Title of Invention

a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(3S,5R)-cyclohexan-1-one useful as an intermediate for Beta-hydroxy Game-lactone

Abstract A process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(3S,5R)-cyclohexan-1-one useful as an intermediate for ß-hydroxy γ-lactone by reacting a compound 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S.3R, 5R) -cyclohexan-1-one with magnesium bromide in an aliphatic organic solvent at a temperature ranging from 5 to 30°C for a period from 1 to 12 hours, quenching the above reaction with ammonium chloride, separating organic layer, drying and on evaporating to obtain 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(3S,5R)-cyclohexan-1-one.
Full Text The present relates to a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(3S,5R)-cyclohexan-1-one useful as an intermediate for ß-hydroxy -lactone.
More particularly it relates to a process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(3S,5R)-cyclohexan-one having formula 9
(Formula Removed)
useful as an intermediate for 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone ß-hydroxy -lactone) having formula 1.
(Formula Removed)
The compound (3-hydroxy 5-lactone (1) is an important intermediate in the synthesis of biologically active drugs e.g. compactin, atorvastatin, fluvastatin, cholesterol lowering drugs.
Hitherto known processes for the synthesis of ß-hydroxy -lactone) (1) involves
a) Addition of lithium enolate of ethylacetate to (S)-2,2-dimethyl-1,3-dioxlane-4-ethanol, which in derived from L-malic acid, followed by acid treatment. (T.
Rosen, M.J. Taschner & C.H. Heathcock, J. Org. Chem., 1984, 49, 3994-4003)
b) Multistep chemical manipulation of tri-acetyl-D-glucal (T. Rosen, M.J.
Taschner, C.H. Heathcock, J Org. Chem., 1984, 49, 3994; F.G. Kathawala,
Mountain Lake N.J. USP 4739,073)
c) Coupling of (S)-2,2-dimethyl-l,3-dioxalane-4-ethanal with optically active
(R)-methyl-p-tolylsulphoxide which in turn obtained by oxidation of methyl-
p-tolylsulphide with baker yeast, followed by desulphurization and few
chemical manipulation (J. Beecher, I. Brackerridge, S.M. Roberts, J. Tang &
A.J. Willetts, J. Chem. Soc. Perkin Tran.I 1995, 1641; Tetrahedron 1995,
51,13217)
d) Deprotection and hydrolysis of 6-cyanomethyl-2,2-dimethyl-l,3-dioxane-4-acetate, which in turn obtained by two carbon homologation on optically active ethyl-3-hydroxy-4-cyanobutyrate and followed by stereoselective reduction (P.L. Brower, D.E. Butler, C.F. Deering, T.V. Le, A. Millar, T.N. Nanninga & B.D. Roth, Tet. Lett, 1992,33 279-82
e) Racemic and optically active P-hydroxy-5-lactone from cis-cyclohexane-1,3,5-triol (K. Prasad & O. Repic, Tet. Lett., 1984, 25., 2435-38; H. Suemune, M. Takahashi, S. Maeda, Z. Fxi & K. Sakai, Tet. Asymm. 1990,1, 425-8, M. Canda, V.Eyken & M. Vandewalle, Tet. Asymmetry 1990,1, 17-20).
f) Enzymatic kinetic resolution of racemic p-hydroxy-5-lactone by transesterification with vinyl acetate in THF using Chromobacteriun viscosum lipase as catalyst at 40 °C. [Crosby, J. B.; Andrew, J. H.; John, A. L. WO 9306235 Al CA 119:936292 (1993)]
g) Chemoenzymatic route involving kinetic resolution through lactone formation
in ether catalyzed by PPL [Bonini, C; Pucci, P.; Viggiani, L. J Org. Chem.
1991,56,4050] h) Chemoenzymatic route involing enzymatic desymmetrization of intermediate
diacetate, followed by chemical conversions. [Bonni, C; Racioppi, R.; Righi,
G.; Viggiani, L. J Org. Chem. 1991, 58, 802] i) Chemoenzymatic synthesis starting from endohydroxylacto which is obtained
by enzymatic resolution [MaCague, R.; Olivo, H. F.; Roberts, S. M.
Tetrahedron Lett. 1993, 34, 3785] j) Diastereoselective synthesis of lactone based on Eu(fod)3 catalyzed highly
diastereoselective [4+2] cycloaddition of l-methoxybuta-l,3-diene to (2R)-N-
glyoxyloxyborane-10,2-sultam and further chemical transformations [ Bauer,
T.; Kozak, J.; Chauis, C; Jurczak, J. . Chem. Soc; Chem. Commun. 1990,
1178 and Tetrahedron: Asymmetry 1996, 7, 1391] k) Chiral synthesi using (R)-O-benzylglycidol as starting material [Takano, S.;
