WO2007020659A2 - A process for the preparation of irbesartan form a - Google Patents
A process for the preparation of irbesartan form a Download PDFInfo
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- WO2007020659A2 WO2007020659A2 PCT/IN2006/000298 IN2006000298W WO2007020659A2 WO 2007020659 A2 WO2007020659 A2 WO 2007020659A2 IN 2006000298 W IN2006000298 W IN 2006000298W WO 2007020659 A2 WO2007020659 A2 WO 2007020659A2
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- irbesartan
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- 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 a process for the preparation of Irbesartan Form-A.
- Irbesartan which is chemically known as 2-n-butyl-3-[[2-(lH-tetrazol-5-yl) [l,l-biphenyl]-4-yl]methyl]-l,3-diazaspiro [4.4]non-l-en-4-one having the following structure
- angiotensin-II antagonist used in treatment of cardiovascular diseases, such as hypertension & heart failure.
- U.S. Pat. No. 5,270,317 discloses N-substituted heterocyclic derivatives including Irbesartan.
- the process disclosed in this patent involves the formation of trityl protected Irbesartan and deprotection of trityl group by hydrochloric acid in THF & methanol. After evaporation of the solvents, the residue is taken up in water & ION sodium hydroxide to get pH 12. The aqueous phase is washed with ether, toluene & ether again. The aqueous phase is acidified to pH 2 by HCl acid & extracted with ethyl acetate. Evaporation of Ethyl acetate yielded Irbesartan.
- J Med Cherri. (1993); 36, 3371-3380 discloses a process for the preparation of Irbesartan by treating cyano derivative with tributyl tin azide in xylene under refluxed condition, after completion of reaction, reaction mass is extracted with IN sodium hydroxide solution. Acidified to pH ⁇ 5 using 3N HCl & extracted the- product with methylene chloride. Residue obtained after removing methylene chloride is crystallized from 96% ethanol to give Irbesartan.
- Indian Pat. Appl.No.809/MAS/2001 discloses a process for the preparation of Form A of Irbesartan by re-crystallizing the crude Irbesartan or Form-B from ketone solvents selected from acetone, methyl ethyl ketone, dimethyl ketone or methyl isobutyl ketone.
- Indian Pat. Appl.No.809/MAS/2001 also discloses the preparation of Form-B, which involves treating Irbesartan in a solution of inorganic base (viz. sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate) or organic base (viz. dimethylamine, triethylamine, tributylamine) followed by acidification using inorganic or organic acid (viz. hydrochloric acid, sulphuric acid, acetic acid) accompanied by stirring.
- inorganic base viz. sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate
- organic base viz. dimethylamine, triethylamine, tributylamine
- inorganic or organic acid viz. hydrochloric acid, sulphuric acid, acetic acid
- Chinese Pat. No. CN 1415614 discloses a process to synthesize Irbesartan features that the cyano derivative is converted to tetrazole & directly used in next step without purification.
- PCT publications WO 2005/051929 & WO 2005/051943 discloses a process the conversion of aromatic nitriles to tetrazoles, comprising treatment of the cyano compound with trialkyl tin chloride and sodium azide in the presence of a phase transfer catalyst.
- Irbesartan can be prepared from its cyano derivative to tertrazole ring. This is further converted to its sodium salt & extracted from organic media to aqueous media using the highly basic solution such as sodium hydroxide solution. This leads to the degradation of the product at higher pH, resulting in lowering the yield & purity of the product.
- the main object of the present invention is to provide a commercially feasible process for the preparation of Irbesartan form-A free from degradation & residual impurities.
- Yet another object of the present invention is to provide a commercially feasible process for the preparation of Irbesartan form-A by crystallizing the crude product in a mixture of water and water miscible solvent in any ratio.
- preparation of Irbesartan comprises of the following steps:
- reaction of 2-n.butyl-3-[(2'-cyanobiphenyl -4-yl)methyl]-l, 3-diazaspiro-[4.4]-non-l- en-4-one, sodium azide & tributyl tin chloride in xylene is carried out at about 50°- 150 0 C, preferably at 120- 150°C.
- the reaction mass is filtered to remove the undissolved inorganic solid.
- the organic layer is extracted using sodium hydroxide solution.
- the resulting aqueous layer containing the product is washed with organic solvent such as toluene, n-Hexane, Heptane or cyclohexane to remove the residual impurities.
