SE422209B - INTERMEDIATE FOR USE FOR THE PREPARATION OF NEW 1.3-O X 20L AND 1,3-THIAZOLD DERIVATIVES - Google Patents

Description

1 and R 2 have the meaning given above and R represents a (wherein X, R straight or branched aliphatic carbohydroxy group having 2 to 4 carbon atoms, its salts, esters, amides and nitrile derivatives, or groups of the formula -A-cH (Cozy ) 2 and their diesters, wherein A represents alkylene having up to 2 carbon atoms).

A well-known drug with anti-inflammatory effect is phenylbutazone, but this drug has certain disadvantages, e.g. ulcerogenic activity. Another drug used to treat inflammation is aspirin, but this drug requires high dosage and is also highly ulcerogenic.

The present invention relates to a new group of trisubstituted heterocyclic compounds which can be used for the preparation of new products with anti-inflammatory effect, more particularly of oxazoles and thiazoles of the type specified in Swedish patent 369,307.

By the term "lower" in the present context is meant that the group contains 1-6, preferably 1-4 carbon atoms.

The compounds of the above general formula Ia show pharmacological activity, e.g. anti-inflammatory activity, usually with little or no ulcerogenic activity, in laboratory experiments on animals, and / or anti-bacterial activity, and the compounds of formula Ib are intermediates in the preparation of other substituted, aromatic, heterocyclic compounds. Examples of experiments which may indicate that a compound of formula Ia has anti-inflammatory activity are those described by Winter et al in Proc. Soc. Biol. With. lll (1962), 544; Buttle et al in Nature 179 (1957), 629; Konzett and Rossler in Arch. Path.

Pharmac. 195 (1940), 71 and Newbould in Brit. Jour. Pharm. Chemoth. 21 (1963), 127-137.

Examples of the groups R and R are phenyl, which is substituted by fluorine, chlorine or bromine, by methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl, by methoxy, ethoxy, propoxy or butoxy, by amino, especially dialkylamino such as dimethylamino, with trifluoromethyl, with methoxy and halogen or with methyl and halogen (although generally no more than one substituent is present in each phenyl ring); 1- and 2-naphthyl, 2- and 3-furyl, 1 2 U are unsubstituted phenyl or 2- or 3-thienyl and 2-, 3- and 4-pyridyl.

The compounds of the above general formula I can be prepared by well-known methods for the synthesis of such aromatic heterocyclic rings as a process for the preparation of compounds of the general formula I, which process is characterized by cyclizing one or more reactants which are substituted suitably with the groups R 1, R 2 and R 4 (wherein R 1 and R 2 have the meaning given above and R 4 has the same meaning as R 3 or is a group which can be converted thereto) and optionally the group R 4 converts to the group R 3.

R3 can e.g. be an acid (eg acetic, n-propion, iso-propion, n-butter, iso-butter or an ethylenically unsaturated acid, such as acrylic acid) or a salt or ester thereof. While R4 is usually an acid or an ester thereof, R4 may also e.g. be a cyanoalkyl, hydroxyalkyl or haloalkyl group or other group, which can be directly or indirectly converted to an acid group, and after the heterocyclic ring is formed, the group R4 can be converted to the acid or a desired derivative thereof, either directly or via syran. Usually it is possible to e.g. convert a haloalkyl (eg the chloromethyl derivative) to the acid by reaction with an alkali metal cyanide (eg sodium or potassium cyanide) or by reaction with an alkali metal derivative of a 4 diester, e.g. as detailed below. R may likewise be a CO 2 H group which can be converted to R 3 by an Arndt-Eistert reaction.

Particularly suitable compounds are those in which X is sulfur, R 1 is 1 2-position, R 2 is 1 4-position and R 3 is 1 5-position and represents a saturated, aliphatic carbohydroxy group, which contains 2-6, preferably 2 -4 carbon atoms. These compounds include thiazoles of the general formula xi (II) in which R 1 and R 2 are the same or different and each represents an unsubstituted phenyl, halophenyl, (lower alkyl) -phenyl-, (lower alkoxy) - phenyl, trihalomethylphenyl, naphthyl, thienyl or furyl group and R? denotes a saturated aliphatic carbohydroxy group containing 2-6 carbon atoms, or a derivative thereof. Preferably R 1 and R 2 are a phenyl, chloro or bromophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, 1-naphthyl, 2- or 3-thienyl or 2- or 3-furyl group and R 3 is an acetic acid. , n-propionic acid or isopropionic acid group or a salt, ester or amide thereof.

The compounds of general formula II are preferably prepared by reacting an α-haloketone of general formula 114 - cn - i: - Rz (III) I 1 Hal O to react with a thioamide of general formula - SH R1 - <1: - NH2-¿_-> __ R1 - lc = NH (iv) wherein R1, R2 and R4 have the meaning given above and Hal represents a halogen atom, e.g. a chlorine or bromine atom, and that the thiazole obtained may be converted to another thiazole of the general formula II.

It has been found particularly convenient to bring an acid of the general formula III (ie in which R 4 contains a COOH group and is preferably an acetic acid or n-propionic acid group), in which Hal is a bromine atom, with a suitable thioamide. The reaction is preferably carried out in a solvent at room temperature or above, e.g. up to the boiling point of the solvent. When the reaction is carried out in the absence of a base and in the presence of an alcohol, e.g. ethanol, usually the product obtained is an ester which can be hydrolyzed to the acid, if desired. If instead another solvent is used or if an alcohol, preferably isopropanol, is used as solvent in the presence of a base (eg an alkali metal carbonate), the acid group R is usually obtained; directly, thus eliminating the need for hydrolysis, if the acid is desired.

In any case, it is convenient to add a base (eg an aqueous solution of sodium carbonate) to the reaction mixture after completion of the reaction to facilitate the separation of the desired product. The Q-halogen ketones of the general formula III can be prepared in a known manner, e.g. by halogenation (eg bromination) of the products of Friedel-Crafts reactions between arbitrarily substituted, aromatic (or heteroaromatic) hydrocarbons and suitable anhydrides, e.g. succinic acid, glutaric acid or methyl succinic anhydride. Ether has been preferred as the solvent for the halogenation. The thioamides of the general formula IV are usually prepared by the method described by Fairful et al (Journal of the Chemical Society, 1952, 742), from corresponding nitriles.

Alternatively, phosphorus pentasulfide can be used to cyclize an acacylaminocarbonyl compound of the general formula R 4 - c --- cn - R 2, wherein R 1, R 2 and R 4 are as defined above, and the group R is then converted to a group R 3, if required. The cyclization reaction is usually carried out at room temperature or above, e.g. at temperatures from 15 ° C up to the boiling point of the solvent used.

The compounds of the general formula V can be prepared by bringing a compound of the formula R 2 - cH - c ~ R 4 (VI) Hal O (which can be prepared by reacting an aryl acetic acid in the form of an ester to react with an acetic acid ester in the presence of of a base and halogenates the product) to react with an amide of the general formula O R 1 - 1c - NH 2 (VII) in the form of a sodium salt, wherein R 1, R 2, Hal and R 4 have the meaning given above.

If R 4 is a COOH group or a derivative thereof or a halomethyl group of the formula III, the first product obtained is a thiazole of the general formula I, in which, however, R 3 has been replaced by the group R 4. In such circumstances, the group R4 must therefore be converted into a group R3 by means of a homologation reaction in order to obtain a compound of general formula I.

For example, if R4 is a carboxyl group, homologation can take place by an Arndt-Eistert reaction by forming the corresponding acid halide, reacting it with diazomethane and treating the formed diazoketone with water and a catalyst (eg colloidal silver). Likewise, if R4 is a halomethyl group, reaction with a cyanide (eg potassium cyanide) gives the nitrile, which can be hydrolyzed.

After the preparation of a thiazole of the general formula II, the group R3 can be arbitrarily converted to another group R3 in a known manner. If e.g. R 3 is an aliphatic acid ester group, the acid can be obtained therefrom by hydrolysis, if desired. The ester can be obtained from the acid by reaction with an alcohol. An acyloxymethyl ester can be obtained by reacting the acid or a salt thereof (eg, an alkali metal or amine salt) with an acyloxymethyl halide such as an acetoxymethyl halide.

Another group of compounds of general formula I, in which X is a sulfur atom, are thiazoles of general formula Rz Rs Rz RI I I and I | R 1 -R 5 in (vIIIa) (vIIIb) wherein R 1 and R 2 are the same or different and each represents an unsubstituted phenyl-, halophenyl-, (lower alkyl) -phenyl-, (lower alkoxy) -phenyl-, naphthyl- , thienyl or furyl group and R 3 has the meaning given in connection with formula I. Suitable groups are those which are also preferred for the thiazoles of the general formula II.

The thiazoles of general formula VIII may be prepared according to methods known for the preparation of thiazoles and preferably in a manner analogous to that of compounds of general formula II described above.

An α-halogen ketone of the general formula 7316107-7 R2-cH-c-R4 Rz-cn-c-R1 | "or II Hal O Hal 0 (IXa) (Ixb) can thus be reacted with a thioamide of the general formula SH NH S NH SH NH S NH \\ 47 Qšš // 2 resp \\ C47 šäbx / 2 f- sc II Ring R 4 R 4 (Xa) (Xb) wherein R 1, R 2 and R 4 are as defined above, and if necessary the group RQ may be converted to the group R 3.

The halogen ketones of the general formula IXa or IXb can be prepared by halogenation of the corresponding ketoester or deoxybenzoin. The thioamides of the general formula Xa and Xb are known compounds or can be prepared in a manner analogous to the method indicated for the preparation of the known compounds.

A compound of general formula VIIIa is preferably prepared according to the above procedure using an α-haloketone in which R 4 is an ester group (eg an acetic acid or propionic acid ester group), while a compound of general formula VIIIb is preferably is prepared according to the above procedure using a thioamide in which R 4 is an ester group (eg the ethyl ester). If R4 in formula Xb is a benzoyloxymethyl group, this group in the thiazole formed can be converted to a hydroxymethyl group and consequently to either a halomethyl group, which can be reacted with a malonic acid ester and hydrolyzed, or to a formyl group and consequently to a acrylyl group by a Knoevenagel reaction. All these after-steps are known per se.

Another series of compounds of general formula I are those in which X is an oxygen atom, and a preferred group of these compounds are oxazoles of general formula I wherein X 1 and R 2 are the same or different and each represents an unsubstituted phenyl, halophenyl, (lower alkyl) phenyl, (lower alkoxy) phenyl, trifluoromethylphenyl, naphthyl, thienyl or furyl group and R 3 is as defined in formula I . R 1 and R 2 are preferably phenyl, chloro or bromophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, 1-naphthyl, 2- or 3-thienyl and 2- or 3-furyl groups and R 3 is an n-propion- or n ~ butyric acid group or a salt, an ester or an amide thereof.

The compounds of the above general formula may be prepared by suitable, conventional methods known for the formation of an appropriately substituted oxazole ring. Such methods are well known. See e.g. Robert E. Elderfield: "Heterocyclic Compounds", vol. 5 (1957), Wiley and Sons, pp. 302-323.

A suitable general method for the preparation of the oxazoles of the general formula XI is based on Davidson's oxazole synthesis and is characterized in that a ketone ester of the general formula 2 RI 1 _ C _ O ~ CH _ C _ R (XII) oo HH R react with ammonia or a salt thereof or with urea (in which R 1, R 2 and R 4 have the 4 to R 3 given in formula XI).

The reaction can be carried out with or without the use of a solvent. If a solvent is used, it is convenient to heat the solution from an elevated temperature up to the boiling point of the solvent, e.g. under reflux. Alternatively, the reactants can be heated in a closed tube. The use of urea is usually preferred) and that, if necessary, R is converted for use of an ammonium salt (eg ammonium acetate) in ice vinegar, as the product is easier to process.

The ketoesters of general formula XII, which have not been previously described, can be prepared by esterifying an m-hydroxy ketone of general formula R 2 - cH - c - R 1 (XIII) OH 0 or a corresponding compound in which OH the group has been replaced by halogen (eg bromine), with an esterifying agent which can convert the Q-hydroxy group or the u-halogen group to a GO-CO-R4 group or to a group which in turn can converted to an α-OCO-R 4 group. The esterification can e.g. is carried out on the OH group with a suitable anhydride, acid, acid halide or other esterifying agent or the halogen group may be reacted with the monoalkali metal salt of the acid. It is very convenient to use the acid anhydride (eg succinic or glutaric anhydride) or the corresponding acid chlorides for acylation of the hydroxy group. The esterification can be carried out by heating the reactants together at elevated temperature either in solution or in a closed tube. Temperatures of up to 180oC are usually suitable, e.g. 100-14000.