Shimazaki, Y.; Sekiguchi, Y.; Ogasawara, K. Synthesis 1989, 539] 1) Asymmetric synthesis based on Red-Al promoted intramolecular reductive
cleavage of Benzyl 4-hydroxy-2-butenyl ether structures. [Hatakeyama, S.;
Satoh, K.; Takano, S. Tetrahedron Lett. 1993, 34, 7425]
The prior art processes have following drawbacks:
1. The processes use chemicals such as butyl lithium, lithium aluminum hydride, methoxy-diethylborane which are costly and difficult to handle and therefore make the process difficult.
All known process are however involves large number of synthetic steps resulting in low over all yields.
The main object of the present invention is to provide a process for the preparation of a novel 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexan-1-ol useful as an intermediate for 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone.
Another object of the present invention is to provide a process for the
preparation of 6-hydroxymethyl-4-(tert.butyldimethyl silyloxy)-(4R, 6S)-tetrahydro-
2H-2-pyranone(1) which obviates the drawbacks of the prior art proceses and use
cheaper and easily accessible chemicals.
Accordingly, the present invention provides a process for the preparation of a
novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(3S,5R)-cyclohexan-1-one having
formula 9
(Formula Removed)
useful as an intermediate for ß-hydroxy -lactone which comprises reacting a
compound 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,
5R) -cyclohexan-1-one with magnesium bromide in an aliphatic organic solvent such as herein described at a temperature ranging from 5 to 30°C for a period from 1 to 12 horrs, quenching the above reaction with ammonium chloride, separating organic layer, drying and on evaporating to obtain 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(3S,5R)-cyclohexan-1-one.
In an embodiment of the present invention the organic solvent used for the reaction is selected from the group consisting of ethyl acetate, chloroform, dichloromethane, methanol and diethyl ether.
The compound 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate is prepared by a procedure as described and claimed in our co-pending Patent No.19217.0....
The process of the present invention is described herein below with reference to the following examples, which are illustrative only and should not be construed to unit the scope of the present invention in any manner.
Example 1 Preparation of cis, cis-3-hydroxy-5-methylcarbonyioxy-cyclohexylacetate
Finely powdered cis, cis-3,5-di(methylcarbonyloxy)cyclohexylacetate (6.5 parts, 25.19 mmol parts) was suspended in 0.1 M sodium phosphate buffer (pH 7) (135 parts) and stirred vigorously. To the stirred suspension Porcine Liver Esterase (0.110 parts) was added and reaction mixture was stirred vigorously at 30°C for 20 hr. pH of the reaction mixture was monitored at every 2 hours and was maintained at pH 7 using IN NaOH solution. After completion of reaction (20 hours), it was extracted with ethyl acetate (2x150 parts). Organic layers were combined and washed with brine, dried
on anhydrous sodium sulfate and concentrated under vacuum to yield cis,cis-3-
hydroxy-5-methylcarbonyloxycyclohexylacetate yield (4.8 g parts, 88%).
1H NMR (CDCl3): δ 1.20-1.58 (qn, 3H), 2.08 (s, 6H), 2.28 (m, 3H), 3.78 (m, 1H), 4.78 (m, 2H)
13C NMR (CDC13): δ 21.15, 36.33, 39.93, 64.83, 67.65, 170.42
IR(KBr): 754.60,884.15, 1029.29, 1140.34, 1250.00, 1367.64, 1738.92,2871.17, 2953.14,3445.47
Mass: Base m/e = 96 other m/e: 156, 138, 114, 73, 67, 67, 60, 55 Elemental analysis: calculated for C10H16O5: 055.56%, H 7.40%
Found : C 55.30%, H 8.00%
Example 2
Preparation of cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy) cyclo-
hexylacetate
