DE3320175A1 - Amino-acid or peptide derivatives, processes for their preparation and use as pharmaceuticals - Google Patents

Abstract

The invention relates to peptide derivatives with antibacterial activity and the formula I <IMAGE> in which m and n can assume the values 0, 1, 2 and 3 with the proviso that the total of m + n is not more than 3, R1 to R9 are hydrogen and/or conventional substituents, R10 is hydroxyl, alkoxy, amino or alkylamino and R11 is an optionally substituted alkyl group, X is oxygen or sulphur and Y is a C atom or <IMAGE> , <IMAGE> or <IMAGE> , physiologically tolerated salts of these compounds, processes for their preparation and pharmaceuticals which contain these compounds. The invention also relates to all the optical isomers resulting from the numerous asymmetric C atoms.

Description

Amino acid or peptide derivatives, processes for their preparation and Use as a medicament The present invention relates to a-amino acid and Peptide derivatives that have an aliphatically bound hydroxyl or mercapto group the side chain carry an ester-like linked phosphonic acid.

Phosphonic and phosphonic acid-containing peptides have been recently discovered Time written several times (e.g. DT-OS 2602 193, DT-OS 2732 454, DT-OS 2721 760, DT-OS 2730 524, EP 000 2822, EP 000 2039, Heterocycles 16 1205 (1981), 18 295 (1982)). However, these are exclusively peptides that instead of the C-terminal a-Aminocarbonsäure a «-Aminoalkanphosphon- or phosphonigsaeure carry the Is connected to the rest of the peptide residue in an amide-like manner via the amino group.

In contrast, the compounds of the present invention are previously unknown monoesters of phosphonic acids with oligopeptides or amino acids, which contain at least one aliphatically bonded hydroxyl or mercapto group.

The compounds of the invention have the general structure I. where m and n can assume the values 0, 1, 2 and 3 with the proviso that the sum m + n should not be more than 3, R, hydrogen, lower alkyl, lower cycloalkyl, aryl-lower alkyl, lower alkanoyl and these radicals can also mean through Oarboxy or lower alkoxycarbonyl groups can be substituted, R4 and R7 have the same meaning as R1 and can be identical or different, R2 stands for hydrogen, lower alkyl, aryl, aryl-lower alkyl, these radicals by hydroxy, lower alkoxy, amino, lower alkylamino, mercapto, lower alkylthio , Lower alkylsulphinyl, lower alkylsulphonyl, carboxy, lower alkoxycarbonyl, aminocarbonyl, lower alkylaminocarbonyl, lower alkanoylamido, N-hydroxy-lower alkanoylamido, N-hydroxyformamido, guanidino, cyano or a heterocyclic radical which can contain one or more nitrogen atoms, can be substituted or together, R1 and R2 can be substituted can form unsaturated hydrocarbon chains, which are caused by oxygen or r sulfur interrupted and substituted by hydroxy, lower alkoxy, oxo, or lower alkyl groups, R3, Rs, R6 and Rg stand for hydrogen or lower alkyl and can be identical or different, R6 has the same meaning as R2 and together with R7 a saturated or unsaturated hydrocarbon chain which can be interrupted by oxygen or sulfur and substituted by hydroxy-lower alkoxy, oxo or lower alkyl groups, Rto can be hydroxy, lower alkoxy, amino or lower alkylamino, R1 t stands for lower alkyl and aryl-lower alkyl radicals, which are represented by one or more hydroxy- , Amino, lower alkoxy, lower alkylamino, lower alkylamino, oarboxy, aminocarbonyl, lower alkoxycarbonyl, lower alkylaminocarbonyl, lower alkanoylamido groups, substituted by lower alkoxycarbonyl, may be substituted, where a primary or secondary amino group occurring as a substituent may be substituted by a radical of the formula II a be acylated ka nn, in which R1, R2, R, and m can have the meaning explained above, and asymmetric C atoms occurring in R1 1, independently of one another, can have the R, S or R, S configuration, which is marked with an asterisk (*) marked C atoms can be in the R, S, or R, S configuration if an asymmetric C atom is formed by four different substituents, X is oxygen or sulfur and y can be a carbon atom or - P-OH, -P-O-lower alkyl or -PO-aryl can mean.

Preferred compounds according to the invention are peptides of the formula I with m + n = 2, especially where the configuration of the with an asterisk (*) marked C-atom is the same as that of naturally occurring L-amino acids.

The term "lower alkyl" used in this specification means straight-chain or branched alkyl radicals with preferably 1-6 carbon atoms. Examples therefor are the methyl, ethyl, propyl, isopropyl, isobutyl or the tert. Butyl group. The term lower cycloalkyl means cyclic hydrocarbons with three to six carbon atoms e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "nryl" denotes. preferably mononuclear radicals such as the phenyl group substituted in one or more places by the specified substituents can be substituted.

"Aryl lower alkyl" means a residue of any of the above Lower alkyl group is substituted by an aryl group described above. Aryl lower alkyl radicals can be added both in the aryl and in the lower alkyl part by the radicals given in the description of R1 and R2 e.g.

Hydroxy, carboxy, amino may be substituted. Examples of such Aryl lower alkyl groups are benzyl, hydroxybenzyl, methoxybenzyl, phenylethyl, 2-phenylethyl, α-carboxyphenylmethyl, α-ethoxycarbonylphenylmethyl, α-hydroxyphenylmethyl group.

Lower alkanoyl radicals are acyl radicals of aliphatic carboxylic acids with 1 - 6 carbon atoms, e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl.

Lower alkylsulphonyl radicals can be e.g. methanesulphonyl, ethanesulphonyl, Propanesulfonyl.

In the case of the arylsulfonyl radical, the aryl group has that already given above Meaning. Examples are benzenesulfonyl and toluenesulfonyl.

The meaning described above for lower alkyl, lower cycloalkyl, Aryl-lower alkyl, aryl also applies in extended substituents that these groups included as part e.g.

Lower alkylamino, lower alkylureido, lower alkylthio.

A "heterocyclic radical" as a possible substituent of a radical R2 or R8 is preferably a mono- or bicyclic radical which is saturated may contain isolated> C = C <or> C = N double bonds, or else can have an aromatic character. Examples are pyrrolidinyl, imidazolyl or Indolyl radical, preferably 3-indolyl.

R1 and R2 or R7 and Re together can be saturated or unsaturated Form hydrocarbon chain. Such a group can be 2-10, preferably 2-5 Include carbon atoms.

Examples are - (CH2) 5-, - (CH2) 3-, -CH2-CH = CH-CH2-, -CH = CH- (CH2) 3-. A hydrocarbon chain interrupted by an oxygen atom or a sulfur atom can, for example, have the following structures; -CH2-O-CH 2 -, -CH2-S-CH2-, - (CH 2) 2 -O- (CH2) 2-, -CH = CH-CH2-O-CH2-, - (CH2-S- (CH2) 2-CH = CH-).

Examples of polymethylene chains substituted by one or more hydroxy, lower alkoxy, oxo or lower alkyl groups are If m or n stands for 2 or 3, then the radicals R1, R2 and R3 or Rv, Rs and Rg in the respective units can be identical or different. If the respective units contain an asymmetrical carbon atom, this can have the R, S or R, S configuration.

The compounds of the formula I can be used in particular for the case that the sum of m + n is 0, 1 or 2, as intermediate products for production other products of formula I are used.

The peptide derivatives according to the invention can be obtained by adding the protective groups of a compound of the general formula IIf wherein the radicals R1, R2, Ra, R4, R5, R6, Rz, R8, R9, R11, X, Y, n, m and * have the same meaning as described above, R1 2 is an amino protective group known from peptide chemistry and R13 either means the same as the radical Rlo described above or, if Y = -C-, represents a carboxyl protective group known from peptide chemistry, split off according to methods known per se and, if desired, converted into a pharmaceutically acceptable salt in a further reaction.

The compounds of the formula II can be prepared once by adding a compound of the formula III, wherein the radicals R1 to R13, X, Y, *, m and n have the meaning described above with the proviso that any functional groups occurring in R1, R2, R41, R7 or R8 are, if necessary, in protected form, with a Converts phosphonic acid of the general formula IV, where R1 has the meaning of R1 1 already given above and furthermore any functional groups occurring in R11 are, if necessary, protected by suitable protective groups known from peptide chemistry, condensed according to methods known per se. Carbodiimides, especially dicyclohexylcarbodiimide, arylsulphonic acid halides, especially 2,4,6-triisopropylphenylsulphonyl chloride or mesitylsulphonyl chloride, trichloroacetonitrile or N, N'-carbonyldiimidazole can be used as condensation agents. The condensation can be carried out in inert organic solvents, preferably in pyridine, dimethylformamide, tetrahydrofuran or mixtures of these solvents.

Protected peptides of the general formula III can be prepared by methods of peptide chemistry known per se by condensation of an amino acid of the general formula V where R41 Rs, R6, * and X have the meaning explained above and R15 is either hydrogen or a hydroxyl or mercapto protecting group known from peptide chemistry, which can be split off selectively in addition to any amino or carboxyl protecting groups that may be present, or if X is S , R15 can be the same as the rest of the compound V, with a compound of the general formula VI or VII, in which the radicals R1, R2, R3, R7, Rs, R9, R12, R13, Y and * have the meaning described above and any functional groups occurring in R1, R2, R7 or Rs are protected if necessary, wherein the amino acid V carries a protective group either on the nitrogen atom or on the carboxyl group in order to ensure a clear amide formation with a compound of the formula VI or VII.

Some of the partially protected compounds of the general formulas VI and VII with m or n equal to 1 are known or can be synthesized in analogy to the preparation of known compounds. Peptides of the general formula VI or VII with m or n greater than or equal to 2 can, according to the processes known from peptide chemistry, in each case by condensation of compounds of the formula VIII or IX, in which the radicals R1, R2, RJ or R7, R8, Rg, Y and * have the meanings already mentioned above, are obtained. The amino groups or acid groups which are not to react must be protected by suitable protective groups which can be split off again selectively in addition to other protective groups after the condensation.

Compounds of the formula VI or VII with m or n greater than 2 can be used can be prepared in an analogous manner from the intermediate products just described.

The phosphonic acids of the general formula are known or can be prepared in analogy to known compounds.

In a further process, compounds of the general formula II can be prepared by adding a compound of the formula V in R15 is hydrogen, the amino group and the carboxyl group is a protective group carry with a phosphonic acid of the general formula IV according to known Methods condensed. Carbodiimides can be used as condensation agents, especially dicyclohexylcarbodiimide, arylsulfonic acid halides, in particular 2,4 , 6-triisopropyl penylsulfonyl chloride or mesitylsulfonyl chloride, trichloroacetonitrile or N, N'-carbonyldiimidazole. The condensation can be carried out in inert organic solvents, preferably in pyridine, dimethylformamide, tetrahydrofuran or mixtures thereof, be performed.

After splitting off the amino protective group or the carboxyl protective group can the connection obtained with according to the method already explained above Peptide chemistry with compounds of the general formula VI or VII to the desired Compounds of the general formula II are condensed.

The protecting groups used in the procedures outlined above are known from peptide chemistry and described in detail, for example, in Houben / Weyl Vol. 15/1. Aralkyloxycarbonyl groups, in particular, are preferably used as amino protective groups Benzyloxycarbonyl, or alkoxycarbonyl groups, preferably tert. Butyloxycarbonyl. However, it can also be a formyl, trityl, trifluoroacetyl or trichloroethoxycarbonyl group be used. Protective groups for hydroxyl groups e.g. R15 can be aralkyloxycarbonyl groups such as benzyloxycarbonyl, aralkyl or lower alkyl such as benzyl or tert. Butyl groups be. Acetal protecting groups such as tetrahydropyranyl or lower alkanoyl groups can also be used how to use the acetyl group. A mercapto group can also go through a series Protective groups known from peptide chemistry can be protected, for example, by Aralkyl groups such as benzyl or trityl, lower alkylthio groups such as tert. Butylthio or by lower alkanoylamidomethyl groups, for example acetamidomethyl, mercapto groups can also be protected by conversion into disulfides. Carboxylic acids can by conversion into an aralkyl ester, e.g. the benzyl ester, into a lower alkyl ester e.g. the methyl ester or tert. Butyl ester or a trialkylsilyl ester, preferably the trimethylsilyl ester or by salt formation with an inorganic base, preferably an alkali metal base.

Phosphonic acids can be replaced by lower alkyl ester groups e.g.

Methyl or ethyl esters, aralkyl esters e.g. benzyl esters or diphenyl methyl esters, Aryl esters e.g.

Phenyl ester or trialkylsilyl ester groups, especially trimethylsilyl, to be protected.

The condensation of a compound of the general formula V, which ever after the intended further reaction, an amino or a carboxyl protective group carries, with a compound of the general formula VI or VII can according to itself known methods of peptide chemistry are carried out.

As reactive derivatives of the carboxylic acid components of the formula VI or V with an amino protective group come mixed anhydrides, in particular with carbonic acid mono-lower alkyl esters such as ethyl or isobutyl esters, or active esters, especially p-nitrophenyl, 2,4,5-trichlorophenyl, Pentachlorophenyl, N-hydroxysuccinimide or 1-N-hydroxybenzotriazolyl esters are suitable. Activation of the carboxyl group can also be carried out by the carbodiimide or azide method be performed. In the case of the carbodiimide process, known racemination dampeners can be used Additives such as 1 -N-hydroxybenzotriazole or N-hydroxysuccinimide can be added.

The condensation reaction is preferably carried out in inert organic Solvents, for example methylene chloride, acetone, ethyl acetate, acetonitrile, Dimethylformamide, tetrahydrofuran, dioxane or mixtures of these solvents carried out at temperatures from -70 to + 1000C, preferably between -30 and +20 cm. In a condensation reaction, the carboxyl group of an amino component passes through Protected salt formation, the reaction with the carboxylic acid component can also are carried out in water or alcohol / water mixtures as solvents, if the reactive derivative of the latter component is a mixed anhydride or an active ester, preferably the N-hydroxysuccinimide ester is used.

The splitting off of the protective groups after the condensation has taken place can be carried out in the usual way. Benzyl esters or benzyloxycarbonyl groups can be achieved by catalytic hydrogenation in the presence of noble metal catalysts, e.g.

Palladium on charcoal, tert. Butyl ester or tert. Butoxycarbonyl groups due to the action of strong acids in organic solvents e.g. hydrogen chloride in ether, ethyl acetate or tetrahydrofuran or also split off by trifluoroacetic acid. Trimethylsilyl esters are easily, mildly already hydrolyzed by water. Are trichloroethoxycarbonyl groups reductively, e.g. splittable by the action of zinc in glacial acetic acid.

Carboxylic acid lower alkyl ester groups are formed by alkaline hydrolysis or to cleave by the action of trimethyliodosilane. The release of a mercapto group which is protected by benzyl, can be caused by the action of sodium in liquid Ammonia take place, S-Tritylgruppen can be removed by the action of strong acids such as trifluoroacetic acid, S-lower alkylthio groups through thiols or Na2 SO3 / Na2S204 remove.

Lower alkanoylamidomethyl groups can be split off with Hg2 + salts will. A mercapto group protected as a disulfide can by reduction with sodium released in liquid ammonia.

Lower alkyl esters or aralkyl esters of phosphonic acids can through strong acids like HBr in glacial acetic acid or by the action of trimethylsilyl bromide or iodide and subsequent aqueous hydrolysis are cleaved. A phosphonic acid aryl ester group can be split by hydrogenolysis.

The compounds of the formula I are amphoteric and can with acids or bases can be converted into salts. Strong acids such as hydrochloric acid, Sulfuric acid, methanesulfonic acid and, as bases, e.g. potash or caustic soda are used will.

The compounds of the formula I show an antimicrobial activity. They are particularly effective against a wide range of gram-positive and gram-negative Bacteria.

Excellent effects against E. coli, Salmonella, Enterobacter species and Proteus, both in vitro and in vivo, were observed.

The compounds according to the invention are antibacterial in their nature Effect superior to comparable compounds containing phosphonic acid. In the following Table 1 shows some in vitro data. For comparison, the data are from L-alanyl-R-1-aminoethanephosphonic acid (alafosfalin) described in DOS 2602 193 specified. The minimum inhibitory concentration was determined in an agar dilution test carried out in the following way: Nutritional medium: 1.5 g fumaric acid, 0.5 g D-glucose, 0.5 g dipotassium hydrogen phosphate trihydrate, 1.0 g L-asparagine, 1.0 g L-proline, 1.0 g L-cysteine, 1.0 g glycine, 25 mg uracil, 2.5 ml phenol red solution (20 mg in 20 ml 70 percent Ethanol), 1.0 ml mineral salt solution (50 g MgSOI. 7 H20, 0.5 g FeSO4. 7 H20, 80 mg ZnSO4. 7 H20, 36 mg MnSO4. 4 H20, 1.5 ml concentrated HCl, distilled water. ad 100 ml) and 15 g of agar were dissolved in 700 ml of distilled water pH 8.0 - 8.5 adjusted and autoclaved. 5 mg of biotin were in 50 ml of MOPS / Tris buffer [158.9 g of 2- (N-morpholino) propanesulfonic acid and 100.8 g of tris (2-amino-2-hydroxymethyl-1,3-propanediol) dissolve in 1 liter of distilled water and autoclave] dissolved and sterile-filtered with 50 ml of a sterile-filtered vitamin solution and 200 ml of a sterile-filtered one Amino acid solution added to the autoclaved medium. 50 ml of the vitamin solution contained 5 mg Ca-D (+) - panthothenate, 5 mg choline chloride, 5 mg folic acid, 10 mg meso-inositol, 5 mg nicotinic acid amide, 5 mg pyridoxal. HCl, 0.5 mg riboflavin and 5 mg thiamine. HOl. 200 ml of the amino acid solution contained 1.26 g of L-arginine. HCl, 313 mg L-cystine. 2 IlCl, 419 mg L-ilistidine. HOl. H2O, 525 mg L-isoleucine, 525 mg L-leucine, 731 mg L-lysine. HCl, 149 mg L-methionine, 330 mg L-phenylalanine, 476 mg L-threonine, 102 mg L-tryptophan, 362 mg L-tyrosine and 469 mg of L-valine.

After adding these substitution solutions, the pH was increased to 7.4 set.

Determination method: The substances to be compared were stored in Sorensen phosphate buffer pH 7.2 dissolved and a pre-dilution series made with this solvent, which includes dilutions with a factor of 2 starting from 10,240 mg / l. 2 ml each this pre-digestion series were carried out with 18 ml of the agar described above at temperatures mixed well below 50 ° C and poured into agar plates. An included growth control contained 2 ml of the specified phosphate buffer instead of pre-digestion.

For the production of the inoculum, a maximum of 2 days was allowed out of 10 old colonies of the relevant gram-negative bacterial strain to the described Material taken from agar plates and rubbed in physiological saline solution.

The turbidity became physiological through appropriate dilution with Saline solution adjusted to a barium sulfate standard (0.5 ml 1% BaCl2 and 99.5 ml l per cent.

H2SO4). This germ suspension was also 1:10 with physiological saline solution diluted, so that a bacterial suspension with approximately 10 7 colony-forming Units / ml arose. The gram positive bacteria were identified in the above Liquid medium (all components with the exception of agar-agar) in a shaking water bath Precultured over 3 hours.

The bacterial suspensions produced in this way were transferred to the inoculum container of a multi-inoculator and transferred to the rows of plates. The inoculum density in the gram-negative bacteria corresponded to approximately 104 colony-forming units per inoculation point. After incubation for 18 + 2 hours at 36 + 100, the test was read. The end point was determined where there was no longer any visible growth or only a few individual colonies (less than 99.9% of the inoculum applied) or micro-growth could be determined. en - - "-" .a. - 1120175 :::: a 'u N cO v) P: ao tl ") Ci) ts I21 m 0) w Table 1 ui u USU z 11 > 1 , -H, 4, {4 4 nc, ro Connection *) TI ci c (ri o- 0 o *) oooo Ln uu 0 0 0 Q) No. uu U lt, <d N k 1 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 . 2 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 3 <0.5 <0. 5 <0.5 <0.5 1> 1024 4 <0.5 0.125 <0.5 <0.5 <0.5 <0.5 4 <0.5 5 0.5 0.125 0.031 0.125 0.5 0.24 2 6 - <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 . 7 1 0.125 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 8 - <0.5 - <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 9 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 10 1 (0.5 <0.5 1 <0.5 <0.5> 1024 Alafosfalin 8 16 4 8 4 64 4 16 *) Connection no.

1 = O- (aminomethanephosphonyl) -L-seryl-L-alanyl-L-alanine 2 = O- (N-methylaminomethanephosphonyl) -L-seryl-L-alanyl-L-alanine 3 = O- (aminomethanephosphonyl) -L-seryl-L-lysyl-L-alanine 4 = 0- (1R, S-1-aminoethanephosphonyl) -L-seryl-L-alanyl-L-alanine 5 = O- (1R, S-1-aminoethanephosphonyl) -L-seryl-L-alanyl-L-arginine 6 = L-alanyl-L-alanyl-O- (1S-1-aminoethanephosphonyl) -L-serine 7 = sarcosyl-L-norvalyl-O- (1S-1-aminoethanephosphonyl) -L-serine 8 = L-arginyl-L-alanyl-O- (aminomethanephosphonyl) -L-serine 9 = L-norvalyl-L-norvalyl-O- (1S-1-aminoethanephosphonyl) -L-serine 10 = L-Prolyl-L-alanyl-O- (aminomethanphosphonyl) -L-serine Alafosfalin = 1 R- 1 - (Alanylamido) ethanephosphonic acid (comparison substance) The connections of the present invention show in combination with other antibiotics in particular Penicillins and cephalosporins enhance the effect.

The P-X-C bonds in the compounds of formula I are among the Biological test conditions stable. There will be no cleavage of these bonds observed by bacterial or animal enzymes.

The compounds according to the invention are used for the production of medicaments of the general formula I or their pharmacologically acceptable salts per se known way with suitable pharmaceutical carrier substances, aroma, taste and dyes mixed and shaped, for example, as tablets or dragees or with the addition of appropriate auxiliaries in water or Qel, such as e.g.

Olive oil, suspended or dissolved.

The novel substances I according to the invention and their salts can be used in liquid or solid form can be administered parenterally. Comes as the injection medium preferably water for use, which is usual for injection solutions Contains additives such as stabilizers, solubilizers or buffers. Such Additives are e.g. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and their non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carriers are e.g.

Starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silica, higher molecular fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, Magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols), preparations suitable for oral administration can be used if desired contain flavorings and sweeteners.

The daily dose of the peptide derivatives administered to adults will vary within wide limits, depending on factors such as the peptide derivative chosen, the mode of administration and the infection to be treated. For example, the daily dose for oral administration can be up to 2000-4000 mg and the daily dose for parenteral administration can be up to 800-2000 mg. It it is understood that the daily dose as a single dose or in several partial amounts can be administered and that the dosages mentioned both downwards as can be varied upwards, depending on individual requirements and in adaptation of the special circumstances as encountered by the attending physician.

The invention is illustrated in more detail by the following examples. In the examples is used to designate the configuration of asymmetric carbon atoms in addition to the R, S convention according to Cahn, Ingold and Prelog, this also applies to amino acids used D, L system used.

Example 1 1.1.

85 g of N-tert-butoxycarbonyl-L-alanine are dissolved in 1 liter of methylene chloride dissolved, mixed with 49.5 g of N-methylmorpholine and the solution cooled to -150C. A solution of 71.2 g of isobutyl chloroformate is added dropwise with stirring in 100 ml of methylene chloride and the reaction mixture is kept at -15 ° C. for 10 min. A solution of 158 g of L-alanine benzyl ester tosylate is then added in portions in 300 ml of methylene chloride and 45.5 g of N-methylmorpholine. The reaction mixture is stirred for 2 hours at temperatures between -10 and -5 ° C, then to room temperature warmed up and evaporated. The residue is between water and ethyl acetate distributed. The organic phase is separated off with Sproz. Citric acid solution and Sproz.

Washed sodium bicarbonate solution, dried with magnesium sulfate and evaporated. The remaining oil is crystallized from ether / ligroin. Man receives 127.5 g N-tert.

Butoxy-L-alanyl-alanine-benzyl ester.

127 g of N-tert-butoxy-L-alanyl-alanine benzyl ester are dissolved in 400 ml of ether dissolved and under cooling in an ice bath and stirring with 800 ml of 6 N ethereal HCl offset. The cooling bath is removed. After standing for 3 hours at room temperature the precipitated crystals are suctioned off. 87.8 g of L-alanyl-alanine benzyl ester hydrochloride are obtained.

1.3.

45.6 g of N-benzyloxycarbonyl-L-serine are in a mixture of 100 ml of dimethylformamide and 400 ml of ethyl acetate and dissolved with 19.3 g of N-methylmorpholine offset. The solution is cooled to -15 ° C and placed drop by drop with stirring a solution of 26.3 g of isobutyl chloroformate in 60 ml of methylene chloride to. After 10 minutes, a solution of 52 g of L-alanyl-alanine benzyl ester hydrochloride is obtained in 100 ml of dimethylformamide, 250 ml of ethyl acetate and 18.4 g of N-methylmorpholine added dropwise. The reaction mixture is kept at -100 ° C. for 1 hour and then left warm up to room temperature. After a further 2 hours, the deposited precipitate is filtered off. The crystals are suspended in water, stirred for 30 min and filtered off with suction and dried. The filtered reaction mixture is treated with 1 N hydrochloric acid, Sproz. Washed sodium bicarbonate solution and water, dried with MgSO4 and evaporated. The residue is filtered off with suction from the reaction mixture and with water treated crystals combined and recrystallized from ethanol. You receive 74.5 g of N-benzyl-oxycarbonyl-L-seryl-L-alanyl-alanine benzyl ester of m.p. 193-1940C.

4. 73 g of N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester and 1.65 g of methanephosphonic acid are dissolved in 50 ml of dry pyridine and added dropwise mixed with a solution of 7.1 g of dicyclohexylcarbodiimide in 10 ml of pyridine. the The reaction mixture is stirred for 2 hours at room temperature.

The precipitate is filtered off and the filtrate is evaporated.

The remaining residue is saturated with sodium bicarbonate solution are added and the residues that remain undissolved are filtered off. Ethyl acetate is added to the aqueous phase, acidified with 2 N HOl, separates the organic phase and the aqueous phase extracted twice more with ethyl acetate. The organic Phases are combined, dried with magnesium sulfate and evaporated. You get 1.2 g (23%) N-benzyloxycarbonyl-O- (methanphosphonyl) -L-seryl-L-alanyl-alanine benzyl ester of m.p. 148 cm (decomposition).