If an inert organic solvent is used (eg a hydrocarbon) the esterification can be carried out under reflux.

A less suitable preparation process for formation 3 represents one of compounds of the general formula XI, in which R is saturated, aliphatic acid group, characterized in that an oxazole of the general formula R2 R1, R1 R1 or O2 is formed in a known manner. NN CnH2n-M CH3 (XIVa) (XIVb) (in which R1 and R2 have the meaning given above, n is an integer from 1 to 5 and M is an alkali metal atom) and converts the 2-substituent to the desired acid, t. ex. by reacting the compound of formula (a) with a haloaliphatic acid ester, followed by hydrolysis or by halogenating a compound of formula (b), following reaction with a nitrile or a malonic acid ester and subsequent hydrolysis. Alternatively, the compound of general formula XIVb can be converted to the aldehyde by a Sommelet reaction, followed by a Knoevenagel reaction with a malonic acid ester to produce the acrylic acid derivative, which can be reduced to the propionic acid derivative.

The following less suitable methods of preparation, which are known for the preparation of oxazoles, may, if necessary, be used for the preparation of the novel oxazoles of the general formula XI, wherein R 1, R 2 and R 3 have it in connection with this formula stated meaning.

A) According to the Robinson-Gabriel synthesis, wherein an α-abylamino ketone of the general formula 2 R - g - CH - R1 i I NH xv ço ¿4 can be cyclized, e.g. by means of a cyclizing agent such as sulfuric acid, phosphorus pentachloride, phosphonyl chloride or phosphorus pentoxide.

The starting material of the general formula XV can be prepared from an aminodeoxybenzoin and a suitable acid chloride or from a halodeoxybenzoin and the sodium salt of an amide.

B) According to Japp's synthesis, a hydroxyketone of the formula R2 - cn - c - P1 XVI 1 H OH

C) An imino ether of the general formula I / NH: R4 - cf / xvII 2 Alkyl n can be reacted with an α-amino ketone, or a salt thereof, of the general formula I NH 1 2 2 - CHR - co - R ~ XVIII e.g. in hot acetic acid: The starting material of the general formula XVIII can be prepared by forming the imino ether of benzoyloxymethylnitrile.

A further group of compounds in the series of oxazoles of the general formula I are those which have the general formula 73 (R).

Wherein R 1 and R 2 are the same or different and each represents an unsubstituted phenyl, halophenyl, (lower alkyl) phenyl, (lower alkoxy) phenyl, trifluoromethyl) phenyl, naphthyl, thienyl or furyl group and R 3 and "lower, has the meaning given in connection with formula I. Suitable groups R 1 and R 2 are those which have been given in connection with formula II.

The oxazoles of the general formula XIX are preferably prepared by reacting a ketone of the general formula R4-C-'CH-'R2 p § xx 0 Hal with a amide of the general formula o on R1 - Ö - NH2 ; r: š R1 - É = NH XXI or a salt thereof (wherein R4 is a group which can be converted to R3, Hal is a halogen atom and R1, R2 and R3 have the meaning given in connection with formula XIX) and that , if required, converts the group R4 to R3.

Preferably the group R 4 is an ester (eg acetic acid ethyl ester) in this reaction.

To obtain R4 in the 5-position, the amide of the general formula XXI is first converted to the alkali metal salt, and this salt is then reacted with a compound of the general formula XX, preferably by heating in solution in a solvent. If care is taken, it is usually possible to isolate the intermediate of the general formula R4 - Écn - R2 o o XXII (a) Oš / NH Rl 7316107-7 12 and to cyclize it with a cyclizing agent such as sulfuric acid, phosphorus pentachloride, phosphonyl chloride or phosphorus pentoxide.

To obtain R4 in the 4-position, the amide of the general formula XXI can be heated directly with the compound of the general formula XX. If the heating is performed in the presence of an acid acceptor, e.g. a carbonate of an alkaline earth metal, such as calcium carbonate, the compound of general formula XIX is formed together with an intermediate which is believed to be a compound of general formula 132-cH-- C Ä xxx: (b) The crude product may be treated with an acid, for example sulfuric acid, due to the cyclization of this intermediate.

A further preparation process comprises hydrolysis of the corresponding nitriles, which have or have not been prepared according to the above procedure, as desired in the presence of an alcohol.

A very suitable procedure is to cycle a compound of the general formula. : <2 - c - - R 5 u: g xxn: on 5 represents an alkyl group, such as a methyl group, or a hydroxyalkyl group) and converts R 5 to 123.

The resulting oxazole is a compound of the general formula XIX having the meaning given above and R in the form of the N-oxide, wherein R 5 replaces R 3, and this can be halogenated and reduced (eg with phosphorus trichloride), whereby a compound of the general formula XIX, in which R 3 is a haloalkyl group. This type of compound can also be prepared by reacting a compound of general formula XIX, in which R 3 has been replaced by a methyl group, and reacting it with N-bromosuccinimide. In either case, the haloalkyl compound formed can be reacted with an alkali metal cyanide and hydrolysis. It is usually also possible to form an oxazole of the formula XIX by bringing a compound of the general formula NH XXIV. 4 N in which R is a halogen atom, to react with a malonic acid ester and cyclize by treatment with an acid or by cyclizing a compound of the general formula Rz-lcl-CIH-zäl o o o \ R1 with ammonia, an ammonium salt or urea. R4 can then be converted to R3.

It is possible to prepare derivatives containing 3 carbon atoms in the chain of the R3 group by reducing the corresponding acrylic acid derivatives. A 4- or 5-formyloxazole can e.g. is formed from the halomethyloxazoles in a known manner and heated with malonic acid ester in anhydrous pyridine, after which the mixture is poured into dilute acid (eg HCl) to give 4- or 5-acrylic acid, which can then be reduced, e.g. catalytically using hydrogen.

Optionally, in addition, an Arndt-Eistert reaction can be carried out on the corresponding carboxyloxazole by forming the acid halide, reacting it with diazomethane and treating the formed diazoketone under known conditions to give acetic acid or an amide or an ester thereof (treatment with water and a catalyst, such as colloidal silver, gives, for example, acetic acid). The homologation can be repeated if desired upwards in the series.

The method of preparation used for the preparation of a particular compound depends on the compound in question, and the most suitable method is preferably used in each particular case.

The starting materials in the above processes are known or can be obtained in ways analogous to methods for the preparation of similar known compounds.

If the product obtained after carrying out one of the above processes is not the desired one but a derivative thereof, it can be converted into the desired compound in a known manner, e.g. by following the instructions given in the present context.

In all the reactions mentioned above, it is apparent that substituents present in the phenyl rings must be inert under the reaction conditions, if required by blocking by standard methods while the reaction is being carried out and formation thereof only after a compound having the general formula I has been prepared. Since the compounds of general formula I contain a basic nitrogen atom, they can form salts with pharmaceutically acceptable acids (although they can be readily hydrolysed to the free base) and the invention therefore also includes such salts.

The invention is further illustrated by the following examples, in which the temperatures are given in degrees Celsius.

Example 1. 2,4-Diphenylthiazol-5-yl-acetic acid ethyl ester 3-bromo-3-benzoylpropionic acid (40 grams) and thiobenzamide (2.1 grams) were heated together in ethanol (500 ml) under reflux for 8 hours. Most of the ethanol was then evaporated, and a solution of sodium carbonate (10 grams) in water (300 ml) was added. The mixture was extracted with ether, the ether extracts were combined, washed with water, dried over Na 2 O 4 and evaporated to give pale yellow, needle-shaped crystals (46.1 grams), m.p. 85 DEG-910 DEG. Recrystallization from ethanol gave the pure ester. . Yield 35.2 grams (70 percent) of colorless, needle-shaped crystals. melting point 95 - 96 °.

Analysis: Found: C, 70.6; H, 5.2; N, 4.3; S, 10.1; Calculated: C, 70.6; H, 5.3; N, 4.3; S, 9.9; percent of C 19 H 17 NO 28: A certain amount of this ester was then hydrolyzed to the acid, as described in Example 4 below. Example 2. 2-Phenyl-4- (4'-methoxyphenyl) thiazol-5-yl-acetic acid ethyl ester Using the procedure described in Example 1, 3-bromo-3- (4'-methoxybenzoyl) propionic acid (11 grams ) and thiobenzamide (5.25 grams) to react to give 2-phenyl-4- (4'-methoxyphenyl) thiazol-5-ylacetic acid ethyl ester, which was recrystallized from ethanol as colorless needles. Yield 8.3 grams (62 percent). melting point 67.5 - ss, s °.

Analysis: Found: C, 68.0; H, 5.4; N, 3.9; S, 9.2; Calculated: C, 68.0; H, 5.4; N, 4.0; S, 9.1; percent of C 20 H 19 N 3 O 3 A certain amount of this ester was then hydrolyzed to the acid, as described in Example 5 below.

Example 3. 2-Phenyl-4- (4'-chlorophenyl) thiazol-5-yl-acetic acid ethyl ester Using the procedure described in Example 1, 3-bromo-3- (4'-chlorobenzoyl) propionic acid (29.2 grams) and thiobenzamide were brought (1.3.7 grams) to react to form 2-phenyl-4- (4'-chlorophenyl) thiazol-5-yl-acetic acid ethyl ester, which was recrystallized from ethanol as colorless needles. Yield 19.9 grams (56 percent). melting point 69 - 7ø °.

Analysis: Found: C, 63.8; H, 4.7; N, 3.8; S, 9.1; Calculated: C, 63.7; H, 4.5; N, 3.9; S, 9.0; percent of C 19 H 16 ClNO 28 A certain amount of this ester was then hydrolyzed to the acid, as described in Example 6 below.

Example 4. 2,4-Diphenylthiazol-5-yl-acetic acid 2,4-Diphenylthiazol-5-yl-acetic acid ethyl ester (15 grams) was dissolved in hot ethanol (150 ml) and potassium hydroxide (10 grams) in water (20 ml) was added. After 1 hour, most of the ethanol had been evaporated off and the solution was diluted with water. Concentrated hydrochloric acid was then added until the mixture became slightly acidic and the oily solid was extracted with ether. The ether extracts were combined, washed with water, dried over Na 2 SO 4 and evaporated to give a viscous oil (13.5 grams) which crystallized slowly. Recrystallization from benzene gave colorless, needle-shaped crystals of the above compound. Yield 12.2 grams us percent). melting point 152; 1s3 °.

Analysis: Funnetz-C, 69.4; H, 4.2; N, 4.7; S, 10.8; Calculated: C, 69.2; H, 4.4; N, 4.7; S, 10.9; percent for ° 17H13N ° 2S Example1'5. 2-Phenyl-4- (4'-methoxyphenyl) thiazol-5-yl-acetic acid Using the procedure described in Example 4, the ethyl ester of Example 2 (5 grams) was hydrolyzed to 2-phenyl-4- (4'-methoxyphenyl) thiazol-5-yl-acetic acid, which was recrystallized from benzene as colorless needles. Yield 3.9 grams (85 percent). Melting point 178.5 - 179.s °.

Analysis: Found: C, 66.5; H, 4.5; N, 4.3; S, 10.0; Calculated: C, 66.5; H, 4.6; N, 4.3; S, 9.9; percent of C 18 H 15 N 3 O 3 S Example 6. 2-Phenyl-4- (4'-chlorophenyl) thiazol-5-yl-acetic acid Using the procedure described in Example 4, the ethyl ester of Example 3 (10 grams) was hydrolyzed to 2-phenyl- 4- (4'-chlorophenyl) thiazol-5-yl-acetic acid, which was recrystallized from benzene as colorless needles. Yield 4.9 grams (63 percent). Melting point 161 - 162 °.

