SU480216A3 - The method of obtaining - (aminophenyl) aliphatic derivatives of carboxylic acids or their salts, or their oxides - Google Patents

Description

This invention relates to a process for the preparation of new a- (aminophenide) -aliphatic carboxylic acid derivatives that can be found in pharmaceutical pharmaceutical form. A method of producing amino acids of the general formula R, O.Cji Ph-C-C-OH RO is known, where RI is hydrogen, lower alkyl; R2 is hydrogen, aliphatic or dicloaliphatic hydrocarbon; Ph-- phenyl; A is lower alkylene, lower alkenylene, azanized alkylene, oxyfine alkylene or thianized alkylene, which is included in the interaction of a compound of the formula where X is the formula g (R,) (R2) -Y where Y is an alkali metal or a halogen-magnesium group; RI and R2 are as defined above, with a reactive derivative of angle or formic acid. However, there are no references in the literature about methods for producing a- (aminophenyl) aliphatic carboxylic acid derivatives of the general formula where R is a carboxyl group, functionally modified in some cases; RI is a hydrogen atom or lower alkyl, or cycloprone; R2 is a hydrogen atom, halogen or trifluoromethyl; oo or p. six-membered 3-alkenylene amino residue, or their salts, or their N-oxides. The 3-alkenylene iamine moiety A b1 is a 3-pyrrolin-1-yl as well as 1,2,5,6-tetragndro-1-cyridyl group. By halogen atoms is meant fluorine atoms, especially chlorine. Functionally modified carboxyl groups R are esterified carboxyl groups, preferably substituted in some cases, lower carbalkoxy groups, as well as functionally modified carboxyl groups in which the carbon atom is replaced with at least one nitrogen atom similar to that substituted lower alkyl groups, lower alkylene groups containing s tsegi-1 heteroatom, i.ch monobasic and disubstituted hydroxyl groups with carbamyl or thiocarbamyl oh group In addition, R represents a carboxyl group in the form of a salt, for example in the form of a metal salt or an ammonium salt. Lower kills contain mostly up to 4 carbon atoms. These include, for example, methyl, ethyl, n-propyl, isopronyl, -butyl, isobutyl,.-Butyl or tert-butnl. Substituted lower alkyls include, for example, hydroxyl, lower alkoxy or substituted in some cases, tertiary amino groups, and these replace; Preferably, the lower alkyl residue is separated from the carbon bonding atom by at least one carbon atom. Lower alkoxy groups contain Glamas. In general, up to 4 carbon atoms n may represent the methoxy, ethoxy, n-cropoxy, isopropoxy or i-butoxy groups. Substituted s in some cases of the amino group include, for example, lower alkyl, lower alkylene, lower oxyalkyl / gene or lower azaalkylene residues 3 as substituents and can be, in particular, such lower alkylamino or lower dialkylamino groups, such as methyl-amino-dimethylamino -, to ethyls: 1 Yu- or diethylaminogroups, or also alkyleneamine groups with 3-7 membersiv:; f in the ring, as pyrrolidine or pipernut groups, Morpholium or piperazium groups, substituted by some cases in the sex over 4, for example, a lower alkyl moiety. The above substituted amino groups can also be formed with the nitrogen atom of the amide or thioamide group. The proposed method for the preparation of compounds of general formula 1 consists of IB in that the compound of general formula // VCH-Y, where RI and P, 2 are as defined above; YI - In the corresponding case, the functionally modified carboxycarbonyl group, is decarbonated by pyrolysis, preferably in a fine iron or copper or glass. The compounds obtained can be converted one into the other using known methods. Thus, the resulting free acids can be esterified with alcohols in the presence of such etherifying agents as strong acids, in particular hydrochloric, sulfuric or l-toluenesulfonic acid, and dicyclotohexylcarbodiimide, or in the presence of diazo compounds, and after treatment with halogenating agents, for example thionyl halide mi, in particular, thionyl chloride, or phosphorus 1 halides and phosphorus oxyhalides, for example phosphorus chlorides or phosphorus oxychloride, the resulting free acids can be converted in acid halides. The esters obtained can be hydrolyzed to free acids, for example: by treating the esters with suitable basic substances, in particular aqueous solutions of alkali metal hydroxide, or can be transesterified by exposure to alcohols in the presence of such acidic or alkaline agents as acids heavy metals, as well as alkali metal carbonates or alkoxides. Esters can be converted to amides by treatment with ammonia or the corresponding amines. By acting on acid halides with alcohols, as well as with ammonia or amines, the corresponding esters or amides can be obtained. The obtained metal salts of acids after treatment with alcohols or the corresponding halides, for example, chlorides or bromides, or such suitable organic halogen sulfites as lower alkyl chlorosulfites, can be converted into esters. The resulting metal salts of acids are treated with halogenating agents, for example phosphorus halides, ... in particular phosphorus phosphorus, or phosphorus oxyhalides, in particular phosphorus oxychloride, (they are converted to the corresponding galvanic acid anhydrides, while processing the ammonium salts obtained and dehydrated). As phosphorus pentoxide, thionyl halides, phosphorus halides or phosphorus oxyhalides, amyls and nitriles can be formed. Sulfur containing compounds, in particular and thioamides can be obtained from the corresponding oxygen analogues, their influence on the phosphorus pentasulfide. The resulting amides may PLD thioamides

be hydrolyzed, in an acidic or alkaline environment by treating them with aqueous solutions of mineral and / or carboxylic acids or alkali metal hydroxides, and may also be subjected to alcoholysis or transaminization. In addition, as a result of treatment with mercury oxide | I (II); and lower alkylhalogenyl diamides followed by hydrolysis can be desulfurized.

