Patent GB-1420509-A (GB)
Title: Imidazol-2-one derivatives as intermediates for the production of optically-active -thio-lactones useful in preparing biotins
IPC: C07D491/04
Filed: 1973-06-22
Abstract: 1420509 1,3-Dibenzyl-imidazol-2-one derivatives; biotin SUMITOMO CHEMICAL CO Ltd 22 June 1973 [22 June 1972 23 March 1973] 29838/73 Headings C2C and C2V Novel compounds have the Formula XV wherein R is a benzyl group and wherein X is a group of the formula-CO-NHR<SP>1</SP> in which R<SP>1</SP> is the residue of an optically active primary amine and Y is a group of the formula -CH 2 OH or wherein X and Y together represent a dione group of formula -CO-NR<SP>1</SP>.CO-. The compounds of Formula XV are prepared by (a) reacting a dicarboxylic acid or a reactive derivative thereof (e.g. an anhydride, ester or halide), the acid having the Formula I with an optically active primary amine, R<SP>1</SP>-NH 2 , to produce a compound of Formula XV wherein X and Y are joined (Formula II) and optionally (b) reducing this product with a metal hydride to form the compound of Formula XV in which X is -CONHR<SP>1</SP> and Y is -CH 2 OH (Formula III). Reaction (a) is preferably carried out in an inert solvent (e.g. an aromatic hydrocarbon or an ether) and in the presence of a basic substance (e.g. pyridine, triethylamine or tri-nbutylamine) whilst azeotropically eliminating by-produced water and the reduction (b) is generally effected in an inert solvent (e.g. an alcohol, ether, aromatic amine, an amide or water or a mixture of water and one or more of said organic solvents) and in the presence of a tertiary amine, an inorganic base or a salt of an organic or inorganic acid. Preferred reducing agents in step (b) are diborane, alkali metal or alkaline earth metal borohydrides or mixtures thereof with AlCl 3 , alkali metal or alkaline earth metal alkoxyborohydrides, or alkali metal or alkaline earth metal alkoxyaluminohydrides. The reduction may proceed via isolation of the intermediate cyclic dione of Formula XIII The compounds of Formula XV (i.e. II and III) are intermediates for the production of optically active lactones and thiolactones which are themselves used to prepare biotin. Examples prepare the following specific compounds of Formula XV Cis - 1,3 - dibenzyl - 5 - [(R) - 1 - phenethyl]- hexahydropyrro-[3,4-d]-imidazole-2,4,6-trione, Cis - 1,3 - dibenzyl - 4 - [N - (R) - 1 - phenethylcarbamoyl] - 5 - hydroxymethyl - tetrahydroimidazol-2-one, Cis - 1,3 - dibenzyl - 5 - [(+) - 1 - phenyl - 2- (p - tolyl)ethyl] - hexahydropyrro - [3,4 - d]- imidazole-2,4,6-trione, Cis - 1,3 - dibenzyl - 4 - {N - [(+) - 1 - phenyl- 2 - (p - tolyl) - ethyl] - carbamoyl} - 5 - hydroxymethyl-tetrahydroimidazol-2-one, Cis - 1,3 - dibenzyl - 5 - [( + ) - 1 - (2 - naphthyl) ethyl] - hexahydro - pyrro - [3,4-d] - imidazole- 2,4,6-trione, Cis - 1,3 - dibenzyl - 4 - {N - [(+) - 1 - (2- naphthyl) - ethyl] - carbamoyl} - 5 - hydroxymethyl-tetrahydroimidazol-2-one, Cis - 1,3 - dibenzyl - 5 - [1 - (2 - thienyl)ethyl]- hexahydropyrro-[3,4-d]-imidazole-2,4,6-trione, Cis - 1,3 - dibenzyl - 4 - {N - [1 - (2 - thienyl)- ethyl] - carbamoyl} - 5 - hydroxymethyl - tetrahydroimidazol-2-one,  Cis - 1,3 - dibenzyl - 5 - [(1S,2S) - (+) - threo- 1 - hydroxymethyl - 2 - (p - nitrophenyl) - 2- hydroxyethyl] - hexahydropyrro - [3,4 - d]- imidazole-2,4,6-trione, Cis - 1,3 - dibenzyl - 4 - {N - [(1S,2S) - (+)- threo - 1 - hydroxymethyl - 2 - (p - nitrophenyl)- 2 - hydroxyethyl] - carbamoyl} - 5 - hydroxymethyl-tetrahydroimidazol-2-one, Cis - 1,3 - dibenzyl - 5 - [(1S,2S) - (+) - threo- 1 - hydroxymethyl - 2 - (p - methylsulfonylphenyl) - 2 - hydroxyethyl] - hexahydropyrro- [3,4-d]-imidazole-2,4,6-trione, Cis - 1,3 - dibenzyl - 4 - {N - [(1S,2S) - (+)- threo - 1 - hydroxymethyl - 2 - (p - methylsulfonylphenyl) - 2 - (hydroxy) - ethyl] - carbamoyl} - 5 - hydroxymethyl - tetrahydroimidazol- 2-one, Cis - 1,3 - dibenzyl - 5 - [(S) - (1-benzyl - 2- hydroxyethyl)] - hexahydropyrro - [3,4 - d]- imidazole-2,4,6-trione, Cis - 1,3 - dibenzyl - 4 - [N - (S) - 1 - benzyl - 2- hydroxyethyl - carbamoyl] - 5 - hydroxymethyltetrahydroimidazol-2-one, Cis - 1,3 - dibenzyl - 5 - {(S) - [1 - carboxy - 2- phenyl] - ethyl} - hexahydropyrro - (3,4 - d]- imidazole-2,4,6-trione and Cis - 1,3 - dibenzyl - 4 - [N - (S) - 1 - carboxy- 2 - phenethyl - carbamoyl] - 5 - hydroxymethyltetrahydroimidazol - 2 - one. Example 35 prepares d-biotin starting from the compound of Formula V via (i) cis-1,3- dibenzyl - 4 - hydroxy - 4 - (3 - ethoxypropyl)- hexahydrothieno-[3,4-d]-imidazol-2-one by reaction with the corresponding Grignard reagent, (ii) cis-1,3-dibenzyl-4-(3-ethoxypropylidene)- hexahydrothieno-[3,4-d]-imidazol-2-one by reaction with 95% H 2 SO 4 , (iii) cis-1,3-dibenzyl-4- (3-ethoxypropyl) - hexahydro - thieno - [3,4 - d]- imidazol-2-one by reduction using H 2 /PdO, (iv) cis - 1,3 - dibenzyl - 2 - oxo - decahydroimidazo- [4,5 - c]-thieno-[1,2-a]-thiolium chloride by cyclization using HAc/HCl and (v) cis-1,3- dibenzyl - 4 - (4,4 - dicarboxybutyl) - hexahydrothieno-[3,4-d]-imidazol-2-one diethyl ester by reaction with sodium methoxide/diethyl malonate. The d-biotin is obtained from the latter (v) by reaction with HBr followed by phosgene.