- Aqueous layer pH is adjusted to 3.0- 7.0, preferably 4.0-6.0 with hydrochloric acid.
- the precipitated crude product is isolated by filtration.
- the above-obtained crude product is further purified by crystallization in water & water miscible solvent having the ratio less than 10% or more than 10% and the obtained • product is confirmed as crystalline Form-A.
- the purification of crude Irbesartan containing mainly degradation impurity is carried out by suspending the crude Irbesartan in a mixture of water & water miscible solvent such as alcohols, acetonitrile, acetone, dioxane, tetrahyrofuran, preferably ethanol, isopropanol, acetonitrile & acetone.
- the ratio of water & water miscible solvent can be varied depending upon the solvent used. It is observed that the variation in ratio does not affect the polymorphism.
- the traces of degradation impurity present in the Irbesartan Form-A can be further removed by refluxing the product in ethyl acetate or in a mixture of ethyl acetate and ethanol, preferably ethyl acetate to give pure Irbesartan Form-A as per pharmacopoeias requirements.
- the invention can be further illustrated by the below non-limiting examples.
- the crude Irbesartan used for purification is having purity about 90%.
- the invention can be further illustrated by the below non-limiting examples.
- a mixture of 100 g. of 2-n.butyl-3-[(2'-cyanobiphenyl-4-yl) methyl] l,3-diazaspiro-p4.4]- non-l-en-4-one, 59 g of sodium azide and 240 g of tributyl tin chloride are refluxed in 800 ml of xylene for 24 hrs. After completion of the reaction, the reaction mixture is cooled to room temperature, filtered and extracted with 2 x 1.0 lit of IN sodium hydroxide solution. The combined aqueous layer containing the product is washed with toluene and the pH of the aqueous layer is adjusted to 4.0 - 6.0 with dilute hydrochloric acid. The product is filtered and dried at 50-65 0 C till constant weight to get Irbesartan form-A.
- Example-4 Preparation of Irbesartan form-A 1O g of crude Irbesartan is suspended in 100 ml of -84% ethyl alcohol & 16% water. The mixture is heated to reflux to get a clear solution. The solution is filtered while hot and cooled slowly to 25-30 0 C, filtered and washed with 10 ml of -84% ethyl alcohol. The product is filtered and dried at 50-65°C till constant weight to get Irbesartan Form-A.
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Abstract
The present invention relates to a process for the preparation of Irbesartan Form-A by crystallization in water & water miscible solvent having the ratio 1 :99 to 99: 1.
Description
"A process for the preparation of Irbesartan Form A"
The present invention relates to a process for the preparation of Irbesartan Form-A.
Background of the invention:
Irbesartan which is chemically known as 2-n-butyl-3-[[2-(lH-tetrazol-5-yl) [l,l-biphenyl]-4-yl]methyl]-l,3-diazaspiro [4.4]non-l-en-4-one having the following structure
Irbesartan
is a non-peptide angiotensin-II antagonist used in treatment of cardiovascular diseases, such as hypertension & heart failure.
U.S. Pat. No. 5,270,317 discloses N-substituted heterocyclic derivatives including Irbesartan. The process disclosed in this patent involves the formation of trityl protected Irbesartan and deprotection of trityl group by hydrochloric acid in THF & methanol. After evaporation of the solvents, the residue is taken up in water & ION sodium hydroxide to get pH 12. The aqueous phase is washed with ether, toluene & ether again. The aqueous phase is acidified to pH 2 by HCl acid & extracted with ethyl acetate. Evaporation of Ethyl acetate yielded Irbesartan.
J Med Cherri. (1993); 36, 3371-3380, discloses a process for the preparation of Irbesartan by treating cyano derivative with tributyl tin azide in xylene under refluxed condition, after completion of reaction, reaction mass is extracted with IN sodium hydroxide solution. Acidified to pH ~5 using 3N HCl & extracted the- product with methylene chloride. Residue obtained after removing methylene chloride is crystallized from 96% ethanol to give Irbesartan.
i
U.S. Pat. No. 5,629,331 discloses two polymorphic forms Form-A and Form-B of " Irbesartan. This patent involves the preparation of these polymorphic forms comprises:
• Treating the 2-n.butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-l,3-diazaspiro-[4.4]- non-l-en-4-one with an alkaline azide and triethylamine hydrochloride in an inert polar aprotic solvent (e. g. N-methyl pyrrolidone)
• Recovering the resulted 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-l,3- diazaspiro [4.4] non-l-en-4one in the form of its alkaline salt in aqueous solution.
