PROCESS FOR PREPARING BIOTIN

Abstract: A process for preparing biotin, characterized in that a compound of the formula: wherein R¹ and R² are each hydrogen or benzyl and R³ is hydrogen or carboxyl, with the proviso that R¹ and R² are not simultaneously hydrogen, or a mixture of two or more differ­ ent compounds of the formula [I] is heated in the presence of an alkanesulfonic acid.

Description: " Process for Preparing Biotin The present invention relates to a process for preparing biotin. In this specification, the term "lower" is intended to mean a group having not more than eight carbon atoms, particularly having not more than five carbon atoms. Biotin, the chemical name of which is cis-tetra hydro-2-oxothienof3,4-d]imidazoline-4-valtEric acid, has an asymmetric carbon, and the term "biotin" in the present invention includes ioth of d-biotin and dl-biotin. Biotin (also called "Vitamin H") s a valuable substance exerting a growth accelerative effect as well as a preventive and therapeutic effect on dermatoses, etc. For the production of biotin, there is known a method wherein 3,4-(1',3' -dibenzyl-2 '-ketoimidazolido) -2- (w- carboxybutyl)t'hiophane is heated under reflux in 48 % hydrobromic acid to affect debenzylation (U.S. Patent No. 3,740,416). However, this method is not favorable because it gives the objective compound only in a poor yield in spite of the troublesome operation due to the use of an irritative reagent. As the result of an extensive study, it has now been established an improved process for preparing biotin in an excellent yield with a high purity and without any disadvantage as seen in the said conventional process. Thus, the present invention provides an industrially advantageous process for preparing biotin which comprises heating a compound of the formula: EMI2.1 wherein R1 and R2 are each hydrogen or benzyl and R3 is hydrogen or carboxyl, with the proviso that RÚ and Rê are not simultaneously hydrogen in the presence of a lower alkanesulfonic acid. According to the invention, a mixture of one part by weight of the starting compound [I] and 1 to 100 parts by weight, preferably 3 to 50 ports by weight, of a lower alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid) is heated at a temperature of 80 to 1800C, preferably of 110 to 1500C, for a period of 10 minutes to 20 hours, preferably of 0.5 to 10 hours. The reaction mixture is cooled and then admixed with water. Precipitated crystals are collected by filtration and recrystallized from water to give purified crystals of biotin. It is not requisite but preferred to add to the reaction system a hydrocarbon having a boiling point higher than 1000C (e.g., chlorobenzene, toluene, xylene, octane, decane, anisole) and/or an alkanoic acid, preferably having 2 to 4 carbon atoms (e.g., acetic acid, propionic acid), in order to minimize the formation of by-products and easily control the reaction temperature. The starting compound [I] may be derived from 3,4 (1',3'-dibenzyl-2l-ketoimidazolido)-2-( di(lower)alkoxy- carbonylbutyl)thiophane {nereinafter referred to as "compound [II]") by saponification; optionally followed by decarboxylation and/or partial debenzylation. Specific examples of the compound [II] are 3,4-(1',3'-dibenzyl-2' ketoimidazolido)-2-(,-dimethoxvcarbonylbutyl)thiophane, 3,4(1' , 3'-dib'nzyl-2' -ketoimidazolido)-2- (w,w-diethoxy- carbonylbutyl)thiophane, 3,4-(1',3'-dibenzyl-2'-ketoimida- zolido)-2-(X-methoxycarbonyl-U-ethoxycarbonylbutyl)thio- phane, etc. The starting compound tI] thus prepared may be separated from the reaction mixture and subjected to the process of the invention. However, it can be directly converted to biotin in situ, i.e., without separation from the reaction mixture. The typical example for preparing biotin from the compound [II] without separation of the compound [11 is illustrated below. A mixture of the compound [11) and a lower aSane- sulfonic acid containing water (water content, usually not more than 40 % by weight) is heated at a temperature of 40 to 1000C, preferably of 70 to 950C, for 2 to 20 hours in the presence or absence of an alkanoic acid, preferably having 2 or 3 carbon atoms, whereby saponification proceeds to give. a reaction mixture containing 3,4- (1' , 31 -dibenzyl-2 '-keto- imidazolido)-2" -dicarboxybuttl)thiophane. The reaction mixture is continuously heated at a temperature of 100 to 1800C, preferably of 110 to 1500C, for 1 to 20 hours while distilling off volatile components (e.g., water, alcohols, esters), whereby decarboxylation and debenzylation proceed to give a reaction mixture containing biotin. The reaction mixture is worked up in the same manner as previously mentioned to give purified crystals of biotin. This modified process for preparing biotin from the compound ±11] without separation of the compound [I] constitutes one embodiment of the present invention. The compound [II] is obtainable by reacting 3,4 (1',3'-dibenzyl-2'-ketoimidazolido)-1,2-trimethylenethiophanium bromide or d-camphor-sulfonate with a malonic diester according to U.S. patent 3,740,416 or 2,489,235. As stated above, the process of this invention can advantageously afford biotin in an excellent yield with a high purity. It is particularly notable that biotin of high optical purity is obtainable by the use of the starting compound [I] which is optically active. Accordingly, this invention can provide an extermely important and valuable process for the synthesis of d-biotin which is, in particular, physiologically active. Practical and presently preferred embodiments of the invention are illustratively shown in the following Examples. Example 1 d-Monobenzylbiotin (1.0 g) and methanesulfonic acid (3.0 g) are introduced into a 10 ml volume flask, and the flask is heated in an-oil bath kept at 1300C while vigorous stirring with a magnetic stirrer for 6 hours. The reaction mixture is cooled to room temperature and poured into 10 ml of ice water while stirring. Precipitated crystals are collected by filtration and recrystallized from water to give biotin (white needles, 0.58 g). Yield, 79 %. 20 IMP. 2300C. [a]D = +910 (C=l in 0.1 % NaOH aq.). Reference Example 1 Diethyl malonate (45.0 g) is dropwise added to a suspension of sodium methoxide (11- g) in toluene (200 ml) kept at 800C, and the mixture is stirred for one hour while keeping this temperature. The reaction mixture is cooled to 5aOC, t (-)-3,4- (1',3'-dibenzyl-2'-ketoimidazolido)-l,2- trimethylenethiophanium bromide (30.0 g) is added thereto and the resultant mixture is heated under reflux for 4 hours. The reaction mixture is cooled to room temperature and admixed with water (270 g). The organic layer is separated, washed with water (250 g), -dried and distilled in vacuo to give the residue primarily containing Z-(-)-3,4- (1',3w-dibenzyl-2'-ketoimidazolido)-2-(w,w-diethoxycarbonyl- butyl)thiophane. To the residue, there is added ethanol (160;g) containing 24.1 % by weight of KOH, and the mixture is healed under reflux for one hour. By removing the solvent in vacuo, there is obtained the residue, which is admixed with water (300 g). The resulting mixture is neutrali7.ed with conc. h?