temperature ~ 110°C). This is allowed to cool, extracted three times with ether, the organic phases are combined, dried over MgSO 4 , filtered and evaporated. 5-acetoxy-2-methylene-pentanal is obtained as a yellowish oil which can be reacted without further purification.

9.6 g (61.5 mmol) of 5-acetoxy-2-methylene-pentanal and 7.38 ml (67.6 mmol) of isocyanoacetic acid ethyl ester are placed in 70 ml of toluene at room temperature and mixed with 250 mg of copper I oxide. After cessation of the exothermic reaction, it is stirred for a further 1 hour, filtered over "Hyflo" and evaporated. The residue is taken up in 50 ml of tetrahydrofuran, mixed with 10 ml of water and kept at reflux for 3 hours. Evaporate to dryness, mix with toluene and evaporate once more. Chromatography on silica gel with toluene/acetic acid ethyl ester (4:1) gives 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester as an orange oil.

5.9 g (20.5 mmol) of 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester are dissolved in 60 ml of dichloromethane and mixed at room temperature dropwise with 1.9 ml (24.6 mmol) of thionyl bromide. After 1 hour, add 40 ml of water and stir vigorously for 10 minutes. The organic phase is separated, washed step by step with water, 1 N KHCO 3 solution and once more with water, dried over MgSO 4 , filtered and evaporated. 7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained as a brown oil, which can be reacted further in the crude state.

6.1 g (17.4 mmol) 7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester and 19.1 ml (69.6 mmol) triisopropylphosphite (90%) are heated to 80° C and stirred for 18 hours under a pressure of approx. 130 mbar. The excess triisopropyl phosphite is distilled off and the residue is purified on silica gel with acetic acid

ethyl ester. 7-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained as a yellow oil.

Example 12

1.1 g (3.9 mmol) of 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester in 8 ml of water is stirred for 18 hours at 130°C in a bomb tube. The dark reaction solution is treated with activated carbon and filtered over "Hyflo". The colorless filtrate is evaporated to ~3 ml and mixed with ~25 ml of ethanol. The resulting suspension is filtered off and dried in a high vacuum at 50°C. 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid is obtained with m.p. from 190°C (decomposition).

Example 13

1.10 g (2.8 mmol) of 5-ethoxy-4-diisopropylphosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane and mixed at room temperature dropwise with 1.6 ml (12.3 mmol) of trimethylbromosilane. This is allowed to stand at room temperature for 7 hours, 20 ml of ethanol is added dropwise and left to stand for 15 hours, evaporated, the residue is dissolved in 10 ml of ethanol and a mixture of 10 ml of propylene oxide and 10 ml of ethanol is added dropwise. A suspension is formed which is stirred for 2 hours at room temperature, and then suctioned off. After drying, 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester is obtained with m.p. 217-218°C (decomposition).

The starting material can e.g. produced as follows:

50 g (283 mmol) of 3-ethoxy-propionaldehyde diethyl acetal, 27.3 g (335 mmol) of dimethylammonium chloride and 30 ml (392 mmol) of 36 # formaldehyde solution are heated with stirring for 2 hours at 110°C. It is cooled and extracted 3 times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and evaporated to dryness. 2-ethoxypropanal is obtained as a yellow liquid, which can be reacted further without further purification.

4.2 g (36.1 mmol) of 2-ethoxypropanal and 4.4 ml (40 mmol) of isocyanoacetic acid ethyl ester are dissolved in 50 ml of toluene and mixed with 200 mg of copper I oxide. After the end of the exothermic reaction, it is stirred for 11 hours, filtered over "Eyflo" and evaporated to dryness. The residue is taken up in 50 ml of tetrahydrofuran, mixed with 12 ml of water and heated with stirring for 1 hour to reflux. Evaporate to dryness, mix with toluene and evaporate again. Chromatography on silica gel with toluene/isopropanol (9:1) as eluent gives 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester as a yellow oil.

3.70 g (15.1 mmol) of 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are dissolved in 100 ml of 1,2-dichloroethane and mixed at room temperature dropwise with 1.8 ml (22.8 mmol) thionyl bromide. After 1 hour, add 100 ml of water and stir vigorously for 15 minutes. The organic phase is separated, washed step by step with 1 N potassium hydrogen carbonate solution and sol, dried over sodium sulphate, filtered and evaporated. 5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained as a yellow-brown oil, which is reacted further in the crude state.

3.12 g (10.1 mmol) 5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester and 30 ml (118 mmol) triisopropyl phosphite (90%) are heated to 80° C and stirred under a pressure of about. 130 mbar for 7 hours. The excess triisopropyl phosphite is distilled off and the residue is purified chromatographically on silica gel with methylene oxide/methanol (97:3 to 95:5). 5-ethoxy-r4-diisopropylphosphon onrety 1-2-formylamino-pent-3-enoic acid ethyl ester is obtained as a yellow oil.

Claims (8)

1. Analogous process for the preparation of therapeutically useful unsaturated aminocarboxylic acid derivatives of formula I where R 1 stands for hydroxy-C 1 -C 7 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 7 -alkyl, amino-C 4 -C 7 -alkyl or halo-C 1 -C 7 -alkyl, whereby halogen means chlorine or fluorine and R 2 means carboxy or C₁-C₄₄ alkoxycarbonyl and salts thereof, characterized in that in a compound of formula II where Z]_, Z2 stands for optionally protected hydroxy, Z3 stands for an optionally protected residue R^ and Z4 means protected amino, transfers protected amino Z4 and, if present, as a constituent of Z3 to amino and, if present, transfers protected hydroxy Z±, Z2 and/or as a component of Z3 to hydroxy and, if present, a protected 5- to 7-membered azacycloalkyl residue Z3 is set free and, if desired, a compound obtained is transferred to another compound of formula I, one by the method obtained isomeric mixture is divided into its components and the isomer preferred in each case is separated and/or a free compound obtained by the method is transferred to a salt or a salt obtained by the method to the corresponding free compound. 2. Analogous method according to claim 1 for the production of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof, characterized in that corresponding starting materials are used. 3. Analogous method according to claim 1 for the production of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt thereof, characterized in that corresponding starting materials are used. 4. Analogous method according to claim 1 for the production of 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester or a salt thereof, characterized in that corresponding starting materials are used. 5. Analogous method according to claim 1 for the production of 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid or a salt thereof, characterized in that corresponding starting materials are used. 6. Analogous method according to claim 1 for the production of 2-amino-5-hydroxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester or a salt thereof, characterized in that corresponding starting materials are used. 7. Analogous method according to claim 1 for the production of 2-amino-5-hydroxy-4-phosphonomethyl-pent-3-enoic acid or a salt thereof, characterized in that corresponding starting materials are used. 8. Analogous process according to claim 1 for the production of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid, 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester, 2-amino-6-fluoro-4 -phosphonomethyl-hex-3-enoic acid ethyl ester, 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid, 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester, 2-amino-8-hydroxy -4-phosphonomethyl-oct-3-enoic acid, 2-amino-6-(N-methylamino)-4-phosphonomethyl-hex-3-enoic acid, 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester , 2-amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid ethyl ester, 2-amino-10-hydroxy-4-phosphonomethyl-dec-3-enoic acid ethyl ester or 5-ethoxy-2-amino-4-phosphonomethyl-pent -3-monoacid ethyl ester or a salt thereof, characterized in that corresponding starting materials are used.