FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
IMPROVED PROCESS FOR THE PREPARATION OF SARTANS
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT,
1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI - 400 102,
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

IMPROVED PROCESS FOR THE PREPARATION OF SARTANS
TECHNICAL FIELD OF THE INVENTION:

Where R is suitable organic substituent, preferably the following groups
The present invention relates to the process for the preparation of sartans such as candesartan cilexetil, olmesartan medoxomil, losartan, valsartan and irbesartan. The present invention provides an improved, novel and simple detritylation process for trityl sartans (I-V).


BACKGROUND OF THE INVENTION:
Sartans are angiotensin II receptor antagonist, useful in the treatment of hypertension and related disease. Sartans (VI-X) can be prepared from the detritylation of trityl sartans (I-
V).
The process for the synthesis of trityl Candesartan cilexetil (I) is disclosed in US5196444 (Takechiko Naka et al, 1991). Under '444 patent, the key chemical reaction in the synthetic process disclosed is de-tritylation or de- protection of l-[[( cyclohexyloxy)carbony] oxy ] ethyl-2-ethoxy-l-[[2'-(N-triphenylmethyltetrazol-5-yl)-l-r-biphenyl-4-yl] methyl]-l-H-benzimidazole-7-carboxylate (trityl candesartan cilexetil), which is done in methanol by using 1 N HC1. The main disadvantage of this process is that the purification of the final product requires column chromatography on silica gel to obtain colorless powder of candesartan cilexetil which limits the scale up.
US5763619 (Yasushi Shida et al, 1995) disclosed a detritylation process using hydrogen chloride in methanol solvent at a low temperature to give the desired product. The disadvantage of this process is that the methyl ether of triphenyl methanol, substantial amount of alcohol and acid impurity are getting formed as a by products under this reaction conditions. The other disadvantage of this process is use of corrosive hydrochloric acid gas for the preparation of Candesartan cilexetil.
WO2007074399 (Soldevilla, Madrid, Nuria; 2005) covered a process to obtain candesartan cilexetil from trityl candesartan cilexetil using Lewis acids like AICI3, TiCU, ZnBr2 and ZnCi2 in presence of an inert solvent and alcohol. Lewis acids are used in excess and are expensive which negates its use in commercial scale.

WO2007094015 (Gorantla Seeta Ramajaneyulu et al, 2006) disclosed the process of detritylation of trityl Candesartan cilexetil by using phosphoric acid or boric acid in ethanol. The acids used in the said process are costly and higher temperature is required for the reaction, which leads to the formation of impurities.
WO2009157001 (Parthasaradhi Reddy, Bandi et al, 2008) disclosed the process for detritylation of trityl Candesartan cilexetil by hydrogenating the trityl candesartan cilexetil with hydrogen in presence of Palladium catalyst. For the purpose of hydrogenation, special pressure reactor is required which limits its use in commercial scale.
US 5616599 (Hiroaki Yanagisawa et al, 1993) disclosed the method of formation of olmesartan medoxomil (VII) from trityl olmesartan medoxomil (II) using aqueous acetic acid. The yield of the reaction in this process is very low due to formation of olmesartan acid impurity, which limits its use in commercial scale.
WO2007148344 (Ramajaneyulu Gorantla Seeta et al, 2006) disclosed the detritylation method of trityl olmesartan medoxomil (II) using hydrochloric acid in toluene to obtain olmesartan medoxomil (VII). The main disadvantage of this process is the formation of acid impurity due to pH adjustment in the extraction procedure, which will reduce the overall yield and quality of final olmesartan medoxomil (VII).
WO2011014611 (Kolla, Naveen kumar, et al, 2009) described the detritylation process using aqueous hydrogen chloride. The main disadvantage of this process is the yield is poor yield due to formation of acid impurity which was generated by the pH adjustment during extraction procedure.

