An improved process for the synthesis of D(+) Biotin

Abstract: The invention discloses an improved process for the synthesis of D(+) biotin of the Formula where R² represents hydrogen or methyl. Biotin is one of the B-complex group of vitamins having immense commercial importance in the area of animal health and nutrition.

Description: This invention relates to an improved process for synthesis of D D(+) biotin or the methyl ester thereof. Biotin (Vitamin H), is one of the B-complex group of vitamins, has immense commercial importance, in the area of animal health and nutrition. It is one of the biocatalysts of the reversible metabolic reactions of carbon dioxide transport in micro and macro organisms. It is used in poultry feeds for rapid growth of chicks and healthy hatching of eggs. Biotin - avidin complex finds a vital role in the area of biochemistry. Prepared by the process of the present invention has the Formula. as herein referred to as Formula I and as also shown in D (+) biotin (Fig. 1) in the drawings accompanying this specification. It has hitherto been known to prepare (+) biotin from amino acids viz. cystine, cysteine and serine. Prior art processes involving L-cystine as the precursor incorporate intramolecular radical cyclization (E.J. Corey, M.M. Mehrotra, Tetrahedron Letters 29, 57 (1988) as the key step to construct tetrahydrothiophene moiety of biotin. Another prior art process revolves around intramolecular cycloaddition (3+2) of derivatives derived from L-cystine (E.G. Baggiolini, H.L. Lee, G. Pizzolato and M.R. Uskokovic, J. Amer. Chem. Soc., 104, 6460-6462 (1982), and L-cysteine (H.L. Lee, E.G. Baggiolini and M.R. Uskokovic, Tetrahedron, 43 , 4887 (1987). In an other process starting from L-cysteine, a bicyclic hydantoin is the key intermediate leading to D(+) biotin. E. Poetsch and M. Casutt, EP 242,686 (1986); CA 108 : 112077K (1988); Chimia 41 , 148-150 (1987). In a totally different and novel approach, L-cysteine was converted to its thiazolidine derivative which on treatment with bromine is converted stereospecifically to a bicyclic intermediate as a single stereosomer and eventually transformed to D(+) biotin (P.N. Confalone, E.G., Baggiolini, D. Lollar, and M.R. Uskokovic, J. Amer. Chem. Soc., 99 , 7020-7026 (1977). Hitherto known processes involve highly toxic and hazardous chemicals (e.g. phosgene as in Corey and Mehrotra as cited above) for the formation of hydantoin. Moreover the intramolecular radical cyclization leads to both six as well as the desired five membered ring system along with tin inclusion compounds as the undesired by-products. In another prior art process involving intramolecular 3+2 cycloaddition reaction of nitrone, the precursor olefin is obtained as a mixture (9:1) of which the desired olefin has to be purified and separated by chromatography. Moreover, the chiral intermediates obtained during the above mentioned sequence of reactions were prone to racemisation. Another prior art process involving the intramolecular cyclization of thiazolidine required Collins oxidation as one of the steps. Use of heavy metals on an industrial scale would lead to problems during waste disposal. Moreover, Wittig reaction, on the aldehyde leads to a mixture of isomers which should be separated and the desired isomer subjected to further reactions leading to biotin. A process for the synthesis of D (+) - biotin from L-cysteinhydantoin is described in DE-A-3926690. DE-A-3018109 discloses a method of synthesis of racemic biotin from 2-formyl-3,4-diamino-thiophene derivatives. Synth.commun., 1988, 18(15), 1855-1861 discloses a method of synthesis of a hydantoin as a potential chiral intermediate for (+) biotin. C.A., 1964, 60 (2) 1677e-1678b describes the alkylation of cystine by the Dieckmann