Cis, cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate (2 parts, 9.26 mmol) and DMAP (0.113 parts, 0.926 mmol) were placed in 100 ml two-necked round bottom flask equipped with dropping funnel and two-way stopcock. It was evacuated and flushed with argon. To it, dry dichloromethane (10 parts) and dry HMPA (2 part) was added and stirred to dissolve. The solution was cooled to -10°C with stirring. To it, solution of tert-butyldimethylsilyl chloride in 10 part dry dichloromethane was added dropwise while maintaining temperature below 0°C. Reaction mixture was stirred for 15 min and to it dry triethylamine (2.02 g, 20 mmol) was added dropwise. Reaction mixture was stirred at room temperature for 12 hr. It was then transferred to a separating funnel and washed successively with cold, dil. HC1 water, aq. NaHCO3 and then brine. Organic layer was dried on anhydrous sodium sulfate and solvent was removed under vacuum. Residue was purified by flash column chromatography, (eluent 2-4% ethyl acetate in petroleum ether) to yield Cis,cis-3-
(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cyclohexylacetate ( yield 2.85 parts, 90%).
1H NMR (CDCl3): δ 0.06(s, 9H), 0.87 (s, 6H), 1.20-1.45 (m, 3H), 2.03 (s, 6H),
2.2 (m, 3H), 3.38 (m, 1H), 4.73 (m, 2H).
2.3 13C NMR (CDCl3): δ -5.07, 17.61, 25.40, 36.17, 40.40, 65.43, 67.01, 169.64
IR(CHC13): 758.90, 838.05, 1034.91, 1106.32, 1246.82, 1368.91, 1734.01,2858.81, 2955.07
Mass: Base m/e = 117 other m/e: 273, 213, 171, 159, 129, 117, 97, 79, 75, 57
Elemental analysis: calculated for C26H30O5Si: C 58.185%, H 9.10%
Found :C 58.19%, H 9.50%
Example 3
Preparation of 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(lS,3R,5R)-cyclohexyl
acetate
Cis, cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cyclohexylacetate ( 5
patrs, 147 mmol) was dissolved in tert-butanol (20 parts). To the solution, 0.1 M
sodium phosphate buffer (230 parts, pH 8) was added and mixture was stirred
vigorously. To the stirred emulsion, Porcine liver esterase (0.150 parts) was added
and the mixture was stirred vigorously at 30°C for 54 hrs. During reaction pH was
maintained at 8 using IN sodium hydroxide solution. Reaction mixture was extracted
with ethyl acetate (3 x 200 parts). Organic layers were combined and washed with
brine. It was then dried on anhydrous sodium sulfate and solvent was removed under
vacuum. Oily residue contained 3-hydroxy-5-(tert.butyldimethylsilyloxy)-
(lS,3i?,5R)-cyclohexylacetate along with unreacted Both were separated by
flash column chromatography. Cis,cis-3-(methylcarbonyloxy)-5-
(tert.butyldimethylsilyloxy)cyclo- hexylacetate recovered: 1.07 parts; 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(15',3R,5R)-cyclohexylacetate (5, yield 2.8 parts, 70% based on recovered starting material.
1H NMR (CDCl3): δ 0.06 (s, 9H), 0.87 (s, 6H), 1.35-1.60, (m, 3H), 2.06 (s, 3H), 2.15 (m, 3H), 3.7 (m, 2H), 4.75 (m, 1H)
13C NMR (CDCl3): δ -4.60, 18.15, 21.38, 25.90, 39.98, 40.31, 43.93, 65.45, 66.40, 68.17, 170.68
IR(CHCl3): 758.43, 838.93, 1049.42, 1109.15, 1218.09, 1254.01, 1370.09, 1725.03, 2859.8, 2887.95, 2952.33, 3017.48
Mass: Base m/e = 75 other m/e: 231, 171, 129, 117, 105, 97, 79, 75, 67, 59 Elemental analysis: calculated for C14H28O4Si: C 58.33%, H 9.72%
Found : C 58.15%, H 10.20%
Specific rotation [ct]D = -4.8 (c 1, CHC13) e.er >95% (determined by chiral HPLC of
corresponding Mosher ester. Column: Whelk-Ol [4.0 mm Id x 25 cm] AT-256; X
=254 nm, flow rate: 1 ml/min; mobile phase: Hexane:isopropanol 98:02; retention
time for Mosher ester ~ = 4.59, for Mosher ester of 4.34).
Example 4:
Preparation of 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-
(15,3R,5R)-cyclohexylacetate
3-hydroxy-5-(tert.butyldimethylsilyloxy)-(15',3R,5R)-cyclohexylacetate ( 2.9 parts, 9.73 mmol) was dissolved in dry dichloromethane (30 parts). The solution was cooled below 0°C in ice-salt bath. To the stirred solution, dihydropyran (1 part, 12 mmol) was added and p-toluenesulfonic acid monohydrate (0.1 part) was added as catalyst. Reaction mixture was stirred at -10°C for 2 hr. Reaction was quenched by adding aqueous sodium bicarbonate solution. Both the layers were separated. Aqueous layer was extracted dichloromethane (10 part). Organic layers were combined and washed with water followed by brine wash. It was then dried on anhydrous sodium sulfate and solvent was removed under vacuum. Residue was

purified by flash column chromatography to yield 3-tetrahydro-2H-2-pyranyloxy-5-
(tert.butyldimethylsilyloxy)-(15',3R,5R)-cyclohexylacetate 6 (yield 3.7 parts, 99.5%).
1H NMR (CDCl3): δ 0.07 (s, 6H), 0.87 (s, 9H), 1.25-1.90 (m, 9H), 2.04 (s, 3H), 2.05-40 (m, 3H), 3.40-3.75 (m, 3H), 3.86 (m, 1H), 4.55-4.80 (m, 2H)
l3C NMR (CDC13): δ -4.90, 18.00, 19.40, 19.50, 25.20, 25.80, 30.90, 36.80, 40.70, 41.00, 42.80, 62.00, 62.50, 66.00, 68.00, 69.70, 95.00, 96.80
IR(CHC13): 752.08, 768.22, 838.35, 1029.76, 1114.56, 1215.63, 1251.94, 1727.19, 2858.86, 2950.80, 3016.74

Mass: Base m/e = 85 other m/e: 231, 211, 171, 159, 129, 117, 105, 101,85,79,75, 67,55
Elemental analysis: calculated for C,9H36O5Si: C 61.29%, H 9.68%
Found : C 61.37%, H 10.03%
Specific rotation [a]D = +1.39 (c 1, CHC13)
Example 5
Preparation of 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-
(15,5R,5R)-cyclohexan-l-ol
3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(15',3R,5R)-cyclohexyl-acetate ( 3.5 parts, 9.16 mmol) was dissolved in dry methanol (25 parts). To the solution anhydrous potassium carbonate (0.828 parts, 6 mmol) was added and the mixture was stirred at room temperature for 2 hr. Methanol was removed under vacuum and residue was extracted several times with dichloromethane. Dichloromethane layers were combined and washed with water followed by brine wash. It was dried on anhydrous sodium sulfate. Solvent was removed under vacuum and residue was purified by flash column chromatography to yield 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-( 15',3R,5R)-cyclohexan-1 -ol (7, yield 3 parts, 96%).
1H NMR (CDCl3): δ 0.06 (s, 6H), 0.87 (s, 9H), 1.35-1.90 (m, 10H), 2.05-2.35 (m, 3H), 3.40-3.75 (m, 4H), 3.80-3.98 (m, 1H), 4.73 (s, 1H)
13C NMR (CDCl3): δ -4.90, 18.00, 19.50, 25.20, 25.80, 30.90, 40.00, 40.70, 42.00, 42.30, 44.70, 62.00, 62.50, 65.80, 66.90, 69.50, 70.00, 96.40, 96.80
IR(CHC13): 753.06, 766.83, 838.54, 867.39, 1020.84, 1048.02, 1114.23, 1215.02, 1253.72, 2858.73, 28884.47, 2947.49, 3013.80, 3418.48
Mass: Base m/e = 75 other m/e: 309, 189, 171, 129, 119, 101, 85, 79, 75, 67, 55
Elemental analysis: calculated for C17H34O4Si: C 61.82%, H 10.30%
Found : G 61.83%, H 11.00%
Specific rotation [α]D = +0.93 (c 1, CHC13)
Example 6
Preparation of 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-
(3.R,5R)-cyclohexan-l-one
3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(l.S',3R,5R)cyclohexan-l-ol ( 2.85 parts, 8.38 mmol) was dissolved in dry dichloromethane (25 parts) under argon atmosphere. To it, anhydrous sodium acetate (0.2 part, 2.6 mmol) and pyridinium chlorochromate (13 part, 2.6 mmol) were added in one portion and the mixture was stirred under argon atmosphere for 8 hr. Then reaction mixture was diluted with diethyl ether (30 parts) and stirred well. The solution was decanted and the remaining black tar was extracted with diethyl ether (13 x 15 parts). Organic layers were combined and were filtered through small ceilite bed. Then, the organic layer was washed with water (3 x 20 parts) followed by brine wash. Then it was dried on anhydrous sodium sulfate and solvent was removed under vacuum. Residue was purified by flash column chromatography. Yield of 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyl oxy)-(3R,5R)-cyclohexan-l-one (8, 2.24 parts, 80%).
1H NMR (CDCl3): δ 0.07 (s, 6H), 0.87 (s, 9H), 1.35-1.95 (m, 8H), 2.2-2.8 (m, 4H), 3.50 (m, 1H), 3.85 (m, 3H), 4.60 & 4.75 (2s, 1H)
13C NMR (CDC13): δ -4.9, 18.0, 19.5, 19.9, 25.8, 26.0, 30.9, 41.0, 42.5, 47.0, 48.5, 51.5, 62.5, 63.0, 69.0, 69.8, 97.5, 206.5, 207.0
IR(CHC13): 858.87,980.49, 1028.79, 1053.00, 1254.14, 1360.70, 1377.86, 1462.85,
1717.24,2857.60,2892.24 Mass: Base m/e = 187, 85 other m/e: 271, 227, 169, 159, 143, 127, 95, 75, 67
Elemental analysis: calculated for C17H32O4Si: C 62.19%, H 9.75%
Found :C61.9%,H 10.10%
Specific rotation [α]D = +3.71 (c 1, CHC13)
Example 7
Preparation of 3-hydroxy-5-(tert-butyldimethylsilyloxy)-(3S,5R)-cyclohexan-l-
one ( 9)
3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(3R,5R)-cyclohexan-l-one (8- 1 part, 2.959 mmol) was placed in 50 parts two necked round bottom flask equipped with two-way stopcock and rubber septum. Flask was evacuated and flushed with argon. To it, dry ether (10 parts) was added and the resulting solution was stirred vigorously. To the stirred solution magnesium bromide etherate (2.3 parts, 8.9 mmol) was added and the mixture was stirred for 10 hr. The reaction mixture was cooled in ice-bath and reaction was quenched by adding saturated ammonium chloride solution. Both the layers were separated. Aqueous layer was extracted with ether (2x10 parts). Organic layers were combined and washed with brine. Then it was dried on anhydrous sodium sulfate and solvent was removed under vacuum. Residue was purified to yield 3-hydroxy-5-(tert-butyldimethylsilyloxy)-(35,5R)-cyclohexan-1 -one (9, 0.67 parts, 89%).
1H NMR (CDCl3): δ 0.10 (s, 6H), 0.88 (s, 9H), 1.95-2.30 (m, 2H), 2.45-2.78 (m, 4H), 3.95 (d, 1H), 4.36 (m, 1H), 4.56 (m, 1H)
13C NMR (CDCl3): δ -5.28, -5.50, 17.55, 25.34, 38.24, 49.56, 49.89, 68.86, 70.48, 206.78
IR(CHCl3): 777.13, 835.81, 1010.66, 1045.71, 1095.81, 1254.55, 1381.17, 1413.71, 1464.09, 1715.72.2857.70, 2892.64, 2932.26, 2951.84, 3439.28
Mass: Base m/e = 75 other m/e: 187, 169, 145, 129, 101, 95, 75, 69, 59
Elemental analysis: calculated for CI2H24O3Si: C 59.01%, H 9.83%
Found : C 58.65%, H 10.18%
Specific rotation [α]D = +16.20 (c 1, CHC13)