WO2007047838 (Sebastian, Sonny, et al, 2005) disclosed the deprotection process using methanolic hydrochloric acid in methylene dichloride and methanol. The disadvantage of this process is the formation of olmesartan acid impurity, which negates its commercial scale production.
US5138069 (David, J. Carini, et al, 1986) disclosed a method for the detritylation of losartan from trityl losartan by using aqueous hydrogen chloride in methanol. The main disadvantage of this process is the formation of ester impurity and also use of corrosive hydrochloric acid for the preparation of losartan which limits its commercial production.
W09517396 (Campbell, Gordon, Creston Jr. et al, 1993) and EP253310 (Carini, David John et al, 1987) disclosed the detritylation of trityl group using the sulfuric acid and hydrochloric acid in methylene chloride respectively. Under '396 sulfuric acid used in the hydrolysis of trityl Losartan (II). The removal of corrosive acids used in this process involves harsh conditions and lengthy azeotropic distillation which is a limiting factor during scale up process.
WO2008004110 (Budidet, Sankar Reddy, et al, 2006) disclosed the deprotection of trityl Valsartan (IV) to obtain Valsartan (IX) in the presence of acid reagent selected from isopropanol hydrogen chloride, methanol hydrogen chloride, ethanol hydrogen chloride and concentrated hydrogen chloride acid. The disadvantage of this process is the use of the corrosive hydrochloric acid gas and halogenated solvent.
WO2004094392 (Zvi Hard, et al, 2004) disclosed the deprotection of trityl Valsartan (IV) to get Valsartan (IX) using aqueous sulphuric acid. The removal of mineral acids in this process involves tedious conditions such as pH adjustment by

adding sodium hydroxide, which will produce decarboxylation impurities that will ultimately reduce the yield.

WO2008027385 (Kansal, Vinod Kumar, 2006), US7227026 (Gennady Nisnevich, 2004) disclosed the detritylation of trityl Irbesartan (V) to obtain Irbesartan (X) in presence of aqueous hydrogen chloride. The disadvantages of the process in these patents are the use of corrosive hydrochloric acid during synthesis. The removal of this acid involve harsh reaction conditions such as pH adjustment by adding potassium hydroxide, which might open the bicyclic spiro ring and can generate impurity.
WO2005021535 (Radl, Stanislav, 2003) disclosed the detritylation reaction of sartans such as Losartan, Irbesartan, Valsartan and Candesartan cilexetil using anhydrous methanol under refluxing conditions. The disadvantages of the detritylation reaction in these patents are impurities such as methyl ether of triphenyl methanol and substantial amount of alcohol impurity formed as side products.


Most of the above existing detritylation processes of trityl sartans (I-V) to obtain sartans (VI-X) has many disadvantages. In view of this, there exists a need to develop an efficient, cost effective, simple, environmental friendly, high yielding detritylation process which requires minimum capital investment.
OBJECT OF THE INVENTION
The object of the present invention is to provide an efficient process for detritylation of trityl sartans (I-V) to obtain sartans (VI-X) with high yields and purity of corresponding products.
Another object of the present invention is to provide a simple process for producing sartans.
Another object of the present invention is to provide an efficient and ecofriendly process for the synthesis of sartans.
Yet another object of the present invention is to provide an industrially scalable process for the preparation of sartans which is free from impurity.

SUMMARY OF INVENTION

Wherein -R is
Present invention provides an improved process for the preparation of sartans (VI-X) which comprises de-tritylation of trityl sartans (I-V) in a chlorinated solvent or alcoholic solvent or mixture thereof, with or without catalytic amount of water and in presence of chlorinated protecting group like trimethylsilyl chloride (TMSC1) at suitable temperature


Further, Candesartan cilexetil (VI), prepared as per present invention comprises reacting
trityl candesartan cilexetil (I) with trimethyl silyl chloride (TMSC1) in a chlorinated
solvent or an alcoholic solvent or mixture thereof with or without catalytic amount of
water at -5 °C to 5°C.
Also, Olmesartan medoxomil (VII) preparation comprises reacting reacting trity
olimesartan medoxomil (II) with trimethyl silyl chloride (TMSC1) in a chlorinated
solvent or an alcoholic solvent or mixture thereof with or without catalytic amount of
waterat-5°C to5°C.
Further more, the formation of unwanted impurity can be minimized as per present
invention; more particularly in the case of olmesartan medoxomil, wherein the formation
of acid impurity is less than 0.1 % which is advantageous over other existing processes.
DETAILED DESCRIPTION

Wherein -R is
The present invention relates to an efficient, improved and simple process for the preparation of sartans (VI-X) from trityl sartans (I-V).


