Process for producing glufosinates and phosphorous containing aminonitriles as intermediates

Description

DescriptionProcess for preparing glufosinate and phosphorus-containing a-aminonitriles as intermediatesThe invention relates to the technical field of the processes for preparing biologically active compounds and precursors thereof, preferably of crop protection agents, in particular the herbicide glufosinate, also known as phosphinothricin.Glufosinate (see formula (la)) is the common name for the active compound (D,L)-2-amino-4-[hydroxy(methyl)phosphinyl]butanoic acid, which is commercially available as monoammonium salt and is used as foliar herbicide (see DE-A-2717440, US-A-4168963).COOH(la)The herbicide can be employed for the non-selective control of weeds in fruit growing and viticulture, in plantation crops, in vegetable growing prior to sowing or transplanting, prior to direct sowing of maize or soya beans, and also on uncultivated land, such as roadsides, industrial terrain and railroad tracks (cf. Z.PflKrankh.PfISchutz, Special Edition IX, 431-440,1981). Also known is the selective use for controlling weeds in crops of useful plants, such as, inter alia, maize and rapeseed, which have been made resistant by gene technology (cf. EP-A-0242246).A large number of processes for preparing glufosinate have been disclosed. According to the variant described in EP-A-0011245 (US-A-4521348), phosphorus-containing cyanohydrin derivatives of the formulaR'CNOROR"in which R is a hydrocarbon radical sucli as alkyl, haloalkyl, cycloalkyl, phenyl or benzyl, with or without substitution, R' is hydrogen, alkyl, phenyl or benzyl and R" is hydrogen, acyl, trialkylsilyl or alkylsulfonylalkyl,can be converted into aminonitriles, which in turn can be hydrolyzed to give glufosinate. According to EP-A-0011245, the preparation of the cyanohydrin derivatives is carried out by reaction of a monoalkyl methanephosphonate and an acroleincyanohydrin derivative of the formulaR'CNOR"in which R' and R" are as defined above. The described process has the disadvantage that the phoshorus-containing derivative and its precursors have to be provided in the form of esters, whereas in the desired product glufosinate (la), the (hydroxy)(methyl)phosphinyl radical is present in hydrolyzed form.It is an object of the present invention to provide an alternative process to the process described above, said process allowing the number of ester precursors to be reduced and being suitable for preparing glufosinate and related compounds.The invention provides a process for preparing compounds of the formula (I),COOHOHNH2in which R* is hydrogen or (C,-C4)-alkyl, preferably H or methyl, or salts thereof with acids or bases, which comprisesa) (Step 1)reacting a trivalent methylphosphorus compound of the formula (II) with an unsaturated derivative of the formula (III), if appropriate in the presence of a condensing agent or activator and, if appropriate, alcohols, to give an adduct (IV),Step 1:.R1R*(II)                             (III)Adduct IV(IV)where in the formulaeR1 and R2 independently of one another are halogen, such as, for example, fluorine, chlorine, bromine or iodine, (C,-C,B)alkoxy with or without substitution, benzyloxy or phenoxy, which may also be substituted, or one of the radicals R1 and R2 is hydroxyl, andR* is as defined in formula (I),b)    (Step 2)the adduct (IV) is, if appropriate after hydrolytic ring opening to aldehydes (R* = H) or ketones (R* = alkyl) of the formula (IV) or salt thereof,o(IV)in which Z is OH, R1 or R2, reacted under the conditions of a Strecker synthesis with ammonia / ammonium chloride and sodium cyanide or alternatively with mixtures of ammonia and hydrocyanic acid or with ammonia and a salt of hydrocyanic acid, such as, for example, ammonium cyanide or potassium cyanide, if appropriate in the presence of ammonium chloride, to give the a-aminonitriles of the formula (V) or a salt thereof,Step 2:Adduct IVe.g. NH3 / NaCN / NH4CIh3c—P(V)NH2where in the formulae (IV’) and (V) the radical R* is as defined in formula (I) and Z is )10 as defined in formula (IV‘) or is OH, andc) (Step 3)the compound of the formula (V) is hydrolyzed under acidic or basic conditions to give the compound of the formula (I) or the salt thereof.15 In the abovementioned formulae and in the formulae used hereinbelow, the radicals alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino and alkylthio, and also the corresponding unsaturated radicals and / or radicals which are substituted in the carbon skeleton, may in each case be straight chain or branched. Unless specifically indicated, preference for these radicals is given to the lower carbon skeletons, for20 example those having 1 to 4 carbon atoms and, in the case of unsaturated groups, those having 2 to 4 carbon atoms. Alkyl radicals, also in the composed meanings such as alkoxy, haloalkyl, etc., are, for example, methyl, ethyl, n- or i-propyl, n-, i-, t-or 2-butyl, pentyls, hexyls, such as n-hexyl, i-hexyl and 1,3-dimethylbutyl, heptyls, such as n-heptyl, 1-methylhexyl and 1,4-dimethylpenlyl; cycloalkyl is a carbocyclic25 saturated ring system, for example having 3 to 8 ring atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; alkenyl, alkynyl and cycloalkenyl radicals have the meaning of the possible unsaturated radicals which correspond to the alkyl or cycloalkyl radicals, alkenyl is, for example, allyl, 1-methyl-prop-2-en-1-yl, 2-methylprop-2-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, methylbut-3-en-1-yl and 1-methylbut-2-en-1-yl; cycloalkenyl is, for example, cyclopentenyl or cyclohexenyl; alkynyl is, for example, propargyl, but-2-yn-1-yl, but-3-yn-1-yl or 1-methylbut-3-yn-1-yl. Alkenyl in the form "(C3-C4)-alkenyl" or "(C3-C6)-alkenyl” is preferably an alkenyl radical