We claim :
1. A process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(3S,5R)-cyclohexan-1-one having formula 9 (Formula Removed)
useful as an intermediate for ß-hydroxy -lactone which comprises reacting a compound 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R, 5R) -cyclohexan-1-one with magnesium bromide in an aliphatic organic solvent such as herein described at a temperature ranging from 5 to 30°C for a period from 1 to 12 hours, quenching the above reaction with ammonium chloride, separating organic layer, drying and on evaporating to obtain 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(3S,5R)-cyclohexan-1-one.
2. A process as claimed in claim 1 wherein the organic solvent used is selected from the group consisting of ethyl acetate, chloroform, dichloromethane. methanol and diethyl ether.
3. A process for the preparation of a novel 3-hydroxy-5-(tert.butyldimethyl silyloxy)-(3S,5R)-cyclohexan-1-one useful as an intermediate for ß-hydroxy -lactone substantially as herein described with reference to the examples. Dated this 30th day of January, 2001.


Documents:

0088-del-2001-abstract.pdf

0088-del-2001-claims.pdf

0088-del-2001-complete specification granted.pdf

0088-del-2001-correspondence-others.pdf

0088-del-2001-correspondence-po.pdf

0088-del-2001-description (complete).pdf

0088-del-2001-form-1.pdf

0088-del-2001-form-2.pdf

0088-del-2001-form-4.pdf


Patent Number 199869
Indian Patent Application Number 0088/DEL/2001
PG Journal Number 36/2008
Publication Date 05-Sep-2008
Grant Date 05-Jan-2007
Date of Filing 31-Jan-2001
Name of Patentee Council of Scientific and Industrial Research
Applicant Address Rafi Marg, New Delhi
Inventors:
# Inventor's Name Inventor's Address
1 Sandeep Raghunath Ghorpade National Chemical Laboratory, Pune-411008
2 Uttam Ramrao Kalkote National Chemical Laboratory, Pune-411008
3 Subhash Prataprao Chavan National Chemical Laboratory, Pune-411008
4 Sunil Ramchandra Bhide National Chemical Laboratory, Pune-411008
5 Thottappillil Ravindranathan National Chemical Laboratory, Pune-411008
PCT International Classification Number A 61 K 31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA