FI57593C - SAOSOM CHEMICAL MELLAN PRODUCTS WITH FRAMSTAELLNING AV TIAZOLER ANVAENDBARA 4-HYDROXITIAZOLINDERIVAT - Google Patents

Description

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Patent · and Register Held · NlhtMWpwou |. month publication date

Patent and registration register '' AraMan utitgd och uti. «Krift« n pubUnrad 30.05.8O

(32) (33) (31) Requested «tuollcMs — B« firt prtoritet 09.OU.68

England-England (GB) 16909/68 (71) John Wyeth & Brother Limited, Huntercombe Lane South, Taplow, Maidenhead, Berkshire, England-England (GB) (72) Robert Anthony Newberry, Bourne End, Buckinghamshire, England

England (GB) (7U) Oy Kolster Ab (5U) U-hydroxytiazoline derivatives used as chemical intermediates in the preparation of thiazoles 985/69 (patent 5U921)

The invention relates to chemical intermediates of the general formula R3_F =} - R2

R

4-Hydroxytiazoline derivatives of the formula H OH used in the preparation of thiazoles

R3 — t-i_R2 E N (I »

X

wherein R 1 is a phenyl group which may be substituted by one or more halogen atoms or a lower alkoxy group, or R is a cycloalkyl-2 group, R is a lower aliphatic acid group having 2 to 6 carbon atoms or a 57593 thereof ..3. . . .

a lower alkyl ester derivative and R is a hydrogen atom or a lower alkyl or phenyl group which may be substituted by one or more halogen atoms or a trifluoromethyl group, and in which either U and 5 "contains a substituent R and the remaining h or 5- the position contains the substituent 3 R, and their acid addition salts.

It is known from GB patent 1,099,389 that heated p-bromothiobenzamide is heated with ethyl 4-bromoacetoacetate to give ethyl 2- (p-bromophenyl) -thiazol-1-yl acetate. The same patent specification also discloses that a number of similar thiazoles can be obtained in a similar manner using other substituted haloketoesters and other substituted thiobenzamides. Other thiazoles that can be prepared in this manner are described in GB patents 1 1 ^ 5 88t and 1 1 UT 626 and GB patent applications H86U0 / 67 and U86U1 / 67. The products of the inventions disclosed in these applications include Thiazoles having two aryl or heteroaryl groups as substituents, and Thiazoles having a cycloalkyl radical in the 2-position.

Compounds of general formula I in the form of a hydrohalide can be prepared by administering the following compound of formula R3 - CH - C - R2 or R2 - CH - C - R3 I "1 tt

Hai 0 Hai 0 II (a) II (b)

react with thioamide of the formula S SH

1 H 11 R - C - NH2 - R - C = NH (III) 12.3. . . . .

wherein R, R and R are as defined above and Hal is a halogen atom, under mild conditions. The temperatures used for the reaction must be below the dehydration temperature of the thiazoline hydrohalide. The optimum temperature therefore depends on the reactants used and temperatures up to 80 ° C can be used, in most cases preferably below 50 ° C. It is also preferred to carry out the reaction in an inert organic solvent to which. 2 The thiazoline hydrohalide formed is insoluble. If R is an aliphatic acid group and if the reaction is carried out in isopropanol in the presence of an early metal carbonate, the free aliphatic thiazolinic acid can be obtained. It is often more convenient 2 to use a reactant in which R is a lower alkyl ester of an aliphatic acid (i.e. one containing 1-U carbon atoms), e.g. an ethyl ester. It is convenient to use equimolar amounts of reactants and the reaction mixture is heated at the required temperature, such as 60-70 ° C, for several hours or, in some cases, 5,57593, only kept at room temperature overnight. The thiazolines can be separated in a known manner, e.g. by filtration, and the filtrate can be acidified to precipitate more product.

The free bases of thiazolines can be prepared from hydrohalides by treatment with a base, e.g. alkali metal carbonate.

R 1 may be, for example, phenyl, halophenyl (e.g. chlorine, bromine or fluorophenyl) lower alkoxyphenyl (e.g. methoxyphenyl), cyclopentyl or. 2. . ....

cyclohexyl, R may be, for example, an acid radical of an aliphatic containing 2 to 6 carbon atoms or a lower alkyl ester of such an acid. As examples of preferred 2. . . ..... . ...

among the radicals R, mention may be made of acetic, n-propionic and isopropionic acids and nn- ^. 3. . The methyl and ethyl esters of R 1 are preferably hydrogen, methyl or one of the phenyl radicals listed for R.