The present invention relates to an improved and economical process for the synthesis of candesartan cilexetil (VI), olmesartan medoxomil (VII), losartan (VIII), valsartan (IX) and irbesartan (X) more particularly candesartan cilexetil (VI), olmesartan medoxomil (VII)

Further, the present invention avoids stringent and harsh reaction conditions and provides simple extraction and purification and easy to scale-up process.

The present invention provides very high quality candesartan cilexetil (VI), olmesartan medoxomil (VII), losartan (VIII), valsartan (IX) and irbesartan (X) by selective de-tritylation or removal of protecting groups of trityl sartans (I-V).
The present invention relates to a de-tritylation of trityl sartans (I-V) to obtain candesartan cilexetil (VI), olmesartan medoxomil (VII), losartan (VIII), valsartan (IX) and irbesartan (X) more particularly candesartan cilexetil (VI), olmesartan medoxomil (VII) using chlorinated protecting group like trimethylsilyl chloride (TMSC1) or acetyl chloride or thionyl chloride, preferably trimethylsilyl chloride (TMSC1) in a chlorinated solvent or alcoholic solvent or mixture thereof, with or without catalytic amount of water at suitable temperature. The chlorinated solvents includes methylene dichloride (MDC), Ethylene chloride (EDC) or chloroform preferably methylene dichloride, and an alcoholic solvent includes methanol, ethanol, n-propanol, iso propanol, n-butanol, isobutanol, tert. Butanol preferably methanol. The temperature of the reaction medium is from -10 °C to 50 °C, preferably-5 °C to 30 °C, more preferably-5 °C to 5 °C.
The starting materials, which are trityl sartans may be prepared according to known literature reported under US5196444, EP0459136A1, EP503785, US5616599, EP253310, US 5138069, EP443983, US5399578 , W09114679, US5270317.
To accelerate the reaction, trityl sartans (I-V) (1 molar equivalent) are taken in a mixture of 1.0 volume to 20.0 volume, preferably 5.0 to 10.0 volume of methylene dichloride (MDC) and 1.0 volume to 20.0 volume, preferably 1.0 to 5.0 volume of methanol. The reaction mixture is then stirred to room temperature. The reaction mixture is cooled to -5 to 0°C. 1.0 to 10.0 molar equivalents, preferably 3.0 to 5.0 molar equivalents of

trimethylsilyl chloride (TMSC1), in methylene dichloride (MDC) (1 volume) is added in the reaction mixture at -5 to 0 °C and stirred at that temperature.
The reaction mass can be quenched in water and the organic layer is separated and extracted from the aqueous layer. When water and methanol is used in the reaction medium, triphenyl methanol, methyl ether of triphenyl methanol formation takes place as a by-product and the final product is obtained by distilling the organic layer under reduced pressure. The final product thus obtained can be crystallized from suitable solvents like methanol, ethanol, n-propanol, isopropanol, ethyl acetate, acetone, methylene dichloride, hexanes or mixture thereof.
Using this process, formation of any unwanted impurity can be minimized; more particularly in case of olmesartan medoxomil, wherein the formation of olmisartan acid impurity is less than 0.1 % which is advantage over other existing processes. Candesartan cilexetil is highly sensitive to strong acids due to the presence of bulky cilexetil ester group and ether moiety. Under harsh de-tritylation reaction conditions, the ester group can easily be hydrolyzed to acid and the ether linkage to alcohol and hence possibility of forming impurities cannot be avoided. Removal of this kind of impurity involves tedious purification process which will reduces the yield of end product.

Candesartan cilexetil (VI), can be prepared according to the present invention by reacting trityl candesartan cilexetil (I) with trimethyl silyl chloride (TMSC1) in a chlorinated

solvent or an alcoholic solvent or mixture thereof with or without catalytic amount of water at -5°C to 5°C by which formation of any unwanted impurity can be minimized
Similarly Olmesartan medoxomil (VII) is very sensitive to strong acids due to the presence of bulky medoxomil ester group. Under harsh detritylation reaction conditions, the ester group can easily be hydrolyzed to acid and there is also a possibility that other impurities like trans esterification of olmesartan medoxomil might takes place. As a result of the formation of several impurities, the overall yield of the formation of olmesartan medoxomil (II) is very less.

Olmesartan medoxomil (VII) can be prepared according to the present invention by reacting trityl olimesartan medoxomil (II) with trimethyl silyl chloride (TMSC1) in a chlorinated solvent or an alcoholic solvent or mixture thereof with or without catalytic amount of water at -5 °C to 5°C by which formation of any unwanted impurity can be minimized

The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in any way.
EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
Example-1: Preparation of sartans (VI-X) from trityl sartans (I-V)
To a three neck round bottomed flask, equipped with thermometer and overhead stirrer, was charged methylene dichloride (MDC) (10 volume) at room temperature. Trityl sartans (I-V) (1 molar equivalent) was added to the MDC and then stirred for 5-10 min at room temperature. Charged methanol (2 volumes) to the reaction mixture and stirred for 5 min. The reaction mixture was then cooled to -5 to 0 °C. Trimethylsilyl chloride (TMSC1) (3.5 equivalent) in methylene dichloride (1 volume) was added in the reaction mixture at -5 to 0 °C. The stirring was continued at -5 to 0 °C for 30 minutes. The progress of the reaction was monitored by HPLC or TLC. Charged water (0.2 volume) into the reaction mixture and stirred for 3-6 hrs as monitored by HPLC or TLC. After the completion of the reaction, water was added to the reaction mixture and stirred for 30 minutes and then separated the layers. The aqueous layer was re-extracted with methylene dichloride (MDC) (2 volume). Both the organic layers were combined, washed with water (20 volume) and brine solution (5 volume) and distilled out the organic layer under reduced pressure to get thick oil. 1 volume of ethyl acetate was

charged and distilled off under vacuum to remove traces of methylene dichloride (MDC). Charged 1 volume of ethyl acetate and stirred for 30 min at 50 °C and cooled to RT. Charged 10 volume of hexanes, heated to 50 °C and maintained for 30 min. The mixture was then cooled to RT and stirred for 3 hours at 25-30 °C. The reaction mass was filtered and washed with 2 volumes of hexanes. The product was unloaded and dried in air oven at 55-60 °C for 2 hrs till constant weight to give sartans (85-90%) with a purity of more than 98.0%. Example-2: Preparation of sartans (VI-X) from trityl sartans (I-V)
To a three neck round bottomed flask, equipped with thermometer and overhead stirrer, was charged methylene dichloride (MDC) (10 volume) at room temperature. Trityl sartans (I-V) (1 molar equivalent) was added to the MDC and then stirred for 5-10 min at RT. Charged methanol (2 volumes) into the reaction mixture and stirred for 5 min. The reaction mixture was then cooled to -5 to 0 °C. Trimethylsilyl chloride (TMSC1) (3.5 equivalent) in methylene dichloride (1 volume) was added in the reaction mixture at -5 to 0 °C. The stirring was continued at -5 to 0 °C for 3-6 hrs. The progress of the reaction was monitored by HPLC or TLC. After the completion of the reaction, water was added to the reaction mixture and stirred for 30 minutes and then the layers were separated. The aqueous layer was re-extracted with methylene dichloride (MDC) (2 volumes). Both the organic layers were combined, washed with water (20 volumes) and brine solution (5 volumes) and distilled out the organic layer under reduced pressure to get thick oil. After that, 1 volume of ethyl acetate was charged and distilled off under vacuum to remove traces of methylene dichloride (MDC). Charged 1 volume of ethyl acetate and stirred for 30 min at 50 °C and cooled to RT and then charged 10 volumes of hexanes and again

