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    • 专利摘要:
    The present invention relates to new phosphonous acid derivatives, especially to alpha -amino-phosphonous acids and processes for their production. The new phosphonous acids are valuable chemotherapeutica in the treatment of pathogenic bacteria, gram-negative bacteria and yeast.
    公开号:SU805948A3
    申请号:SU772484356
    申请日:1977-05-20
    公开日:1981-02-15
    发明作者:Грей Дингволл Джон；Кейт Бейлис Эрик；Деннис Кемпелл Колин
    申请人:Циба-Гейги Аг (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING O6-AMINOPHOSPHONIC ACIDS
    If R is lower alkyl, then it may be a linear or branched lower alkyl residue with 1-6 carbon atoms.
    Lower alkyl residues may be substituted with a hydroxy group / -halogeno lower alkoxy, carbonylthio or carboxy groups, lower alkoxycarbonyl, phenyl or indolyl, amino or di-lower alkylamino group
    If a. R, as lower alkyl, is substituted by halogen, halogen means bromine or iodine, preferably all the same fluorine or chlorine.
    If R is a cycloalkyl group, o is a cycloalkyl group with 5-6 carbon atoms and may be cyclopent or cyclohexyl. If appropriate, substituted phenyl may be single or once substituted with hydroxy, lower alkyl, methylene, DIOXY, lower alkoxy, halogen, carboxy, lower alkoxycarbonyl, lower alkylthio, amino, mono- or di-lower alkylamino or adhiiigo groups.
    Salts of these compounds of general formula (l) are preferably acid addition salts with therapeutically useful inorganic or organic acids.
    The novel compounds have valuable pharmacological properties. For example, these compounds are antimicrobial agents that inhibit the multiplication of pathogenic bacteria in low concentrations (0.850 mg / ml) in vitro, for example, bacteria such as Escherlchia coli, Enterobacter cloacae and other enterobacter, Pseudomanas aeruginosa, a . also yeast bacteria such as Candida albicans and tropical is. New compounds inhibit the development of both gram-negative and yeast bacteria.
    The resulting compounds also act in vivo. At doses of 15-100 mg / kg, these compounds administered subcutaneously or orally, for example, in mice, protect 50% of the animals (lethal infections caused by a lethal dose of pathogenic bacteria, for example, klebslella pneumontae or Pseudomonoas aerugtnosa.
    Newly combined can be applied chemically, either alone or with other antibacterial agents. Another valuable property of the new compounds is their synergistic antibacterial activity with other antimicrobial agents, such as taksh, such as rifamyicin, trimethoprim, O-cyclerin, fluoro-B-alanine and amphotericin B ..
    Purebreds have very low toxicity to mammals and can be used to treat diseases in, especially mammals, animals, as antiseptics, as well as to protect hydrophobic and other organic substances that are decomposed by bacteria and other microbes.
    For the production of oC-aminophosphonic acids of formula (1), hydrogen sulfide; acids, such as hydrobromic acid or carboxylic acids, such as trifluoroacetic acid or formic acid, can be used. The compounds can be obtained in free form by amino-acid based methods, for example, with ion exchangers or with propylene oxide.
    Depending on the conditions of the process and the raw materials, the desired substance is obtained in free form or in the form of a salt with acids or a base. For example, basic neutral or mixed salts can be obtained, in this case also hemimono-, sesqui-, or polyhydrates. The acid addition salts of the new compounds can be converted into the free compounds in the usual way using a basic agent, such as alkali or an ion exchanger. On the other hand, the resulting free bases can form salts with organic or inorganic acids. For the preparation of acid addition salts are used, in particular, those acids which prgodny to form therapeutically acceptable salts: hydrohalic, sulfuric, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acetic, propionic, succinic, Cole gly, dairy, block, vinna, citric, ascorbine, mgceicine, hydroxymaleic or pyruvic acid, phenylacetic acid, benzoic, p-aminobenzoic, antr Nilova, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, zmbonova acid, methanesulfonic, ztansulfonova, oksietansulfova, etilensulfonova acid galogenbenzosulfonova, toluolulfonova, naphthalenesulfonic acid or sulfanilic acid, methionine, tryptophane, lysine or arginine. Particularly commonly used. Optic active salts are D-and 1-forc & 1 tartaric acid, di-o-toluene acid, block acid, almondic acid or camphor-10-sulfonic acid.
    The resulting free compounds of the general formula (.1) can also form salts with bases, for example, lithium alkali metal hydroxides.
    attri or potassium, carbonates or HMPogencarbonates, carbonates of alkaline metals, such as alcium, magnesium hydroxides, magnesium carbonates, acidic carbonates or substituted estermyl bases or heterocyclic bases. features common optics active bases. ow lt O- and L-forms oi / -methylbvzzil 4iia brucine, enegedrin. and cinchonin.
    These or other salts of the new compounds, for example, picrates, can also be used to purify the resulting free bases, by converting the free bases to salts, separating them, and releasing the bases from the salts. . - /
    Depending on the. R to R values of the compounds obtained. There can be at least one optical center. Depending on the number of asymmetric carbon atoms and the choice of starting materials, as well as on the method of work, new compounds can be in the form of racemic mixtures, in atoms and in the form of optical compounds. Aytkpodov.
    Racemic mixtures based on physicochemical differences and "; ingredients can be separated in the usual way into pure racemates, for example, by chromatography and / or by fractional crystallization.
    Numeric racemates can be resolved into diastereomers by known methods, for example, by recrystallization from an optically active solvent, using microorganisms, or by reacting with an optically active acid that forms salts with the racemic compound and separating the salts thus obtained. diastereomers, from which the antipode can be released by exposure to suitable agents. In particular, the usual active acids are the D- and L-forms of tartaric acid, d-o-thluyl acid, malic acid, polyllamino acid, camphorsulphonic acid or quinic acid. You can also get the target product as a pure racemate or optical antipode if you use one or more asymmetric C atoms containing the starting material as a pure racemate or optical antipode.
