Patent GB-1460533-A (GB)
Title: 3- 4- or 5-substituted thiazol-2-oxy- 1,2-epoxypropane
IPC: C07D417/12
Filed: 1974-03-21
Abstract: 1460533 3(4- or 5-Substituted thiazol-2-oxy)- 1,2-epoxypropane SYNTEX (USA) Inc 21 March 1974 [22 March 1973 14 March 1974] 48248/75 Divided out of 1460532 Addition to 1410513 Heading C2C The invention comprises compounds of the formula wherein Z is one of the following groups R<SP>4</SP>R<SP>3</SP>NCO-, R<SP>4</SP>CONR<SP>3</SP>- or R<SP>4</SP>OCONR<SP>3</SP>-, wherein one of R<SP>3</SP> and R<SP>4</SP> is C 7 -C 12  alkyl, C 3 - C 12  cycloalkyl, terminally substituted C 2 -C 12  alkyl, wherein the substituent is OH, C 2 -C 12  acyloxy or C 1 -C 6  alkoxy, or one of the groups -(CH 2 ) n+1 NR<SP>8</SP>R<SP>9</SP> or -(CH 2 ) n R<SP>10</SP> wherein n is 1 to 4, R<SP>8</SP> and R<SP>9</SP> are H or C 1 -C 4  alkyl and R<SP>10</SP> is C 3 -C 8  cycloalkyl; and the other of R<SP>3</SP> and R<SP>4</SP> is H, C 1 -C 12  alkyl, C 3 -C 12  cycloalkyl, phenyl, phenyl(C 1 -C 6 )alkyl which may be substituted by one or two substituents selected from OH, halogen and (C 1 -C 6 ) alkyl or alkoxy, terminally substituted C 2 -C 12  alkyl wherein the substituent is OH, C 2 -C 12  acyloxy or C 1 -C 6  alkoxy, or one of the groups -(CH 2 ) n+1 NR<SP>8</SP>R<SP>9</SP> or -(CH 2 ) n R<SP>10</SP> with the proviso that when Z is R<SP>4</SP>OCONR<SP>3</SP>- then R<SP>4</SP> cannot be H. They may be obtained by reacting a compound of the formula with a strong base. These compounds are useful intermediates in the preparation of pharmaceutically active compounds. Compounds of Formula D above may be obtained by treating a compound of the formula with an organic or inorganic acid to give a compound of the formula which is then treated with an alkyl or phenyl sulphonyl chloride or bromide in an organic solvent to give the required compounds. Compounds of Formula A above in which Z is an aminocarbonyl group may be obtained by the following reaction scheme wherein R<SP>1</SP> is C 1 -C 6  alkyl and X is Cl or Br; in which thiazole compounds A<SP>1</SP> and A<SP>11</SP> are treated with glycerol acetonide in an inert solvent in the presence of an alkali metal hydride to give compounds A and A<SP>111</SP> respectively and treating compounds A<SP>111</SP> with appropriate amines to also give compounds A. Compounds of Formula A above in which Z is R<SP>4</SP>OCONH- may be obtained by either of the following reaction schemes (1) in which the nitro compound A** is hydrogenated and reacted with an appropriate chloroformate without separation of the intermediate amine product; or (2) in which the compound of formula A*** is treated with hydrazine hydrate to give a hydrazide of Formula A** which is then treated with nitrous acid followed by heating at temperatures in the range from 60 to 150 C. under anhydrous conditions in an inert organic solvent to give an isocyanate of Formula A* which is then reacted with an alcohol of formula R<SP>4</SP>OH to give the 2-chloro compound of formula A<SP>1</SP> which is finally treated with glycerol acetonide as described above to give a compound of Formula A. Compounds of Formula A above in which Z R<SP>3</SP> is R<SP>4</SP>OCON-may be obtained by the following reaction scheme in which an isocyanate of Formula J is treated with an alcohol R<SP>4</SP>OH to give a carbamate of Formula H which when R<SP>3</SP> is to be other than H is further reacted in two steps firstly by treating with a strong alkali and then adding a reagent of formula R<SP>3</SP>X<SP>1</SP> wherein X<SP>1</SP> is Cl, Br or I thereto. 2-Bromo-5-methoxycarbonylthiazole may be obtained by reacting 2-amino-5-methoxycarbonyl thiazole with amyl nitrate and bromoform at 95 to 100 C. 2-Amino-5-methoxycarbonylthiazole may be obtained by reacting thiourea and methyl chloroformyl acetate (which is formed in situ by reacting methyl acetate with methyl chloroacetate in the presence of sodium methoxide). 2 - Bromo - 4 or 5 - substituted - aminocarbonylthiazoles may be obtained by either reacting 2-bromo-4 or 5-methoxycarbonylthiazole with appropriate amines, or reacting 2- bromo-5-carboxythiazole with thionyl chloride in DMF and treating the resulting product with appropriate amines. 2 - Bromo - 4 or 5 - carboxythiazole may be obtained by hydrolysis of the corresponding methyl ester with aqueous NaOH. Compounds of Formula A above in which Z is may be obtained by the following reaction scheme in which 2,4- or 5-dibromothiazole is treated with glycerol acetonide in an inert organic solvent in the presence of an alkali metal hydride to give compounds of Formula D which are then treated with an alkyl lithium reagent followed by bubbling anhydrous CO 2  through the resulting reaction product solution, adding an alkyl chloroformate directly thereto to form a compound of Formula G and adding NaN 3  thereto to form a compound of Formula H which is then heated in an inert aromatic solvent to 100 to 110 C. for about ¢ to 2 hrs. to form the isocyanate of Formula J which is then subjected to a Grignard type reaction to give a compound of Formula A in which R<SP>3</SP> is H and when compounds in which R<SP>3</SP> is other than H are required further reacting the compounds in which R<SP>3</SP> is H in two steps firstly by treating with a strong alkali and then adding a reagent of Formula R<SP>3</SP>X<SP>1</SP> thereto.