Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-12
2002-11-26
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S303700
Reexamination Certificate
active
06486328
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to novel substituted 2-[-6-benzyl-5-oxo-3-phenyl-(3s,7s,7aR)-perhydroimidazol[1,5-c][1,3]thiazol] compounds having general formula (7)
Wherein R=benzyl, R1=alkyl group exemplified by 1-phenyl-1-ethanone, 1-(4-chlorophenyl)-1-ethanone, 1-(4-methoxypheny)-1-ethanone,2-oxocyclohexyl, 1-trimethylsilyloxy-2-oxocyclohexyl, allyl,1-hexanyl,4-dimethylaminophenyl, or 2-methylpropanoate. Still more particularly it relates to methyl 6-[benzyl-5-oxo-3-phenyl-(3S,7aR)-perhydroimidazo[1,5-c][1,3]thiazol-7yl]-6-oxohexanoic acid of formula (1) which is very useful intermediate for D(+)-Biotin
BACKGROUND
Biotin (Vitamin H) is one of the B-complex group of vitamins and 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 of rapid growth of chicks and healthy hatching of eggs. Biotin avidin complex finds a vital role in the area of biochemistry. D(+)-Biotin prepared by the process of the present invention is represented by formula 2
D(+) Biotin is prepared in the prior art from amino acids viz., cysteine, cyctine and serine. These processes involving L-cystine as the precursor, incorporate intramolecular radical cyclization (E. J. Corey, M. M. Mehrotra,
Tet.Lett.,
29, 57 1988) as the key step is construct the tetrahydrothiophene moiety of biotin.
Another prior art process involves intramolecular cycloaddition (3+2) of derivatives of L-cystine (E. G. Baggiolini, H. L. Lee, G. Pizzolato and M. R. Uskokovic,
J.Am.Chem.Soc.,
104, 6460, 1982), and L-cysteine (, H. L. Lee, E. G. Baggiolini and M. R. Uskokovic,
Tetrahedron
43, 4887, 1987).
In another process starting from L-cysteine, a bicyclic imidazolidine is the key intermediate leading to D(+)-biotin (E. Poetsch and M. Casutt, EP 242,686 1986 CA:108:1612077k 1988; Chimia 41, 148 1987). In an totally different and novel approach. L-cysteine was converted to its thiazolidine derivative which on treatment with bromine is converted stetreospecifically to a bicyclic intermediate as a single stereoisomer and eventually transformed to D(+)-biotin (P. N. Confalone, E. G. Baggiolini, D. Lollar, and M. R. Uskokovic,
J. Am. Chem. Soc.,
99, 7020 1977). Process for stereospecific synthesis of D(+)-Biotin from sugars of suitable configuration are known. [From Mannose
Tet. Lett.,
32, 2765 1975].
The use of L-cysteine in known from U.S. Pat. Nos. 4,000,972, 4,130,713, 4,337,345 and
J. Am. Chem. Soc.,
99, 7020, 1977 avoids the handling of labile intermediate steps but involves 18 steps, in all with the separation of undesired isomer leading to unsatisfactory yields of optically active D(+)-Biotin.
In another process
J. Am. Chem. Soc.,
105, 5946, 1983 and EP 0094776, substituted 3H, 5H-Imidazo[1,5-C]tetra hydro thiazole are described from which after racemate resolution, synthesis of optically active biotin is described.
In another process by Moolenaer, M. J.; Speckamp, W. N.; Hiemstra, H.; Poetsch, E.; Casutt, M.
Angew. Chem., Int. Ed. Engl.
1995, 34,2391 and DE 3,926,690 involves the intramolecular version of the condensation of a silyl enol ether with N-acyliminium intermediates to effect the ring closure of thio ether to the thiophane nucleus.
In yet another process by Poetsch, E.; Casutt, M., EP 242,686 1986; CA: 108: 112077K 1988;
Chimia
41, 141-150, 1987 describes the formation of keto acid and further elaboration of acid to D(+)-Biotin. The main draw back of this method is use of hazardous 2 eq of diisobutylaluminium hydride (DIBAL-H). Potassium cyanide (KCN), Carbonyldiimidazole and involves reactions to be performed under anhydrous conditions.
In yet another prior art of biotin syntheses by Chavan, S. P.; Chittiboyina, A. G.; Kamat, S. K., Indian Patents NF135/98, 136/98 and Ravindranathan, T.; Chavan, S. P.; Tejwani, R. B. U.S. Pat. No. 5,274,107 (1993) describes the formation of substituted imidazolidines from L-cysteine and further elaboration of hydantoin to D(+)-biotin. This process also involves the use of expensive and hazardous chemicals viz., DIBAL-H, tertiary butyl dimethyl silyl chloride (TBDMSCI), trifluoromethane sulphonic acid (Triflic acid) etc.,
Hitherto known processes involve highly toxic and hazardous chemicals e.g., phosgene for the formation of imidazolidine. Moreover the intramolecular radical cyclization leads to both desired five membered as well as undesired six membered ring along with tin inclusion compounds as the undesired byproducts.
In another prior art process involving the intramolecular (3+2) cylcoaddition 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 racemization.
In 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.
All these processes are however characterized by large number of synthetic steps resulting in low overall yields. The non crystallizable intermediate stages mostly due to sugar nature are often obtained in impure form and require tedious purification on account of their polyfunctionality and chemical liability connected with it maintenance of comparatively very narrow range of reaction parameters. Additionally these sugars are not easily available in nature which leads to high prices.
Hitherto known processes involve highly toxic, expensive and hazardous chemicals for example carbonyldiimidazole, Methyl Iodide, potassium cyanide DIBAL-H etc., for the formation of keto acid (1). More over these reactions required anhydrous conditions.
An object of the present invention is to provide substituted [6-benzyl-5-oxo-3-phenyl-(3S,7S,7aR)-perhydroimidazo[1,5-c][1,3]thiazol]-7yl compounds of formula (7) especially as given table-1 which can be used for synthesis of D(+)-biotin of formula (2).
Another object of the present invention is to provide selective Baeyer Villiger oxidation and new methodology for nucleophilic addition to imidazolodine of the formula (6) at C-7 position for the synthesis of compound having formula (7).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly the present invention provides substituted [6-benzyl-5-oxo-3-phenyl-(3S, 7S, 7aR)-perhydroimidazo[1.5-c][1,3]thiazol]-7yl compounds having general formula (7)
Wherein R=benzyl, R
1
=alkyl exemplified by 1-phenyl-1-ethanone, 1-(4-chlorophenyl)-1-ethanone, 1-(4methoxypheny)-1-ethanone, 2-oxocyclohexyl, 1-trimethylsilyloxy-2-oxocyclohexyl, allyl, 1-hexynyl, 4-dimethylaminophenyl, or 2-methylpropanoate
The present invention also provides a process for the preparation of compounds having formula (7) which comprises reacting the compound of formula (6) with Lewis acid and a nucleophile at a temperature ranging between 0° to 30° C. in an organic solvent for 10-30 minutes quenching the reaction mixture with either water or saturated aqueous solution of quenching agent, separating and concentrating the organic layer, purifying by conventional methods such as chromatography to obtain compounds of formula (7a) to (7g) as mentioned in the following table.
TABLE 1
S. No
Nucleophile
Product
Yield
1.
98
2.
98
3.
98
4.
98
5.
7e = 76 7e′ = 22
6.
98
7.
98
In one of the embodiment of the present invention the compound the alkyl group may be 1-phenyl-1-ethanone, 1-(4-chlorophenyl)-1-ethanone, 1-(4-methoxypheny)-1-ethanone,2-oxoc
Chavan Subhash Prataprao
Chittiboyina Amar Gopal
Kalkote Uttam Ramrao
Kamat Subhash Krishnaji
Ravindranathan Thotapallil
Council of Scientific and Industrial Research
Gerstl Robert
Smith , Gambrell & Russell, LLP
LandOfFree
Substituted 2-[-6-benzyl-5-oxo-3-phenyl-(3s,7s,... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted 2-[-6-benzyl-5-oxo-3-phenyl-(3s,7s,..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted 2-[-6-benzyl-5-oxo-3-phenyl-(3s,7s,... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2942362