    New active principles or pharmaceutically applicable salts. Can be used entertainingly, for example orally, rectally, as well as parenteral agents.
    A therapeutic composition can also be prepared consisting of an antimicrobially effective amount of the compounds of the general formula (1) or an acid addition salt and a pharmacologically applicable solid carrier or liquid diluent.
    The pharmaceutical compositions may contain at least one compound of the general formula (l) as an active principle together, with a conventional pharmaceutical carrier. The type of carrier used in most cases depends on the purpose of the application. For external use, for example for
    o disinfecting healthy skin as well as disinfecting wounds and treating dermatoses and mucosal lesions caused by the action of bacteria are mainly used
    5 ointments ,, porksiki and tinctures. Bases for ointments may be anhydrous, for example, consisting of mixtures of lanolin and vaseline, or they may consist of aqueous emulsions in which the active substance is suspended. Powder carriers for suitable powders may be starchy, such as rice whose bulk density may be reduced, for example, by adding finely chopped silicon
    5 acid, or may be increased by adding talc.
    Jasper can contain at least one active ingredient in 45-75% aqueous ethanol, to which 1020% glycerol can be added if desired. In particular, solutions prepared with polyethylene glycol and other substances can be used to disinfect healthy skin.
    5 common dissolving agents and, if appropriate, with emulsifiers. The content of active substance in pharmaceutical compositions for external use is preferably 1.0-5%.
    0
    For disinfection of the mouth and throat, are suitable on the one hand, rinsing with alcoholic solutions with a 1-5% content of active principle, to which glycerin can be added and / or
    5 flavors, on the other hand, suck tablets, i.e. solid unit doses, preferably with a relatively high content of sugar and similar substances and with a relatively low content of active principle, approximately 0.2–20 wt.%, as well as with common additives, such as binders, and aromatic substances.
    five
    For disinfection of the intestine and for oral treatment of ureteral infections, in particular solid unit doses are used, such as tablets, dragees, and capsules, preferably containing 10-90% of the active.
    0 of general formula (1), so that it is possible to use daily dosages from 0.1 to 2.5 g for an adult and lower dosages for children. For tablets
    and a dragee with a core combine the compounds o6i4g c. Formula (1) with solid pulverized powders such as lactose, sucrose, sorbitol, corn starch, potato starch or amylopectin, cellulose derivatives or gelatins, preferably with the addition of lubricants like magnesium or calcium stearate, or suitable polyethylene glycols molecular weight. Dragee cores may be coated with a concentrated sugar solution, which also contains gum arabic talcum and / or titanium dioxide, or they may be coated with lacquer dissolved in a volatile organic solvent or mixture of solvents. A coloring agent can be added to these coatings in order to indicate the various doses of the active principle. Soft gelatin capsules and other closed capsules consist of a mixture of gelatin and glycerin and may contain a mixture of compounds of formula (|) with polyethylene glycol. Split capsules contain granules of the active substance with solid particulate carriers, such as lactose, sucrose sorbitol, mannitol, starches, for example, potato, corn, or amylopectin, cellulose derivatives or gelatins, as well as magnesium stearate or stearic acid.
    The compounds of formula 1 may be the single active ingredient in pharmaceutical compositions or may be combined with other known pharmacologically active, and especially antibacterial and / or antimycotic or other antimicrobially active substances, in order to broaden their scope. They can be used with 5,7-dichloro-2-methyl-8-quinolinol or other 8-quinolinol derivatives, with sulfamerazine, sufofurazole or other sulfanilamide derivatives, with chloramphenicol, tetracycline or other antibiotics, with 3,4, 5-tribromosalicylanilide with other halogenated salitsilanilidagli, carbanilides, benzoxazolyl or benzoxazolone with polihloroksidifekilmetanami with galogendioksidifenilsulfidami with 4,4-dichloro-2-hydroxydiphenyl ether, 2, 4,4-trichloro-2-01 SIdifenilovshk zfyrom or others. poly-halo-oxydiphenyl esters, with bactericidal quaternary compounds or with some derivatives of dithiocarbamic acid, like tetramethylthiuramide sulfide. You can also use carriers that have beneficial pharmacological properties, for example} sulfur, as the basis for powders or zinc stearate. Kai is the main ingredient for ointments.
    Example a) 14.4 g of isobutyraldehyde are added to 36.6 g of benehydrylamine in 100 g of dry benzene at room temperature with stirring. A cloudy, heated mixture with a reverse fridge with water separation for 4 hours. The solution is filtered while cooling a small amount of solid insoluble substances. When evaporating the solution, the isobutylidene benzhydrylamine required for further use is obtained.
    b) 15.8 g of a 100% hypophosphonic acid dissolved in absolute alcohol is added to solution 41, 3 of isobutylidene benzhydrylamine in Absolute ethanol with stirring, the mixture being heated due to an exothermic reaction. After one hour of incubation, the reaction mixture is filtered and the resulting white solid is dried under vacuum, this gives D, L-1-benzhydrylamino-2-methylpropanephosphonic acid with m.p. (with decomposition).
    at). 25 g of D, 1-1-benzhydrylamino-2-methylpropanephosphonic acid are rapidly stirred in 100 g of a 60% aqueous solution of hydrobromic acid for 30 minutes at room temperature and then heated for 45 minutes on a steam bath. After cooling, the oily benzhydryl bromide is extracted thoroughly with ether and the aqueous layer of the acid is evaporated to dryness in vacuo. The semi-solid residue is dissolved in 40 g of ethanol and 10 g of propylene oxide is added. As a result, the filtration gives O, 1-1-amino-2-methylpropanephosphonic acid with m.p. 198198, 5 ° С (with decomposition).
