WO2007119246A2

WO2007119246A2 - An improved process for the manufacture of losartan potassium

Info

Publication number: WO2007119246A2
Application number: PCT/IN2006/000365
Authority: WO
Inventors: Arul Ramakrishnan; Vasant Dabholkar Bhushan; Deore B. Dinesh; Singh Shekhawat Kundan
Original assignee: Unichem Laboratories Limited
Priority date: 2006-04-17
Filing date: 2006-09-12
Publication date: 2007-10-25
Also published as: WO2007119246A3

Abstract

The present invention relates to an improved process for the manufacture of Losartan potassium. The process comprises of condensation of 2-butyl-4-chloro-5-formyl imidazole with 2-cyano-4-bromomethyl biphenyl in a biphasic solvent system under phase transfer catalysis followed by insitu reduction using sodium borohydride. The obtained product is converted to Losartan by treating with sodium azide and an amine salt. Losartan is then converted to its potassium salt by treating it with potassium hydroxide in alcohol.

Description

TITLE - AN IMPROVED PROCESS FOR THE MANUFACTURE OF LOSARTAN POTASSIUM.

FIELD OF THE INVENTION

This invention relates to an improved process for the manufacture of Losartan potassium and its intermediates.

BACKGROUND OF THE INVENTION

2-butyl-4-chloro-l-{[2'-(lH- tetrazol-5-yl)[l,l'-biphenyl]-4 -yl]methyl}-lH-irnidazole-5- methanol commonly known as Losartan, is useful in the treatment of hypertension. Losartan is formulated as its potassium salt. Several methods for the preparation of Losartan are known in literature.

US 5138069 and EP 253310 discloses a process (scheme A), wherein 2-n-butyl-4-chloro- l-H-imidazolyl-5-methanol (formula-I) is coupled with 5- (4'-bromomethyl-l, l'-biphenyl- 2-yl)-2-triphenylmethyl-2H-tetrazole of formula-(II) in N,N-dimethylformamide (DMF) in presence of sodium methoxide as the base to furnish a mixture of trityl Losartan of formula (III) and its regio-isomer of formula (IV) which were separated by column chromatography. After isolation trityl group is deprotected by aqueous HCl in Methanol to obtain Losartan, which is converted to Losartan potassium using potassium hydroxide in propan-2-ol.

SCHEME A US 5138069 and US 5155118 disclose another process (scheme BJ for making Trityl Losartan, wherein coupling between the compound of formula (V) and the compound of formula (II) is carried out in a biphasic solvent system comprising of chlorinated solvent and water. The reaction is carried out at room temperature in presence of sodium hydroxide as the base and aliquat 336 as the phase transfer catalyst. The resulting intermediate (VI) is then reduced in situ with sodium borohydride to furnish trityl Losartan of formula (III) in low yield.

SCHEME B

These patents also discussed another process (scheme C) in which compound of formula (I) was condensed with compound of formula (XIII) using sodium methoxide in N₅N- dimethyl formamide. The product was isolated by quenching in water followed by extraction with ethyl acetate .The crude product obtained after concentration of solvent was purified by column chromatography. Yield of the obtained product is very low.

SCHEME C Another process for preparing Losartan (scheme D) was disclosed in the US 5206374, US 5310928 and US 5962500. A 5-phenyltetrazole of formula (IX) is treated with trityl chloride in presence of a non-nucleophilic base to get compound of a formula (X), which is converted into the boronic acid derivative formula (XI). Compound of formula (VIII) which was prepared by alkylation of 2-n-butyl-4-chloro-imidazole-5-carboxaldehyde (formula V) with 4- bromobenzylbromide of formula (VII), followed by reduction using sodium borohydride was coupled under Suzuki reaction condition with compound of formula (XI) to get Trityl Losartan of formula (III)

SCHEME D

US 5130439 and US 5310928 discloses a method for coupling a compound of [formula (V)] with compound of formula (II) in N,N-dimethylacetamide in the presence of anhydrous potassium carbonate to obtain the imidazole aldehyde of formula (VI). The intermediate is then reduced with sodium borohydride to furnish the Trityl Losartan. The product is isolated by extraction into toluene from aqueous N,N-dimethylacetamide, concentration of the toluene solution and crystallization using ethyl acetate or ethanol as solvent.

The process published in J. Med. Chem. (1991), 34, 2525-2547, describe the synthesis of Losartan by coupling of compound . of formula (V) and compound of formula (II) in solvent N,N-dimethylformamide in the presence of sodium methoxide. The intermediate compound is isolated after vacuum distillation of solvent followed by extractive work-up. The resultant product is purified by chromatography. Isolated compound is detritylated by aqueous HCl in THF to obtain Losartan.