Analysis: Found: C, 62.0; H, 3.7; N, 4.2; S, 9.8; Cl, 10.7; Calculated: C, 62.0; H, 3.7; N, 4.2; S, 9.7; C1, 10.7; % for C 17 H 12 ClNO 2 S Example 7. α- (2,4-Diphenylthiazol-5-yl) propionic acid 3-bromo-3-benzoylisobutyric acid (13.6 grams) and thiobenzamide (6.9 percent) were heated in isopropanol (75 ml) at 60 ° C. ° for 30 minutes. Sodium carbonate (2.5 grams) was then added and heating was continued for another 10 minutes. After allowing the mixture to stand overnight, it was diluted with water, after which the aqueous solution was decanted from the oil obtained. The oil was taken up in ether and extracted with a dilute aqueous solution of sodium carbonate. The basic extract is washed with ether, acidified with hydrochloric acid to a pH of 4, after which the resulting oil is extracted with ether. The ether extract was washed with water, dried over Na 2 SO 4 and evaporated to give a light yellow, viscous oil which crystallized slowly. Recrystallization from glacial acetic acid / water gave d- (2,4-diphenylthiazol-5-yl) propionic acid as prismatic crystals. Yield 8.6 grams (55 percent). Melting point: 142 - 1440.

Analysis: Found: C, 69.9; H, 4.9; N, 4.7; S, 10.3; Calculated: C, 69.9; H, 4.9; N, 4.7; S, 10.3; percent of C 15 H 15 N 2 O 2 S Exemgel 8. 2-Phenyl-4- (2'-thienyl) thiazol-5-yl-acetic acid Using the procedure described in Example 7, 3-bromo-3- (2'-theonyl) propionic acid (1.3.2 grams) and thiobenzamide (6.9 grams) to react to form 2-phenyl-4- (2'-thienyl) thiazol-5-yl-acetic acid as acicular crystals.

Yield 7.2 grams (48 percent). Melting point 134.5 - 135.00.

Analysis: Found: C, 59.9; H, 3.7; N, 4.5; S, 21.0; Calculated: C, 59.9; H, 3.7; N, 4.65; S, 21.3; percent for C 15 H 11 N 2 O 2 Exemgel 9. 2-Phenyl-4- (4'-methylphenyl) thiazol-5-yl-acetic acid Using the procedure described in Example 7, 3-bromo-3- (4'-methylbenzoyl) propionic acid was brought (27.1 grams) and thiobenzamide (1.3.7 grams) to react to form 2-phenyl-4- (4'-methylphenyl) thiazol-5-yl-acetic acid. Yield 9.6 grams (31 percent).

Melting point 168 - 1690 from benzene.

Analysis: Found: C, 70.0; H, 5.1; N, 4.6; S, 10.6; Calculated: C, 69.9; H, 4.9; N, 4.5; S, 10.3; percent for C 15 H 15 N 5 Z 5 Exemgel 10. 2- (4'-Methoxyphenyl) -4-phenylthiazol-5-yl-acetic acid ethyl ester 4-methoxythiobenzamide (4.2 grams) and 3-benzoyl-3-bromopropionic acid (6.4 grams ) was refluxed in ethanol (50 ml) for 1.5 hours. After the mixture was allowed to stand overnight at room temperature, a crystalline solid separated. The whole reaction mixture was poured into water with stirring and the oil layer was separated. The aqueous layer was washed with ether (3 x 200 ml) and the extracts were combined with the oil. The ether solution was washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness. The resulting yellow oil crystallized rapidly to a light yellow crystalline solid. Recrystallization from denatured alcohol gave a light off-white solid with a melting point of 60.5-62 °. Yield 3.8 grams (43 percent).

Analysis: Found: C, 67.7; H, É, 3; N, 3.8; S, 9.0; Calculated: C, 68.1; 1H, 5.4; N, 4.0; S, 9.1; percent, C for C 20 H 19 N 3 O 3 S Example 11. 4- (2'-thienyl) -2- (2'-methylphenyl) thiazol-5-yl-acetic acid 2-methylthiobenzamide (5.7 grams), 3-bromo-3- (2'-tenoyl) propionic acid ( 10 grams) and anhydrous sodium carbonate (1.8 grams) were heated together in isopropanol (55 ml) with stirring at §0 ° for 30 minutes. The mixture was then cooled to 400 and stirred for an additional 60 minutes. After cooling to room temperature got among? The mixture was allowed to stand overnight and poured slowly into cold water (1 liter).

A few drops of concentrated hydrochloric acid were added to acidify the mixture, and after allowing the mixture to stand for another 30 minutes, the resulting solid was filtered off.

The aqueous phase was extracted with ether and the extracts were combined with the solid. The ether solutions were carefully extracted with a saturated aqueous solution of sodium bicarbonate and the aqueous extracts were acidified with concentrated hydrochloric acid. The oil-like precipitate from the aqueous phase solidified rapidly and recrystallized after drying from benzene. Yield 6.7 grams (46.2 percent). Melting point 136 - 13a °.

Analysis: Found: C, 61.0; H, 4.2; N, 4.3; S, 20.3; Calculated: C, 60.9; H, 4.2; N, 4.4; S, 20.3; % for ° 16H13N ° 2Sz 7316107-7 19 Example 12. V 2- (4'-chlorophenyl) -4- (4'-methoxyphenyl) thiazol-5-yl-acetic acid Following the procedure described in Example 11, chlorothiobenzamide (6.25 grams) and 3-bromo-3- (4'-methoxybenzoyl propionic acid (10.3 grams) to react with each other in isopropanol (50 ml) in the presence of sodium carbonate (1.8 grams) After working up in the manner described in Example 11 and recrystallization from glacial acetic acid / water, the above compound was obtained, yield 7.5 grams (57.1 percent), melting point 199 - 2010.

Analysis: Found: C, 60.0; H, 4.2; N, 3.7; S, 9.0; Cl, 9.7; Calculated: C, 60.1; H, 3.9; N, 3.9; S, 8.9; Cl, 9.9; % for C 18 H 14 ClNO 2 Example 13. 2- (4'-chlorophenyl) -4-phenylthiazol-5-yl-acetic acid Following the procedure described in Example 11, 4-chlorothiobenzamide (14.6 grams) and 3-benzoyl-3- bromopropionic acid (2.1, 8 grams) to react with each other in isopropanol (127 ml) in the presence of sodium carbonate (4.3 grams). After working up in the manner described in Example 11 and recrystallization from benzene, the above compound was obtained. Yield 12.4 grams (44.2 percent). melting point 153 - 1s5 °. Analysis: Found: C, 62.1; H, 3.8; N, 4.1; S, 9.8; Cl, 10.8; Calculated: C, 61.9; H, 3.7; N, 4.3; S, 9.7; Cl, 10.8; % for C 17 H 12 ClNO 2 Example 14. 2- (4'-chlorophenyl) -4- (2'-thienyl) thiazol-5-yl-acetic acid Following the procedure S described in Example 11, 4-chlorothiobenzamide (6.3 grams) was brought and 3-bromo-3- (2'-tenoyl) propionic acid (10 grams) to react with each other in isopropanol (55 ml) in the presence of sodium carbonate (1.8 grams). After working up in the manner described in Example 11 and recrystallization from benzene, the above compound was obtained. Yield 4.8 grams (31.2 present). melting point 137 - 139 °.

Analysis: Found: C, 53.6; H, 3.2; N, 4.0; S, 19.0; Cl, 10.5; Calculated: C, 53.6; H, 3.0; N, 4.2; S, 19.1; Cl, 10.6; % for C 15 H 10 OClNO 2 S 2 7316107-7 Example 1S. ë, 4-Di- (4'-methoxyphenyl) thiazol-silyl-acetic acid Following the procedure described in Example 11, 4-methoxythiobenzamide (6.0 grams) and 3-bromo-3- (4'-methoxy) benzoyl) propionic acid (10, 3 grams) to react with each other in isopropanol (50 ml) in the presence of sodium carbonate (1.8 grams). After working up in the manner described in Example 11 and recrystallization from glacial acetic acid / water, the above compound was obtained. Yield 8.0 grams (56.3 percent). melting point 176 - 17s °.

Analysis: Found; C, 64.3; H, 5.0; N, 3.9; S, 9.1; Calculated: C, 64.2; H, 4.8; N, 3.9; S, 9.0; percent for C19H17NS ° 4 Example 16. 4- (4'-Methoxyphenyl) -2- (2'-methylphenyl) thiazol-5-yl-acetic acid Following the procedure described in Example 11, 2-methylthiobenzamide (5.4 grams ) and 3-bromo-3- (4'-methoxybenzoyl) -propionic acid (10, 3 grams) to react with each other in isopropanol (50 ml) in the presence of sodium carbonate (1.8 grams). After working up in the manner described in Example 11, the above compound was obtained. Yield 5.4 grams (44.6 percent). Melting point 140 - 141 °. - _. Analysis: Found: C, 67.2; H, 5.1; N, 4.3; S, 9.4; Calculated: C, 67.2; H, 5.1; N, 4.1; S, 9.5; percent for C 19 H 17 NSO 3 Example 17. 2- (2'-methylphenyl) -4-phenylthiazol-5-yl- acetic acid 2-methylthiobenzamide (7.5 grams), 3-benzoyl-3-bromopropionic acid (1.2.85 grams) and isopropanol (75 ml) were heated together with stirring at 60 ° for 30 minutes After cooling to 400, anhydrous sodium carbonate (2 g) was added. .5 grams) to the orange solution and the mixture was kept at 40 ° for another 60 minutes.

After allowing the mixture to stand overnight, it was slowly poured with stirring into cold water (1 liter) and a few drops of concentrated hydrochloric acid were added to acidify the mixture. After allowing the mixture to stand for 30 minutes, the oily, semi-solid layer was separated. The aqueous phase was extracted with ether and the extracts were combined with the oil layer. The resulting ether solution was carefully extracted with a saturated aqueous solution of sodium bicarbonate and the aqueous extracts were acidified with concentrated hydrochloric acid. The resulting oil-like precipitate solidified rapidly and after drying it was recrystallized from benzene petroleum ether (60-800) to give the above compound. urbyte = 3.0 grams (19.4 percent); melting point 165 Å 167 °.

Analysis: Found: C, 69.7; H, 5.0; 'N, 4.4; S, 10.5; Calculated: C, 69.9; H, 4.9; N, 4.5; S, 10.4; percent for f C 18 H 15 NO 2 S x Example 18. 2- (5'-methylphenyl) -4-phenylthiazol-5-yl-acetic acid Following the procedure described in Example 17 using 3-methylthiobenzamide (7.5 grams), 3-benzoyl -3-Bromopropionic acid (1.2.85 grams), isopropanol (75 ml) and sodium carbonate (2.5 grams) gave the title compound, which was recrystallized from benzene petroleum ether. Yield: 2.3 grams (15 percent). Melting point 123 - 1250.

Analysis: Found: C, 69.7; H, 4.9; N, 4.5; S, 10.3; Calculated: C, 69.9; H, 4.9; N, 4.5; S, 10.3; percent for C 18 H 15 NO 2 S Example 19. 2- (4'-Methoxyphenyl) -4-phenylthiazol-5-yl-acetic acid Following the procedure described in Example 17 and using 4-methoxythiobenzamide (8.35 grams), 3-benzoyl-3-bromopropionic acid (12 85 grams), isopropanol (75 ml) and sodium carbonate (2.5 grams) gave the title compound, which was recrystallized from benzene.

Yield 6.6 grams (40, 6 percent). melting point 149.5 ~ 1s2 °.

Analysis: Found: C, 66.4; H, 4.6; N, 4.2; S, 9.7; Calculated: C, 66.4; H, 4.7; N, 4.3; S, 9.9; percent of C 15 H 15 N 3 O 3 Example 20. 2- (2'-chlorophenyl) -4-phenylthiazol-5-yl-acetic acid Following the procedure described in Example 17 using 2-chlorothiobenzamide (8.60 grams), 3-benzoyl- 3-Bromopropionic acid (1.2.85 grams), isopropanol (75 ml) and sodium carbonate (2.5 grams) gave the above compound, which was recrystallized from benzene.

Yield 4.6 grams (27.6 percent). Melting point 168 - 1710.

Analysis: Found: C, 62.0; H, 3.7; N, 4.2; S, 9.9; Cl, 10.8; Calculated: C, 61.9; H, 3.7; N, 4.3; S, 9.7; Cl, 10.8; for C 17 H 12 NO 2 SCCl Example 21. 2- (4'-methylphenyl) -4-phenylthiazol-5-yl-acetic acid Following the procedure described in Example 17 using 4-methylthiobenzamide (7.5 grams), 3-benzoyl-3- bromopropionic acid (12.85), isopropanol (75 ml) and sodium carbonate (2.5 grams) g / o gave the title compound, which was recrystallized from benzene.

Yield 7.9 (s1.2 percent). melting point 170 - 171 °.

Analysis: Found: C, 70.1; H, 5.0; N, 4.3; S, 10.5; Calculated: C, 69.9; H, 4.9; N, 4.5; S, 10.4; percent for C 18 H 15 NO 2 S Example 22. 2- (1'-Naphthyl) -4-phenylthiazol-5-yl-acetic acid Following the procedure described in Example 17 and using thionaphthamide (14.1 grams), 3-benzoyl-3 bromopropionic acid (19.3 grams) isopropanol (115 ml) and sodium carbonate (3.75 grams) gave the title compound, which was recrystallized from benzene / petroleum ether. Yield 8.6 grams (29.7 percent). Melting point 145 - 14s °.

Analysis: Found: C, 73.1; H, 4.4; N, 4.1; S, 9.3; Calculated: C, 73.2; H, 4.4; N, 4.0; S, 9.3; percent for C 21 H 13 N 2 O 2 Example 23. 2- (3'-Trifluoromethylphenyl) -4-phenylthiazol-5-yl-acetic acid Following the procedure described in Example 17 using 3-trifluoromethylthiobenzamide (15.3 grams), 3-benzoyl -3-Bromopropionic acid (19.3 grams), isopropanol (115 ml) and sodium carbonate (3.75 grams) gave the title compound, which was recrystallized from benzene / petroleum ether. Yield 6.4 grams (723.4 percent). Melting point 143 - 14s °.

Ane1ye = runner; c, 59.6; H, 3.7; N, 3.8; FZ 15.6; s, 8.6; Calculated: C, 59.6; H, 3.3; N, 3.9; F, 15.7; S, 8.8; % for C 18 H 12 NO 2 SF 3 Exemgel 24. 4- (2'-thienyl) -2- (4'-methoxyphenyl) thiazol-5-yl-acetic acid By following the procedure described in Example 17 and using 4-methoxythiobenzamide (6.3 grams) 3-Bromo-3- (2'-tenoyl) -propionic acid (1.0 g), isopropanol (55 ml) and sodium carbonate (1.8 g) gave the title compound, which was recrystallized from benzene. yield 1.9 grams (13.3 percent). mp 149 - 1s1 °.

Analysis: Found: C, 58.0; H, 3.9; N, 4.3; S, 19.5; Calculated: C, 58.0; H, 4.0; N, 4.2; S, 19.4; percent for C16H13N ° 3S2 Example Gel 25. 2- (2'-Naphthyl) -4-phenylthiazol-5-yl-acetic acid Following the procedure described in Example 17 and using 2-thionaphthamide (14.1 grams), 3-benzoyl -3-Bromopropionic acid (19.3 grams) isopropanol (115 ml) and sodium carbonate (3.75 grams) gave the above compound, which was recrystallized from benzene.

Yield 14.0 grams (50, 6 percent). mp 171 - 172 °.

Analysis: Found: C, 72.9; H, 4.6; N, 3.9; S, 9.2; Calculated: C, 73.2; H, 4.4; N, 4.0; S, 9.3; percent for C 21 H 15 N 2 O 2 S Example Gel 26. 2- (4-Methoxyphenyl) -4- (2'-naphthyl) thiazol-5-yl-acetic acid Following the procedure described in Example 17 using 4-methoxythiobenzamide (22.5 grams), 3-Bromo-3- (2'-naphthoyl) -propionic acid (40.5 grams), isopropanol (200 ml) and sodium carbonate (6.6 grams) gave the above compound, which was recrystallized from glacial acetic acid / water. Yield 22.4 grams (44.4 percent). Melting point 160 - 16z °.

Analysis: Found: C, 70.3; H, 4.5; N, 3.7; S, 8.4; Calculated = C. 70.4; H, 4.6; N, 3.7; s, 8.5; percent for C 22 H 17 NSU 3 7316107-7 '24 Example 21 - β- (2- (4'-chlorophenyl) -4-phenylthiazol-5-yl) propionic acid 4-benzoyl-4-bromobutyric acid (26.5 grams) and 4-chlorothiobenz amide (16.7 grams) was heated together by refluxing in ethanol (80 ml) for 3.5 hours. After cooling, the solvent was evaporated and the residue was extracted into benzene. The benzene solution was washed with 2N sodium carbonate solution, water and then dried (MgSO 2) and evaporated to give the ethyl ester of B- [2- (4'-chlorophenyl) -4-phenylthiazol-5-yl] propionic acid as a yellow oil. Yield 39.0 grams.

This ester was dissolved in hot ethanol (50 ml) and treated with a solution of potassium hydroxide (5.7 grams) in ethanol (50 ml).

After 1 hour, most of the solvent had evaporated and water was added, after which 2N hydrochloric acid was added to control the pH to 4. The mixture was extracted with ether and the combined extracts were washed with ZN sodium carbonate solution. The alkaline solution was acidified and extracted with ether.

This ether solution was washed with water, dried (MgSO 4) and evaporated to give B- [2- (4'-chlorophenyl) -4-phenylthiazol-5-yl] propienoic acid as a solid (1.2.6 grams, 37 g). percent). Recrystallization from benzene gave acicular crystals with a melting point of 177 - 1780.

Analysis: Found: C, 63.0; H, 4.2; N, 4.0; S, 9.4; Cl, 10.1; Calculated: C, 62.9; H, 4.1; N, 4.1; S, 9.3; Cl, 10.3; % for C 18 H 14 ClNO 2 S Example 28. 4- (1'-naphthoyl) -2-phenylthiazol-5-yl-acetic acid Following the procedure described in Example 27, 3-bromo-3- [1'-naphthoyl) propionic acid (30, 7 grams) and thiobenzamide (13.7 grams) to react with each other in ethanol to give 34.2 grams of the crude ethyl ester of the above compound, which ester was hydrolyzed to the acid. This was recrystallized from benzene to give 4.2 grams (12 percent) of the title compound. Melting point 166 - 167 °.

Analysis: Found: C, 73.0; H, 4.6; N, 4.0; S, 9.4; Calculated: C, 73.1; H, 4.4 ;. N, 4.1; S, 9.5; percent of C 21 H 15 NSO 2 7316107-7 Example 4. In 4- (2'-naphthoyl) -2-phenylthiazol-3-yl-acetic acid - Following the procedure described in Example 27, methyl 3-bromo-3- ( 2'-naphthoyl) propionate (29.6 grams) and thiobenzamide (1.2.6 grams) to react with each other in ethanol to give the crude methyl ester of the above compound (31.8 grams), which ester was then hydrolyzed to acid . Recrystallization from benzene gave 9.9 grams of acid (31 percent). Melting point 168 - 1e9 °.

Analysis: Found: C, 73.0; H, 4.4; N, 4.0; S, 9.4; Calculated: C, 73.1; H, 4.4; N, 4.1; S, 9.3; percent for C 21 H 15 NSO 2 Exemgel 30.

B- (2- (4 '- methoxyphenyl) -4-phenylthiazol-5-yl] propionic acid »Following the procedure described in Example 27, 4-benzoyl-4-bromobutyric acid (27.1 grams) and 4-methoxythiobenzamide ( 16.7 grams) to react with each other in ethanol to give the crude ethyl ester of the above compound (39.5 grams) which ester was then hydrolyzed to the acid Recrystallization from benzene gave 6.9 grams of acid (2.1 percent). l74 ~ 1750.

Analysis: ~ Found: C, 67.1; H, 5.0; N, 4.0; S, 9.6; Calculated: C, 67.2; H, 5.1; N, 4.1; S, 9.4; percent for C19H17N ° 3S Éëgmgel 31.

B- (2- (2'-methylphenyl) -4-phenylthiazol-5-yl) propionic acid Following the procedure described in Example 27, 4-benzoyl-4-bromobutyric acid (27.1 grams) and 2-methylthiobenzamide were brought (1.5.1 grams) to react with each other in ethanol to give the crude ethyl ester of the above compound (37.5 grams), which ester was then hydrolyzed to the acid. Recrystallization from benzene gave 5.7 grams of acid (18 percent). Melting point l07 - 1090.

Analysis: Found: C, 70.6; H, 5.4; N, 4.2; S, 9.8; Calculated: C, 70.6; H, 5.3; N, 4.3; S, 9.9; percent for CH ND 19 17 28 7316107-7 26 Example 32. In 2,4-diphenylthiazol-5-yl-acetic acid methyl ester 3-benzoyl-3-bromopropionic acid (29.5 grams) and thiobenzamide (1.57 grams) were heated together for 5 hours in methanol (300 ml) under reflux. Upon cooling, acicular crystals of the methyl ester separated. Yield 24 grams (70 percent).

Yield 24 grams (70 percent). melting point 122 - 123 °. Analysis: Found: N, 4.5; S, 1.06; Calculated: N, 4.5; S, 10.3; percent for H NO S C18 15 Exemgel 33. ß- (2,4-diphenylthiazol-5-yl) propionic acid 4-benzoyl-4-bromobutyric acid (27.1 grams) and thiobenamide were heated under reflux in methanol (300 ml ) for 6 hours. Most of the methanol was evaporated and water was added. The resulting mixture was extracted with ether and the combined extracts were washed with sodium carbonate solution, water and then dried (Na 2 SO 4). Evaporation of the solvent gave the methyl ester of β- (2,4-diphenyl-thiazol-5-yl) -propionic acid (23.3 grams) as a yellow oil.

The ester was dissolved in hot ethanol (200 ml) and treated with a solution of potassium hydroxide (10 grams) in water (20 ml). After 1.5 hours, the solution had been partially evaporated and then poured into water. Acidification with concentrated hydrochloric acid gave an oil, which was extracted with ether. The combined extracts were washed with water, dried (Na 2 SO 4) and evaporated to give an oil which solidified slowly. Yield l5.6 grams (50 percent). Recrystallization from ethanol gave the acid as long, colorless needles.

Melting point 150 °.

Analysis: Found: C, 69.6; H, 5.0; N, 4.4; S, 10.2; Calculated: C, 69.9; H, 4.9; N, 4.5; S, 10.3; percent for ° 1sH1sN ° 2S Exemgel 34.

B- (4,5-Diphenyloxazol-2-yl) propionic acid (a) Benzoin (2.1 grams) and succinic anhydride (1.0.0 grams) were heated together at 1200 for 6 hours. After cooling, the glass-like solid formed was dissolved in ether and extracted with a dilute aqueous solution of sodium carbonate. The basic extract was washed once with ether and then acidified with hydrochloric acid. The resulting oil was extracted with ether and the extract was washed with water, dried over Na 2 SO 4 and evaporated to give an oil which solidified to form prismatic crystals of benzoin hemisuccinate ester (27 grams, 87 percent). Melting point 86 - 880. An analytical sample was recrystallized from aqueous acetone to give prisms. Melting point 88.5 - s9, s °. (b) Benzoin hemisuccinate ester (15 grams) and ammonium acetate (30 grams) were heated under reflux in glacial acetic acid (100 ml) for 1.5 hours. After cooling, the solution was poured into water and the resulting crystalline precipitate was filtered off, washed with water and recrystallized from methanol to give acicular crystals of β- (4,5-diphenyloxazol-2-yl) propionic acid (11, 7 grams, 83 percent ). Melting point 160.5 - 161.50.

Analysis: Found: C, 73.9; H, 5.4; N, 5.0; Calculated! C, 73.8; H, 5.2; N, 4.8; percent for cis ss lssNos Exemgel 35. _ ß- [4,5-di- (4'-methoxyphenyl) oxazol-2-yl] -propionic acid (a) Anisoin (1.3.6 grams), succinic anhydride (5.5 grams) and toluene (3 ml) was heated with stirring for 5 hours, the internal temperature of the reaction mixture being 135-1400.

The mixture was then allowed to cool, ether (100 ml) was added and the insoluble succinic anhydride was removed by filtration. The filtrate was added to a stirred 0.5N sodium bicarbonate solution (250 mL), the organic layer was separated and extracted with an additional 9.5N NaHCO 3 solution (2 x 50 mL). The combined aqueous layers were extracted with ether (250 mL) and acidified with concentrated HCl. The liberated oil was extracted into ethyl acetate (1 x 100, 2 x 50 ml), and the combined organic phase was washed well with water, dried (MgSO 4) and evaporated in vacuo to give a sticky foam of anisoinhemisuccinate. Yield 8.28 grams (44.4 percent). (b) Anisoinhemisuccinate (S, 52 grams) and urea (2.05 grams) in glacial acetic acid (30 ml) were heated under reflux for 3 hours.