    Example 2. a) 19.8 g of isobutyraldehyde and 62.2 g of benzhydrylammonium hypophosphite are dissolved in 75 g of ethanol and the mixture is heated for 3 hours under reflux. After cooling, the mixture is filtered. Obtain the residue D, L-benzhydryl 4-2-methylpropane phosphonic acid with so pl. 189-192s.
    b) 25 g of O, 1-1-benzhydrylamino-2-methylpropanephosphonic acid are well mixed with 100 g of a 60% aqueous solution of hydrobromic acid for 30 minutes at room temperature and then heated for another 45 minutes on the steam bath. After cooling, the oily benzhydryl bromide is carefully extracted with ether and the aqueous layer of acid is evaporated in vacuo. Dry. The semi-solid residue is dissolved in 40 g of ethanol and 10 g of propylene oxide is added. During filtration, 0.1-1-amino-2-methylpropanephosphonic acid is obtained with a mp. 201-201.5s (with decomposition).
    L and Rm 3. a) Analogously to example 1a), but using 2-methyl-butyraldehyde instead of isobutyraldehyde, is obtained with quantitative. yield 2-methylbutylidenebenzhydrylamine,
    b). Similarly; Example 1b, but using 2-methylbutylidenebenzhydryl amine as the starting material instead of zhydrylamine instead of isobutylidenebe, give benzhydrylamino-2-methylbutano-phosphonous acid with mp. 174-176 ° C.
    c) Described in example 1c by, but with the use of D | l.l-benzy and ylamino-2-methylbutane phosphoric acid instead of O, 1-1-benzhydrylamino-2-methylpropanophosphonic acid as the starting material and in those
    the same reaction conditions give D, 1-1-amino-2-methylbutanophosphonist "o acid with m.p. 203 ° C (with decomposition)
    EXAMPLE 4. A) In analogy to Example 1a, but using 3-methylbutyraldehyde instead of isobutyraldehyde, 3-methylbutylidenebenzhydrylamine is obtained.
    b) Analogously to example 1b), in s. using 3-methylbutylIdenbenzhydrylamine as a starting material instead of isobutyrylidenebenzhydrylamine, benzhydrylamino-3-methylbutylphosphonic acid with m.p. 220 ° C.
    c) By the method described in Example 1c, but using O, L-1-benzhydryl--. amino-3-methylbutanophosphonic acid instead of 01-1-benzhydrylamino-2-methylpropanophosphonic acid as the starting material, with
    O, L-1-amino-3-methylbutano-phosphonic acid with m.p. 222 ° C (with decomposition.
    Example 5 a) This method is carried out as described in Example 1a, under the same reaction conditions. N-heptanal is used in place of isobutyraldehyde and heptylidenebenzhydrylamine is obtained.
    b) Analogously to Example 1b, but using n-heptylidenebenzhydrylamine instead of isobutylidenebenzhydrylamine as a starting material, D, L-1-benzhydrylaminoheptanephosphonic acid with m.p. 201-203
    c) Described in Example 1c by, but using O, Ll-benzhydrylaminoheptanephosphonic acid instead of D, 1-1-benzhydrylamino-2-methylpropanophosphonic acid as starting material, under the same reaction conditions, 0.1-1-amino- n-heptane phosphonic acid with
    m.p. 208-210 ° С (with decomposition).
    Example a) As described in Example 1a, using benzaldehyde as the starting material, together with isobutyraldehyde, benzylidenebenzhydrylamine with a mp. 99-lOl C
    ) Described in example 1b by BUT using benzylidenebenzhydrylamine instead of isobutylidenebenzhydrylamine as a starting material, 0.1-1-benzhydrylaminophenylmethanophosphonic acid is obtained with m.p. 202-204 ° C.
    c) In the same way as described in example 1c), the preparation of 0.1-1-benzhydrylaminobenzylphosphonic acid as a source material D, L-1-aminophenylmethanophosphonic acid with m.p. 239-240 ° С (with decomposition).
    Example a) In the same way as described in Example 1a, using p-chlorobenzaldehyde as the starting material, p-chlorobenzylidenebenzhydrylamine with mp. 8383,.
    b) By using the p-hlc benzylidenebenzhydrylamine as the starting material described in Example 16, D, L-1-benzhydrylamino chlorophenylmethane-phosphonic acid with m.p. 221-222 C.
    c) In Example 1c, using D, L-1-benzhydrylamino-p-chlorophenylmethanephosphonic acid, 0.1-1-amino-p-chlorobenzene phosphonous is obtained
    acid with so pl. 228-230 s.
    Example8. a) As described in Example 1a, methylstilidenebenzhydrylamine is obtained using acetone as the starting material.
    b) In the manner described in Example 16, 1-benzylhydrylamino-1-methylethanephosphonic acid is obtained, m.p. 207210 ° C, using methyl ethylidene benenehydrylamine as a starting material.
    c) According to the method described in Example 1c, using 1-benzhydrylamino-1-methylethanophosphonic acid, 1-amino-1-methylmethanephosphonic acid is obtained with a mp. (with decomposition).
    Sample a) The method described in Example 1a is repeated using cyclopentanone as a starting material. Cyclopentylidene benzhydrylamine is obtained with m.p. Ab-Yuo S.
    b) In a manner similar to that described in Example 1b, it is obtained from cyclopentylidenebenzhydrylsmina 1-benzhydrylaminocyclopentachophosphonic acid with mp. 204-205 ° C.
    c) According to the method described in example 1c, using 1-benzhydrylaminocyclopentane phosphonous acid, y-1-aminocyclopentane phosphonic acid with m.p. 223-225 C.