having 3 to 4 and 3 to 6 carbon atoms, respectively, where the double bond is not adjacent to the carbon atom which is attached to the rest of the molecule moiety of the compound (I) ("yl" position). This applies correspondingly to (C3-C4)-alkynyl, etc..Halogen is, for example, fluorine, chlorine, bromine or iodine. Haloalkyl, -alkenyl and -alkynyl are alkyl, alkenyl and alkynyl, respectively, which are partially or fully substituted by halogen, preferably by fluorine, chlorine and / or bromine, in particular by fluorine or chlorine, for example CF3, CHF2, CH2F, CF3CF2, CH2FCHCI2, CCI3, CHCI2, CH2CH2CI; haloalkoxy is, for example, OCF3, OCHF2, OCH2F, CF3CF2O, OCH2CF3 and OCH2CH2CI; this applies correspondingly to haloalkenyl and to other halogen-substituted radicals.If substitutions are defined by "one or more radicals selected from a group of radicals", this includes both the substitution by one or more identical radicals and mono- or polysubstitution by different radicals.Substituted radicals, such as substituted hydrocarbon radicals, for example substituted alkyl, alkenyl, alkynyl, aryl, phenyl and benzyl, or substituted heterocyclyl, are, for example, a substituted radical derived from the unsubstituted parent radical, where the substituents are, for example, one or more, preferably 1,2 or 3, radicals selected from the group consisting of halogen, alkoxy, haloalkoxy, alkylthio, hydroxyl, amino, nitro, cyano, azido, alkoxycarbonyl, alkylcarbonyl, formyl, carbamoyl, mono- and dialkylaminocarbonyl, substituted amino such as acylamino, mono- or dialkylamino, and alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl and, in the case of cyclic radicals, also alkyl and haloalkyl, and unsaturated aliphatic radicals corresponding to the abovementioned saturated hydrocarbon-containing radicals, such as alkenyl, alkynyl, alkenyloxy, alkynyloxy etc. Preferred radicals having carbon atoms are those having 1 to 4 carbon atoms, in particular 1 or 2 carbon atoms. Preferred substituents are usually those from the group consisting of halogen, for example fluorine and chlorine, (C,-C4)-alkyl, preferably methyl or ethyl, (C,-C4)-haloalkyl, preferably trifluoromethyl, (CrC4)-alkoxy, preferably methoxy or ethoxy, (CrC4)-haloalkoxy, nitro and cyano. Particular preference is given to the substituents methyl, methoxy and chlorine.Phenyl with or without substitution is preferably phenyl which is unsubstituted or mono- or polysubstituted, preferably up to trisubstituted, by identical or different radicals selected from the group consisting of halogen, (CrC4)-alkyl, (C,-C4)-alkoxy, (C1-C4)-haloalkyl, (C,-C4)-haloalkoxy and nitro, for example o-, m- and p-tolyl, dimethylphenyls, 2-, 3- and 4-chlorophenyl, 2-, 3- and 4-trifluoro- and -trichlorophenyl, 2,4-, 3,5-, 2,5- and 2,3-dichlorophenyl, o-, m- and p-methoxyphenyl.An acyl radical is the radical of an organic acid, for example the radical of a carboxylic acid, and radicals of acids derived therefrom, such as the thiocarboxylic acid, iminocarboxylic acids with or without N-substitution, or the radical of carbonic acid monoesters, carbaminic acids with or without N-substitution, sulfonic acids, sulfinic acids, phosphonic acids, phosphinic acids. Acyl is, for example, formyl, alkylcarbonyl such as (Ci-C4-alkyl)-carbonyl, phenylcarbonyl, where the phenyl ring may be substituted, for example as shown above for phenyl, or alkyloxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, alkylsulfonyl, alkylsulfinyl, N-alkyl-1-iminoalkyl and other radicals of organic acids.Compounds of the formula (II) are known or can be prepared by known processes, see, for example, J.B. Miles et al. in Org. Prep. Proc. Int., 11 (1), 11 (1979); B.M. Gladshtein et al., Zh. Obshch. Khim. 39,1951 (1969); DAS 1098940 (1959), Farbf. Bayer, Boetzel et al., J. Fluorine Chem. 68,11 (1994); Hoffmann et al., JACS 80, 1150 (1958).In the compounds of the formula (II), R1 and R2 independently of one another are preferably halogen, such as, for example, fluorine, chlorine, bromine or iodine,(C^CgJalkoxy, (C,-C6)haloalkoxy, benzyloxy or phenoxy, where each of the two last-mentioned radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, alkyl, haloalkyl, alkylthio, nitro, cyano, alkylsulfonyl and haloalkylsulfonyl, preferably in each case having 1 to 6 carbon atoms, in particular 1 to 4 carbon atoms, in the alkyl moiety, or one of the radicals R1 and R2 is preferably hydroxyl.Particularly preferably, R1 and R2 are each (CrC4)alkoxy.The compounds of the formula (III) are basic chemicals and therefore also known.The adducts (IV) may have various structures. Intermediates which are possible in some cases are 2-methyl-1,2-oxa-4-phospholenes of the formula (IV*), i.e. the subsequent reactions are consistent with an intermediate of the formula (IV*):H.(iv*)In certain cases, the compounds of the formula (IV*) occur as intermediates which cannot be detected, or do not occur as intermediates at all, depending on which activators or condensing agents or reactive additives such as alcohols are employed in the addition / condensation reaction.In a preferred embodiment, preference is given to reacting compounds of the formula (11-1) with a compound of the formula (III) in the presence of anhydrides A2O, preferably carboxylic anhydrides, and alcohols ROH, to give adducts (IV-1), the latter being semiacetals, or a salt thereof,(H-1)O—XH3c---p / +Y(IV-1)in which-0-X and -0-Y correspond to the radicals R1 and R2, respectively, if these are radicals of alcohols, i.e.each of the radicals X and Y independently of one another is H or (C,-C18)-alkyl which is unsubstituted or substituted, benzyl or phenyl, where each of the two abovementioned radicals is unsubstiluted or substituted, preferably unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, alkyl, haloalkyl, alkylthio, nitro, cyano, alkylsulfonyl