FORM-2
THE PATENTS ACT, 1970
COMPLETE SPECIFICATION
SECTION 10
TITLE : AN IMPROVED PROCESS FOR MANUFACTURE OF
LOSARTAN POTASSIUM
APPLICANTS : IPCA LABORATORIES LIMITED.,
48, KANDIVLI INDUSTRIAL ESTATE, MUMBAI - 400 067, MAHARASHTRA, INDIA, AN INDIAN COMPANY.
The following Specification particularly describes the nature of this invention and the manner
in which it is to be performed :-

ORIGINAL
335/MUM/2003
3-4-2003

GRANTED
30-4-2004

AN IMPROVED PROCESS FOR MANUFACTURE OF LOSARTAN POTASSIUM
Technical Field:
[0001] The invention is related to an improved process for the synthesis of
Losartan Potassium, an angiotensin II receptor antagonist.
Background and Prior Art:
[0002] Among cardiovascular drugs, Angiotensin II receptor antagonists like
losartan potassium are prominently used as an active ingredient in the management of hypertension. Losartan potassium plays an effective role in patients having difficulty in tolerating ACE (Angiotensin Converting Enzyme) inhibitors. The chemical name of losartan potassium is 2-n-Butyl-4-Chloro-l[((2'-tetrazol-5-yl)-l,l'-bisphenyl-4-yl)methyl]-imidazole-5-methanol potassium. This product of formula (I) is synthesized from its acidic counterpart of formula (II) by reacting with KOH as per the prior art. The product of formula II is synthesized by detritylation of the corresponding tritylated derivative of the formula (III), namely 2-n-butyl-4-chloro-5-hydroxymethyl-l-[((2'-triphenylmethyltetrazole-5-yl) biphenyl-4-yl)methyl] imidazole.

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[0003] US Patent 5608075 discloses two polymorphic forms of Losartan
Potassium, which are form I and form II. Their method of preparation and characterization by X-ray powder diffraction pattern, DSC thermograms, FT-IR spectra, Raman spectra and C13 NMR (solid state) spectra is also given. The disclosed procedure for polymorphic form I is the addition of aqueous solution of (I) to a refluxing mixture of cyclohexane and isopropyl alcohol followed by azeotropic distilling out cyclohexane / isopropyl alcohol / water ternary azeotrope at 64° C while the form I crystallizes out at 69° C.
[0004] Patent application number W09818787 describes a method which also
starts with a solution of Losartan Potassium (I) in aqueous isopropyl alcohol and is heated to distill out water-isopropyl alcohol mixture to lower the water content upto 2.6%. Further excessive seeding is carried out with slurry of I in cyclohexane till the seed remains undissolved. The precipitation of the product is then achieved by continuous distillation of ternary azeotrope with simultaneous addition of cyclohexane to the reaction mass. This azeotrope distillation is carried out till moisture level comes in a range from 0.2 to 0.11 %. The crystallized product thus obtained is filtered.
[0005] The preparation of free Losartan (II) from (III) carried out by acid
catalyzed cleavage of trityl group of III is disclosed in US 5281603. Another method disclosed in US 5281604 in which III is refluxed in a mixture of methanol and tetrahydrofuran for 18 hours to get (II).
[0006] The synthesis of III is very well described in the literature (J Med. Chem.
1991, 34, 2525-27; J. Org. Chem. 1994, 59, 6391-94 and US 5138069). Losartan free acid and Trityl Losartan may be prepared using the reactions and techniques described in US Patent 5138069 and patent application number WO 9310106. In patent application number WO 0181336, Richter Gedeon describes treatment of Trityl Losartan (III) with potassium hydroxide in primary alcohols and crystallization of the product (I) from methanol with the help of anti-solvents such as dipolar aprotic solvent
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(acetonitrile), aprotic solvent (straight or branched chain or cyclic aliphatic hydrocarbons) or a protic solvent (sec-butanol).
[0007] The Richter Gedeon approach was found to be easy and superior to the
existing methods, however was found to suffer from various drawbacks as summarized below:
The product obtained does not pass desired solubilities in various solvents. To make the product improve in quality, it needs an extra purification as per the Richter Gedeon application.
[0008] Purification step in the process, the resultant purity and the yields thereof,
depend on very precise ratios of solvent mixture (e.g. methanol, cyclohexane or acetonitrile)
High volume of solvents in combination is used in purification which leads to capacity reduction of plant production / facilities.
[0009] Recovery and recyclability of the solvents (methanol and anti-solvents)
from its mixture is difficult and needs careful purification by distillation to get recyclable solvents. Production of waste is more with no economic value and high pollution load in the non-recovery option.
[0010] Patent application number WO 02094816, discloses use of acetone, ethyl
acetate, acetonitrile and toluene as anti-solvents and has similar problems of recovery and reuse of solvents and high cost of production. Since isolation of the product is simply by precipitation using anti-solvents, the product needs further purification to pass the required tests, in this case also.
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Summary of Invention:
[0011] The invention is related to a process for the synthesis of Losartan
Potassium of formula (I), which comprises detritylation of Trityl Losartan of formula (III) in primary alcohol, ROH (wherein alkyl group is C1 to C4 chain) with potassium t-butoxide as a reagent without isolating the corresponding free acid of formula II. The product is finally isolated by crystallization from single solvent such as Isopropyl alcohol or tetrahydrofuran or optionally a combination of both in suitable ratio.
Detailed Description:
[0012] The invention deals with the single pot synthesis of Losartan Potassium (I)
of very high purity starting from Trityl Losartan (III) requiring no extra purification of (I) using a single solvent such as isopropyl alcohol or tetrahydrofuran, which leads to reduction of the solvent usage and losses. The use of single solvents (isopropyl alcohol or tetrahydrofuran) also makes them easily recoverable and reusable in the process, reducing the cost of production significantly.
[0013] In an optional embodiment a combination of isopropyl alcohol and
tetrahydrofuran in suitable proportions have also been used, giving high yields and purity. However, in this case the solvent mixture require fractional distillation after recovery.
[0014] The present process involves refluxing a mixture of (III) and equimolar
amount of potassium t-butoxide (KOBut) in primary alcohol ranging from 3-6 volumes with respect to III for 3-10 hours, preferably for 4-8 hours with continuous monitoring the process by TLC for the completion. After the complete detritylation, the reaction mixture is cooled down to 0 to -10° C as it is or after removal of 50 % primary alcohol, and is filtered to remove the by-product namely trityl methyl ether. The filtered reaction mass is concentrated to remove primary alcohol. It is preferable to remove primary alcohol before crystallizing the product from isopropyl alcohol or tetrahydrofuran but the complete removal upto last traces is not essential as far as quality of the product is concerned.
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[0015] The advantage of the modified process disclosed herein over prior art is
that though visibly the product contains almost similar profile but gives a product of high quality meeting all the requirements without applying extra purification step. The other major advantage of the use of single solvent (isopropyl alcohol or tetrahydrofuran) from 1.0-6.0 volumes as against larger volumes of a mixture of solvents (as in prior art) and recovery and reusability of the same making process cost effective, eco-friendly as well as plant friendly.
[0016] The following examples of the present invention are illustrated:
EXAMPLES:
Example 1:
Under nitrogen atmosphere, in a 500 ml flask solution of potassium tertiary butoxide (8.44 gm, 0.075 mole) in methanol (275 ml) is prepared. To this solution, 50.0 gm of trityl losartan (0.075 mole) is added and refluxed for 8 hours. The completion of reaction is monitored on TLC. The reaction mass is concentrated to 50% and cooled to -5±2° C. The by-product is removed by filtration. After charcoalisation, the filtrate is filtered through celite. Methanol is distilled out completely and stripped out solvent using isopropyl alcohol (25 ml each) twice. Isopropyl alcohol (75 ml) is charged and kept for 12 hour at 25-30° C. The reaction mass is cooled to 0-5° C and filtered the product Losartan Potassium which is washed with chilled isopropyl alcohol (15 ml). The final product is dried at 45-50° C under vacuum for 6 hours. The percentage yield of the product (I) is 81.63%.
Example 2:
Under nitrogen atmosphere, in a 500 ml flask solution of potassium tertiary butoxide (8.44 gm, 0.075 mole) in methanol (275 ml) is prepared. To this solution, 50.0 gm of trityl losartan (0.075 mole) is added and refluxed for 8 hours. The completion of reaction is monitored on TLC, The reaction mass is concentrated to 50% and cooled to -5±2° C.
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The by-product is removed by filtration. After charcoalisation, the filtrate is filtered through celite. Methanol is distilled out till sticky mass obtained. Jsopropyl alcohol (75 ml) is charged and cooled to 30° C. This reaction mass is kept for 12 hour and then it is cooled to 0-5° C. The product Losartan Potassium is separated out which is filtered and washed with chilled isopropyl alcohol (15 ml). The final product is dried at 45-50° C under vacuum for 6 hours. The percentage yield of the product (I) is 78%.
Example 3:
Under nitrogen atmosphere, in a 500 ml flask solution of potassium tertiary butoxide (8.44 gm, 0.075 mole) in methanol (275 ml) is prepared. To this solution, 50.0 gm trityl losartan (0.075 mole) is added and refluxed for 8 hours. The completion of reaction is monitored on TLC. The reaction mass is concentrated to 50% and cooled to -5±2° C. The by-product is removed by filtration. After charcoalisation, the filtrate is filtered through celite. Methanol is distilled out. Terahydrofuran (200ml) is charged and refluxed for 1.0 hour. The reaction mass is cooled to 30° C and stirred for 5 hours. The reaction mass is cooled to 0-5° C and filtered the product Losartan Potassium which is washed with chilled tetrahydrofuran (15 ml). The final product is dried at 45-50° C under vacuum for 6 hours. The percentage yield of the product (I) is 90.62%.
Example 4:
Under nitrogen atmosphere, in a 500 ml flask solution of potassium tertiary butoxide (8.44 gm, 0.075 mole) in methanol (275 ml) is prepared. To this solution, 50.0 gm trityl losartan (0.075 mole) is added and refluxed for 8 hours. The completion of reaction is monitored on TLC. The reaction mass is cooled to -5±2° C and by-product obtained is filtered. After charcoalisation, the filtrate is filtered through celite. Methanol is distilled out completely and stripped out solvent using 25 ml of isopropyl alcohol. Isopropyl alcohol (75 ml) is charged and kept for 12 hour. The reaction mass is cooled to 0-5° C and filtered the product Losartan Potassium which is washed with chilled isopropyl alcohol (15 ml). The final product is dried at 45-50° C under vacuum for 6 hours. The percentage yield of the product (I) is 79.95%.
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Example 5:
Under nitrogen atmosphere, in a 500 ml flask solution of potassium tertiary butoxide (8.44 gm, 0.075 mole) in methanol (275 ml) is prepared. To this solution, 50.0 gm trityl losartan (0.075 mole) is added and refluxed for 8 hours. The completion of reaction is monitored on TLC. The reaction mass is concentrated to 50 % and cooled to -5±2° C. The by-product is removed by filtration. After charcoalisation, the filtrate is filtered through celite. Methanol is distilled out Tetrahydrofuran (120ml) is charged and stirred at 50-55° C for 15 minutes. The reaction mass is cooled to 30° C and stirred for 5 hours. The reaction mass is cooled to 0-5° C and filtered the product losartan potassium which is washed with chilled tetrahydrofuran (15ml). The final product is dried at 45-50° C under vaccum for 6 hours. The percentage yield of the product (I) is 90.04%.
While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its scope, as defined by appended claims.
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We claim:
1) An improved process for manufacture of losartan potassium of formula (I), starting from trityl Losartan of formula (III) characterized in that the said comprises mixing equimolar amounts of trityl losartan (III) and a potassium tertiary alkoxide in a primary alcohol to create a reaction mixture; reacting and concentrating the reaction mass leading to complete or partial recovery of primary alcohol; and isolating the said pure losartan potassium (I) by crystallization from a single solvent other than primary alcohol.
2) A process as claimed in claim 1 (a) wherein the potassium tertiary alkoxide used is potassium t-butoxide.
3) A process as claimed in claim 1 wherein the primary alcohol (R-OH) used in the process in step 1 (a) and recovered in step 1 (b) have alkyl group containing C1 to C4 carbon chain.
4) A process as claimed in claims 1 to 3 wherein the quantity of primary alcohol used is more than 2 times the starting material.
5) A process as claimed in claims 1 to 4 wherein the quantity of primary alcohol used is 3 to 6 volumes of trityl losartan (III).
6) A process as claimed in claims 1 to 5 wherein the preferred primary alcohol is methanol.
7) A process as claimed in claim 1(c) wherein the preferred single solvent for crystallization is isopropyl alcohol.
8) A process as claimed in claim 1(c) wherein the altimate optional single solvent for crystallization is tetrahydrofuran.
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9) A process as claimed in claims 1(c), 7 and 8 wherein the quantity of crystallization -solvent used is 1 to 6 times that of trityl losartan (III).
10) A process as claimed in claims 1 to 9 wherein the resultant product (I) is obtained in high purity without subjecting to additional purification step.
11) A process as claimed in claims 1 to 10 wherein the losartan potassium (I) is obtained in high purity by a single step crystallization.
Dated this the 3rd day of April 2003
Dr. Gopakumar G. Nair Agent for the Applicant GOPAKUMAR NAIR ASSOCIATES

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