    PRI me R 10. a) Using cyclohexanone as a starting material, proceeding in the manner described in Example 1a, cyclohexylidenebenzhydrylamine is obtained, m.p. 7172 ° C.
    b) In a similar way, as described in Example 1b, from the cyclohexylidenebenzhydrylamine, 1 benzhydrylaminocyclohexanephosphonous with m.p. 194-196 0.
    c) According to the method described in Example IE f using 1-ben31 | zdrylaminocyclohexanephosphonic acid, 1-amino-cyclohexane-phosphonic acid is obtained with m.p. 228-229 ° С (with decomposition)
    Example 11. a) Using n-butyraldehyde as a raw material instead of isobutyraldehyde, as in Example 2a, D, L-1benzhydrylamine-butane-phosphonous acid with m.p. 215-21b ° C.
    b) According to the method described in example 26), using O, L-1-benzhydrylaminobutane phosphonic acid instead of D, 1-1-base hydrylamino-2-methylphosphonic acid as a starting material, 0.1-amino-n-butane-phosphonic acid is obtained with t .pl. 236236, 5 ° C (with decomposition).
    EXAMPLE 12 a) Using valerian Eld aldehyde as a starting material is obtained according to the method described in Example 2a), O, L-1-ben 3-hydrylamino-benptane phosphonic acid with mp. 209-210 ° C,. .
    b) According to the method described in Example 26), using D, L-1-benzhydrylaminophenylphosphonic acid as a starting material, O, L-1-amino-n-pentane-phosphonic acid with m.p. 230-232 0 (with decomposition.
    Example 13. a) Similar to that described in example 2b). from the 2-methylbutyraldehyde as a starting material, 0, L-1-benzhydrylamine-2-methylbutane-phosphonous acid is obtained, m.p. 172-172,5 ° C.
    b) Using 0.1-1-benzhydrylamino-2-methylbutanophosphonic acid as a starting material, is prepared according to the method described in Example 2b) B, 1-1-amino-2-methylbutanophosphonic acid with m.p. 203205 ° С (with decomposition).
    EXAMPLE 14 a). According to the method described in Example 2a, using 3-methylbutyraldehyde. As the starting material, D, L-1benzohydrylamino-3-and / iTylbutano-phosphonous acid is obtained, m.p. 242-245 0.
    b) According to the method described in Example 2b), D, L-1-acid-3-methylbutano-phosphonic acid with m.p. 222-223 ° C.
    Example 15. a) 0.5 g of freshly distilled acetaldehyde is added to a suspension of 2.5 g of benzylammonium hypophosphite in 10 g of dioxane at KOtfnaTHoQ. temperature and the mixture is stirred for 15 minutes. Then the mixture is slowly heated until complete dissolution occurs and. subsequent formation of flocculent sediment. The reaction mixture is cooled to room temperature with strong stirring and the yellow-orange precipitate is filtered off, washed with dioxane and ether and then with cold ethanol. At the same time, the preparation of OD-1-benzgidfi rilaminoethane-phosphonic acid with
     m.p. 220-221 ° C.
    b) 7.2 g of the obtained 0.1-1-benzhydrylamino-ethanephosphonic acid is added to 70g of a 60% aqueous solution of hydrobromic acid, mixed with heat for 30 minutes and then heated for 45 minutes on a steam bath. After cooling, the oily benzhydryl bromide is carefully extracted with ether and spinning water.
    0 acid. The half tartar is dissolved in 70 g of water and 5 g of propylene oxide is added. Filtration is obtained as a precipitate.
    D, L-1-aminoethanesulfonyl acid with so pl. 223-224 0.
    Example 16. a) 5.8 g of freshly distilled 3-carbomethoxypropionic aldehyde in 10 g of sodium-dried dioxane is added to the suspension
     from 12.4 g of benzhydrylammonium hypophosphite to 60 g of high sodium dioxane, and kept under nitrogen. During the addition, 40 g of a water-dioxane mixture is removed by distillation in order to maintain
     the temperature of the reaction mixture at 100 ° 0 and above. The remaining clear solution is cooled and diluted with an equal volume of alcohol, whereby it forms -. with O, L-1-benzhydrylamino-3-carbome0 toxipropane phosphonist acid with m.p. 162-164 0.
    b) 5 g of the obtained D, L-1-benzhydrylamino-3-carbomethoxypropan-phosphonic acid is added to 50 g
    With a 60% solution of hydrobromic acid and stirred for 4 hours at. After cooling, the oily benzhydryl bromide is extracted with ether and the aqueous phases are evaporated to dryness. The solid residue is dissolved in 10 g of icy methanol and 5 g of propylene oxide is added. D, L-1-amino-3-carboxypropane phosphonic acid, m.p. .
    A sample of the residue obtained from (a) is heated in isopropanol for 4 hours and under reflux. Upon cooling, the mixture is treated with propylene oxide until complete precipitation. D, L-1-amino-3-carboxy-propoxy-propanephosphonic acid with m.p. 156 ° 0.
    PRI me R 17. a) 12 g of freshly distilled phenylacea: thaldehyde in
    20 g of sodium-dried dioxane is added to a suspension of 25 g of hypophosphite benzhydrylammonium in 100 g of sodium-dried dioxane and, as in Example 16, heated under reflux and held under a nitrogen atmosphere. During the addition, 60 g of a water-dioxane mixture are removed by distillation in order to maintain the temperature of the reaction mixture at 100 ° C and higher. The remaining clear solution is cooled and diluted with 50 g of alcohol. Get D, L-l-benzgidropylamino-2-phenylethanephosphonyl acid with so pl. 208 ° C.
    b) 5 g of the obtained D, L-1-bvnzgidrylaminr-2-phenylethanephosphonic acid is added to 50 g of a 60% raster of hydrobromic acid and heated to 70 ° C for 1.5 hours. After cooling, the oily benzhydryl bromide is extracted with ether and aq. the layer is evaporated to dryness. The solid residue is dissolved in 45 g of ethanol and 1.5 g of propylene oxide is added. O, 1-1-amino-2-phenylethanephosphonic acid is obtained with a mp. 227-228 ° C.
