Title of Invention

"AN IMPROVED PROCESS FOR THE PREPARATION OF HEMIACETAL, 4-HYDROXY-6,6-DIMETHYL-3-OXABICYCLO [3,1,0]-HEXAN-2-ONE (HEMIACETAL) FROM THE ENOL-LACTONE OF (-)-1R-CIS-2,2-DIMETHYL-3-(2'-OXOPROPYL)-CYCLO PROPANE CARBOXYLIC ACID (C9-ENOL LACTONE)"

Abstract This invention relates to an improved process for the preparation of Hemiacetal, 4- Hydroxy-6, 6-dimethyl -3- oxabicyclo [3,1,0] - hexan -2-one from the Enol-lactone of (-)-lR-cis-2,2-Dimethyl -3-(2'- oxopropy )- cyclo propane carboxylic acid (C9-Enol lactone) comprising: dissolving C9 Enol lactone in anhydrous methanol in the ratio of 1:1 to 10:1 w/v ( moisture content < 0.05 %) cooling the above solution to -10 °C to -15 °C and passing ozonized oxygen at -10 ° to - 5 °C until ozonolysis is complete removing traces of dissolved ozone from the solution by purging nitrogen at -10 °C to -5 °C, and adding this slowly to a solution of Dimethyl sulphide (DMS) in anhydrous methanol at -10 °C to - 5°C under stirring raising the temperature of the reaction mass to 30 ° C +/- 2 ° C and stirring until the reaction mass shows absence of peroxide stripping off methanol at 40 to 45 ° C/ 200 to 10 mm. Hg to obtain a residual mass adding 20-30 parts of 0.5% aqueous oxalic acid solution with respect to C9 Enol lactone to said residual mass, stirring the above at 30 to 35 ° C until hydrolysis is complete extracting the product with ethyl acetate stripping off ethyl acetate at 50 to 55 ° C/ 200 to 10 mm Hg to get crude Hemiacetal purifying the crude Hemiacetal using acetone - petroleum ether mixture to get pure Hemiacetal in 75.12% yield
Full Text The present invention relates to an improved process for the preparation of Hemiacetal 4- Hydroxy-6, 6-dimethyl -3- oxabicyclo [3,1,0] - Hexan 2-one (Hemiacetal) from the Enol-lactone of (-)-lR-cis-2, 2-Dimethyl -3-(2'- oxopropyl)-cyclo propane ca'rboxylic acid (C9-Enol lactone).
Hemiacetal is an important intermediate for many insecticides such as Deltamethrin, Lambdacyhalothrin, Alphamethrin and Tralomethrin.
BACKGROUND
The preparation of Hemiacetal from C9- Enol-lactone by ozonolysis followed by reductive quenching is known in prior art. Many reducing agents such as Sodium sulphite, Sodium bi-sulphite, Dimethyl sulphide, Thiourea, Zinc and acetic acid are known. Catalytic hydrogenation of the ozonide for the preparation of Hemiacetal is also reported. These are described in the following patents:
US 5,276,167 (EP 541,446), US 4,837, 341(EP 277, 052), US 4,769,478 (EP 23,454), US 4,132, 717, US 4, 409, 398, FR 1, 580,474 and IN 155, 125 read with an article published by the same authors in Tetrahedron, Volume 49, 1989, p-767-774.
Indian Patent No. 155, 125 read with an article published by the same authors in Tetrahedron, Volume 49, 1989, p-767-774, reports a yield of 57.8% of Hemiacetal, in addition to a side product, namely the methyl ester of 3-Formyl-2, 2-dimethyl cyclopropane carboxylic acid, of structural formula III, in 25.2% yield. The real
disadvantage in the Indian patent No. 155,125, read with an article published by the same authors in Tetrahedron, Volume 49, 1989, p-767-774, is the formation of side product methyl ester of 3-Formyl-2, 2-dimethyl cyclopropane carboxylic acid of structural formula III in 25.2% yield. The total yield of Hemiacetal, I, and the side product, III, was 83 % based on C 9 Enol lactone.
We have overcome the above disadvantage by modifying the work -up and isolation techniques.
Hemiacetal can be readily converted into lR-Cis-2, 2-dimethyl-3-(l'-hydroxy-2 ,2',2'- tri bromoethyl) - cyclopropane caorboxylic acid ( Bromoacid) of structural formula IV, which can be ultimately converted into Deltamethrin. These have been shown in our Indian Patent applications Numbers 2228/Del/98, 2227/Del/98, 2262/Del/98 and 3262/Del/98.
The reaction of Hemiacetal with Bromoform in the presence of alcoholic potassium hydroxide and a suitable solvent at -10° C to - 15° C, gives Bromoacid in > 77% yield, in 2 to 3 hours.
However, under similar conditions the methyl ester of 3-Formyl-2,2-dimethyl cyclopropane carboxylic acid of formula III, does not completely react to give the Bromoacid. The yield of Bromoacid is very low ( ~ 25%) and substantial quantity of methyl ester of 3-Formyl-2,2-dimethyl cyclopropane carboxylic acid, remains unreacted. Even at higher temperatures (upto 40°C ) and prolonged reaction time (12 hours) the reaction does not proceed to completion.