The nitriles formed can be either gil rolue or alcohol: izu, natfimer, the action on them of concentrated aqueous or alcoholic solutions of acids, acidic or alkaline agents such as alkali metal hydroxides, and alkaline hydrogen peroxide.

The resulting esters, salts or H, it1p, silts, in which group RI (represents a hydrogen atom, can metallize into the a-position with the formation of a functionally modified carboxyl group, and then can interact with reactive esters formed from the alcohols of the formula. In this way, the organic grouping R |

The synthesized compounds, in which the residue R2 represents a hydrogen atom, are capable of halogenation, in particular, chlorination to position 3, for example, when they interact with halogens, in particular chlorine, mostly in the presence of "Lewis hypotheses, for example halides of iron (P1), aluminum, antimony (III) or tin (IV) or halogenating agents, in particular hydrochloric acid, in the presence of hydrogen peroxide or chlorates of alkali metals, for example sodium chlorate, such nitrosylhalide, as nitrosyl chloride, and and N-galogenimida such as N-hlorimid, particularly M-hlor.suktsinnmid or Nhlorftalimidy.

The resulting free acids can be converted into salts by known methods, for example, by the action of free acids with suitable salt-forming agents, for example, ammonia, amines, alkali or alkaline earth metal hydroxides. or with carbonic and acidic carbonate salts of m. and alkaline and alkaline-earth metals,. for these reactions, the salt-forming component must be taken approximately; in stoichiometric amounts. The resulting ammonium salts or salts, including a metal atom and corresponding to this type of compound, can be converted into free compounds by the action of an acid on them, for example, hydrochloric, sulfuric or acetic, until the desired pH is reached.

The resulting compounds of the main type due to their interaction with nonorganic or organic acids or the appropriate anti-exchangers iH release of the abrading salt can be lost. They are converted into salts resulting from hydrogenation; (1 and the acids to the basic compounds. Salts obtained are Additize compounds with acids - can be converted into free organic compounds by treating them with bases, for example, hydroxide alkali metal compounds, ammonia or ion exchangers in hydroxyl form. Whether are .The product

additions with such inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or with such organic acids, in particular carboxylic or sulfonic, such as formic, acetic, prolonic, succinic, glycolic, milky , Blochna, vinna, citric, ascorbic, maleinav, 1hydroxymalein, T1iro.vino, hail, phenylacetic, benzoic,

4-aminob. , sulfonyl or cyclohexylsulfamine acid, 1ta.

The above salts or others, for example picrate, can also be used; e., G. Identification. Or purification of free compounds. So the latter can be .nr.evroshcheny .in their salts, which can then be isolated from the crude mixture, and .of

isolated compounds can be obtained again, but in a more pure form.

N-oxides can be obtained by known methods, for example, by reaction with hydrogen peroxide or with such inorganic or organic peracids, in particular carobic acid peracids, such as peracetic, trifluoro-acetic acid or perbenzoic acid.

The resulting isomeric mixture can be separated into individual isomers by known methods, for example, by performing fractional distillation or crystallization and / or by chromatography. Racemic products can be divided into optical antipodes, for example, by preparation and subsequent separation, in particular, by means of fractional crystallization. Mixtures

diastereomeric salts, for example, with d-or-tartaric acid or with-α-phenyllethylamine, da- (1-naphthyl) ethylamine or / -cysononylum, and in yellow cases, the antipodes can be converted from free state.

The above reactions can be carried out in the absence or in the presence of diluting agents, ... mainly in the presence of thinning inert with respect to the reaction components and able to dissolve it.

In necessary cases, the reactions can be carried out in the presence of catalysts, condensing agents or neutralizing agents, in an inert gas medium, for example under a nitrogen atmosphere, and also with cooling or heating and / or with increased pressure.

Example 1. 30.8 g of a-oxo-p-3-chloro-4- (3-pyrrolin-1-yl) -phenyl-ethyl ester, are heated: slowly to 175 ° C in -vacuum (15 mm. Hg. Art.) And kept at this temperature, until the process of carbon monoxide release is completed. After 6 hours, the oily residue, containing a-3-chloro-4- (3-pyrrolin-1-yl) -phenyl-lropionic acid ethyl ester, was dissolved in 100 ml of ethanol and 100 ml of a 10% ethanolic solution of potassium hydroxide. The mixture was boiled under reflux for 4 hours, then evaporated and the residue was dissolved in 100 ml of water. Next, the solution is washed with diethyl ether. Set with HELP. And hydrochloric acid pH 5.5 and extracted with diethyl ether. - The organic extract is washed with water, dried and evaporated, and the residue is recrystallized from toluene. A-3-chloro-4- (3-pyrrolin-1-yl) -phenyl propionic acid is obtained, which, after recrystallization from toluene, melts at 96-98 ° C.