1.5.

2.3 g of N-benzyloxycarbonyl-O- (methanphosphonyl) -L-seryl-L-alanyl-L-alanine benzyl ester are dissolved in a mixture of 300 ml of ethanol and 100 ml of water and over Pd / C hydrogenated as a catalyst at normal pressure. After the hydrogen uptake has ceased the catalyst is filtered off and the filtrate is evaporated. The residue will dissolved hot in ethanol. Something undissolved is filtered off and the filtrate concentrated. The product crystallizes out on cooling.

0.4 g (55%) of O- (methanephosphonyl) -L-seryl-L-alanyl-L-alanine are obtained of melting point 160-1700C (with decomposition) 1D20 = -52.20 (c = 1, H20) example 2 In analogy to examples 1.4. and 1.5. obtained from N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester and 1R, S-1- (benzyloxycarbonylamino) -ethanephosphonic acid O- (1R, S-1-aminoethanephosphonyl) -L-seryl-L-alanyl-L-alanine mp 170-175 ° C (with decomposition).

[«] 20 = -49.9 ° (c = 1, H20) Example 3 3.1.

Analogous to example 6.1. obtained from 1S-1-aminoethanephosphonic acid and benzyl chloroformate 1S-1- (benzyloxycarbonylamido) ethanephosphonic acid of m.p. 136 ° C.

[α] D20 = +13.30 (c = 1, OH3OH) 3.2.

In analogy to examples 1.4. and 1.5. obtained from N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester and 1S-1- (benzyloxycarbonylamino) -ethanephosphonic acid O- (1S-1-aminoethanephosphonyl) -L-seryl-L-alanyl-L-alanine. For purification, it is recrystallized from methanol, a little water and acetone. rp. 188 ° C (decomposition) [«] D ° = -52.40 (c = 1, H20) Example 4 4.1.

Analogous to example 6.1. obtained from 1R-1-aminoethanephosphonic acid and benzyl chloroformate 1R-1- (benzyloxycarbonylamido) ethanephosphonic acid of m.p. 128 "C.

[α] D20 = -14.4 ° (c = 1, OH3OH) 4.2.

In analogy to examples 1.4. and 1.5. obtained from N-benzyloxycarbonyl-L-seryl -L-alanyl -L-alanine benzyl ester and 1R-1- (benzyloxycarbonylamino) -ethanephosphonic acid 0- (1R-1-aminoethanephosphonyl) -L-seryl-L-alanyl-L-alanine of m.p. 16517OCO (decomposition) [a] D ° = -47.4 ° (c = 1, H20) Example 5 5.1.

10 g of R, S-1-Aminoethanphosphonsäure are in a mixture of 15 ml of acetic anhydride and 40 ml of glacial acetic acid were heated under reflux for 4 hours. The reaction mixture is concentrated in vacuo, taken up in water and evaporated again in vacuo.

The residue is recrystallized from ethanol. You get 9.4 g (70%) 1R, S-1-acetamido-ethanephosphonic acid with a melting point of 182-185 ° C.

5.2.

In analogy to examples 1.4. and 1.5. obtained from N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester and 1R, S-1-acetamido-ethanephosphonic acid O- (1R, S-1-acetamidoethanephosphonyl) -L-sery.l-L-alanyl-L-alanine of m.p. 155-160 ° C (decomposition).

[a] ZO = -43.2 (c = 1, H20) D Example 6 6.1.

8.88 g of aminomethanephosphonic acid are suspended in 60 ml of water. The suspension is adjusted to pH 10 with 4 N NaOH, cooled in an ice bath and taken under Stir slowly with 41 ml of a 50 per cent.

Solution of benzyl chloroformate added in toluene. Of the The pH of the reaction mixture is maintained between 9 and 10 by adding 4N NaOH. The cooling is removed. The mixture is stirred for a further 3 hours at room temperature and then let it stand overnight. The reaction mixture is extracted with ether, the aqueous phase acidified with 6 N HOl and the reaction product by multiple Extraction with ethyl acetate isolated. The organic phases are combined, dried and evaporated. The residue is recrystallized from ethyl acetate. 16.8 g (85 t) of N-Ben'yloxycarbonylaminomethanphosphonsaeurc with melting point 127-1280C (decomposition) are obtained.

6.2.

In analogy to examples 1.4. and 1.5. obtained from N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester and 1-benzyloxycarbonylamino-methanephosphonic acid O- (aminomethanephosphonyl) -L-seryl-L-alanyl-L-alanine of m.p. 165-170 ° C (decomposition) [α] D20 = -53.1 ° (c = 1, H20). The raw product is purified by recrystallization from water / ethanol.

Example 7 7.1.

By reacting benzyl chloroformate with 1R, S-1-aminopropanephosphonic acid analogous to example 6.1. 1R, S-1- (Benzyloxycarbonylamino) propanephosphonic acid from Mp. 147-148 ° C (Z).

7.2.

In analogy to examples 1.4. and 1.5. obtained from N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester and 1R, S-1- (benzyloxycarbonylamino) -propanephosphonic acid O- (1R, S-1-aminopropanephosphonyl) -L-seryl-L-alanyl-L-alanine of melting point 167-172 ° C. (decomposition) after recrystallization of the crude product from ethanol / water [α] D20 = -48.7 ° (c = 1, H2O).

Example 8 8.1.

By reacting benzyl chloroformate with 1R, S-1-amino-2-methyl-propanephosphonic acid analogous to example 6.1. becomes 1R, S-1- (Benzyloxycarbonylamino) -2-methyl-propanephosphonic acid with a melting point of 120-121 ° C.

8.2.

In analogy to examples 1.4. and 1.5. obtained from N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester and 1R, S-1- (benzyloxycarbonylamino) -2-methyl-propanephosphonic acid 0- (1R, S-1-amino-2-methyl-cropanphosphonyl) -L-seryl-L-alanyl-L-alanine of melting point 185 ° C. (decomposition) after purification by recrystallization from methanol / ethanol.

[a] 20 = 41.6C (c = 1, H2O) Example 9 9.1.

By reacting benzyl chloroformate with (methylamino) -methane-phosphonic acid analogous to Example 6. 1. (N-benzyloxycarbonyl-N-methyl) aminomethane-phosphonic acid is obtained as a colorless syrup that can be processed without further purification.

9.2.

In analogy to examples 1.4. and 1.5. obtained from N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester and (N-Benzyloxycarbonyl-N-methyl) -aminomethanephosphonic acid O - ((methylamino) methanphosphonyl) -L-seryl-L-alanyl-L-alanine, which comes from a concentrated aqueous solution Addition of ethanol crystallized out.

M.p. 156-1580C (decomposition) [alD ° = -50.2 ° (c = 1, H20) Example 10 10.1.

4.7 g of N-phosphonomethylglycine are suspended in 17 ml of methanol. The mixture is cooled to -5 "C., 2.2 ml of thionyl chloride are added dropwise and stirred for 30 min at -5 ° C and room temperature. Now you warm up for 5 hours to 50 ° C, leave to stand overnight and evaporate the reaction vessel. The residue is dissolved in methanol and the solution is evaporated again. The evaporation residue is dissolved in methanol and propylene oxide is added to the solution until there is no precipitate more fails.

The crystals are filtered off with suction, washed with ether and dried. 4.9 g (96%) of N-phosphonomethylglycine methyl ester, melting point 208-2110C, are obtained according to the thin-layer chromatogram still contains a small amount of starting material.

10.2.

N-phosphonoglycine methyl ester is as in Example 6.1. described reacted with benzyl chloroformate.

The reaction mixture is extracted with a little ethyl acetate. The aqueous phase is transferred to a strongly acidic ion exchanger DOWEX 50 H + form given and the product eluted with water. The product-containing fractions are evaporated. An oil is obtained that still contains some N-benzyloxycarbonyl-phosphonomethylglycine contains. By treating the crude product for 3 hours at 500C with approx.

2 N methanolic hydrogen chloride and evaporation of the mixture obtained one ((N-benzyloxycarbonyl) -phosphonomethyl) -glycine methyl ester which is uniform according to thin-layer chromatography as an oily product.

10.3.

In analogy to examples 1.4. and 1.5. becomes N-Benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester reacted with ((N-benzyloxycarbonyl) -N-phosphonomethyl) -glycine methyl ester. The hydrogenolytic The protective groups are split off in a mixture of methanol-water (2: 1).

One obtains O- (methoxycarbonylaminomethylphosphonyl) -L-seryl-L-alanyl-L-alanine. The crude product is recrystallized by dissolving it in a little water and adding ethanol and melts at 120 ° C with decomposition.

[α] D20 = -41.5 ° (c = 1, H2O) Example 11 11.1.

10.5 g L-serine and 34.2 g t-butyl-2,4,5-trichlorophenyl carbonate in 80 ml of water, 120 ml of t-butanol and 35 ml of triethylamine are suspended and heated 2 hours at 60/65 "C, add 150 ml of water to the resulting solution, make with saturated, water. Citric acid to pH 3, extracted with 150 ml and then twice with 80 ml of ethyl acetate each, extracted the combined ethyl acetate extracts with 100 ml of water. 1 N NaHCO3 solution and then 3 more times with 50 ml of this solution each time. The United aqueous solutions are now adjusted to pH 3 with citric acid, then extracted often with ethyl acetate and evaporate the combined ethyl acetate extracts in a vacuum, with 19.9 g of oil, namely crude N- (t-butoxycarbonyl) -L-serine remaining.

11.2.

This is dissolved in 900 ml abs. Methylene chloride, gives 10.5 ml of N-methylmorpholine to, mixed at -15 ° C with 12.6 ml of isobutyl chloroformate, stirred for 30 min at -150 ° C., added dropwise to the mixed anhydride of N-t-butoxycarbonyl-L-serine obtained in situ in this way and isobutoxycarboxylic acid at -150C a solution of 33.69 g of L-alanine benzyl ester p-toluenesulfonate in 900 ml abs. Methylene chloride and 10.5 ml of N-methylmorpholine, stir for 1 hour -15 ° C, 1 h at 0 ° C and 2 h at 250C. Now one extracts 2 times with Sproz., Water.

NaHCO3 solution and then 2 times with Sproz., Water. Citric acid and finally 2 more times with water. After drying with Na2SO4, the organic Phase in a vacuum, with 27.2 g of orange-yellow oil remaining. This one cleans at a silica gel column (1200 g gel; mobile phase is ethyl acetate) and thus obtained after evaporation of the identical fractions in a vacuum 13.55 g of N-t-butoxycarbonyl-L-seryl-L-alanine-benzyl ester as a colorless oil, which forms crystals of melting point 73 / 820C on standing. 14.1 g the substance obtained in this way is dissolved in 50 ml of tetrahydrofuran and added dropwise while cooling with ice 120 ml of 6N ethereal oil in, stir for 15 min at OOC and 6 h at 250C, leave Stand overnight, suck off the resulting crystals, wash with ether and thus obtained 11.86 g of crude HCl salt of L-seryl-L-alanine benzyl ester of melting point 135 / 1420C.

11.3.

2.23 g of N-benzyloxycarbonyl-sarcosine are dissolved in 100 ml of methylene chloride and 1.1 ml of N-methylmorpholine, 1.3 ml of isobutyl chloroformate added dropwise at -15 ° C a, stir 20 min at -15 ° C, added dropwise to the so obtained in situ, mixed Anhydride a suspension of 3.02 g of crude L-seryl-L-alanine benzyl ester. Hydrochloride in 100 ml of methylene chloride and 1.1 ml of N-methylmorpholine and stir for 1 hour at -15 ° C, 1 hour at OOC and 2 hours at 23 ° C. The resulting extract is then extracted Solution 2 times with 5% water. Citric acid and water, dries the org. phase with Na2SO4, and evaporated it, leaving 3.57 g of crude N-Benzyloxycarbonylsarcosyl-L-seryl-L-alanine benzyl ester of m.p. 131 / 1330C remain.

11.4.

2.35 g of the substance thus obtained and 1.3 g of D, L-1- (benzyloxycarbonylamino) ethanephosphonic acid is dissolved in 40 ml of dry pyridine, a solution of 3.1 g of dicyclohexylcarbodiimide is added dropwise in 10 ml of pyridine, stir for 6 hours at room temperature and leave overnight stand. Now the resulting dicyclohexylurea is suctioned off and the filtrate is evaporated in a vacuum, dissolves the evaporation residue in ethyl acetate, washes it Solution with 5% water.

NaHOO3 and then with 0.5 N HCl and water, the organic phase evaporates after drying with Na2 SO4 in a vacuum and rub the remaining oil with ether on, with 2.77 g of crystals with a melting point of 154/162 cm remaining, namely the crude monoester of D, L-1- (benzyloxycarbonyl-amino) -ethanephosphonic acid with N-benzyloxycarbonyl-sarcosyl-L-seryl-L-alanine benzyl ester.

11.5.

2.7 g of the substance thus obtained are dissolved in 300 ml of a mixture of methanol-water 2: 1, gives 1 g of 10 per. Pd-C catalyst and hydrogenated at normal pressure and room temperature with vigorous shaking (20 min), then sucks the catalyst off, the methanol evaporates in a vacuum, sucks in little precipitated dicyclohexylurea from, extracted the water. Solution with ethyl acetate, narrows the water.

Phase falls in a vacuum to a small volume and falls when ethanol is added 0.93 g of crystals, namely the monoester of D, L-1-amino-ethanephosphonic acid with sarcosyl-L-seryl-L-alanine. After drying for 10 hours (in a vacuum at room temperature over P205) the mp is 184cm (decomp.). For every 1 mol of this substance there is 1/3 mol of ethanol and 1 mol of water is added.

Example 12 Analogous to example 11.3. obtained from 2.09 g of crude N-benzyloxycarbonylglycine (Mp. 121 / 1250C) and 1.3 ml of isobutyl chloroformate in situ the mixed Anhydride and after its reaction with 3.03 g of L-Seryl-L-alanine-benzyl ester hydrochloride 1.97 g of crude N-benzyloxycarbonyl-glycyl-L-seryl-L-alanine benzyl ester, melting point 130 / 1400C (Decomposition), whereby this substance is crystalline after washing with citric acid fails.

1.5 g of this compound are obtained analogously to Example 11.4. with 0.99 g of D, L-1- (benzyloxycarbonyl-amino) -ethanephosphonic acid 1.6 g of crude monoester of D, L-1- (benzyloxycarbonyl-amino) -ethanchosphonic acid with N-Benzyloxycarbonyl-glycyl-L-seryl-L-alanine-benzyl ester as an oil, which after hydrogenation analogous to example 11.5. 0.58 g monoester of D, L-1-amino-ethanephosphonic acid with glycyl-L-seryl-L-alanine supplies, with 1.5 mol of water being added per 1 mol of substance. M.p. 18700 (dec.).

Example 13 Analogous to example 11.3. obtained from 2.23 g of N-benzyloxycarbonyl-L-alanine about the mixed anhydride with chloroformic acid sabutyl ester (in situ) and 3.03 g L-Seryl-L-alanine-benzyl ester ftyclrochioid (after purification of the crude reaction product an de Sleselgelsaeulc with 500 g gel and with chloroform, which contains 50 methanol, as mobile phase) 3.1 g of N-benzyloxycarbonyl-L-alanyl-L-seryl-L-alanine benzyl ester of m.p. 168/171 ° C.

2.3 g of this compound and 1.3 g of D, L-1- (benzyloxycarbonylamino) ethanephosphonic acid deliver analogous to example 11.4. with 3.1 g of dicyclohexylcarbodiimide, 2.47 g of crystals of melting point 173 / 1850C, namely the crude monoester of D, L-1- (benzyloxycarbonyl-amino) -ethanephosphonic acid with N-benzyloxycarbonyl-L-alanyl-L-seryl-L-alanine-benzyl ester, which after hydrogenation with 1.5 g of catalyst analogous to Example 11.5.

0.85 g monoester of D, L-1-amino-ethanephosphonic acid with L-alanyl-L-seryl-L-alanine supplies as a white powder. There are 1.5 mol of water and 0.5 mol of ethanol per 1 mol of substance added, fp. from 165 "C decomp.

Example 14 Analogous to example 11.4. obtained from 6.61 g of N-benzyloxycarbonyl-L-alanyl-L-seryl-L-alanine benzyl ester (Example 13) and 4.5 g of D, L-a {benzyloxycarbonylamini-benzyl-phosphonic acid 5.4 g crude monoester, of which 5 g analogously to Example 11.5.

(in a 600 ml mixture of methanol and water 3: 1 with 3 g of catalyst hydrogenated in 30 min). This gives 0.7 g of crystals, namely the monoester of D, L - «- amino-benzylphosphonic acid with L-alanyl-L-seryl-L-alanine. Per mole of substance 1.5 mol of water and 0.25 mol of ethanol are added. Fp. From 18300 dec.

Example 15 Analogous to example 11.4. obtained from 4.71 g of N-benzyloxycarbonyl-alanyl-L-seryl-L-alanine benzyl ester and 2.45 g of benzyloxycarbonylamino-methanephosphonsae (m.p. 126/128 ° C) 1.85 g of crude Monoester, the ethyl acetate solution not evaporating at the end of the work-up, but the monoester formed is precipitated by adding ether.

After hydrogenation of this substance with 0.5 g of catalyst (in 300 ml of mixture from methanol-water 3: 1) precipitates 0.62 g of white monoester of aminomethylphosphonic acid with L-alanyl-L-seryl-L-alanine. To one mole of this substance there are 2 moles of water and 0.25 mol of ethanol was added. Fp. From 18700 dec.

Preparation of benzyloxycarbonylamino-methanephosphonic acid: 15 a 5.55 g of aminomethanephosphonic acid (melting point 260/265 ° C.) suspended in 40 ml of water brings one enters with 4 N NaOH to pH 9 to 9.5 until solution. In the course of 6 to 7 hours 11.7 ml of benzyl chloroformate are added dropwise while cooling with ice, the pH is always kept at 9 to 9.5 with NaOH. Extracted after standing overnight one 3 times with ether, then pour the water. Phase to 75 ml half-conc. HCl and 100 g ice, now extracted with ethyl acetate, evaporated the dried with Na2 SO4, combined Ethyl acetate extracts in a vacuum, rub the evaporation residue with 20 ml ethyl acetate and thus obtained 7.5 g of benzyloxycarbonylamino-methanephosphonic acid with a melting point of 126/128 ° C.

Example 16 Analogous to example 11.4. obtained from 7.05 g of crude N-benzyloxycarbonyl-L-alanyl-L-seryl-L-alanine benzyl ester (Example 13) and 3.9 g of 2-benzyloxycarbonylamino-ethanephosphonic acid (melting point 103/106 ° C.), (as well as 9.6 g of dicyclohexylcarbodiimide and 100 ml of pyridine) 6.75 g of crude monoester of melting point 190/192 ° C, of which 3 g as in Example 11.5. with 0.6 g of catalyst in 1200 ml of methanol-water 3: 1 hydrogenated, 0.5 g of white monoester of 2-amino-ethanephosphonic acid with L-Alanyl-L-seryl-alanine.

2 mol of water and 1/3 mol of ethanol are added to 1 mol of this substance. Fp. From 193cm, decomp.

The preparation of 2-Benzyloxycarbonylamino-ethanphosphonsaeure from 2-Amino-ethanephosphonic acid (melting point 2780C) is carried out analogously to Example 15 a for Benzyloxycarbonylaminomethanphosphonsaeure described.

Example 17 Analogous to example 11.3. obtained from 2.49 g of crude N-benzyloxycarbonyl-L-proline (M.p. 77 / 800C) and 3.02 g of crude L-seryl-L-alanine benzyl ester. Hydrochloride 3.68 g crystal. i'I-Benzyloxycarbonyl-L-prolyl-L-seryl-alanine benzyl ester, from the 2.48 g with 1.22 g benzyloxycarbonylamino-methanephosphonic acid (Example 15 a) analogously Example 11.4. Provide 1.62 g of crude monoester. 1.5 g of it yield after hydrogenation analogous to example 11.5. (with 0.5 g of catalyst and 400 ml of a mixture of methanol-water 3: 1) 0.57 g monoester of aminomethanephosphonic acid with L-prolyl-L-seryl-L-alanine. 1.5 mol of water and 0.5 mol of ethanol have been added to 1 mol of this substance. Fp. From 1600C, dec.

Example 18 Analogous to example 11.3. obtained from 2.07 g of crude N, N'-dibenzyloxycarbonyl-L-lysine and 0.65 ml isobutyl chloroformate (after stirring for 45 min at -20 ° C) in situ the mixed anhydride and after its reaction with 1.51 g of crude L-seryl-L-alanine benzyl ester . Hydrochloride 2.34 g of crude N, N'-dibenzyloxycarbonyl-L-lysyl-L-seryl-L-alanine benzyl ester.

2.2 g of this substance are obtained analogously to Example 11.4. with benzyloxycarbonylamino-methanephosphonic acid (Example 15 a) 1.52 g of crude monoester. 2 g of this substance bring after hydrogenation analogous to example 11.5. (in 400 ml of methanol-water 3: 1) 0.55 g of white monoester of Aminomethanephosphonic acid with L-lysyl-L-seryl-L-alanine. To 1 mol of this substance 2 mol of water and 0.33 mol of ethanol are added. Mp. From 173 ° C, decomp.

Example 19 Analogous to example 11.2. obtained from 1.5 g of N-t-butoxycarbonyl-L-serine, 0.78 g of N-methylmorpholine, 0.94 ml of isobutyl chloroformate and 100 ml of methylene chloride in situ the mixed anhydride, from which by reaction with the HOl salt of 1.76 g of L-proline benzyl ester (melting point 1450C) (0.74 ml of N-methylmorpholine in 100 ml of methylene chloride) 2.8 g of crude N-t-butoxycarbonyl-L-seryl-L-proline benzyl ester are formed. These Compound dissolved in 60 ml of ether and added dropwise with 18.6 ml while cooling with ice 6 N ethereal oil is added, and after stirring for 15 minutes at 0 ° C. and 3 hours, it is obtained Room temperature 1.43 g of crude L-seryl-L-proline benzyl ester as hydrochloride. By Reaction of this substance with the mixed anhydride generated in situ from N-benzyloxycarbonyl-L-proline (1.06 g) and 0.55 ml of isobutyl chloroformate are prepared analogously to Example 11.3. 2.1 g of crude N-benzyloxycarbonyl-L-prolyl-L-seryl-L-proline benzyl ester were obtained. Analogue Example 11.4. obtained from this substance after reaction with 0.98 g of benzyloxycarbonylamino-methanophosphonic acid (using 2.47 g of dicyclohexylcarbodiimide in 30 ml of abs.

Pyridine and trituration of the evaporation residue with petroleum ether at the end) 2 grams of raw monoester. Analogous to example 11.5. one obtains 0.8 from this by hydrogenation g monoester of aminomethanephosphonic acid with L-prolyl-L-seryl-L-proline. At 1 mol 2.5 mol of water and 0.2 mol of ethanol are added to this compound.

Fp. From 182 "C, dec.

Example 20 20.1.

To a solution of 10 g of N-benzyloxycarbonyl-L-serine in 400 ml of methylene chloride and 4.58 ml of N-methylmorpholine are added dropwise at -15 ° C, 5.8 ml of isobutyl chloroformate, stirs for 15 min at -150C, contributes to the mixed anhydride generated in situ a solution of 7.5 g of crude L-alanine butyl ester. Hydrochloride (m.p. 165 / 1680C) in 300 ml of methylene chloride and 4.58 ml of N-methylmorpholine drop by drop, stir 1 hour at -150C, 1 hour at OOC and 2 hours at room temperature, leave overnight stand, shakes the approach with 5% water. NaHOC3 solution and then with 5% water.

Citric acid off, the org. Phase after drying with Na 2 S04 in a vacuum, cleans the syrupy evaporation residue obtained on a silica gel column (approx. 60 cm long, approx. 6 cm clear width), whereby ethyl acetate with 5% heptane serves as a mobile phase. 6.12 g of colorless syrup are obtained in this way. From the mixed fractions are cleaned again on the column, another 5.25 g of the same syrup obtained, namely N-Benzyloxycarbonyl-L-seryl-L-alanine-t-butyl ester.

Preparation of L-alanine t-butyl ester. Hydrochloride: To 11.25 g of N-benzyloxycarbonyl-L-alanine and 125 ml of t-butanol, dissolved in 50 ml of pyridine, are added dropwise at -5 "C 5.5 ml of POOl3, stir for 3 h at room temperature, then pour into 1 liter of a mixture of water and ethyl acetate 1: 1, separate the organic layer, wash it 2 times with 150 ml of 1 N HCl, then with 5 i aq. NaHCO3 solution and with water and re-steamed it Drying with Na2SO4 in a vacuum, whereby 13.5 g of pale yellowish oil, namely crude N-benzyloxycarbonyl-L-alanine-t-butyl ester can be obtained. 13.3 g of this substance it is hydrogenated at normal pressure and room temperature with 2 g 10% Pd-C catalyst (30 min). After the catalyst has been filtered off with suction, the filtrate is evaporated and the Evaporation residue in ether, precipitated by the addition of 6 N ethereal HOl 5.41 g the desired substance from (mp. 165 / 1680C).

20.2.

6.12 g of N-benzyloxycarbonyl-L-seryl-L-alanine t-butyl ester and 4.12 g of benzyloxycarbonylamino-methanephosphonic acid in 100 ml of abs. Pyridine, you stir 24 h at room temperature with 10.33 g of dicyclohexylcarbodiimide, then sucks the resulting Dicyclohexylurea from, the filtrate evaporates in a vacuum, stirs the evaporation residue with ethyl acetate, sucks off something undissolved, shakes the filtrate with 5 % water. NaHCO3 solution and then with 0.5 N HOl, the org. Phase after Dry with Na2 SO4 in a vacuum, stir the evaporation residue with ether and This gives 6.75 g of raw monoester.

1.5 g of it dissolved in 40 ml of methylene chloride, 3 ml are added 6 N ethereal HCl, stir for 24 h, add another 1.5 ml of 6 N ethereal HCl, let stir again for 24 hours, then suck off the excreted material, namely 0.94 g of crude monoester of benzyloxycarbonylamino-methanephosphonic acid with N-benzyloxycarbonyl-L-seryl-L-alanine 20.3.

