FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
PROCESS FOR CLEAVAGE OF HYDROXY PROTECTING GROUPS OF HYDROXYACID HMG CoA REDUCTASE INHIBITORS
Applicant
Name; Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road,
Near Dinesh Hall,
Ahmadabad 380 009.
Gujarat, India
The following specification particularly describes the invention and the manner in which it is to be performed:

PROCESS FOR CLEAVAGE OF DlHYDROXY PROTECTING GROUPS OF HYDROXYACID HMG CoA REDUCTASE INHIBITORS
FIELD OF THE INVENTION
The present invention relates to process for a cleavage of compound of formula II, useful intermediate in the preparation of statin, particularly rosuvastatin and its salts thereof.
BACKGROUND OF THE INVENTION
Rosuvastatin is chemically known as (3R, 5S, 6E)-7-[4-(4-fluorophenyl)-6-(l- methyl ethyl)-2-[methyl (methylsulfonyl) amino-5-pyrimidinyl]-3, 5-dihydroxy-6- heptenoic acid, is a synthetic lipid-lowering agent, which is an inhibitor of 3- hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.
US RE 37,314 discloses an amorphous form of the calcium salt of rosuvastatin and the sodium salt is obtained therein as powdery crystals. The calcium salt of rosuvastatin is presently available in the market as CRESTOR. Further, this patent describes the preparation of calcium salt of rosuvastatin by dissolving the corresponding sodium salt in water and adding calcium chloride and collecting the resultant precipitate by filtration.
US RE 37,314 discloses the deprototection of one hyrdroxy group using hydrofluoric acid.
US 6784171 discloses the deprototection of acetonide protecting group using HCI in acetonitrile or Tetrahydrofuran.
US 6,875,867 also describes the deprototection of acetonide protecting group using Trifluroacetic acid and HCI in suitable solvent such as isopropyl alcohol, ethyl acetate, Tetrahydrofuran.

SUMMARY OF INVENTION
In one aspect, there is provided a process for a cleavage of compound of formula II, a useful intermediate in the preparation of statin, particularly rosuvastatin and its salts thereof.
In another aspect, there is provided a process of preparation of Statins or salt of statins includes cleavage of the A1 and/or A2 alcohol or 1, 3-diol protecting groups using alkali or alkaline salt of hydrogen sulphate.
In another aspect, there is provided a process of preparation of Statins or salt of statins includes cleavage of the A1 and/or A2 alcohol or 1, 3-diol protecting groups using potassium hydrogen sulphate.
In another aspect, there is provided a process for preparation of compound of formula III includes a cleavage of the A1 and/or A2 alcohol or 1, 3-diol protecting groups from a compound of Formula II using alkali or alkaline salt of hydrogen sulphate.optionally cleavage of R3 carboxylic acid protecting group to form a compound of the Formula III in which R3 is a pharmaceutically acceptable cation or salt ; optionally followed by neutralization to give a compound of the Formula III in which R3 is hydrogen or salt ; and/or optionally followed by conversion to another compound of the Formula III in which R3 is a pharmaceutically acceptable cation.
In another aspect, there is provided a process for preparation of Compound of formula III includes a cleavage of the A1 and/or A2 alcohol or 1, 3-diol protecting groups from a compound of Formula II using alkali or alkaline salt of hydrogen sulphate particularly potassium hydrogen sulphate ;optionally cleavage of R3 carboxylic acid protecting group to form a compound of the Formula III in which R3 is a pharmaceutically acceptable cation or salt or hydrogen ; optionally followed by neutralization to give a compound of the Formula III in which R3 is hydrogen or salt; and/or optionally followed by conversion to another compound of the Formula III in which R3 is a pharmaceutically acceptable cation.


DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, there is provided to process for a cleavage of compound of formula II, a useful intermediate in the preparation of statin, particularly rosuvastatin and its salts thereof.
In another embodiment, there is provided a process of preparation of Statins or salt of statins includes cleavage of the A1 and/or A2 alcohol or 1, 3-diol protecting groups using alkali or alkaline salt of hydrogen sulphate.
In another embodiment, there is provided a process of preparation of Statins or salt of statins includes cleavage of the A1 and/or A2 alcohol or 1, 3-diol protecting groups using potassium hydrogen sulphate.
The statins or salt of statins may include Rosuvastatin, atrovastatin, lovastatin, fluvastatin, pravastatin and the like.