heated to 50 °C and maintained for 30 min. The mixture was then cooled to RT and stirred for 3 hours at 25-30 °C. The reaction mass was filtered and washed with 2 volumes of hexanes. The product was unloaded and dried in air oven at 55-60 °C for 2 hrs till constant weight to give sartans (85-90%) with a purity of more than 98.0%. Example-3: Preparation of olmesartan medoxomil from trityl olmesartan medoxomil
To a three neck round bottomed flask, equipped with thermometer and overhead stirrer, was charged 1000 ml methylene dichloride (MDC) (10 volume) at room temperature. 100 g of Trityl olmesartan medoxomil (1 molar equivalent) was added to MDC and then stirred for 5-10 min at RT. Charged 500 ml methanol (5 volumes) in the reaction mixture and stirred for 5 min. The reaction mixture was then cooled to -5 to 0 °C. 56 ml of Trimethylsilyl chloride (TMSC1) (3.5 equivalent) in 100 ml of methylene dichloride (1 volume) was added to the reaction mixture at -5 to 0 °C. The stirring was continued at -5 to 0 °C for 3-6 hrs. The progress of the reaction was monitored by HPLC or TLC. After the completion of the reaction, 1000 ml brine solution was added to the reaction mixture and stirred for 30 minutes and then the layers were separated. The aqueous layer was re-extracted with 3x200 ml of methylene dichloride. Both the organic layers were combined, washed with 3x1000 ml of water and distilled out the organic layer under reduced pressure to get a thick oil. After that 100 ml of ethyl acetate was charged and distilled off under vacuum to remove traces of methylene dichloride (MDC). Charged 100 ml of ethyl acetate and stirred for 30 min at 50 °C and cooled to RT. Charged 1000 ml of hexanes and again heated to 50° C and maintained for 30 min. The mixture was then cooled to RT and stirred for 3 hours at 25-30 °C. The reaction mass was filtered and washed with 2

volumes of hexanes. The product was unloaded and dried in air oven at 55-60 °C for 2 hrs till constant weight to give Olmesartan medoxomil (85-90%) with a purity of more than 98.0%. Example-4: Preparation of candesartan cilexetil from trityl candesartan Cilexetil
To a three neck round bottomed flask equipped with thermometer and overhead stirrer, was charged 1500 ml methylene dichloride (MDC) (20 volumes) at room temperature. 75 g of Trityl candesartan cilexetil (1 molar equivalent) was added to the MDC and then stirred for 5-10 min at RT. Charged 150 ml of methanol (2 volume) in the reaction mixture and stirred for 5 min. The reaction mixture was then cooled to -5 to 0 °C. 77.8 ml of Trimethylsilyl chloride (TMSC1) (7 equivalent) in 75 ml of methylene dichloride (1 volume) was added to the reaction mixture at -5 to 0 °C. The stirring was continued at -5 to 0 °C for 15-30 min. The progress of the reaction was monitored by HPLC or TLC. After the completion of the reaction, 750 ml of water was added to the reaction mixture and stirred for 30 minutes and then the layers were separated. The aqueous layer was re-extracted with 2x150 ml methylene dichloride. Both the organic layers were combined, washed with 3x1000 ml water and distilled out the organic layer under reduced pressure to get thick oil. 100 ml of ethanol was charged and distilled off under vacuum to remove traces of methylene dichloride (MDC). Again charged 100 ml of ethanol and stirred for 30 min at 60 °C and cooled to RT. Charged 1000 ml of hexanes and again heated to 60 °C and maintained for 30 min. The mixture was then cooled to RT and stirred for 14-15 hours at 25-30 °C. The reaction mass was filtered and washed with 150 ml of hexanes. The product was unloaded and dried in vacuum oven at 35-40 °C for 2 hrs till constant weight to give of Candesartan Cilexetil (85-90%) with a purity of more than 98.0%.

Example-5: Preparation of olmesartan medoxomil from trityl olmcsartan mcdoxomil
To a three neck round bottomed flask, equipped with thermometer and overhead stirrer, was charged 500 ml methanol (5 volume) at room temperature. 100 g of Trityl olmesartan medoxomil (1 molar equivalent) was added to methanol and then stirred for 5-10 min at RT. The reaction mixture was then cooled to -5 to 0 °C. 56 ml of Trimethylsilyl chloride (TMSC1) (3.5 equivalent) was added to the reaction mixture at -5 to 0 °C. The stirring was continued at -5 to 0 °C for 1-5 hrs. The progress of the reaction was monitored by HPLC or TLC. After the completion of the reaction, 1000 ml (10 volume) MDC, followed by 1000 ml brine solution was added to the reaction mixture and stirred for 30 minutes and then the layers were separated. The aqueous layer was re-extracted with 3x200 ml of methylene dichloride. Both the organic layers were combined, washed with 3x1000 ml of water and distilled out the organic layer under reduced pressure to get a thick oil. After that 100 ml of ethyl acetate was charged and distilled off under vacuum to remove traces of methylene dichloride (MDC). Charged 100 ml of ethyl acetate and stirred for 30 min at 50 °C and cooled to RT. Charged 1000 ml of hexanes and again heated to 50° C and maintained for 30 min. The mixture was then cooled to RT and stirred for 3 hours at 25-30 °C. The reaction mass was filtered and washed with 2 volumes of hexanes. The product was unloaded and dried in air oven at 55-60 °C for 2 hrs till constant weight to give Olmesartan medoxomil (85-90%) with a purity of more than 98.0%.

CLAIMS: We claim
1. An improved process for the preparation of sartans (VI-X) which comprises de-tritylation of trityl sartans (I-V) in a chlorinated solvent or alcoholic solvent or mixture thereof, with or without catalytic amount of water and in presence of chlorinated protecting group like trimethylsilyl chloride (TMSC1) at suitable temperature


2. An improved process according to claims 1, wherein the chlorinated solvent comprises of methylene dichloride (MDC), chloroform, 1,2-dichloroethane preferably methylene dichloride (MDC).
3. An improved process according to claims 1, wherein the alcoholic solvent comprises of C1-C5 alcohols like methanol, ethanol, n-propanol, iso propanol, n-butanol, isobutanol, tert. butanol, preferably methanol.
4. An improved process according to claim 1, wherein the chlorinated protecting group is selected from trimethylsilyl chloride (TMSC1) or acetyl chloride or thionyl chloride preferably, trimethylsilyl chloride (TMSC1)
6. An improved process according to claims 1, wherein the temperature of the reaction
medium is from -10 °C to 50 °C, preferably -5 °C to 30 °C, more preferably -5 °C to 5
°C.
7. An improved process according to claims 1, wherein the saltans (VI-X) are
candesartan cilexetil (VI), olmesartan medoxomil (VII), losartan (VIII), valsartan (IX)
and irbesartan (X) preferably, candesartan cilexetil (VI), olmesartan medoxomil (VII)
8. An improved process according to claim 7, wherein the formation of acid impurity is
less than 0.1 % particularly in olmesartan medoxomil (VII).
9. Candesartan cilexetil (VI), prepared as per claim 1 comprises reacting trityl candesartan cilexetil (I) with trimethyl silyl chloride (TMSC1) in a chlorinated solvent or an alcoholic solvent or mixture thereof with or without catalytic amount of water at -5 °C to 5°C.
10. Olmesartan medoxomil (VII) prepared as per claim 1 comprises reacting

reacting trityl olimesartan medoxomil (II) with trimethyl silyl chloride (TMSC1) in a chlorinated solvent or an alcoholic solvent or mixture thereof with or without catalytic amount of water at -5 °C to 5°C.
11. An improved process for the preparation of sartans as herein described in any of the preceding claims