3.15 g of the substance thus obtained and 1.37 g of N-hydroxysuccinimide (in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride) one with 1.21 g of dicyclohexylcarbodiimide at -10 ° C, stirred for 2 h at -100C and 24 h at room temperature, sucks off the resulting dicyclohexylurea, evaporates the filtrate in a vacuum, takes up the evaporation residue in ethyl acetate, shakes this solution several times with water, the org. Phase after drying with Na2SO4 in vacuum a, rubs the evaporation residue with ether, whereby 1.02 g of crystals are obtained, namely crude monoesters of (benzyloxycarbonyl-amino) -methanephosphonic acid with N-benzyloxycarbonyl-L-seryl-L-alanine-N-hydroxysuccinimide ester.

1.9 g of this substance dissolved in 12 ml of hot ethanol are worn in a solution of 0.36 g of D, L-1-amino-ethanephosphonic acid in 12 ml of water and 0.6 g NaHCO3 so that the temperature does not rise above OOC, stir for 1 h at 0 ° C and After 24 h at room temperature, the ethanol is then evaporated in a vacuum, then extracted the remaining water phase with ether and purifies the water. Solution on an ion exchange column (DOWEX-50, H-form), eluting with water. The combined, in the thin-layer chromatogram uniform identical fractions are extracted with ether and then with ethyl acetate, if the water phase evaporates in a high vacuum, rubs the evaporation residue with ether and thus obtained 0.66 g of crystalline monoester of (benzyloxycarbonylamino) methanephosphonic acid with D, L-1 - [(Benzyloxycarbonyl-L-seryl-L-alanyl) -amino] -ethanephosphonic acid.

20.4.

After 20 minutes of hydrogenation of this compound (0.66 g) in 25 ml of a mixture from ethanol-water 3: 1 with 0.16 g of 10% Pd-C catalyst at normal pressure, one sucks remove the catalyst, evaporate the ethanol in the filtrate in vacuo, extract the remaining one water. Solution with ethyl acetate, the water layer in the vacuum strongly constricts and falls by adding ethanol.

The crystallizate obtained in this way is redissolved in water and falls again crystals are extracted by the addition of ethanol, these are filtered off with suction and washed with ethanol and acetone and thus obtained 0.13 g of monoester of aminomethanephosphonic acid with D, L-1- (L-seryl-L-alanyl-amino) ethanephosphonic acid.

After drying in vacuo over P205, 1 mol of this substance is 1 mol of water and 0.33 mol of ethanol added.

Fp. From 200es, dec.

Example 21 1.67 g of N-benzyloxycarbonyl-L-serine and 0.77 ml of N-methylmorpholine it is dissolved in 70 ml of methylene chloride, a solution of 0.91 ml of isobutyl chloroformate is added dropwise at -10 ° C in 21 ml of methylene chloride, stir for 30 min at -100C, then add dropwise to the so Mixed anhydride generated in situ at -100C was a solution of 2.5 g of hydrobromide of the crude D, L-1-amino-ethanephosphonic acid diphenyl ester of melting point 1400C and 0.77 ml N-methylmorpholine in 70 ml of methylene chloride, stir for 1 hour at -100C, 1 hour at OOC and 2 h at room temperature, then wash with 5% aq. NaHCO3 solution and then with 5% water. Citric acid and finally with water. After drying the org. Phase with Na2 SO4 and evaporation in a vacuum leave 3.3 g of oil, namely crude D, L-1 - [(N-Benzyloxycarbonyl-L-seryl) -amino] -ethanephosphonic acid-diphenyl ester.

3 g of this are esterified analogously to Example 11.4. with 1.62 g of benzyloxycarbonylamino-methanephosphonic acid (in a total of 120 ml of absolute pyridine) using 3.74 g of dicyclohexylcarbodiimide and obtained so 2.9 g of crude monoester (melting point from 1400 ° C., decomposition) 1.4 g of which is hydrogenated at normal pressure with 0.45 g of 10% Pd-C catalyst in 140 ml of a mixture of methanol-water 3: 1 (9 hours), then add the same amount of catalyst again and hydrogenate more 8 hours. Now the catalyst is suctioned off and the filtrate is evaporated in a vacuum Methanol, sucks off some precipitated dicyclohexylurea, extracts the Filtrate with ethyl acetate, the water phase is strongly concentrated in a vacuum and falls through Addition of ethanol 0.5 g of monoester of aminomethanephosphonic acid with D, L-1- (L-seryl-amino) ethanephosphonic acid monophenyl ester.

0.5 mol of water is added to 1 mol of this substance.

M.p. 200/210 ° C, dec.

Example 22 3 g of [(N-Benzyloxycarbonyl-L-alanyl) -amino] -methanephosphonic acid and 2.96 g of N-benzyloxycarbonyl-L-serine benzyl ester in 50 ml of abs. Pyridine dissolved, it is mixed with 5.6 g of dicyclohexylcarbodiimide, stirred for 5 hours at room temperature, let stand overnight, then completely evaporate the pyridine in a vacuum, take the Evaporation residue in ethyl acetate sucks up the resulting dicyclohexylurea off, the filtrate washes with 5% aq. NaHCO3 solution and then with 0.5 N aq. HOl and water and steams the org.

Phase after drying with Na2S04 in a vacuum. So you win 4.82 g of raw monoester as a glassy, hard mass. 1.5 g of it is dissolved in for cleaning 40 ml 5% aq. NaHCO3 solution and a little acetone, then extracted with 20 ml of ether and then with ethyl acetate; the ethyl acetate solution obtained in this way was extracted one with 1 N HOl and the org. Phase after drying with Na2SO4 in a vacuum, the monoester of [(N-benzyloxycarbonyl-L-alanyl) -amino] -methanephosphonic acid with N-benzyloxycarbonyl-L-serine benzyl ester of melting point 158 / 1620C.

1 g of the aforementioned crude product is hydrogenated (with 0.3 g of 10% Pd-C catalyst 25 min at normal pressure in 150 ml of a mixture of methanol-H 2 O 2: 1) analogously to the example 11.5. and thus obtained 0.15 g of monoester, the (L-alanyl-amino) -methanephosphonic acid with L-serine. 1.5 mol of water and 0.125 mol of ethanol adhere to 1 mol of this substance. Mp. 168/172 ° C, decomp.

Example 23 Analogously to Example 22, 0.78 g of L-1 - [(N-BenzyloxyCarbonyl-L-alanyl-L-alanyl) -amino] -methanephosphonic acid is obtained (Mp. 188 / 1920C, decomp.) And 0.72 g of N-benzyloxycarbonyl-L-serine benzyl ester (with 24 ml abs. Triturated pyridine, then with 1.25 g of dicyclohexylcarbodiimide in 24 ml of pyridine added dropwise and worked up as in Example 22, after evaporation of the Ethyl acetate) 1 g of crude monoester of [(N-BenzylOxyCarbonyl-L-alanyl-L-alanyl) -amino] -methanephosphonic acid with N-benzyloxycarbonyl-L-serine benzyl ester of melting point 135/138 ° C. and after its hydrogenation 0.35 g monoester of [(L-alanyl-L-alanyl) -amino] -methanephosphonic acid with L-serine. 1 mol of water and 0.66 mol of ethanol are added to 1 mol of this substance.

M.p. 168/172 ° C, dec.

Example 24 24.1.

6.25 g of N-benzyloxycarbonyl-L-norvaline (melting point 85 / 860C) are dissolved in 25 ml of methylene chloride, gives 3 g of N-hydroxysuccinimide dissolved in 10.5 ml of tetrahydrofuran, a solution of 5.4 g of dicyclohexylcarbodiimide in 12.5 ml of methylene chloride is added dropwise at -100C to, stirs 1 hour at -100C, 1 h at -50C, 1 h at OOC and 2 h at room temp. after, let stand overnight, suck off the resulting dicyclohexylurea, evaporate the filtrate in a vacuum, dissolves the evaporation residue in ethyl acetate, washes this Solution with 5% water.

NaHCO3 solution, then twice with water and, after drying, the org. Phase in a vacuum, with 8 g oily residue, namely crude N-benzyloxycarbonyl-L-norvaline (N-hydroxysuccinimide ester) remain.

2.75 g of L-1-amino-ethanephosphonic acid are suspended in 100 ml of water and 50 ml of ethanol, 5 g of NaHCO3 are added in portions at 5 to 10 ° C., then added dropwise in 30 min at 0 ° C a solution of 6.96 g of crude N-benzyloxycarbonyl-L-norvaline (N-hydroxysuccinimide ester) read in 70 ml of ethanol, add, stir for 2 hours at 0 ° C, leave to stand overnight, evaporates in a vacuum at room temperature, the remaining oil is taken up in 100 ml of water and extracted this solution 3 times with chloroform. The truebe waessr.

Phase is filtered, with half-conc. HCl adjusted to pH 2 and again extracted with chloroform. The water phase is now reduced to approx. 50 ml in a vacuum in, sucks off the precipitated substance and dries it in a vacuum over P205. 3.4 g of crude L-1 - [(N-benzyloxycarbonyl-L-norvalyl) -amino] -ethanephosphonic acid are obtained in this way of m.p. 181/182 ° C.

2.4 g of this were hydrogenated with 0.8 g of Pd-C catalyst (10%) in 36 ml of methanol and 36 ml of water and 1 drop of glacial acetic acid for 2.0 hours at normal pressure, sucks off the catalyst, the filtrate evaporates in a vacuum, finally 3 more times prior addition of n-propanol in each case. This leaves 1.4 g of evaporation residue of melting point 284/285 ° C., decomposition, namely crude L-1- (L-norvalyl-amino) ethanephosphonic acid.

24.2.

To 1.12 g of it in 30 ml of water and 10 ml of ethanol and 1.26 g of NaHCO3 dissolved, a solution of 1.92 g of N-benzyl-oxycarbonyl-sarcosine- (N-hydroxysuccinimide ester) is added dropwise at 0 ° C in 25 ml of ethanol, stirred for 2 hours at 0 ° C and 1 hour at room temperature, leave Stand overnight, then the solution evaporates (in a vacuum), takes the oily Residue in approx. 50 ml of water, extracted the cloudy solution 3 times with chloroform, adjusts the water phase to pH 2 with HCl, extracted again 3 times with chloroform, strongly restricts the water phase in the vacuum, sucks off the gel-like substance, and dries over P205 in a vacuum, whereby 2.0 g of crude L-1- (N-benzyloxycarbonyl-sarcosyl-L-norvalyl) -amino-ethanephosphonic acid remain. After rubbing with approx.

7 ml abs. Isopropanol or abs. Acetone sucks off the undissolved, rubs it through with ether and thus wins 1.45 g of crystals with a melting point of 204/206es, decomp., namely crude L-1 - [(N-Benzyloxycarbonyl-sarcosyl-L-norvalyl) -amino] -ethanephosphonic acid.

24.3.

Analogously to Example 23, 0.86 g of this substance is mixed with 0.72 g of N-benzyloxycarbonyl-L-serine benzyl ester to the monophosphonic acid ester, which already occurs when the ethyl acetate solution is concentrated precipitates (0.5 g, melting point 142/146 "C) and after hydrogenation (0.15 g 10% Pd-C catalyst, 15 min in 50 ml methanol-water mixture 3: 1) 0.18 g monoester of L-1- [(Sarcosyl-L-norvalyl) -amino] -ethanephosphonic acid with L-serine. At 1 mol 3 mol of water are added to this substance. M.p. 178 / 1800C, dec.

Preparation of N-Benzyloxycarbonyl-sarcosine- (N-hydroxysuccinimide ester): To 8.92 g of N-benzyloxycarbonylsarcosine and 4.8 g of N-hydroxysuccinimide in 40 ml of methylene chloride and 16.8 ml of tetrahydrofuran are added dropwise at -100 ° C. to a solution of 8.64 g of dicyclohexylcarbodiimide in 18 ml of tetrahydrofuran, stir for 1 hour at -100C, 1 hour at OOC and 2 hours at room temperature after, let stand overnight, then sucks the resulting dicyclohexylurea off, the filtrate evaporates in a vacuum, the remaining oil is absorbed in ethyl acetate, filtered, the filtrate shakes with 5% aq. NaHCO3 solution and 2 times with water off, the org. Phase after drying with Na2SO4 in a vacuum, with 11.2 g the desired substance remain as an oil.

Example 25 Analogous to example 24.1. obtained from 13.92 g of N-benzyloxycarbonyl-L-norvaline- (N-hydroxysuccinimide ester), 4.88 g aminomethanephosphonic acid (240 ml ethanol and 200 ml of water) 8.1 g of crude [(N-Benzyloxycarbonyl-L-norvalyl) -amino] -methanephosphonic acid, which after the subsequent hydrogenation and grinding of the crude hydrogenation product with approx. 50 ml abs. Acetone 5.35 g (L-norvalyl-amino) -methanephosphonic acid of m.p. 236 / 2420C, dec. supplies. 5.3 g of it give after reaction with N-benzyloxycarbonyl-sarcosine- (N-hydroxysuccinimide ester) analogous to Example 24.2. 4.2 g crude [(N-Benzyloxycarbonyl-sarcosyl-L-norvalyl) -amino] -methanephosphonic acid, which, after rubbing with water, has a melting point of 146 / 1480C.

Analogous to example 24.3. obtained from 1.5 g of this substance and 1.2 g of N-benzyloxycarbonyl-L-serine benzyl ester using 2.2 g of dicyclohexylcarbodiimide under extremely anhydrous conditions 1.12 g of crude monoester. You solve this in 112 ml 95% Methanol, then 35 ml of water are added dropwise and obtained afterwards Hydrogenation 0.25 g of monoester of (Sarcosyl-L-norvalyl-amino) -methanephosphonic acid with L-serine.

2 moles of water adhere to one mole of this substance.

M.p. 172 / 1740C, dec.

Example 26 26.1.

To 6.7 g of N-benzyloxycarbonyl-L-alanine in 134 ml of methylene chloride and 3.3 ml of dissolved N-methylmorpholine are added dropwise at -150C 3.94 ml of isobutyl chloroformate, stir for 15 min at this temp., add dropwise to the mixed product created in situ in this way Anhydride at -15 ° C is a solution of silylated L-1-amino-ethanephosphonic acid (3.75 g of L-1-aminoethanephosphonic acid suspended in 300 ml of methylene chloride, added it is heated to reflux with 12.1 ml of chlorotrimethylsilane, and 12.5 ml of triethylamine are added dropwise so that the backfiow remains without external heating and then cooks 1 Hour under reflux), leave 1 hour at -15 ° C, 1 h at 0 ° C and 2 h at room temp. stir and then stand overnight. Now the methylene chloride is evaporated, dissolve the residue in water, extract 2 times with ether, leave the water layer Run over an ion exchange column (800 ml Dowex-50, H-Form), elutes with Water and evaporate the combined identical, uniform fractions in a vacuum a. 7.75 g of L-1 - [(N-benzyloxycarbonyl-L-alanyl) -amino] -ethanephosphonic acid are obtained in this way of m.p. 165/169 ° C. 7.7 g of this are hydrogenated with 1.0 g of 10% Pd-C catalyst Normal pressure (in 400 ml of ethanol-water 2: 1, 20 min), the catalyst sucks off, evaporates the filtrate in a vacuum, stirs the residue with ethanol and thus gets 3.85 g of crude 1-L- (L-alanyl-amino) -ethanephosphonic acid.

26.2.

To a solution of 4.2 g of this substance and 5.4 g of Nah003 in 76 A solution of 8.23 g of N-benzyloxycarbonyl-L-alanine (N-hydroxysuccinimide ester) is added dropwise to 2: 1 ml of water-ethanol in 150 ml of ethanol, stir for 4 hours, let stand overnight, distilled then the ethanol is removed in vacuo, the remaining water is extracted with ether, there the water phase on an ion exchange column (800 ml Dowex-50, H-form), eluted with water1 the combined, identical, uniform fractions are evaporated in a vacuum a, stirs the dry evaporation residue with 300 ml of acetone, with 6.1 g Crude 1-L - [(N-Benzyloxycarbonyl-L-alanyl-L-alanyl) -an'no] -ethanephosphonic acid obtained will.

Mp. From 198 ° C, decomp.

26. 3.

Analogously to Example 23, 0.8 g of the phosphonic acid thus obtained is obtained and 0.72 g of N-benzyloxycarbonyl-L-serine benzyl ester using 0.63 g of dicyclohexylcarbodiimide 1.24 g of viscous Qel which, after trituration with ethyl acetate, 0.62 g of crystals with a melting point of 790/194es delivers, namely the corresponding monoester.

26.4.

0.5 g of this substance is dissolved in 50 ml of 95 percent. Methanol, drips Add 15 ml of water and hydrogenate analogously to Example 11.5., Whereby 0.2 g of monoester of L-1 - [(L-alanyl-L-alanyl) -amino] -ethanephosphonic acid can be obtained with L-serine. 2 mol of water and 1 mol of ethanol have been added to 1 mol of this substance.

M.p. 290 / 2990C, dec.

Example 27 2 g of crude, finely powdered L-1 - [(N-benzyloxycarbonyl-L-alanyl-L-alanyl) -amino] -ethanephosphonic acid (prepared according to Example 26.2.) and 0.86 g of N-acetyl-L-serine-benzyl ester suspended one in 60 ml abs. Pyridine, a solution of 3.12 g of dicyclohexylcarbodiimide is added dropwise in 60 ml abs. Pyridine, stir for 30 minutes, then add 20 g of molecular sieve, stir 9 hours further, leave to stand for 2 days, suck off, wash with pyridine and ether, if the filtrate evaporates in a vacuum, the evaporation residue is absorbed in ethyl acetate, wash this solution with 0.2 N HOl and 3 times with water, the org.

Phase after drying with Na2 SO4 in a vacuum, rub the evaporation pressure with ether and thus obtained 0.83 g of crude monoester of L-1- [(N-benzyloxycarbonyl-L-alanyl-L-alanyl) -amino] -ethanephosphonic acid with L-N-acetylserine benzyl ester.

0.4 g of this substance is hydrogenated [20 min in 40 ml of water.

Ethanol (8%) at normal pressure with 0.1 g Pd-C catalyst (10%)] analogous to example 11.5. and thus obtain 0.1 g monoester of L-1 - [(L-alanyl-L-alanyl) -amino] ethanephosphonic acid with L-N-acetylserine. 1 mol of water and 0.33 mol of ethanol are used in 1 mol of this substance added up.

M.p. 182 / 1840C, dec.

Example 28 Analogous to example 11.4. obtained from 4 g of N-benzyloxycarbonyl-L-seryl-L-alanine benzyl ester (Melting point 1180C) and 3.9 g of D, L-1- (benzyloxycarbonyl-amino) -ethanephosphonic acid by means of 6.2 g of dicyclohexylcarbodiimide 4.5 g of crude monoester (melting point 140 / 1450C) from 3.2 g after hydrogenation analogous to Example 11.5. 1.19 g monoester of D, L-1-amino-ethanephosphonic acid with L-Seryl-L-alanine delivers. 1.5 mol of water adheres to 1 mol of this substance.

Fp. From 165 "C, dec.

Example 29 Analogous to example 11.2. obtained from 1.4 g of crude N-t-butoxycarbonyl-sarcosine (M.p. 800C) (dissolved in 100 ml of methylene chloride) and 1.3 ml of isobutyl chloroformate, and 3.51 g of L-alanine benzyl ester. p-toluenesulfonate 2.4 g of crude product as an oil, which after purification on the silica gel column (240 g gel, chloroform as mobile phase) 1.37 G of N-t-butoxycarbonyl-sarcosyl-L-alanine-benzyl ester as a practically colorless oil. 1.27 g of this substance is dissolved in 6 ml of ether, and 8.6 ml of 6N ethereal are added at OOC Add HOl, stir for 15 min at 0 ° C. and 2 h at 230 ° C. and suck the crystallizate obtained from (0.72 g). It's crude sarcosyl-L-alanine benzyl ester. Hydrochloride, m.p. 155/157 "C.

Analogous to example 11.3. is obtained from 5.75 g of this substance and 4.8 g N-Benzyloxycarbonyl-L-serine crude, waxy reaction product, which after Trituration with ether 6. 1 5 g of N-benzyloxycarbonyl-L-seryl-sarcosyl-L-alanine benzyl ester results. M.p. 128 / 1310C.

Analogous to example 11.4. 5.2 g of this substance react with 2.84 g of D, L-1-benzyloxycarbonylamino-ethanephosphonic acid (using 7.13 g of dicyclohexylcarbodiimide in 45 ml of abs.

Pyridine) to the monoester. The crude product obtained is dissolved in Sproz., water. NaHCO3 solution, this solution extracted 5 times with 100 ml of ether each time, then 5 times with 100 ml of ethyl acetate each time, the combined ethyl acetate solutions evaporate in a vacuum and thus obtained 4.95 g of monoester of D, L-1- (benzyloxycarbonylamino) ethanephosphonic acid with N-benzyloxycarbonyl-L-seryl-sarcosyl-L-alanine-benzyl ester as the sodium salt.

Analogous to example 11.5. obtained by hydrogenation of this substance (1 g of Pd-C catalyst, 50 ml of water and 100 ml of ethanol) and complete evaporation the water solution in a vacuum 1.1 g monoester of D, L-1-amino-ethanephosphonic acid with L-Seryl-sarcosyl-L-alanine as the sodium salt. Hang on 1 mol of this substance 2.5 mol of water. Fp. From .10500, decomp.

Example 30 Analogous to example 11.2. is obtained from 6.58 g of N-t-butoxycarbonyl-glycine (Mp. 940C) in 140 ml of methylene chloride and 4.1 ml of N-methylmorpholine with 5 ml of isobutyl chloroformate in 15 ml of methylene chloride in situ the mixed anhydride, from which after reaction with 13.2 g of L-alanine benzyl ester. p-toluenesulfonate 10.4 g of a viscous oil, namely crude N-t-butoxycarbonyl-glycyl-L-alanine-benzyl ester, from which one Dissolve 10 g in 50 ml of ether, slowly add 70 ml of 6 N ethereal HCl at OOC, Let it stir for 15 min at OOC and 2 h at 23 "C and after suctioning off the precipitated Materials so 7.8 g of crude glycyl-L-alanine benzyl ester. Hydrochloride obtained. Fp. 206 / 2100C.

Analogous to example 11.3. is obtained from 6.4 g of N-benzyloxycarbonyl-L-serine (in 75 ml of methylene chloride and 3.2 g of N-methylmorpholine with 4.3 ml of isobutyl chloroformate) the mixed anhydride. After its reaction with a suspension of 7.14 g of glycyl-L-alanine benzyl ester . Hydrochloride in 80 ml of methylene chloride, 20 ml of dimethylformamide and 2.9 ml of N-methylmorpholine and then washing with 0.5 N HOl and water, and rubbing the residue the evaporated methylene chloride solution with ether are 8.2 g of crystals of melting point. 132/136 ° C, namely N-benzyloxycarbonyl-L-seryl-glycyl-L-alanine benzyl ester.

Analogous to example 11.4. is obtained from 2.35 g of this substance and 2 g of D, L-1- (benzyloxycarbonylamino) ethanephosphonic acid, 3 g of crude monoester; M.p. 134/138 ° C.

Analogous to example 11.5. obtained from 1.5 g of this substance in 150 ml of ethanol and 38 ml of water dissolved, after the hydrogenation 0.65 g of monoester of D, L-1-amino-ethanephosphonic acid with L-seryl-glycyl-L-alanine as monohydrate.

M.p. 1480C, dec.

Example 31 Analogously to Example 30, 7.1 g of N-t-butoxycarbonyl-L-alanine are obtained (M.p. 780C) and 5 ml of isobutyl chloroformate, the mixed one formed in situ Anhydride and after its reaction with 13.2 g of L-alanine benzyl ester. p-toluenesulfonate 10.3 g of N-t-butoxy-L-alanyl-L-alanine benzyl ester of melting point 74 / 760C. 10 g of this compound let in 50 ml abs. Dissolved ether, with 68 ml of 6 N ethereal HOl for 15 min OOC and react for 3 h at 25 "C, then evaporate in a vacuum, stir the evaporation residue with 100 ml of fresh ether through, let stand overnight and now sucks the obtained Crystals from (7.6 g); M.p. 158 / 160dz. It's crude L-alanyl-L-alanine benzyl ester . Hydrochloride.

Analogous to example 11.3. obtained from 12 g of this substance after reaction with the mixed anhydride, which is obtained from 10.0 g of N-benzyloxycarbonyl-L-serine and 6.72 g of isobutyl chloroformate is formed in situ, 11.2 g of crystals of melting point. 196-1990C and from the analogous example 11.3. processed mother liquor 4.9 g crystals, which melt after recrystallization from ethanol at 194/1980C. It is N-Benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester.

Analogous to example 11.4. provides the conversion of 4.7 g of this thus obtained Substance with 2.59 g of 2- (benzyloxycarbonyl-amino) -ethanephosphonic acid (melting point 103/106 "C) 3.9 g of crude monoester.

Analogous to example 11.5. is obtained from 1.5 g of this monoester Hydrogenation 0.3 g of monoester of 2-amino-ethanephosphonic acid with L-seryl-L-alanyl-L-alanine as a dihydrate. Mp. From 187 ° C, decomp.

The production of 2- (benzyloxycarbonyl-amino) -ethanephosphonic acid from 2-amino-ethanephosphonic acid and benzyl chloroformate takes place analogously Example 15 a.

Example 32 Analogous to example 11.4. results in the reaction of 0.9 g of D, L- (c-benzyloxycarbonyl-amino) -benzylphosphonic acid (Mp. 151/154 "C) with N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester (Example 31) 2 g of crude monoester, of which 1 g as in Example 11.5. hydrogenated, 0.32 g monoester which delivers D, L- (a-amino) -benzylphosphonic acid with L-seryl-L-alanyl-L-alanine. 1.5 mol of water and 0.25 mol of ethanol adhere to 1 mol of this substance. Fp. From 1840C, Decomp.

The preparation of D, L- (a-Benzyloxvcarbonylamino) -benzylphosphonic acid from α-amino-benzylphosphonic acid (melting point 2830C) is carried out analogously to Example 15a.

Example 33 33.1.

11.6 g of crude L-glutamic acid y-benzyl ester (melting point 1800C), 17.1 g of t-butyl-2,4,5-trichlorophenyl carbonate, 8.4 ml of triethylamine, 40 ml of water and 60 ml of t-butanol are stirred for 3 hours at 60 - 62 "C, then evaporates the t-butanol in a vacuum, adds 70 ml of water, extracted with ether, provides the water layer with conc. HOl to pH 3, now extracted with ethyl acetate, evaporates the combined ethyl acetate extracts and thus receives 9 g of raw, oily N-t-Butoxycarbonyl-L-glutamic acid-γ-benzyl ester.

Analogous to example 11.2. one generates from 2.5 g of this substance (in 75 ml of methylene chloride and 0.83 ml of N-methylmorpholine with 0.99 ml of isobutyl chloroformate) in situ the mixed anhydride, which after reaction with 2.59 S L-alanine benzyl ester . p-Toluenesulfonate (in 75 ml of methylene chloride and 0.83 ml of N-morpholine) 3.6 g of oily (N-t-Butoxycarbonyl-Y-benzyl) -L-glutaminyl-L-alanine benzyl ester gives.

This substance, dissolved in 50 ml of ether, is left with 23 ml of 6N ethereal HCl 15 min at 0 ° C and 48 hours at 25 "C, then evaporated in a vacuum and get 3 g of crude y-benzyl-L-glutamyl-L-alanine-benzyl ester as hydrochloride, in the form of a tough mass.

Analogous to example 11.3. by reacting with this substance, one also counts the mixed anhydride generated in situ from 1.62 g of N-benzyloxycarbonyl-L-serine and 0.9 ml isobutyl chloroformate (and finally rubbed with ethyl acetate) 2.43 g of crude N-benzyloxycarbonyl-L-seryl-L-Y-benzyl-L-glutamyl-L-alanine benzyl ester of m.p. 156 / 1600C.

Analogous to example 11.4. provide 7 g of this compound with 2.93 g of D, L-1- (Benzy1oxycarbonyl-amino) -ethanephosphonic acid (using 7.25 g of dicyclohexylcarbodiimide and finally rubbing with ethyl acetate) 2.12 g of crude monoester of m.p.

150/153 ° C, which after hydrogenation analogous to Example 11.5. in 200 ml Mixture of methanol-H20 3: 1 0.8 g of white monoester of D, L-1-amino-ethanephosphonic acid with L-seryl-L-glutaminyl-L-alanine results. There are 2.5 mol of 1 mol of this substance Water and 0.25 mol of ethanol are added. Mp. From 180 ° C, decomp.

Example 34 Analogous to example 11.4. one sets with 0.94 d N-benzyloxycarbonyl-L-seryl-sarcosyl-L-alanine-benzyl ester (Example 29) and 0.54 g of benzyloxycarbonylamino-methanephosphonic acid (using 1.23 g of dicyclohexylcarbodiimide and after final trituration with ether) 1.15 g of crude Monoester.

(M.p. 104 / 1080C). 1.1 g of this is hydrogenated analogously to Example 11.5. in 110 ml of tiethanol-water 3: 1 and obtained after final rubbing with isopropanol 0.35 g monoester of amino-methanephosphonic acid with L-seryl-sarcosyl-L-alanine. 1 mol of this substance contains 1.5 mol of water and 0.33 mol of ethanol. Fp. 150 / 1560C, dec.

Example 35 Analogous to example 11.4. obtained from 1.83 g of N-benzyloxycarbonyl-L-seryl-glycyl-L-alanine-benzyl ester (Example 30) and benzyloxycarbonylamino-methanephosphonic acid (1.08 g) and finally Trituration with ether 2.05 g of crude monoester of melting point 158 / 1620C. This 2.05 g hydrogenated analogous to example 11.5. (in 150 ml of methanol and 50 ml of water for 40 min at normal pressure) and after final trituration with isopropanol, 0.75 g of monoester of aminomethanephosphonic acid is obtained with L-seryl-glycyl-L-alanine. There are 1.5 mol of water and 0.5 of 1 mol of this substance mol of ethanol added.

M.p. 148 / 1500C, dec.

Example 36 Analogous to example 11.4. is obtained from 3.84 g of N-benzyloxycarbonyl-L-seryl-L-alanine benzyl ester (Example 28) and benzyloxycarbonylamino-methanephosphonic acid using 6.4 g of dicyclohexylcarbodiimide and finally concentration of the ethyl acetate solution 3.8 g crystalline, crude monoester, of the 3 g as in Example 11.5. hydrogenated, 1.15 g of monoester of amino-methanephosphonic acid with L-Seryl-L-alanine.

1.5 mol of water are added to 1 mol of this substance.

Fp. From 187 "C, dec.

Example 37 Analogous to example 11.4. formed from 6.56 g of crude N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester (Example 31) and 1.76 coarse methoxymethanephosphonic acid (using 8.92 g of dicyclohexylcarbodiimide) 4.7 g of crude monoester, of which 4 g as in Example 11.5. hydrogenated (in 800 ml of methanol-water 1: 1) 1.2 g crystalline, crude monoester of methoxymethanephosphonic acid with L-seryl-L-alanyl-l-alanine result. 0.5 mol of water and 0.33 mol of ethanol have been added to 1 mol of this substance.

Mp. From 155 ° C, decomp.

To prepare methoxymethanephosphonic acid, 3.2 g are added Methoxy-methanephosphonic acid diethyl ester (kot6 = 650C) 13.5 g BrSi (CH3) 3, stir 4 hours at room temperature, then the excess BrSi (CHJ) 3 is distilled off to the remaining substance 75 ml of water, stir for 20 min, separates the org. phase from (hexamethyldisiloxane) the water layer evaporates in a vacuum, dissolves the evaporation residue in ethyl acetate, this evaporated after drying with Na2S04 in a vacuum, whereby 1.76 g of the desired substance remain as a crude product (yellow oil).

Example 38 Analogous to example 11.4. is obtained from 1.42 g of crude N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester (Example 31) and 0.88 g of crude 3- (benzyloxycarbonyl-amino) -n-propanephosphonic acid (Mp. 74 / 760C) using 1.86 g of dicyclohexylcarbodiimide and finally grinding of the reaction product with hexane 1.67 g of crude monoester of melting point 54 / 560C, of which 1.5 g analogous to example 11.5. hydrogenated (in 150 ml of methanol-water 3: 1), 0.5 g of monoester of 3-amino-n-propanephosphonic acid with L-seryl-L-alanyl-L-alanine. At 1 mol 1.5 mol of water and 0.5 mol of ethanol adhere to this substance. M.p. 140 / 1500C, dec.

The preparation of 3- (benzyloxycarbonyl-amino) -n-propanephosphonic acid from crude 3-amino-propanephosphonic acid (melting point 2580C) takes place (with 3 ml Soproz. solution of benzyl chloroformate in toluene) analogously to Example 15a.

M.p. 74 / 760C.

Example 39 Analogous to example 11.2. is made from 1.89 g of N-t-butoxycarbonyl-L-alanine (in 100 ml of methylene chloride and 1.3 ml of isobutyl chloroformate at -200C) the mixed anhydride in situ, from which after reaction with 4.81 g of L-nitroarginine benzyl ester . p-Toluenesulfonate 4.3 g N-t-Butoxvcarbonyl-L-alanyl-L-nitroarginine-benzyl ester can be obtained as a crude product.

4 g of the substance obtained in this way are dissolved in 20 ml of abs.

Methylene chloride and about 10 ml of absl. Ether, gives 5 ml of 6N ethereal at OOC HCl, stir for 15 min at OOC and 1 hour at room temperature and sucks the resulting crude L-alanyl-L-nitroarginyl benzyl ester. Hydrochloride from (2.7 g).

Analogous to example 11.3. obtained from 2.5 g of the compound thus obtained and the mixed anhydride generated in situ (from 1.43 g of N-benzyloxycarbonyl-L-serine and 0.78 ml isobutyl chloroformate at -20 ° C) after washing with the water. Citric acid, a gel-like precipitate of crude N-benzyloxycarbonyl-L-seryl-L-alanyl-L-nitroarginine benzyl ester, which is washed with ether after suction. 0.6 g thereof and 0.26 g D, L-1- (Benzyloxycarbonyl-amino) -ethanephosphonic acid, and 0.62 g of dicyclohexylcarbodiimide (in 10 ml of absolute pyridine) are stirred for approx.

2 hours at room temperature, sucks the resulting dicyclohexylurea off, the filtrate evaporates in a vacuum, takes the evaporation residue in ethyl acetate, this solution shakes with 5% water. NaHCO3 solution and then with 0.5 N HCl, the org. Phase with Na2SO4 and then evaporate it in a vacuum one, 0.43 g of crude product remaining after trituration of the evaporation residue with ether, which is dissolved in methylene chloride for further purification and shaken out with water will. After evaporation of the org. The monoester remains in the phase and trituration with ethyl acetate. A portion of the same substance is made from the ethyl acetate grinding mother liquor obtain. 4.2 g of the crude monoester obtained in this way are dissolved in 120 ml of glacial acetic acid, hydrogenated with 4 g of 10% Pd-C catalyst at normal pressure (1 hour), then sucks off the catalyst, evaporates the filtrate, stirs the remaining material with ethanol, the crystals obtained in this way are filtered off with suction, washed with ether and obtained 1.72 g of monoester of D, L-1-amino-ethanephosphonic acid with L-seryl-L-alanyl-L-arginine. 1 mol of acetic acid and 2 mol of water are added to 1 mol of this substance. M.p. 158 - 165 ° C, dec.

Example 40 Analogous to example 11.4. obtained from 1.37 g of benzyloxymethanephosphonic acid, 2.36 g of crude N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine benzyl ester (Example 31) and 3.1 g of dicyclohexylcarbodiimide after vigorous concentration of the ethyl acetate solution of the reaction product and falling with ether 2.56 g of monoester, of which 2.2 g is analogous Example 11.5. hydrogenated (40 min). This gives 0.63 g of monoester of hydroxymethanephosphonic acid with L-Seryl-L-alanyl-L-alanine. 1 mol of this substance is 1 mol of water and 0.5 mol of ethanol added. Fp. From 1050C, decomp.

Synthesis of benzyloxy-methanephosphonic acid: 6.26 g of crude benzyl-chloromethyl-ether it is heated with 6.72 ml of triethyl phosphite for 24 h at 110 ° C., then held at 0.2 mm Hg to 1600C, with 8.41 g of crude benzyloxy-methanephosphonic acid diethyl ester remaining. 3.9 g of this are mixed with 10 ml of bromotrimethylsilane, stirred for 4 hours, and then distilled Then the excess trimethyl-bromosilane is obtained and thus 5.6 g of crude benzyloxy-methanephosphonic acid-di-trimethyl-silyl ester are obtained. This is stirred for 20 min with 100 ml of water, the upper layer is separated (hexamethyldisiloxane) off, the water layer evaporates in a vacuum, takes the evaporation residue in ethyl acetate on, this solution evaporates in a vacuum (after drying with Na2SO4) and wins in this way 2.54 g of benzyloxymethanephosphonic acid as a yellow Qel. Example 41 In analogy to Example 23 is obtained using N-benzyloxycarbonyl-D-serine benzyl ester instead of the corresponding L compound O - ((N-benzyloxycarbonyl-L-alanyl-L-alanylamido) -methanphosphonyl) -N-benzyl-oxycarbonyl-D-serine benzyl ester. The crude product is digested with ether and the product is uniform by thin layer chromatography The residue (2.8 g) is dissolved in 224 ml of a 2: 1 mixture of ethanol and water and hydrogenated over palladium on carbon as a catalyst. The catalyst is filtered off off, evaporate, dissolve the residue in a little water, filter again and precipitate the product by adding ethanol.

1.2 g (88%) of O - ((L-alanyl-L-alanyl) -amidomethanephosphonyl) -D-serine are added . Monohydrate of m.p. 216-2200C (dec.).

[a] 20 = 18.00, c = 1, H20 Example 42 By analogy for Example 24 is obtained using N-benzyloxycarbonyl-D-serine benzyl ester instead of the corresponding L compound O- (1R-1- (N-benzyloxycarbonylsarcosyl-L-norvalylamido) -ethanphosphonyl) -N-benzyl-oxycarbonyl-D-serine benzyl ester. The crude product is purified by recrystallization from ethanol. To the spin-off the substance (4.5 g) is added to the protective groups in a mixture of ethanol-methanol-water (1: 1: 1) suspended, mixed with 1 g of palladium (10%) on charcoal and the suspension shaken in a hydrogen atmosphere for 30 min. Except for the catalytic converter everything in solution. The catalyst is filtered off and the filtrate is evaporated. The residue is stirred with ethanol and the remaining solid is filtered off with suction. 1.6 g (69%) of O- (1R-1- (Sarcosyl-L-norvalylamido) -ethanephosphonyl) -D-seri are obtained of m.p. 148-162 ° C (decomposition) as hemihydrate.

D20 = 41.20 (c = 1, H20) Example 43 Obtained in analogy to Example 25 using N-benzyloxycarbonyl-D-serine benzyl ester instead of the corresponding L-compound 0- ((N-Benzyloxycarbonylsarcosyl-L-norvalylamido) -methanphosphonyl) -N-benzyloxycarbonyl-D-serine benzyl ester. 4.2 g of this by thin-layer chromatography uniform product are in 420 ml of a mixture of ethanol and water (2: 1) suspended, mixed with 1 g of palladium (10 t) on carbon and 20 min in a Shaken hydrogen atmosphere. Except for the catalytic converter, everything works out well. It is filtered off and the filtrate is evaporated to almost dryness. The remaining, concentrated aqueous solution is mixed with ethanol and the precipitated product sucked off. You get 1.6 g (76%) O- (Sarcosyl-L-norvalylamido) -methanphosphonyl) -D-serine. Monohydrate of m.p. 147-1630C (decomposition) [a] 20 = -17.40 (c = 1, H20) D Example 44 In analogy to Example 26, using of N-benzyloxycarbonyl-D-serine benzyl ester instead of the corresponding L-compound 0- (1R-1- (N-Benzyloxycarbonyl-L-alanyl-L-alanylamido) -ethanephosphonyl) -N -benzyl-oxycarbonyl-D-serine benzyl ester. For purification, the crude product is in Sproz. Sodium hydrogen carbonate solution under Dissolved addition of a little acetone. The aqueous phase is extracted with ether and then the product by extraction of the aqueous phase with ethyl acetate isolated. The ethyl acetate phase is washed with 1 N hydrochloric acid and water. Some of the product already precipitates in the organic phase. This is separated and evaporated. The raw product is processed further without additional purification. 5 g of it are heated in 300 ml of a mixture of ethanol and water (2: 1) dissolved while warming and after cooling over palladium (10%) Activated charcoal hydrogenated as a catalyst for 20 min. The catalyst is filtered off, the The filtrate was evaporated, the residue was dissolved in a little water and the product was added by adding precipitated by ethanol and then suctioned off. 1.9 g (76%) of O- (1R-1- (L-alanyl-L-alanylamido) ethanephosphonyl) -D-serine are obtained . Monohydrate, melting point 200-207 ° C (decomposition).

[α] D20 = -40.3 ° (c = 1, H2O) Example 45 45.1.

4.8 g of N-benzyloxycarbonyl-L-serine and 2.2 ml of N-methylmorpholine are used dissolved in 200 ml of dried methylene chloride. The solution becomes dropwise at -159C 2.6 ml of isobutyl chloroformate were added and the mixture was stirred at -150 for 15 min. A suspension of 8 g of glycyl glycine benzyl ester tosylate is then added in portions in 200 ml of methylene chloride and 2.2 ml of N-methylmorpholine are added and the reaction mixture is stirred 1 hour each at -10 °, 0 "and 2 hours at room temperature. After standing over Night the reaction mixture with Sproz. Sodium hydrogen carbonate solution, Sproz. Citric acid solution and water. The organic phase is with MgSO 4 dried and evaporated.

The residue is recrystallized from ethanol. You get 6.4 g (72%) of N-benzyloxycarbonyl-L-seryl-glycylglycine benzyl ester, melting point 143-145 ° C.

45.2.

Analogous to that in example 1.4. described manner is used N-benzyloxycarbonyl-L-seryl-glycyl-glycine benzyl ester with IR, S-1- (benzyloxycarbonylamido) ethanephosphonic acid.

The evaporation pressure of the filtrate of the reaction mixture is below Addition of a little acetone in Sproz. Dissolved sodium hydrogen carbonate solution. The aqueous phase is extracted twice with ether. Then extract that Product with ethyl acetate, washes the ethyl acetate extracts with it 1 N hydrochloric acid and water, dry with MgSO4 and evaporate to dryness. The residue is recrystallized once each from 100 ml of ethanol and 50 ml of methanol. You get 5.4 g (56 "o) O- (1R, S- (benzyloxycarbonylamido) -etnanphosphonyl) -N-benzyloxycarbonyl-L-seryl-glycyl-glycine benzyl ester.

The product still shows traces of impurities in the thin-layer chromatogram and is used without further purification.

45.3.

5.2 g of the in Example 45.2. Established connection will be under Warming dissolved in a mixture of 100 ml each of methanol, ethanol and water. To 1 g of palladium (10%) on charcoal is added to the cooling and the mixture is hydrogenated For 20 minutes. The catalyst is filtered off and the filtrate is concentrated Solution evaporated.

The product is precipitated by adding ethanol. For cleaning the crude product is dissolved in a little water and methanol is added to the solution. The precipitate is filtered off with suction. 1.6 g (64 i) O- (1R, S-1-aminoethanephosphonyl) -L-seryl-glycyl-glycine are obtained, which crystallizes with 1.5 mol of water and melts at 155-1580C (decomposition).

[a] 20 = +15.00 (c = 1, H20) Example 46 46.1.

In analogy to example 1.1. is obtained by reacting 10.8 g of N-tert-butoxycarbonyl-L-norvaline with 19 g of L-norvaline benzyl ester, 17.5 g (86%) of N-tert-butoxycarbonyl-L-norvalyl-norvaline benzyl ester made from m.p. 66-680C. The crude product, which initially appears as an oil, is carried through Addition of crystalline ligroin.

46.2.

1 7. 5 g of N-tert-butoxycarbonyl-L-norvalyl-L-norvaline benzyl ester dissolved in 175 ml of ether and mixed with 350 ml of 5N ethereal hydrochloric acid while cooling with ice offset. After one hour at room temperature, the reaction product is obtained by adding precipitated by ligroin and processed without further purification. You get 9.7 g (66%) L-norvalyl-L-norvaline benzyl ester. Hydrochloride.

46.3.

Analogous to example 45.1. obtained from 6.8 g of N-benzyloxycarbonyl-L-serine and 9.7 g of L-norvalyl-L-norvaline benzyl ester. Hydrochloride 10.4 g (69%) N-benzyloxycarbonyl-L-seryl-L-norvalyl-L-norvalylbenzyl ester of m.p. 162-1660C.

46.4.

3.3 g of 1S-1- (benzyloxycarbonylamido) ethanephosphonic acid are analogous Example 45.2. with 5.2 g of N-benzyloxycarbonyl-L-seryl-L-norvalyl-L-norvaline benzyl ester implemented. 5.4 g (71%) which are not entirely uniform by thin-layer chromatography are obtained 0- (1S-1- (Benzyloxycarbonylamido) ethanphosphono) -N -benzyloxycarbonyl-t-seryi-L-norvalyl-L-norvaline benzyl ester. The product is processed without further purification.

46.5.

Hydrogenation of 5.3 g of O- (15-1- (Benzyloxycarbonyl-L-seryl-L-norvalyl-L-norvaline benzyl ester analogous to Example 45. 3. gives a crude product which by digestion with ethanol is cleaned. 1.7 g (60%) of O- (1S-1-aminoethanephosphonyl) -L-seryl-L-norvalyl-L-norvaline are obtained of m.p. 188-1940C (decomposition).

The product contains 4% water.

1D20 = 31.90 (c = 1, H20) Example 47 The reaction sequences are listed of Example 46 by using 1R-1- (benzyloxycarbonylamido) ethanephosphonic acid instead of the corresponding 1S compound, one finally obtains 0- (1R-1-aminoethanephosphonyl) -L-seryl-L-norvalyl-L-norvaline of m.p. 189-193 ° C (decomposition). The crude product of the hydrogenation is used for purification recrystallized from water / ethanol.

[a] 20 = -26.80 (c = 1, H20) Example 48 48.1.

4.3 g of N £ -benzyloxycarbonyl-L-lysine are dissolved in 120 ml of methylene chloride suspended and mixed with 4.1 ml of trimethylchlorosilane. The mixture will boil heated and, after removing the heating, quickly mixed with 3.1 g of triethylamine. Man keep the reaction mixture at boiling temperature for 1 h, let it cool down and filter the residue with exclusion of moisture.

3.4 g of N-benzyloxycarbonyl-L-serine are dissolved in 120 ml of dry methylene chloride dissolved and added 1.54 ml of N-methylmorpholine. This solution is added in drops -150C 1.84 ml of isobutyl chloroformate, the mixture is stirred for a further 15 min this temperature and then dropwise the filtrate obtained above, which is the silyl ester des N # -benzyloxycarbonyl-L-lysine, too.

The reaction mixture is 2 hours at -10 ° C, 1 hour at OOC, Stirred for 2 hours at room temperature and then left to stand overnight. Man concentrated to dryness, takes the residue in ethyl acetate and sprout.

Sodium hydrogen carbonate solution. After shaking through the two phases are separated and the aqueous phase is acidified with 2N HCl. The product is extracted with ethyl acetate. The organic phase will dried, partially concentrated and mixed with ligroin. The crystals are sucked off and dried. 5.1 g (71%) are largely obtained in a thin-layer chromatogram uniform N-benzyloxycarbonyl-L-seryl-N-benzyloxycarbonyl-L-lysine.

48.2.

5.6 g of N-benzyloxycarbonyl-L-seryl-N £ -benzyloxycarbonyl-L-lysine, 4.6 g L-alanine benzyl ester tosylate, 1.33 g N-methylmorpholine and 3.7 g 1-hydroxybenzotriazole hydrate are dissolved in 150 ml of tetrahydrofuran and the solution is cooled to 0 ". Under A solution of 2.5 g of dicyclohexylcarbodiimide in 25 ml of tetrahydrofuran is used for this purpose dripped.

The reaction mixture is stirred for 2 hours at 0 "and for 1 hour Room temperature. The precipitate is filtered off and the filtrate is evaporated. The residue is taken up in ethyl acetate and the solution is filtered and the filtrate with Sproz. Sodium hydrogen carbonate solution, 0.5 N hydrochloric acid and Water washed.

The product begins to precipitate out of the organic phase, which becomes concentrated and the precipitated crude product isolated by suction. For cleaning is recrystallized from ethanol. 2.9 g (39%) of N-benzyloxycarbonyl-L-seryl-N £ -benzyloxycarbonyl-L-lysyl-L-alanine benzyl ester are obtained from m.p. 179-1810C.

48.3.

In analogy to Example 45.2. we put 6.3 g of the in Example 48.2. obtained tripeptide with 3.5 g of benzyloxycarbonyl-amidomethanephosphonic acid. 6.6 g (78%) of O- (benzyloxycarbonyl-amidomethanephosphonyl) -N-benzylOxyCarbonyl-L-seryl-N £ -benzyloxycarbonyl-L-lysyl-L-alanine benzyl ester are obtained of m.p. 160-162 ° C (decomposition).

48.4.

6.5 g of the compound obtained in Example 48.3 are in a mixture dissolved from 490 ml of ethanol and 240 ml of water and dissolved over 1.5 g of palladium (10%) Hydrogenated coal. The catalyst is filtered off, the filtrate is concentrated and the Crude product precipitated by adding ethanol. It is crystallized from water / ethanol and receives 2.4 g (82%) O- (aminomethanephosphonylfL-seryl-L-lysyl-L-alanine from M.p. 186-1880C (decomposition). 5% ethanol and 8% water adhere to the product.

1D20 = -30.7 (c = 1, H20) Example 49 49.1.

In analogy to examples 46.1., 46.2. and 46.3. is going out of the starting materials N-tert-butoxycarbonyl-L-proline, L-alanine benzyl ester and N-benzyloxycarbonyl-L-serine the protected tripeptide N-benzyloxycarbonyl-L-seryl-L-prolyl-L-alanine benzyl ester manufactured.

M.p. 171-1720C.

49.2.

3. 7 g of N-benzyloxycarbonyl-L-seryl-L-prolyl-L-alanine benzyl ester become analogous to example 1.4. reacted with 2.5 g of benzyloxycarbonylamido-methanephosphonic acid. The reaction mixture is filtered, the filtrate evaporated and the residue dissolved in ethyl acetate and left to stand overnight in the refrigerator. The precipitated crystals are filtered off with suction, the filtrate is mixed with water and the aqueous phase is acidified by adding 2N hydrochloric acid. The organic Phase is separated off and washed with water. The product crystallizes from the organic phase. It is filtered off with suction and suspended in 100 ml of methylene chloride and the suspension was washed in portions with a total of 1000 ml of water.

The aqueous phases are separated off and discarded.

The methylene chloride phase is evaporated. You get 5.3 g (97%) O- (Benzyloxycarbonylamidomethanephosphonyl) -L-seryl-L-prolyl-L-alanine benzyl ester as a practically uniform substance according to thin-layer chromatography, which without additional Cleaning is processed further.

49.3.

Analogous to example 48.4. 5.3 g of the above in example 49.2. received Hydrogenated compound. 2.6 g of a crude product are obtained, which in a thin-layer chromatogram has multiple spots. 0.5 g of the crude product are placed over a column with 750 ml of Sephadex G 10 was chromatographed and the substance was eluted with water. The product-containing Fractions are pooled and freeze-dried. 0.25 g of O- (aminomethanephosphonyl) -L-seryl-L-prolyl-L-alanine is obtained of m.p. 15500 (decomposition). The product contains 10 U of water.

Example 50 50.1.

As in Example 49.2. 7.35 g of benzyloxycarbonylamidomethanephosphonic acid are described reacted with 6.58 g of N-benzyloxycarbonyl-L-serine benzyl ester. The raw product will recrystallized from ethyl acetate. 9 g (80%) of O- (Benzyloxycarbonylamidomethanphosphonyl) -L-serine benzyl ester are obtained, which is contaminated with some dicyclohexylurea and without additional cleaning is further processed.

50.2.

27.8 g of the in Example 50.1. obtained connection are in a Dissolved mixture of 500 ml of acetone and 200 ml of water. You sit under ice cooling 95 ml of 1 N NaOH are added and the mixture is slowly allowed to reach room temperature while stirring come. After 2 hours, the acetone is distilled off from the reaction mixture, the pH value, if necessary, set to 9 and the mixture with ethyl acetate extracted. The aqueous phase is acidified with 2N hydrochloric acid and with ethyl acetate extracted. The organic phase is dried and evaporated. The raw product is recrystallized from ethyl acetate / ether. You get 8.1 g (38%) O- (Benzyloxycarbonvlamidomethanphosphonyl) -N-benzylOxycarbonyl-L-serine, which without additional cleaning is processed.

50.3.