US 5608075 disclose the polymorphic forms of Losartan Potassium, wherein the Trityl Losartan of formula (III) is deprotected using sulphuric acid in aqueous acetonitrile. After treatment with KOH solution, the aqueous solution containing Losartan potassium is added slowly to a refluxing azeotropic mixture of cyclohexane - isopropanol and the ternary azeotrope of cyclohexane - isopropanol - water is distilled till the water content of the reaction mass is less than 0.05%. The white crystalline solid thus obtained is of polymorphic Form-I, which is characterized by DSC, XRD and IR.

The process described in patent US 5859258 and US 6710183 discloses the synthesis of Losartan potassium starting from trityl Losartan of formula-Ill, wherein trityl Losartan is treated with 0.1 to 1.0 equivalent of KOH in solvent Ci to C₄ straight chain alcohol. Losartan potassium is isolated after crystallizing out after the addition of aprotic solvent.

EP1294712 (WO02/094816) discloses a one pot process for the manufacture of Losartan potassium of Form-I, by treating trityl Losartan with KOH in solvents such as methanol, ethanol, and butanol preferably methanol and by the addition of an anti-solvent such as ethyl acetate, acetonitrile, toluene and acetone, the preferred one is acetone.

US patent application 2004/0006237 & EP1458693 relates to novel amorphous and novel crystalline forms III, IV, V of Losartan potassium and the processes for their preparation. The patent also discloses a novel process for preparation Losartan potassium of forms I and II. The amorphous Losartan potassium is prepared by dissolving crystalline Losartan potassium in a solvent to form a solution and distilling the solvent to dryness. Losartan potassium of form III (hydrated) is obtained by exposing Losartan potassium amorphous or form-I to an atmosphere having high relative humidity. Losartan potassium form-IV is obtained by treating a saturated solution of Losartan potassium in ethanol with methylene chloride. Losartan form-V is obtained by adding a hexane to a saturated solution of Losartan potassium in Ethanol.

US application 2004/0097568 discloses a process for preparation of form III of Losartan potassium, wherein Trityl Losartan is treated with aqueous solution of potassium hydroxide in methanol to obtain Losartan potassium. After removal of solvent, residue obtained is purified by the treatment with activated carbon in methanol. On cooling to 20- 25⁰C Losartan potassium of form III is obtained.

SCHEME E (XIi) (X IV)

US 5138069 describes (scheme E) the synthesis of tetrazole of formula (XIV) directly from nitrile of formula (XII) by treatment of sodium azide and ammonium chloride in DMF. This process involves a great risk in industrial manufacture of tetrazoles as the ammonium chloride used in this process reacts with sodium azide to form an explosive ammonium azide as a sublimate attached to the condenser tube. When a catalyst other than ammonium chloride, e.g. LiCl is used, a tetrazole is produced in a significantly low yield. Further the process requires a high reaction temperature and a prolonged reaction time. Since tetrazole is soluble in DMF₃ an additional step of adding water is needed to reduce the solubility of the tetrazole in DMF. In this case, since DMF is a water-soluble solvent, unreacted substances would remain along with the product, consequently necessitating an additional step for purification of tetrazole compound of formula (VIII). Japanese unexamined Patent Publication 53,489/1995 describe a process for preparation of compound of formula (XIV), where l-(cyanobiphenylmethyl)imidazole derivative of formula (XII) is reacted with tributyltin azide, which was prepared insitu from tributyl tin chloride and Sodium azide, after which the reaction mixture is hydrolyzed in diluted aqueous solution of Sodium hydroxide, followed by neutralization of the aqueous layer with an acid. The yield of l-(tetrazolylbiphenylmethyl)imidazole derivative of the formula (XIV) is 54%.

US 5138069, US 5128355 and US 5155118 also describe another process for the preparation of Losartan, wherein the tetrazole ring of Losartan is formed by reacting 1- (2'-cyanobiphenyl-4-yl)methyl-2-butyl-4-chloro-5-hydroxymethyl imidazole of formula (XII) with trimethyl tin azide. The reaction results in trimethylstannyl substituted tetrazol compound, which is then reacted with trityl chloride and sodium hydroxide. The trityl Losartan thus formed is treated with 3.4 N hydrochloric acid in methanol at about 1O⁰C to give Losartan of formula (XIV).

WO 2005/051929 describes the use of Tetra alkyl tin azide in presence of phase transfer catalyst like PEG, Tetrabutyl ammonium bromide.

