CH528531A - Substd oxazoles and thiazoles - Google Patents

Abstract

Preparation of subst. oxazoles and thiazoles of general formula (I) and their salts:- (X = O or S; R1 and R2 = phenyl- optn. subst. by one or more hal-, alkyl-, alkoxy-, nitro-, amino-, subst. amino-, halogenalkyl-, mercapto-, alkylthio-, alkylsulphonyl-, naphthyl- or heteroaryl, which may be subst. R3 = C2-6 aliphatic acid deriv. e.g. salt, ester or amide R1 R2 and R3 are situated in positions 2-, 4- and 5- preferably thiazoles (II) and oxazoles (XI) where R1 and R2 = phenyl-, chlorophenyl-, bromophenyl-, methylphenyl-, methoxyphenyl-, trifluormethylphenyl-, 1-naphthyl-, 2- or 3-thienyl-, 2- or 3-furyl- R3 = acetic acid, n-propionic acid, isopropionic acid, n-butyric acid and their salts, ester or amide) Anti-inflammatories.

Description

  

  
 



  Process for the preparation of new heterocyclic compounds of aromatic character
The invention relates to a process for the preparation of new heterocyclic aromatic compounds.



   A well-known anti-inflammatory compound is phenylbutazone, but it has disadvantages, e.g. B. that of an ulcerogenic effect.



  Another medicine used to treat inflammation is aspirin (trade name for acetylsalicylic acid), but high doses are required and the compound is very ulcerogenic.



   In the search for compounds with an anti-inflammatory effect, a new group of trisubstituted aromatic heterocyclic compounds has now been found, which of the formula I
EMI1.1
 correspond and which can also be in the form of their acid addition salts. In formula I:
X oxygen or sulfur;

  R1 and R2, which are identical or different, each have an unsubstituted phenyl group, a phenyl group substituted with one or more halogen atoms, an alkyl or alkoxy group with 1 to 6 carbon atoms, a nitro, amino, substituted amino group, a haloalkyl group with 1 to 6 carbon atoms, a mercapto, alkylthio, alkylsulfonyl group or a substituted or unsubstituted naphthyl or heteroaryl group; and R8 is a straight-chain or branched aliphatic acid group with 2 to 6, preferably 2 to 4, carbon atoms in the chain or a salt, hydroxamic acid, ester, amide or thioamide derivative of such, and where each of the groups Rt, R2 and R8 is in the 2-, 4- and 5-positions.

  This means that one of the groups mentioned in the formula I is in the 2-position, another of the groups mentioned is in the 4-position and the third of the groups mentioned is in the 5-position,
If certain groups are to contain 1 to 6 carbon atoms, they preferably have 1 to 4 carbon atoms.



   The compounds of the above formula I are characterized by pharmacological activity, e.g. B. by anti-inflammatory effect, with little or practically no ulcerogenic effect, as animal experiments have shown, and / or by antibacterial effectiveness. In addition, some of them produce intermediates for the production of other substituted aromatic heterocyclic compounds.



  Test methods for detecting the anti-inflammatory effect of the compounds are described, for example, in the following publications: Winter u. a., Proc. Soc. Biol. Med. 111: 544 (1962); Buttle et al. et al., Nature 179: 629 (1957); Konzett and Rossler, Arch.



  Path. Pharmac. 195: 71 (1940); and Newbould, Brit.



  Jour. Pharm. Chemoth. 21: 127-137 (1963).



   The compounds of the above formula I are obtained analogously to methods known for the synthesis of such aromatic heterocyclic rings.



   The invention relates to a process for the preparation of compounds of the formula I, which is characterized in that a haloketone of the formula II
EMI1.2
 wherein Hal represents a halogen atom with an amine or thioamide of the formula III
EMI2.1
 or a salt thereof.



   In these formulas, the substituents Rz, Rb and RG, Rs, R2 and R8 are in any order.



  There is the possibility of converting the group R8 into another group R3, which can be done by generally known methods, e.g. B. by conversion into hydroxamic acid derivatives, esterification, amidation, thioamidation, hydrolysis, alcoholysis, chain extension, oxidation, splitting off of carbon dioxide or reduction.



   Specifically, this means that in cases in which R8 is not the desired group R3, the group RS can be converted into another group R3 by means of a suitable agent. For example, the following options are to be mentioned:
I. An ester or amide group is reacted with a hydrolysis agent to form a carboxyalkyl group.



   II. An acid group R8 is reacted with an alcohol to form a carbalkoxyalkyl group.



   III. An ester group R3 is reacted with hydroxylamine to form a hydroxamic acid group.



   IV. An acid group R3 or its salt, e.g. B. an alkali metal or amine salt, with an acyloxymethyl halide, z. B. an acetoxymethyl halide, converted to an acyloxymethyl ester of a carboxyalkyl group.



   V. An acid group Ra or its functional derivative is reacted with ammonia or an ammonium salt with heating to give a carboxamidoalkyl group.



   VI. An acrylic acid or acrylic ester group R8 is converted into a propionic acid or propionic ester group by catalytic hydrogenation.



   Examples of the groups Rt and R2 are: unsubstituted or substituted by one or more, but preferably one substituent phenyl groups, with fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, methoxy as substituents , Ethoxy, propoxy, buto, xy, nitro, amino, especially dialkylamino, e.g. B. dimethylamino, trifluoromethyl, mercapto, methylthio or methylsulfonyl and methoxy and halogen or methyl and halogen together come into consideration, also 1- and 2-naphthyl, 2- and 3-furyl, 2- or 3-thienyl and 2- , 3- and 4-pyridyl.



     RS can stand, for example, for an acid residue, the acids z. B. acetic acid, n-propionic acid, isopropionic acid, n-butyric acid, isobutyric acid or olefinically unsaturated acids, e.g. B. acrylic acid, come into question; also for the remainder of an acid derivative, e.g. B. a salt, ester, amide, thioamide or hydroxamic acid derivative.



   A preferred group of the compounds obtainable according to the invention include those in which X is sulfur, Rt is in the 2-position and R2 in the 4-position and R3 is in the 5-position and a saturated aliphatic acid group with 2 to 6, preferably 2 to 4 , Corresponds to carbon atoms. This group includes thiazoles of the formula IV
EMI2.2
 where R1 and R2, which are the same or different, each have an unsubstituted phenyl, halophenyl group, an alkylphenyl group with 1 to 6 carbon atoms in the alkyl radical, an alkoxyphenyl group with 1 to 6 carbon atoms in the alkoxy radical, a trihalomethylphenyl, naphthyl, thienyl or furyl group and R3 represents a saturated aliphatic acid group having 2 to 6 carbon atoms or a derivative thereof.

  Preferably Rl and R2 are phenyl, chlorine or bromophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, 1-naphthyl, 2- or 3-thienyl or 2- or 3-furyl groups and R3 is acetic acid, n- Propionic acid or isopropionic acid group or a salt, ester or amide of such.



   The compounds of the formula IV are conveniently prepared by adding an α-haloketone of the formula V
EMI2.3
 wherein Hal is, for example, chlorine or bromine, with a thioamide of the formula VI
EMI2.4
 reacted and optionally converted the thiazole obtained into another thiazole of the formula IV.



   It is particularly useful to use an acid of the formula V, i. H. reacting a compound in which R4 contains a COOH group and preferably an acetic acid or n-propionic acid group, in which Hal is bromine, with a suitable thioamide. The reaction is conveniently carried out in a solvent at room temperature or higher temperatures, e.g. B. at temperatures up to the boiling point of the solvent carried out. If the reaction is carried out in the absence of a base and in the presence of an alcohol, for example ethanol, the product obtained is generally the corresponding ester which, if desired, can be hydrolyzed to the acid.



  If, on the other hand, another solvent or an alcohol, preferably isopropanol, is used as the solvent in the presence of a base, e.g. B. an alkali carbonate is used, the acid group R8 is generally obtained directly, so that, if the acid is desired, the need to carry out hydrolysis is eliminated. In both cases, it is advantageous to add a base to the reaction mixture after the reaction has ended, e.g. B. aqueous sodium carbonate solution to add to facilitate the separation of the desired product.



   The α-haloketones of the formula V can be prepared in a known manner, for example by halogenation, e.g. B. bromination, the product of Friedel-Crafts reactions between optionally substituted aromatic or heteroaromatic hydrocarbons and suitable anhydrides, e.g. B.



     Succinic, glutaric or methyl succinic anhydride. The solvent used for the halogenation is preferably ether. The thioamides of the formula VI can in general from the corre sponding nitriles by the method of Fairful u. a., J.



   Chem. Soc. 1952, manufacture 742.



   Another group of compounds of the formula I, where X is a sulfur atom, are the thiazoles of the formulas VIIa and VIIb
EMI3.1
 wherein Ri and R2, which are the same or different, each represent an unsubstituted phenyl group or a halophenyl group, an alkylphenyl group with 1 to 6 carbon atoms in the alkyl radical, an alkoxyphenyl group with 1 to 6 carbon atoms in the alkoxy radical, a nitrophenyl, trihalomethylphenyl, naphthyl, thienyl - or furyl group, and R3 has one of the meanings defined above in connection with the formula I. Preferred groups are those which are also preferred for the thiazoles of the formula IV.



   The thiazoles of the formulas VIIa and VIIb can be prepared in a manner analogous to that described above for the compounds of the formula IV.



   For example, an a-halo ketene of the formulas VIIIa or VIIIb
EMI3.2
 or
EMI3.3
 with a thioamide of formula VI or IX
EMI3.4
 convert and if necessary convert group R4 into group R3.