The original product is obtained as follows.

A mixture of 93 g of 4-ethyl-2-chloronitrobenzyl, 127 g of oxalyl chloride and 300 ml of dry nitrobenzene was boiled for 48 hours with a reflux condenser. Then it is cooled, diluted with water and extracted with diethyl ether. The organic extract is dried and evaporated. A-oxo-p- (3-chloro-4-1Nitrofenil) -butyric acid is obtained.

A mixture of 100 g of a-oxo-p- {3-chloro-4-nitrophenyl) -butyric acid and 200 ml of acetic acid is hydrogenated in Prisutsbvi 3 g of catalyst (10% palladium on coal) under a pressure of 3 atm. At the end of the hydrogen uptake, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. A-oxo-p- (4-amino-3-chlorophenyl) -butyric acid is obtained.

A mixture of 95 g of a-oxo-p- (4-amino-3-chlorfell) -butyric acid, 120 g of 1,4-dibromo-2-butene, 106 g of sodium carbonate and 300 ml of dimethylformamide is heated for 5 hours at 100 ° С l then decant. The solution is evaporated under reduced pressure. A-oxo-p-3-chloro-4- (3-pyrrolin-1-yl) -phenyl-β-butyric acid is obtained, which is converted into ethyl ester by a-oxo-p using ethanol in the presence of chlorine-pure hydrogen. 3-hl: op-4- (3-1PIrrolin-1-yl) -epyl - oil acid. The latter is further processed without purification.

Similarly, using the appropriate

starting materials, the following compounds can be obtained:

(3-pyrrolin-1-yl) -phenyl - propionic acid, m.p. 197-199 ° C after recrystallization from a mixture of benzene-hexane;

a-3-chloro-4- (3-pyrrolin-1-yl) -phenyl - butyric acid, so pl. 103-105 ° C (from hexane);

a-3-chloro-4 - (3-pyrrolin-1-yl) -phenyl-acyclopropyl acetic acid, m.p. 152-156 ° C (from diethyl ether);

4- (1,2,5,6-tetrahydropyridyl) -phenylacetic acid, obtained by hydrolysis of 4- (1,2,5,6-tetrahydro. Pyridyl) ethyl ester ethyl ester, detecting in the IR spectrum characteristic absorption bands at 5.86 microns. and 6.08 microns, and 4- (3-pyrrolin-1-yl) -phenylacetic acid, so pl. 162--165 ° C, obtained by hydrolysis of

4- (3-pyrrolin-1yl) -phenylacetic acid ethyl ester.

Example 2. To a plant solution prepared from 25.1 g of dJ / -a 3-chlorop-4- (3-pyropolin-l- "l) phenyl-propionic acid, which was prepared in example 1, and 450 ml ether, was added with stirring to 17.1 g (1-11 naphthyl) ethylamine. The reaction mixture is evaporated under reduced pressure, and the residue after evaporation.

times from a mixture of ethyl alcohol - ether. Solution 5 2 of the salt obtained in this way (mp. 133-135 ° C) in a minimum amount of a 5% aqueous solution of sodium hydroxide is washed with ether. Then using

hydrochloric acid was adjusted to pH 5.5 and extracted with ether m. The organic extract is dried, filtered. And evaporated. Receive-a-3-chloro-4- (3-.P1I | rrolin-1yl) -phenyl-prolionic acid.

.4-34.8 ° (ethyl alcohol).

Example 3. A mixture of 5ga-3-.chloro-4- (3-pyrrolin-1- .yl) -phenyl-propionic acid, 200 ml of 1,2-dichloroethane and 42.6 g of anhydrous disodium phosphate are treated for 40 minutes with stirring and temperature from -5 to 0 ° С with a solution of trifluorone acetic acid, obtained from 2.2 ml of 90% hydrogen peroxide in one and 12.6 ml of anhydrous acid and fluorosoic acid in 50 L1L of 1,2-dichloroethane . In 2 hours

300 g of ice are added to the reaction mixture, the organic phase is separated, and the aqueous layer is extracted with methylene chloride. The combined organic solutions are dried, filtered and concentrated. A-3-chloro-4- (3-pyrrol-1-yl) -phenyl-propionic acid N-oxide is obtained, i.e. 140 - 142 ° C.

Example 4. To a mixture of 5.5 g of ethyl ether. Pa 4- (3-lyrroles: - -1-yl) -phenylacetic acid: UOml, l:. | methylethylformamide and 100 liters of toluene are added in portions with stirring 1.25 g of sodium hydroxide 54% in mineral oil After this, the reactive mixture is stirred for an additional hour.

30 min at room temperature. Then to