In order to carry out the processes on industrial scales all the prior arts discussed above have many limitations, some of which were listed bellow

(1) The formation of undesired regioisomer during coupling of imidazole moiety with biphenyl moiety for which the product needs to be purified

(2) The additional steps involved like detritylation of trityl Losartan

(3) Use of hazardous reagent like alkyl tin azide, hazardous reaction conditions like sodium azide in combination with ammonium chloride for the formation of the tetrazole intermediate

(4) Use of hazardous solvent like dimethyl formamide, higher temperature required for formation of tetrazole from nitrile

(5) Use of organo tin azide, which is difficult to separate from (tetrazolyl biphenyl methyl) imidazole derivative

(6) Organotin compounds are highly toxic and require additional care in handling Hence there is a need to develop a process for the manufacture of Losartan potassium, which is simple, economical, commercially viable and uses less hazardous reagents.

DESCRIPTION OF THE INVENTION

The first aspect of the invention is to provide a process for the manufacture a Losartan Potassium, which is economical, commercially viable, less hazardous and simple.

The process for the manufacture of Losartan potassium comprises of the following steps

1. Condensation of 2-butyl-4-chloro-5-formyl imidazole with 2-cyano-4- bromomethyl biphenyl in a biphasic solvent system of water and aromatic solvent in presence of base and a phase transfer catalyst

2. Reduction of the condensed product insitu using sodium borohydride in alcoholic solvent

3. Conversion of the obtained product to Losartan by treating with sodium azide and amine salt in an organic solvent.

4. Conversion of the Losartan into its potassium salt by treating it with potassium hydroxide in alcohol

STEP 2

STEP 3

STEP 4

The second aspect of the invention is to provide a method, which reduces the formation of unwanted regioisomer during condensation of imidazole compound of formula (V) with bromo compound of formula (XIII). This is achieved by using a biphasic reaction media of water and low polar non chlorinated solvent like 'Toluene' in presence of a phase transfer catalyst, such as Tetrabutyl ammonium bromide, results- high selectivity in product formation reducing unwanted isomer below 5%.

The third aspect of the reaction is to form Losartan from nitrile intermediate of formula (XII). The tetrazole is produced with high purity in a high yield by a simple procedure, an inorganic azide is reacted with an amine salt in the presence of an aromatic hydrocarbon solvent to form hydrogen azide salt of amine, which is dissolved in the aromatic hydrocarbon reacted with a nitrile. The reaction of the invention easily proceeds without use of an organometallic compound and ensures a high efficiency and gives the desired product in a higher yield than conventional techniques. Because of the absence of an organometallic compound, the work up is simplified.

As described above, this invention is directed to a pronouncedly advantageous process for preparing a Losartan on an industrial scale. According to the present invention, a Losartan can be easily and safely prepared from inexpensive raw materials in a high yield while the reaction is easily controlled to inhibit the side reaction.

DETAILED DESCRIPTION OF THE INVENTION

1) Step-1:

According to the invention, the coupling reaction between intermediates of formula (V) and formula (XIII) is carried out in a biphasic non-chlorinated solvent system in presence of a base and a phase transfer catalyst to form a compound of formula (XV)

Where the organic solvent is selected from toluene, xylene etc. Preferably the reaction is carried out in toluene.

The reaction temperature varies from 15⁰C to reflux temperature of the solvent, preferably 20-40⁰C, most preferably between 25 and 3O⁰C. The phase transfer catalyst is selected from any of the tetra alkyl ammonium halides or tetra alkyl phosphonium halides. The preferred catalyst is tetra butyl ammonium bromide. The quantity of the catalyst used varies from about 0.1 to 5 mol% with respect to nitrile compound of formula (XIII) however about 2 mol% being most suitable.

The base employed is selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide the preferred base is sodium hydroxide in about 100 mol% to 300 mol% with about 130 mol% with respect to nitrile compound of formula (XIII) being most suitable.

After the completion of reaction as judged by HPLC analysis, the reaction mixture is diluted with water and allowed to settle. The organic phase separated, washed with water to remove any traces of phase transfer catalyst and base and used as such for next reduction step.

2) Step-2

The organic phase is then diluted with an alcohol selected from any of alkyl C1-C4 alcohols, preferably methanol and product of stage 1 is reduced by addition of sodium borohydride in quantities ranging from 0.2 equivalents to 2 equivalents with respect to nitrile compound of formula (XIII). Typically, about 0.5 equivalent of sodium borohydride is used.

The reduction is carried out in a temperature range of about 10 to 3O⁰C with 25-3O⁰C being most appropriate.

When the reaction has proceeded to a desired stage, it is quenched by the addition of water. The desired product which precipitates from the reaction mass is isolated by filtration.

3) Step-3

Losartan intermediate of formula (XIV) is converted into its 5-substituted tetrazole represented by the formula (XIV) by treating it with an inorganic azide in an aromatic organic solvent in the presence of an amine salt: M(Ns)n wherein M is an alkali metal or an alkaline earth metal, and n is 1 to 2.

Examples of useful inorganic azide include azides of alkali metals or alkaline earth metals such as sodium, potassium, lithium, calcium, magnesium, etc. Azides of alkali metals are suitable and sodium azide is most suitable.

The amount of the inorganic azide used is 1 to 5 moles, preferably 1 to 3 moles, and calculated as hydrogen azide, per mole of a nitrile of the formula (XII). Desirably the inorganic azide is used in an equimolar amount relative to the amine salt.

Amine salts, which can be used in the invention, are formed from an amine and an acid. Useful amines can be any of alkyl primary, secondary and tertiary amines, and aliphatic amines are preferred. Useful amine salts include primary amine salts such as methylamine salt, ethylamine salt, propylamine salt, butylamine salt, amylamine salt, hexylamine salt, cyclohexylamine salt, heptylamine salt, octylamine salt, allylamine salt, benzylamine salt, alpha-phenylethylamine salt, beta-phenylethylamine salt, etc., Secondary amine salts such as dimethylamine salt, diethylamine salt, dipropylamine salt, dibutylamine salt, diamylamine salt, dihexylamine salt, dicyclohexylamine salt, diallylamine salt, morpholine salt, piperidine salt, hexamethyleneimine salt, etc.; and tertiary amine salts such as trimethylamine salt, triethylamine salt, tripropylamine salt, tributylamine salt, triamylamine salt, trihexylamine salt, triallylamine salt, pyridine salt, triethanolamine salt, N-methylmorpholine salt, N,N-dimethylcyclohexylamine salt, N₃N- dimethylaniline salt, N,N,N',N'-tetramethylethylenediamine salt, 4- dimethylaminopyridine salt, etc. These amine salts can be used either alone or in combination.

Acids to be used for forming such salt are basically those, which, together with an amine, are capable of producing a salt. Useful acids include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, and the like, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like to which useful acids are not limited. Preferred acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen azide, acetic acid, trifluoro acetic acid, etc.

Preferred amine salts are triethylamine hydrochloride.

The amount of the amine salt used is 1 to 5 moles, preferably 1 to 3 moles, and calculated as an amine per mole of a nitrile of the formula (XII). The molar ratio of the amine salt affects the reaction rate and yield. Especially it is preferred to use the amine salt in an equimolar amount relative to the inorganic azide.

Solvents preferred in the reaction include aromatic hydrocarbons inert to the reaction, for example, toluene, xylene, mesitylene, ethylbenzene, chlorobenzene, cumene, chlorotoluene etc. among which toluene and chlorobenzene are preferred. A mixture of at least two of these aromatic hydrocarbons can be used in the reaction. The amount of the aromatic hydrocarbon used may be a minimum amount, which allows the reaction to proceed. The amount is usually 1 to 100 ml, preferably 2 to 50 ml, per gram of the nitrile of the formula (XII).

The reaction temperature is selected from a wide range of 20 to 15O⁰C, preferably 80 to 100 ⁰C. The reaction time usually in the range of 1 to 120 hours, preferably 14 to 28 hours.

After the completion of reaction, unreacted l-(cyanobiphenylmethyl)imidazole derivative of the formula (III) remains dissolved in the aromatic hydrocarbon solvent. The aromatic hydrocarbon solvent can be easily recovered by distillation and can be re-used.

4) Step-4

Losartan obtained from above process is treated with potassium hydroxide in alcoholic solvent. The alcohol is selected from any of C1-C4 alkyl alcohols, preferably propan-2- ol.

The reaction is carried out in a temperature range of about 25-55⁰C preferably 35-45⁰C. Product is isolated by azeotropic distillation of solvent and addition of an anti solvent. Anti-solvent is selected from n-hexane, n-heptane, preferably n-heptane." Solid obtained by means of filtration is highly pure Losartan potassium.

The present invention is described below in more detail with reference to the following Examples. The examples are not intended to limit the scope of the invention as defined herein above and as claimed herein below.

Example-l

Preparation of 2-butyl-4-chloro-l-{[2'-cyno[l,l'-biphenyI]-4-yl]methyl}-lH- imidazole-5-methanol.

A) To a solution of ortho toluyl benzonitrile (400gm; 2.07moles) in Dichloromethane (600ml), N-bromo succinamide (405.78gm; 2.30moles) was added followed by Benzoyl peroxide (5 gm). The Reaction mass was refluxed for 5-6 hours. The reaction mass was cooled to room temperature, washed with water. After concentration of reaction mass, the obtained solid was slurried in 700ml of Toluene.

B) To a solution of NaOH (134gm; 3.35mole) in water (2000ml), 2-Butyl4-Chloro-5- formyl Imidazole (BCFI) (313gm; 1.68mole) and Tetra butyl ammonium bromide (5.4gm; 0.59moles) was added. The toluene slurry prepared in part A was added to reaction mixture and stirred for 24 hours. Reaction was monitored by HPLC. After completion of reaction, organic layer was separated and methanol (1100ml) was added. Sodium Borohydride (23.75gm; 0.62mole) was added to the reaction mass. After completion of reaction, water was added to obtain solid, which was filtered and dried. Weight-556.85gm

ExampIe-2

Preparation of 2-butyI-4-chIoro-l- {[2'- (IH- tetrazoI-5-yI) [1, l'-biphenyl]- 4 -yl] methyl} IH -imidazoIe-5-methanoI To a mixture of Triethyl amine hydrochloride (90gm; 0.65moles) in chlorobenzene (350 ml), Sodium azide (42.0gm; 0.64mole) was added. Reaction mass stirred for lhour and compound obtained in Example I (50gm; 0.13 moles) and PEG400 (12.5ml) were charged. Reaction mass was heated to 95-98⁰C and maintained for 34 hours .The progress of reaction was monitored by HPLC and after completion, reaction mass was cooled to 0-5° C and. methanol (250ml) was added. The pH of reaction mass was adjusted to 3.5 by 1:1HC1 solution. Resultant mixture was stirred for 10-15rninute and again the pH of reaction mass was adjusted to 11 by KOH solution. Aqueous layer separated and washed with toluene. Ethyl acetate (450ml) was added to reaction mass and pH was adjusted to 4.5 and stirred overnight and obtained solid was filtered and dried. Weight-48.0gm

Example-3

Preparation of potassium salt of 2-butyl-4-chloro-l-{[2'- (IH- tetrazoI-5-yl) [1, T- biphenyI]-4-yl] methyl} IH -imidazole-5-methanol

To the product obtained in Example 2 i.e. 2-butyl-4-chloro-l-{[2'- (IH- tetrazol-5-yl) [1, l'-biphenyl]-4-yl] methyl} IH -imidazole-5-methanol (38gm) is suspended in propan-2- ol (130 ml) and solution is heated to 40+2⁰C. A solution of potassium hydroxide (6.05gm) dissolved in water (6 ml) and propan-2-ol (50 ml) was added while maintaining the temperature at 40+2⁰C. proρan-2-ol (100 ml) was distilled from reaction mass and fresh propan-2-ol (100 ml) and Heptane (30ml) was added. Reaction mass was cooled to 20-25⁰C and n-Heptane (50ml) was added. The slurry was stirred for lhour and obtained solid was filtered, dried. Weight-38.12 gm

Claims

Claims:

1. A process for manufacture of Losartan potassium comprising a) Condensation of 2-butyl-4-chloro-5-formyl imidazole with 2-cyano-4- bromomethyl biphenyl in a biphasic solvent system of water and an aromatic organic solvent in presence of a base and a phase transfer catalyst b) Reduction of condensed product from l(a) in presence of alcohol and sodium borohydride. c) Converting obtained reduced product into Losartan by treating with inorganic azide and amine salt in an organic solvent in presence of phase transfer catalyst d) Converting Losartan obtained from the process above into its potassium salt by treating it with potassium hydroxide in alcohol

2. A process according to claim- 1 -a, wherein the aromatic organic solvent is toluene, xylene or chlorobenzene, wherein the preferred organic solvent is Toluene.

3. The process according to claim 1-a, wherein the base used is sodium hydroxide or potassium hydroxide.

4. The process of claim 1-b, wherein C₁-C₄ alkyl alcohol solvent is selected from methanol, ethanol preferably methanol.

5. A process according to claim 1-c, wherein the aromatic organic solvent is toluene, xylene or chlorobenzene, wherein preferred organic solvent is chloro benzene.

6. A process according to claim l(c) wherein the inorganic azide salt is sodium azide

7. A process according to claim l(c) wherein the amine salt is triethylamine hydrochloride.

8. The process according to claim l(c), wherein the phase transfer catalyst is PEG 400.

9. A process according to claim lwherein step 1-a and Ib are performed in one pot.