When H-hydroxy-thiazolines are used as intermediates in the preparation of the corresponding thiazoles, they are dehydrated by heating above the dehydration temperature, possibly in the presence of an acid. The U-hydroxytiazolines of the invention are readily dehydrated by heating when in the form of a hydroacid salt; free bases are more stable. Dehydration can be accomplished by refluxing the compound in the presence or absence of an organic solvent in the presence of a sulfonic acid, e.g., benzenesulfonic acid or p-toluenesulfonic acid, using a water separator until no more water develops, or more simply by heating in aqueous acetic acid or glacial acetic acid such as glacial acetic acid. When the reaction is complete, the thiazole can be recovered in the usual manner, for example, the reaction mixture can be evaporated to a small volume and the product crystallized from a solvent, for example alcohol.

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The following examples illustrate the invention:

Example 1 4- (p-Bromophenyl) -4-hydroxy-2-phenyl-2-thiazoline-5-acetic acid.

Thiobenzamide (3/43 g), 3- (p-bromobenzoyl) -3-bromopropionic acid (8.4 g) and sodium carbonate (1.33 g) in isopropanol (50 ml) are stirred at 60-70 ° C $ 1 an hour. The cooled reaction mixture is poured into water and solid sodium carbonate is carefully added until a pH of 8 is reached. The basic aqueous solution is extracted with ether, treated with carbon and filtered. The solid filtrate is collected "(6.12 g). Recrystallization gives the title compound as colorless microneedles (3.14 g, 32%), mp 135-137 ° C.

Analysis: Found: C, 51.8; H, 3.7; Br, 20.3; N, 3.8; S, 8.3. ~

Calculated for C 17 H 14 BrNO 3 S: C, 52.1; H 3.6; Br, 20.4; N, 3.6; S, 8.2.

Example 2 4- (p-Chlorophenyl) -4-hydroxy-2-phenyl-2-thiazoline-5-acetic acid

A mixture of 3-bromo-3- (p-chlorobenzoyl) propionic acid (94.5 g), anhydrous sodium carbonate (34.3 g) and isopropanol (200 ml) was stirred and heated to 60-65 ° C: C. The temperature is maintained in this range while thiobenzamide (44.3 g) is added portionwise. When the addition is complete, the mixture is stirred and heated to 60-70 ° C for another half hour, then left to stand at room temperature for eighteen hours. The resulting solid is separated and suspended in water. The mixture is filtered to give 4- (p-chlorophenyl) -4-hydroxy-2-phenyl-2-thiazoline-5-acetic acid (10 g), m.p. 148-150 ° C. The aqueous filtrate is acidified with hydrochloric acid to precipitate an additional 48 g of 4- (p-chlorophenyl) -4-hydroxy-2-phenyl-2-thiazoline-5-acetic acid, m.p. 148-150 ° C.

Analysis: Found: C, 58.88; H, 4.02; N, 3.97; Cl, 9.84; S, 9.56.

Calcd for C 11 H 18 N 2 O 3 C, 58.70; H, 4.06; N, 4.03; Cl, 10.20; S, 9.22%.

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The above 4- (p-chlorophenyl) -4-hydroxy-2-phenyl-2-thiazoline-5-acetic acid (55 g) is refluxed in toluene in the presence of toluenesulfonic acid (0.36 g) in a flask equipped with a water separator until water no longer develops. The mixture is then evaporated to dryness in vacuo and the residue is crystallized from ethanol to give 4- (p-chlorophenyl) -2-phenyl-5-thiazole-acetic acid, m.p. 161-162 ° C Analysis: Found: C, 62.0; H, 3.7; N, 4.2; S, 9.8.

Calculated for C 11 ClNO 3 S: C, 61.9; H, 3.7; N, 4.2; S, 9.7%.

Example 3 4-Hydroxy-2-phenyl-4- (p-trifluoromethylphenyl) -2-thiazoline-5-acetic acid

A mixture of 3-bromo-3- (p-trifluoromethylbenzoyl) propionic acid (11.5 g), anhydrous sodium carbonate (3.7 g), isopropanol (100 ml) and thiobenzamide (4.7 g) is added. react as in Example 2. This mixture is filtered, the filtrate is evaporated to dryness and the oily residue solidifies on standing. After crystallization from aqueous ethanol, 4-hydroxy-2-phenyl-4- (p-trifluoromethylphenyl) -2-thiazoline-5-acetic acid is obtained, m.p. 160-1 ° C.

Analysis: Found: C, 56.68; H, 3.57; N, 3.70.

Calculated for C „0Η„ .F.NSO: :ο Ί 4 o C, 56.69; H, 3.70; N, 3.68%.

By repeating the procedure of Example 2, the 4-hydroxy-2-phenyl-4- (p-trifluoromethylphenyl) -2-thiazoline-5-acetic acid prepared above is converted to the corresponding 2-phenyl-4- (p-trifluoromethylphenyl) -5-thiazoleacetic acid, m.p. 168-9 ° C.

Example 4 4- (p-Bromophenyl) -4-hydroxy-2-phenyl-2-thiazoline-5-acetic acid.

A mixture of 3-bromo-3- (p-bromobenzoyl) propionic acid (95 g), anhydrous sodium carbonate (35 g), thiobenzamide (45 g) and ethanol (200 ml) was stirred at room temperature for half an hour, then left to stand at room temperature. temperature for two to ten hours. The resulting solid is separated and suspended in water. The mixture is filtered to remove 4- (p-bromophenyl) -4-hydroxy-2-phenyl-2-thiazoline-5-acetic acid. The aqueous filtrate is then acidified with hydrochloric acid to precipitate additional 4- (p-bromophenyl) -4-hydroxy-2-phenyl-2-thiazoline-5-acetic-6,57593 acid.

The 1- (1- (p-bramiphenyl) -1 * -hydroxy-2-phenyl-2-thiazoline-5-acetic acid prepared above is refluxed in 50 # aqueous acetic acid for 1 hour. Crystals of 1- (p-bromophenyl) -2-phenyl-5-thiazoleacetic acid are obtained, m.p. 1T8-180 ° C.

Example 5 2- (p-Bromophenyl) -1 * -hydroxy-1 - (p-chlorophenyl) -2-thiazoline-5-acetic acid A mixture of 8.75 g (0.03 moles) of 3-bromo-3 - (1 * -chlorobenzoyl) -propionic acid, equimolar amount (6.1 * 8 g) of U-bromothiobenzamide and 6.1 * g (0.06 mol) of sodium carbonate, in 75 ml of isopropanol, are stirred overnight at room temperature. - - Lassa. The precipitate is collected by filtration, dissolved in water and the solution is slowly neutralized with dilute hydrochloric acid to precipitate the title compound. It is recrystallized from methanol to give 1 *, 5 g of the title compound, m.p. 193 ~ ^ 19 ° C. ^

Analysis: Found: C; 1 * 8.25; H, 3.05; N, 3.17%

Calculated for C 18 H 18 BrClNO 2: C, 1 * 7.85; H, 3.07; N, 3.28%

Example 6 1 * - (p-Chlorophenyl) -1 * -hydroxy-2- (p-methoxyphenyl) -2-thiazoline-5-acetic acid A mixture of 8.75 g (0.03 moles of 3- (p-chlorobenzoyl) -3-bromopropionic acid, 6 kg (0.06 moles) of sodium carbonate and 5.01 g (0.03 moles) of p-methoxythiobenzamide in 75 ml of isopropanol are stirred at room temperature overnight.

The precipitate is collected by filtration, dissolved in water and the solution is slowly neutralized with dilute hydrochloric acid to precipitate the title compound. It is recrystallized from ethanol to give 6.78 g of the title compound, m.p. 159 ~ 161 ° C.

Analysis: Found: C, 57.3; H 1 *, 1 * 1; N 3.73%

Calculated for C 18 H 18 ClNO 2 O 2 S: C, 57.2; H 1 *, 27; N, 3.7%.

Example 7

Ethyl-U-hydroxy-2-phenyl-2-thiazoline-U-asetaattihydrobromidi. Ethyl U-brami-3-oxybutyrate (5 g) in acetone (10 ml) is added to thiobenzamide (3.3 g) in acetone (50 ml). After standing for 16 hours at room temperature, the hydrobromide salt is filtered off (2.0 g, 2k%), m.p. 77 ~ 78 ° C.

Analysis: Found: C, 1 * 1 *, 8; H, 1 *, 8; N, 1 * .0 Calculated: for C 18 H 19 BrNO 2: C, 1 * 5.1; H, U, 7; N, U, 0%.

Example 8

Ethyl 2,5-diphenyl-1 * -hydroxy-2-thiazoline-1 * -acetate.

A mixture of 1 * bromo-3-oxo-U-phenylbutyrate (7.12 g), thiobenzamide (3.1 * g) and anhydrous sodium carbonate (1.2 g) in ethanol (50 ml, 95/0 After stirring for 5 hours at 60 DEG-70 DEG C., the mixture is evaporated and the organic matter is taken up in ether, washed with water, 2N hydrochloric acid, water, dried (MgSO4) and evaporated to give an oil (6.0 g). ), which is chromatographed on alumina, and extraction with benzene gives the desired ester as a crystalline white solid (1.8 g, 21%), mp 90-91 ° C.

Analysis: Found: C, 66.8; H, 5.5; N, U, 1; S, 9.6

Calculated for C 18 H 18 NO 3: C, 67.0; H, 5.3; N, U, 1; S, 9.1%.

Example 9 1β-Chlorophenyl-1 + -hydroxy-2-phenyl-2-thiazoline-5-acetic acid.

A stirred mixture of 3 “bromo-Up-chlorophenyl-U-oxobutyric acid (1 + 00 g) thiobenzamide (188 g) and sodium carbonate (73> 0 g) in isopropyl alcohol (1 liter) is heated at 60 ° C for 1 hour and then poured into water. The precipitated yellow solid is filtered off, washed with acetone and dried to give 325 g of the title compound, m.p. 1U1-1U2 ° C. The analytical sample is crystallized from isopropyl alcohol.

Analysis: Found: C, 58.7; H, U, 1; N, 3.9

Calculated for C 18 H 18 Cl 2 O 3 S: C, 58.7; H, U, 1; N, U, 0%.

Example 10

Ethyl 2-cyclohexyl-U-hydroxy-l +-methyl-2-thiazoline-5-acetate.

A solution of cyclohexylthiocarboxamide (7.15 g> 0.0 mol) in acetone (25 ml) is added to a solution of ethyl 3-acetyl / 3-bromopropionate (11.5 g, 0.05 mol). ) in acetone (25 ml) and the mixture is kept at room temperature for 0.5 hours and then at 0 ° C for 3 hours. The white crystalline material is filtered off, washed with acetone and dried to give 6.8 U (37.6%) of the thiazoline ester as the hydrobromide salt, m.p. 117-118 ° C.

8 57593

Analysis: Found: c, 45.9; H, 6.7; N, 3.8.

Calcd for C 18 H 18 N 2 O 3 S.SNBr: C, 46.1; II, 6.7 · N, 3.9

Example 11 2-Cyclohexyl-4-hydroxy-4-methyl-2-thiazolin-5-acetic acid

Cyclohexyl] γ-carboxamide (7.15 g, 0.05 moles) and β-acyl-β-Iyroin! reaction of propionic acid (9.75 g, 0.05 mol) according to the method of Example 10 affords 10.16 g (60.5 #) of thiazolic acid as the hydrobromide salt, m.p. 129-130 ° C.

Analysis: Found: C, 43.1; H, 6.0; N, 4.5

Calculated for C12H19NO3S.IIBr. C, 42.8; H, 6.0; N, 4.2%.

Example 12

Ethyl 4-hydroxy-2-sylcloheksyyli-2-thiazoline-4-acetate. Reaction of cyclohexylthiocarboxamide (7.15 g, 0.05 mol) with ethyl 4-bromoacetoacetate (10.41 g, 0.05 mol) according to the method of Example 10 affords 11.0 g (62.5%) of the title compound. as the hydrobromide salt, m.p. 124-125 ° C.

Analysis: Found: C, 44.5; H, 6.3; N, 4.05 Calculated: C 19 H 19 N 2 O 2 S.NBr; II, 6.3; N, 4.0

Example 13

Ethyl 2-p-chlorophenyl-4-hydroxy-2-thiazoline-4-acetant.

A solution of p-chlorothiobenzamide (8.59 g, 0.05 mol) in acetone (40 ml) is added to a solution of ethyl 4-bromoacetoacetate (10.41 g, 0.05 mol) in acetone and the mixture is stirred. allow to stand at room temperature for 21 hours. Filtration gives a crystalline substance which is washed with ice-cold acetone and ice-cold ether and dried. The product is the title compound (8.05 g, 42.3%) as the hydrobromide salt, m.p. 97-98 ° C.

Analysis: Found: C, 41.0; H, 3.8; N, 3.5;

Calcd for C 11 H 11 ClNO-J 5 .BBr: C, 41.0; H, 4.0; N, 3.7%.

Treatment of the hydrobromide with sodium bicarbonate gives a yield of $ 72.8 of the free base, m.p. 109-110 ° C after crystallization from ether.

Analysis: Found: C, 41.0: K, 3.8; N, 3.5 Calculated for C 11 H 18 NO, S: C, 41.0; H, 4.0; N, 3.7 '#.

J j i '1 J

Claims (1)

9 57593 Patents: U-hydroxytiazoline derivatives of the formula ^ qjj 3 -1 2 RT t ~ r (nk ') used as chemical intermediates in the preparation of thiazoles of the general formula R3___ p = -j-R2 S \ N) L' wherein R 1 is a phenyl group which may be substituted by one or more halogen atoms or a lower alkoxy group, or R 1 is a cyclo-2-alkyl group, R is a lower aliphatic acid group having 2 to 6 carbon atoms or a lower alkyl ester derivative thereof and R is a hydrogen atom or a lower alkyl or phenyl group which may be substituted by one or more halogen atoms or a trifluoromethyl group, in which one of the U and 5 positions contains a substituent R and the remaining U or 5 position contains 3 substituents R, and their The acid addition salts.