In another embodiment, there is provided a process for preparation of Compound of formula III includes a cleavage of the A1 and A2 alcohol or 1, 3-diol protecting groups from a compound of Formula II using alkali or alkaline salt of hydrogen sulphate, ceric ammonium nitrate and ceric ammonium phosphate ;optiona!ly cleavage of R3 carboxylic acid protecting group to form a compound of the Formula III in which R3 is a pharmaceutically acceptable cation or salt or hydrogen ; optionally followed by neutralization to give a compound of the Formula III in which R3 is hydrogen or salt ; and/or optionally followed by conversion to another compound of the Formula III in which R3 is a pharmaceutically acceptable cation.

In another embodiment, there is provided a process for preparation of Compound of formula III includes a cleavage of the A1 and/or A2 alcohol or 1, 3-diol protecting groups from a compound of Formula II using alkali or alkaline salt of hydrogen sulphate,particularly potassium hydrogen sulphate ; optionally cleavage of R3 carboxylic acid protecting group to form a compound of the Formula III in which R3 is a

pharmaceutically acceptable cation or salt or hydrogen ; optionally followed by neutralization to give a compound of the Formula III in which R3 is hydrogen or salt ; and/or optionally followed by conversion to another compound of the Formula III in which R3 is a pharmaceutically acceptable cation.
The compound of formula II and III in which R3 is a carboxylic acid protecting group, for example (1-8C) alkyl, such as (1-4C) alkyl, and A1 and/or A2 are alcohol protecting groups, or A1 and A2 taken together is a 1, 3-diol protecting group, such as those described in EPA 0319845, REUS 37,314 and GB 2244705 which are included herein by reference. For example, in some preferred embodiments, the 1, 3-diol protecting groups can be

wherein R1 and R2 are independently (1-4C) alkyl or R1 and R2, taken together with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl or cycloheptyl ring.
In another embodiment, compound of formula II in which any one of A1 and A2 is protected as mentioned above, preferably silyl protecting group, this is further reduced to form compound of formula III.
Solvents may be used for dissolving or suspending compound of Formula II or cleavage of the A1 and A2 alcohol or 1, 3-diol protecting groups useful for preparation of statins or salt of statins include, but are not limited to, nitriles such as acetonitrile and propionitrile; alcohols, such as methanol, ethanol, isopropyl alcohol, and n-propanol; ketones, such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate,

n-propyl acetate, n-butyl acetate, and t-butyl acetate; ethers, such as diethyl ether, dimethyl ether, diisopropyl ether, and 1 ,4-dioxane; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, n-hexane; or mixtures thereof or their combinations with water. The preferred solvent is methanol.
Compound of Formula II may prepared from the process known in art, such as US patent No.RE US37,314, US 6784171, WO 2007125542,WO2008044243. Compound of formula II may be isolated or may not be isolated.The starting mass is a solution or a suspension depending on the choice of the solvent. Temperatures which are adopted for preparation of the mixture may range from about 25 °C to about 100 °C, preferably 30 °C (± 5°C).
Alkali or alkaline salt of hydrogen sulphate may include sodium, potassium and the like, preferably potassium hydrogen sulphate.
Cleavage of R3 carboxylic acid protecting group to form a compound of the Formula III in which R3 is a pharmaceutically acceptable cation or salt ; optionally followed by neutralization to give a compound of the Formula 111 in which R3 is hydrogen or salt ; and/or optionally followed by conversion to another compound of the Formula III in which R3 is a pharmaceutically acceptable cation can be prepared by the process known in art, such as US patent No.RE US37.314, US 6784171, WO 2007125542,WO2008044243,1795/MUM/2010and 1796/MUM/2010.
The present invention is avoiding the use of HCI, HF etc., which yields high anti-isomer whereas the use of KHS04 results in low anti-isomer and generation of hazardous waste in reaction. The present invention also provides a mild, an efficient and cost-effective process for the deprotection of silyl group as well as actonide protecting group.
Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.

Example 1
PREPARATION OF METHYL 7-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-{N-METHYL-N-METHYLSULFONYLAMINO) PYRIMIDIN-5-YL]-(3R)-3-HYDROXY-5-OXO-(E)-6-HEPTENATE (KETO ESTER)
To a 2000ml_ 4 neck flask was equipped with thermo pocket, stopper, moisture guard, (3R,6E)-3[(1,1-dimethylethyf)dimethylsilyl-oxy]-7-[4-(4-fluorophenyl-6-(1-methyl ethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-5-oxo-6-heptanoic acid methyl ester (54g) and methanol (1350m() were charged. RO water (270ml) was charged. Potassium hydrogen sulphate (14.51g) was added. Reaction mass was maintained at 30°C for 24Hrs. and pH 7 to 7.5 was adjusted using Sodium bicarbonate solution. Methanol was distilled out completely under reduced pressure and sticky residue remained at 40-45°C. Toluene (150ml) was charged to reaction mass. Reaction mass was stirred for 15-10min. Layers were separated, Org layer was kept aside. Aqueous layer was again extracted with toluene (50ml). Organic layer was combined and dried over Na2SO4 (10g). Filtered through cotton and washed with toluene (10ml). Filtrate ML was distilled out completely under reduced pressure to give oil. Weight of Oil=46g.
Example 2
PREPARATION OF 1-(DIPHENYLMETHYL) PIPERAZINE SALT OF ROSUVASTATIN
Tert.Butyl-6-[(1E)-2-[4-(4-fluorophenyl-6-(1-methylethyl)-2-[methyl(methylsulfonyl) amino] -5-pyrimidinyl] ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate was taken into 750ml of methanol. 9.16g of potassium hydrogen sulphate was dissolved in 30ml of RO Water at 30 °C and charged to reaction mass. Reaction mass was stirred for 8-10Hrs. 7.52g of Sodium hydroxide was dissolved in 25ml of RO water and was charged to reaction mass. Reaction mass was stirred for 4-8Hrs. Methanol was distilled out completely up to oily aqueous residue. 250ml of RO water was added to the residue. Aq. Layer was extracted with 3X150ml of ethyl acetate. Separated aqueous Layer was cooled to 10-15°C. 250ml of ethyl acetate was charged to reaction mass and pH 3.5 to 4.0 was adjusted using 15 %( v/v) HCI solution at 10-15°C. Reaction mass was stirred for 10-15min. Layers were separated. Aqueous layer was again extracted with 150 ml of ethyl acetate. Ethyl acetate layer were combined and dried over Sodium Sulphate 25g.

Filtered through cotton and washed with 10ml of ethyl acetate. Filtrate ethyl acetate was charged in 1.0 lit RBF. 11.86g of benzhydril piperazine was added. Reaction mass was stirred for 8-12 hrs at 25-30°C. Solid was filtered and washed with 2X10 ml of ethyl acetate. Solid was dried in VTD at 30-35°C for 6-8 hr. Weight of dry solid=6.5g
Example 3
PREPARATION OF TERTIARY BUTYL ROSUVASTATIN ESTER
To a 500 ml 4 neck flask was equipped with thermo pocket, stopper, moisture guard, ice bath etc., keto ester (As per example 1) 10g and 350 ml of tetrahydrofuran and 90ml of methanol were charged. Reaction mass was cooled to -78°C,18.7ml 1M diethyl methoxy borane was added at -78°C. Reaction mass was stirred for 30 min.at -78°C.1.07g of sodium borohydride was charged slowly at -78°C.Reaction mass was stirred for 3hrs at-78°C16 ml of acetic acid was added slowly. Temperature was raised to 5-10°C and pH 8 was adjusted using Sat. bicarbonate solution. Temperature was allowed to 25-30°C300 ml of ether was charged & stirred for 5-10min.Layers were separated, org layer kept a side. Aq.layer was again extracted with ether (50ml).Organic layer was combined and washed with 2X100ml of RO water.Seperated organic layer was distilled out completely to give the title product as syrup.
Example 4
PREPARATION OF 1-{DIPHENYLMETHYL) PIPERAZINE SALT OF ROSUVASTATIN
To a 250ml_ 4 neck flask was equipped with thermopocket, stopper, moisture guard, water bath etc., 5 gm tertiary butyl rosuvastatin ester and methanol were charged. 56 ml of 0.5N sodium hydroxide solution was charged. Reaction mass was heated up to 40-45°C. Reaction mass was stirred for 30min.at 40-45cC. Methanol was distilled out completely up to aqueous layer was remained. 5-5.5 pH was adjusted using 7.5%w/w HCI solution. 50 ml of ethyl acetate was added. Reaction mass was stirred for 5-10 minute. Layers were separated; organic Layer was kept a side. Aqueous Layer was again extracted with 50ml of ethyl acetate. Layers were separated. Organic Layer was kept a side, aqueous layer was discarded. Organic layers were combined and taken into 250 ml RBF 50 ml of ethyl acetate followed by 2.69 gm. of 1-(diphenyl methyl) piperazine was added.Reaction mass was heated to 45-50°C.Reaction mass was stirred

for 30 minute at 45-50°C.Reaction mass was allowed to come to 25-30°C.Reaction mass was cooled to 0-5°C.Reaction mass was stirred for 1 hours at 0-5°C.Solid was filtered and washed with 2X10 ml of chilled ethyl acetate. Solid was dried in air tray dryer at 40-45°C for 12-16 hours. Purity:99.7%
Example 5
PREPARATION OF ROSUVASTATIN CALCIUM FROM t-(DIPHENYLMETHYL) PIPERAZINE SALT OF ROSUVASTATIN
To a 250mL 4 neck flask was equipped with thermopocket, stopper, moisture guard, water bath etc., 1-(dlprieny(metriyl) piperazine salt of Rosuvastatin 3gm, RO Water 50ml and 50ml of Ethyl acetate were charged.Reaction mass was cooled to 0-5 X.Acetic acid (1.71g) was added drop wise at 0-5°C.Temperature was raised up to 15cC.Reaction mass was stirred for 60min.at 15 °C. Layers were separated; Organic Layer was kept a side. Aqueous layer was again extracted with 50ml of ethyl acetate. Layers were separated. Aqueous Layer was discarded. Organic layers were combined and ethyl acetate was distilled up to thick oil.50ml 1N NaOH solution was added to the residue.30 ml ethyl acetate +30 ml of toluene were charged to reaction mass. Reaction mass was stirred for 30 minute. Layers were separated; Organic Layer was discarded. Aqueous Layer was again washed with 60ml of ethyl acetate + toluene (1:1) mixture. Layers were separated; Organic Layer was discarded. Aqueous layer was degassed under reduced pressure to remove traces of organic volatile in aqueous Layer.0.720g calcium acetate was dissolved in 5 ml of RO Water and added drop wise to the above aqueous Layer. Reaction mass was stirred for 2 hour. Solid was filtered and washed with 2X10ml of RO Water. Solid was dried in air tray dryer at 45-50°C for 12-16 hours. Purity: 99.85 by HPLC. Content of antiisomer (3R, 5R):0.05% Content of Enantiomer (3S,5R):not detected.

We claim:
1. A process for preparation of statins or salt of statins includes the cleavage of the A1 and/or A2 alcohol or 1, 3-diol protecting groups using alkali or alkaline salt of hydrogen sulphate.
2. A process of preparation of statins or salt of statins includes cleavage of the A1 and/or A2 alcohol or 1, 3-diol protecting groups using potassium hydrogen sulphate.
3. The process according to claim 1 or 2, wherein statin includes rosuvastatin,
atorvastatin, lovastatin, fluvastatin, pravastatin and the like.
4. The process according to claim 3, wherein statin includes rosuvastatin.
5. A process for preparation of Compound of formula III includes a cleavage of the A1 and/or A2 alcohol or 1, 3-diol protecting groups from a compound of Formula II using alkali or alkaline salt of hydrogen sulphate, ceric ammonium nitrate and eerie ammonium phosphate ;optionally cleavage of R3 carboxylic acid protecting group to form a compound of the Formula III in which R3 is a pharmaceutically acceptable cation or salt or hydrogen ; optionally followed by neutralization to give a compound of the Formula III in which R3 is hydrogen or salt ; and/or optionally followed by conversion to another compound of the Formula III in which R3 is a pharmaceutically acceptable cation.
6. A process for preparation of Compound of formula III includes a cleavage of the A1 and/or A2 alcohol or 1, 3-diol protecting groups from a compound of Formula II using alkali or alkaline salt of hydrogen sulphate.particularly potassium hydrogen sulphate ; optionally cleavage of R3 carboxylic acid protecting group to form a compound of the Formula III in which R3 is a pharmaceutically acceptable cation or salt or hydrogen ; optionally followed by neutralization to give a compound of the Formula IIl in which R3 is hydrogen or salt; and/or optionally followed by conversion to another compound of the Formula III in which R3 is a pharmaceutically acceptable cation.
7. The process according to claim 1, 2, 5 or 6, wherein alkali or alkaline salt of hydrogen sulphate include sodium, potassium and the like, preferably potassium hydrogen sulphate.

8. The process according to claim 1, 2, 5 or 6, wherein protecting group A1 and/or A2 are alcohol protecting group, preferably silyl protecting group, more preferably (1,1-dimethylethyl) dimethylsilyl.
9. The process according to claim 1, 2, 5 or 6, wherein R3 is a carboxylic acid protecting group such C1-8 alkyl, preferably C1-4 alkyl and 1,3-diolol protecting groups are independently (1-4C) alkyl or taken together with the carbon atom to which they are attached, form a cycfopentyl, cyclohexyl or cydoheptyl ring.
10. The process according to claim 1, 2, 3 or 6, wherein solvents used for dissolving or
suspending compound of formula II or cleevage of the A1 and/or A2 alcohol or 1, 3-diol
protecting groups are nitriles such as acetonitrile and propionitrile; alcohols, such as
methanol, ethanol, isopropyl alcohol, and n-propanol, preferably methanol; ketones,
such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl
acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; ethers, such as diethyl
ether, dimethyl ether, diisopropyl ether, anq 1 ,4-dloxane; hydrocarbons such as toluene,
xylene, n-heptane, cyclohexane, n-hexane; or mixtures thereof or their combinations
with water.