and haloalkylsulfonyl, preferably in each case having 1 to 6 carbon atoms, in particular 1 to 4 carbon atoms in the alkyl moiety, andX and Y are preferably identical radicals, and in particular X, Y and R are identical radicals,R* is as defined in formula (I), preferably H,A is an acyl radical, preferably the acyl radical of a carboxylic acid having 1 to 6 carbon atoms, in particular 1 to 4 carbon atoms,R is a radical selected from the group of the radicals defined for X and Y, preferably the same radical as X or Y.Particularly preferablyX, Y and R are in each case identical radicals selected from the group consisting of (C1-C6)alkyl, phenyl or benzyl, in particular (CrC4)alkyl, for example methyl, ethyl, n-, i-propyl, n-, i-, s- or t-butyl.Correspondingly, the compounds (IV) and (V) are, in the preferred variant (starting from compounds (11-1)), compounds of the formula (IV'-1) and (V-1) or salts thereof, respectively,oin which X' = H or X and R* and X are as defined above.2-Methyl-1,2-oxa-4-phospholenes of the formula (IV*) and the semiacetals of the formula (IV-1) have hitherto been unknown, as have been the aminonitriles of the formula (V-2) (= formula (V) where Z = OH) and they therefore also form part of the subject matter of the present invention.From the 1,2-oxa-4-phospholenes (IV*), only some higher homologs are known.Thus, phenyldichlorophosphane (Ila) reacts with a,p-unsaturated ketones (VI) withaddition of acetic anhydride to give the 2-phenyl-2-oxo-1,2-oxa-4-phospholenes (VII)(K. Bergesen, Acta Chem. Scand. 19, 1784 (1965)),Ac20(Ha)                           (VI)in which R3 and R4 are hydrogen, methyl or phenyl and R5 is methyl or phenyl.Furthermore, it is known that ethyldichlorophosphane lib reacts with methyl vinyl ketone (Via) to give 5-methyl-2-ethyl-2-oxo-1,2-oxa-4-phospholene (Vila) (A.N. Pudovik et al., Isv. Akad. Nauk. SSSR, Ser. Khim. (Engl, version) 2543 (1970)); Et = ethyl in formula lib; Me = methyl in formula Vila; Ac = acetyl;(lib)                  (Via)Ac2O(Vila)Finally, the reaction of 2-thienyldichlorophosphane (lie) with a,p-unsaturated ketones gives 2-thienyl-2-oxo-1,2-oxa-4-phospholenes (Vllb) (R.Z. Aliev, Isv. Akad. Nauk., SSSR, Ser. Khim (Engl, version), 2719 (1973)),in which Ra is hydrogen or methyl.Analogous reactions, for example with methyldichlorophosphane which is highly reactive compared to phenyldichlorophosphane (cf. H. Heydt et al., Methoden der Organischen Chemie XII E2, p. 29 (1982)) and methanephosphonous acid diesters have hitherto not been described in the literature. Analogous reactions with acrolein (III; R2 = H) are likewise not known.Because the components (II) and (III) are much more reactive, and because of the complex reaction mixture or the complex course of the reaction in step 1, it is extremely surprising that the process according to the invention can be realized in high yields via the intermediates (adducts IV) to give the a-aminonitrile derivatives (V) or (V-1) and subsequently the compounds (I).In step 1, the process according to the invention is generally carried out by reacting compounds of the formula (II) or (11-1) with unsaturated compounds of the formula (III), preferably in the presence of a condensing agent or activator. Suitable activators / condensing agents are substances which are suitable for promoting or catalyzing the addition of the phosphorus component to the a,p-unsaturated keto compound (III). Suitable condensing agents or activators are carboxylic anhydrides, preferably anhydrides of alkanecarboxylic acids having 1 to 6 carbon atoms, for example acetic anhydride or propionic anhydride.Also suitable are mixtures of the anhydrides with certain proportions of alcohols ROH, where R is as defined above.The reaction of compounds (II) and (III) can be carried out without solvent or in the presence of an organic solvent, for example in the presence of aliphatic or aromatic hydrocarbons which may be halogenated, such as dichloromethane, toluene, xylene, chlorobenzene, or ethers, such as dioxane, or alcohols, such as ethanol, n-butanol, etc., or mixtures of these exemplary solvents.The phosphorus components of the formula (II) are employed in molar ratios which can deviate considerably from the stoichiometry, preferably in molar ratios of 1:2 to 2:1, but in particular essentially in equimolar amounts, based on the component (III).If the reaction of the components (II) and (III) is carried out in the presence of an anhydride A2O, such as, for example, acetic anhydride or propionic anhydride, suitable anhydride inputs are usually in the range of from more than 0 to 400 mol%, preferably amounts of from 50 to 150 mol%, based on the starting component (II) or (III), which is employed in the lowest molar amount.If the reaction of the components (11-1) and (III) is carried out in the presence of the anhydride A2O, for example acetic anhydride, and an alcohol ROH, for example (C,-C5)alkanol such as ethanol, preference is given to using 50 to 150 mol% of acetic anhydride and 50 to 200 mol% of alcohol, in particular in the anhydride:alcohol ratio of 1:1 to 1:1.5, based on the starting component (II) or (III), which is employed in the lowest molar amount.The reaction, according to the invention, of compounds (II) and (III) succeeds generally at reaction temperatures between -80°C and +200°C, preferably between -10°C and +60°C. The duration of the reaction depends in general on the reaction temperature, the size of the batch, the specific reactants, the solvent and the condensing agents / activators and is, for example, in the range of 0.5 - 48 hours (h), preferably 0.5-18 h.Surprisingly, the reaction, according to the invention, of the intermediates (IV) and (IV-1) to give the desired a-aminonitriles (V) and (V-1), respectively, (step 2) can be carried out under conditions which are known analogously to the preparation of aminonitriles from aldehydes or ketones by the type of the "Strecker synthesis" (see textbooks and handbooks of organic chemical synthesis). According to one possible procedure, the reaction solution which contains the crude product (IV) or (IV-1) is added to a solution or suspension comprising an alkali metal cyanide and ammonium chloride in aqueous ammonia solution.It is also possible to employ mixtures of the abovementioned organic solvents, such as, for example, toluene, xylene, chlorobenzene, dichloromethane, ethanol, butanol etc., for this purpose. Instead of alkali metal cyanides, it is also possible to use alkaline earth metal cyanides or ammonium cyanide, or solutions of hydrocyanic acid in ammonia.The cyanides or the hydrocyanic acid are employed, for example, in amounts of 80 -130 mol%, but preferably in essentially equimolar amounts, based on the components of the formula (IV). The amount of ammonia based on the compound (IV) is, for example, between 100 and 800 mol%, preferably from 100 to 400 mol%. The reactions of the compounds (IV) under the conditions of the Strecker synthesis are carried out, for example, at from -10°C to 100°C, preferably at 0-45°C.The compounds of the formula (V) or (V-1) are preferably obtained as salts in which the acidic hydrogen atom at the phosphinoyl group is replaced by a cation equivalent, preferably by a cation equivalent such as, for example, Li*. Na+, K+, (Mg2+)1 / 2, (Ca2+)1 / 2, NH4*.Alternatively, it is possible to initially purify the intermediates (IV) or (IV-1) by distillation or extractive methods and to react them in purified form to give the aminonitriles (V) or (V-1).In a further variant, the intermediates (adducts IV) or (IV-1) are initially hydrolyzed with water to give the aldehydes or ketones of the formula (IV') or (IV-1) and reacted in a further step to give the a-aminonilriles (V) or (V-1).In the formula (IV'), R* is hydrogen or (Ct-C4)-alkyl. The compound where R* = hydrogen and Z = hydroxyl or salts thereof are novel compounds in the methylphosphinic acid series and therefore also form part of the subject matter of the invention, i.e. the compound of the formula (IV-2) or salts thereofOH        hHowever, the compound (IV) where R* = methyl and Z = hydroxyl is known(L.D. Quin et al., J. Org. Chem. 39, 686 (1974)).According to step 3 of the process according to the invention, the a-aminonitriles of he formula (V) or (V-1) are useful intermediates which, in analogy with the process I onditions known from the literature (Houben - Weyl, Methoden der Organischen Chemie XI / 2, p. 305 and p. 371, 1958),. can be hydrolyzed both in acidic and in basic medium, to give the biologically active amino acids of the formula (I), in particular glufosinate of the formula (la).Compared with known processes for the synthesis of the herbicidal amino acid (la), the process according to the invention has a number of advantages, for example, the additional esterification of the phosphorus components of the intermediates (IV), (IV) and (V) of the intermediates is unnecessary. Moreover, the process can optionally be carried out separately for each step, or as a one-pot process over all 3 teps.Thus, the essential PC linkage for building up the amino acid side chain can be arried out in one step, for example with methyldihalophosphanes or preferably 25 methanephosphonous acid diesters (II) or (11-1) and olefins (III), without the omplicated conversion of, for example, methyldichlorophosphane to methanephosphonous acid monoeslers being necessary. Moreover, in contrast to he process known from EP-A-0011245, the radical addition of the methanephosphonous acid monoesters to acrolein derivatives, which readily leads 30 o by-products, is avoided.In the process according to the invention it is possible to employ, for example, the eadily obtainable olefin components acrolein or methyl vinyl ketone directly, without derivatization being necessary. Furthermore, the a-aminonitriles (V) or (V-1) are obtained in the process according to the invention with a free phosphinic acid or hosphinate grouping, so that in the last step of the synthesis only the nitrile group as to be hydrolyzed to give the free amino acid. Deblocking of the phosphinic ester roup to the free phosphinic acid, which is required in the prior art method mentioned above, is thus superfluous.The examples below illustrate the process, without limiting the possible process onditions. Unless specifically defined otherwise, the amounts stated are based on weight.Example 12-Amino-2-methyl-4-(hydroxymethylpliosphinyl)bulyric acid, ammonium saltAt room temperature and under an atmosphere of inert gas, 7.01 g (0.10 mol) of methyl vinyl ketone are admixed with 10.21 g (0.10 mol) of acetic anhydride. With cooling at at most 25-30°C, 13.61 g (0.10 mol) of diethyl methanephosphonate are subsequently added dropwise. The reaction mixture is stirred at 30°C for approximately 6 hours. At 20-25°C, the mixture is then added dropwise to a solution of 4.41 g (0.09 mol) of sodium cyanide and 9.63 g (0.18 mol) of ammonium chloride in 50 ml of ammonia solution (25% strength). The mixture is stirred at 25°C for another 4 hours and the crude aminonitrile is then rapidly added dropwise without isolation to 200 ml of hydrochloric acid (37% strength). The reaction mixture is subsequently boiled under reflux for approximately 4 hours, while ethanol and acetic acid are distilled off. The mixture is concentrated using a rotary evaporator, a pH of approximately 9 is set using ammonia solution and the desired product is freed of salts by recrystallization from methanol.This gives 19.1 g (corresponding lo 94.5% of theory) of 2-amino-2-methyl-4-hydroxymethylphosphinyl)butyric