• Acidifying the alkaline salt in aqueous medium followed by • Crystallizing residue in a mixture of isopropanol and water to get crude
Irbesartan.
• Purification of the crude Irbesartan in water miscible solvent containing less than 10% in volume of water to isolate the Irbesartan in its Form A;
Or • Purification of the crude Irbesartan in water miscible solvent containing more than 10% in volume of water to isolate the Irbesartan in its Form B.
Acta. Cryst. (1998), C54, 808-810 described the two polymorphic forms of Irbesartan i.e., Form-A & Form-B exhibits in tautomeric equilibrium as shown below in the liquid state and these individual tautomers can be isolated in the solid state.
F0RM "A FORM-B
Indian Pat. Appl.No.809/MAS/2001 discloses a process for the preparation of Form A of Irbesartan by re-crystallizing the crude Irbesartan or Form-B from ketone solvents selected from acetone, methyl ethyl ketone, dimethyl ketone or methyl isobutyl ketone.
Indian Pat. Appl.No.809/MAS/2001 also discloses the preparation of Form-B, which involves treating Irbesartan in a solution of inorganic base (viz. sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate) or organic base (viz. dimethylamine, triethylamine, tributylamine) followed by acidification
using inorganic or organic acid (viz. hydrochloric acid, sulphuric acid, acetic acid) accompanied by stirring. The product that separates out is filtered and dried to yield Irbesartan Form-B.
Chinese Pat. No. CN 1415614 discloses a process to synthesize Irbesartan features that the cyano derivative is converted to tetrazole & directly used in next step without purification.
PCT publications WO 2005/051929 & WO 2005/051943 discloses a process the conversion of aromatic nitriles to tetrazoles, comprising treatment of the cyano compound with trialkyl tin chloride and sodium azide in the presence of a phase transfer catalyst.
As discussed above in the prior art Irbesartan can be prepared from its cyano derivative to tertrazole ring. This is further converted to its sodium salt & extracted from organic media to aqueous media using the highly basic solution such as sodium hydroxide solution. This leads to the degradation of the product at higher pH, resulting in lowering the yield & purity of the product.
It is a longstanding need to provide an industrially viable cost-effective process for the preparation of Irbesartan form-A free from degradation, organic & inorganic residual impurities.
Surprisingly, it has been found that upon treating cyano derivative with tributyl tin azide in xylene and crystallizing the crude product in a mixture of water and water miscible solvent to get Irbesartan as Form-A.
Summary of the invention:
The main object of the present invention is to provide a commercially feasible process for the preparation of Irbesartan form-A free from degradation & residual impurities.
Another object of the present invention is to provide the process for the preparation of Irbesartan without using any catalyst.
Another object of the present invention is to provide a process for the preparation of Irbesartan by avoiding the need of extracting the product in large quantity of solvents.
Yet another object of the present invention is to provide a commercially feasible process for the preparation of Irbesartan form-A by crystallizing the crude product in a mixture of water and water miscible solvent in any ratio.
Detailed description of the invention:
Thus in accordance with the present invention preparation of Irbesartan comprises of the following steps:
• Treating 2-n-butyl-3- [(2'-cyanobiphenyl -4-yl) methyl]-l,3-diazaspiro-[4.4]-non- l-en-4-one with tributyl tin chloride & sodium azide
• Separating the inorganics by filtration,
• Extracting product from organic layer with sodium hydroxide solution
• Washing the aqueous layer with organic solvent
• Acidifying the aqueous layer and isolating crude product • Crystallizing the crude product in a mixture of water and water miscible solvent
The reaction of 2-n.butyl-3-[(2'-cyanobiphenyl -4-yl)methyl]-l, 3-diazaspiro-[4.4]-non-l- en-4-one, sodium azide & tributyl tin chloride in xylene is carried out at about 50°- 1500C, preferably at 120- 150°C. When the reaction is completed, the reaction mass is filtered to remove the undissolved inorganic solid. The organic layer is extracted using sodium hydroxide solution. The resulting aqueous layer containing the product is washed with organic solvent such as toluene, n-Hexane, Heptane or cyclohexane to remove the residual impurities. Aqueous layer pH is adjusted to 3.0- 7.0, preferably 4.0-6.0 with hydrochloric acid. The precipitated crude product is isolated by filtration.
The above-obtained crude product is further purified by crystallization in water & water miscible solvent having the ratio less than 10% or more than 10% and the obtained • product is confirmed as crystalline Form-A.
The purification of crude Irbesartan containing mainly degradation impurity is carried out by suspending the crude Irbesartan in a mixture of water & water miscible solvent such as alcohols, acetonitrile, acetone, dioxane, tetrahyrofuran, preferably ethanol, isopropanol, acetonitrile & acetone. The ratio of water & water miscible solvent can be varied depending upon the solvent used. It is observed that the variation in ratio does not affect the polymorphism.
As mentioned above the suspension is heated to reflux temperature of mixture to get a clear solution. This solution is filtered to remove undissolved material & cooled to room temperature and the resulting precipitate is filtered & dried to get Irbesartan Form-A.
The traces of degradation impurity present in the Irbesartan Form-A can be further removed by refluxing the product in ethyl acetate or in a mixture of ethyl acetate and ethanol, preferably ethyl acetate to give pure Irbesartan Form-A as per pharmacopoeias requirements.
The invention can be further illustrated by the below non-limiting examples. The crude Irbesartan used for purification is having purity about 90%.
The invention can be further illustrated by the below non-limiting examples.
Example-1: Preparation of Irbesartan form-A
A mixture of 100 g. of 2-n.butyl-3-[(2'-cyanobiphenyl-4-yl) methyl] l,3-diazaspiro-p4.4]- non-l-en-4-one, 59 g of sodium azide and 240 g of tributyl tin chloride are refluxed in 800 ml of xylene for 24 hrs. After completion of the reaction, the reaction mixture is cooled to room temperature, filtered and extracted with 2 x 1.0 lit of IN sodium hydroxide solution. The combined aqueous layer containing the product is washed with toluene and the pH of the aqueous layer is adjusted to 4.0 - 6.0 with dilute hydrochloric acid. The product is filtered and dried at 50-650C till constant weight to get Irbesartan form-A.
Yield= 110 g; HPLC purity = 96%.
Example-2: Preparation of Irbesartan form-A
100 g of crude Irbesartan is suspended in 1000 ml of -96% alcohol. The mixture is heated to reflux to get a clear solution. The solution is filtered while hot and cooled slowly to 25-300C, filtered and washed with 100 ml of 96% alcohol. The product is filtered and dried at 50-650C till constant weight to get Irbesartan Form-A. Yield =70 g.; HPLC purity =99.7%.
Example-3: Preparation of Irbesartan form-A 100 g of crude Irbesartan is suspended in 1000 ml of ~96% alcohol & 4% water. The mixture is heated to reflux to get a clear solution. The solution is filtered while hot and cooled slowly to 25-350C, filtered and washed with 100 ml of 96% alcohol. Wet material is suspended in 1500 ml of ethyl acetate and heated to reflux. The suspension is cooled slowly to 25-350C, filtered and washed with 100 ml of ethyl acetate. The product is filtered and dried at 50-65° C till constant weight to get Irbesartan Form-A. YIeId= 65 g.; HPLC purity= 99.8%.
Example-4: Preparation of Irbesartan form-A 1O g of crude Irbesartan is suspended in 100 ml of -84% ethyl alcohol & 16% water. The mixture is heated to reflux to get a clear solution. The solution is filtered while hot and cooled slowly to 25-300C, filtered and washed with 10 ml of -84% ethyl alcohol. The product is filtered and dried at 50-65°C till constant weight to get Irbesartan Form-A.
Yield= 6.7 g.; HPLC purity =99.8%.
Example-5: Preparation of Irbesartan form-A
1O g of crude Irbesartan is suspended in 100 ml of -76% ethyl alcohol & 24% water. The mixture is heated to reflux to get a clear solution. The solution is filtered while hot and cooled slowly to 25-300C, filtered and washed with 10 ml of -76% ethyl alcohol. The product is filtered and dried at 50-65° C till constant weight to get Irbesartan Form-A. Yield=7.0 g. ; HPLC purity=99.8%.
Example-6: Preparation of Irbesartan form-A
1O g of crude Irbesartan is suspended in 120 ml of ~87% Isopropyl alcohol & 13% water. The mixture is heated to reflux to get a clear solution. The solution is filtered while hot and cooled slowly to 25-300C, filtered and washed with 10 ml of -87% Isopropyl alcohol & 13% water. The product is filtered and dried at 50-650C till constant weight to get Irbesartan Form-A. Yield= 7.7 g.; HPLC purity=99.7%.
Example-7: Preparation of Irbesartan form-A
10 g of crude Irbesartan is suspended in 100 ml of 87.5% Acetone & 12.5% water. The mixture is heated to reflux to get a clear solution. The solution is filtered while hot and cooled slowly to 25-350C, filtered and washed with 10 ml of 87.5% Acetone & 12.5% water. The product is filtered and dried at 50-65°C till constant weight to get Irbesartan Form-A.
Yield= 4.0 g.; HPLC purity= 99.6%.
Example-8: Preparation of Irbesartan form-A 25 g of crude Irbesartan is suspended in 200 ml of 87.5% Acetonitrile & 12.5% water. The mixture is heated to reflux to get a clear solution. The solution is filtered while hot and cooled slowly to 25-350C, filtered and washed with 10 ml of -87.5% Isopropyl alcohol & 12.5% water. The product is filtered and dried at 50-650C till constant weight to get Irbesartan Form-A. Yield= 12.8 g.; HPLC purity= 99.7%.
Example-9: Preparation of Irbesartan form-A
50 g of crude Irbesartan is suspended in 700 ml of 75% ethanol & 25% ethyl acetate. The mixture is heated to reflux to get a clear solution. The solution is filtered while hot and cooled slowly to 25-350C, filtered and washed with 50 ml of 75% Ethanol & 25% Ethyl acetate. The product is filtered and dried at 50-65 "C till constant weight to get Irbesartan Form-A.
Yield=23.6 g.; HPLC purity=99.6%.
Example-10: Preparation of Irbesartan form-A
35 g of Irbesartan (HPLC purity =99.78%) is suspended in 750 ml of ethyl acetate. The mixture is heated to reflux. The solution is allowed cool slowly to 30-350C over a period of 4 - 5 hours. The product is filtered and dried at 50-65°C till constant weight to get Irbesartan Form-A. Yield= 34 g; HPLC purity=99.9%.
Claims
We claim: 1. A process for the preparation of Irbesartan form - A comprising steps
• Treating 2-n-butyl-3- [(2'-cyanobiphenyl -4-yl) methyl]-l,3-diazaspiro- [4.4]-non-l-en-4-one with tributyl tin chloride & sodium azide
• Separating the inorganics by filtration, . • Extracting product from organic layer with sodium hydroxide solution
• Washing the aqueous layer with organic solvent
• Acidifying the aqueous layer and isolating crude product
• Crystallizing the crude product in a mixture of water and water miscible solvent
2. The process as claimed in claim 1, wherein the reaction is carried out in Xylene
3. The process as claimed in claim 1, wherein the reaction is carried out at about 50°- 150°C
4. The process as claimed in claim 2, wherein the preferable temperature is 12O0C-
150°C
5. The process as claimed in claim 1, wherein the organic solvent used for washing is toluene, n-Hexane, Heptane or cyclohexane
6. The process as claimed in claim 1, wherein the aq.layer is acidified by with inorganic . acids or organic acids
7. The process as claimed in claim 1, wherein the aqueous layer is acidified to pH 7.0 to 3.0, preferably 4.0 to 6.0.
8. The process as claimed in claim 1, wherein the water miscible solvent is ethanol, isppropanol, acetonitrile, acetone, dioxane or tetrahyrofurane
9. The process as claimed in claim 1, wherein the ratio of water and water miscible solvent is 1:99 to 99:1
10. The process as claimed in claim 1, wherein the process further comprises the removal of degradation impurities by refluxing the product in ethyl acetate or in a mixture of ethyl acetate and ethanol
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WO2005051943A1 (en) * | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Processes for the preparation of highly pure irbesartan |
WO2005051929A1 (en) * | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Conversion of aromatic nitriles into tetrazoles |
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WO2005051943A1 (en) * | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Processes for the preparation of highly pure irbesartan |
WO2005051929A1 (en) * | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Conversion of aromatic nitriles into tetrazoles |
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