   The haloketones of the formulas VIIIa or VIIIb can be prepared by halogenation of the corresponding ketoesters or of deoxybenzoin. The thioamides of the formulas VI and IX are either known compounds or can be prepared in a manner analogous to the known compounds.



   Compounds of the formula VIIa are preferably prepared by the above process using an α-haloketone in which R4 is an ester group, e.g. B. an acetic acid or propionic acid ester group, while compounds of the formula VIIb are preferably prepared by the above process by using a thioamide in which R3 is an ester group, e.g. B. the ethyl ester group.



   Another group of compounds of the formula I, where X is an oxygen atom, are the oxazoles of the formula X.
EMI3.5
 wherein R 'and R2, which are the same or different, each represent an unsubstituted phenyl group or a halophenyl group, an alkylphenyl group with 1 to 6 carbon atoms in the alkyl radical, an alkoxyphenyl group with 1 to 6 carbon atoms in the alkoxy radical, a trifluoromethylphenyl, naphthyl, thienyl or Furyl group, and R3 has one of the meanings defined above in connection with the formula I.

  Preferably R1 and R2 are phenyl, chloro or bromophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, 1-naphthyl, 2- or 3-thienyl or 2- or 3-furyl groups, and R3 is an n-propionic acid or n-butyric acid group or a salt, ester or amide of such.



   These compounds can be prepared by the method described above.



   Another group of oxazoles of the formula T are those of the formula XI
EMI4.1
 where R1 and R2, which are the same or different, each have an unsubstituted phenyl group or a halophenyl group, an alkylphenyl group with 1 to 6 carbon atoms in the alkyl radical, an alkoxyphenyl group with 1 to 6 carbon atoms in the alkoxy radical, a nitrophenyl group, a haloalkylphenyl group with 1 to 6 Carbon atoms in the alkyl radical, a naphthyl, thienyl or furyl group, and R3 has the meanings defined in connection with the formula I. Preferred groups R1 and R2 are those listed in connection with the formula IV.



   The oxazoles of the formula XI are preferably prepared by using a ketone of the formula VITla
EMI4.2
 with an amide of the formula XII
EMI4.3
 or a salt of such.



   In this reaction, R3 is preferably an ester group, e.g. B. ethyl acetate group.



   In order to obtain R3 in the 5-position, the amide of the formula XII is first converted into the alkali salt; this is then reacted with a compound of the formula VIOLA, preferably by heating in solution in a solvent. If one proceeds carefully, it is often possible to obtain the intermediate of the formula Xffi
EMI4.4
 to isolate and bring about a ring closure with the help of a Cychsie- rungsmittel such as sulfuric acid, phosphorus pentachloride, phosphonyl chloride or phosphorus pentoxide.



   In order to get R3 in the 4-position, the amide of the formula XII can be heated directly with the compound of the formula VIIIa. If the heating is carried out in the presence of an acid acceptor, for example an alkaline earth carbonate such as calcium carbonate, the compound of the formula XI is formed together with an intermediate which is assumed to be the formula XIV
EMI4.5
 comes to. The intermediate product obtained as a crude product can be cyclized with an acid, e.g.



  Sulfuric acid.



   Derivatives which have 3 carbon atoms in the chain of group R3 can be prepared by reducing the corresponding acrylic derivatives.



   The actual procedure to be used to make a particular connection depends on the connection in question. Of course, one will choose the most suitable method for the particular case.



   The starting materials for the above processes are known or can be prepared by methods for the preparation of similar, known compounds.



   If the product obtained in the above-mentioned process is not the desired one but a derivative thereof, it can be converted into the desired compound in a known manner, e.g. 13. be transferred according to the working methods described here.



   The substituents possibly present in the phenyl rings in any of the above reactions must of course be inert under the reaction conditions. If necessary, they can be blocked by generally customary methods for carrying out the reaction and only released again after the compounds of the formula I have been formed.



   Since the compounds of the formula I contain a basic nitrogen atom, they can form salts with pharmacologically acceptable acids. However, these are easily hydrolyzed back to the free base.



   The compounds of the formula I obtainable according to the invention can be formulated into pharmaceutical preparations in the customary manner.



   A pharmacologically active form of a compound of the formula I and a non-toxic carrier are expediently used for the production of pharmaceutical preparations. A pharmacologically active form is generally present when R3 is a carboxylic acid group, which can also be present in salt or ester form.



   example 1
2,4-Diphenylthiazol-5-yl acetic acid ethyl ester
40 g of 3-bromo-3-benzoylpropionic acid and 21.3 g of thiobenzamide are refluxed together in 500 ml of ethanol for 8 hours. Most of the ethanol is then evaporated off and a solution of 10 g of sodium carbonate in 300 ml of water is added. The mixture is extracted with ether. The ethereal extracts are combined, washed with water, dried over NaSO4 and evaporated, 46.1 g of pale yellow, needle-shaped crystals with a melting point of 85-91 ° C. being obtained. Recrystallization from ethanol gives the pure ester. Yield 35.2 g (70% of theory), m.p. 95-96 ° C., colorless needles.



   C19H17NO2S:
Calculated: C 70.6 H 5.3 N 4.3 S 9.9 0/0
Found: C 70.6 H 5.2 N 4.3 5 10.1 0/0
The hydrolysis of this ester to the corresponding acid is described in Example 4.



   Example 2 2-Phenyl-4- (4'-methoxyphenyl) thiazole
5-yl-acetic acid ethyl ester
In the manner described in Example 1, 11 g of 3-bromo-3- (4'-methoxybenzoyl) propionic acid and 5.25 g of thiobenzamide are mixed together to form 2-phenyl-4- (4'-methoxyphenyl) thiazol5-yl-acetic acid ethyl ester implemented. Colorless needles are obtained on recrystallization from ethanol. Yield 8.3 g (620/0 of theory), m.p. 67.5-685 C.



     C20H10NO5S:
Calculated: C 68.0 H 5.4 N 4.0 5 9.1 0/0
Found: C 68.0 H 5.4 N 3.9 S 9.2 0 / #
The hydrolysis of this ester to the corresponding acid is described in Example 5.



   Example 3
2-phenyl-4- (4'-chlorophenyl) thiazole
5-yl-acetic acid ethyl ester
In the manner described in Example 1, 29.2 g of 3-bromo-4- (4'-chlorobenzoyl) propionic acid and 13.7 g of thiobenzamide are combined to form 2-phenyl-4- (4'-chlorophenyl) thiazole-5 -yl-acetic änre-ethyl ester implemented. Colorless needles are obtained on recrystallization from ethanol. Yield 19.9 g (560 / o of theory), m.p. 69-70 ° C.



   C19H16CINO2S:
Calculated: C 63.7 H 4.5 N 3.9 S9.0%
Found: C 63.8 H 4.7 N 3.8 S 9.1%
The hydrolysis of this ester to the corresponding acid is described in Example 6.



   Example 4
2,4-diphenylthiazol-5-yl-acetic acid
15 g of 2,4-diphenylthiazole 5-y-acetic acid ethyl ester are dissolved in 150 ml of warm ethanol, and 10 g of potassium hydroxide in 20 ml of water are added.



  After 1 hour, most of the ethanol is evaporated and the solution is diluted with water. Then concentrated hydrochloric acid is added until the solution just reacts acidic, and the oily solid is extracted with ether. The essential extracts are combined, washed with water, dried over Na2SO4 and evaporated to give 13.5 g of a viscous oil which slowly crystallizes. Recrystallization from benzene gives colorless needle-shaped crystals of the title compound. Yield 12.2 g (89 / o of theory), m.p. 1521530 C.



     Ct7Ht3NO2S:
Calculated: C62.9 H4.4 N4.7 S 10.9 / o
Found: C 69.4 H 4.2 N 4.7 5 10.8 0 / o
Example 5
2-phenyl-4- (4'-methoxyphenyl) thiazol-5-yl-acetic acid
In the manner described in Example 4, 5 g of the ethyl ester from Example 2 are hydrolyzed to 2-phenyl-4- (4'-methoxyphenyl) thiazol-5-yl-acetic acid. Colorless needles are obtained on recrystallization from benzene. Yield 3.9 g (85 / o of theory), m.p. 178.5-179.5 ° C.



     C18H15NO3S:
Calculated: C66.5 H 4.6 N 4.3 S 9.90 / o
Found: C 66.5 H 4.5 N 4.3 5 10.0 0/0
Example 6 2-Phenyl4- (4'-chlorophenyl) -thiazol-5-yl-acetic acid
In the manner described in Example 4, 10 g of the ethyl ester from Example 3 are hydrolyzed to 2-phenyl-4- (4'- ± chlorophenyl) thiazol-5-yl-acetic acid. Colorless needles are obtained on recrystallization from benzene. Yield 4.9 g (63% of theory), m.p. 161-162 OC.



     C17H12ClNO3S:
Calculated: C 62.0 H 3.7 N 4.2 S 9.7 Cl 10.7 0 / o
Found: C 62.0 In 3.7 N 4.2 S 9.8 C @ 107.7%
Example 7 a- (2,4-Diphenylthiazol-5-yl) propionic acid
13.6 g of 3-bromo-3-benzoylisobutyric acid and 6.9 g of thiobenzamide are heated to 600 ° C. in 75 ml of isopropanol for 30 minutes. Then 2.5 g of sodium carbonate are added and heating is continued for 10 minutes. After standing overnight, the mixture is diluted with water and the aqueous solution is decanted from the precipitated oil.



  The oil is taken up in ether and extracted with dilute aqueous sodium carbonate solution. The basic extract is washed with ether, acidified with hydrochloric acid to a pH of 4 and the oil formed is extracted with ether. The ethereal extract is washed with water, dried over Na2SO4 and evaporated to give a pale yellow viscous oil which slowly crystallizes.



   On recrystallization from glacial acetic acid / water, a- (2,4-diphenylthiazol-5-yl) propionic acid is obtained as prismatic crystals, yield 8.6 g (55 / o of theory), melting point 142-144 ° C.



     Ct8Ht5NO2S:
Calculated: C69.9 H 4.9 N 4.7 S10.30 / o
Found: C 69.9 H 4.9 N 4.7 5 10.3 O / o
Example 8 2-Phenyl-4- (2'-thienyl) thiazole
5-yl acetic acid
In the manner described in Example 7, 13.2 g of 3-bromo-3- (2'-thenoyl) propionic acid and 6.9 g of thiobenzamide are combined to give 2-phenyl-4- (2'-thienyl) -thiazol-5- yl-acetic acid implemented. Needle-shaped crystals, yield 7.2 g (4 sol, d. Th.), M.p. 134.5-135.0 ° C.



     # 5H11N02S2:
Calculated: C 59.9 H 3.7 N 4.65 5 21.3 0 / o
Found: C 59.9 H 3.7 N 4.5 S 21.0 O / o
Example 9 - 2-Phenyl-4 - (4'-methylphenyl) - thiazol-5-yl-acetic acid
In the manner described in Example 7, 27, log 3-bromo-3- (4-methylbenzoyl) propionic acid and 13.7 g of thiobenzamide together to give 2-phenyl-4- (4'-methylphenyl) thiazol-5-yl- acetic acid implemented. Yield 9.6 g (310 / o of theory), m.p. 1681690 C from benzene.



     C18H15NO2S:
Calculated: C 69.9 H 4.9 N 4.5 5 10.3 0/0
Found: C 70.0 H 5.1 N 4.6 5 10.6 0/0
Example 10 2- (4'-Methoxyphenyl) -4-phenylthiazole-
5-yl-acetic acid ethyl ester
4.2 g of 4-methoxythiobenzamide and 6.4 g of 3-benzoyl3-bromopropionic acid are refluxed in 501 mol of ethanol for 1 ½ hours. After standing overnight at room temperature, a crystalline solid has separated out. The entire reaction mixture is poured into water with stirring, and the oily layer is separated off. The aqueous layer is washed 3 times with 200 ml of ether each time; the extracts are combined with the oil.

  The ethereal solution is washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness. The yellow oil obtained quickly crystallizes to a pale yellow crystalline solid.



  When recrystallizing from industrial alcohol denatured with methanol, a pale yellowish white solid is obtained. Yield 3.8 g (43 / o of theory), m.p. 60.5 620 C.



     C20H19N03S:
Calculated: C 68.1 H 5.4 N 4.0 5 9.1 0/0
Found: C 67.7 In 5.3 N 3.8 S9.00 / o
Example 11
4- (2'-thienyl) -2- (2'-methylphenyl) thiazol-5-yl-acetic acid
5.7 g of 2-methylthiobenzamide, 10 g of 3-bromo-3- (2'-thenoyl) propionic acid and 1.8 g of anhydrous sodium carbonate are heated together in 55 ml of isopropanol to 600 ° C. for 30 minutes while stirring. The mixture is then cooled to 40 ° C. and stirred for a further 60 minutes. After cooling to room temperature, the mixture is left to stand overnight and slowly poured into 1 liter of cold water. A few drops of concentrated hydrochloric acid are added to acidify the mixture; after standing for 30 minutes, the solid formed is filtered off.

  The aqueous phase is extracted with ether and the extracts are combined with the solid. The ethereal solution is extracted thoroughly with saturated aqueous sodium bicarbonate solution, the aqueous extracts are acidified with concentrated hydrochloric acid. The oily precipitate from the aqueous phase solidifies quickly and, after drying, is recrystallized from benzene. Yield 6.7 g (46.2 / o of theory), melting point 136-138 ° C.



     C16H12N02S2:
Calculated: C 60.9 H 4.2 N 4.4 5 20.3 O / o
Found: C 61.0 H 4.2 N 4.3 520.3 0 / o
Example 12
2- (4'-Chlorophenyl) -4- (4'-methoxyphenyl) thiazol-5-yl-acetic acid
In the manner described in Example 11, 6.25 g of 4-chlorothiobenzamide and 10.3 g of 3-bromo-3- (4'-methoxybenzoyl) propionic acid are reacted with one another in 50 ml of isopropanol in the presence of 1.8 g of sodium carbonate. After working up in the manner described in the example mentioned and recrystallization from glacial acetic acid / water, the title compound is obtained. Yield 7.5 g (57.1ovo of theory), m.p. 199-201 OC.



      cI8H14ClNSO2:
Calculated: C60.1 H 3.9 N 3.9 S 8.9 Cl 9.9 0 / o
Found: C 60.0 H 4.2 N 3.7 S 9.0 C 19.7 / o
Example 13
2- (4'-Chlorophenyl) -4-phenyl thiazol-5-yl-acetic acid
In the manner described in Example 11, 14.6 g of 4-chlorothiobenzamide and 21.8 g of 3-benzoyl3-bromopropionic acid are reacted with one another in 127 times isopropanol in the presence of 4.3 g of sodium carbonate. After working up in the manner described in the example mentioned and recrystallization from benzene, the title compound is obtained. Yield 12.4 g (44.2 / o of theory), m.p. 153-155 C.



     Ct, Ht2CINO2S:
Calculated: C61.9 H 3.7 N 4.3 S 9.7 Cl10.80 / o
Found: C 62.1 H 3.8 N 4.1 S 9.8 Cl 10.80 / o
Example 14 2- (4'-Chlorophenyl) -4- (2'-thienyl) -thiazol-5-yl-acetic acid
In the manner described in Example 11, 6.3 g of 4-chlorothiobenzamide and 10 g of 3-bromo-3- (2'-thenoyl) propionic acid are reacted with one another in 55 ml of isopropanol in the presence of 1.8 g of sodium carbonate. After working up in the manner described in the example mentioned and recrystallization from benzene, the title compound is obtained. Yield 4.8 g (31.2 / o of theory), m.p.



  137-139 OC.



     C15H10C1NO2S2:
Calculated: C 53.6 H 3.0 N 4.2 S 19.1 Cl 10.6%
Found: C 53.6 H 3.2 N 4.0 5 19.0 C110.50 / o
Example 15
2,4-di- (4'-methoxyphenyl) thiazol-5-yl-acetic acid
In the manner described in Example 12, 6.0 g of 4-methoxy-thiobenzamide and 10.3 g of 3-bromo-3- (4'-methoxybenzoyl) propionic acid are reacted with one another in 50 ml of isopropanol in the presence of 1.8 g of sodium carbonate. After working up in the manner described in the example mentioned and recrystallization from glacial acetic acid / water, the title compound is obtained. Yield 8.0 g (56.3 / o of theory), m.p. 176 # 1780 C.



     C19H17N504:
Calculated: C 64.2 H 4.8 N 3.9 5 9.0 0/0
Found: C 64.3 H 5.0 N 3.9 5 9.1 0 / o
Example 16
4- (4'-Methoxyphenyl) -2- (2'-methyl phenyl) thiazol-5-yl-acetic acid
In the manner described in Example 11, 5.4 g of 2-methylthiobenzamide and 10.3 g of 3-bromo-3- (4'-methoxybenzoyl) propionic acid are reacted with one another in 50 ml of isopropanol in the presence of 1.8 g of sodium carbonate. After working up in the manner described in the example mentioned, the title compound is obtained. Yield 5.4 g (44.60 / o of theory), m.p. 140-141 ° C.



     C19H17N5O3:
Calculated: C67.2 H 5.1 N 4.1 S9.50 / o Found: C 67.2 H 5.1 N 4.3 5 9.4 0 / o
Example 17 2- (2'-methylphenyl) -4-phenyl-thiazol-5-yl-acetic acid
7.5 g of 2-methylthiobenzamide, 12.85 g of 3-benzoyl-3-bromopropionic acid and 75 ml of isopropanol are heated together with stirring to 60 ° C. for 30 minutes. After cooling to 40 ° C., 2.5 g of anhydrous sodium carbonate are added to the orange-colored solution, and the mixture is kept at 40 ° C. for a further 60 minutes.

  After standing overnight, the reaction mixture is slowly poured into 1 liter of cold water with stirring, and a few drops of concentrated hydrochloric acid are added to acidify the mixture. After standing for 30 minutes, the oily semi-solid layer is separated off and retained. The aqueous phase is extracted with ether and the extracts are combined with the oily layer. The resulting ethereal solution is extracted thoroughly with saturated sodium bicarbonate solution; the aqueous extracts are acidified with concentrated hydrochloric acid. The resulting oily precipitate solidifies quickly and, after drying, is recrystallized from benzene / petroleum ether (60-80 ° C.) to give the title compound. Yield 3.0 g (19.4 / o d.

  Th.), M.p. 165-167 C.



     Ct8HtsNO2S:
Calculated: C69.9 H4.9 N4.5 5 10.4 0 / o
Found: C 69.7 H 5.0 N 4.4 5 10.5 0 / o
Example 18 2- (3-methylphenyl) -4-phenylthiazole-
5-yl acetic acid
7.5 g of 3-methylthiobenzamide, 12.85 g of 3-benzoyl-3-bromopropionic acid, 75 ml of isopropanol and 2.5 g of sodium carbonate are converted to the title compound in the manner described in Example 17. This is recrystallized from benzene / petroleum ether. Yield 2.3 g (150 / o of theory), m.p. 123-125 C.



     ClsHtsNO2S:
Calculated: C 69.9 H 4.9 N 4.5 5 10.3 0 / o
Found: C 69.7 H 4.9 N 4.5 5 10.3 0 / o
Example 19
2- (4'-methoxyphenyl) -4-phenyl-thiazol-5-yl-acetic acid
In the manner described in Example 17, 8.35 g of 4-methoxythiobenzamide, 12.85 g of 3-benzoyl-3bromopropionic acid, 75 ml of isopropanol and 2.5 g of sodium carbonate are converted to the title compound. This is recrystallized from benzene. Yield 6.6 g (40.6 / o of theory), m.p. 149.5-152 C.



     Ct8HtsNO3S:
Calculated: C 66.4 H 4.7 N 4.3 5 9.9 0 / o
Found: C 66.4 In 4.6 N 4.2 5 9.7 0 / o
Example 20 2- (2'-Chlorophenyl) -4-phenyl-thiazol-5-yl-acetic acid
In the manner described in Example 17, 8.60 g of 2-chlorine-iobenzamide, 12.85 g of 3-benzoyl-3-bromopropionic acid, 75 ml of isopropanol and 2.5 g of sodium carbonate are converted to the title compound. This is crystallized from benzene. Yield 4.6 g (27.60io of theory), m.p. 168-171 OG.



   C17H12NO2SCl:
Calculated: C 61.9 H 3.7 N 4.3 S 9.7 Cl10.8%
Found: C 62.0 H3.7 N4.2 S9.9 CI 10.8%
Example 21
2- (4'-methylphenyl) -4-phenyl thiazol-5-yl-acetic acid
7.5 g of 4-methylthiobenzamide, 12.85 g of 3-benzoyl-3-bromopropionic acid, 75 ml of isopropanol and 2.5 g of sodium carbonate are converted into the title compound in the manner described in Example 17. This is recrystallized from benzene. Yield 7.9 g (51.2 / o of theory), m.p. 170-171 C.



     Cl8Ht5NO2S:
Calculated: C 69.9 114.9 N 4.5 5 10.4 0/0
Found: C 70.1 H 5.0 N 4.3 5 10.5 0/0
Example 22 2- (1'-Naphthyl) -4 # henyl-thiazol-5-yl-acetic acid
In the manner described in Example 17, 14.1 g of 1-thionaphtharmide, 19.3 g of 3-benzoyl-bromopropionic acid, 115 ml of isopropanol and 3.75 g of sodium carbonate are converted to the title compound. This is recrystallized from benzene petroleum ether. Yield 8.6 g (29.70 / o of theory), m.p. 145-148 C.



     C2tHtSNO2S:
Calculated: C 73.2 114.4 N 4.0 S9.3%
Found: C 73.1 in 4.4 N 4.1 S 9.3%
Example 23
2- (3'-Trifluoromethylphenyl) -4-phenyl-thiazol-5-yl-acetic acid
In the manner described in Example 17, 1573 g of 3-trifluoromethylthiobenzamide, 19.3 g of 3-benzoyl-3-bromopropionic acid, 115 ml of isopropanol and 3.75 sodium carbonate are converted to the title compound.



  This is recrystallized from benzene / petroleum ether.



  Yield 6.4 g (23.40 / o of theory), m.p. 143-145 C.



     Cl8Ht2NO2SF3:
Calculated: c 59.6 11 3.3 N 3.9 S15.7 S8.8%
Found C 59.6 H 3.7 N 3.8 F 15.6 S 8.6%
Example 24 4- (2'-Thienyl) -2- (4'-methoxyphenyl) -thiazol-5-yl-acetic acid
In the manner described in Example 17, 6.3 g of 4-methoxythiobenzamide, 10.0 g of 3-bromo-3- (2'-thenoyl) propionic acid, 55 ml of isopropanol and 1.8 g of sodium carbonate are converted to the title compound. This is recrystallized from benzene. Yield 1.9 g (13.30 / o of theory), m.p. 149-151 ° C.



     C10Hl @ NO3S2:
Calculated C 58.0 114.0 N 4.2 5 19.4 0 / o
Found: C 58.0 113.9 N 4.3 8 19.5 0/0
Example 25
2- (2'-naphthyl) -4-phenyl thiazol-5-yl-acetic acid
In the manner described in Example 17, 14.1 g of 2-thionaphthamide, 19.3 g of 3-benzoyl-3-bromopropionic acid, 115 ml of isopropanol and 3.75 g of sodium carbonate are converted to the title compound. This is recrystallized from benzene. Yield 14.0 g (50.60 / # d. Th.), M.p. 171-172 OC.



   C21H15NO2S:
Calculated: C73.2 H4.4 N 4.0 S9.3%
Found: C 72.9 H 4.6 N 3.9 59.20 / 0
Example 26
2- (4'-Methoxyphenyl-4- (2'-naphthyl) -thiazo # 5-yl-acetic acid
In the manner described in Example 17, 22.5 g of 4-methoxythiobenzamide, 40.5 g of 3-bromo 3 - (2 # naphthoy-1) propionic acid, 200 ml of isopropanol and 6.6 g of sodium carbonate are converted to the title compound. This is recrystallized from glacial acetic acid / water.



     Yield 22.4 g (44.4% of theory), m.p. 160-162 C.



     C22H17NSO @:
Calculated: C 70.4 114.6 N 3.7 5 8.5%
Found: C 70.3 114.5 N 3.7 S 8.4%
Example 27 ss- [2- (4'-chlorophenyl) 4-phenyl-thiazol-5-yl-propionic acid
26.5 g of 4-benzoyl-4-bromobutyric acid and 16.7 g of 4-chlorothiobenzamide are refluxed together in 80 times ethanol for 3¸ hours.



   After cooling, the solvent is evaporated and the residue is extracted with benzene. The benzene solution is washed with a 2N sodium carbonate solution and water and then dried (MgSo4). Evaporation gives the ethyl ester of ss- (4'-chlorophenyl) -4-phenylthiazol-5-yl] propionic acid as a yellow oil. Yield 39.0g.



   This ester is dissolved in 50 ml of warm ethanol and treated with a solution of 5.7 g of potassium hydroxide in 50 ml of ethanol. After 1 hour, most of the solvent is evaporated and water is added. The pH is then adjusted to 4 using 2N hydrochloric acid. The mixture is extracted with ether and the combined extracts are washed with 2N sodium carbonate solution. The alkaline solution is then acidified and extracted with ether.



  This ethereal solution is washed with water, dried (MgSO4) and evaporated to give ss- thiazol-5-yl] propionic acid as a solid. Yield 12.6 g (37 / o of theory). Recrystallization from benzene gives needle-shaped crystals, m.p. 177-178 C.



     Cl8Ht4ClNO2S:
Calculated: C62.9 114.1 N 4.1 S 9.3 Cl 10.3 0 / o
Found: C 63.0 H4.2 N4.0 S9.4 Cl 10.1 # / o
Example 28
4- (1'-naphthyl) -2-phenyl-thiazol-5-yl-acetic acid
In the manner described in Example 27, 30.7 g of 3-bromo-3- (1'-naphthyl) propionic acid and 13.7 g of thiobenzamide are reacted with one another in ethanol to give 34.2 g of the crude ethyl ester of the title compound. This is then hydrolyzed to acid. Recrystallization from benzene gives 4.2 g (12 / o of theory) of the title compound, mp 166-167 C.



     C211115NS02:
Calculated: C73.1 114.4 N 4.1 S9.3%
Found: C 73.0 114.6 N 4.0 S 9.4 O / #
Example 29
4- (2'-naphthyl) -2-phenyl thiazol-5-yl-acetic acid
In the manner described in Example 27, 29.6 g of methyl 3-bromo-3- (2'-naphthyl) propionate and 12.6 g of thiobenzamide are reacted with one another in ethanol to give 31.8 g of the crude methyl ester of the title compound. This is then hydrolyzed to acid. Recrystallization from benzene gives 9.9 g (310 / o of theory) of the title compound, melting point 168-169 ° C.



     C2tHt5NSO2:
Calculated: C73.1 114.4 N 4.1 S9.3%
Found: C 73.0 114.4 N 4.0 5 9.4 0 / #
Example 30 ss- [2- (4'-methoxyphenyl) -4-phenyl thiazol-5-yl] propionic acid
In the manner described in Example 27, 27.1 g of 4-benzyl-4-bromobutyric acid and 16.7 g of 4-methoxythiobenzamide are reacted with one another in ethanol to give 39.5 g of the crude ethyl ester of the title compound. This is then hydrolyzed to acid. Recrystallization from benzene gives 6.9 g (21 / o of theory) of the title compound, mp 174-175 C.



     C19H17N035:
Calculated: C67.2 115.1 N 4.1 59.40 / o
Found: C 67.1 115.0 N 4.0 5 9.6 0 / #
Example 31 ss- [2- (2'-methylphenyl) -4-phenyl thiazol-5-yl @ propionic acid
In the manner described in Example 27, 27.1 g of 4-benzoyl-4-bromobutyric acid and 15.1 g of 2-methylthiobenzamide are reacted with one another in ethanol to give 37.5 g of the crude ethyl ester of the title compound.



  This is then hydrolyzed to acid. Recrystallization from benzene gives 5.7 g (18 / o of theory) of the title compound, mp 107-109 C.



     C151117NO2S:
Calculated: C70.6 115.3 N 4.3 59.90 / o
Found: C 70.6 11 5.4 N 4.2 S9.8%
Example 32
2,4-Diphenylthiazol-5-yl-acetic acid methyl ester
29.5 g of 3-benzoyl-3-bromopropionic acid and 15.7 g of thiobenzamide are refluxed together for 5 hours in 300 ml of methanol. On cooling, the methyl ester separates out as needle-shaped crystals. Yield 24 g (700/0 of theory), m.p. 122-123 OC.



     C181115N02S:
Calculated: N 4.5 5 10.3 O / o
Found: N 4.5 5 10.6 0 / o
Example 33 ss- (2,4-Diphenylthiazol-5-yl) propionic acid
27.1 g of 4-benzoyl-4-bromobutyric acid and thiobenzamide are refluxed in 300 ml of methanol for 6 hours. Most of the methanol is then evaporated and water is added. The mixture obtained is extracted with ether; the combined extracts are washed with a sodium carbonate solution and water and then dried (Na2SO4). When the solvent is evaporated, 23.3 g of the methyl ester of ss- (2,4-diphenylthiazol-5-yl) propionic acid are obtained as a yellow oil.



   The ester is dissolved in 200 ml of warm ethanol and treated with a solution of 10 g of potassium hydroxide in 20 ml of water. After 1 1/2 hours, the solution is partially evaporated and then poured into water. Acidification with concentrated hydrochloric acid gives an oil which is extracted with ether. The combined extracts are washed with water, dried (Na2SO4) and evaporated. An oil is obtained that slowly solidifies. Yield 15.6 g (50 / o of theory).



  When recrystallizing from ethanol, the acid is obtained as long, colorless needles, m.p. 150 C.



     C18H15NO2S:
Calculated: C 69.9 114.9 N 4.5 5 10.3 0/0
Found: C 69.6 115.0 N 4.4 5 10.2 O / o
Example 34
2,4-diphenylthiazol-5-yl-acetamide
1.9 g of methyl 2,4-diphenylthiazol-5-yl acetate in 25 ml of methanol and 25 ml of 0.88N ammonium hydroxide solution are heated to 90 ° C. for 5 hours in a sealed tube. After cooling, the needle-shaped crystals of the amide which have precipitated out are filtered off. Yield 0.6 g (33 / o of theory). Recrystallization from benzene gives long needles, m.p. 209-210 ° C.



     C171114N20S:
Calculated: C 69.5 114.8 N 9.5 5 10.9 0 / o
Found: C 69.1 114.9 N 9.7 5 11.0 0 / o
Example 35
4- (4'-Chlorophenyl) -2-phenyl thiazol-5-yl-acetamide
2.0 g of 4- (4'-chlorophenyl) 2-phenylthiazol-5-yl-acetic acid in 50 ml of dry tetrahydrofuran are cooled to 0 C; then 0.68 g of dry triethylamine and then 0.73 g of ethyl carbonate are added dropwise. The reaction temperature is kept between 0 and 5 C; a mixed anhydride is obtained. After 0.5 hours, 0.35 g of aqueous ammonia (specific weight 0.88) are added dropwise.

  The mixture is stirred at room temperature overnight (14 hours) and then evaporated to dryness. Water and ethyl acetate are added to the solid; Separate the ethyl acetate layer, dry (MgSO4) and evaporate to give a solid. This is washed well with benzene, needle-shaped crystals of the amide remaining. Yield 0.32 g (15 lo of theory), m.p. 223-224 OC.



   Example 36
2- (2'-methoxyphenyl) -4-phenyl thiazol-5-yl-acetic acid
4.20 g of 2-methoxythiobenzamide, 6.40 g of 3-benzoyl3-bromopropionic acid and 1.25 g of anhydrous sodium carbonate are added to 40 ml of isopropanol, and the mixture is heated to 600 ° C. for 30 minutes while stirring. After a further hour at 400 ° C., the mixture is cooled to room temperature and poured into 500 ml of water. The mixture is acidified by adding a few drops of concentrated hydrochloric acid, whereupon a thick oil precipitates. The aqueous phase is extracted twice with 100 ml of ether each time, and the extracts are combined with the oil.

  The solution obtained is extracted 3 times with 100 ml of saturated sodium bicarbonate solution each time; the extracts are acidified with concentrated hydrochloric acid. The pale yellow solid obtained is filtered off, dried and recrystallized from glacial acetic acid / water. Yield 6.4 g (78.30 / # d.

  Th.), M.p. 179-180.5 OG C18H15NO @ S:
Calculated: C66.45 H4.65 N4.3 S9.85%
Found: C 66.4 H 4.6 N 4.5 5 9.8 O / o
Example 37 2- (4'-chloro-2'-methoxyphenyl) -
4-phenylthiazol-5-yl-acetic acid a) In the manner described in Example 36, 50 g of 4-chloro-2-methoxythiobenzamide, 6.4 g of 3-benzoyl-3-bromopropionic acid, 1.25 g of anhydrous sodium carbonate and 40 ml Isopropanol converted to the title compound. Yield 4.5 g (64.6% of theory), m.p. 204-205% C.



     CtsHt4ONOsS:
Calculated: C 60.1 113.9 N 3.9 C1 9.85 S8.9%
Found: C 58.9 113.9 N 3.8 C @ 10.1 S 9.2% b) The 4-chloro-2-methoxythiobenzamide is prepared as follows, the process being generally applicable to the preparation of the thioamides:
26.5 g of 4-chloro-2-methoxybenzonitrile are dissolved in a mixture of 22 times dry pyridine and 21 times triethylamine; then hydrogen sulfide is bubbled into the mixture until the nitrile is completely converted to thioamide (about 15 hours).



  The reaction mixture is poured into 500 ml of water and the precipitate formed is filtered off. After drying in air, the product is recrystallized from benzene. Yield 24.1 g (75.70 / 0 of theory), m.p. 149-150 ° C.



   Example 38 2- (2'-chloro-6'-methylphenyl) -
4-phenylthiazol-5-yl-acetic acid a) In the manner described in Example 36, 4.65 g of 2-chloro-6-methylthiobenzamide, 6.4 g of 3-benzoyl-3-bromopropionic acid, 1.25 g of anhydrous sodium carbonate are added and 40 ml of isopropanol converted to the title compound. Yield 5.4 g (63 / o of theory), m.p.



     217-219 OC.



     C18H14ClNO2S:
Calculated: C62.9 114.1 N 4.1 C @ 10.3%
Found: C 62.8 114.2 N 3.9 Cl 10.3 0 / ob) The 2-chloro-6-methylthiobenzamide is obtained in the manner described in Example 37b from 58 g of 2-chloro-6-methylbenzonitrile, 54 ml of dry pyridine and 53 ml of triethylamine were prepared with the introduction of hydrogen sulfide for 10 hours. Yield 59.1 g (83% of theory)



   Th.), M.p. 1261290 C.



   Example 39 2- (4'-Methoxy-2'-methylphenyl) -
4-phenylthiazol-5-yl-acetic acid a) In the manner described in Example 36, 2.7 g of 4-methoxy-2-methylthiobenzamide, 3.85 g of 3-benzoyl-3-bromopropionic acid, 0.75 g of anhydrous sodium carbonate and 22.5 ml of isopropanol converted to the title compound. Yield 1.4 g (27.5% of theory), m.p. 136-138 ° C.



     Cl9Ht7NOSS:
Calculated: C 67.2 11 5.05 N 4.1 S 9.45 <> /,
Found: C 67.1 115.0 N 3.9 5 9.3 O / ob) The 4-methoxy-2-methylthiobenzamide is obtained in the manner described in Example 37b from 68.2 g of 4-methoxy-2-methylbenzonitrile, 65 ml of dry pyridine and 64.2 g of triethylamine and prepared with sulfuric hydrogen introduction for 15 hours. Yield 60.3 g (7logo of theory), m.p. 124-126 OC.



   Example 40 2- (4'-Chloro-2'-methylphenyl) -4-phenylthiazol-5-yl-acetic acid a) In the manner described in Example 36, 4.65 g of 4-chloro-2-methylthiobenzamide, 6.4 g of 3-benzoyl-3-bromopropionic acid, 1.25 g of anhydrous sodium carbonate and 40 ml of isopropanol converted to the title compound. Yield 5.3 g (58 / o of theory), m.p.



     175-177 OC.



     C181114ClN025:
Calculated: C 62.9 ei 4.1 N 4.1 C110.30 / o
Found: C 63.05 114.1 N 4.1 C @ 10.3% O / ob) The 4-chloro-2-methylthiobenzamide is prepared in the manner described in Example 37b from 26 g of 4-chloro-2-methylbenzonitrile, 25, 5 ml of dry pyridine and 25 ml of triethylamine and prepared with 15 hours of hydrogen sulfide introduction. Yield 22 g (69 / o of theory) mp 86-880 C.



   Example 41
4- (2'-naphthyl) -2- (2'-methylphenyl) thiazol-5-yl-acetic acid
In the manner described in Example 36, 20 g of 2-methylphenylthiobenzamide, 40.5 g of 3-bromo-3 - (2'-naphthoyl) propionic acid, 6.6 g of anhydrous sodium carbonate and 200 ml of isopropanol are converted to the title compound. M.p.



  171-172 OC.



   Example 42
2- (2 ', 4'-Dimethoxyphenyl) 4-phenylthiazol-5-yl-acetic acid a) In the manner described in Example 36, 2.5 g of 2,4-dimethoxythiobenzamide, 3.2 g of 3-benzoyl3-bromopropionic acid, 0.6 g of anhydrous sodium carbonate and 19 ml of isopropanol converted to the title compound. Yield 2.0 g (44.4 / o of theory), m.p.



     157-1590C.



   b) The 2,4-dimethoxythiobenzamide is prepared in the manner described in Example 37b from 7.7 g of 2,4-dimethoxybenzonitrile, 7 ml of dry pyridine and 7 ml of triethylamine and 8 hours of hydrogen sulfide introduction. Yield 6.3 g (680 / o of theory).



   Example 43
2- (4'-N, N-Dimethylaminophenyl) 4-phenylthiazol-5-yl-acetic acid a) In the manner described in Example 36, the 9; Og 4- (N, N-dimethylamino) thiobe.nzamide, 12.0 g of 3-benzoyl-3-bromopropionic acid, 2.5 g of anhydrous sodium carbonate and 75 ml of isopropanol converted to the title compound. After 4 recrystallization from benzene: yield 2.1 g (12.40 / o of theory), melting point 144-146 ° C.



   b) The 4- (N, N-dimethylamino) thiobenzamide is prepared in the manner described in Example 37b from 25 g of 4- (N, -l-dimethyl) benzonitrile, 23.8 ml of dry pyridine and 23.5 ml of triethylamine and with the introduction of hydrogen sulfide for 7 hours manufactured. Yield 27 g (87.60 / o of theory), m.p. 218 OC.



   Example 44 2- (2 ', 3'-Dimethylphenyl) -
4-phenylthiazol-5-yl-acetic acid a) In the manner described in Example 36, 2.5 g of 2,3-dimethyl-thiobenzamide, 3.85 g of 3-benzoyl-3-bromopropionic acid, 0.75 g of anhydrous sodium are added carbonate and 22.5 ml of isopropanol converted to the title compound. Yield 3.2 g (64.20 / o of theory), m.p.



  143-145 OC.



   b) The 2,3-dimethylthiobenzamide is prepared in the manner described in Example 37b from 100 g of 2,3-dirnethylbenzonitrile, 117 ml of dry pyridine and 114 ml of triethylamine and with the introduction of hydrogen sulfide for 15 hours. Yield 116.2 g (92 / o of theory), m.p. 137-138 C.



   Example 45
2- (2 ', 4'-dichlorophenyl)
4-phenylthiazol-5-yl-acetic acid a) 5.2 g of 2,4-dichlorothiobenzamide, 6.4 g of 3-benzoyl3-bromopropionic acid, 1.25 g of anhydrous sodium carbonate and 40 ml of isopropanol are added in the manner described in Example 36 Title compound implemented. M.p. 158-160 CC.



   b) The 2,4-dichlorophenylthiobenzamide is prepared in the manner described in Example 37b from 12.5 g of 2,4 dichlorobenzonitrile, 11 ml of dry pyridine and 10 ml of triethylamine and hydrogen sulfide for 16 hours.



   Example 46
2,4-di- (4'-chlorophenyl) thiazol-5-yl-acetic acid
In the manner described in Example 36, 3.85 g of 4-chlorothiobenzamide, 6.6 g of 3- (4'-chlorobenzoyl) -3-bromopropionic acid, 1.4 g of anhydrous sodium carbonate and 35 ml of isopropanol are converted to the title compound. Yield 2.5 g (30.6 / o of theory), m.p. 194-196 OL.



   Example 47
4- (2'-chlorophenyl) -2-phenylthiazole
5-yl-acetic acid and its methyl ester Methyl 3- (2'-chlorophenyl) propionate is prepared as described in J. O. C. 15 (1950), 785 and brominated to give meffiyl 3-bromo-3- (2'-chlorobenzoyl) propionate. This intermediate is reacted with thiobenzamide in the manner described in Example 36. The methyl ester obtained is hydrolyzed to the corresponding acid.



   Example 48
2,5-diphenylthiazol-4-yl-acetic acid
5.15 g of ethyl 4-phenylacetoacetate are brominated in anhydrous ether (4 g). After standing at room temperature for 18 hours, water is carefully added. The ethereal layer is washed, dried, and evaporated to give ethyl 4-bromo-4-phenyl acetoacetate. Yield 7.14g.



   7.14 g of this ester in 20 ml of acetone are treated with a solution of 3.4 g of thiobenzamide in 30 ml of acetone at room temperature and then refluxed for 2 hours. After evaporation to dryness, water and ether are added. The ethereal extract is washed with sodium bicarbonate solution and water, dried (MgSO4) and evaporated to give 2,5-diphenylthiazol4-yl-acetic acid-ethyl ester. Yield 8.07 g (approximately 1000 hours of theory).



   8.07 g of this ester in 50 mg of ethanol are treated with a solution of 2 g of potassium hydroxide in 10 ml of water. After 15 minutes of heating on a steam bath, the solution is left to stand for 1 hour at room temperature. The solution is evaporated to dryness and ether and water are added. After purification with activated charcoal, filtration and acidification, 3.2 g of the crude acid are filtered off and recrystallized from benzene. Yield 2.5 g (33.5ovo of theory), m.p. 1710C.



   Example 49
2,4-diphenyloxazol-5-yl-acetic acid
3.02 g of benzamide are added to a suspension of sodium hydride (1.2 g, 50/0 in oil) in 200 ml of benzene; the mixture is refluxed with stirring for 1/2 hour. Then 7.14 g of ethyl 4-bromo-4-phenylacetoacetate, which has been prepared as in Example 48, in 30 ml of benzene are added dropwise in the course of 1/2 hour, and heating is continued for a further 11/2 hours. Then water is added and the benzene layer washed with water and saturated NaCl solution, dried (MgSO4) and evaporated. 6.6 g of a brown solid are obtained.

  This is dissolved in 25 ml of concentrated sulfuric acid and the solution is left to stand at room temperature for 18 hours. The solution is poured into excess water and ether is added. The ethereal layer is washed with saturated NaHCO2 solution and water, dried (MgSO4) and evaporated. 1.2 g of the crude title compound are obtained. These 1.2 g of the crude ester are dissolved in 20 ml of ethanol, then 1 g of potassium hydroxide in 5 ml of water is added.



  The solution is heated on a steam bath for 5 minutes and then left to stand for 2 hours at room temperature. Evaporation of the solution gives an oil; to this water and ether are given. The aqueous layer is treated with activated charcoal, filtered, acidified. 2,5-Diphenyloxazol-5-yl-acetic acid is obtained, the structure of which is confirmed by the I.R. spectrum.



   Example 50
3- (2,4-Diphenylthiazol-5-yl) propionic acid
A mixture of 3.07 g of 3- (2,4-diphenylthiazol-5-yl) acrylic acid and 5.0 g of prereduced 100% palladium on charcoal in 100 ml of ethanol is shaken in a hydrogen atmosphere for 1 hour. A further amount of 5.0 g of 100% pre-reduced palladium on charcoal is then added and the mixture is shaken for another hour. After adding a further 5.0 g of 100% of the above prereduced palladium on charcoal, the shaking is continued for another hour. The catalyst is removed by filtration and the filtrate is evaporated. 0.9 g of the title compound with a melting point of 1500 ° C., which is identical to the product of Example 33, is obtained after recrystallization from ethanol.



   Example 51
3 - (2,4-Diphenylthiazol-5-yl) -propionic acid a) 5.0 g of 2,4-diphenylthiazol-5-yl-acetic acid are dissolved in a minimum amount of warm ethanol, the solution is made strongly acidic with ethanolic hydrogen chloride and then ether added to induce crystallization of the hydrochloride of the starting material. This hydrochloride is dissolved in 2.0 times thionyl chloride, stirred for 15 minutes at room temperature and then heated to 45 ° C. in a water bath for half an hour. The solution is evaporated to dryness and the acid chloride hydrochloride of the starting material is obtained as a dark tarry substance.



   b) A stirred and ice-cooled suspension of the above acid chloride hydrochloride in 25 ml of ether is treated with a solution of 1.42 g of diazomethane and 3.4 g of triethylamine in 75 ml of ether. After stirring for 16 hours, the precipitated amine hydrochloride is filtered off and the filtrate is evaporated to dryness. The crude diazoketone remains. A solution of this diazoketone in 30 ml of dioxane is slowly added to a stirred solution of 1.1 g of sodium carbonate, 0.67 g of sodium thtosulphate and 0.45 g of silver oxide in 50 ml of water at 50-160.degree. Stirring is continued for 1 hour during which time the temperature rises to 90-100 ° C.

  After the reaction mixture has cooled, it is acidified with dilute nitric acid, whereupon the crude title compound is obtained. After two crystallizations from ethanol, 1.3 g of the title compound with a melting point of 150 ° C. which is identical to the product of Example 33 are obtained.



   Example 52 Dimethylaminoethyl-4- (p-chlorophenyl) -
2-phenylthiazol-5-ylacetate
14.32 g of ethyl 4- (p-chlorophenyl) - 2-phenylthi azol-5-ylacetate and 50 ml of N, N-dimethylaminoethanol in 300 ml of dry benzene are heated under reflux with an azeotropic separator. Two small pieces of sodium metal are added and the azeotropic mixture is collected until the temperature has reached 81 ° C., which takes about 2t / 2 hours. The mixture is then refluxed for a further hour. The cooled solution is evaporated in vacuo and kept at 50 ° C. under high vacuum to remove excess ethanol.

   The remaining brown oil is dissolved in dilute hydrochloric acid and washed three times with ether. The aqueous phase is made basic and extracted three times with ether. The combined ether extracts are washed with water, dried over MgSO4, evaporated in vacuo and kept at 50 ° C. under high vacuum until constant weight. The 13.4 g of light brown oil obtained are dissolved in dry ether, then ethereal hydrogen chloride is added and the sticky yellow solid is collected.