acid, ammonium salt.1H NMR (D2O): 1.56 (d, J = 14Hz, 3H); 1.63 (s, 3H); 1.7-2.3 (m, 4H)31P NMR (D2O): 54.4.Example 2 2-Amino-2-methyl-4-(hydroxymethylphosphinyl)butyric acid, ammonium saltAt room temperature, 2.10 g (0.03 mol) of methyl vinyl ketone and 3.06 g (0.03 mol) of acetic anhydride are dissolved in 20 ml of dichloromethane. At 25-28°C, 3.51 g 0.03 mol) of methyldichlorophosphane are subsequently rapidly added dropwise and the mixture is stirred at approximately 30°C for 3 hours and then added dropwise to a solution of 1.375 g (0.0275 mol) of sodium cyanide and 2.94 g (0.055 mol) of ammonium chloride in 25 ml of ammonia (25% strength). The mixture is stirred at 28-30°C for approximately 4 hours and the two-phase crude aminonitrile solution is added dropwise at 25-30°C to 100 ml of hydrochloric acid (37% strength). The mixture is subsequently heated under reflux for approximately 4 hours and worked-up as under Example 1. This gives 5.83 g (corresponding to 92% of theory) of 2-amino-2-methyl-4-(hydroxymethylphosphinyl)butyric acid, ammonium salt. 1H NMR (D2O): 1.57 (d, J = 14 Hz, 3H); 1.65 (s, 3H); 1.7-2.3 (m, 4H).31P NMR : 54.5Example 3 2-Amino-4-(hydroxymethylphosphinyl)butyric acid, ammonium saltAt room temperature, 5.61 g (0.10 mol) of freshly distilled acrolein are added to10.21 g (0.10 mol) of acetic anhydride. At25-30°C, 13.61 g (0.10 mol) of diethyl methanephosphonate are subsequently added dropwise. The mixture is stirred at 30°C for 2 hours and then, at 25-28’C, added dropwise to a solution of 4.9 g (0.10 mol) of sodium cyanide and 10.7 g (0.20 mol) of ammonium chloride in 50 ml of ammonia (25% strength). After 2 hours at 30°C, the crude aminonitrile is added dropwise to 200 ml of hydrochloric acid (37% strength). The mixture is subsequently heated under reflux for 2 hours, while ethanol and acetic acid are distilled off. The mixture is concentrated using a rotary evaporator, a pH of approximately 9 is set using ammonia solution and the product is purified by crystallization from methanol. This gives 19.4 g (98% of theory) of 2-amino-4-(hydroxymethylphosphinyl)butyric acid, ammonium salt.1H NMR (D2O): 1.60 (d,14Hz, 3H); 1.8-2.4 (m, 4H); 4.28 (t, J = 6 Hz, 1H).31P NMR (D2O): 55.9.Example 4 2-Amino-2-methyl-4-(hydroxymethylphosphinyl)butyric acid, ammonium saltAt room temperature and under an atmosphere of inert gas, 14.02 g (0.20 mol) of methyl vinyl ketone are admixed with 20.42 g (0.20 mol) of acetic anhydride. With cooling and at at most 25 to 30°C, a mixture of 27.22 g (0.20 mol) of diethyl methanephosphonate and 9.2 g (0.2 mol) of ethanol is subsequently added dropwise. The reaction mixture is stirred at 30°C for approximately 6 hours. At 20 to 25°C, the mixture is then added dropwise to a solution of 8.82 g (0.18 mol) of sodium cyanide and 19.26 g (0.36 mol) of ammonium chloride in 100 ml of ammonia solution (25% strength). The mixture is stirred at 25°C for another 4 hours and the crude aminonitrile is then rapidly added dropwise without isolation to 400 ml of hydrochloric acid (37% strength). The reaction mixture is subsequently boiled under reflux for approximately 4 hours, while ethanol and acetic acid are distilled off. The mixture is concentrated using a rotary evaporator, a pH of approximately 9 is set using ammonia solution and the desired product is freed of salts by recrystallization from methanol.This gives 38.8 g (corresponding to 96% of theory) of 2-amino-2-methyl-4-(hydroxymethylphosphinyl)butyric acid, ammonium salt (physical data see Ex. 1).Example 5 2-Amino-4-(hydroxymethylphosphinyl)bulyric acid, ammonium saltAt room temperature, 5.61 g (0.10 mol) of freshly distilled acrolein are added to10.21 g (0.10 mol) of acetic anhydride. At 25 to 30°C, this mixture is subsequently added dropwise to 13.61 g (0.10 mol) of diethyl methanephosphonate and 4.6 g 0.1 mol) of ethanol. The mixture is stirred at 30°C for 2 hours and then, at 25 to 28°C, added dropwise to a solution of 4.9 g (0.10 mol) of sodium cyanide and 10.7 g 0.20 mol) of ammonium chloride in 50 ml of ammonia (25% strength). After 2 hours at 30°C, the crude aminonitrile is added dropwise to 200 ml of hydrochloric acid (37% strength). The mixture is subsequently heated under reflux for 2 hours, while ethanol and acetic acid are distilled off. The mixture is concentrated using a rotary evaporator, a pH of approximately 9 is set using ammonia solution and the product is purified by crystallization from methanol. This gives 19.6 g (99% of theory) of 2-amino-4-(hydroxymethylphosphinyl)butyric acid, ammonium salt.’HNMR (D2O): 1.60 (d, 14Hz, 3H); 1,8-2.4 (m, 4H); 4.28 (t, J = 6 Hz, 1H).31P NMR (D2O): 55.9.Example 62-Amino-4-(hydroxymethylphosphinyl)butyric acid, ammonium saltAt room temperature, 5.61 g (0.10 mol) of freshly distilled acrolein are added to10.21 g (0.10 mol) of acetic anhydride. At 25 to 30°C, this mixture is subsequently dded dropwise to 16.41 g (0.10 mol) of dibutyl methanephosphonate and 14.8 g(0.2 mol) of n-butanol. The mixture is stirred at 30°C for 2 hours and then, at 25 to 28°C, added dropwise to a solution of 4.9 g (0.10 mol) of sodium cyanide and 10.7 g (0.20 mol) of ammonium chloride in 50 ml of ammonia (25% strength). After 2 hourst 30°C, the crude aminonitrile is added dropwise to 200 ml of hydrochloric acid( 7% strength). The mixture is subsequently heated under reflux for 2 hours, while ^ethanol and acetic acid are distilled off. The mixture is concentrated using a rotary evaporator, a pH of approximately 9 is set using ammonia solution and the product i purified by crystallization from methanol. This gives 17.8 g (90% of theory) of 2-mino-4-(hydroxymethylphosphinyl)butyric acid, ammonium salt.H NMR (D2O): 1.60 (d, MHz, 3H); 1.8 - 2.4 (m, 4H); 4.28 (t, J = 6 Hz, 1H).P NMR (D2O): 55.9.

Claims

What is claimed is:What is claimed is:

1. A process for preparing compounds of the formula Iftin which R* is hydrogen or (Ci -C4)-alkyl, or salts thereof with acids or bases, which comprisesa) (Step 1)reacting   a   trivalent methylphosphoruscompound of the formula (II) with an unsaturated derivative of the formula(III) , in the presence of a condensing agent or activator selected from substances which promote or catalyze the addition of the phosphorous component to the 01,0-unsaturated keto compound and, if appropriate, alcohols, to give an adduct(IV) ,where in the formulaeR1 and R2 independently of one another are (Ci-Cis) -alkoxy with or without substitution, benzyloxy or phenoxy, which10                may also be substituted, or one of theradicals R1 and R2 is hydroxyl, andR* is as defined in formula (I),b) (Step 2)the adduct (IV) is, if appropriate after15               hydrolysis to aldehydes (R*=H) or ketones(R*=alkyl) of the formula (IV'), or to a salt thereofin which Z is OH, R1 or R2, reacted underthe conditions of a Strecker synthesis withammonia / ammonium   chloride and sodiumcyanide or alternatively with mixtures ofammonia and hydrocyanic acid or withammonia and a salt of hydrocyanic acid, if appropriate in the presence of ammonium 10             chloride, to give the a-aminonitriles ofthe formula (V) or a salt thereof,Step 2-.AtatctlVwhere in the formulae (IV' ) and (V) theradical R* is as defined in formula (I) andZ is as defined in formula (IV') or is OH,andc) (Step 3)the compound of the formula (V) is hydrolyzed under acidic or basic conditions to give the compound of the formula (I) or salts thereof.

2. The process, as claimed in claim 1, wherein R1. and R2 independently of one another are (Ci-Cg) alkoxy, (Ci -Cg) haloalkoxy, benzyloxy or phenoxy, where each of the two last-mentioned radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, alkyl, haloalkyl, alkylthio, nitro, cyano, alkylsulfonyl and haloalkylsulfonyl having in each case 1 to 6 carbon atoms in the alkyl moiety, or one of the radicals R1 or R2 is hydroxyl.