cyclisation. Chem. Ber., 1948, 81 (3) 210-214 is concerned with conversion of cystein to hydantoin. EP-A-0084377 is concerned with the preparation of biotin. The main objective of the present invention is to synthesize D (+) biotin or the methyl ester thereof from substituted hydantoins of the Formula A of the accompanying drawings. The optically pure hydantoin of the Formula A are prepared from racemic or optically pure chiral amino acids. The present invention provides a process for the synthesis of D(+) biotin or the methyl ester thereof, of the Formula herein referred 10 as Formula 1, which process comprises: (a) reducing by known methods a hydantoin of the Formula A in its R(+) form to the corresponding compound of the Formula B; (b) selectively protecting the compound of the Formula B with thiopenol to furnish the compound of the Formula C: (c) converting the compound of the Formula C to the silyl enol ether of the Formula D by conventional silation methods; (d) cyclising the ether of the formula D in the presence of methylene chloride and p-nitro benzaldehyde employing Lewis acids such as BF 3 , Ag0Ac, silver trifluoro methane sulphonates, SnCl 4 , AlCl 3 , trimethyl silyl trifluoromethane sulphonate, tert-butyldimethylsilyl trifluoromethane-sulphonate as catalyst to furnish the tetrahydro thiophene aldehyde of the Formula E; (e) treating the aldehyde of the Formula E with 3 (methoxycarbony-2-propenylidene) triphenyl-phosphorane at room temperature to furnish compound of the Formula F; (f) deconjugating the compound of the Formula F with lithium diisopropylamide, NaOMe, NaOH, potassium tert-butoxide or KOH to furnish the deconjugated ester or acid of the Formula G; (g) catalytically hydrogenating the compound of the Formula G using pearlmans catalyst Pd(OH) to furnish the compound of the Formula H, where R 2 represents hydrogen or methyl; (h) deprotecting the-compound of the Formula H to yield the biotin or methyl ester thereof of the Formula I All the conditions employed in the process are mild, simple, efficient and of short duration. Preferably according to the invention steps (c), (d), (e) and (g) in the process of the present invention are carried out at room temperature. The reduction of the compound of the Formula A to compound of the Formula B may be effected by employing diisobutyl aluminium hydride, The selective protection of compound of the Formula B may be effected by using para-toluene sulphonic acid or benzene sulphonic acid. The deprotection of the compound of the Formula H may be effected employing aqueous HBr. The invention is described with reference to the following examples which are given by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1: 5,6-(1,3-dibenzyl-ketoimidazolido)-3-hydroxy-1,4-oxathiepin compound of the Formula B A solution of R(+) 1,3 dibenzyl 1-5 (methoxycaronylmethylthiomethyl hydantoin of the Formula A 0.398 parts (1 mmol part) in dry toluene (10 parts) was added D IBAL-H 1.023 parts (2.2 mmol part) at -78°C during 1 hr. The reaction mixture was stirred for additional 2 h and quenched by addition of methanol (5 parts). Filtration through celite and concentration of the solvent furnished a residue which on purification by column (SiO 2 ) using ethylacetate-pet ether (60%) as eluent afforded lactol of the Formula B in 0.266 parts (72%), (α) D = +36.2 c=1.08 (MeOH). Example 2 : 2-imidazolidone-4-(formylmethylthiomethyl)-1, 3-dibenzyl-5-thiophenyl compound of the Formula C To a solution of 5,6-(1,3 dibenzyl-2-ketoimidazolido)-3-hydroxy-1,4-oxathiepin of the Formula B 0.370 parts (1 mmol part) in thiophenol (1 part) was added p-TSA (catalytic) at 0°C. The reaction mixture was stirred at 0° for 5 min. Water (2 parts) was added and extraction with dichloromethane and removal of solvent after drying (anhyd. Na 2 SO 4 ) furnished a residue which on purification by chromatography (SiO 2 ) using ethylacetate-petroleum ether (20%) furnished the 2-imidazolidone-4-(formylmethylthiomethyl)-1,3-dibenzyl-5-thiophenyl of the formula C 0.323 parts (70%). Example 3 : 2-imidazolidone-4-(2-tert-butoxydimethylsilyloxy-1-ethenylthiomethyl)-1,3-dibenzyl-5-thiophenyl compound of the Formula D To a solution of aldehyde of the Formula C 0.576 parts (1 mmol part) in dry dichloromethane (10 parts) was added DBU 0.182 parts (1.2 mmol part). TBDMSCl 0.165 parts (1.1 mmol part) was introduced in the reaction and stirred for 2 h. Purification of the residue, obtained by removal of solvent, by chromatography (SiO 2 ) using 15% EtOAc-pet ether as eluent furnished the silyl enol ether of the Formula D 0.529 parts (92%). Example 4 : 3,4-(1,3-dibenzyl-2-ketoimidazolido)-2-formylthiophane of the Formula E To a solution of enol ether (D) 0.576 parts (1 mmol part) and p-nitrobenzaldehyde 0.188 parts (1.25 mmol part) in dichloromethane (10 parts) was added TBSOTf (catalytic) at room temperature. After 10 min. aq. NaHCO 3 solution was added. Extraction with dichloromethane and purification by chromatography (SiO 2 ) using ethylacetate-petroleum ether (60%) as the eluent gave the aldehyde (E) 0.316 parts (90%) (α) D = -60 c = 0.9 (CHCl 3 ). Example 5 : 3S, 4R-(1,3-dibenzyl-2-ketoimidazolido)-2R-[(1E, 3E)-4-methoxycabutadienyl] thiophane of the Formula F A mixture of aldehyde of formula E, 0.352 parts ( 1mmol part), and phosphorane 0.432 parts (1.2 mmol part) in dichloromethane (5 parts) was stirred for 12 hrs. Removal of the solvent and chromatography (SiO 2 ) of the residue furnished ester of the Formula F 0.386 parts (89%) [α] = +85.51 c = 1.160 (MeOH). Example 6 : Pentanoic acid, 5-[Hexahydro-2-oxo-1,3-dibenzyl-4H-thieno (3,4-d) imidazol 3,5-dienyl] of the Formula G where R = hydrogen To a solution of ester of formula F, 334 parts (1 mmol part), in MeOH (5 parts) was added 1 M NaOH (5 parts) and the reaction mixture was stirred for 3 hrs and left at 0°C for 12 hrs. MeOH was removed under reduced pressure. Water (5 parts) was added followed by 1 N HCl. Extraction of the aqueous solution by dichloromethane furnished the acid of the Formula G where R = hydrogen 310 parts (97%) [α ] +210.41 c=0.48 (MeOH). Example 7 : 1H Thieno (3,4-d)-imidazol-4-pentanoic acid hexahydro-2-oxo-1,3-dibenzyl) 3aS-(3aα ,4B, 6aα ) of the Formula H where R = hydrogen. Acid of the Formula G where R 2 = hydrogen 320 parts (0.1 mmol part) was dissolved in methanol (5 parts) and the solution was hydrogenated at 3 kPa(3 atm) in the presence of 10% Pd/C (150 mg) for 8 hrs. Catalyst was filtered and removal of solvent under reduced pressure and purification of the residue (SiO 2 ) using 5% EtOAc-pet. ether furnished 310 parts (96%) of the desired acid of the formula H where R 2 = hydrogen [α] D = -39.16 c=0.24 (MeOH). Example 8 : Pentanoic acid, 5-[Hexahydro-2-oxo-1,3-dibenzyl-4H thieno (3,4-d) imidazol 3,5-dienyl], methyl ester of the Formula G where R 2 = CH 3 To a solution of ester of the Formula F 0.434 parts (1 mmol part) in dichloromethane (5 parts) was added DBU 0.152 parts (1 mmol part) and stirred for 12 hrs. Removal of the solvent and purification of the residue by chormatography (SiO 2 ) using 25% EtOAc-pet ether furnished (0.326 parts, 75%) the deconjugated ester of the Formula G where a = CH 3 . Example 9: 1H Thieno (3,4-d)-imidazol-4-pentanoic acid hexahydro-2-oyo-1, 3-dibenzyl, methyl ester. 3aS-(3aα, 4B, 6aα) of the Formula H where R = CH 3 A solution of ester of the Formula G where R 2 = CH 3 0.438 parts (1 mmol part) 10% Pd on charcoal (20 mg) in methanol (10 parts) was hydrogenated at 3 kPa(3 atm) for 4 hrs. Filtration of the catalyst and removal of the solvent under reduced pressure furnished a residue which was purified by chromatography (SiO 2 ) to furnish compound of the Formula H where R 2 = CH 3 in 0.420 parts (96%) [α ] D = -4 .05 c=0.38 (CHCl 3 ). Example 10 : 1H Thieno (3,4-d)-imidazol-4-pentanoic acid hexahydro-2-oxo methyl ester. 3aS-(3aα, 4B, 6aα). [D(+) BIOTIN METHYL ESTER] of the formula I where R 2 = CH 3 Ester 0.438 parts (1 mmol part) was refluxed with 48% aq. HBr (20 parts) and methanol (1 part) for 6 hrs. Removal of the water furnished a residue (vacuum dried). The residue was taken in methanol (10 parts) and refluxed for 2 hrs in the presence of con. H 2 SO 4 (1 drop). Neutralization with NaHCO 3 and removal of methanol furnished a residue which was extracted with ethylacetate to furnish a residue which on purification by chromatography (SiO 2 ) using 75% EtoAc-pet. ether furnished biotin methyl ester of the Formula I where R 2 = CH 3 0.206 parts (80% [α] D = + 83.75 c=0.4 (MeOH). AgOTf Silver trifluoromethanesulfonate TMSOTf Trimethylsilyl trifluoromethanesulfonate TBDMSOTf tert-Butyldimethylsilyl trifluoromethanesulfonate PTSA para-Toluenesulfonic acid CSA Camphorsulfonic acid TBDMSC1 tert-Butyldimethylsilyl chloride Et3N Triethylamine LDA Lithium diisopropylamide KOBut Potassium tert-butoxide TMSCl Chlorotrimethylsilane DIBAL Diisobutylaluminium hydride.

Claims: A process for the synthesis of D(+) biotin or the methyl ester thereof, of the Formula herein referred to as Formula 1, which process comprises: (a) reducing by known methods a hydantoin of the Formula A in its R(+) form to the corresponding compound of the Formula B; (b) selectively protecting the compound of the Formula B with thiopenol to furnish the compound of the Formula C: (c) convening the compound of the Formula C to the silyl enol ether of the Formula D by conventional silation methods; (d) cyclising the ether of the formula D in the presence of methylene chloride and p-nitro benzaldehyde employing Lewis acids such as BF 3 . Ag0Ac silver trifluoro methane sulphonates. SnCl 4 , AlCl 3 , trimethyl silyl trifluoromethane sulphonate, tert-butyldimethylsilyl trifluoromethane-sulphonate as catalyst to furnish the tetrahydro thiophene aldehyde of the Formula E; (e) treating the aldehyde of the Formula E with 3 (methoxycarbony-2-propenylidene) triphenyl-phosphorane at room temperature to furnish the compound of Formula F; (f) deconjugating the compound of the Formula F with lithium diisopropylamide, NaOMe, NaOH, potassium tert-butoxide or KOH to furnish the deconjugated ester or acid of the Formula G: (g) cataiytically hydrogenating the compound of the Formula G using pearlmans catalyst Pd(OH) to furnish the compound of the Formula H, where R 2 represents hydrogen or meihyl; (h) deprotecting the compound of the Formula H to yield the biotin or the methylester thereof of the Formula I A process as claimed in claim 1 wherein steps (c), (d), (e) and (g) are effected at room temperature. A process os claimed in any of the claims 1 and 2 wherein the reduction of the compound of the formula A to compound of Formula B is effected by employing diisobutyl aluminium hydride, A process as claimed in any of the claims 1 to 3 wherein the selective protection of the compound of the Formula B is effected in the presence of para-toluene sulphonic acid or benzene sulphonic acid. A process as claimed in any of the claims 1 to 5 wherein deprotection of the compound of the Formula H is elected by employing aqueous HBr.

Inventors: CHAVAN SUBHASH PRATAPRAO, RAVINDRANATHAN THOTTAPPILLIL, TEJWANI RAJKUMAR BHAGWANDAS, CHAVAN, SUBHASH PRATAPRAO, RAVINDRANATHAN, THOTTAPPILLIL, TEJWANI, RAJKUMAR BHAGWANDAS
Applicants: COUNCIL SCIENT IND RES, COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH
Application year: 1992
Main classification: C07D495
IPC codes: C07D495