The mixture was cooled and poured into ice / water (500 ml). The liberated oil was extracted into ethyl acetate (3 x 150 ml). The combined organic phases were washed with water until the wash water was substantially neutral and then extracted with 0.5N sodium bicarbonate solution (3 x 75 ml) The combined aqueous extracts were extracted with ethyl acetate (100 ml), acidified with concentrated HCl, then the resulting oil was extracted with ethyl acetate (3 x 100 ml) After washing with water and drying (MgSO After removal of the solvent, a sticky solid (3.96 grams) was kept Recrystallization from benzene / petroleum ether (60 - 80) gave brown crystals of the above substance Yield 2.65 grams (50.7 percent Melting point 78 - 820.

A sample was recrystallized for analysis (from benzene) and showed a melting point 81.5 - 840.

Analysis: Found: C, 67.8; H, 5.8; N, 4.0; Calculated: C, 68.0; H, 5.4; N, 4.0; percent for C20H19N ° s An additional sample was converted to the sodium salt by neutralization with sodium hydroxide.

Example 36.

B- [4- (4'-Methoxyphenyl) -5-phenyloxazol-2-yl] propionic acid The procedure described in Example 35 (a) was followed to give 4-methoxybenzoin (1.2.1 grams) and succinic anhydride (5.5 grams). was reacted for 5 hours at 135-140 ° to give 4-methoxybenzoin hemisuccinate. Yield 10 grams (58.3 percent).

The procedure described in Example 35 (b) was then followed, using the above-obtained hemisuccinate (8.6 grams), urea (3.6 grams) and glacial acetic acid (25 ml) to give the title compound.

Yield 6.1 grams (75.1 percent). Melting point ll8 - 1200.

Analysis: Found: C, 70.5; H, 5.4; N, 4.5; Calculated: C, 70.7; H, 5.3; N, 4.3; percent for C19H17N ° 4 Exemgel'37.

B- [4- (4'-Methoxyphenyl) -5- (4'-chlorophenyl) oxazol-2-yl] -oropionic acid The procedure described in Example 35 (a) was followed, substituting 4'-chloro-4 -methoxybenzoin (1.3.8 grams) and succinic anhydride (5.5 grams) were reacted for 7 hours at 135: 140 ° to give 4'-chloro-4-methoxybenzoin hemisuccinate. Yield 10.8 grams (57.3 percent).

The procedure described in Example 35 (b) was followed, but using the above-obtained hemisuccinate (9.4 grams), urea (3.6 grams) and glacial acetic acid (25 ml) to give the above compound. Yield 6.7 grams (75.2 percent). Melting point 130.5 - 132.50.

Analysis: Found: C, 63.75; H, 4.5; N, 3.8; Cl, 9.9; Calculated: C, 63.8; H, 4.5; N, 3.9; Cl, 10.1; percent for C 19 H 16 ClNO 4 Example 38.

W '- (4,5-Diphenyloxazol-2-yl) butyric acid (a) Benzoin (2.1, 2 grams) and glutaric anhydride (11, 4 grams) were reacted using the procedure described in Example 34, wherein benzoin hemiglutarate (18.3 grams, 56 percent) was obtained as an oil. The association had an IR spectrum in accordance with its structure. (b) Benzoin hemiglutarate (18.3 grams) and ammonium acetate (30 grams) were heated together in glacial acetic acid under reflux (100 ml) for 2.5 hours. Separation in the manner of Example 36 gave β- (4,5-diphenyloxazol-2-yl) butyric acid (1.54 grams, 89 percent) as needle crystals, m.p. 125-160.

Analysis: Found: C, 74.5; H, 6.0; N, 4.5; Calculated: C, 74.3; H, 5.6: N, 4.6; percent for C 19 H 17 NO 3 Example 39.

B- (4,5-Diphenyloxazol-2-yl) propionic acid ethyl ester The acid of Example 34 (5 grams) in abs. ethanol (100 mL) was heated at reflux with concentrated H 2 SO 4 (1 mL) for 16 h.

The mixture was cooled, evaporated in vacuo to about 50 ml and poured into water (200 ml). The resulting colorless solid was filtered, washed with water, sodium bicarbonate and water again. Yield 5.32 grams. The solid was recrystallized from ethanol to give colorless needles of the above compound. Yield 4.4 grams. An additional 0.21 grams crystallized out of the mother liquor at the standing part. Total yield 4.61 grams (84.3 percent). melting point 69.5 - 71 °. Analysis: Found: C, 74.7; H, 6.1; N, 4.4; Calculated: C, 74.8; H, 6.0; N, 4.4; percent for C 20 H 19 N 3 Example 40.

B- (4,5-Diphenyloxazol-2-yl) propionamide Isobutyl chloroformate (1.23 grams) was added to a stirred suspension of B- (4,5-diphenyloxazol-2-yl) propionic acid (2.5 grams) in a mixture of dry tetrahydrofuran (10 ml), dry dioxane (10 ml) and triethylamine (0.85 ml, 9 mM), cooled in ice. The mixture was stirred in ice for 30 minutes and then at room temperature for 1 hour. The mixture was then cooled in ice. Ammonia (1 ml, specific gravity 0.88) was added, followed by stirring for 16 hours. The mixture was poured into water (150 ml), and the resulting solid was collected. Yield 1.7 grams (72 percent). Melting point 146-147 ° after recrystallization from ethanol.

Analysis: Found: C, 74.2; H, 5.6; N, 9.6; Calculated: C, 74.0; H, 5.5; N, 9.6; % for ° 1sH1eNz ° 2 Example 41. β- [5- (4'-Chlorophenyl) -4-phenyloxazol-2-yl] propionic acid The procedure described in Example 35 (a) was followed, yielding 4 * -chlorobenzoine (6.2 grams) (ie the adjacent phenyl ring is substituted) and succinic anhydride (2.75 grams) was reacted at 135 DEG-1400 for 6 hours to give 4'-chlorobenzoine hemisuccinate. Yield 6.24 grams (69.7 percent).

The procedure described in Example 37 (b) was then followed using the above-obtained hemisuccinate (6.24 grams), urea (3.0 grams) and glacial acetic acid (20 ml) to give the title compound. Yield 3.52 grams (6l, 7 percent). Melting point 180 - 1s2 °.

Analysis: Found: C, 66.1; H, 4.3; N, 4.1; Cl, 10.7; Calculated: C, 66.0; H, 4.3; N, 4.3; Cl, 10.8; percent for C 18 H 14 ClNO 3 7316107-7 31 Example 42.

B- [4-Phenyl-5- (4'-methylphenyl) oxazol-2-yl] propionic acid The procedure described in Example 35 (a) was followed, reacting 4'-methylbenzoin (11.3 grams) and succinic anhydride with 135-1400 for 5 hours to give 4'-methylbenzoin hemisuccinate. Yield 11.0 grams (67.2 percent).

The procedure described in Example 35 (b) was then followed, using the above-obtained hemisuccinate (7.5 grams), urea (4.1 grams) and glacial acetic acid (20 ml) to give the above compound. Yield 4.1 grams (63 percent). Melting point 169-170 (Analysis: Found: C, 74.3; H, 5.7; N, 4.5; Calculated C, 74.3; H, 5.6; N, 4.6;% for ° 1øH17 Example 43.

B- [4- (4'-chlorophenyl) -5-phenyloxazol-2-yl] propionic acid The procedure described in Example 35 (a) was followed to give 4-chlorobenzoine (9.9 grams) and succinic anhydride (4.5 grams). reacted for 5 hours at 135-140 ° to give 4-chlorobenzoinhemisuccinate. Yield 10.5 grams (76 percent).

The procedure described in Example 35 (b) was then followed, using the above-obtained hemisuccinate (7.8 grams), urea (3.75 grams) and glacial acetic acid (20 ml) to give the title compound. Yield 4.16 grams (56.4 percent). Melting point 155 - 1s7 °.

Analysis: Found: C, 65.9; H, 4.3; Cl, 11.4; Calculated: C, 66.0; H, 4.3; Cl, 10.8; percent 44 for C 18 H 14 ClNO 3 Example 44- [1- (4- (4'-chlorophenyl) -5- (4'-methoxyphenyl) oxazol-2-yl] -propionic acid The procedure described in Example 35 (a) was followed, substituting 4-chloro -4'-Methoxybenzpine (10.4 grams) and succinic anhydride (4.05 grams) were reacted at 135-1400 for 5 hours to give 4-chloro-4'-methoxybenzoin hemisuccinate. Yield 9.8 grams (67 percent). The procedure described in Example 35 (b) was then followed, using the hemisuccinate obtained above (9.2 grams) to give the above compound. Yield 5.0 grams (55.5 percent). 7316107-7 32 melting point 126 - 12s °. Analysis: Found: C, 63.7; H, 4.6; Cl, 10.05; Calculated C, 63.8; H, 4.5; N, 3.9; Cl, 10.1; percent for H CINO4 C19 16 Example 45. β- (4,5-Diphenyloxazol-2-yl) -propionic acid acetoxymethyl ester B- (4,5-diphenyloxazol-2-yl) propionic acid (5.8 grams) was reacted with acetoxymethyl bromide (1.84 ml) in dimethylformamide (50 ml) in the presence of triethylamine (2.8 grams). The mixture was allowed to stand overnight at room temperature and then poured into water.

The reaction mixture was extracted with ether, and the extract was washed with water, sodium bicarbonate and then with water again, before it was dried (MgSO 4) and evaporated to a solid.

Yield 6.2 grams. An additional 1.1 grams was obtained when performing a second extraction. The product was recrystallized from ethyl acetate to give 5.0 grams (68.1 percent). Melting point 86 * - 86.50.

Analysis: Found: C, 69.2; H, 5.35; N, 4.05; Calculated C, 69.0; H, 5.2; N, 3.8; percent for C21H12N ° s Exemgel 46. 2- (2'-methoxyphenyl) -4-phenylthiazol-5-yl-acetic acid 2-methoxythiobenzamide (4.2O grams), 3-benzoyl-3-bromopropionic acid (6.40 grams ) and anhydrous sodium carbonate (1.25 grams) were added to isopropanol (40 ml), and the mixture was heated with stirring at 600 for 30 minutes. After a further 1 hour at 40 °, the mixture was cooled to room temperature and poured into water (500 ml). The mixture was acidified by adding a few drops of concentrated hydrochloric acid and a thick oil was separated.

The aqueous phase was extracted with ether (2 x 100 ml), and the extracts were combined with the oil. The resulting solution was extracted with a saturated solution of sodium bicarbonate (3 x 100 ml), and the extracts were acidified with concentrated hydrochloric acid. The resulting pale yellow solid was filtered off, dried and recrystallized from glacial acetic acid / water. Yield 6.4 grams (78.3 percent). Melting point 179 - 1ßo, s °. 73-16107-7 33 Analysis: Found: C, 66.4; H, 4.6; N, 4.5; S, 9.8; Calculated C, 66.45; H, 4.65; N, 4.3; S, 9.85; percent for C 18 H 15 NO 3 S Example 47. 2- (4'-chloro-2'-methoxyphenyl) -4-phenylthiazol-5-yl-acetic acid (a) The procedure described in Example 46 was followed using 4-chloro-2-methoxythiobenzamide (50 grams), 3-benzoyl-3-bromopropionic acid (6.4 grams), anhydrous sodium carbonate (1.25 grams) and isopropanol (40 ml) to give the title compound.

Yield 4.5 grams (64.6 percent). Melting point 204 - 2050.

Analysis: Found: C, 58.9; H, 3.9; N, 3.8; Cl, 10.1; S, 9.2; Calculated C, 60.1; H, 3.9; N, 3.9; Cl, 9.85; S, 8.9; % for C 18 H 14 ClNO 3 S (b) The 4-chloro-2-methoxythiobenzamide was prepared as follows (this procedure is generally applicable to the preparation of thioamides): 4-chloro-2-methoxybenzonitrile (26.5 grams) was dissolved in a mixture of dry pyridine (22 ml) and triethylamine (Z1 ml), and hydrogen sulphide were passed through the mixture until the nitrile had been completely converted to the thioamide (about 15 hours). The reaction mixture was poured into water (500 ml), and the resulting precipitate was filtered off. After air drying, the product was recrystallized from benzene. Yield 24.1 grams (75.7 percent). Melting point 149 - 1 50 °.