    EXAMPLE 18 a) 10 g of freshly distilled l-methoxyphenylacetaldehyde in 20 g of sodium-dried dioxane is added to a suspension of 17 g of benzhydrylac & unius phosphite in EO2 of sodium-dried dioxane and, analogously to example 17, is heated under reflux and kept under nitrogen atmosphere . During the addition of 70 g of a water-dioxane mixture, 125 g of ethyl alcohol was removed by distillation to the reaction mixture, whereby D, L-1-benzhydrylamino-2- (4-methoxyphenyl) ethane phosphonist acid was formed, mp. 199-200s.
    b) 6 g of the obtained 0., L-1-benzhydrylamino-2- (4-methoxyphenyl) -ethanephosphonic acid is added to 40 g of hydrobromic acid solution and heated for 2 hours. After cooling the benzhydryl bromide oily substance is extracted with ether and the aqueous layer is evaporated to dryness. The solid residue is dissolved in 15 g of ethanol and 3 g of propylene oxide is added. 0.1-1-amino-2- (4-hydroxyphenyl) ethane phosphonous acid is obtained with m.p. 235 ° C.
    PRI me R 19. Apply freshly distilled 3,4-dimethoxyphenylacetaldehyde as a starting material instead of p-methoxyphenylacetaldehyde, as in Example 18, D, 1-1-benzhydrylamino-2- (3,4-dimethoxyphenyl) -ethanephosphonic acid is obtained from m.p. 205 C. After the treatment of this obtained phosphonous acid with a solution of hydrobromic acid and propylene oxide, 0.1-1-amino-2- (3,4-dioxyphenyl) -ethanephosphonous acid with m.p. 237-238 0.
    Example 20. Using 3-methylthiopropionic aldehyde instead of p-methoxyphenyl acetadehyde as a starting material, as described in Example 18, is obtained O, 0.1 6 benzhydrylamino-3-methylthiopropylphosphonic acid, m.p. 207-208С. After treating this obtained phosphonous acid with a solution of brs of hydrostatic acid and propylene oxide, 0.1-1 ami-3-methylthiopropanophosphonic acid is obtained with a melting point of 200 ° C.
    EXAMPLE 21 Using 3-methylbutan-2-one instead of p-cytoxyphenylacetaldehyde, as described in Example 18, 0.1-1-venehydrylamino-1, 2-dig1Utilpropa-phosphonous acid with m.p. . after treatment of this obtained acid with brO1 "1stovO | preroditic acid solution and propylene oxide, S, 1.-1-amino-1,2-dimethyl opan-phosphonic acid
    from m.p. .
    Example 22. Using 2,4-dichlorobenzaldehyde instead of p-methoxyphenyl acetic dehydrate as a starting material, as described in Example 18, 0.1-1-benzhydrylamino-1- (2,4-dichlorophenyl) -methanophosphon l with thuy is obtained. acid with so pl. 204-205 - C. After treatment of this obtained acid with a solution of hydrobromic acid and propylene oxide, 0.1-1-a1-shno-1- (2,4-dichlorophenyl) -methanophosphonic acid is obtained with m.p. 244 С
    Example 23. Using hexahydrobene-3 aldehyde instead of p-methoxyphenylacetaldehyde as a starting material, D, L-1benzhydrylamino-1-cyclohexylmethanophosphonic acid with m.p. 199 C. After treatment of this acid with a solution of hydrobromic acid and propylene oxide, O, L-1-amino-1-cyclohexyl methanephosphonic acid with m.p. 225 C.
    Example 24. Using 2-naphthaldehyde instead of p-methoxyphenylacetaldehyde, D, L-1-benzhydrylaglino-1- (2-naphthyl) -methanophosphonic acid with m.p. 205-207 ° C. After treating this obtained acid with a solution of hydrobromic acid and an oxide of hpfilene, O, L-1-amino- (2-naphthyl} -methanephosphonic acid) is obtained, mp 237-239 0.
    Example 25. Using p-methylben-3 aldehyde instead of p-methoxyphenylacetaldehyde, 0.1-1-benzhydrylamino-1- {4-methylphenyl) -methanine-phosphonyl acid is obtained with a melting point of 208-209 ° C. After treating this obtained acid with hydrobromic acid solution and propylene oxide,
    D, L-1-amino-1- (4-methylphenyl) -methane-phosphonous acid with so pl. 235 ° C.
    Example 26. 1g OD-1-amino-2-methylpropanephosphonic acid is transferred from 1 g of sodium hydroxide in
    15 g distilled water to obtain a solution. The mixture is evaporated to dryness and the residue is stirred with absolute alcohol. The filtered precipitate is the sodium salt of D, 1-1-amino-2-methylpropanephosphonic acid with m.p. 231-233 ° C.
    Example 27. 0.1-1-amino 2-methylpropanephosphonic acid is stirred with excess hydrobromic acid for 15 minutes. The mixture is evaporated to dryness in vacuo and the precipitate washed with ascheton. The filtered solid precipitate is Hydrobro 1d O, 1-1-amino-2-methylpropanephosphonic acid: / so pl. 134-136 ° C (with decomposition).
    Example 28 a) 2.75 g of 0, L-1-amino-2-methylpropanophosphonic acid are transferred into 100 g of water until complete dissolution. The pH of the solution is adjusted to 9.5 with 4N sodium hydroxide and the mixture is cooled to OC. 34 g of chloroformic acid benelyl ester are added over time periods of more than 1 hour and the mixture is stirred at a further pH of 9.0-9.5 by the periodic addition of 4N sodium hydroxide. The mixture is then warmed to room temperature and washed with diethyl ether. The aqueous portion is slowly added to a mixture of 120 g of water and 80 g of concentrated hydrochloric acid in 400 g of ice water. The resulting solid is dried and recrystallized from a mixture of ethyl acetate and petroleum ether. Get D, L-l-Kap6obenzyloxyamino - 2-methylpropanophosphonic acid C.t. lOS-lll C.
    b) To 3.4 g of O, L-l-carboxybenzoic-amino-2-methylpropanophosphonic acid in 500 g of absolute ethanol was added 15 g (+) :. -methylbenzylamine in 75 g of absolute ethanol under reflux conditions. 22 g of 1-carbobenzyloxyamino-2-methylpropanephosphonic acid crystallized out with a specific rotation () p 9.5 and
    m.p. 1bЗ-1b8 ° С. This product obtained is recrystallized once more from absolute alcohol, with the constant melting point rising to 169 ° C and a constant specific rotation to (, 4 ° (dimethylformamide: water 9: 1).
    c) An excess of 45% hydrobromic acid is added to the resulting α-methylbenzylamine salt of (-) - 1-carbobenzyloxyamino-2-methylpropanphroic acid, (cL) 16.4
    in acetic acid at 0 ° C and stirred for 1 hour. Then, propylene oxide is added until a precipitate forms. Ethyl ether is added to complete the precipitation. The resulting (-) -1-amino-2-methymptyanophosphonist1 acid melts your alkali 209 ° C and has
    specific rotation (dL) 25-3.6 (1.5% in water).
    Example 29., a) Analogous I by O, L-L-carbobenzyloxy-amino-2-methylpropane phosphonic acid is prepared as described in Example 2a.
    The method described in Example 286 is repeated. The mother liquor obtained by filtering L-methylbenzylamine salt of {-) -, carbobenzyloxyamino-2-methylpropanephosphonic acid with specific rotation (o) 5 -9, 5 is evaporated in vacuo to dryness and get oC-methylbenzylamine salt 1-carboben 3 il symium n o-2 tmethylpropanophosphonic acid with a specific rotation () + 8 ° and so pl. 144-145 ° C. An excess of dilute hydrochloric acid is added to the obtained product with stirring, and 1-carbobenzyloxyamino-2-methylpropanophosphonic acid is obtained with a specific rotation (cA.) +19. (- - I-methylbenzylamine in the same ratios as in example 286) is added to the obtained acid, and one obtains -methylbe :: zylamine salt of 1-carbobenzyloxyamino-2-methylpropophosphonic acid with specific rotation (oC) | f +13 , 8 ° and so pl. 164-167Я ::. This product is recrystallized from absolute ethanol (j part of the active principle on 15 parts of alcohol), and a constant so-called pl.1b9- and constant specific rotation (-) +16.2 and methylformamide: water 9: 1 is obtained.
    c) By the method described in Example 28c, a (f) -1-carbobenzyloxyamino-2-methylpropanephosphonic acid (cA-) +16,2 ° C (α-methylpropanephosphonic acid) cA-methylbenzylamine salt is used in place of the (+) -isomers -methylpropanophosphonic acid () § 3.5 ° (1.5% in water) so pl. 209 ° C.
    Example 30. Using 0.1-1-aminoethanephosphonic acid instead of D, 1-1-amino-2-methylpropanephosphonic acid, similarly to the procedure described in examples 28a b), (1) -1-aminoethanephosphonic acid with m.p. 236.5-237 C (with decomposition.
    Example 31. Using D, L-1-aminoethanephosphonic acid instead of the one described in examples 28a, b, and O, 1-1-amino-2-methylpropanephosphonic acid, gives C + -1 -1-aminoethane phosphnistic acid with mp. 233-233.5 ° C (with decomposition).
    Example 32. a) Using benzylamine (32 g) instead of benzylhydrylamine and isobutyraldehyde (22 g) as in Example 1a, isobutylidenebenzylamine is obtained
    权利要求:
    Claims (2)
    [1]
    b) Using 49 g of isobuty lidene benzylamine instead of isobutylidene benzhydrylamine, analogously to Example 1b, 0 is obtained, and -1-benzylamino-2-methylpropanophosphonic acid with m.p. 220 ° C. c) Using D, 1-1-benzylamine-2-methylpropanephosphonic acid instead of D, 1-1-benzhydrylamino-2-methylpropanophosphonic acid, as in Example 1c), get D, 1-1-amino-2-methylpropanophosphonic acid, identical to with the compound obtained in example 1B). Example 33. Using p, p-dimethoxybenzhydrylamine instead of benzhydryl 1a is prepared analogously to example 1a), b) and in isobutyrylidene-p, p-dimethoxybenzhydrylamine example 1a D L-1 t (p, p-dimethoxybenzhydrylamino -2-methylpropanfone hydroxymethyl). ) and 0.1-1-a-Mino-2-methylpropanephosphonic acid, identical to the compound obtained in Example 1c Example 34. Using pp-dime toxibenzhydrylamine glonium hypophosphite instead of benzhydrylammonium hypophosphite in an analogous manner to example 17, O, L-1-amino-2- is obtained phenylethanephosphonic acid., Example 35. a) 17.2 g of isobuti raldehyde in 15 g of sodium-dried dioxane is added to a suspension of 25 g of benzgidropylafonehypofofit phitol in 150 g of dried sodium dioxane and heated to reflux. 80 g of dioxane are removed from this reaction mixture and 150 g of alcohol are added. After cooling by filtration, the D, L-1-benzhydrylamino-2-methylpropanophosphonic acid with m.p. 189-192 ° C, identical with the compound obtained in Example 2a). b) 5 g of obtained O, 1-bonzhydrylamino-2-methylpropanophosphonic acid, 5 g of anisole and 50 g of trifluoroacetic acid, stirred at room temperature and then heated under reflux for 30 minutes. The reaction mixture is cooled and poured into 100 g of water, the resulting oily layer is extracted with diethyl ether and the aqueous layer is evaporated to dryness in vacuo. The resulting white residue is stirred with alcohol. During filtration, D, L-1-amine no-2-methylpropane phosphonic acid is obtained with a mp. 201-202 C identical compound obtained in Example 26J. P D and meper 36. a) According to the method of opioid in example 35a), using phen-2-aldehyde instead of the isobutyralide of the guide, you get, 1.-1-benzhydrylamino -1- (thien-2-yl) - methanophosphonic acid with m.p. . b) Analogously to example 356), but instead of D, 1-1-benzhydrylamino-2-methyl propanephosphonic acid, 0, L-1-benzhydrylamino-1- (2-thienyl) -methanophosphonic acid is used as the starting material and | 0 , 1-1-amino-1- (thien-2-yl) -methanephosphonic acid with so pl. 229-230 ° C. PRI me R 37. a) According to the method, written in example 35a), using piperonal- (3,4-methylenedioxybenzaldehyde), instead of isobutyraldehyde, teach 0., 1-1-benzhydrylamino-1- (3,4-methylenedioxyphenyl) -methane acid with t.pl. 194-195 ° C. b) In a similar way, as described in example 356), instead of 0.1-1-6-benzhydrylamino-2-methylpropanephosphonic acid, O, 1-1-benzhydrylamino-1- (3,4-methylenedioxyphenyl) 1 yutanephosphonic is used as a starting material. acid and get 0, L-1-amino-1- (3,4-methylenedioxyphenyl) -methanesulfonate acid with so pl.235236 C Example 11. a) According to the method described in npHNffipe 35a), use 4-dimethylaminobenzaldehyde instead of isobutyraldehyde, obtained from 0, L-1-benzhydryl-1-1- (4-dimethylaminophenyl) -methanophosphonic acid with so pl. 205C. . b) Analogously to example 35b, but used instead of 0.1-1-benzhydrylamino-2-methylpropg1Nophosphonic acid as the starting material D, L-1-benzhydrylamino-1- (4-dimethylaminophenyl) -methanophosphonic acid, get O, L - 1 -amino-1-. (4-dimethylaminophenyl) -methanephosphonic acid, with so pl. 223-224 C. PRI me R 39. According to the method described in example 35a), using D, 1-1-benzhydrylamino-2-methylphosphonic acid and trifluoroacetic acid, D, Ll-amino-2-methylpropane-phosphonous acid, which melts at 201-202 ° C and is identical with the product from example 35b). EXAMPLE 40. According to the method described in Example 35a), using formic acid (99-100%) instead of trifluoroacetic acid, O, L-1-amino-2-methyl-propane-phosphonous acidus, m.p. 201-2020С. The product is identical with the product from example 356). PRI me R 41. a) For example 35a, but using 2,4-dioxybenzaldehyde instead of isobutyryeshdehyde, D, 1-1-benzhydrylamino-1- (2,4-dioxyphenyl) -methanephosphonic acid is obtained, m.p. 25С) ° С. b) For example, 35b), using 0.1-1-benzoxyhydrylamino-1- (2,4-dioxnphenyl) -methanephosphonic acid as a starting material, to obtain O, L-1-amino-1- (2,4- dioxyphenyl) -methanephosphonic acid with so pl. 260 C {with decomposition). Example 42. a) In Example 35a, using p-acetamidobenzaldehyde as a starting material, D, 1-1-benzidyryl-amino-1- (4-acetamidophenyl) -methanlophonous acid with m.p. 19b-200 ° C. b) According to the method described in Example 36b), using D, L-1-bvnzgidrylamino-1- (4-acetamidophenyl) -1-datanephosphonic acid as the starting material, O, L-1-am Ho-1- (4- acetamidophenyl) -methanephosphonic acid. After treatment with diluted hydrobromide with a reflux condenser and then with propylene oxide, 0.1-1-amino-1g (4-acetaglyldophenyl) methanephosphonic acid is obtained. . . Example 43. a) Using pyridyl-3-aldehyde as a starting material, is prepared according to the method described in size 35a), O, Ll-benzgirylamino-1-pyrid 3-yl-methanophosphonic acid with T.Sh1, 129-132 C. b) According to the method described in example 35tj), using the OD-benzhyd) rilamo-1-pyrid-3-yl-m-panthophonyl acid to the lot, O, 1 is obtained as the starting material. -1-amino (pyrid-3- or) -membrane sour y monotrifluoroacetate with so pl. 194-197 p. Example 44. According to the method described in Example 53 b), use 0.1-1-benzhydrylamino-2- (3,4-dimetho-siphenyl) -ethane phthalic acid (prepared as in Example 20.) as the starting material , get D, L-1-amino-2- (3,4-dimethoxyphenyl) -ethanephosphonic acid. It is processed with 60% hydrogen bromide at 80 ° C and then with propylene oxide, whereby 0, -1-amino-2- (3,4-dioxyphenyl) -ethanephosphonous acid is obtained with m.p. 237-238s. The product is identical with the product from Example .20. P RIM a p 45. According to the method described in Example 18, using hexene-2-one (allyl acetone) as the starting material, 0.1-1-benzhydrylamino-1-methylpent-4-ene en osate acid is obtained with m.p. . 180c, It is treated with hydrogen bromide and then with propylene oxide. Poluchaio O, 1-1-amino 1-methyl-4-bromopentane; A phosphonic acid with m.p. 146-148 C. EXAMPLE 46. a) In Example 35a), using acetaldehyde as starting material, D, 1.-1-benzg and iryl-ethane-phosphonic acid, identical to the product from Example 15, is obtained. B) Use 0.1-1-benzhydrylamine ethanephosphonic acid as a starting material, obtained according to the procedure described in Example 35b), -1-aminoethanephosphonic acid, identical to the product of Example 1 Example47. a) Analogich {; M by, as described in psmmer 35a), get furfuraldehyde, as a starting material, o i-l-benzhydrylamino-1- (fur-2-yl) -methane phosphonous acid with t.yl. . b) Similarly to the pr 35sher 6 6), from D, C-1-benzhydrylamino-1- (fur-2-1b) -methanephosphonic acid as starting material, obtained from D, L-1-amino- (fur-2-yl) - methanephosphonic acid with so pl. 221 ° C. Example 48 a) According to the method described in example 35a), using indol-3-ylacetaldehyde as the original material, D, L-1-benzhydrylamino-2- (indol-3-yl) -t-phosphorous is obtained. acid, so pl. 221-222 C. b) According to the method described in Example 35b), 0.1-1-amino-2 is obtained from D, 1-1-benzhyd "lamino-2- (indol-3-yl) -ethanephosphonic acid - (indol-3-yl) -ethanephosphonous acid, mp.253-254 C. Example 49. a) According to the method described in Example 35, OD-1-benzhydrylmino-2-benzyloxyethane-phosphonous acid was obtained from t-2-benzyloxyethane-phosphonic acid. square 208-211 C. b) In a similar way as described in Example 35 b, from 0.1-1-benzhydrylgio-2-benzyloxyethanephosphonic acid, 0.1-1-amino-2-oxy-istanophosphonic acid is obtained, m.p. 210 C (with decomposition). PRI m 6 p 50. a) The method of priming 35 a) is repeated using 5-hydroxypente al instead of isobutyraldehyde, obtaining D, 1-1-benzhydrylamino-5-oxypentane phosphonic acid, m.p. 179184 ° e. b) The method of Example 35b) is repeated using O, 1-1-benzhydrylamino-5-hydroxypentaphosphonic acid instead of D, 1-1-benzgIdrylamino-2-methylpropanophosphonic acid, to obtain O, L-1-amino-5-hydroxypentane phosphonic acid from m.p. 216-217 ° C. c) Sample D, 1-1-benzhydrylamino-5-hydroxypentanephosphonic acid is treated with a 60% solution of hydrobromic acid under reflux for 2 hours: After cooling, the mixture is washed with ether in order to remove benzhydryl bromide and evaporate the aqueous portion to dryness. The residue was dissolved in ethanol to give 0.1-1-amino-5-bromopentanephosphonic acid, propylene oxide, with a m.p. I72-174C. Example 51. a) Repeat the procedure of Example 35a) using 3,4-dimethoxyphenylacetone instead of isobutyraldehyde to obtain 0.1-1-benzhydrylamino-1-methyl-2- {3, 4-diletoxyphenyl) ethanephosphonic acid with t, square 152.5-154 ,, b) Pre-shredder 356 is repeated using ethanesulfonic acid instead of D, L-1-benzhydrylamine-2-methylpropanophosphonic acid, to give O, 1-1-amino-1-methyl-2- (3 4-dimethoxyphenyl ) -ethanphos phonist acid with so pl. . Example 52. a) Repeats the procedure of Example 35a) using 4-hydroxybenzaldehyde instead of isobutyraldehyde to obtain OD-1-benzhydryl ino-l- (4-oxyphenyl) -methanone phosphonic acid. Mp. 199-201 C. b) Repeat the procedure of Example 356 with the methane phosphonist 4e. you instead of 1,1-1-benegid1ri g1mino-2-methylpropanophosphonic acid, to obtain O, 1-1-amino-1- (4-hydroxyphenyl) -methanophosphonic acid with so pl. 227-23 ° C. Example 53. a) Repeat the procedure of Example 35a) using 3,4-dioxybenealdehyde, completely one-isobutyraldehyde, to obtain 0.1-1-benehydrylamino-1- (3,4-dioxyphenyl) -mutane phosphonic acid, s-mp, 2082100C . b) Repeat the procedure of Example 35b) with the addition of methanephosphoric acid instead of 0.1-1-benzgiD1 lamino-2methylpropanophosphonic acid to give O, 1-1-amino-1- (3,4-dioxyphenyl) methanophosphonic acid with a mp of 266,6650 . Formula of the invention. A method for producing ot-aminophosphonous acids of the general formula / OH n-c-Rlu I. I II H. where L is non-identical or substituted lower alkyl, cycloalkyl with C atoms from 5 to 6, unsubstituted or substituted phenyl, naphthyl, pyridyl, furyl, thieyl, indolyl hydrogen, or R and R are together -cyclopentyl, cyclohexyl or cycloheptyl residue, or their salts, or -optical isomers, 3 and to the end and with the fact that the ft -eucino phosphonic acid of the formula yiv G where R and R have the indicated values R -benzyl, benzgildil or p, n ,,, dimethoxybenzhydryl, is exchanged. and the action of c-halogen-hydrogen or Xbonic acid in the medium of an organic solvent at 20-90 s, followed by release of the product in a free form, either as a salt, or as an optical isomer. Sources of information taken into account during the examination 1. U.S. Patent 3,505,579, cl. 252-107, published. 1970.
    [2]
    2. Purdela D. R. Valchanu. Chemistry of Organic Phosphorus Compounds M, Hsley 1972, 167.
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