   After two recrystallizations from isopropyl alcohol, 9.36 g of the dimethylaminoethyl ester are obtained as monohydrochloride as colorless microneedles with a melting point of 176-178 ° C. (decomp.).



   For C2H21CIN202S. HCI:
Calculated: C57.7 115.1 N6.4o / o
Found: C 57.7 115.0 N 6.20 / 0
Example 53 2; (p-Bromophenyl) -4 (p-fluorophenyl) -thiazol-5-ylacetic acid
A mixture of 13.75 g of ß-bromo-ss- (p-fluorobenzoyl) propionic acid and 10.8 g of p-bromothiobenzamide in 12.5 ml of dimethylformamide is heated to 70 ° C. for 2 hours, poured into 500 ml of water and left to stand overnight calmly. The solid is filtered, washed well with water and, after drying, recrystallized from benzene. 17.3 g of the acid mentioned in the title are obtained, melting point 192-193 C.



   For C17H11BrFN02S:
Calculated: C52.0 H2.8 N 3.60 / o
Found: C 52.3 112.3 N 3.6 0 / o
Example 54
2- (p-isopropylphenyl) -
4-phenylthiazol-5-ylacetic acid
A mixture of 10.04 g of ß-bromo-ß-benzoylpropionic acid and 6.99 g of p-isopropylthiobenzamide in 10.0 ml of dimethylformamide is heated to 80 ° C. for 1/4 hour and then poured into 500 ml of water. The solid is filtered, washed well with water and, after drying, recrystallized from benzene. 13.1 g of the abovementioned acid are obtained, melting point 146-147 C.



   For C20H19NOS2S:
Calculated: C 71.3 115.7 N 4.2 # / o
Found: C 71.1 115.7 N 4.1 0 / o
Example 55 4- (p-Chlorophenyl) -2- (2'-pyridyl) thiazol-5-ylacetic acid
A mixture of 2.36 g of pyridine-2-thiocarboxamide and 5.0 g of s-bromo-ss- (p-chlorobenzoyl) propionic acid in 5 ml of dimethylformamide is heated to 70 ° C. for 1 hour and then poured into 20 ml of water. After half an hour, the solid is filtered off, dried and recrystallized from ethyl alcohol. 2.7 g of the acid mentioned in the title with a melting point of 202 ° C. (decomp.) Are obtained.



   For C16H11CIN2O2S:
Calculated: C 58.0 H3.4 N 8.5%
Found: C 58.0 11 3.3 N 8.4 <) / o
Example 56 4- (p¯-chlorophenyl) -2-13'-pyridyl> thiazol-5-ylacetic acid
A mixture of 2.76 g of pyridine-3-thiocarboxamide and 5.83 g of ss-bromo-ss- (p-chlorobenzoyl) propionic acid in 5 ml of dimethylformamide is heated to 70 ° C. for 1 hour and to 100 ° C. for 1/4 hour. After the mixture has been poured into 400 ml of water, the solid is filtered off, dried and recrystallized twice from a mixture of dimethylformamide and ethanol. 1.5 g of the abovementioned acid are obtained, melting point 238-239 ° C. (decomp.).



   For C16H11ClN202S:
Calculated: C 58.0 H 3.4 N 8.5%
Found: C 57.8 113.3 N 8.4 0 / o
Example 57
4- (p-Chlorophenyl) -2- (4'-pyridyl) -thiazol-5-ylacetic acid
A mixture of 2.76 g of pyridine-4-thiocarboxamide and 5.83 g of ss-bromo-ss- (p-chlorobenzoyl) propionic acid in 5 ml of dimethylformamide is heated to 70 ° C. for one hour and then poured into 400 ml of water. The solid is filtered off, washed well with water, dried and then recrystallized a few times from a mixture of dimethylformamide and ethyl alcohol.



  0.49 g of the title acid is obtained, melting point 215-216 ° C. (decomp.).



   For C16H11CIN2O2S:
Calculated: C58.0 113.4 N8.50 / o
Found: C 58.2 11 3.2 N 8.3 0 / o
Example 58
2- (p-Bromophenyl) -4-phenyl-thiazol-5-ylacetic acid
A mixture of 6.4 g of ß-bromo-ß-benzoylpropionic acid and 5.4 g of p-bromothiobenzamide in 10 ml of dimethylformamide is heated to 70 ° C. for 2 hours, poured into 500 ml of water and left to stand overnight. The solid is filtered, washed well with water and, after drying, recrystallized from benzene. 7.5 g of the acid mentioned in the title are obtained, melting point 173.5-174.5 ° C.



   For C17H12BrNO2S:
Calculated: C 54.6 H 3.2 N 3.8%
Found: C 54.7 113.2 N 3.7 0io
Example 59 2- (p-Bromophenyl) -4- (p-chlorophenyl) -thiazol-5-ylacetic acid
A mixture of 7.28 g of ss-bromo-ss- (p-chlorobenzoyl) propionic acid and 5.4 g of p-bromothiobenzamide in 10 times dimethylformamide is heated to 70 ° C. for 2 hours, poured into 500 ml of water and left to stand overnight. The solid is filtered, washed well with water and, after drying, recrystallized from benzene. 8.16 g of the acid mentioned in the title, melting point 202-203 CC, are obtained.



   For Ct7H, 1BrCINO2S:
Calculated: C 50.0 112.7 N 3.40 / 0
Found: C 49.9 112.7 N 3.5 0 / o
Example 60 2- (p-Chlorophenyl) -5-phenyl-thiazol-4-ylacetic acid
A mixture of 10.0 g of ethyl 4-bromo-3-oxo-4-phenylbutyrate and 6.0 g of p-chlorothiobenzamide in 100 ml of ethyl alcohol is refluxed for 3 hours. A solution of 8.0 g of sodium hydroxide in 15 ml of ethyl alcohol is added to the cooled solution and the resulting solution is heated on the steam bath for 5 minutes.



  The red-colored solution is evaporated to dryness, the residue is redissolved in water, washed with ether and acidified with concentrated hydrochloric acid, whereupon a white solid is obtained. After recrystallization from benzene, 5.3 g of the above-mentioned acid with a melting point of 200-201 C. are obtained.



   For C171112ClN02S:
Calculated: C61.9 113.7 N 4.20 / o
Found: C 61.8 113.6 N 4.3 0 / o
Example 61 4 # (p-Chlorophenyl) -2-phenyl-thiazol-5-ylpropionic acid
A mixture of 14.2 g of y-bromo-y- (p-chlorobenzoyl) butyric acid and 7.1 g of thiobenzamide in 10 ml of dimethylformamide is heated to 70 ° C. for 2 hours, poured into 500 ml of water and left to stand overnight. The solid is filtered off, washed well with water and, after drying, recrystallized from benzene. 6.45 g of the abovementioned acid, melting point 143-144 ° C., are obtained.



   For C18H14ClNO2S:
Calculated: C 62.9 H 4.1 N 4.1%
Found: C 63.0 114.1 N 3.90 / o
Example 62 4- (pFluorophenyl-2-phenulthlazol-5-ylacetic acid
A mixture of 10.0 g of ss-bromo-ss- (p-fluorobenzoyl) propionic acid and 5.0 g of thiobenzamide in 10 ml of dimethylformamide is heated to 70 ° C. for 2 hours, poured into 500 times water and left to stand overnight. The solid is filtered off, washed well with water and, after drying, recrystallized from benzene. 7.49 g of the acid indicated in the title are obtained, melting point 173-174 C.



   For C17H12FNO2S:
Calculated: C 65.2 H 3.9 N 4.5 5 10.2 # / o
Found: C 65.1 11 3.8 N 4.8 5 10.1 0 / o
Example 63
2- (p-Chlorophenyl) -4- (p-fluorophenyl) thiazol-5-ylacetic acid
A mixture of 10 g of ss-bromo-ss- (p-fluorobenzoyl) propionic acid and 6.25 g of p-chlorothiobenzamide in 10 times dimethylformamide is heated to 70 ° C. for 2 hours, poured into 500 ml of water and left to stand overnight. The solid is filtered off, washed well with water and, after drying, recrystallized from benzene.



  4.3 g of the title acid are obtained, melting point 194-196 C.



   For C17H11CIFNO2S:
Calculated: C 58.7 113.2 N 4.0 5 9.2%
Found: C 58.7 11 3.2 N 4.2 5 9.2 O / o
Example 64 4- (p-Bromophenyl) -2- (p-chlorophenyl) -thiazol-5-ylacetic acid
A mixture of 5.04 g of ss-bromo-ss- (p @ bromobenzoyl) propionic acid and 1.67 g of p-chlorothiobenzamide in 10 ml of dimethylformamide is heated to 70 ° C. for 2 hours, poured into 500 ml of water and left to stand overnight. The solid is filtered off, washed well with water and, after drying, recrystallized from benzene.



  1.42 g of the acid mentioned in the title are obtained, melting point 206-207 CC.



   For C17H11BrClN02S:
Calculated: C 50.0 112.7 N 3.4 / o
Found: C 49.7 112.7 N 3.5 0 / o
Example 65
4 (p-Chlorophenyl) -2- (p-methoxyphenyl) -thiazol-5-ylacetic acid
A mixture of 8.4 g of p-methoxythiobenzamide and 14.6 g of s-bromo-ss- (p-chlorobenzoyl) propionic acid in 30 ml of dimethyllortiamide is heated to 70 ° C. for 2 hours. After pouring into ice water, a yellow solid is obtained which is dissolved in excess sodium carbonate solution. After acidification with concentrated hydrochloric acid, a solid precipitate results, which is filtered, dried and recrystallized from ethyl alcohol.

   13.0 g of the acid mentioned in the title are obtained, melting point 173-174 ° C.



   For Cl8Hl4CINO3S:
Calculated: C 60.1 H 3.9 N 3.9%
Found: C 60.0 113.8 N 3.80 / o
Example 66 4- (p-Chlorophenyl) -2- (p-dimethylaminophenyl) thiazol-5-ylacetic acid
A mixture of 5.8 g of ss-bromo-ss- (p-chlorobenzoyl) propionic acid and 3.6 g of p-dimethylaminothiobenzamide in 5.0 ml of dimethylformamide is heated to 80 ° C. for 1 hour, poured into water and left to stand overnight. The solid is filtered off, washed well with water and, after drying, recrystallized from ethyl alcohol. 2.8 g of the abovementioned acid, melting point 205-207 ° C., are obtained.



   For C19H17CIN2O2S:
Calculated: C61.2 114.6 N7.50 / o
Found: C 61.3 114.7 N 7.4 / o
Example 67 n-Butyl-4- (p-chlorophenyl) -
2-phenylthiazol-5-ylacetate
A mixture of 5.43 g of 4- (p-chlorophenyl) -2-phenylthiazol-5-ylacetic acid, 50 ml of n-butyl alcohol and 1.0 ml of concentrated sulfuric acid is refluxed for 16 hours, treated with the same volume of water and on evaporated a small volume. 200 ml of water are added to the mixture and the oil is extracted into ether. The organic extract is washed with water, sodium bicarbonate solution and again with water, dried over magnesium sulfate and evaporated. A yellow oil is obtained which is distilled under high vacuum.

  4.95 g of the ester mentioned in the title are obtained, boiling point 205-218 ° C. / 0.1-0.15 mm Hg, which solidifies after standing and has a melting point of 43-44 ° C.



   For C211120ClN02S:
Calculated: C65.3 H 5.2 N 3.60 / o
Found: C 65.4 115.2 N 3.8 # / o
Example 68 4- (p-Bromophenyl) -2-phenyl-thiazol-5-ylacetic acid
A mixture of 3.43 g of thiobenzamide, 8.4 g of s-bromo-ss- (p-bromobenzoyl) propionic acid in 10 ml of dimethylformamide is heated to 80 ° C. for 1 hour, poured into water and left to stand overnight. The solid is filtered off, washed well with water and dried. 1.86 g of the acid mentioned in the title are obtained, melting point 178-180 C.



   For Cj7Hl2BrNO2S: Calculated: C 54.55 113.2 N 3.75 S8.75 Br 21.35% Found: C 54.9 H 3.1 N 3.9 S 8.7 Br20.3%
Example 69 2,4-Di # (p-chlorophenyl) thiazol-5-ylpropionic acid
A mixture of 5.9 g of 4-bromo-4- (p-chlorobenzoyl) butyric acid and 3.4 g of p-chlorothiobenzamide in 10 ml of dimethylformamide is heated to 95 ° C. for 18 hours, poured into water and left to stand overnight. The solid is filtered off, washed well with water, dried and recrystallized from a mixture of ethyl acetate and petroleum ether (boiling point 60-80 ° C.).



  3.3 g of the abovementioned acid, melting point 179-181 ° C., are obtained.



   For C181113Cl2N02S:
Calculated: C 57.2 11 3.5 N 3.7 0 / o
Found: C 57.1 H3.3 N 3.4%
Example 70 Ethyl-5- (p-chlorophenyl) -
2-phenylthiazol-4-ylacetate
A mixture of 15.5 g (0.048 mol) of ethyl-4-bromo-4- (p-chlorophenyl) -3-oxo-butyric acid, 6.6 g (0.048 mol) of thiobenzamide and 2.6 g (0.049 equivalents) of anhydrous Sodium carbonate in 60 mol of ethyl alcohol is refluxed for 3 hours and then evaporated to dryness under reduced pressure. The residue is taken up in ethyl acetate, washed with water, dried over magnesium sulfate and evaporated in vacuo. 10.3 g of the thiazole ester (59.2% of theory) are obtained.

  Th.), Melting point 112-114 C (from ethyl alcohol).



   For Cl9H16CINO2S:
Calculated: C 63.75 114.5 N 3.9 # / o
Found: C 64.1 114.5 N 3.8 / o
Example 71
5- (p-Chlorophenyl) -2-phenyl thiazol-4-ylacetic acid
A solution of 5.0 g (0.014 mol) of sithyl-5- (p-chlorophenyl) -2-phenylthiazol-4-ylacetate in 30 ml of hot ethyl alcohol is combined at once with a solution of 5.0 g (0.09 mol) Potassium hydroxide treated in 5 ml of water and left to stand at room temperature for 16 hours. After dilution with 50 ml of water and acidification with concentrated hydrochloric acid, a light yellow precipitate is obtained, which is filtered off, washed with water, dried and recrystallized from benzene. 2.3 g of thiazolic acid are obtained (50 / o d.

  Th.), Melting point 202.5-204.5 C.



   For C171112ClN02S:
Calculated: C 61.9 113.7 N 4.25 lo
Found: C 62.1 113.6 N 4.3 O / o
Example 72 2- (4'-Chlorophenyl) -4-phenyl-thiazol-5-ylacetic acid 125 mg
Milk sugar 120 mg
Magnesium stearate 5 mg
The above ingredients are mixed thoroughly and filled into hard gelatin capsules (250 mg).



   Example 73 2- (4'-Chlorophenyl) -4-phenyl-thiazol-5-ylacetic acid 125 mg
Milk sugar 100 mg Avicel 30 mg dry corn starch 40 mg
Magnesium stearate 5 mg
Tablets of the above composition are produced by grinding the active ingredient to a mesh size of 0.385 mm internal width, sieving through a mesh sieve of 0.385 mm internal width, mixing the ground material with the other ingredients and compressing to form tablets.



   The active ingredient of Examples 72 and 73 can also be replaced by other compounds produced according to the invention.

 

Claims (1)

PATENT CLAIM Process for the preparation of new compounds of the formula I. EMI16.1 wherein X is oxygen or sulfur, R1 and R2, which are identical or different, are unsubstituted or one or more than one by halogen, lower alkyl, lower alkoxy, nitro, amino, substituted amino, halo-lower alkyl, mercapto, alkylthio - or Alkylsulfonylgruppsen substituted phenyl group, or a substituted or unsubstituted naphthyl or heteroaryl group and R3 an aliphatic, an optionally functionally modified carboxyl group having 2 to 6 carbon atoms, where Rt, R2 and Rs are arranged in the 2-, 4 and 5-position , as well as their acid addition salts, characterized in that that a halogen ketone of the formula II EMI16.2 wherein Hal is a halogen atom, with an amide or thioamide of the formula III EMI16.3 wherein the substituents Ra, Rb and Rc, Rl, R2 and R3 mean in any order, or a salt thereof is converted. SUBSTANTIAL 1. The method according to claim, characterized in that a compound of the formula I is prepared in which the functionally modified carboxyl group of R3 is a salified carboxyl group. 2. The method according to claim, characterized in that a compound of the formula I is prepared in which the functionally modified carboxyl group of R3 is an esterified carboxyl group. 3. The method according to claim, characterized in that a compound of the formula I is prepared in which the functionally modified carboxyl group of R3 is an amide or thioamide group. 4. The method according to claim, characterized in that a compound of the formula I is prepared in which the functionally modified carboxyl group of R> is a hydroxaminated carboxyl group. 5. The method according to claim, characterized in that the haloketone of the formula II is reacted with a thioamide of the formula III. 6. The method according to claim, characterized in that the haloketone of the formula II is reacted with an amide of the formula III. 7. The method according to claim, characterized in that the haloketone of the formula II is reacted with an alkali metal salt of an amide of the formula III. 8. The method according to claim, characterized in that the compound of formula I obtained is converted into an acid addition salt. 9. The method according to claim, characterized in that the compound of formula I, in which the functionally modified carboxyl group of R3 is an esterified carboxyl group, is reacted with hydroxylamine to give the corresponding hydroxamic acid derivative. 10. The method according to claim, characterized in that the compound of formula I, wherein Rs has a free carboxyl group, is esterified with the aid of an alcohol. 11. The method according to claim, characterized in that the compound of the formula I, wherein R3 has a free carboxyl group, is converted into the corresponding amide by reaction with ammonia. 12. The method according to claim, characterized in that the compound of formula I obtained, in which the functionally modified carboxyl group of Rs is a nitrile group, is converted into the corresponding amide by hydrolysis. 13. The method according to claim, characterized in that the compound of the formula I, in which the functionally modified carboxyl group of R3 is a nitrile group, is converted into the corresponding thioamide by reaction with hydrogen sulfide. 14. The method according to claim, characterized in that the compound of formula I obtained, in which the functionally modified carboxyl group of R2 is an esterified carboxyl group, is converted into the corresponding free acid by hydrolysis. 15. The method according to claim, characterized in that the compound of the formula I obtained is converted into the corresponding amide in the form of the ammonium salt by heating. 16. The method according to claim, characterized in that in the product obtained, in which R3 is the remainder of acrylic acid, its salt, its ester, its amide or its hydroxamic acid derivative, this remainder is converted to the corresponding propionic acid, its salt or ester, its amide or Hydroxamic acid derivative reduced.