Example 48. 2- (2'-Chloro-6'-methylphenyl) -4-phenylthiazol-5-yl-acetic acid (a) The procedure described in Example 46 was used using 2-chloro-6-methylthiobenzamide (4, 65 grams), 3-benzoyl-3-bromopropionic acid (6.4 grams), anhydrous sodium carbonate (1.25 grams) and isopropanol (40 ml) to give the title compound.

Yield 5.4 grams (ss percent). melting point 217 - 219 °.

Analysis: Found: C, 62.8; H, 4.2; N, 3.9; C1, 19.3; Calculated C, 62.9; H, 4.1; N, 4.1; cl, 10.3; percent of C 18 H 14 ClNO 2 S 7316107-7 34 (b) The 2-chloro-6-methylthiobenzamide was prepared by the procedure described for the corresponding thioamide in Example 47 (b), but using 2-chloro-6-methylbenzonitrile (58 grams). , dry pyridine (54 ml) and triethylamine (53 ml). The hydrogen sulfide was in this case passed through the mixture for 10 hours. Yield 59.1 grams (83 percent). melting point 126 - 129 °. Example 49. 2- (4'-Methoxy-2,2-methylphenyl) -4-phenylthiazol-5-yl-acetic acid (a) The procedure described in Example 46 was followed using 4-methoxy-2-methylthiobenzamide (2, 7 grams), 3-benzoyl-3-bromopropionic acid (3.83 grams), anhydrous sodium carbonate (0.75 grams) and isopropanol (22.5 ml) to give the title compound. yield 1.4 grams (27, s percent). melting point 136 - 13s °.

Analysis: Found: C, 67.1; H, 5.0; N, 3.9; S, 9.3; Calculated: C, 67.2; H, 5.05; N, 4.1; S, 9.45; percent of 3 ° 19H17N ° 3S '(b) The 4-methoxy-3-methylthiobenzamide was prepared by the procedure described in Example 42 (b) but using 4-methoxy-2-methylbenzonitrile (68.2 grams), dry pyridine (65 ml) and triethylamine 7 (64.2 grams), the hydrogen sulfide was allowed to pass through the mixture for 15 hours.

Yield 60.3 grams (71 percent). Melting point 124 - 1260.

Example 50. 2- (4 '- Chloro-2'-methylphenyl) -4-phenylthiazol-5-yl-acetic acid (a) The procedure described in Example 46 was followed using 4-chloro-2-methylthiobenzamide ( 4.65 grams), 3-benzoyl-3-bromopropionic acid (6.4 grams), anhydrous sodium carbonate (1.25 grams) and isopropanol (40 ml) to give the title compound. Ut- g byte 5.3 grams (sa percent). melting point 175 - 177 °.

Analysis: Found: C, 63.05; H, 4.1; N, 4.1; Cl, 10.3; Calculated: C, 62.9; H, 4.1; N, 4.1; Cl, 10.3; percent of CISHIAC1NO2S (b) The 4-chloro-2-methylthiobenzamide was prepared by the procedure described in Example 47 (b) but using 4-chloro-2-methylbenzonitrile (26 grams), dry pyridine (23.3 ml) and triethylamine (25 ml). The hydrogen sulfide was allowed to pass for 15 hours. Yield 22 grams (69 percent). Melting point 86-880. Example 51. 2,3-Diphenyloxazol-4-yl-acetic acid 4-chloromethyl-2,5-diphenyloxazole was prepared according to the procedure described by K. Bodendorf and H. Towliate and Aren. Pharm. § 2 (1963), 293. This chloromethyl compound (14 grams) was heated with potassium cyanide (7 grams) in ethanol (80 ml) under reflux and water (10 ml) for 5 hours, after which it was filtered while hot. After removing a certain amount of the ethanol, water was added and the crystalline solid was filtered.

Recrystallization from ethanol gave 9.8 grams of acicular crystals.

Yield 72 percent. Melting point 137 - 1380.

This cyano compound (9 grams) was heated in 6N HCl under reflux and for 90 minutes. On cooling, crystals were separated, which were extracted into ether. The ether layer was washed with water, dried (MgSO 4) and evaporated to give 8.4 grams of crystalline solid. Recrystallization from benzene gave 4.2 grams of white, needle-shaped crystals. A second batch (2.9 grams) was obtained and recrystallized from benzene / petroleum ether (80-1000). Yield 74 percent. Melting point 177 - 17s °.

Example 52. 4- (2'-Naphthyl) -2- (2'-methylphenyl) thiazol-5-yl-acetic acid The procedure described in Example 46 was followed using 2-methyl-phenylthiobenzamide (20 grams), 3- bromo-3- (2'-naphthoyl) propionic acid (40.5 grams), anhydrous sodium carbonate (6.6 grams) and isopropanol (200 ml) to give the title compound. melting point 171 - 172 °.

Example 53. 2- (2 ', 4'-Dimethoxyphenyl) -4-phenylthiazol-5-yl-acetic acid (a) The procedure described in Example 46 was followed using 2,4-dimethoxythiobenzamide (2.5 grams ), 3-benzoyl-3-bromopropionic acid (3.2 grams), anhydrous sodium carbonate (0.6 grams) and isopropanol (19 ml) to give the title compound. Yield 2.0 grams (44.4 percent). Melting point 157 - 155 °. (b) The 2,4-dimethoxythiobenzamide was prepared by the procedure described in Example 46 (b), but using 2,4-dimethoxybenzonitrile (7.7 grams), dry pyridine (7 ml) and triethylamine (7 ml). .

Hydrogen sulfide was allowed to pass through the reaction mixture for 8 hours. Yield 6.3 grams (68 percent). Example 54. - 2- (4'-N, N-dimethylaminophenyl) -4-phenylthiazol-5-yl-acetic acid (a) The procedure described in Example 46 was followed, using 4- (N , N-dimethylamino) thiobenzamide (9.0 grams), 3-benzoyl-3-bromopropionic acid (1.2.9 grams), anhydrous sodium carbonate (2.5 grams) and isopropanol (75 ml) to give the title compound. . Yield 2.1 grams (12.4 percent) after recrystallization 4 times from benzene. Melting point l44 - l46 °. (b) The 4- (N, N-dimethylamino) thiobenzamide was prepared by the procedure described in Example 47 (b) but using 4- (N, N-dimethyl) benzonitrile (25 grams), dry pyridine (23.8 ml). ) and triethylamine (23.5 ml). Hydrogen sulfide was allowed to pass through the reaction mixture for 7 hours. Yield 27 grams (87.6 percent). Melting point 2180. 'oExempelf55. 2- (2 ', 3-Hamethylphenyl) -4-phenyl-iazol-5-y-acetic acid (a) The procedure described in Example 46 was followed, using 2,3-dimethylthiobenzamide (2.5 grams), 3- benzoyl 3-bromo-propionic acid (3.85 grams), anhydrous sodium carbonate (0.75 grams) and isopropanol (22.5 ml) to give the title compound. Yield 3.2 grams (64.2 percent). Melting point 143 - 1450. (b) The 2,3-dimethylthiobenzamide was prepared by the procedure described in Example 47 (b) but using 2,3-dimethylbenzonitrile (100 grams), dry pyridine (117 ml) and triethylamine (114 grams), allowing hydrogen sulfide to pass through the reaction mixture for 15 hours.

Yield ll6.2 grams (92 percent). Melting point 137 - 1380.

Example 56. 2- (2 ', 4'-Dichlorophenyl) -4-phenylthiazol-5-yl-acetic acid (a) The procedure described in Example 46 was followed using 2,4-dichlorothiobenzamide (5, 2 grams), 3-benzoyl-3-bromopropionic acid (6.4 grams), anhydrous sodium carbonate (1.25 grams) and isopropanol (40 ml) to give the title compound. Melting point 158 - 16o °. (b) The 2,4-dichlorophenylthiobenzamide was prepared by the procedure described in Example 47 (b) but using 2,4-dichlorobenzonitrile (1.2 grams), dry pyridine (11 ml) and triethylamine (10 ml). whereby hydrogen sulfide was allowed to pass the solution for 16 hours.

Example 57. 2,4-Di- (4'-chlorophenyl) thiazol-5-yl-acetic acid The procedure described in Example 46 was followed, using 4-chlorothiobenzamide (3.85 grams), 3- ( 4'-chlorobenzoyl) -3-bromopropionic acid (6.6 grams), anhydrous sodium carbonate (1.4 grams) and isopropanol (35 ml) to give the title compound.

Yield 2.5 grams <3o, percent). melting point 194 -19th °.

Example 58. 4- (2'-Chlorophenyl) -2-phenylthiazol-5-yl-acetic acid and its methyl ester Methyl 3- (2'-chlorophenyl) -propionate was prepared according to the procedure described in J.O.C. 15 (1950), 785 and brominated to give methyl 3-bromo-3- (2'-chlorobenzoyl) propionate. This intermediate was reacted with thiobenzamide according to the procedure described in Example 46, and the resulting methyl ester was hydrolyzed to the desired acid.

Example 59. 2,5-Diphenylthiazol-4-yl-acetic acid Ethyl 4-phenylacetoacetate (5.5 grams) was brominated (4 grams) in anhydrous ether. After allowing the reaction mixture to stand for 18 hours at room temperature, water was carefully added. The ether layer was washed, dried and evaporated to give ethyl 4-bromo-4-phenyl-acetoacetate. Yield 7.14 grams.

This ester (7.14 grams) in acetone (20 ml) was treated with a solution of thiobenzamide (3.4 grams) in acetone (30 ml) at room temperature and then refluxed for 2 hours. After evaporation to dryness, water and ether were added, and the ether extract was washed with sodium bicarbonate solution and water, dried (MgSO 4) and evaporated to give 2,5-diphenylthiazol-4-yl-acetic acid ethyl ester. Yield 8.07 grams (approximately 100 percent).

This ester (8.07 grams) in ethanol (50 ml) was treated with an aqueous solution of potassium hydroxide (2 grams in 10 ml). After heating on a steam bath for 15 minutes, the solution was allowed to stand at room temperature for one hour. The solution was evaporated to dryness, and ether and water were added. After purification with charcoal, filtration and acidification, the crude acid (3.2 grams) was filtered off and recrystallized from benzene. Yield 2.5 grams (33.5 grams). Melting point 1710.

Example 60. 4,5-Diphenylthiazol-2-yl-propionic acid α-bromodeoxybenzoin (68.8 grams) and benzoyloxyacetioamide (68.3 grams) were reacted, following the general procedure described in JACS 55 (1931). 1470 for 2-benzoyloxy-methyl-4-phenylthiazole to give 2-benzoyloxymethyl-4,5-diphenylthiazole. yield 58.5 grams. melting point 157 - 16o °.

This benzoate (58.5 grams) was heated on a water bath for 30 minutes with calcium hydroxide (10 grams) in ethanol and then poured into ice water. The oily solid was extracted with ether, and the ether solution was evaporated to give 2-hydroxymethyl-4,5-diphenylthiazole. yield 13.7 grams (sa, 4 per cent). melting point vs - 7s °.

A warm solution of the chloromethyl compound (8.59 grams) in absolute ethanol (100 ml) was added to a refluxing ethanolic solution of sodium diethyl malonate (of 5.55 grams of sodium and 40.7 grams of diethyl malonate). After refluxing for 2 hours, the mixture was cooled, evaporated to a small volume and poured into water. Dilute hydrochloric acid was added until the mixture was acidic. The product was extracted into ether (three times) and the ether extracts were combined, washed with water (MgSO 4) and evaporated. the excess diethyl malonate was removed under high vacuum to give diethyl (4,5-diphenylthiazol-2-ylmethyl) malonate as a colorless oil (11, 8 grams).

The oil (11, 8 grams) and potassium hydroxide (20 grams) in water (20 ml) were heated under reflux for 2 hours. The mixture was then cooled, diluted with water, extracted with ether and the aqueous phase was acidified and extracted into ether (three times). The ether extracts were combined, washed with water, dried and evaporated to give a yellow foam, which was dissolved in ether, dried (MgSO 4) and evaporated to give (4,5-diphenylthiazol-2-ylmethyl) malonic acid as a yellow foam (8, 65 grams).