Methyl ester of 3-Formyl-2,2-dimethyl cyclopropane carboxylic acid of formula III can be converted into Deltamethrin by first carrying out a Wittig reaction with Bromoform to get the methyl ester of Deltamethric acid and this in turn can be converted into Deltamethrin. However, this process is comparatively very expensive.
It is therefore profitable to either minimize or eliminate the formation of methyl ester of 3-Formyl-2,2-dirnethyl cyclopropane carboxylic acid.
In our improved process, we have reduced the quantities of methanol and DMS, but increased the time of hydrolysis with aqueous oxalic acid solution from 3 to 6 hours at 25- 30 ° C in order to increase the yield of Hemiacetal from 57.8 to 75. 12 % and simultaneously reduce the quantity of the side product III from 25. 2 to Accordingly, the present invention provides an improved process for the preparation of Hemiacetal, 4- Hydroxy-6, 6-dimethyl -3- oxabicyclo [3,1,0] - Hexan -2-one from the Enol-lactone of (-)-lR-cis-2,2-Dimethyl -3-(2'- oxopropyl )- cyclo propane carboxylic acid (C9-Enol lactone) comprising.
dissolving C9 Enol lactone in anhydrous methanol in the ratio of 1:1 to 1:10 w/v ( moisture content cooling the above solution to -10 °C to -15 °C and passing ozonized oxygen at -10 ° to - 5 °C until ozonolysis is complete
removing traces of dissolved ozone from the solution by purging nitrogen at
-10 °C to -5 °C, and adding this slowly to a solution of Dimethyl sulphide (DMS) in anhydrous methanol at -10 °C to -5 °C under stirring, the mole ratio of DMS to C9-Enol lactone being in the range of 1 : 1 to 1 : 2
raising the temperature of the reaction mass to 30 ° C +/- 2 ° C and stirring until the reaction mass shows absence of peroxide in conventional tests
stripping off methanol at 40 to 45 ° CI 200 to 10 mm. Hg to obtain a residual mass
adding 20-30 parts of 0.5% aqueous oxalic acid solution with respect to C9 Enol lactone to said residual mass, the mole ratio of oxalic acid to C9 Enol lactone being in the range of 1 : 0.1 to 1 : 0.5
stirring the above at 30 to 35 ° C for 5 to 8 hours until hydrolysis is complete
extracting the product with ethyl acetate
stripping off ethyl acetate at 50 to 55 ° C/ 200 to 10 mm Hg to get crude Hemiacetal
purifying the crude Hemiacetal using acetone - petroleum ether mixture to get pure Hemiacetal in 75.12% yield
The quantity of methanol with respect to C9 Enol lactone varies between 1:4 and
1:5.
The mole ratio of DMS with respect to C9 Enol lactone 1:1 and 1:2, preferably 1 : 1.2 to 1.4.
The mole ratio of oxalic acid with respect to C 9 Enol lactone varies between 1: 0.1 to i: 0.5. preferably 1: 0.18- 0.22
The time of hydrolysis varies between 5 and 8 hours, preferably 6 to 7 hours.
The composition of acetone - petroleum ether mixture employed for purification of Hemiacetal is 1: 1 w/w
The methanol recovery according to the process of the present invention is more than 80%.
The ethyl acetate recovery according to the process of the present invention is more than 90%
4-5 volume by parts of ethyl acetate are used for extraction of the product.
The invention is now described with reference to the following example:
Example
C9 Enol lactone ( 59.18 gm, 90.84%, 0.3537 mole) was dissolved in methanol ( 262 ml, moisture content 0.05%). The solution was cooled to -15 °C and ozonized oxygen passed at -15 to -10 °C for 3 hours, until ozonolysis was complete. Nitrogen was purged through the solution to remove traces of dissolved ozone. The solution was added slowly to a pre-cooled solution of Dimethyl sulphide (24 gm, 91%, 0.4243 mole) in methanol (30 ml) during 30 minutes, under stirring. The temperature of the reaction mass was raised to 30 °C and the mass was further
stirred for 3 hours more, until peroxide test was negative. Methanol was stripped off at 40 to 45 º C/200 to 10 mm Hg ( recovered methanol 235 ml, moisture content ~ 2 %). To the residue obtained ( 108 gm) aqueous oxalic acid solution ( 0.5 % , 1240 ml) was added and the mass was stirred at room temperature ( 25 ± 5 C ) for six hours , until the hydrolysis was complete ( TLC, silica gel plate, 20% ethyl acetate-petroleum ether eluent), and the product was extracted with ethyl acetate ( 120 + 60 + 60 ml) . Solvent was stripped off at 50 to 55 ° C/ 200 to 10mm Hg, (recovery of ethyl acetate 200 ml) to yield 50 gms of a crude Hemiacetal which was purified by crystalization from acetone - petroleum ether mixture (48 gm, 1:1 w/w ) to get pure Hemiacetal ( 38 .5 gm, mp: 111- 112 ° C, yield 75. 12% )
The mother liquor obtained ( 10.03 gm ) contained methyl ester of I ( 50.88 %), methyl caronaldehydic ester, III ( 18.93 % ) and Hemiacetal (4.7 % ) by GLC. The over all yield of Hemiacetal, I, and the side product, III together is ~ 83 %.S




We claim:
1. An improved process for the preparation of Hemiacetal, 4- Hydroxy-6, 6-dimethyl -3- oxabicyclo [3,1,0] - hexan -2-one from the Enol-lactone of (-)-lR-cis-2,2-Dimethyl -3-(2'- oxopropy )- cyclo propane carboxylic acid (C9-Enol lactone) comprising:
dissolving C9 Enol lactone in anhydrous methanol in the ratio of 1:1 to 10:1 w/v (moisture content cooling the above solution to -10 °C to -15 °C and passing ozonized oxygen at -10 °to - 5 °C until ozonolysis is complete
removing traces of dissolved ozone from the solution by purging nitrogen at -10 °C to -5 °C, and adding this slowly to a solution of Dimethyl sulphide (DMS) in anhydrous methanol at -10 °C to -5 °C under stirring, the mole ratio of DMS to C9-Enol lactone being in the range of 1 : 1 to 1 : 2
raising the temperature of the reaction mass to 30 ° C +/- 2 ° C and stirring until the reaction mass shows absence of peroxide in conventional tests
stripping off methanol at 40 to 45 ° C/ 200 to 10 mm. Hg to obtain a residual mass
adding 20-30 parts of 0.5% aqueous oxalic acid solution with respect to C9 Enol lactone to said residual mass, the mole ratio of oxalic acid to C9 Enol lactone being in the range of 1 : 0.1 to 1 : 0.5
stirring the above at 30 to 35 C for 5 to 8 hours until hydrolysis is complete
extracting the product with ethyl acetate
stripping off ethyl acetate at 50 to 55 ° C/ 200 to 10 mm Hg to get crude Hemiacetal
purifying the crude Hemiacetal using acetone - petroleum ether mixture to get pure Hemiacetal in 75.12% yield
A process as claimed in claim 1 wherein the quantity of methanol with respect to C 9 Enol lactone varies between 1: 4 to 1:5.
A process as claimed in claim 1 wherein the mole ratio of DMS with respect to C9 Enol lactone is preferably 1 : 1.2 to 1.4
A process as claimed in claim 1 wherein the mole ratio of oxalic acid with respect to C 9 Enol lactone is preferably 1: 0.18 to 0.22
A process as claimed in claim 1 wherein the time of hydrolysis is preferably 6 to 7 hours.
A process as claimed in claim 1 wherein the composition of acetone -petroleum ether mixture employed for purification of Hemiacetal is 1: 1
w/w
7. A process as claimed in claim 1 where 4-5 volume by parts of ethyl acetate are used for extraction of the product.
8. An improved process for the preparation of Hemiacetal, 4-Hydroxy-6, 6-dimethyl-3-oxabicyclo [3,1,0] - hexan -2-one from the Enol-lactone of (-)-lR-cis-2,2-Dimethyl -3-(2'-oxopropyl)- cyclo propane carboxylic acid (C9-Enol lactone) substantially as herein described with reference to and as illustrated by the foregoing example.

Documents:

786-del-1999-abstract.pdf

786-del-1999-claims cancelled.pdf

786-del-1999-claims.pdf

786-del-1999-complete specification (granted).pdf

786-del-1999-correspondence-othes.pdf

786-del-1999-correspondence-po.pdf

786-del-1999-description (complete).pdf

786-del-1999-drawings.pdf

786-del-1999-form-1.pdf

786-del-1999-form-2.pdf

786-del-1999-form-3.pdf

786-del-1999-gpa.pdf

786-del-1999-pa.pdf


Patent Number 190150
Indian Patent Application Number 786/DEL/1999
PG Journal Number 04/2011
Publication Date 28-Jan-2011
Grant Date
Date of Filing 25-May-1999
Name of Patentee MONTARI INDUSTRIES LIMITED
Applicant Address 78 NEHRU PLACE, NEW DELHI-110 019, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 INDER KUMAR PANDEY MONTARI INDUSTRIES LIMITED, 78 NEHRU PLACE, NEW DELHI-110 019, INDIA.
2 DHANANJAY SHRIVASTAVA MONTARI INDUSTRIES LIMITED, 78 NEHRU PLACE, NEW DELHI-110 019, INDIA
3 JANAKIRAM RAJARAM MONTARI INDUSTRIES LIMITED, 78 NEHRU PLACE, NEW DELHI-110 019, INDIA
4 SUNDARESAN MADHUSOODANAN MONTARI INDUSTRIES LIMITED, 78 NEHRU PLACE, NEW DELHI-110 019, INDIA
PCT International Classification Number A61K 31/075
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA