WO2010029457A2 - An improved process for preparing losartan potassium - Google Patents
An improved process for preparing losartan potassium Download PDFInfo
- Publication number
- WO2010029457A2 WO2010029457A2 PCT/IB2009/053759 IB2009053759W WO2010029457A2 WO 2010029457 A2 WO2010029457 A2 WO 2010029457A2 IB 2009053759 W IB2009053759 W IB 2009053759W WO 2010029457 A2 WO2010029457 A2 WO 2010029457A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- losartan
- give
- potassium
- chloro
- butyl
- Prior art date
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- JLVIHQCWASNXCK-UHFFFAOYSA-N CCCCc1nc(Cl)c(C=O)[nH]1 Chemical compound CCCCc1nc(Cl)c(C=O)[nH]1 JLVIHQCWASNXCK-UHFFFAOYSA-N 0.000 description 1
- FGCNIDUBRIVYBP-UHFFFAOYSA-N CCCCc1nc(Cl)c(CO)[n]1Cc(cc1)ccc1-c(cccc1)c1C#N Chemical compound CCCCc1nc(Cl)c(CO)[n]1Cc(cc1)ccc1-c(cccc1)c1C#N FGCNIDUBRIVYBP-UHFFFAOYSA-N 0.000 description 1
- LFFIEVAMVPCZNA-UHFFFAOYSA-N N#Cc1ccccc1-c1ccc(CBr)cc1 Chemical compound N#Cc1ccccc1-c1ccc(CBr)cc1 LFFIEVAMVPCZNA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- the present invention relates to an improved process for preparing Losartan
- Losartan is used as Antihypertensive. It is non-peptide angiotensin II receptor antagonist. It is used in the treatment of hypertension. It is also used in the treatment of diabetic nephropathy with an elevated serumcreatinine and proteinuria in patients with type 2 diabetes and a history of hypertension. It may be administered with other antihypertensive agents.
- WO2007020654 describes a process for the preparation of Losartan Potassium which is shown in the scheme-II.
- Another object of the present invention is to provide a process which gives Losartan Potassium with high purity.
- Yet another object of the present invention is to provide a process which gives 2-n-butyl-4-chloro-l- [2'-cyanobiphenyl -4-ylmethyl] -5-formylimidazol with minimum formation of unwanted isomeric alcohol impurity.
- Another object of the present invention is to provide a process which is operationally simple and cost effective.
- present invention provides an improved process for the preparation of Losartan Potassium (I)
- present invention provides an improved process for the preparation of Losartan Potassium (I)
- the present invention provides an improved process for the preparation of Losartan
- a mixture of 4'-Bromomethyl - 2-cyanobiphenyl(II), l-Methyl-2-pyrrolidinone (NMP), base and 2-Butyl-4 - chloro-5-formylimidazole (III) is heated at 7O 0 C to 75 0 C for about 4-5 hrs.
- the base is selected from K 2 CO 3 , Na 2 CO 3 , NaHCO 3 , KHCO 3 , NaOH, KOH, LiOH or mixtures thereof.
- the preferred base is anhydrous K 2 CO 3.
- Sodium borohydride is charged to the reaction mixture at 3O 0 C .
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an improved process for preparing Losartan Potassium of formula (I).
Description
Description Title of Invention: AN IMPROVED PROCESS FOR PREPARING
LOSARTAN POTASSIUM
Field of the invention
[1] The present invention relates to an improved process for preparing Losartan
Potassium of formula (I)
[3]
Background of the invention
[4]
[5] The chemical name of Losartan is 2-Butyl-4-chloro-l-[[2'-(lH-tetrazol-5-yl)
[l,l'-biphenyl]-4-yl]methyl]-lH-imidazole-5-methanol and formula is C22H23C1N6O and molecular weight is 422.91. The drug is used in its potassium salt. The current pharmaceutical product containing this drug is being sold by Merck using the tradename Cozaar, in the form of tablets.
[6]
[7] Losartan is used as Antihypertensive. It is non-peptide angiotensin II receptor antagonist. It is used in the treatment of hypertension. It is also used in the treatment of diabetic nephropathy with an elevated serumcreatinine and proteinuria in patients with type 2 diabetes and a history of hypertension. It may be administered with other antihypertensive agents.
[8]
[9] US patent 5138069 describes a process for the preparation of Losartan Potassium which is shown in the scheme-I.
Scheme I
[H] [12] The process involves alkylating 4'bromomethyl-2-cyanobiphenyl with 2-n-butyl-4-chloro-5- (hydroxymethyl)imidazol in the presence of sodium methoxide and DMF to give 2-n-butyl-4-chloro-l- [2'-cyanobiphenyl-4-ylmethyl] - 5-(hydroxymethyl)imidazol which is converted to losartan by reaction with sodium azide in the presence of sodium chloride and DMF. Losartan is converted to its potassium salt using 87% KOH solution.
[13] [14] WO2007020654 describes a process for the preparation of Losartan Potassium which is shown in the scheme-II.
[15]
Scheme Il
[16] [17] The process involves alkylating 4'bromomethyl-2-cyanobiphenyl with 2-n-butyl-4-chloro-5-formyl imidazol in the presence of sodium hydroxide, DMF and phase transfer catalyst (PTC) to give 2-n-butyl-4-chloro-l- [2'-cyanobiphenyl - 4-ylmethyl] -5-formylimidazol which is reduced with sodium borohydride to give 2-n-butyl-4-chloro-l- [2'-cyanobiphenyl -4-ylmethyl] -5-(hydroxymethyl)midazol which is further converted to losartan by reaction of sodium azide in the presence of triethylamine HCl in polar solvent. Losartan is converted to its potassium salt using KOH solution.
[18] [19] In the above processes, alkylation of 4'bromomethyl-2-cyanobiphenyl with 2-n-butyl-4-chloro-5-formyl imidazol in the solvent as mentioned hereinabove, gives an isomer which is reduced in next step to give isomeric alcohol along with the desired product. This unwanted isomeric alcohol is having the structural formula as shown below.
[21] [22] This impurity of unwanted isomeric alcohol is difficult to remove by conventional purification methods. Moreover the use of PTC makes the process economically unviable as it increases the raw material cost.
[23] [24] It is therefore, there exists a need to develop an easy to operate, industrially feasible and yet cost effective process for preparing Losartan potassium. Further, this process should ensure the formation of isomeric impurity to a minimum desirable level. The present invention addresses these needs.
[25] [26] Present inventors have directed their research work towards developing a process for the preparation of Losartan Potassium which is devoid of the above disadvantages. The present inventors used l-methyl-2-pyrrolidonone (NMP) as solvent as well as base in the reaction. Serendipitously, it was observed that the formation of an isomeric impurity is substantially reduced by the use of NMP instead of the use of other solvents as mentioned in prior art processes. This helps in the increasing the purity of desired product i.e. 2-n-butyl-4-chloro-l- [2'-cyanobiphenyl-4-ylmethyl] - 5-formylimidazol which in turn increase the yield and purity of losartan.
[27]
Summary of the invention
[28] [29] Accordingly, it is an object of the present invention to provide an improved process for the preparation of Losartan Potassium.
[30] [31] Another object of the present invention is to provide a process which gives Losartan Potassium with high purity.
[32] [33] Yet another object of the present invention is to provide a process which gives
2-n-butyl-4-chloro-l- [2'-cyanobiphenyl -4-ylmethyl] -5-formylimidazol with minimum formation of unwanted isomeric alcohol impurity.
[34] [35] Another object of the present invention is to provide a process which is operationally simple and cost effective.
[36] [37] Accordingly, present invention provides an improved process for the preparation of Losartan Potassium (I)
(I)
[39] [40] comprising a step of reacting 4'-bromomethyl-2-cyanobiphenyl (IV) [41]
(H)
[43] [44] with 2-butyl-4-chloro-5-formylimidazole (III) [45]
(in)
[47] [48] in the presence of l-Methyl-2-pyrrolidinone (NMP) and base to give an intermediate
which is further reacted with sodium borohydride to give compound of formula (IV);
[49]
[51] [52] Accordingly, present invention provides an improved process for the preparation of Losartan Potassium (I)
[53]
(I)
[55] [56] comprising steps of: [57] (i) reacting 4'-bromomethyl-2-cyanobiphenyl (II)
(III)
[63] [64] in the presence of l-Methyl-2-pyrrolidinone (NMP) and base to give an intermediate which is further reacted with sodium borohydride to give compound of formula (IV);
[65]
[67] [68] (ii) reacting the compound of formula (IV) obtained in step (i) with sodium azide in the presence of triethylamine hydrochloride (TEA-HCl) and l-Methyl-2-pyrrolidinone (NMP) to give losartan (V);
[69]
[71] [72] (iii) reacting Losartan (V) with potassium hydroxide in methanol to give Losartan potassium (I)
[73]
Detailed description of the invention
[75]
[76] The present invention provides an improved process for the preparation of Losartan
Potassium (I)
[78] [79] comprising steps of: [80] (i) reacting 4'-bromomethyl-2-cyanobiphenyl (II) [81]
[83] [84] with 2-butyl-4-chloro-5-formylimidazole (III) [85]
(III)
[87] [88] in the presence of l-Methyl-2-pyrrolidinone (NMP) and base to give an intermediate which is further reacted with sodium borohydride to give compound of formula (IV);
[89] [90]
[92] (ii) reacting the compound of formula (IV) obtained in step (i) with sodium azide in the presence of triethylamine hydrochloride (TEA-HCl) and l-Methyl-2-pyrrolidinone (NMP) to give losartan (V);
[93]
[95]
[96] (iii) reacting Losartan (V) with potassium hydroxide in methanol to give Losartan potassium (I) [97]
[98] The synthetic reaction scheme of the present invention is shown in the scheme-Ill.
Losartan potassium Losartan (T) (V)
Scheme
[101] [102] In the process of present invention, a mixture of 4'-Bromomethyl - 2-cyanobiphenyl(II), l-Methyl-2-pyrrolidinone (NMP), base and 2-Butyl-4 - chloro-5-formylimidazole (III) is heated at 7O0C to 750C for about 4-5 hrs. The base is selected from K2CO3, Na2CO3, NaHCO3, KHCO3, NaOH, KOH, LiOH or mixtures thereof. The preferred base is anhydrous K2CO3. Sodium borohydride is charged to the reaction mixture at 3O0C . Water and isopropanol are added to the wet cake and heated at about 750C to about 8O0C for 1.5 hours. The reaction mixture is cooled at room temperature and filtered. The solid is suck dried and dried in oven to give 2-n-Butyl-4-chloro-l- [2'-(cyanobiphenyl- 4-yl)methyl] -5-(hydroxymethyl)-imidazole (IV).
[103] [104] A mixture of 2-n-Butyl-4-chloro-l- [2'-(cyanobiphenyl-4-yl) methyl] - 5 -(hydroxymethyl) -imidazole (IV), sodium azide, triethylamine hydrochloride (TEA-HCl), l-Methyl-2-pyrrolidinone (NMP) and toluene are heated at HO0C for 30-35 hours. Caustic solution is added to it and the layers are separated. Acetic acid is added to the aqueous layer and pH is adjusted to 4 to 4.5. The product is filtered and solid is washed with water. The solid is purified by triturating it with acetone to give pure Losartan (V).
[105] [106] 85% Potassium hydroxide solution is added to a mixture of Losartan (V) in methanol. The reaction mixture is heated to get clear solution. Activated charcoal is added to the reaction mixture and stirred well. The mixture is filtered through hyflow bed to remove charcoal. The filtrate is distilled to evaporate the solvent completely. Acetone is added to it and stirred. The resulting precipitates are filtered, washed with acetone and suck dried. The solid is dried in oven to give Losartan potassium (I)
[107] [108] The Losartan potassium obtained by above process is having polymorphic Form-I. [109] [HO] The major advantage of this process is that the isomeric impurity formation is minimum in the first step. The percentage of isomer formation is very less compare to prior art process. Using other solvents, unwanted isomer is formed in 15-20 %, whereas using NMP only 4-5 % unwanted isomer is formed. The advantage of the present invention can be understand from the following data depicted in Table- 1
[111] [112] Table-1
[Table 1] [Table ]
[113] [114] The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.
[115] [116] Example-1 [117] [118] Preparation of 2-n-Butyl-4-chloro-l-[2'-(cyanobiphenyl-4-yl) methyl] -5-(hydroxymethyl)-imidazole (IV)
[119] A mixture of 4'-Bromomethyl-2-cyanobiphenyl(II) (125.0 g), l-Methyl-2-pyrrolidinone (NMP) (375.0 ml), anhydrous potassium carbonate (76.0 g)
and 2-Butyl-4-chloro-5-formylimidazole (III) (90.0 g) was heated at 7O0C to 750C for about 4-5 hrs. Sodium borohydride (18.0 g) was charged to the reaction mixture at 3O0C. Water (1875.0 ml) was added to it and isopropanol (562.5 ml) was added to the wet cake and heated at 75-8O0C for 1.5 hours. The reaction mixture was cooled at room temperature and filtered. The solid was suck dried and dried in oven to give the title compound (153.0g).
[120] Yield: 88.0%
[121] Purity (By HPLC): 99.1%
[122]
[123] Example-2
[124]
[125] Preparation of Losartan (V)
[126] A mixture of
2-n-Butyl-4-chloro-l-[2'-(cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole (IV) (125.0 g), sodium azide (85.6 g), triethyl amine hydrochloride (TEA-HCl) (181.0 g), l-Methyl-2-pyrrolidinone (NMP) (125.0 ml) and toluene (500.0 ml) were heated at 11O0C for 30-35 hours. Caustic solution (19.75g in 300ml water) was added to it and the layers were separated. Acetic acid was added to the aqueous layer and pH was adjusted to 4 to 4.5. The product was filtered and solid washed with water. The solid was triturated with Acetone (500.0 ml) to give pure Losartan (V) (105.0 g).
[127] Yield: 75.0%
[128] Purity (By HPLC): 99.25%
[129]
[130] Example-3
[131]
[132] Preparation of Losartan potassium (I)
[133] 85% Potassium hydroxide (15.02 g) solution was added to a mixture of Losartan (V) (100.0 g) in methanol (300.0 ml). The reaction mixture was heated to get clear solution. Activated charcoal was added to the reaction mixture and stirred well. The mixture was filtered through hyflow bed to remove charcoal. The filtrate was distilled to evaporate the solvent completely. Acetone (300.0 ml) was added to it and stirred. The resulting precipitates were filtered and washed with acetone (100.0 ml) and suck dried. The solid was dried in oven to give Losartan potassium (I) (98.0 g).
[134] Yield: 90.0%
[135] Purity (By HPLC):99.85%
[136]
Claims
[Claim 1] 1. A process for preparation of Losartan Potassium (I)
(H) with 2-butyl-4-chloro-5-formylimidazole (III)
(in) in the presence of l-Methyl-2-pyrrolidinone (NMP) and base to give an intermediate which is further reacted with sodium borohydride to give compound of formula (IV);
[Claim 2] 2. A process for preparation of Losartan Potassium (I)
(i) reacting 4'-bromomethyl-2-cyanobiphenyl (II)
(III) in the presence of l-Methyl-2-pyrrolidinone (NMP) and base to give an intermediate which is further reacted with sodium borohydride to give compound of formula (IV);
(ii) reacting the compound of formula (IV) obtained in step (i) with sodium azide in the presence of triethylamine hydrochloride (TEA-HCl) and l-Methyl-2-pyrrolidinone (NMP) to give losartan (V);
(iii) reacting Losartan (V) with potassium hydroxide in methanol to give Losartan potassium (I)
[Claim 3] 3. The process as claimed in claim 1 or 2, wherein the base is selected from K2CO3, Na2CO3, NaHCO3, KHCO3, NaOH, KOH, LiOH or mixtures thereof.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107056756A (en) * | 2016-11-29 | 2017-08-18 | 浙江华海药业股份有限公司 | A kind of method for preparing high-purity Losartan |
WO2021209563A1 (en) | 2020-04-16 | 2021-10-21 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
WO2023007502A1 (en) * | 2021-07-29 | 2023-02-02 | Jubilant Generics Limited | Process for the preparation of angiotensin receptor blockers or pharmaceutically acceptable salts thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5138069A (en) * | 1986-07-11 | 1992-08-11 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
WO2006125592A2 (en) * | 2005-05-24 | 2006-11-30 | Lek Pharmaceuticals D.D. | Process for the preparation of 2-alkyl-1-((2'-substituted-biphenyl-4-yl)methyl)-imidazole, dihydroimidazole or benzimidazole derivatives |
WO2007020654A1 (en) * | 2005-08-16 | 2007-02-22 | Suven Life Sciences | An improved process for the preparation of losartan |
WO2007119246A2 (en) * | 2006-04-17 | 2007-10-25 | Unichem Laboratories Limited | An improved process for the manufacture of losartan potassium |
-
2009
- 2009-08-28 WO PCT/IB2009/053759 patent/WO2010029457A2/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5138069A (en) * | 1986-07-11 | 1992-08-11 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
WO2006125592A2 (en) * | 2005-05-24 | 2006-11-30 | Lek Pharmaceuticals D.D. | Process for the preparation of 2-alkyl-1-((2'-substituted-biphenyl-4-yl)methyl)-imidazole, dihydroimidazole or benzimidazole derivatives |
WO2007020654A1 (en) * | 2005-08-16 | 2007-02-22 | Suven Life Sciences | An improved process for the preparation of losartan |
WO2007119246A2 (en) * | 2006-04-17 | 2007-10-25 | Unichem Laboratories Limited | An improved process for the manufacture of losartan potassium |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107056756A (en) * | 2016-11-29 | 2017-08-18 | 浙江华海药业股份有限公司 | A kind of method for preparing high-purity Losartan |
CN107056756B (en) * | 2016-11-29 | 2021-01-05 | 浙江华海药业股份有限公司 | Method for preparing high-purity losartan |
WO2021209563A1 (en) | 2020-04-16 | 2021-10-21 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
WO2023007502A1 (en) * | 2021-07-29 | 2023-02-02 | Jubilant Generics Limited | Process for the preparation of angiotensin receptor blockers or pharmaceutically acceptable salts thereof |
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