4.6 g of O- (benzyloxycarbonylamidomethanephosphonyl) -N-benzyloxycarbonyl-L-serine are dissolved in 50 ml of dimethylformamide, with 2.34 g of L-alanyl-L-alaninamide hydrochloride and 1.21 g of triethylamine are added. To do this, a solution is dripped in while cooling with ice of 2.26 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide and then leave that Warm the reaction mixture to room temperature.

After a reaction time of 2 hours, the precipitate is filtered off and the Ether was added to the filtrate. An oily precipitate separates out. The ether will decanted and the residue between Sproz. Sodium hydrogen carbonate solution and Ethyl acetate distributed. The organic phase is separated off and the aqueous Phase extracted again with ethyl acetate. The water phase is 2 N hydrochloric acid acidified, the deposited precipitate is filtered off with suction, with water washed and dried. 4.9 g (80 l) of O- (benzyloxycarbonylamidomethanephosphonyl) -N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alanine amide are obtained of m.p. 211-2120C (decomposition).

50.4.

Analogous to example 48.4. becomes O- (Benzyloxycarbonylamidomethanphosphonyl) -N-benzyloxycarbonyl-L-seryl-L-alanyl-L-alaninamide hydrogenated. The raw product will purified by recrystallization from ethanol / water. O- (Aminomethanphosphonyl) -L-seryl-L-alanyl-L-alaninamide is obtained with a melting point of 1650C (decomposition), which, according to thin-layer chromatography, has a purity of about 80%.

[α] D20 = -51.9 ° (c = 1, H2O) Example 51 51 .1 2.3 g of N-tert-butoxycarbonyl-L-asparagine and 3.5 g of L-alanine benzyl ester tosylate are dissolved in 58 ml of dried tetrahydrofuran and mixed with 1. 1 ml of N-methylmorpholine and 3.06 g of 1-hydroxybenzotriazole. Hydrate added. The mixture is cooled to OOC from, gives a solution of 2.3 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran and stir for 2 hours at 0 ° and 2 hours at room temperature. The precipitation is suctioned off, the filtrate evaporated and the residue in a little ethyl acetate recorded. A further amount of precipitate is separated off and the filtrate with Sproz. Sodium hydrogen carbonate solution, Sproz. Lemon acid solution and water washed and dried. 3.1 g (79%) of N-tert-butoxycarbonyl-asparaginyl-L-alanine benzyl ester are obtained, that is pure enough for further processing.

51.2.

7. 3 g of N-tert. -Butyloxycarbonyl-L-asparaginyl-L-alanylbenzyl ester are dissolved under cooling in 55 ml of trifluoroacetic acid and the solution for 30 min stirred at 00 and 60 min at room temperature. The solution is evaporated and the remaining oil is digested with excess trifluoroacetic acid freed. You get 7 g oily L-asparaginyl-L-alanine benzyl ester trifluoroacetate, that is processed further without additional cleaning.

51.3.

Analogous to example 1.3. is obtained from N-benzyloxycarbonyl-L-serine and L-asparaginyl-L-alanine benzyl ester trifluoroacetate N-benzyloxycarbonyl-L-seryl-L-asparaginyl-L-alanine benzyl ester, which still shows traces of impurities in the thin-layer chromatogram and without further purification is used.

51.4.

Analogous to examples 1.4. and 1.5. obtained using N-Benzyloxycarbonyl-L-seryl-L-asparaginyl-L-alanine benzyl ester and methanephosphonic acid O- (methanephosphonyl) -L-seryl-L-asparaginyl-L-alanine. The crude product of the hydrogenation reaction is obtained by chromatography on the strongly acidic ion exchanger DOWEX-50, H + form cleaned.

The column is first washed with water, then with 1 N Formic acid and later eluted with 2N formic acid. The fractions containing the product are combined and evaporated. The isolated product contains 1/2 mol of formic acid and water and melts at 1450C (decomposition).

[a] 20 = ~ 35 7 ° (c = 1, H20) Example 52 52.1 Analogous to example 1.3. obtained using N-benzyloxycarbonyl-L-threonine and L-alanyl-L-alanine benzyl ester hydrochloride N-Benzyloxycarbonyl-L-threonyl-L-alanyl-L-alanine benzyl ester, analogous to Example 49.2. mzt Benzyloxycarbonylamidomethanphosphonsäure is implemented.

You get O- (Benzyloxycarbonylamidomethanphosphonyl) -N-threonyl-L-alanyl-L-alanine benzyl ester, which is recrystallized from methanol for purification. The cleaned product contains but still dicyclohexylurea and is made without additional purification steps further processed.

52.2.

5 g of O- (benzyl-oxycarbonylamidomethanephosphonyl) -N-benzyl-oxycarbonyl-L-threonyl-L-alanyl-L-alanine benzyl ester are dissolved in 450 ml of methanol and 100 ml of water and poured over 1 g of palladium (10 %) hydrogenated on coal. The catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the undissolved dicyclohexylurea is filtered off and evaporates again. The residue is recrystallized from water / ethanol. 0.9 g of O- (aminomethanephosphonyl) -L-threonyl-L-alanyl-L-alanine with melting point are obtained. 178-1880C (decomposition). 0.5 mol of ethanol and 1 mol of water adhere to the product.

[α] D20 = -42.70 (c = 1, H20) Example 53 53.1.

Analogous to example 1.3. obtained from N-benzyloxycarbonyl-N-methyl-L-serine and L-alanyl-L-alanine benzyl ester tosylate, N-benzyl-oxycarbonyl-N-methyl-L-seryl-L-alanyl-L-alanine benzyl ester. The crude product is chromatographed on silica gel with ethyl acetate purified as an eluent. An oily layer is obtained by thin-layer chromatography uniform product.

53. 2.

4.0 g of N-benzyloxycarbonyl-N-methyl-L-seryl-L-alanyl-L-alanine benzyl ester and 3.0 g of benzyloxycarbonylamidomethanephosphonic acid in 80 ml of dry pyridine dissolved, with a solution of .5.1 g of dicyclohexylcarbodiimide in 25 ml of dry Added pyridine and stirred for 4 hours at room temperature. The precipitation will filtered off, the filtrate evaporated and the residue in ethyl acetate recorded. Let stand in the cold for some time and filter another one Amount of precipitation. The filtrate is evaporated and the residue is added of a little acetone in Sproz. Dissolved sodium hydrogen carbonate solution. The watery one Phase is extracted with ether. The ether extracts are discarded.

The product is then extracted with ethyl acetate.

The extract is washed with 1N hydrochloric acid and water and dried and evaporated. The residue is purified by digestion with ether and is pure enough for further processing. 4.2 g (72%) of O- (benzyl-oxycarbonylamidomethanephosphonyl) -N-benzyl-oxycarbonyl-N-methyl-L-seryl-L-alanyl-L-alanine benzyl ester are obtained.

53.3.

Analogous to example 48.4. this is discussed in section 53.2. received product hydrogenated. One obtains O- (aminomethanephosphonyl) -N-methyl-L-seryl-L-alanyl-L-alanine of m.p. 145-1830C (decomposition).

0.5 mol of water and 0.5 mol of ethanol adhere to the product.

[a] D20 = 64.60 (c = 1, H20) EXAMPLE 54 54. 1.

Analogous to example 1.3. 11.5 g of S-benzyl-N-tert-butoxycarbonyl-L-cysteine are used with 10.2 g of L-alanyl-L-alanintert.-butyl ester acetate. You get 11.2 g (60%) S-Benzyl-N-tert-butoxy-carbonyl-L-cysteinyl-L-alanyl-L-alanine-tert-butyl ester of m.p. 152-1550C. For purification, it is recrystallized from ethyl acetate.

54.2.

In 3 batches, 2.5 g of S-benzyl-N-tert-butoxycarbonyl-L-cysteinyl-L-alanyl-L-alanine-tert. -butyl ester dissolved in 100 ml of dry ammonia and at the boiling point of the Ammonia reduced by adding 0.23 g of sodium. The ammonia is distilled off, the residue dissolved in ice-cold water and the pH of the solution with 1 N hydrochloric acid set to 7-8. The aqueous phase is extracted with ethyl acetate, the starting material remaining undissolved is filtered off and the filtrate is evaporated. The residue is digested with ligroin. A total of 3.5 g (57%) of N-tert-butoxycarbonyl-L-cysteinyl-L-alanyl-lalanine tert-butyl ester are obtained, which, according to the thin-layer chromatogram, is still somewhat contaminated, but for further processing is pure enough.

54.3.

3. 5 g of N-tert. -Butoxycarbonyl-L-cysteinyl-L-alanyl-L-alanint.-butyl ester and 3.1 g of Benzyloxycarbonylamidomethanphosphonsäure are in 66 ml of dry pyridine dissolved in the absence of atmospheric oxygen and with a solution of 7.75 g of dicyclohexylcarbodiimide added in 77 ml of dry pyridine. The mixture is stirred for 3 days at room temperature, the precipitate is filtered off and the filtrate is evaporated.

The residue is in Sproz. Dissolved sodium hydrogen carbonate solution. The alkaline water phase is first extracted with ether. The ether phase is discarded. It is then extracted with methylene chloride. Leave part of the product extract yourself. The aqueous phase is adjusted to pH 3 and 1N hydrochloric acid extracted with methylene chloride.

The methylene chloride phases are combined with 1 N hydrochloric acid and Washed water, dried and evaporated.

The residue is digested with ether / ligroin, filtered off with suction and with Washed ligroin. 1.6 g (30%) of S- (BenzylOxyCarbonylamidomethanphosphonyl) -N-tert-butylOxycarbonyl-L-cysteinyl-L-alanyl-L-alanine-tert-butyl ester are obtained.

The raw product is processed further without purification.

54.4.

0.8 g of S- (Benzllloxycarbonylamidomethanphosphonyl -N-tert-butyloxycarbonyl-L-cysteinyl-L-alanyl-lalanine-tert . -butyl ester are cooled with ice in 16 ml 4Oooz. Hydrogen bromide in glacial acetic acid solved. The mixture is stirred for 1 hour at ice bath temperature and 1 hour at room temperature and the product then precipitates by adding diethyl ether.

The precipitate is filtered off and washed well with ether. That Hydrobromide is dissolved in a little water and over the weakly basic ion exchanger IR 45 filtered off in the acetate form. It is eluted with water and the product-containing ones are combined Fractions and subjects them to freeze-drying. The product thus obtained is stirred with ethanol, filtered off with suction and dried. You get 0.12 g (26%) 5- (aminomethanephosphonyl) -L-cysteinyl-L-alanyl-L-alanine, that is still 1 mol of water and, according to the nuclear magnetic resonance spectrum, 15% aminomethanephosphonic acid contains.

The product melts from 247 "C with decomposition.

Example 55 55.1.

In analogy to example 1.1. is obtained starting from N-tert. -Butoxycarbonyl-L-alanine and L-serine p-nitrobenzyl ester tosylate, N-tert-butoxycarbonyl-L-alanyl-L-serine p-nitrobenzyl ester. Cleavage of the N-tert-butoxycarbonyl group by hydrogen chloride in ether in accordance with Example 1.2. provides L-Alanyl-L-serine-p-nitrobenzyl ester hydrochloride.

55.2.

N-Benzyloxycarbonyl-L-alanine is analogous to Example 1.3. with L-alanyl-L-serine-p-nitrobenzyl ester . Hydrochloride implemented. Tetrahydrofuran is used as the solvent.

The crude product precipitated from the reaction mixture is used for purification suspended in ethanol, stirred for 30 min and filtered off with suction. It is obtained by thin-layer chromatography uniform N-benzyloxycarbonyl-L-alanyl-L-alanyl-L-serine-p-nitrobenzyl ester from Mp. 225-226 ° C.

55.3.

3.9 g of 1R, S-1- (benzyloxycarbonylamido) -ethanephosphonic acid are analogous Example 45.2. with 5.2 g of N-benzyloxycarbonyl-L-alanyl-L-alanyl-L-serine-p-nitro-benzyl ester implemented.

The crude product is recrystallized from ethanol / ether.

6.2 g (82%) of N-benzyloxycarbonyl-L-alanyl-L-alanyl-O- ((lR, S-1-benzyloxycarbonylamido) ethanphosphonyl) -L-seryl-p-nitrobenzyl ester, which is pure enough for further processing.

55.4.

Hydrogenation of 6.2 g of the in Example 55.3. obtained compound analogously Example 45.3. delivers a product made from a concentrated aqueous solution crystallized out with the addition of ethanol. You get 2.9 g (99%) L-alanyl-L-alanyl-O- (1R, S-1-amino-ethanephosphonyl) -L-serine, melting point 175-180 ° C (decomposition).

[c120 = -9.3 ° (c = 1, H20) Example 56 Analogous to example 55.3. and 55.4. obtained using 1S-1- (benzyloxycarbonylamido) ethanephosphonic acid instead of the 1R, S compound L-alanyl-L-alanyl-O- (1S-l-aminoethanphosphonyl) -L-serine of m.p. 780-1850C (decomposition). The product contains 12% water.

[α] D20 = -10.1 ° (c = 1, H2O) Example 57 Analog Example 55.3. and 55.4. obtained using ethanephosphonic acid L-alanyl-L-alanyl-O- (ethanphosphonyl) -L-serine of melting point 18300 (, decomposition) Example 58 Analogous to Example 55.3. and 55.4. you get using methanephosphonic acid L-alanyl-L-alanyl-O- (methanphosphonyl) -L-serine as a dihydrate, m.p. 18600 (decomposition).

[a] 20 = -70.20 (c = 1, H20) D Example 59 59.1.

Analogous to example 1.1. is obtained from N-benzyloxycarbonyl-L-alanine and L-serine-p-nitrobenzyl ester, N-benzyloxycarbonyl-L-alanyl-L-serine-p-nitrobenzyl ester. The crude product is recrystallized from ethanol and is according to the thin-layer chromatogram pure enough for further processing.

59.2.

Analogous to example 1.4. provides the implementation of methanephosphonic acid with N-benzyloxycarbonyl-L-alanyl-L-serine-p-nitrobenzyl ester N-benzyloxycarbonyl-L-alanyl-O- (methanphosphonyl) -L-serine-p-nitrobenzyl ester, without further purification according to Example 1.5. is hydrogenated. L-Alanyl-O- (methanphosphonyl) -L-serine is obtained of melting point 15000 (decomposition) [α] D20 = + 14.5 ° (c = 1, H2O) example 60 If one uses instead of methanephosphonic acid in Example 59.2.

1R, S4iBenzyloxycarbonylamido) ethanephosphonic acid is obtained L-Alanyl-O- (1R, S-1-aminoethanephosphonyl) -L-serine as monohydrate, melting point 163-167 ° C (decomposition).

[a] 2 0 = +20.80 (c = 1, H20) D Example 61 Analogous to example 11.3. obtained from 0.92 g of L-alanyl-L-alanine benzyl ester. Hydrochloride and de in situ mixed anhydride generated from 0.8 q D, L- (N-benzyloxycarbonyl-amethyl) serine and 0.42 ml isobutyl chloroformate 1.4 g syrupy D, L- (N-benzyloxycarbonyl-α-methyl) seryl-L-alanyl-L-alanine benzyl ester, from which, analogously to Example 11.4. with 0.7 g of benzyloxycarbonylamino-methanephosphone acidic (using 1.78 g dicyclohexylcarbodiimide) 1.38 g glassy, hard monoester as a raw product. After hydrogenation of this substance as in Example 11.5. fall 0.41 g monoester of amino-methanephosphonic acid with D, L- (a-methyl) -seryl-L-alanyl-L-alanine where 1.5 mol of water and 0.3 mol of ethanol are added per mol of substance.

Mp. From 182 ° C, decomp.

Synthesis of D, L- (N-benzyloxycarbonyl-α-methyl) -serine: 0.6 g Crude D, L - «- methylserine (melting point 258 / 2620C) is suspended in 15 ml of water, gives up to pH 11 2 N NaOH, with solution entering, now drips at 0 ° C. in 2 hours 2.33 ml of benzyl chloroformate, leave to stir for 2 h at 0 ° C (keep pH at 11!), then extracted with ether, acidified the water phase to pH 1.7, extracted with Ethyl acetate, the combined, org. Extracts in the vac. and thus receives D, L- (N-Benzyloxycarbonyl-α-methyl) -serine as a raw product.

Example 62 Analogous to example 11.4. obtained from 1.28 g of crude N-benzyloxycarbonyl-L-seryl-L-proline benzyl ester (Mp. 110/112 "C) and 0.81 g of benzyloxycarbonylamino-methanephosphonic acid (by means of 1.86 g of dicyclohexylcarbodiimide) 2.06 g of crude monoester of melting point 72 / 750C). 2.6 g of this Provide substance after hydrogenation analogously to Example 11.5. 0.57 g of monoester of amino-methanephosphonic acid with L-Seryl-L-proline (as an adduct with 1.5 mol of water and 0.25 mol of ethanol per mol Substance).

M.p. 140 / 1450C, dec.

Preparation of the N-benzyloxycarbonyl-L-seryl-L-proline benzyl ester: From the in situ from 1.44 g of N-benzyloxycarbonyl-L-serine (in 60 ml of methylene chloride and 0.66 ml of N-methylmorpholine and 0.78 ml of isobutyl chloroformate in 15 ml of methylene chloride in 30 min at -: OOC), mixed anhydride and 1.46 g L-proline benzyl ester. Hydrochloride (melting point 1450C) is obtained analogously to Example 11.3. and after trituration with ether 1.8 g of N-benzyloxycarbonyl-L-seryl-L-proline benzyl ester as a crude product with a melting point of 110/112 "C.

Example 63 Analogous to example 11.2. obtained from 3.7 g of crude N-t-butoxycarbonyl-L-a-phenylglycine (prepared analogously to Example 11.1.) in 150 ml of methylene chloride with 1.9 ml of isobutyl chloroformate in situ the mixed anhydride, from which one can with 5.2 g of L-alanine benzyl ester. p-toluenesulfonate 6 g of crude N-t-butoxycarbonyl-L-phenylglycyl-L-alanine benzyl ester are obtained.

This substance is dissolved in 60 ml of ether, and 60 ml are added at 0 ° C 6 N ethereal HCl, left to stand for 15 min at 0 ° C. and 12 hours at 25 ° C. and sucked the precipitated crystals from (3.99 g), namely the crude L-phenylglycyl-L-alanine benzyl ester (Mp. 184/190 "C). 3.9 g of this substance are left out with the analogous to Example 11.3 3.3 g of N-benzyloxycarbonyl-L-serine and 1.8 ml of isobutyl chloroformate in 300 ml of methylene chloride generated in situ, mixed anhydride react and recover so 5.27 g of crude N-BenzylOxyCarbonyl-L-seryl-L-phenylglycyl-L-alanine-benzyl ester, of the 3.81 g with 1.85 g of D, L-1- (benzyloxycarbonylamino) ethanephosphonic acid analogously Example 11.4. (using 4.45 g of dicyclohexylcarbodiimide in 100 ml of absolute pyridine) for raw monoester are implemented (3.46 g).

3 g of it yield after hydrogenation analogously to Example 11.5.

(in 400 ml of methanol-H 2 O 3: 1) the monoester of D, L-1-aminoethanephosphonic acid with L-Seryl-L-a-phenl-glycyl-alanine (1 g) as an adduct with 1.5 mol of water and 0.33 moles of ethanol per mole of substance. Mp. From 175 ° C, decomp.

Example 64 5.9 g of L-glutamic acid-γ-benzyl ester in 100 ml of 1 N water.

Suspended NaHCO3 solution, stirred for 10 min, then added dropwise in 4 to 5 hours 11.7 ml of a Soproz. Solution of benzyl chloroformate in toluene to, stir for 1 hour, extracted several times with ether, provides the water phase with half conc. HOl to pH 2, extracted 3 times with methylene chloride, evaporated the combined org. Extract solutions and thus obtained 7.69 g of crude N-benzyloxycarbonyl-L-glutamic acid benzyl ester. A solution of 11.3 g of this substance in 300 ml of methylene chloride is used with 3.9 ml isobutyl chloroformate in analogy to Example 11.3. the mixed Anhydride (at -200C), which is mixed with 9.06 g of L-alanyl-L-serine benzyl ester. Hydrochloride (Example 77) reacted and so 16.75 g (N-benzyloxycarbonyl-y-benzyl) ~ L ~ glutamyl-L-alanyl-L-serine benzyl ester received. After purification on the silica gel column, 21.42 g (600 g gel; methylene chloride + 5% methanol as eluent) 15.8 g of melting point 123 / 1260C.

Analogous to example 11.4. obtained with 3.08 g of this substance and 1.23 g of N- (benzyloxycarbonylamino) methanephosphonic acid (140 ml of absolute pyridine, 3.2 g of dicyclohexylcarbodiimide and 48 hours of standing) after the strongly concentrated ethyl acetate solution has finally fallen with ether 1.47 g yield of crude monoester. 3 g of this substance are hydrogenated analogously Example 11.5. (in 400 ml of methanol-H20 3: 1) and thus achieves a yield of 1.12 g monoester of aminomethanephosphonic acid with L-glutaminyl-L-alanyl-L-serine as Adduct with 1.5 mol of water and 0.66 mol of ethanol per mol of substance. Mp. From 165 ° C, decomp.

Example 65 Analogous to example 11.3. obtained from 1.21 g of L-alanyl-L-serine benzyl ester . Hydrochloride after conversion with the mixed anhydride generated in situ from N-benzyloxycarbonyl-L-alanine and 0.52 ml isobutyl chloroformate 1.4 g of crude N-benzyloxycarbonyl-L-alanyl-L-alanyl-L-serine benzyl ester of melting point 188 / 1900C, decomposition, which after reaction with 0.81 g of N-benzyloxycarbonylamino-methanephosphonic acid (using 1.86 g of dicyclohexylcarbodiimide) analogous to Example 11.4. 1.7 g crude monoester results (melting point 224/228 "C). After hydrogenation as in Example 11.5. (in 170 ml of methanol-water 3: 1, 40 min), 0.6 g of monoester of aminomethanephosphonic acid is obtained therefrom L-Alanyl-L-alanyl-L-serine as an adduct of 1.5 mol of water and 1/3 mol of ethanol per mole of substance. M.p. 172 / 1800C, dec.

Example 66 Analogous to example 11.2. becomes from 1.89 g of crude t-butoxycarbonyl-sarcosine (Mp. 80 "C) and 1.3 ml of isobutyl chloroformate (100 ml of methylene chloride, 1.1 ml of N-methylmorpholine at -20 ° C, 30 min) get the mixed anhydride in situ, which with 2.31 g of L-serine benzyl ester. Hydrochloride (in 100 ml of methylene chloride and 1.1 ml of N-methylmorpholine) reacted, 3.56 g of crude N- (t-butoxycarbonyl) -sarcosyl-L-serine benzyl ester results as a yellowish oil. It is obtained therefrom in a manner analogous to that described in Example 63 with ethereal oil 2.35 g of crude sarcosyl-L-serine benzyl ester. Hydrochloride from M.p. 156 / 1620C.

Analogous to example 11.3. obtained after reaction (48 hours, 25 "C) of 6 g of this substance in 200 ml of abs. Tetrahydrofuran with the in situ generated, mixed anhydride from 4.48 g of N-benzyloxycarbonyl-L-alanine (in 200 ml of absolute tetrahydrofuran and 2.2 ml N-methylmorpholine) and 2.6 ml isobutyl chloroformate (at -20 ° C, 0.5 hours) subsequent evaporation of the filtered solution in a vacuum, loosening this evaporation residue in 200 ml of methylene chloride and work-up analogous to the example 11.3. 4.83 g of crude N-benzyloxycarbonyl-L-alanyl-sarcosyl-L-serine benzyl ester from M.p. 117/119 "C.

Analogous to example 11.4. can be obtained from 4.71 g of this substance and 2.45 g (benzyloxycarbonylamino) methanephosphonic acid (100 ml pyridine, 6.5 g dicyclohexylcarbodiimide; 48 hours at 250C) prepare 3.98 g of crude monoester, of which 3.8 g after hydrogenation analogous to example 11.5. 1.2 g monoester of amino-methanephosphonic acid with L-alanyl-sarcosyl-L-serine delivers (as an adduct with 2 mol of water and 1/3 mol of ethanol per mol of substance). Fp. from 157 ° C, decomp.

Example 67 Analogous to example 11.3. is obtained from 0.9 g of N-benzyloxycarbonyl-sarcosine and 0.52 ml of isobutyl chloroformate prepared in situ, mixed anhydride and 1.21 g of L-alanyl-L-serine benzyl ester. Hydrochloride 1. 6 g of crude N-benzyloxycarbonyl-sarcosyl-L-alanyl-L-serine benzyl ester of mp. 162 / 1660C, of which 1.41 g as in Example 11.4. with 0.82 g (benzyloxycarbonylamino) methanephosphonic acid (by means of 1.88 g of dicyclohexylcarbodiimide) implemented, yielding 1.5 g of crude monoester. Its hydrogenation analogous to Example 11.5. (in 150 ml of methanol-H 2 O 3: 1, 40 min) 0.5 g monoester of amino-methanephosphonic acid with sarcosyl-L-alanyl-L-serine (as Adduct with 1.5 mol of water and 1/3 mol of ethanol per mol of substance).

Mp. From 165 ° C, decomp.

Example 68 Analogous to example 11.3. one generates from the in situ obtained, mixed anhydride from N-benzyloxycarbonyl-L-norvaline (F-, 850C) and 0.98 ml isobutyl chloroformate (0.5 hours, -10 ° C) and 1.75 g of L-serine benzyl ester. Hydrochloride 3.05 g crude N-Benzyloxycarbonyl-L-norvalyl-L-serine benzyl ester of m.p. 145/147 "C, the analog Example 11.4. reacted with 1. 9 g of (benzyloxycarbonylamino) methanephosphonic acid, 3.1 g of crude monoester of melting point 160 / 1660C are obtained and which is analogous after hydrogenation Example 11.5. (in 300 ml of methanol-H 2 O 3: 1) 1 g of monoester of amino-methanephosphonic acid with L-norvalyl-L-serine gives (as an adduct with 2 mol of water and 1/4 mol of ethanol per mol substance).

M.p. 188 / 1920C, dec.

Example 69 Analogous to example 11.3. can be derived from the in situ generated, mixed anhydride from crude N-benzyloxycarbonyl-L-proline (m.p. 77 / 800C) and 0.52 ml isobutyl chloroformate (0.5 hours at -10 ° C), and L-alanyl-L-serine benzyl ester Hydrochloride 1.7 g of crude N-benzyloxycarbonyl-L-prolyl-L-alanyl-L-serine benzyl ester obtained with m.p. 108/114 ° C.