3. The process as claimed in claim 1, wherein instep 1, as compounds (II), compounds of the formula (II-l) are reacted with a compound of the formula (III) in the presence of anhydrides A20 and alcohols ROH to give adducts (IV) of the formula (IV-1),in whicheachis4.<na)of the radicals X and Y independentlyone another is Hunsubstituted orphenyl,whereofor (Ci-Cg) alkyl whichsubstituted, benzyleachoftheisortwoabovementioned radicals issubstituted, andan acyl radical,is (Ci-Cis) alkyl, which issubstituted, benzylof the two radicalsor substituted.The process as claimedunsubstituted orunsubstituted oror phenyl, where eachabove is unsubstitutedin claim 3, whereinX,Y and R are each (Ci -C4)alkyl,A is an acyl radical of an alkanecarboxylic acidhaving 1 to 6 carbon atoms andR* is a hydrogen atom.

5. A process for preparing compounds of theformula (I) ,in whichhydrogen(Ci -C4) alkyl, or salts thereofwith acidsor bases,which compriseshydrolyzing acompound ofthe formula (V-2)or salts thereof,(V-2)R*in whichR* is as defined in formula (I) under acidic orbasic conditions to give the compound of the formula (I) or salts thereof.

6. The process as claimed in claim 5, whereinthe compound of the formula (V-2) or a salt thereofis prepared from compounds of the formula (IV*),in whichR* is as definedappropriate afterto aldehydes orin formula (V-2), if hydrolytic ring opening ketones of the formula(IV'),(tV)in whichZ=OH and R* is as defined in formula (V-2), byreaction under the conditions of a Streckersynthesis with ammonia / ammonium chlorideand sodium cyanide or alternatively with mixtures of ammonia and hydrocyanic acid or with ammonia and a salt of hydrocyanicacid, if appropriate in the presence ofammonium chloride,to give the a-aminonitriles of the formula (V-2) or asalt thereof.

7. A process of preparing compounds of theformula (V) or a salt thereofI                            '(V)NHzin whichZ is OH or OX, whereinX is H or   (Ci-Cig) alkyl with or withoutsubstitution, benzyl or phenyl, with or without substitution, andR* is H or (Ci -C4) alkyl, comprising reacting compounds of the formula (IV-1),in whichX is (Ci-Cis) alkyl, with or without substitution, benzyl or phenyl, with or without substitution, if Z=OH in formula (V), or is as defined in OX in formula (V), if Z=OX in formula (V),A is an acyl radical,R is (Ci-Cis)alkyl, with or without substitution, benzyl or phenyl, with or without substitution, andR* is as defined in formula (V) , if appropriate after hydrolysis to aldehydes or ketones of the formula (IV1),wherein Z is OH or, if Z is OX in formula (V) , is OX as defined in formula (IV) and formula (V) , and R* is defined as in formula (V) , under the conditions of Strecker synthesis with ammonia / ammonium alternatively with mixtures of ammonia and hydrocyanic acid or with ammonia and a salt of hydrocyanic acid, if appropriate in the presence of ammonium chloride, to give the a-aminonitriles of the formula (V) or a salt thereof.

8. A compound of the formula (V-2) or a salt thereof with acids and bases,<V*2)in whichR* is H or (Ci -C4)alkyl.

9. A compound of the formula (IV*),in whichR* is hydrogen or (Ci -C4) alkyl.

10. The process for preparing compounds of the formula (IV*) as claimed in claim 9 wherein a trivalent methylphosphorus compound of the formula (II) is reacted with an unsaturated derivative of the formula (III) in the presence of a condensing agent or activator to give a 1,2-oxa-4-phospholene of the formula (IV*),where in the formulae (II) and (III)R1 and R2 independently of one another are (Ci -Cib)alkoxy, with or without substitution,benzyloxy or phenyloxy, with or without substitution, or one of the radicals R1 and R2 is hydroxyl, andR* is as defined in formula (IV*).

11. A compound of the formula (IV-1),lichX is H or (Ci-Cis) alkyl,   with or withoutsubstitution, benzyl or phenyl, with or without substitution,A is an acyl radical,R is (Ci-Cis)alkyl, with or without substitution, benzyl or phenyl, with or without substitution, andR* is H or (Ci -C4)alkyl, or a salt thereof.

12. The process for preparing compounds of the formula (IV-1) or salts thereof as claimed in claim11, wherein compounds of the formula(II-l) arereacted with a compound of the formula (III) in thepresence of anhydrides A20 and alcoholsROH to givethe adducts of the formula (IV-1) or salts thereof,in whicheach of the radicals X and Y independently ofone another is H or (Ci -Cis)alkyl which isunsubstituted or substituted, benzyl orphenyl, where each of the twoabovementioned radicals is unsubstituted orsubstituted, andA is an acyl radical,R is (Ci -Cig) alkyl, which is unsubstituted orsubstituted, benzyl or phenyl, where each of the two radicals above is unsubstituted or substituted.

13. The process as claimed in claim 12, whereinfrom 50to 150 mol % ofanhydride A2O and from 50 to200 mol % of alcohol ROH,based on the startingcomponent (II-l) or (III) which has the lowest'molarity, are employed.

14. A process for preparing compounds of theformula (I),<0in whichR* is hydrogen or (Ci -C4)alkyl, or salts thereof with acids or bases, which comprises reacting compounds of the formula (IV-I),lichR* is as defined in formula (I) , each of the radicals X and Y independently of one another is H or (Ci-Cig) alkyl which is unsubstituted or substituted, benzyl or phenyl, where each of the two abovementioned radicals is unsubstituted or substituted, andA is an acyl radical, andR is (Ci —Cig) alkyl, which is unsubstituted or substituted, benzyl or phenyl, where each of the two radicals above is unsubstitutedor substituted, if appropriate after hydrolysis to aldehydes (R*=H) or ketones (R*=alkyl) of the formula (IV),in whichZ is OH or OX, or to salts thereof under the conditions of a Strecker synthesis with ammonia / ammonium chloride and sodium cyanide or alternatively with mixtures of ammonia and hydrocyanic acid or with ammonia and a salt of hydrocyanic acid, if appropriate in the presence of ammonium chloride, to give the a-aminonitriles of the formula (V) or a salt thereof:(V)where in the formulae (IV') and (V) theradical R*is as defined in formula(I), X is as defined in formula (IV-1)and Z in formula (V) is as defined in formula (IV') or is OH, andthe compound of the formula (V) or a salt thereof is hydrolyzed under acidic or basic conditions to give the compound of the formula (I) or a salt thereof.

15. The processaccording toclaim 1, whereinthe condensing agentor activatoris a carboxylicacid anhydride .

16. A processfor preparingcompounds of theformula I(Din whichR* is hydrogen or (Ci -C«)-alkyl, or salts thereof with acids or bases, which comprisesa) (Step 1)reacting a trivalent methylphosphorus compound of the formula (II) with an unsaturated derivative of the formula (III), in the presence of a condensing agent or . activator, wherein the condensing agent or activator is a carboxylic acid anhydride, and, if appropriate, alcohols, to give an adduct (IV) ,Step 1:(SD(IV)where in the formulaeR1 and R2 independently of one another are(Ci-Cis) alkoxywithwithoutsubstitution, benzyloxy or phenoxy,which may also be substituted, or oneof the radicals R1 and R2is hydroxyl,andR* is as defined in formula (1),b) (Step 2)the adduct (IV) is, if appropriate after hydrolysis to aldehydes (R*=H) or ketones (R*=alkyl) of the formula (IV'), or to a salt thereofin which Z is OH, R1 or R2, reacted under the conditions of a Strecker synthesis with ammonia / ammonium chloride and sodium cyanide 15          or alternatively with mixtures of ammonia andhydrocyanic acid or with ammonia and a salt of hydrocyanic acid, if appropriate in the presence of ammonium chloride, to give the a-aminonitriles of the formula (V) or a salt 20           thereof,where in the formulae (IV') and (V) the radical R* is as defined in formula (I) and Z-is as defined in formula (IV') or is OH, andc) (Step 3)the compound of the formula (V) is hydrolyzed under acidic or basic conditions to give the compound of the formula (I) or salts thereof.

17. The process according to claim 16, wherein R1 and R2 independently of one another are (Ci-Cg)alkoxy, (Ci-Ce)haloalkoxy, benzyloxy or phenoxy, where each of the two last-mentioned radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, alkyl, haloalkyl, alkylthio, nitro, cyano, alkylsulfonyl andhaloalkysulfonyl having in each case 1 to 6 carbon atoms in the alkyl moiety, or one of the radicals R1 or R2 is hydroxyl.

18. Aprocessfor preparing compounds of theformula Ib3cCOOHin whichR* is hydrogen or (Ci -C4)-alkyl, or salts thereof with acids or bases, which comprisesa) (Step 1)reacting a trivalent methylphosphoruscompound of the formula (II) with anunsaturated derivative ofthe formula(III), in the presence of a condensing agent or activator selected from substances which promote or catalyze the addition of the phosphorous component to the a,(3-unsaturated keto compound and, ifappropriate, alcohols, to give an adduct(IV) ,HgC—PAcUunlvR“amav)wherein the formulaeR1 and R2 independently of one another are(Ci-Ci8) alkoxywithwithoutsubstitution, benzyloxy or phenoxy, which may also be substituted, or one of the radicals R1 and R2 is hydroxyl, andR* is as defined in formula (1),b) (Step 2)the adduct (IV) is, if appropriate after hydrolysis to aldehydes (R*=H) or ketones (R*=alkyl) of the formula (IV), or to a salt thereofin which Z is OH, R1 or R2 , reacted under the conditions of a Strecker synthesis with5           ammonia / ammonium chloride and sodium cyanideor alternatively with mixtures of ammonia and hydrocyanic acid or with ammonia and a salt of hydrocyanic acid, if appropriate in the presence of ammonium chloride, to give 10            the a-aminonitriles of the formula (V) or asalt thereof,Step 2:AMmlV(V>where in the formulae (IV') and (V) the radical15            R* is as defined in formula (I) and Z is asdefined in formula (IV') or is OH, andc) (Step 3)the compound of the formula (V) is hydrolyzed under acidic or basic conditions to give the compound of the formula (I) or salts thereof, wherein in step 1, as compounds (II), compounds of . the formula (II-l) are reacted with a compound of the formula (III) in the presence of anhydrides A2O and alcohols ROH to give adducts (IV) of the formula (IV-1),dW)in whicheach of the radicals X and Y independently ofone another is H or (Ci -Cig) alkyl which isunsubstitutedorsubstituted, benzyl orphenyl, where each of the two abovementioned radicals is unsubstituted or substituted, andA is an acyl radical,R is (Ci -Cig) alkyl, which is unsubstituted or substituted, benzyl or phenyl, where each of the two radicals above is unsubstituted or substituted.

19. The process according to claim 18, wherein X, Y and R are each (Ci -C4) alkyl, A is an acyl radical of an alkanecarboxylic acid having 1 to 6 carbon atoms and R* is a hydrogen atom.