The foam (8.65 grams) in dimethylformamide (10 ml) was heated under reflux for 2 hours, cooled, poured into water and extracted into ether (three times). The ether extracts were washed well with water and dried and evaporated. The residue was dissolved in aqueous sodium bicarbonate, treated with carbon, filtered and acidified to give 6.4 grams of a sticky solid. upon recrystallization from benzene (twice), the title compound was obtained, m.p. 115 DEG-116 DEG.

Analysis: Found: C, 69.56; H, 4.82; N, 4.73; Calculated: C, 69.9; H, 4.9; N, 4.5; percent for C18H15Nozs 7316107-7 Example 61. - 2,4-Diphenyloxazol-5-yl-acetic acid «.

Benzamide (3.02 grams) was added to a suspension of sodium hydride (1.2 grams, 50 percent in oil) in benzene (200 ml) and the mixture was heated and stirred at reflux for 0.5 hours.

Ethyl 4-bromo-4-phenyl-acetoacetate (7.14 grams), which had been prepared according to Example 59, in benzene (30 ml) was then added dropwise over a period of 0.5 hours, after which the heating was continued for a further 1 hour. 5 hours. Water was added, and the benzene layer was washed with water, saturated NaCl, dried (MgSO 4) and evaporated to give a brown solid (6.6 grams). This was dissolved in concentrated sulfuric acid (25 ml), and the solution was allowed to stand at room temperature for 18 hours. The solution was then poured into an excess of water and ether was added. The ether layer was washed with saturated NaHCO 3 holding the crude ester of the above compound (1.2 grams). The crude ester (1.2 grams) was dissolved in ethanol (20 ml) and potassium hydroxide (1 gram) in water (5 ml) was added. The solution was heated on a steam bath for 5 minutes and allowed to stand at room temperature for 2 hours. The solution was evaporated to give an oil, water and ether were added to the oil and the aqueous layer was treated with charcoal, filtered and acidified to give 2,4-diphenyloxazol-5-yl-acetic acid, and water, dried (MgSO 4) and evaporated , the structure of which was confirmed by its IR spectrum.

Example 62. 4- (4'-Chlorophenyl) -2- (2'-pyridyl) thiazol-5-yl-acetic acid A mixture of pyrid-2-ylthiocarboxamide (2.36 grams) and B-bromo- 4-chlorobenzoyl) propionic acid (5.0 grams) in dimethylformamide (5.0 ml) was heated at 700 for 1 hour. The solution was then poured into water (20 ml) and after 0.5 hours the precipitated solid was filtered off, dried and recrystallized from ethanol to give 2.7 grams (48%) of the title compound, m.p. decomposition).

Analysis: Found: C, 58.0; H, 3.3; N, 8.4; Calculated for C 16 H 11 ClN 2 O 2 S: C, 58.0; H, 3.4; N, 8.5 percent Example 63. 4, (4'-chlorophenyl) -2- (3'-pyridyl) thiazol-5-yl-acetic acid A mixture of pyrid-3-ylthiocarboxamide (2.76 grams) and B- bromo-β- (4-chlorobenzoyl) propionic acid (5.83 grams) in dimethylformamide (5.0 ml) was heated at 70 ° for 1 hour and then at 1000 for 0.25 hours. The solution was then poured into water (400 ml) and the precipitated solid was filtered off, dried and recrystallized twice from a mixture of dimethylformamide and ethanol to give 1.5 grams (23 percent) of the title acid with a melting point of 238 - 2390 (decomposition).

Analysis: Found: C, 57.8; H, 3.3; N, 8.4; Calculated for C 16 H 11 ClN 2 O 2 S: C, 58.0; H, 3.4; N, 8.5 percent Exemgel 64. 4%''-chlorophenyl) -2- (4'-pyridyl) thiazol-5-yl-acetic acid A mixture of pyrid-4-ylthiocarboxamide (2.76 grams) and B-bromide - (4-Chlorobenzoyl) propionic acid (5.83 grams) in dimethylformamide (5.0 ml) was quenched at 70 ° for 1 hour. The solution was then soaked in water (400 ml) and the precipitated solid was filtered off, dried and recrystallized several times from a mixture of dimethylformamide and ethanol to give 490 mg (8%) of the title compound with a melting point of 215 - 216 ° (decomposition).

Analysis: Found: C, 58.2; H, 3.2; N, 8.3; Calculated for C 16 H 11 ClN 2 O 2 S: C, 58.0; H, 3.4; N, 8.5 percent Example 65.

B- (4,5-Diphenyloxazol-2-yl) propionic acid (a) Desylamine hydrochloride (20.0 grams) in chloroform (200 ml) was stirred with sodium bicarbonate solution, the aqueous layer being separated and re-extracted with additional amounts of chloroform. The combined and dried (MgSO 4) chloroform extracts were refluxed for 20 minutes with succinic anhydride (8.1 grams), cooled and the colorless crystalline material was filtered off and recrystallized from aqueous ethanol to give 11.0 grams of N- (1 g). , 2-diphenyl-2-oxo-ethyl) succinic acid, m.p. 180 DEG-182 DEG.

Analysis: Found: C, 69.5; H, 5.5; N, 4.5; Calculated for C 18 H 17 NO: C, 69.45; H, 5.5; (b) The above succinic acid (1.0 gram) was stirred with concentrated sulfuric acid (20 ml) at 50 ° C for 3 hours, cooled, poured into water, (250 ml) and extracted with ethyl acetate. The washed and N 4.5% dried (MgSO 4) organic extract was evaporated to dryness and the residue was recrystallized from aqueous methanol to give 0.59 g of the title acid, m.p. 160-1.2 ° C. 7316107-7 41l Analysis Found: C, 73.95; H, 5.3; N, 4.8; Calculated for C 18 H 15 NO 2: f, 73, T; 1,>,.; 2,26 - 3- (2,4-diphenylthiazol-5-yl) propionic acid (α1 A mixture of 2,4-diphenyl-5-formylthiazole '1', 2 * _s ~ 1 f _ ,, n ~ acid (5 , 2 grams) and pyridine (5.0 ml) in absolute: H were heated under reflux for two hours: f; '' ta se;. 2 ,, o> "a ~ temperature for 18 hours. The fat material was filtered off, was washed with alcohol and ether and dried to give 7.84 grams of 3- (2,4-diphenylthiazol-5-yl) -acrylic acid. (b) A mixture of the above-mentioned acrylic acid (3.07 grams) and for. Charred palladium-on-charcoal (5.0 grams of 10 percent) in ethanol (leo ml) was shaken in a hydrogen atmosphere for one hour, at the end of which time further pre-reduced palladium-on-charcoal (5.0 10%) and the mixture was shaken again for one hour.After adding a third portion of pre-reduced palladium-on-charcoal (5.0 grams of 10 percent), the shaking was continued for another hour.Elimination of the catalyst by filtration and evaporation of the filtrate gave 0.9 grams of the title compound which had melting point 150 ° C after recrystallization from ethanol and s_n was identical to the product of Example 33.

The 2,4-diphenyl-5-formylthiazole used in part (a) was prepared by reacting thiobenzamide and ethyl α-bromo-benzoyl acetate to ethyl 2,4-diphenylthiazol-5-ylmethyl, which reduced: red lithium aluminum hydride in the tetrahydrate; il1 corresponding 5-methyl compound, which in turn was allowed to react '- *? and the resulting chloromethyl compound (7) with naphthanyltrenetramine in alcohol, followed by thione) to give the formyl compound.

Example 67. 3- (2,4-Diphenylthiazol-5-yl) propionic acid (a) 2,4-Diphenylthiazol-5-ylacetic acid (5.0 grams) was dissolved in the least possible amount of hot ethanol, the solution was made strongly acidic with ethanolic hydrogen chloride, and then ether was added to effect crystallization of the hydrochloride of the starting material. This hydrochloride was dissolved in thionyl chloride (2.0 ml), stirred at room temperature for 15 minutes and then heated on a water bath at 45 ° C for half an hour. The solution was evaporated to dryness to give the acid chloride hydrochloride of the starting material as a dark tar. (B) A stirred and ice-suspended suspension of the above-mentioned acid chloride hydrochloride in ether (25 ml) was treated with a solution of diazomethane (1.4z grams) and triethylamine (3.4 grams) in ether (75 ml). . After stirring for 16 hours, the precipitated amine hydrochloride was filtered off and the filtrate was evaporated to dryness with a residue of the crude diazoketone. A solution of this diazoketone in dioxane (30 ml) was slowly added to a stirred solution of sodium carbonate (1.1 grams) of sodium thiosulphate (0.67 grams) and silver oxide (0.45 grams) in water (50 ml) at 50-60 ° C. Stirring was then continued for one hour while raising the temperature to 90 ° -10 ° C. After cooling the reaction mixture, it was acidified with dilute nitric acid to precipitate the crude title compound. Crystallization twice from ethanol gave the title compound (1.3 grams), which had a melting point of 150 ° C and was identical to the production of Example 33.

Example 68.. n-butyl 4- (p-chlorophenyl) -2-phenylthiazol-5-ylacetate A mixture of 4- (p-chlorophenyl) -2-phenylthiazol-5-ylacetic acid (5.43 grams), n-butyl alcohol (50 ml) and concentrated sulfuric acid (1.0 ml) was heated for 16 hours under reflux, treated with the same volume of water and evaporated to a small volume. Water (200 ml) was added to the mixture and the oil was extracted into ether. The organic extract was washed with water, sodium bicarbonate solution, water, dried (MgSO 4) and evaporated to a yellow oil, which was distilled under high vacuum to give 4.95 g of the title ester, b.p. 205-218 ° C. / 0,1 - 0,5 mm, which when allowed to stand turned into a solid, the melting point 43 - 44%.

Analysis: Found: C, 65.4; H, 5.2; N, 3.8; Calculated for C 21 H 21 OClNO 2 S; C, 65.3; H, 5.2; N, 3.6 percent Exemgel 69. 2,4-Diphenyloxazol-5-ylacetic acid (a) A mixture of benzonitrile (3.18 grams) and 2-hydroxypropiophenone (4.2 grams was allowed to stand for 24 hours at room temperature) after which added concentrated sulfuric acid (1.3.0 ml) and stirred for 20 hours at room temperature. The mixture was then poured into water and after one hour the aqueous solution was decanted from the tar-shaped sediment. The tar was washed with 2N sodium carbonate solution and extracted with benzene. The dried benzene extract was evaporated to give a stirred, oily residue, which was fractionally distilled under reduced pressure to give a fraction having a boiling point of 142 - 1550 C / 0.5 7316107-7 43 mm, which crystallized slowly on standing and was recrystallized from light gasoline (b.p. 40-60 ° C) to give 1.41 grams of 2,4-diphenyl-5-methyloxazole, m.p. 69.5-70 ° C.

Analysis: Found: C, 81.3; H, 5.7; N, 5.9; Calculated for C 16 H 13 NO: C, 81.7; H, 5.6; N, 6.0 percent (b) The above 5-methyl compound (6.83 grams) in carbon tetrachloride (60 ml) was treated with N-bromo-succinimide (5.2 grams) and some crystals of benzoyl peroxide and the resulting mixture was heated. was refluxed until the heavy N-bromine succinimide disappeared and the lighter succinimide floated to the surface. The mixture was then filtered and evaporated to dryness to give a dark oily residue. This residue was extracted with boiling petroleum ether (b.p. 80 DEG-100 DEG C.) and the extract was evaporated to give the desired 2,4-diphenyl-5-bromomethyloxazole (8.7 grams) as a colorless oil which crystallized on standing at room temperature. . (c) To a stirred solution of sodium cyanide (1.55 grams) in dimethyl sulfoxide (70 ml) was added the 5-bromomethyl compound (8.7 grams) from part (b) of dimethyl sulfoxide (110 ml) at room temperature and stirred for 2 hours. days. The mixture was poured into water (750 ml), extracted into ether and the dried extract was evaporated to dryness. The remaining nitrile was heated for 16 hours under reflux with a 20% solution of potassium hydroxide in water. The cooled solution was washed with ether and acidified to pH 7 by the addition of concentrated hydrochloric acid to give 1.0 gram of the title compound.