Analogous to example 11.4. is obtained from 1.49 g of this substance and 0.82 g (Benzyloxycarbonyl-amino) -methanephosphonic acid (after 30 hours reaction time at 23 "C) 1.2 g of crude monoester of melting point 103 / 1060C, which after hydrogenation (in 120 ml Methanol-water 3: 1) as in Example 11.5. 0.32 g monoester of amino-methanephosphonic acid with L-prolyl-L-alanyl-L-serine (as an adduct with 1.5 mol water and 1/4 mol ethanol per mole of substance).

M.p. 150/16000, dec.

Example 70 Analogous to example 11.1. one puts 5.8 g L-norvaline with 17.1 g of t-butyl 2,4,5-trichlorophenyl carbonate around (2 h, 60-650 ° C.), then the t-butanol is distilled off, extract the water phase with ether, then make it up with citric acid pH 3 and works analogously to Example 11.1. on, with 8.86 g of N-t-butoxycarbonyl-L-norvaline incurred as a raw product.

Analogous to example 11.2. obtained from 4 g of this substance with 2.4 ml isobutyl chloroformate in situ the mixed anhydride, from which one can use 4.26 g of L-serine benzyl ester. Hydrochloride and finally precipitating it in ether dissolved reaction product with petroleum ether 6.5 g N-t-butoxycarbonyl-L-norvalyl-L- serine benzyl ester is obtained as a crude product and from which 5 g, analogously as in Example 63 described (in 20 ml of ether and 32 ml of ethereal 6th N HCl, 3 h at 250C), 4.66 g of crude L-norvalyl-L-serine benzyl ester. Hydrochloride from Fp. 173 / 1770C. From 3.3 g of this substance one obtains, analogously to the example 11.3., With the mixed anhydride generated in situ from 2.23 g of N-benzyloxycarbonyl-sarcosine and 1.3 ml of isobutyl chloroformate a yield of 4.35 g of N-benzyloxycarbonyl-sarcosyl-L-norvalyl-L-serine benzyl ester as a crude product, of which 3.6 g with 1.76 g (benzyloxycarbonyl-amino) -methanephosphonic acid analogous to example 11.4.

1.85 g of crude monoester are formed (using 4.45 g of dicyclohexylcarbodiimide) leave (after rubbing with petroleum ether).

After hydrogenation of 1.7 g of it (analogously to Example 11.5.) 0.7 fall g monoester of amino-methanephosphonic acid with sarcosyl-L-norvalyl-L-serine (as Adduct with 2 mol of water and 1/6 mol of ethanol per mol of substance).

Mp. From 172 ° C, decomp.

Example 71 Analogous to example 11.4. obtained from 2.45 g of crude N-benzyloxycarbonyl-sarcosyl-L-norvalyl-L-serine benzyl ester (Example 70) and 1.3 g of crude D-1- (benzyloxycarbonyl-amino) -ethanephosphonic acid (Mp. 125 / 1270C) (100 ml of absolute pyridine, 5.1 g of dicyclohexylcarbodiimide) and precipitation of the reaction product dissolved in a little ethyl acetate crude with petroleum ether 2.25 c Monoester, of which 2 g, analogously to Example 11.5. hydrogenated (0.5 g 10% Pd-C catalyst, 15 min) and the crude reaction product rubbed with ether, 0.66 g of monoester D-1-amino-ethanephosphonic acid with sarcosyl-L-norvalyl-L-serine (as adduct with 2 mol of water and 1/3 mol of ethanol per mol of substance).

Fp. From 1740C, dec.

The preparation of D-1- (benzyloxycarbonyl-amino) -ethanephosphonic acid from 7.5 g of D-1-amino-ethanephosphonic acid (melting point 288 / 2920C, decomp.) and 12.7 ml of benzyl chloroformate happens analogously as described in Example 15 a, only that the approach does not over Stops at night. The yield (according to the case of the reaction product from a Solution in 35 ml of ethyl acetate using 60 ml of n-hexane) is 11.15 g (melting point 125 / 1270C).

Example 72 Analogous to example 11.4. is obtained from 2.45 g of crude N-benzyloxy-carbonyl-sarcosyl-L-norvalyl-L-serine benzyl ester (Example 70) and 1.3 g of crude L-1- (benzyloxycarbonyl-amino) -ethanephosphonic acid (after falling the reaction rod from an enriched solution in ethyl acetate by means of petroleum ether) 2.1 g of crude monoester, of which 2 g after hydrogenation as in the example 11.5. (See Example 71) 0.57 g of monoester of L-1-amino-ethanephosphonic acid with Sarcosyl-L-norvalyl-L-serine yield (melting point from 176 "C decomp.) And indeed as a dihydrate die Preparation of L-1- (benzyloxycarbonyl-amino) -ethanephosphonic acid from 5 g of L-1-amino-ethanephosphonic acid (Mp. 283 / 2900C, decomp.) And 8.5 ml of benzyl chloroformate are carried out analogously to Operation as shown in Example 71. The yield of crude substance (based on a solution in 25 ml of ethyl acetate with petroleum ether) 7.45 g (m.p. 128/13100).

Example 73 Analogous to example 11.2. obtained from 1.89 g of N-t-butoxycarbonylalanine and 1.3 ml isobutyl chloroformate in situ the mixed anhydride from which by reaction with 2.31 g of L-serine benzyl ester. Hydrochloride 3.35 g of crude N-t-butoxycarbonyl-L-alanyl-L-serine benzyl ester arises.

From 18.3 g of this substance and 12.3 g (benzyloxycarbonylamino) methanephosphonic acid is obtained analogously to Example 11.4.

15.2 g of crude monoester, mp 124 / 1250C. 1.97 g of it is solved in 20 ml of tetrahydrofuran and 60 ml of ether, treated at 0 ° C. with 15 ml of 6N ethereal HCl, stir for 15 min at OOC and 1 hour at room temperature, then evaporate in Vacuum, dissolves the evaporation residue in approx. 30 ml of ethanol, gives propene oxide up to pH 6 to, then concentrated in a vacuum to about 10 ml and 1.07 g of crude precipitated by the addition of ether Monoester of (benzyloxycarbonylamino) methanephosphonic acid with L-alanyl-L-serine benzyl ester (M.p. 720C, decomp.). This substance (1.02 g) is dissolved in 34 ml of ethanol-water 1: 2, add 0.57 g of NaHCO3 and a solution of 0.76 g of N-benzyloxycarbonyl- (P-4-hydroxy-S-proline hydroxysuccinimide ester in 34 ml of ethanol, stir for 2 hours after, the ethanol is distilled off in a vacuum, the water phase extracted several times with ethyl acetate, washes the combined org. Phases with 5 t water. iQaHCO3 and then with 0.5 N HCl, dry with lea2SO4, evaporate the ethyl acetate in a vacuum, rub the evaporation residue with petroleum ether and thus receives 0.4 g of crude monoester of (Benzyloxycarbonyl-amino) -methanephosphonic acid with N-benzyloxycarbonyl- (R-4-hydroxy-S-prolyl) -L-alanyl-L-serine-benzyl ester.

0.35 g of this yield after hydrogenation analogously to Example 11.5.

(in 60 ml of methanol-H2O 2: 1, 30 min) 0.06 g of monoester of amino-methanephosphonic acid with 4R-4-hydroxy-S-proyl-L-alanyl-L-serine (as an adduct with 2 mol of water and 1/5 mol Ethanol per mole of substance). Mp. From 168 ° C, decomp.

Synthesis of N-Benzyloxycarbonyl- (R-4-hydroxy-S-proli hydroxysuccinimide ester: 2.62 g of R-4-hydroxy-S-proline are dissolved in 80 ml of 1 N aqueous.

NaHCO3, 9.32 ml of benzyl chloroformate are added dropwise in 4 hours (as 50% solution in toluene), stir for 1 h, extracted 2 times with ether, provides with HOl to pH 2, then extracted with ethyl acetate and this is obtained after evaporation org. Solution 4.71 g glassy, hard residue of crude N-benzyloxycarbonyl- (R-4-hydroxy-S-proline).

To 6.7 g of this substance in 21 ml of methylene chloride and 3.04 g of N-hydroxysuccinimide a solution of 5.43 g of dicyclohexylcarbodiimide is added dropwise at -10 ° C. to 15 ml of tetrahydrofuran in 13 ml of methylene chloride, stir for 2 h at -10 ° C, 1 h at -5 ° C, 1 h at 0 ° C, let stand overnight at 20 ° C, suck off the resulting crystals, evaporate the filtrate in a vacuum, the evaporation residue is taken up in ethyl acetate, extracted the org. Phase with 5% water. NaHCO3 and with water, the ethyl acetate evaporates after drying and thus obtained 8.1 g of crude N-benzyloxycarbonyl- (R-4-hydroxy-S-proline) -hydroxysuccinimide ester.

Example 74 Analogous to example 11.3. is obtained from 1.1 g of crude N-benzyloxycarbonyl- (R-4-methoxy-S-proline) and 0.51 ml isobutyl chloroformate in situ the mixed anhydride from after reaction with 1.18 g of L-alanyl-L-serine benzyl ester hydrochloride 0.7 g crude N-benzyloxycarbonyl- (R-4-methoxy-S-prolyl) -L-alanyl-L-serine benzyl ester (m.p. 156 / 1580C).

Analogous to example 11.4. obtained from 2.16 g of this substance and 1 g (benzyloxycarbonyl-amino) -methanephosphonic acid (2.56 g dicyclohexylcarbodiimide, 80 ml abs. Pyridine) after the reaction product has been removed from the concentrated Ethyl acetate solution with ether 1.93 g of crude monoester, 0.9 g of which after hydrogenation analogous to example 11.5. (in 900 ml of methanol-water 2: 1 with 0.5 g of 10% Pd-C-X catalyst) 0.3 g monoester of amino-methanephosphonic acid with R-4-methoxy-S-prolyl-L-alanyl-L-serine results (as an adduct with 2 mol of water per mol of substance). Fp. From 1700C, dec.

Preparation of N-Benzyloxycarbonyl- (R-4-methoxy-S-proline): A suspension of 1.17 g of N-benzyloxycarbonyl- (R-4-hydroxy-S-prolln) (synthesis in Example 73), 2.3 g of Ag, O and 2.82 g of 0H3J in 8 ml of acetone are heated to 30-35 ° C for 6 hours and sucked then off, the filtrate evaporates, another 1.4 g of Ag2O, 1.72 g of 0H3J and 6 ml of acetone are added closed and heated again for 6 h to 30-35 ° C, sucks off after standing overnight, steams the filtrate and thus obtained crude N-benzyloxycarbonyl- (R-4-methoxy-S-proline) methyl ester. This is dissolved in 20 ml of methanol, 5.6 ml of 1 N NaOH are added, the mixture is stirred for 1 h, and the mixture is adjusted then to pH 4, concentrated to about 6 ml, added 12 ml of water, extracted the precipitated Oil with ethyl acetate, this evaporates, whereby 1.1 g of yellow oil remains, namely the raw product of the desired substance.

3 single 75 3.02 c crude L-a-phenyl-glycine (m.p. 2900C) suspended one in 100 ml of water, adjusts to pH 11 with 4N NaOH, is added dropwise to the so obtained Solution 4.68 g of benzyl chloroformate (at 0 to + 5 ° C), the pH value is kept at 10, then extracted repeatedly with ether, provides the water phase to pH 1.5, sucked the precipitated crystals from and receives after washing with petroleum ether 2.45 g of crude N-benzyloxycarbonyl-L-phenylglycine from M.p. 118/123 ° C.

This results in analogy to example 11.3. with 1.1 ml isobutyl chloroformate the mixed anhydride in situ, which after reaction with 2.54 g of crude L-alanyl-L-serine benzyl ester . Hydrochloride immediately 1.98 g of crystals (after washing with water and ether) from Fp. 161 / 1630C supplies. It is recovered from the methylene chloride mother liquor thereof the specified work-up a further 1.22 g of the same substance, which after purification on the silica gel column (mobile solvent: ethyl acetate) also melts at 161/163 ° C (0.64 g); it is N-benzyloxycarbonyl-L-phenylglycyl-L-alanyl-L-serine benzyl ester.

2.62 g of this substance after reaction with 1.28 g of D, L-1- (benzyloxycarbonyl-amino) ethanephosphonic acid analogous to Example 11.4. 1.5 g of crude monoester from which, after hydrogenation analogous to example 11.5. 0.58 g monoester of D, L-1-aminoethanephosphonic acid with L-a-phenyl-glycyl-L-alanyl-L-serine can be obtained (as an adduct with 2 mol of water and 1/3 mol of ethanol per mol of substance). Fp. From 185 "C, dec.

Example 76 From 28 g of D, L-serine, as well as 260 ml of methanol and 69.6 ml SOC12 is obtained after 2 days at 230C 39.3 g of crude D, L-serine methyl ester. Hydrochloride of m.p. 137 / 1400C. 30 g of it is carried in a suspension of 45 g PC15 in 180 ml of chloroform at OOC, stir for 4 hours at OOC, leave the resulting solution Stand overnight, cool to 0 ° C and precipitate with ether 27.75 g of crude methyl D, L-2-amino-3-chloropropionate . Hydrochloride with a melting point of 130/134 ° C.

To a solution of 25 g of this substance in 148 ml of water is added 36.2 g of NaHOC3 in portions, 24 ml of benzyl chloroformate are added dropwise in 30 minutes to, stirs for 4 hours, sucks off, washes with water, suspends the filter residue in 200 ml of water, add so much methanol (approx. 100 ml) until it is in solution takes place, cools down, adds 200 ml of water, and extracts the oil which has separated out Ethyl acetate, the combined ethyl acetate extracts are evaporated in a vacuum and obtained so 30.45 g of crude methyl 2- (benzyloxycarbonylamino) -3-chloropropionate. 30th g of it and 30.9 g of phthalimide-K in 120 ml of abs. Suspended dimethylformamide, heated 7.5 hours at 90 ° C., then 420 ml of water are added, and the mixture is extracted 4 times with 70 ml Chloroform, the combined chloroform solutions extracted with 280 ml of 0.1 N NaOH and 2 times with 140 ml of water, the chloroform solution evaporates (in a vacuum), whereby 26.6 g of crude D, L-2- (benzyloxy-carbonyl-amino) -3-phthalimido-propionic acid methyl ester attack.

This substance is suspended in 60 ml of tetrahydrofuran, 112 is added ml 1 N NaOH, stir for 2 hours, leave to stand overnight, separate from one gummy mass from, the tetrahydrofuran evaporates in a vacuum, gives to the evaporation residue 237 ml of 1 N HCl, refluxed for 4 hours, extracted after receiving with ether, adjusts the water phase to pH 6 with 2N NaOH, cools in an ice bath and gets so 22 g of crude D, L-2- (benzyloxycarbonyl-amino) -3-aminopropionic acid. 7 g of it touches one with 9 ml of acetic anhydride and 80 ml of glacial acetic acid for 5 to 6 hours until solution occurs.

Now let stand overnight, evaporate in a vacuum, lastly 2 times after each addition of 50 ml of ethanol and thus receives 9 g of crude D, L-2- (benzyloxycarbonyl-amino) -3-acetamido-propionic acid, as a yellow del. 8 g of it are prepared analogously to Example 11.3. with 3.7 ml isobutyl chloroformate the mixed anhydride and leave this with 8.62 g of L-alanyl-L-serine benzyl ester . Hydrochloride react, wherein the reaction product after specified reaction time precipitates in crystalline form. After filtering off, the yield was 9.25 g of crude D, L- [2- (benzyloxycarbonyl-amino) -3-acetamido] -propionyl-L-alanyl-L-serine benzyl ester.

Analogous to example 11.4. obtained with 9 g of this substance and 4.18 g N- (benzyloxycarbonyl-amino) -methanephosphonic acid (225 ml pyridine; 10.8 g dicyclohexylcarbodiimide) 4.35 g yield of crude monoester, of which 1.1 g analogously to Example 11.5. hydrogenated (200 ml of methanol-water 1: 1). 0.3 g of monoester of aminomethanephosphonic acid is obtained in this way with D, L- (2-amino-3-acetamido) -propionyl-L-alanyl-L-serine (as an adduct with 2 mol of water and 1/3 mol of ethanol per mol of substance).

Mp. From 177 ° C, decomp.

Example 77 Analogous to example 11.2. obtained from 5.67 g of N-t-butoxycarbonyl-L-alanine and 4 ml isobutyl chloroformate in situ the mixed anhydride and after its implementation with 10.6 g of L-serine benzyl ester. Hydrochloride 11.2 g of crude N-t-butoxycarbonyl-L-alanyl-L-serine benzyl ester. To 11 g of it in 150 ml abs. Dissolved ether, 69 ml of 6 N HOl are added dropwise at OOC Ether, leave for 15 min at 0 ° C and 3 hours at 230C, the suspension evaporates a, stir the evaporation residue with 250 ml of ether (3 h), let stand for 2 days, sucks off and thus achieves a yield of 8 g of crude L-alanyl-L-serine benzyl ester. Hydrochloride from fp. 180/19000, decomp.

2.42 g of it are left with the mixed anhydride generated in situ from 2.96 g of D, L- 2- (benzyloxycarbonyl-amino) -3- (benzyloxycarbonyl-amino) propionic acid and 1.04 ml of isobutyl chloroformate analogous to Example 11.3. react and This gives 4 g of crude D, L- 2- (benzyloxycarbonyl-amino) -3- (benzyl-oxycarbonyl-amino) -propionyl-X-alanyl-L-serine benzyl ester of m.p. 124/128 "C.

Analogous to example 11.4. you get from 3.72 g of this compound and 1.64 g (benzyloxycarbonylamino) methanephosphonic acid (3.7 g dicyclohexylcarbodiimide, 30 hours reaction time) 3.2 g of crude monoester with a melting point of 162 ° C., decomposition, of which 1.8 g analogous to 11.5. are hydrogenated (180 ml of methanol-water 3: 1). The residue that after Evaporation (in a vacuum) of the hydrogenation solution remains, yields after trituration with ethanol O.5 g monoester of amino-methanephosphonic acid with D, L- (2-amino-3-amino) -propionyl-L-alanyl-L-serine (as an adduct with 1 mol of water and 2/3 mol of ethanol per mol of substance).

Mp. From 112 ° C, decomp.

EXAMPLE 78 Analogously as described in Example 64, one exhibits 3.06 g of crude N-n-propyl-glycine with 9.6 ml of benzyl chloroformate (50% in Toluene) 3.8 g of crude, oily [N- (benzyloxycarbonyl) -N-n-propyl] -glycine, from to which one 2.08 g analogous to example 11.3. with 1.04 ml isobutyl chloroformate in situ converted into the mixed anhydride, which after reaction with 2.64 g crude L-norvalyl-L-serine benzyl ester. Hydrochloride (Example 70), 3.95 g [N- (Benzyloxycarbonyl) -N-n-propyl] -glycyl-L-norvalyl-L-serine benzyl ester of m.p. 162/168 ° C provides.

Analogous to example 11.4. gives this substance with 2.03 g of (benzyloxycarbonylamino) methanephosphonic acid (150 ml of absolute pyridine, 4.68 g of dicyclohexylcarbodiimide) 4.5 g of crude monoester, after Hydrogenation analogous to Example 11.5. (400 ml of methanol-water 3: 1) and evaporation of the water. Solution in a vacuum 1.4 g monoester of aminomethanephosphonic acid with N-n-propylslycyl-L-norxzalyl-L-serine (as monohydrate) delivers.

Mp. From 172 ° C decomp.

Example 79 The exhibition is analogous to that described in Example 64 1.95 g of 3-t-butoxy-L-alanine (melting point 2250C) and 1.95 ml of benzyl chloroformate 2.34 g of crude t-butyl ether of N-benzyloxycarbonyl-L-serine, from which one analogously Example 11.3. (with 1.02 g of isobutyl chloroformate) the mixed in situ Prepares anhydride and this with 2.39 g of crude L-alanyl-L-serine benzyl ester. Hydrochloride (Example 77) reacted (360 ml of methylene chloride), whereby 2.81 g of crude (N-benzyloxycarbonyl-O-t-butyl) -X-seryl-L-alanyl-L-serine benzyl ester of m.p. 127/131 "C".

Analogous to example 11.4. is produced from 2.8 g of this substance and 1.28 g (Benzyloxycarbonyl-amino) -methanphosphonsaeure 2 g of crude monoester, which with petroleum ether is rubbed.

Analogous to example 11.5. prepared from it after hydrogenation (370 ml Methanol-water 3: 1; 0.5 g catalyst) 0.63 g monoester of aminomethanephosphonic acid with O-t-butyl-L-seryl-L-alanyl-L-serine (as an adduct with 2.5 mol of water per mol of substance). Fp. From 1600C, decomp.

Example 80 To 1.89 g of N- (D, L-1-ethoxycarbonyl-ethyl) -L-alanine (m.p. 135/137 ° C) in 70 ml of water and 30 ml of acetone, as well as 2.23 g of NaHOO3 dissolved, dropwise one solution of 5.4 g of benzyl chloroformate in 30 ml of acetone in 2 hours, leave to stir for 3 h (pH kept at 7.5 with NaHCO3!), the acetone is distilled in a vacuum, extract the remaining water solution with ether, provide the water phase with HOl to pH 2, it is then extracted with ethyl acetate, the combined ethyl acetate extracts evaporate in a vacuum and get 1.75 g of crude [N-benzyloxycarbonyl-N- (D, L-1-ethoxycarbonyl-ethyl) ] -L-alanine as a yellow oil.

Analogous to example 11.3. prepared therefrom with 0.73 ml of isobutyl chloroformate in situ the mixed anhydride, leave this with 1.64 g of L-alanyl-L-serine benzyl ester . Hydrochloride (Example 77) react and purify the crude product obtained on the Silica gel column (ethyl acetate as eluent), 1.5 g of [N-benzyloxycarbonyl-N- (D, L-1-ethoxycarbonyl-ethyl)] - L-alanyi-L-alanyl-L-serine-benzyl ester as a viscous, yellowish syrup.

Analogous to example 11.4. one puts this compound with 0.67 g of L-1- (benzyloxycarbonyl-amino) -ethanphosphonic acid around (16 hours of stirring!) whereby 1.64 g of crude monoester fell off.

This is in water. NaHCO3 solution and some acetone dissolved, and this solution extracted several times with ether. The waessr.

Phase is then acidified with HOl, extracted with ethyl acetate and the united, org. The extracts evaporated in a vacuum, leaving 1.2 g of monoester.

Analogous to example 11.5. this is hydrogenated. This gives 0.45 g Monoester of L-1-amino-ethanephosphonic acid with N (D, L-1-ethoxycarboryl-ethyl) -L-alanyl-L-alanyl-L-serine as a dihydrate. Fp. From 1300C, decomp.

Preparation of N- (D, L-1-ethoxycarbonyl-ethyl) -L-alanine: To one Solution of 35 g of L-alanine benzyl ester. p-toluenesulfonate in 300 ml of abs. Tetrahydrofuran and 20.2 g of triethylamine, a solution of 21.8 g of ethyl 2-bromopropionate is added dropwise in 100 ml abs. Tetrahydrofuran, leave 7 days at room temp. stand, vacuum, steam the filtrate, absorbs the evaporation residue in ethyl acetate, extracts this Sol. With 10% water. Citric acid and then with water, after drying the steamed Essigesterloesung in, dissolves the evaporation pressure in 6 N HCl, shakes it Solved with ethyl acetate, makes the water phase alkaline with N32CO), extracted the oil separated out with ethyl acetate and the combined ethyl acetate extracts are steamed in a vacuum. This leaves 10.2 g of an orange-brown liquid, which you can use at the Silica gel column cleans (800 g gel, chloroform as eluant), as a result of which 9.37 g of N- (D, L-1-ethoxycarbonyl-ethyl) -L-alanine benzyl ester are obtained as a yellowish Syrup wins. 5.58 g of this is hydrogenated in 100 ml of methanol-water 2: 1 with 1 g of Pd-C catalyst (10 percent.) 30 min at normal pressure, the filtrate evaporates after the catalyst has been filtered off with suction in a vacuum and rub the remaining material with ether, giving 3 g of the desired Substance of melting point 135 / 1370C incurred.

Example 81 Analogous to example 11.2. obtained from 2.17 g of N- (t-butoxycarbonyl) -L-norvaline with 1.35 g of isobutyl chloroformate in situ the mixed anhydride from which by reaction with 3.3 g of L-norvalyl-L-serine benzyl ester. Hydrochloride (example 70) crude N- (t-butoxycarbonyl) -L-norvalyl-L-norvalyl-L-serine-benzyl ester, after loosening with ether and falling with petroleum ether 3.47 g of this substance from M.p. 112 / 1160C supplies. By reacting this compound with 16 ml of 6N ethereal HOl in 40 ml of ether (20 min at OOC and 3 hours at room temp.) Is obtained after Suction 1.97 g of crude L-norvalyl-L-norvalyl-L-serine benzyl ester. Hydrochloride.

Analogous to example 11.3. is obtained from the reaction of 1.02 g of N-benzyloxycarbonyl-sarcosine with 0.62 ml of isobutyl chloroformate in situ produced mixed anhydride and 1.96 g of L-norvalyl-L-norvalyl-L-serine benzyl ester . Hydrochloride, (after triturating the evaporation residue with ether) 1. 7 g crude N-Benzyloxycarbonyl-sarcosyl-L-norvalyl-L-norva lyl-L-serine benzyl ester of m.p. 165/17000, which after reaction with 0.73 g of L-1- (benzyloxycarbonyl-amino) ethanephosphonic acid analogous to example 11.4. and precipitating the crude monoester thus obtained with petroleum ether (from the concentrated ethyl acetate solution) 1.63 g of this monoester results.

Analogous to example 1.5. 1.6 g of it is hydrogenated (in 300 ml of methanol-water 2: 1), whereby 0.66 g of monoester of L-1-amino-ethanephosphonic acid with sarcosyl-L-norvalyl-L-norvalyl-L-serine arise (as an adduct with 1.5 mol of water and 1 mol of ethanol per mol of substance).

Mp. From 175 ° C, decomp.

Example 82 Analogous to example 11.3. is produced from 2.13 g of crude [N-benzyloxycarbonyl-N- (D, L-4-phenyl-2-n-butyl-L-alanine and 0.78 ml isobutyl chloroformate in situ the mixed anhydride and sets this with 1.82 g of L-alanyl-L-serine benzyl ester . Hydrochloride (Example 77) to give 2.93 g of crude [N-benzyloxycarbonyl-N- (D, L-4-phenyl-2-n-butyl)] -L-alanyl-L-alanyl-L-serine benzyl ester received as oil.

Analogous to example 11.4. is obtained from 2.89 g of this substance and 1.52 g L-1- (benzyloxycarbonyl-amino) -ethanephosphonic acid (using 3 g dicyclohexylcarbodiimide) 3.14 g of crude monoester as oil, of which 3 g as in Example 11.5. be hydrogenated (300 ml methanol-water 3: 1). The water is then steamed at the end. Solution in vacuum a, dissolves the remaining substance in approx. 10 ml of ethanol and falls by adding ether 0.52 g monoester of L-1-amino-ethanephosphonic acid with N- (D, L-4-phenyl-2-n-butyl) -L-alanyl-L-alanyl-L-serine (as an adduct with 2.5 mol of water per mol of substance). Mp. From 145 ° C, decomp.

Preparation of [N-Benzyloxycarbonyl-N- (D, L-4-phenyl-2-nbutyl)] - L-alanine: A solution of 2.67 g of D-2-bromopropionic acid (boiling point 1.5 = 780 ° C.) in 10 ml of water is added dropwise one stirs to a solution of 8.75 g of D, L-2-amino-4-phenyl-n-butane in 35 ml of dioxane 1 hour after, then refluxed for 5 hours, then distilled the Dioxane from, now 35 ml of 2 N NaOH are added while cooling, extracted 3 times with ether, cleans the water.

Phase with HOl, the acidic solution then evaporates in a vacuum and rub the remaining substance 3 times with ether.

The solid substance obtained in this way is rubbed with 50 ml of ethanol, Then sucks off the undissolved NaCl, the ethanol mother liquor evaporates in a vacuum and rub the evaporation residue 3 times with ether, giving 2.9 g of crude N- (D, L-4-phenyl-2-n-butyl) -L-alanine with a melting point of 141/142 ° C.

2.57 g of it and 5.5 ml of triethylamine in 100 ml of abs. Dimethylformamide at OOC, 5.6 ml of 50 percent are added. Solution of benzyl chloroformate in toluene (in 1 hour) let stir for 15 min at OOC and 5 hours at 23 "C, now sucks off, the filtrate evaporates in a vacuum, adds the evaporation residue with 30 ml of water, adjusts to pH 10 with 2N NaOH, extracted 3 times with ether, evaporated the combined ether extracts and thus gets 4 oily residue. This one taken up in 40 ml of ether, this solution is shaken with 0.5 N Hol and with water off, the ether solution evaporates and thus receives 2.3 g of the desired substance as oil.

Example 83 Analogous to example 11.3. is made from 3.4 g of crude tN-benzyloxycarbonyl-N-D, L- (a-methyl-benzyl) ] glycine and 1.45 g of isobutyl chloroformate in situ the mixed anhydride forth, which after reaction with 3.15 g of L-alanyl-L-serine benzyl ester. Hydrochloride (Example 77) 5.15 g of crude product are which, after purification on the silica gel column 2.3 g of white powder provides, namely [N-Benzyloxycarbonyl-N-D, L- (o-methyl-benzyl) glycyl-L-alanyl-L-serine benzyl ester.

Analogous to example 11.4. bring 0.84 g of it with 0.52 g of L-1- (benzyloxycarbonyl-amino) -ethanephosphonic acid (with 1.6 g dicyclohexylcarbodiimide; stirring for 21 hours in 50 ml abs.

Pyridine) 1.16 g of crude monoester as a white powder.

Analogous to example 11.5. obtained after hydrogenation of 1 g of this monoester (75 ml methanol-water 4: 1, 15 min), evaporation of the water. Solved in vacuum and rubbing of the evaporation residue with ether 0.37 g of monoester of L-1-aminoethanephosphonic acid with N-D, L-1-phenylethyl-glycyl-L-alanyl-L-serine (as an adduct with 1.5 mol of water and 1/2 mol of ethanol per mol of substance). Mp. From 156 ° C, decomp. a) Preparation of [N-D, L- (α-methyl-benzyl) -N-benzyloxycarbonyli-glycine: 13.9 g of bromessl acid in 44 ml of water are mixed with aq.

Na2C03 neutralized, then 36.3 g of D, L - methylbenzylamine, in 180 ml of dioxane dissolved, added, stirred for 30 minutes, refluxed for 5 hours, the dioxane is distilled off in vacuo, 150 ml of 2 N NaOH are added while cooling with ice, and the mixture is extracted with ether, represents the water.

Phase with HOl to pH 1, evaporate in a vacuum, stir the dry Evaporation residue with 160 ml abs. Ethanol, sucks off and the filtrate evaporates in a vacuum; now rub the remaining material with it Ether, sucks the crystals obtained and thus gets 13 g of crude N-D, L- (1-phenyl-ethyl) -glycine . Hydrochloride of m.p. 169 / 1730C. b) 2.5 g of it is dissolved in 40 ml of water with 4 N NaOH to pH 10, 2.85 ml of benzyl benzylic acid ester are added dropwise at OOC in 5 hours one, the pH value is always kept at 9-10 and then extracted with ether. The water phase is adjusted to pH 1, extracted with methylene chloride and obtained after its evaporation 1.27 g of the desired substance as a yellowish syrup.

Example 84 Analogously to Example 83 b, 9.67 g of N-cyclohexylglycine are obtained . Hydrochloride with 13.25 ml benzyl chloroformate (50 ml water; extraction the acidic water solution with ethyl acetate, instead of methylene chloride) 3.85 g of crude (N-benzyloxycarbonyl-N-cyclohexyl) -glycine as a colorless syrup.

Analogous to example 11.3. arises in situ from 3.85 g of this substance and 1.82 ml of isobutyl chloroformate the mixed anhydride from which after Reaction with 3.93 g of L-alanyl-L-serine benzyl ester. Hydrochlorld 4.91 g raw (N-Benzyloxycarbonyl-N-cyclohexyl) -glycyl-L-alanyl-L-serine benzyl ester. M.p. 171/17500.

Analogous to example 11.4. arise from 2.16 g of this substance and 1. 6 g of L- 1 - (benzyloxycarbonyl-amino) -ethanephosphonic acid 2.54 g of crude monoester, of the O.54 g analogous to example 11.5. is hydrogenated (30 ml of methanol-water 4: 1, 0.05 g Pd-C catalyst, 40 min hydrogenation time).

After evaporation of the water. Loosening and grinding those who remained Substance with ether is obtained 0.15 g of monoester of L-1-amino-ethanephosphonic acid with N-cyclohexylglycyl-L-alanyl-L-serine (as an adduct with 2.5 mol of water per mol of substance). Fp. From 1700C, dec.

Example 85 To 1.13 g of crude D, L-3,4-dehydroproline (m.p. 2430C, decomp.) in 40 ml 1 N, aq. NaHCO3 solution one drips in 4 hours 4.7 ml of a 50 per cent. Solution of benzyl chloroformate in toluene, leave to stir for 1 hour, extracted 3 times with ether, then makes the water phase acidic (pH 2), extracted 3 times with methylene chloride and after it has evaporated it yields 2.48 g of crude D, L- (N-benzyloxycarbonyl) -3,4-dehydroproline as oil.

2.47 g of this substance are given analogously to Example 11.3. with 1.4 ml isobutyl chloroformate in situ the mixed anhydride, which with 3.04 g of L-alanyl-L-serine-benzyl ester. Hydrochloride (Example 77) 5 g of crude D, L- (N-benzyloxycarbonyl) -3, 4-dehydroprolyl-L-alanyl-L-serine benzyl ester and which, after trituration with ether, melts at 154/158 ° C (3.8 g).

Analogous to example 11.4. give 2.97 g of this compound with 1.61 g (benzyloxycarbonyl-amino) methanephosphonic acid (after concentration of the ethyl acetate solution) 2.3 g of crude monoester (Mp. 134/140 "C). 0.55 g of this is suspended in 2.3 ml of anisole, and added dropwise at 0 ° C. 7.6 ml of methanesulfonic acid, stir for 30 min, precipitate with 100 ml of ether, pour in The ether stand for 1 hour, stir the sediment 3 more times with ether and then rub it with isopropanol, with 0.4 g of monoester of amino-methanephosphonic acid with D, L-3,4-dehydroprolyl-L-alanyl-L-serine remain (as an adduct with 2 mol methanesulfonic acid, 1 mol water and 1/3 mol isopropanol). M.p. 78 / o00C (decomp.) Example 86 Analogous to example 11.3. is prepared from 4.68 g of [N- (D, L-aethoxycarbonyl) -benzyl-N-benzyloxycarbonyl] -L-alanine and 1.65 ml isobutyl chloroformate (stirring for 30 min at -20 ° C) in situ the mixed anhydride, which after reaction with 3.66 g of L-alanyl-L-serine benzyl ester Hydrochloride (Ex. 77) gives 5.7 g of crude product. After cleaning on the silica gel column (Mobile phase: ethyl acetate and 5% heptane), 2.26 g of [N- (D, L-phenylethoxycarbonyl-methyl) -N-benzyloxycarbonyl] -L-alanyl-L-alanyl-L-serine benzyl ester are obtained therefrom of m.p. 54 / 580C.

Analogous to example 11.4. give 1.46 g of this substance with 0.9 g L-1- (Benzyloxycarbonyl-amino) -ethanphosphonic acid (using 1.42 g of dicyclohexylcarbodlimide) 1.85 g of crude monoester (after trituration with petroleum ether), of which 1.6 g after hydrogenation analogous to example 11.5. (0.15 g 10 8 Pd-C catalyst, 100 ml methanol-water 4: 1) and grinding the evaporated water. Solved with ether 0.55 g of monoester of L-1-amino-ethanephosphonic acid with N- (D, L-phenyl-ethoxycarbonyl-methyl) -L-alanyl-L-alanyl-L-serine (as adduct with 1.5 mol of water). Mp. From 160 ° C, decomp.

Production of crude [N- (D, L-phenyl-ethoxycarbonylmethyl) -N-benzyloxycarbonyl] -L-alanine: To a solution of 8.75 g of L-alanine benzyl ester. p-Toluenesulfonate in 75 ml of tetrahydrofuran and 6.9 ml of triethylamine are added dropwise a solution of 7.3 g of D, L-a-bromo-phenylacetic acid ethyl ester (Kp0.5 = 98 / 1000C) in 75 ml of tetrahydrofuran, leave to stand for 5 days, suction off, evaporate the filtrate in a vacuum, dissolves the evaporation residue in ethyl acetate, shakes with 1O per cent. Citric acid and then with water, evaporate the ethyl acetate (in a vacuum) , dissolve the remaining substance in 100 ml of 6 N HCl, extracted with ethyl acetate, makes the water phase alkaline with arC03, extracted immediately with ethyl acetate and steam this org. Phase in a vacuum, with 9.14 g of orange Oil remain.

After cleaning on the silica gel column (ethyl acetate-heptane serves as the mobile phase 1: 3) you get 2.19 g of yellowish oil, namely N- (D, L-phenyl-ethoxycarbonylmethyl) -L-alanine benzyl ester.

30 g of this substance are hydrogenated with 6 g of 10 at normal pressure for 25 minutes % Pd-C catalyst in 1 liter of methanol-water 5: 1, then filtered off with suction and the filtrate evaporated in a vacuum, rubs the residue obtained in this way with ether and thus achieves one Yield of 19 g of N- (D, L-phenyl-ethoxycarbonylmethyl) -L-alanine, melting point 148 / 1510C. 2.5 g of this are dissolved in 30 ml of dimethylformamide, 5.5 ml of triethylamine are added and added dropwise add 2.8 ml benzyl chloroformate in 1 hour at 0 ° C, stir for 24 hours, sucks off, evaporates the filtrate in a vacuum, dissolves the evaporation residue in water, makes slightly alkaline, extracted with ether, acidifies the water phase (pH 1), extracted with methylene chloride and obtained after its evaporation 2.04 g of the desired Compound as yellow syrup.

Example 87 In a suspension of 5.25 g of D, L- (3-benzyloxyamino-2-amino) propionic acid 13 ml of tetramethylammonium hydroxide (as a 20% sol. in methanol), adds 6.23 g of N- (benzyloxycarbonyloxy) to the resulting solution -succinimide (mp. 80 / 820C), holds 6 hours at 500C, leaves overnight at 230C stand, the solution evaporates in a vacuum, adds 80 ml of water to the residue, extracted with ether, evaporate the combined ether extracts, rub the evaporation residue with petroleum ether to give 1.84 g of crude D, L- (3-benzyloxvamino-2-benzyloxycarbonylamino) propionic acid of m.p. 102 / 1070C.

The waessr. Phase is acidified with HOl, with a further 4.5 g of the the same compound are obtained (melting point 107/108 ° C.).

Dissolve 3.44 g of this substance in 21 ml of formic acid OOC 7 ml of acetic anhydride, stir for 3 hours, then add about 50 ml of ice water to, the precipitated substance extracted with ethyl acetate, this org. Sol. in a vacuum, rubs the evaporation residue with ether / petroleum ether and wins so 3.04 g of crude D, L- [3- (N-benzyloxy-N-formyl) -amino-2-benzyloxycarbonyl-amino] -propionic acid of m.p. 1.32 / 1370C.

Analogous to example 11.3. is made at -20 ° C in situ from 1.86 g of this Substance and 0.7 ml of isobutyl chloroformate and the mixed anhydride sets this with 1.51 g of L-alanyl-L-serine benzyl ester. Hydrochloride (example 77) to, whereby (after recrystallization of the reaction product from ethyl acetate) 0.72 g D, L- [3- (N-benzyloxy-N-formyl) -amino-2-benzyloxycarbonyl-amino] -propionyl-L-alanyl-L-serine-benzyl ester can be obtained. After cleaning, the ethyl acetate mother liquor is obtained from the Silica gel column (40 g gel and ethyl acetate as eluent) another 0.66 g of the same Substance.

Analogous to example 11.4. is obtained from 1.38 g of this substance and 0.53 g of (benzyloxycarbonylamino) methanephosphonic acid 1.25 g of crude monoester. Analogue Example 11.5. are made from 1.2 g of this substance by hydrogenation (0.3 g catalyst, 200 ml ethanol-water 3: 1) 0.4 g monoester of aminomethanephosphonic acid with D, L- [3- (N-Formyl) -hydroxyamino-2-amino] -propionyl-L-alanyl-L-serine (as an adduct with 1 mol Ethanol and 1 mol of water per mol of substance).

Mp. From 140 ° C, decomp.

Example 88 88.1.

Analogous to example 1.3. one uses Na NG-Tris-benzyloxycarbonyl-L-arginine with L-Alanyl-L-serine benzyl ester in a methylene chloride-dimethylformamide mixture (1: 1) around. The reaction mixture is evaporated, mixed with water and the product extracted with ethyl acetate. You get Nα, NG-Tris-Benzyloxycarbonyl-L-arginyl-L-alanyl-L-serine benzyl ester, that is processed further without additional cleaning.

88.2.

The above section 88.1. product obtained is analogous to the example 49.2. reacted with benzyloxycarbonylamidomethanephosphonic acid. The crude phosphonic acid monoester is hydrogenated in glacial acetic acid over palladium (10%) on charcoal. The catalyst will filtered off, the filtrate evaporated and the residue dissolved in water. The solution is freeze-dried, the residue is stirred with ethanol and the precipitate sucked off. L-arginyl-L-alanyl-O- (aminomethanephosphonyl) -L-serine is obtained as Monoacetate, melting point 140 ° C. (decomposition). 9% ethanol and 8% still adhere to the product % Water.

[α] D20 = + 1.8 ° (c = 1, H2O) Example 89 89.1.

Analogous to example 1.3. one puts N-benzyloxycarbonyl-sarcosine with L-alanyl-L-serine-p-nitrobenzyl ester hydrochloride around.

The obtained N-benzyloxycarbonyl-sarcosyl-L-alanyl-L-serine-p-nitrobenzyl ester is according to examples 45.2. and 45.3. with 1R, S-1- (benzyloxycarbonyl-amido) ethanephosphonic acid implemented and freed from the protective groups by hydrogenation. Sarcosyl-L-alanyl-O- (1R, S-1-aminoethanephosphonyl) -L-serine is obtained as monohydrate of melting point 164-16900 (decomposition) [α] D20 = -24.7 ° (c = 1, H2O) Example 90 Using N-benzyloxycarbonylaminoisobutyric acid instead of N-benzyloxycarbonylsarcosine As a starting product, aminoisobutyryl-L-alanyl-O- (1R, S-aminoethanephosphonyl) -L-serine is obtained analogously to Example 89 as a monohydrate, which melts from 180 ° C with decomposition.

[a] = +15.70 (c = 1, H20) Example 91 Obtained analogously to Example 89 using N-benzyloxycarbonyl-3-methyl-sulfonyl-L-alanine instead of the Sarcosine derivatives and benzyloxycarbonylamidomethanephosphonic acid as the phosphonic acid component (3-Methylsulfonyl) -L-alanyl-L-alanylO (aminomethanphosphonyl) -L-serine as monohydrate from m.p. 222-225 ° C (decomposition) [aj20 = + 4.7 ° (c = 1, H2O) example 92 Example 89 is obtained using N-benzyloxycarbonyl-γ-benzyl-L-glutamic acid instead of N-benzyloxycarbonylsarcosine and IR, S-1-benzyloxycarbonylamidoethanephonic acid as the phosphonic acid component L-glutamyl-L-alanyl-O- (1R, S-1-aminoethanephosphonyl) -L-serine as a trihydrate, which melts with decomposition from 163 ° C.

[α] D20 = + 2.5 ° (c = 1, H2O) Example 93 N-benzyloxycarbonyl-L-proline is used instead of N-benzyloxycarbonylsarcosine one obtains analogously to Example 89 after the hydrogenolytic Cleavage of the benzyloxycarbonyl or benzyl ester groups, a crude product which is in Water is dissolved and freeze-dried. This product becomes hot in methanol dissolved and cooled. The deposited precipitate is filtered off with suction. You get L-prolyl-L-alanyl-O- (1R, S-1-aminoethanephosphonyl) -L-serine.

10% water adheres to the product. From 17500 it melts with decomposition.

20 = 37.10 (c = 1, H2O) D Example 94 Analogously to example 89 one obtains using D, L-N-benzyloxycarbonyl-α-tert-butylglycine instead of the Sarcosine derivatives and benzyloxycarbonylamidomethanephosphonic acid as the phosphonic acid component a crude product which is purified and separated into the diastereomers as follows.

The filtrate of the reaction mixture from the hydrogenation is up to concentrated a few milliliters and mixed with ethanol. Leave in the refrigerator overnight stand and then sucks off the failed product. This is done again for cleaning dissolved in a little water and precipitated by adding ethanol. You get that first diastereomers a-tert-butylglycyl-L-alanyl-O- (aminomethanephosphonyl) -L-serine of m.p. 250-2550C (destruction). The HPLC analysis shows an isomer ratio from 19:81. [α] 57820 = = 6.2 ° (c = 1, H2O). The other diastereomer becomes as follows isolated. The filtrate from the first precipitate is evaporated to dryness and thoroughly cleaned Purified chromatography over 750 ml Sephadex G-10 with water as the eluent. The peptide-containing fractions are concentrated and the product by adding Ethanol precipitated. The second diastereomer of a-tert.-Butylgylcyl-L-alanyl-O- (aminomethanphosphonyl) -L-serine is obtained of m.p. 270-272 ° C (decomposition).

The KPLC analysis shows an isomer ratio of 81:18.

[«] 20 = -54.60 (c = 1, H2O) Example 95 obtained analogously to Example 89 using N-benzyloxycarbonyl-3-cyano-L-alanine instead of the sarcosine derivative and benzyloxycarbonylamidomethanephosphonic acid as the phosphonic acid component Crude product obtained by chromatography on the weakly acidic ion exchanger IR-45 is cleaned. The column is first washed with water, then the product eluted with 1 N formic acid. L-2,4-diaminobutyryl-L-alanyl-o- (aminomethanephosphonyl) -L-serine is obtained of m.p. 143-175 ° C (decomposition). 1.5 mol of formic acid and 1 mol adhere to the product Water on.

[α] D20 = -5.6 ° (c = 1, H2O) Example 96 96.1.

12.7 g of N-tert-butoxycarbonyl-L-alanyl-L-alanine are obtained analogously to the example 48.2 .. with 20 g of L-serine p-nitrobenzyl ester in the presence of 11.4 g of dicyclohexylcarbodiimide and 15.4 g of 1-hydroxybenzotriazole reacted. The reaction mixture is filtered, the filtrate was evaporated and taken up in ethyl acetate. It crystallizes part of the product from (19 g) and is filtered off. The filtrate is each with Sproz. Citric acid solution and Sproz. Sodium hydrogen carbonate shaken in water, washed with water, dried and evaporated. This part of the product (6.9 g) and the part obtained earlier are combined and recrystallized from ethanol. 18.8 g of N-tert-butoxycarbonyl-L-alanyl-L-alanyl-L-serine-pnitrobenzyl ester are obtained, which, according to the thin-layer chromatogram, is good enough for further processing.

96.2.

The under circumcision 96.1. tripeptide obtained is according to Example 1.2. treated with essential hydrochloric acid. L-alanyl-L-alanine-L-serine-p-nitrobenzyl ester is obtained Hvcrochlor d, which is used further without purification.

96.3.

That in the previous one. Section obtained tripeptide hydrochloride is analogous Example 1.3. reacted with N-benzyloxycarbonyl-sarcosine. N-Benzyloxycarbonyl-sarcosyl-L-alanyl-L-alanyl-L-serine-p-nitrobenzyl ester is obtained. which is pure enough for further processing.

96.4.

The in section 96.3. The tetrapeptide described is analogous to the example 49.2. reacted with 1R, S-1- (benzyloxycarbonylamido) ethanephosphonic acid. With Ethyl acetate phase washed with 2 N hydrochloric acid is dried and evaporated.

For purification, the residue is recrystallized from ethanol. Man gets N-Benzyloxycarbonyl-sarcosyl-L-alanyl-L-alanyl-O- (1R, S-1- (benzyloxycarbonylamido) ethanphosphonyl) -L-serine-p-nitrobenzyl ester, which, according to the thin-layer chromatogram, is pure enough for further processing.

96.5.

5.7 g of the compound obtained above (Section 96.4.) Are in 400 ml of ethanol and 100 ml of water are dissolved and hydrogenated over 1 g of palladium (10%) on charcoal. The catalyst is filtered off, the filtrate is evaporated and the residue is removed Recrystallized water and methanol. You get 1.5 g (43 t) Sarcosyl-L-alanyl-L-alanyl-O- (1R, S-1-aminoethanphosphonyl) -L-serine, mp 178-185 ° C (decomposition). The product contains 3.5 mol of water.

20 = 60.00 (c = 1, H20) D Example 97 97.1.

37 g of N-propylglycine hydrochloride are made analogously to Example 6.1, with benzyl chloroformate implemented. You get N-Benzyloxycarbonyl-N-propylglycine as Del, that without additional Cleaning is implemented further.

97.2.

A solution of 6.0 g of N-benzyloxycarbonyl-N-propylglycine in 20 ml Methylene chloride is mixed with a solution of 2.9 g of N-hydroxysuccinimide in 10 ml of tetrahydrofuran united.

The mixture is cooled to -10 ° C and treated with a solution of 5.2 g Dicyclohexylcarbodiimide in 10 ml of methylene chloride was added. The mixture is stirred 2 hours at -100C, 1 hour at 00O and let stand overnight at room temperature. The precipitate is filtered off, the filtrate is evaporated and the remaining one Oil taken up in ether.

Some precipitate is filtered off, the ether phase with sodium hydrogen carbonate solution and water washed and dried. After evaporation, 6.8 g (81 t) remain of the oily N-benzyloxycarbonyl-N-propyl-glycine-N-hydroxysuccinimide ester, without further purification is used.

97.3.

51 g of tert-butoxycarbonyl-L-alanyl-L-serine benzyl ester are analogous Example 45.2. reacted with benzyloxycarbonylamidomethanephosphonic acid. The raw product is dissolved in methylene chloride and the solution with a total of 3 liters Water washed. The product crystallizes out of the methylene chloride phase. Man receives 40 0 g tert-butoxycarbonyl-L-alanyl-O- (benzyloxycarbonyl-2midomethanphosphonyl) -L-serine benzyl ester, which is pure enough for further processing.

97.4.

20 g of the above section 97.3. obtained connection are in 100 ml of dry tetrahydrofuran dissolved and under ice cooling with 150 ml of 6 N ethereal Hydrochloric acid added. The mixture is stirred for 30 minutes while cooling with ice for 1 hour Room temperature and then sucks off the precipitated crystals. These crystals become dissolved in ethanol and propylene oxide is added to the mixture up to pH 6.

The solution is somewhat concentrated and after storing the Mixture in the refrigerator precipitated crystals are suctioned off. You get 16 g (96%) L-Alanyl-O- (benzylOxycarbonylamidomethanphosphonyl) -L-serine benzyl ester, which still shows traces of impurities in the thin-layer chromatogram, but is pure enough for further processing.

97.5.

8.4 g of the in section 97.4. Dipeptldesters obtained and 4.3 g of sodium hydrogen carbonate are dissolved in a mixture of 120 ml of ethanol and 60 ml of water and stirring with a solution of the in section 97.2. obtained succinimide ester added. That The mixture is stirred for 2 hours at room temperature and then the ethanol is distilled off.

The aqueous phase is extracted 3 times with ethyl acetate and the organic phase is washed with 2N hydrochloric acid and water. The organic Phase is dried and evaporated. The residue is recrystallized from ethanol. 9.3 g (75 t) of N-benzyloxy-N-propylglycyl-L-alanylO- (benzyloxycarbonylamidomethanephosphonyl) are obtained -L-serine benzyl ester, which is further processed without additional cleaning.

97.6.

9 g of the product obtained in the previous section are analogous Example 45.3. hydrogenated. The crude product is dissolved in a little water, the solution mixed with a lot of ethanol and stored in the refrigerator overnight. The fancy ones Crystals are sucked off. 3.7 g (81%) of N-propyl-glycyl-L-alanyl-O- (aminomethanephosphonyl) -L-serine are obtained of m.p. 160-165 ° C (decomposition). The product contains 0.5 mol of water.

[α] D20 -27.4 ° (c = 1, H2O) Example 98 Obtained analogously to Example 97 using N-benzyloxycarbonyl-N-methyl-L-alanine-N-hydroxysuccinimide ester instead of the N-propylglycine derivative N-methyl-L-alanyl-L-alanyl-O- (aminomethanphosphonyl) -L-serine of m.p. 169-186 ° C (decomposition). 0.5 mol of water adheres to the product.

[a20 = -22.30 (c = 1, H2O) Example 99 99.1.

N-tert-butoxycarbonyl-S-methyl-L-cysteine is obtained analogously to Example 97.2. by reaction with N-hydroxysuccinimide into the N-tert-butoxycarbonyl-s-methyl-L-cysteine-N hydroxysuccinimide ester transferred. The crude product can be recrystallized from isopropanol and is pure enough for further processing.

99.2.

Used instead of N-benzyloxycarbonyl-N-propylglycine-N-hydroxysuccinimide ester in Example 97.5. the N-hydroxysuccinimide ester obtained above (Section 99.1.), this is how you get N-tert-butoxycarbonyl-S-methyl-L-cysteinyl-L-alanyl-O- (benzyloxycarbonylamidomethanephosphonyl) -L-serine benzyl ester, which is further processed without additional cleaning.

99.3.

4.9 g of the protected tripeptide obtained above are in 200 ml Ethanol and 100 ml of water and dissolved over 1 g of pre-hydrogenated palladium (10%) Hydrogenated coal. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in 10 ml of trifluoroacetic acid, the solution for 45 minutes Stirred room temperature and finally evaporated. The residue will be in little Dissolved water and over a column with the weakly basic ion exchanger Amberlite IRA-68 in the acetate form chromatographed with water as the eluent. The product-containing fractions are combined and evaporated. The residue is recrystallized from water / ethanol. 1.2 g (44%) of S-methyl-L-cysteinyl-L-alanyl-O- (aminomethanephosphonyl) -L-serine are obtained of m.p. 178-1810C (decomposition). The product contains 3% water.

[α] 57820 = + 13.5 ° (c = 1, H2O) Example 100 0.5 g of the in Example 99.3. obtained product are dissolved in 7.5 ml of glacial acetic acid and with 0.23 ml 30%

Hydrogen peroxide added. After 80 min, the oxidation is according to the thin-layer chromatogram completely, the solvent is distilled off and the residue by adding brought to crystallization by ethanol with stirring.

The precipitate is isolated. 0.46 g (88 t) of S-methylsulfinyl-L-alanyl-L-alanyl-O- (aminomethanephosphonyl) -L-serine are obtained of m.p. 175-1780C (decomposition).

[«] 20 = + 11.8 ° (c = 1, H20) 578 Example 101 101.1.

Analogous to example 97.2. is obtained starting from N-benzyloxycarbonyl-L-thiazolidine- 4-carboxylic acid, N-benzyloxycarbonyl-L-thiazolidine-4-carboxylic acid, N-hydroxysuccinimide ester, as an oil that can be used further without purification.

101 .2.

Is used instead of the N-benzyloxycarbonyl-N-propylglycine-N-hydroxyl succinimide ester in Example 97.5. the N-hydroxysuccinimide ester obtained above (Section 101.1.) the starting product is N-benzyloxycarbonyl-L-thiazolidine-4-carbonyl-L-alanyl-O- (benzyloxycarbonylamidomethanphosphonyl) -L-serine benzyl ester, which, according to the thin-layer chromatogram, is pure enough for further processing.

101.3.

2.7 g of the compound obtained above are in 4 g of anisole and 25 ml a 40 percent Solution of hydrogen bromide dissolved in glacial acetic acid. The solution will be Stirred for 6 hours at room temperature and then mixed with ether. The precipitation is filtered off, dried and over a column with 30 ml of the weakly basic Ion exchanger Amberlite IRA-68 (acetate form) chromatographed with water as the eluent. Fractions 2 and 3 contain the mixed product. They are evaporated and the residue crystallized by adding ethanol.

You get 0.66 g (49%) L-thiazolidine-4-carbonyl-L-alanyl-O- (aminomethanphosphonyl) -L-serine. Acetate of m.p. 139-142 ° C (decomposition).

[a] ZO = 62.8 "(c = 1, H20) Example 102 102.1.

L-5, 5-dimethyl-thiazolidine-4-carboxylic acid is analogous to Example 6.1. converted into N-benzyloxycarbonyl-L-5,5-thiazolidine-4-carboxylic acid, which as an oil is obtained.

102.2.

The thiazolidine carboxylic acid derivative obtained above is analogous to the example 48.2. reacted with L-alanyl-L-serine benzyl ester hydrochloride. The raw product will by chromatography on silica gel and ethyl acetate as eluent obtained as a syrup1 which is immediately reacted further.

102.3.

The protected tripeptide obtained above is analogous to Example 45.2. reacted with benzyloxycarbonylamidomethanephosphonic acid. N-Benzyloxycarbonyl-L-5,5-dimethylthiazolidine-4-carbonyl-L-alanyl-O- (benzyloxycarbonylamidomethanephosphonyl) -L-serine benzyl ester is obtained as a syrup, which without further purification analogous to Example 101.3. with hydrogen bromide is treated in glacial acetic acid.

L-5,5-dimethyl-thiazolidine-4-carbonyl-L-alanyl-O- (aminomethanephosphonyl) -L-serine is obtained mp 171-173 ° C (decomposition). According to the NMR spectrum, the substance still contains 10% aminomethane phosphonic acid.

[α] D20 = -41.3 ° (c = 1, H2O) Example 103 Analogous to Example 97 obtained using the N-benzyloxycarbonyl-O-tert-butyl-L-threonine-N-hydroxysuccinimide ester instead of the N-propylglycine derivative O-tert-butyl-L-threonyl-L-alanyl-O- (aminomethanphosphonyl) -L-serine of m.p. 246-247 ° C (decomposition).

[α] D20 = - 10.3 ° (c = 1, H2O) Example 104 104.1.

4.4 g of L-pyro-glutamic acid-2,4,5-trichlorophenyl ester are in a Mixture of 8 ml of dimethylformamide and 40 ml of dry tetrahydrofuran dissolved and with 1.36 g of N-methylmorpholn and a solution of 4.16 g of L-alanyl-L-serine-p-nitrobenzyl ester hydrochloride added in 16 ml of dimethylformamide and ÖO ml of tetrahydrofuran. The mix will 4 hours smelled, left to stand overnight and 3 hours stored in the fridge. The precipitated crystals are filtered off with suction and dried. You get 4.5 g (75%) L-pyro-glutamyl-L-alanyl-L-serine-p-nitrobenzyl ester which is sufficiently pure for further processing.

104.2.

The product obtained above is analogous to Example 45.2. with 1R, S-1- (benzyloxycarbonylamido) ethanephosphonic acid implemented and according to Example 45.3. hydrogenated. You get L-pyro-glutamyl-L-alanyl-O- (1R, S-1-aminoethanephosphonyl) -L-serine of m.p. 185-1870C (decomposition). The product contains 5 mol of water.

[Qj D0 = -11 90 (c = 1, H2O) Example 105 105.1.

11 g of N-benzyloxycarbonyl-L-alanine are dissolved in 150 ml of dry dimethylformamide dissolved and mixed with 38.3 ml of 1-iodo? ropan. Be under ice cooling and stirring 6.6 g of sodium hydride added in portions. After 1 hour at 0 ° C, 1 hour at Room temperature and 3 hours at 50 ° C, the reaction solution is poured into 3 liters of an ice / water mixture, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and evaporated. The raw product is by chromatography on silica gel with ethyl acetate / ligroin (1: 5) purified as an eluent.

14.2 g (94 tons) of oily N-benzyloxycarbonyl-N- (1-propyl) -L-alanyl- (1-propyl) ester are obtained.

105.2.

14.1 g of the (1-propyl) ester obtained above are dissolved in 36 ml of acetone dissolved and treated with 46 ml of 1 N NaOH.

After standing overnight, the acetone is distilled off, the aqueous Phase extracted with ethyl acetate, filtered, acidified with 2N hydrochloric acid and the product extracted with ethyl acetate. The extract is dried and evaporated. There remain 13 g (100%) oily N-benzyloxycarbonyl-N- (1-propyl) -L-alanine, which analogously to the corresponding glycine derivative according to Examples 97.2., 97.5. and 97.5. will continue to be implemented.

N- (1-propyl) -L-alanyl-L-alanyl-O- (aminomethanephosphonyl) -L-serin monohydrate is obtained of m.p. 200-2050C.

[a] ZO = 26.90 (c = 1, H20) Example 106 106.1.

5.26 g of N-benzyloxycarbonyl-D, L-pipecolinsaeure are analogous to the example 1.3. reacted in methylene chloride with L-alanyl-L-serine benzyl ester hydrochloride. The crude product is chromatographed on 750 g of silica gel with ethyl acetate / methylene chloride or pure ethyl acetate is chromatographed as the eluent. You get 5.9 g N-Benzyloxycarbonyl-D, L-pipecolyl-L-alanyl-L-serine benzyl ester, which is used for the Processing is pure enough.

106.2.

The product obtained above is analogous to Example 49.2. with N-benzyloxycarbonylamidomethanephosphonic acid implemented.

The product obtained is according to Example 45.3. hydrogenated.

The crude product is purified by recrystallization from methanol. D, L-pipecolyl-L-alanyl-O- (aminomethanephosphonyl, -L-serine, melting point 178 ° C.) is obtained (Decomposition). 8 z of water adhere to the product.

[aJD20 = -12.9 ° (c = 1, H20) Example 107 107.1.

7 .. 53 g of N-benzyloxycarbonyl-L-norvaline are analogous to Example 1.3. reacted with L-norvalyl-L-serine benzyl ester hydrochloride. The crude product is made from Recrystallized ethanol.

11.4 g (74%) of N-benzyloxycarbonyl-L-norvalyl-L-norvalyl-L-serine benzyl ester are obtained from m.p. 146-147 ° C.

107.2.

5.1 g of the protected tripeptide obtained above are analogous to the example 49.2. reacted with 3.1 g of IR-1- (benzyloxycarbonylamido) ethanephosphonic acid. That The crude product obtained is recrystallized from ethanol and a little water. You get 3.8 g (51 C.) N-Benzyloxycarbonyl-L-norvalyl-L-norvalyl-0- (1R-1- (Benzyloxycarbonylamido) ethanphosphonyl) -L-serine benzyl ester. According to the thin-layer chromatogram, the product contains some more dicyclohexylurea and is converted further without additional purification.

107.3.

3.6 g of the product obtained above are according to Example 45.3. hydrogenated. 1.3 g (66%) of L-norvalyl-L-norvalyl-O- (1R-1-aminoethanephosphonyl) -L-serine are obtained of m.p. 216-220 ° C (decomposition).

[α] D20 = + 9.7 ° (c = 1.H2O) Example 108 Analogous to example 107.2. and 107.3. obtained using 1S-1- (benzyloxycarbonylamido) ethanephosphonic acid instead of the corresponding 1R isomer L-norvalyl-L-norvalyl-O- (1S-1-aminoethanephosphonyl) -L-serine as a dihydrate, melting point 184 ° (decomposition).

[Q] 0 ° + 7.9 ° (c = 1, H2O) Example 109 Starting from the starting materials N-tert-butoxy-L-proline, L-serine benzyl ester hydrochloride, N-benzyloxycarbonyl-L-proline is set analogously to Examples 55.1. and 55.2. the protected tripeptide N-benzyloxycarbonyl-L-prolyl-L-prolyl-L-serine benzyl ester from which one can, analogously to Examples 55.3. and 55.4. by reaction with N-benzyloxycarbonylamidomethanephosphonic acid and hydrogenation L-prolyl-L-prolyl-O- (aminomethanephosphonyl) -L-serine, mp 165-170 ° C (Decomposition). 12% water adheres to the product.

[α] D20 = -81.9 ° (c = 1, H2O) Example 110 If N-benzyloxycarbonyl-L-proline in Example 109 is replaced by N-benzyloxycarbonyl-L-alanine, L-alanyl-L-prolyl-O- (aminomethanephosphonyl) -L-serine of melting point 2340C is thus obtained (Decomposition). The product contains 10% water.

[a] ZO = -54.8 ° (c = 1, H20) D Example 111 By using N-benzyloxycarbonyl-sarcosine instead of N-benzyloxycarbonyl-L-proline one obtains sarcosyl-X-prolyl-O- (aminomethanphosphonyl) -L-serine analogously to Example 109, which melts from 164 ° C with decomposition.

[α] D20 = -53.6 ° (c = 1, H2O) Example 112 N-Benzyloxycarbonyl-L-seryl-L-alanine benzyl ester are analogous to example 1.4. implemented with methanephosphonic acid.

Hydrogenation of this product according to Example 1.5. supplies O- (methanephosphonyl) -L-seryl-L-alanine, that melts at 280 ° C with decomposition.

[α] D20 = 21.50 (c = 1, H20) Example 113 Analogous to example 62 obtained using methanephosphonic acid as the phosphonic acid component O- (methanephosphonyl) -L-seryl-L-proline, melting point 120-130 ° C (decomposition). The product contains 4% water.

Example 114 Starting from the starting materials N-benzyloxycarbonyl-L-alanine, N-tert-butoxycarbonyl-sarcosine and L-serine-pnitrobenzyl ester are obtained analogously the examples 55.1. and 55.2. the protected tripeptide N-benzyloxycarbonyl-L-alanyl-sarcosyl-L-serine-p-nitrobenzyl ester, that by reaction with 1R, S-1- (Benzyloxycarbonylamido) ethanphosphonic acid and then Hydrogenation analogous to Examples 55.3. and 55.4. L-Alanyl-sarcosyl-O- (1R, S-1-aminoethanephosphonyl) -L-serine dihydrate of m.p. 155-170 ° C (decomposition) provides. fci] D20 = +10.90 (c = 1 t H20) example 115 115.1.

5 g of L-serine p-nitrobenzyl ester are suspended in 25 ml of dimethylformamide and 1.4 ml of N-methylmorpholine are added. The solution is cooled to O0O and a solution of 4. 9 g of N-benzyloxycarbonyl-glycyl-glycine-p-nitrophenyl ester in 25 ml of dimethylformamide were added dropwise. One adds 0.96 g of 1-hydroxybenzotriazole, stir for 30 min at OOC, 3 hours at room temperature and let stand overnight.

The reaction mixture is poured into water, the deposited precipitate is filtered off and washed with sodium hydrogen carbonate solution, lemon acid solution and Washed water, dried and recrystallized from ethanol.

5.2 g (84 t) of N-benzyloxycarbonyl-slycylglycyl-L-serine-p-nitrobenzyl ester are obtained of m.p. 97-1020C.

115.2.

The tripeptide obtained above is analogous to Example 45.2. with 1R, S-1- (benzyloxycarbonylamino) ethanephosphonic acid implemented. You get N-Benzyloxycarbonyl-glycyl-glycyl-O- (IR, S-1-Benzyloxycarbonyl- (aminoethanphosphonyl) -L-serine p-nitrobenzyl ester, which according to thin-layer chromatogram is pure enough for further processing.

115.3.

5 g of the tripeptide obtained above are analogous to Example 45.3. hydrogenated. The crude product is dissolved in a little water and ethanol is added. never fancy Crystals are filtered off and dried. 1.7 g (76%) glycyl-glycyl-O- (1 R 5-1 -aminoethanephosphonyl) -L-serine monohydrate of melting point 155-159 ° C (decomposition).

[α] D20 = + 9.2 ° (c = 1, H2O) Example 116 1.1 g of O- (methanephosphonyl) -L-seryl-L-alanyl-L-alanine are dissolved in 50 ml of water and while cooling with ice, first with 2.9 g of sodium hydrogen carbonate and then drop by drop mixed with 1 g of acetic anhydride. The mixture is stirred for 1 hour at 0 ° C. and for 1.5 hours at room temperature. The reaction mixture becomes strong over a column of 200 ml acidic ion exchanger Dowex 50 filtered in the H + form. Elute with water and collects the acidic peptide fraction, which is freeze-dried. The raw product is recrystallized from ethanol. You get 1 g (81 t) N-acetyl-O- (methanphosphonyl) -L-seryl-L-alanyl-L-alanine? from m.p. 164-16800.

20 = -69.6 ° (c = 1, H20) D Example 1 7 Analogous to example 11.3. can one from 5.56 g of crude D, L-N-benzyloxycarbonyl-thiomorpholine-3-carboxylic acid and 2.56 ml isobutyl chloroformate (250 ml methylene chloride and 2.16 ml N-methylmorpholine, at -20 ° C) prepare the mixed anhydride in situ, which then after reaction with 5.95 g of crude L-alanyl-L-serine benzyl ester. Hydrochloride (Example 77) (in 250 ml Methylene chloride suspended) yields 9.85 g of crude product. After cleaning on the silica gel column (400 c gel and ethyl acetate as the mobile phase), you get 5.6 g of crystalline acid of melting point 65/68 ° C, namely D, L-N-benzyloxycarbonyl-thiomorpholine-3-carbonyl-L-alanyl-L-serine benzyl ester.

Analogous to example 11.4. one obtains by reaction of this substance (5.6 g) with 2.6 g of (benzyloxycarbonylamino) methanephosphonic acid (70 ml of pyridine; 6.6 g of dicyclohexylcarbodiimide, 6 hours at 230C) 7.2 g of crude monoester, which after purification on the silica gel column (250 g gel and CHCl3 + 5 z methanol as eluent and removing of the monoester from the column with a mixture of CHCl 3 + 15% methanol) 3.9 g results.

Analogous to example 11.5. is obtained by hydrogenating this substance (500 ml of methanol-H 2 O 3: 1; 3 g of catalyst Pd-C, 10 pro .; 40 min), evaporation of the water. Dissolve in a vacuum and rub the remaining substance with ethanol and ether 0.22 g monoester of amino-methanephosphonic acid with D, L-thiomorpholine-3-carbonyl-L-alanyl-L-serine (as an adduct with 4 mol of water per mol of substance).

Preparation of the crude D, L-N-benzyloxycarbonyl-thiomorpholine-3-carboxylic acid: To 5.2 g of thiomorpholine-3-carboxylic acid. Hydrochloride in 80 ml of saturated water. N7aHCO3 solution 4.2 ml of chloroform acid benzol ester (as a 50% solution in Toluene) stirred for 2 hours, extracted with ether, and the water phase HOl to pH 2, then extracted with ethyl acetate, these ethyl acetate extracts evaporate in the Vacuum and get 5.56 g of the desired substance as a viscous syrup.

Example 118 Starting from L-proline benzyl ester, N-tert-butoxycarbonyl-L-proline, N-Benzyloxycarbonyl-L-serine is obtained analogously to Examples 1.1. - 1.3. the protected Tripeptide N-BenzylOxyCarbOnyl-L-seryl-L-prolyl-L-prolylbenzyl ester, which by reaction with N-benzyloxycarbonyl-amidomethanephosphonic acid and subsequent hydrogenation analogously the examples 55.3. and 55.4. O- (Aminomethanephosphonyl) -L-seryl-L-prolyl-L-proline as a hygroscopic powder with a melting point of 165 ° C. (decomposition).

Example 119 Analogous to example 49.2. 7.35 g of N-benzyloxycarbonylamidomethanephosphonic acid are used with 6.58 g of N-benzyloxycarbonyl-L-serine benzyl ester. The crude product is made from ethyl acetate recrystallized. 9 g (81%) of O- (BenzylOxycarbonylamidomethanphosphonyl) -N-benzylOxycarbonyl-L-serine benzyl ester are obtained, which, according to the thin-layer chromatogram, is pure enough for further processing.

5 g of this product are dissolved in 400 ml of ethanol and 100 ml of water and hydrogenated over 1 g of palladium (10 t) on carbon. The catalyst is filtered off, the filtrate was evaporated and the residue was recrystallized from water / ethanol. You get 1.4 g (78%)? 0- (Aminomethanphosphonyl) -L-serine, melting point 168 ° C (decomposition. The product contains 0.5 mol of water.

[α] D20 = -14.0 ° (c = 1, H2O) Example 120 Example 120 is obtained starting from 1R-1-benzyloxycarbonylamido-ethanephosphonaeurs O- (1R-1-aminoethanephosphonyl) -L-serine, m.p. 175-178 ° C.

[a] 20 = 6.90 (c = 1, H20) Example 121 obtained analogously to Example 120 starting from 1S-1- (benzyl-oxycarbonylamidoethanephosphonic acid O- (1S-1-aminoethanephosphonyl) -L-serine of m.p. 166-168 ° C (decomposition).

[α] D20 = -16.60 (c = 1, H20) Example 122 Analogous to example 120 starting from ethanephosphonic acid O- (ethanephosphonyl) -L-serine, the decomposes from 210 ° C without melting.

[a] ZO = -11.3 ° (c = 1, H20) D example 123 obtained analogously to example 120 starting from methanephosphonic acid 0- (methanephosphonyl) -L-serine of melting point 162-165 ° C (Decomposition).

[α] D20 = + 4.2 ° (c = 1, H2O)

Claims (4)

Claims X amino acid or peptide derivatives of the formula I where m and n can assume the values 0, 1, 2 and 3 with the proviso that the sum m + n should not be more than 3, R @ can mean hydrogen, lower alkyl, lower cycloalkyl, aryl lower alkyl, lower alkanoyl and these Radicals can also be substituted by carboxy or lower alkoxycarbonyl groups, R4 and R7 have the same meaning as R1 and can be identical or different, R2 stands for hydrogen, lower alkyl, aryl, aryl-lower alkyl, these radicals being hydroxy, lower alkoxy, amino, lower alkylamino, Mercapto, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, carboxy, lower alkoxycarbonyl, aminocarbonyl, lower alkylaminocarbonyl, lower alkanoylamido, N-hydroxy-lower alkanoylamido, N-hydroxyformamido, guanidino, cyano or a heterocyclic radical which may together contain one or more nitrogen atoms, R1 may be substituted, R1 a saturated or unsaturated hydrocarbon chain can be formed by oxygen or r sulfur interrupted and substituted by hydroxy, lower alkoxy, oxo or lower alkyl groups, R3, Rg, R6 and R9 stand for hydrogen or lower alkyl and can be identical or different, R8 has the same meaning as R2 and together with R7 a saturated or unsaturated hydrocarbon chain which can be interrupted by oxygen or sulfur and substituted by hydroxy-lower alkoxy, oxo or lower alkyl groups, R1o can be hydroxy, lower alkoxy, amino or lower alkylamino, R1 1 stands for lower alkyl and aryl-lower alkyl radicals, which are represented by one or more hydroxy- , Amino, lower alkoxy, lower alkylamino, lower alkylamino, carboxy, aminocarbonyl, lower alkoxycarbonyl, lower alkylaminocarbonyl, lower alkanoylamino groups substituted by lower alkoxycarbonyl can be substituted, where a primary or secondary amino group occurring as a substituent may be substituted by a radical of the formula II a be acylated ka nn, in which R1, R2, R3 and m can have the meaning explained above, and asymmetric C atoms occurring in R 1 can independently have the R, S or R, S configuration, which is marked with an asterisk (*) C atoms can be in the R, S, or R, S configuration if an asymmetric C atom is formed by four different substituents, X is oxygen or sulfur and y can be a carbon atom or -P -OH, -P-O-lower alkyl or -PO-aryl can mean and physiologically acceptable salts of these compounds. 2. Process for the preparation of amino acid or peptide derivatives of the formula I. where m and n can assume the values 0, 1, 2 and 3, with the proviso that the sum m + n should not be more than 3, R1 can denote hydrogen, lower alkyl, lower cycloalkyl, aryl-lower alkyl, lower alkanoyl and these radicals can also be represented by Oarboxy - or lower alkoxycarbonyl groups can be substituted, R4 and R7 have the same meaning as R1 and can be identical or different, R2 stands for hydrogen, lower alkyl, aryl, aryl-lower alkyl, these radicals by hydroxy, lower alkoxy, amino, lower alkylamino, mercapto, lower alkylthio, Lower alkylsulfinyl, lower alkylslfonyl, carboxy, lower alkoxycarbonyl, aminocarbonyl, lower alkylaminocarbonyl, lower alkanoylamido, N-hydroxy-lower alkanoylamido, N-hydroxyformamido, guanidino, cyano or a heterocyclic radical which can contain one or more nitrogen atoms, can be substituted or unsaturated, R1 and R2 Hydrocarbon chains can be formed by oxygen or Sulfur can be interrupted and substituted by hydroxy, lower alkoxy, oxo or lower alkyl groups, R3, R5, R6 and R9 stand for hydrogen or lower alkyl and can be identical or different, Re has the same meaning as R2 and together with Rv a saturated or unsaturated one Can form hydrocarbon chain which can be interrupted by oxygen or sulfur and substituted by hydroxy-lower alkoxy, oxo or lower alkyl groups, Rlo can be hydroxy, lower alkoxy, amino or lower alkylamino, R11 stands for lower alkyl and aryl-lower alkyl radicals, which are represented by one or more hydroxy, amino -, lower alkoxy, lower alkylamino, lower alkylamino, oxy-carbonyl, aminocarbonyl, lower alkoxycarbonyl, lower alkylaminocarbonyl, lower alkanoylamido groups can be substituted, where a primary or secondary amino group which occurs as a substituent may be acylated by a radical of the formula II a can , in which R1, R21, R1 and m can have the meaning explained above, and asymmetric C atoms occurring in R.1, independently of one another, can have the R, S or R, S configuration, which is marked with an asterisk (*) C-A + atoms can be in the R, S, or R, S configuration if an asymmetric carbon atom is formed by four different substituents, X is oxygen or sulfur and y can be a carbon atom or -P-OH, -P-O-lower alkyl or -PO-aryl and of physiologically compatible salts of these compounds, characterized in that a) a compound of the formula IIIa where R1 to R10, X, Y, m, n and * have the meaning given above and the amino or acidic group and any functional groups of the substituents R1, R2, R4, R7 and R8 are protected by groups customary in peptide chemistry , with a phosphonic acid of the formula IV a in which R11 has the meaning given above, whose functional groups which may be present are protected by groups customary in peptide chemistry, converts or b) a compound of the formula IIIa where R1 to R10, X, Y and * have the meaning given above, m and n represent the values 0, 1 or 2, with the proviso that the sum m + n should not be more than 2 and the amino or Acid group and any functional groups present of the substituents R1, R2, R4, R7 and R8 are protected by groups customary in peptide chemistry, with a phosphonic acid of the formula IVa in which R11 has the meaning given above, condensed and then, after cleavage of either the amino or acid protective group, the compound obtained with a compound of the formula VIa or formula VIIa wherein the radicals R1 to R3, R7 to R10, Y, m, n and * have the meaning given above, with protection of the corresponding amino or acidic group, condensed, and then present in the compounds obtained by process a) or b) Protective groups are split off and, if desired, these compounds are converted into their physiologically harmless salts. 3. Medicament containing a compound according to claim 1 and Usual carriers and auxiliaries. 4. Use of compounds according to claim 1 for combating bacterial infections.