-drochloric acid and extracted with ethyl acetate. The organic layer is dried and distilled in vacuo to give the residue primarily containing t-(-)-3,4- (1',3'-dibenzyl-2'-ketoimidazolido-2-(,-dicarboxybutyl)thiophene. Example 2 Methanesulfonic acid (90.0 g) is added to the residue obtained in Reference Example 1, and the mixture is heated with stirring in an oil bath kept at 1300C for 5 hours. The reaction mixture is cooled to room temperature, and ice cold water (270 g) is dropwise added thereto to give a slurry. The slurry is filtered with suction, and the obtained crystals are recrystallized from water to give dbiotin (white needles, 12.6 g). Yield, 77 % (basedon±-(-)- 3,4-(1',3'-dibenzyl-2'-ketoimidazolido)-1,2-trimethylene 20 thiophanium bromide). [a]D = +910 (C=l in 0.1 % NaOH aq.). Example 3 Formic acid (75 g) and methanesulfonic acid (10.0 g) are added to the residue containing t-(-)-3,4-(1',3'- dibenzyl-2'-ketoLmidazolido)-2-(,-diethoxycarbonylbutyl)- thiophane, obtained in the same manner as in Reference Example 1, and the mixture is heated with stirring at 900C for 4 hours. By raising the temperature up to about 1500C, the low boiling point compcnents are distilled off. The mixture is cooled to 1000C again, admixed with additional methanesulfonic acid (150 g), and the mixture is heated with stirring at 1400C for 4 hours. The reaction mixture is cooled and poured into ice water (500 g) to obtain a slurry. The slurry i treated in the same manner as in Example 2 to give d-biotin (12.3 g). Yield, 75.1 % (based on (l',3'-dibenzyl-2'-ketoimidazolido)-l,2-trimethylenethio- phanium bromide). Example 4 Methanesulfonic acid (200.0 g) and crude N,Ndibenzylbiotin (20.0 g) are introduced into a four-necked flask, and the mixture is stirred at 1400C for 6 hours. The reaction mixture is cooled to a temperature between 10 and 150C and poured into ice water (1 t) while stirring. The precipitated crystals are collected by filtration and recrystallized from water to-give d-biotin (white needles, 8.30 g). Yield, 72.0 %. Example 5 Methanesulfonic acid (120 g) and acetic acid containing water (water content, about 40 %) (50 ml) are added to the residue containing dE-3,4-(l',3'-dibenzyl-2'- ketoimidazolido)-2-(u,-diethoxycarbonylbutyl)thiopane, obtained in the same manner as in Reference Example 1 but using de-3,4-(l',3'-dibenzyl-2'-ketoimidazolido)-l,2-tri- methylenethiophanium d-camphor-sulfonate (39.9 g) in place of t-(-)-3,4-(l',3'-dibenzyl-2'-ketoimidazolido)-l,2-tri- methylenethiophanium bromide, and the resulting mixture is heated with stirring at a temperature of 93 to 950C for 6 hours By raising the temperature to about 1400C, the low boiling point components are removed. Xylene (100 ml) is added to the residue, and the mixture is heated under reflux for 8 hours, during which a refluxing liquid predominantly containing xylene (about 30 ml) is removed from the reaction system. The reaction mixture is cooled to room temperature, the xylene layer is separated off and the remaining layer is poured into ice water (400 ml). The precipitated crystals are collected by filtration sand recrystallized from water to. give dE-biotin (white needles, 11.5 g). M.P. 233 to 235 C.

Claims: What is claimed is 1. A process for preparing biotin, characterized in that a compound of the formula: EMI10.1 wherein RÚ and Rê are each hydrogen or benzyl and R is hydrogen or carboxyl, with the proviso that RÚ and Rê not simultaneously hydrogen is heated in the presence of a lower alkanesulfonic acid. 2. The process according to claim 1, wherein RI or R is benzyl. 3. The process according to claim 1 or 2,wherein R3 is hydrogen. 4. The process according to any one of claims 1 to 3, wherein the lower alkanesulfonic acid is methane sulfonic acid. 5. The process according to any one of claims 1 to 4, wherein the reaction is effected in the presence of a hydrocarbon having a boiling point higher than 1000C and/or an alkanoic acid having 2 to 4 carbon atoms. 6. The process according to claims 1 to 5, wherein the reaction is effected at a temperature of 110 to 1500C.

Inventors: MAESHIMA, KAORU, SHIMAGO, KOZO, TAKAHASHI, TAKEO
Applicants: SUMITOMO CHEMICAL COMPANY, LIMITED
Application year: 1980
Main classification: C07D495
IPC codes: C07D495