Example 70. 2,5-Diphenyloxazol-4-yl-acetic acid (a) Benzimidomethyl ether was added to a stirred solution of ethyl-nramino-benzoylacetate hydrochloride in glacial acetic acid at 100 ° C. After stirring for 30 minutes at room temperature, the mixture was cooled in ice, diluted with water and extracted repeatedly with ether. The ether extract was washed with dilute hydrochloric acid, dilute sodium hydroxide solution, dried (MgSO 4) and evaporated to a residue of ethyl 2,5-diphenyloxazole-4-carboxylate. (b) The ester (6.8 grams) from part (a) of sodium dried ether (60 ml) was added dropwise to a stirred suspension of lithium aluminum hydride (0.5 grams) in ether (60 ml) at such a rate that maintained a stable backflow. After the addition was complete, the mixture was heated under reflux for one hour, cooled and the complex decomposed by the addition of methanol (2 ml), then water (10 ml) and finally 2N hydrochloric acid. The ether layer was separated, washed with water, dried and evaporated to a residue of 2,5-diphenyl-4-hydroxymethyloxazole. (c) A suspension of the hydroxymethyl compound (5.7 grams) from part (b) in dry methylene chloride (50 ml) was treated with thionyl chloride (2.0 ml).

After 15 minutes at room temperature, excess solvent and thionyl chloride were evaporated to give a residue of 2,5-diphenyl-4-chloromethyloxazole. (d) The chloromethyl compound (14 grams) from part (c) was heated with potassium cyanide (7 grams) in refluxing ethanol (80 ml) and water (10 ml) for 5 hours before being hot filtered. After elimination of some of the ethanol, water was added and the crystalline solid was filtered. Recrystallization from ethanol gave 9.8 g of acicular crystals of 2,5-diphenyl-4-cyanomethyloxazole, m.p. 137 DEG-138 DEG. (6) The cyano compound (9 grams) was heated in refluxing 6N hydrochloric acid for 90 minutes. On cooling, crystals were extracted which were extracted into ether. The ether layer was washed with water, dried (MgSO 4) and evaporated to give 8.4 grams of crystalline solid. Recrystallization from benzene gave 4.2 grams of white needle crystals of the title compound, mp 177-178 ° C. A second batch (2.9 grams) was obtained and recrystallized from benzene / petroleum ether (b.p. 80 DEG-10 DEG C.).

Exemgel 7l. 2,4-Diphenylthiazol-5-yl-acetic acid A solution of 2,4-diphenylthiazol-5-ylacetamide (5.3 grams) in a mixture of ethanol (49 ml) and water (21 ml), containing sodium hydroxide ( 5.3 grams) was heated under reflux for 4 hours. The solvent was evaporated and the residue was dissolved in water, washed with ether and then acidified with concentrated hydrochloric acid. The oily material was extracted into ether, the ether extracts were combined, washed with water, dried over MgSO 4 and evaporated to give a viscous oil which slowly crystallized. Recrystallization from the bones gave the title compound (3.0 g), m.p. 151 DEG-15 DEG C. and Exemgel 72.

B- (4,5-diphenylthiazol-2-yl) propionic acid A solution of the succinic acid (7.0 grams) prepared according to Example 65 and anhydrous tin chloride (1.2.0 grams) in chloroform (500 ml) treated with dry hydrogen chloride for one minute and then hydrogen chloride and hydrogen sulfide are added simultaneously for two hours. After standing for 16 hours at room temperature, the mixture was washed with water and extracted with 2N sodium carbonate solution. The basic extract was then acidified with 2N hydrochloric acid, extracted with chloroform, the organic extract dried (MgSO 4) and evaporated to give the desired product, which is identical to the product obtained according to Example 60.

Example 73. Ethyl β- (4,5-diphenyloxazol-2-yl) propionate A mixture of dd- (4,5-diphenyloxazol-2-yl) propionitrile (5.4 grams) concentrated sulfuric acid (2.0 grams) and absolute ethanol (9.5 grams) was refluxed for three hours. the excess ethanol was then removed under reduced pressure and the residue was poured into water (200 ml). The colorless solid was filtered off, washed with water, sodium bicarbonate solution and then recrystallized from ethanol to give 2.5 grams of the title compound, m.p. 69 DEG-71 DEG.

Example 74. d- [4- (4'-Chlorophenyl) -2-phenylthiazol-5-yl] gropionic acid To a stirred solution of sodium amide (1.8 grams) in liquid ammonia (120 ml) was added ethyl 4- (4 ') -chlorophenyl) -2-phenylthiazol-5-yl acetate (10.75 grams) in diethyl ether (50 ml). The mixture was stirred for 15 minutes, methyl iodide (4.26 grams) was added and the reaction was worked up according to Kenyon et al. [J.0rg.Chem., 30, 2937 (1965)] to give the crude ethyl ester of the title compound (10.6 grams) as an orange oil. A solution of this oil in ethanol (100 ml) and 5N aqueous sodium hydroxide (150 ml) was refluxed for 1 hour before the majority of the ethanol was evaporated. The resulting solution was washed with diethyl ether and then acidified with concentrated hydrochloric acid to pH 2. The product was extracted into diethyl ether and this solution was washed with water and dried (MgSO 4) and the solvent was evaporated. The residual oil was decomposed with benzene to give a solid which was recrystallized from benzene to give the title compound, m.p. 135 DEG-1360 DEG (1.4 grams).

Example Gel 75. 2- (4'-Methoxyphenyl) -4-phenylthiazol-5-yl-acetic acid A sample of the ethyl ester of Example 10 was hydrolyzed in the same manner as in Example 4 in 68% yield to give the title compound, melting point 151 - 1520.

Example 76. 4- (4'-Chlorophenyl) -2-phenylthiazol-5-yl-acetic acid dimethylaminoethyl ester A mixture of ethyl 4- (4'-chlorophenyl) -2-phenylthiazol-5-yl acetate (14 , 3 grams), dimethylaminoethanol (50 ml) and sodium (0.1 gram) in dry benzene (300 ml) were heated at reflux temperature under a reflux ratio head and the ethanol-benzene azeotrope were collected for 3 hours. The solvent was evaporated; dilute hydrochloric acid was added, the product was washed with ether and basified with aqueous ammonium hydroxide. The resulting oil was dissolved in ether, washed with water, dried (MgSO 4) and treated with gaseous hydrogen chloride. The sticky solid that formed was recrystallized from isopropanol to give 9.4 grams of the title compound as its monohydrochloride, m.p. 176-1780 (dec.). In Example 77. 2- (4'-chlorophenyl) -5-phenylthiazol-4-yl-acetic acid A mixture of ethyl 4-bromo-3-oxo-4-phenylbutyrate (10.0 grams) and p-chlorothiobenzamide (6 .0 grams) in ethyl alcohol (100 ml) was heated under reflux for 3 hours. A solution of sodium hydroxide (8.0 grams) in ethyl alcohol (15 ml) was added to the cooled solution and the resulting solution was heated on a steam bath for 5 minutes. The red solution was evaporated to dryness, the residue redissolved in water, washed with ether and then acidified with concentrated hydrochloric acid to give a white solid. Recrystallization from benzene gave 5.3 grams of the titeic acid, m.p.

Analysis: Found: C, 61.8; H, 3.6; N, 4.3; Calculated: C, 61.9; H, 3.7; N, 4.2; percent for H 2 ClNO 2 S C17 Example 78. Ethyl 5- (4'-chlorophenyl) -2-phenylthiazol-4-yl acetate A mixture of ethyl 4-bromo-4- (4'-chlorophenyl) -3-oxo-butyric acid (1.55 grams), thiobenzamide (6.6 grams) and anhydrous sodium carbonate (2.6 grams) in ethyl alcohol were heated under reflux for 3 hours and then evaporated to dryness under reduced pressure. The residue was taken up in ethyl acetate, washed with water, dried (MgSO 4) and evaporated in vacuo to give 10.3 g of the title ester, m.p. 112 DEG-114 DEG (recrystallization from ethyl alcohol).

Analysis: Found: C, 64.1; H, 4.5; N, 3.8; Calculated C, 63.75; H, 4.5; N, 3.9; percent of C 19 H 16 ClNO 2 S. Example 79. 5- (4'-Chlorophenyl) -2-phenylthiazol-4-yl-acetic acid A solution of ethyl 5- (4'-chlorophenyl) -2-phenyl-thiazol-4-yl-acetyl (5.0 grams) in hot ethyl alcohol was treated, all in one batch, with a solution of potassium hydroxide (5.0 grams) in water (5 ml) and allowed to stand at room temperature for 16 hours. Dilution with water and acidification with concentrated hydrochloric acid gave a light yellow precipitate, which was filtered off, washed with water, dried and recrystallized from benzene to give 2.3 grams of the title acid, m.p. 202.5-2.5 °.

Analysis: Found: C, 62.1; H, 3.6; N, 4.3; Calculated C, 61.9; H, 3.7; N, 4.25; percent for Cl7H12ClNO2S 7316107-1 A 18 Pharmacological example.

The anti-inflammatory activity against carrageenan-induced edema in rat hind paw was examined for various 2,4-diaryltiazol-5-yl acetic acids and related compounds according to the procedure of Example 74 in Swedish patent 369 307. Due to the inherent variations in this test procedure expresses ED4O (effective dose for 40% inhibition) for each compound as being within a range.

The areas and their designation in the results are given below. as (mg / kg pt.) in 1-5 0-10 '11-25 20-50 51-100 Result designation in 1 2 I 3 I 4 I 5 Result: Thiazole substituents Designation 2-position 4 ~ position 5-position m.p. (C 174-5 4 IL-methoxy- "" 1 51-2 4 phenyl. ~ 4-dimethyl- "" 154-6 3 aminophenyl 4-isopropyl- "" 145-7 4 phenyl 2,3-dimethyl- "" 143 Phenyl 2,4-dimethoxy-157-9 phenyl 49 7316107-7 Thiazole substituents phenyl Designation 2-position 4-position 5-position m.p. (° c) 4-chloro-2-phenyl -BH CG H 175-7 4 methylphenyl 2 2 4-methoxy-2- "" 136-B 4 methylphenyl phenyl .2-thienyl "15a-5 5-methyl-" "135- s 5 phenyl 2-pyridyl 4-chloro-" 2Û2 ~ 3 4 phenyl 3-pyridyl "" Zßü-9 4 phenyl 4-chloro- -CH BO CH - 59- (Û 5 pfe fl yl '"* -c fl àcozcá fi gj 68-70" "" "-c fi ícfwcoz fi ass-a _11," " - (cH2) 2cn2H 143-5 s 4-k1oi- "" 179 '51 4 ïenyl phenyl "» cnšco-'zfuz fifi z five-s z Hc1'. (cH¿) 2N '"4 ~ flu0r ~ -CHZCÜZH 173-4 Phenyl 4-k chloro- "" 19--6 2 phenyl 4-bromo- "" 192-3 4 phenyl 4-methoxy-4-methoxy- "175-5, 4 phenyl phenyl" 4-chloro- "173-4-phenyl phenyl "¿" ^ 152-5 “1" ll-brom- "'IVÉ-ÉÜ 2 7316107-7 SO. Thiazole substituents _ Designation z-position IL-position s-position m.p. <-C> 4-chloro-4-bphomo- -CH2COH 2U5-7 3 phenyl phenyl 2 phenyl 4-methoxy- "15Ü * 1 4 phenyl 2-methyl-- 4-chloro-" 174-5 3 Ethyl phenyl 3 -methylph "" '152-3 1 phenyl 4-methyl- "" 188-9 4 phenyl 3-chloro- "" 165-166 3 phenyl 4-chloro- ""> 199-201 2 phenyl 4-bromo-1' 202-3 3 phenyl 4-dimethyl-. '1H 205-7 3 aminophenyl phenylbutazone ß

Claims (2)

1. 7316107-7 51 CLAIMS Intermediate for use in the preparation of a compound of the formula R1 \\ [r \ / R u Xøå! (Ia) R 2 is the same or different (wherein X represents oxygen or sulfur; R 1 and R 2 and each represent unsubstituted phenyl, naphthyl, furyl, thienyl or pyridyl, or phenyl substituted by one or more halogen, lower alkyl- , lower alkoxy, di-lower alkylamino or trifluoromethyl groups, and R 3 represents a straight or branched aliphatic carbohydroxy group having -4 carbon atoms or a salt or ester thereof, wherein the group R 3 is selected so that it is not identical to the group R below); characterized in that the intermediate is a compound of the formula other than (m) (wherein X, R 1 and R 2 have the meaning given above and R represents a straight or branched aliphatic carbohydroxy group having 2-4 carbon atoms, its salts, esters, amides and nitrile derivatives , or groups of the formula ~ A-CH (CO 2 H) 2 and their diesters, wherein A represents alkylene having up to 2 carbon atoms). PUBLICATIONS MADE: