WO2008041957A1 - Method for producing pure crystalline form of 2-n-butyl-3-((2-(1h-tetrazole-5-yl) (1,1'-biphenyl)-4-methyl)-1,3-diazapspiro (4,4') non -1- en-4-one - Google Patents

Method for producing pure crystalline form of 2-n-butyl-3-((2-(1h-tetrazole-5-yl) (1,1'-biphenyl)-4-methyl)-1,3-diazapspiro (4,4') non -1- en-4-one Download PDF

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WO2008041957A1
WO2008041957A1 PCT/TR2006/000046 TR2006000046W WO2008041957A1 WO 2008041957 A1 WO2008041957 A1 WO 2008041957A1 TR 2006000046 W TR2006000046 W TR 2006000046W WO 2008041957 A1 WO2008041957 A1 WO 2008041957A1
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Prior art keywords
irbesartan
water
crude
polymorph
alcohol
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PCT/TR2006/000046
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French (fr)
Inventor
Tuncer Aslan
Yildiz Gulkok
Tuba Bicer
Selda Turhan
Melek Koroglu
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Ulkar Kimya Sanayi Ve Ticaret As
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Priority to PCT/TR2006/000046 priority Critical patent/WO2008041957A1/en
Publication of WO2008041957A1 publication Critical patent/WO2008041957A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic 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
    • C07D403/10Heterocyclic 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

  • This invention relates to a method for producing pure 2-n-Butyl-3-(2-(lH-tetrazole-
  • This agent works by blocking the action of angiotensin II on its receptor.
  • Angiotensin II mediates among others smooth muscle contraction especially in blood vessels.
  • Angiotensin II receptor antagonists therefore act as powerful vasodilators.
  • the polymorphs of the active pharmaceuticals provide possibilities for the formulation studies and can increase the stability and solubility of the active ingredients in vivo.
  • Precursors that are generally protected by a triphenylmethyl-protecting group can be used for the formation of the compound of Formula (I) by deprotection of the protecting group on the tetrazole ring by using an acidic agent.
  • US 5,270,317 describes such kind of a process where crude Irbesartan was obtained with a melting point of 180-181 0 C. This melting point shows that Irbesartan obtained in this way corresponds to Polymorph A.
  • the present invention is a process for preparing pure Irbesartan in crystalline form A comprising the following steps; a) suspending crude Irbesartan into an alcohol containing 11 to 50 % of water particularly 11 to 40 % of water; b) dissolving the Irbesartan at a temperature range from 60 0 C to about 90 0 C; c) cooling the solution in 10-60 minutes to 10-55 0 C; and isolating the formed product by filtration.
  • the present invention is a purification process for Irbesartan polymorph A with a purity of higher than 99.85% starting from crude Irbesartan. The purity of the product is determined by HPLC.
  • Figure 1 Shows a representative X-ray diffraction pattern of Irbesartan form A obtained in this study.
  • Figure 2 Shows a representative X-ray diffraction pattern of Irbesartan form A given in US 5,629,331.
  • a Rigaku Miniflex X-ray diffractometer is used for the measurements of X-ray diffractogram.
  • the scanning range was 2-40 degrees two-theta.
  • the samples were grounded before analysis.
  • Irbesartan in crystalline form A is characterized by X-ray diffraction peaks (reflections) at about 4.8, 9.4, 10.5, 12.5, 13.4, 14.2, 17.0, 17.7, 19.3, 19.4, 20.1, 20.6, 21.1, 21.7, 22.7, 23.2, 23.7, 26.7, 27.7, 28.5, 31.9, 33.0 and 37.1 ⁇ 2 degrees two theta as depicted in Figure 1.
  • starting material can be polymorph A, polymorph B or crude Irbesartan, with fast cooling.
  • the compound of Formula (I) is a compound that shows angiotensin II -receptor antagonistic activity. Such compounds are powerful vasodilators and antihypertensive agents and therefore are of high commercial interest.
  • the reaction is carried out in an alcohol, more preferably in a C 1 -C 6 alcohol, especially an alcohol selected from the group consisting of ethanol and isopropanol.
  • Precipitation is a particularly preferred method for isolating of the product since it can be affected by simply stirring the mixture at 0-25 0 C with a fast cooling. This simple method can alternate the need for more complex and expensive purification techniques such as column chromatography.
  • the cooling rate must be for 5 to 90 minutes, preferably for 10 to 60 minutes.
  • IRBESARTAN 2-n-Butyl-3-spirocyclopentane-l-[(2'-(triphenylmethyl-tetrazole-5yl)-biphenyl)-4-yl) methyl]-2-imidazolin-5-one which is a precursor of Irbesartan was obtained by the coupling reaction of N-(Triphenylmethyl)-5-(4'-bromomethylbiphenyl)-2-yl- )tetrazole and 2-n-Butyl-l,3-diazaspiro(4,4')non-l-en-4-one hydrochloride in the presence of a base selected from the group of KOH, K 2 CO 3 , NaOH 5 Na 2 C ⁇ 3 or their mixtures in a polar solvent like DMF or Isopropyl alcohol. Following deprotection of the trityl group under acidic conditions yields crude Irbesartan with a purity of about 98% (based on relative percent area

Abstract

Method for producing pure 2-n-Butyl-3-(2-(1H-tetrazole-5yl) (1,1'-biphenyl)-4-yl) methyl)-1,3-diazaspiro(4,4')non-1-en-4-one that is known as Irbesartan, in crystalline form A starting from crude Irbesartan, by controlling the cooling rate of the purification step.

Description

DESCRIPTION
METHOD FOR PRODUCING PURE CRYSTALLINE FORM OF 2-n-BUTYL-3- ((2-(lH-TETRAZOLE-5-YL) (U '-BIPHENYLM-METHYL)-I^DIAZAPSPIRO
(4,4') NON -1- EN-4-ONE
This invention relates to a method for producing pure 2-n-Butyl-3-(2-(lH-tetrazole-
5yl) (l,l'-biphenyl)-4-yl) methyl)-l,3-diazaspiro(4,4')non-l-en-4-one, that is known as Irbesartan, in crystalline form A by controlling the cooling rate in the purification step.
The chemical structure of the compound is represented as Formula I.
Figure imgf000002_0001
This agent works by blocking the action of angiotensin II on its receptor. Angiotensin II mediates among others smooth muscle contraction especially in blood vessels. Angiotensin II receptor antagonists therefore act as powerful vasodilators.
The polymorphs of the active pharmaceuticals provide possibilities for the formulation studies and can increase the stability and solubility of the active ingredients in vivo. Precursors that are generally protected by a triphenylmethyl-protecting group can be used for the formation of the compound of Formula (I) by deprotection of the protecting group on the tetrazole ring by using an acidic agent. US 5,270,317 describes such kind of a process where crude Irbesartan was obtained with a melting point of 180-181 0C. This melting point shows that Irbesartan obtained in this way corresponds to Polymorph A. However, in the said patent, there is no information about the purity of the compound.
US 5,629,331 describes processes for the preparation of known polymorph A and a novel polymorph B. The teaching of the patent states that, to obtain polymorph A, the resulting crude Irbesartan is crystallized from the solvent containing less than about 10% water, preferably from an anhydrous solvent. The preferred solvents described are the alcohols, particularly 95% ethanol or isopropanol. On the other hand, to obtain Irbesartan Form B, crude Irbesartan is crystallized out in a water miscible solvent containing an amount of water greater than 10%. In the said patent, it is stated that the formation of form A and B is independent from the cooling rate of the purification step, i.e, time is not important for the formation of the desired polymorph.
However, despite of the teachings of US 5,629,331, the inventors of the present invention found such a process in which the formation of polymorph A is dependent to the cooling rate of the purification step. According to the present invention, by controlling the cooling rate, it is still possible to obtain polymorph A although water content of the reaction solvent is more than 10%.
In one aspect, the present invention is a process for preparing pure Irbesartan in crystalline form A comprising the following steps; a) suspending crude Irbesartan into an alcohol containing 11 to 50 % of water particularly 11 to 40 % of water; b) dissolving the Irbesartan at a temperature range from 600C to about 900C; c) cooling the solution in 10-60 minutes to 10-55 0C; and isolating the formed product by filtration. In another aspect, the present invention is a purification process for Irbesartan polymorph A with a purity of higher than 99.85% starting from crude Irbesartan. The purity of the product is determined by HPLC.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 Shows a representative X-ray diffraction pattern of Irbesartan form A obtained in this study. Figure 2 Shows a representative X-ray diffraction pattern of Irbesartan form A given in US 5,629,331.
A Rigaku Miniflex X-ray diffractometer is used for the measurements of X-ray diffractogram. The scanning range was 2-40 degrees two-theta. The samples were grounded before analysis.
Irbesartan in crystalline form A is characterized by X-ray diffraction peaks (reflections) at about 4.8, 9.4, 10.5, 12.5, 13.4, 14.2, 17.0, 17.7, 19.3, 19.4, 20.1, 20.6, 21.1, 21.7, 22.7, 23.2, 23.7, 26.7, 27.7, 28.5, 31.9, 33.0 and 37.1 ± 2 degrees two theta as depicted in Figure 1.
In a typical procedure for obtaining pure Irbesartan polymorph A5 crude Irbesartan is suspended in an alcohol- water mixture (see the examples), heated up to 60-90 0C to get a homogenous clear solution. The solution was then cooled down to 0-25 0C in 10-60 minutes and pure Irbesartan polymorph A was obtained. Pure Irbesartan form
A is formed regardless of the starting material, e,g. starting material can be polymorph A, polymorph B or crude Irbesartan, with fast cooling.
On the other hand, it is worth to note that with a slow cooling rate (2-6 hours) under the same conditions, only pure polymorph B is formed. The results indicates the importance of cooling rate in the purification step. In an embodiment of the invention, the compound of Formula (I) is a compound that shows angiotensin II -receptor antagonistic activity. Such compounds are powerful vasodilators and antihypertensive agents and therefore are of high commercial interest.
In another embodiment of the invention, the reaction is carried out in an alcohol, more preferably in a C1-C6 alcohol, especially an alcohol selected from the group consisting of ethanol and isopropanol.
It has been shown that for this kind of a reaction, particularly alcohols, especially the mixture of C1-C6 alcohols and water give the best results with regard to yield as well as solubility of starting material.
Precipitation is a particularly preferred method for isolating of the product since it can be affected by simply stirring the mixture at 0-25 0C with a fast cooling. This simple method can alternate the need for more complex and expensive purification techniques such as column chromatography.
In a further embodiment of the invention, to get pure Irbesartan polymorph A the cooling rate must be for 5 to 90 minutes, preferably for 10 to 60 minutes.
It has been found that in the above-named time ranges a virtually complete purification can be achieved leading to moderate to high yields of Irbesartan polymorph A.
It is understood that the above features and the features described below can be used not only in their described combination but also in other combinations or in isolation without departing from the scope of the invention.
The invention is now further illustrated by means of examples. These examples are not intended to limit the scope of the invention any way. GENERAL PROCEDURE FOR THE PREPARATION OF CRUDE
IRBESARTAN 2-n-Butyl-3-spirocyclopentane-l-[(2'-(triphenylmethyl-tetrazole-5yl)-biphenyl)-4-yl) methyl]-2-imidazolin-5-one which is a precursor of Irbesartan was obtained by the coupling reaction of N-(Triphenylmethyl)-5-(4'-bromomethylbiphenyl)-2-yl- )tetrazole and 2-n-Butyl-l,3-diazaspiro(4,4')non-l-en-4-one hydrochloride in the presence of a base selected from the group of KOH, K2CO3, NaOH5 Na23 or their mixtures in a polar solvent like DMF or Isopropyl alcohol. Following deprotection of the trityl group under acidic conditions yields crude Irbesartan with a purity of about 98% (based on relative percent area).
EXAMPLE 1
Recrystallisation of Irbesartan by using ethanol containing 15 % water
A 250 mL flask was charged with 10.0 g crude Irbesartan, 90 niL ethanol and 10 ml water. The solution was heated to reflux temperature until a clear solution was obtained. The reaction mixture was then cooled down to 10 0C immediately. The precipitate was stirred for 1.5 hour at 1O0C, filtered and washed with ethanol containing 15% water. After drying Irbesartan form A(7.5g) was obtained as a white powder (75 % yield with a purity of higher than 99.8%) .
EXAMPLE 2 Recrystallisation of Irbesartan by using ethanol containing 20 % water
A 250 mL flask was charged with 10.0 g crude Irbesartan, 85 mL ethanol and 15 ml water. The solution was heated to reflux temperature until a clear solution was obtained. The reaction mixture was then cooled down to 1O0C immediately. The precipitate was stirred for 1 hour at room temperature, filtered and washed with ethanol containing 20 % water. After drying Irbesartan form A (8.4g) was obtained as a white powder (84 % yield with a purity of higher than 99.8). EXAMPLE 3 Recrystallisation of Irbesartan by using ethanol containing 25 % water
A 250 mL flask was charged with 10.0 g crude Irbesartan, 78.9 mL ethanol and 21.0 mL water. The solution was heated to reflux temperature until a clear solution was obtained. The reaction mixture was stirred for 1 hour at this temperature and then cooled down to 1O0C immediately. Irbesartan precipitated in 5 - 10 min. The precipitate was stirred for 1 hour at 1O0C, filtered and washed with ethanol containing % 25 water. After drying Irbesartan form A (8.6g) was obtained as a white powder. (86 % yield with a purity of higher than 99.8)
EXAMPLE 4 Recrystallisation of Irbesartan by using ethanol containing 40 % water
A 250 mL flask was charged with 10.0 g crude Irbesartan, 81.23 mL ethanol and 47.36 mL water. The solution was heated to reflux temperature until a clear solution was obtained, then the solution was cooled down to 10 0C immediately. Irbesartan precipitated in 5 min. The precipitate was stirred for 1 hour at 1O0C, filtered and washed with ethanol containing 40 % water. After drying Irbesartan (9.7g) was obtained as a white solid in form A (97 % yield with a purity of higher than 99.8).

Claims

1. Method for purification of crude 2-n-Butyl-3-(2-(lH-tetrazole-5yl) (I5I'- biphenyl)-4-yl) methyl)-l,3-diazaspiro(4,4')non-l-en-4-one that is known as Irbesartan having the following formula
Figure imgf000008_0001
by dissolving crude Irbesartan in an alcohol-water mixture and obtaining pure Irbesartan polymorph A, characterized in that the cooling rate of the purification step is controlled.
2. Method according to claiml, characterized in that pure Irbesartan polymorph A is prepared comprising following steps: a) suspending crude Irbesartan into an alcohol containing 11 to 50 % of water particularly 11 to 40 % of water; b) dissolving the Irbesartan at a temperature range from 60 0C to 90 0C; c) cooling the solution in 10-60 minutes to 0-55 0C; and isolating the formed product by filtration.
3. Method according to any one of the claims 1 to 2, characterized in that to get pure Irbesartan polymorph A from crude Irbesartan the cooling rate is 5 to 90 minutes, preferably 10 to 60 minutes.
4. Method according to any one of the claims 1 to 3, characterized in that the compound of formula (I) is heated up to 60-90 0C in an alcohol-water mixture to obtain a clear solution.
5. Method according to any one of the claims 1 to 4, characterized in that the alcohol is a Ci-Ce-alcohol containing 11 to 50 % water.
6. Method according to claim 5, characterized in that the alcohol is selected from the group consisting of methanol, ethanol and isopropanol.
7. Method according to any one of the claims 1 to 6, characterized in that the compound of formula ( I ) is obtained with a purity of higher than 99.8.
PCT/TR2006/000046 2006-10-03 2006-10-03 Method for producing pure crystalline form of 2-n-butyl-3-((2-(1h-tetrazole-5-yl) (1,1'-biphenyl)-4-methyl)-1,3-diazapspiro (4,4') non -1- en-4-one WO2008041957A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5629331A (en) * 1994-10-19 1997-05-13 Sanofi Process for the preparation of a tetrazole derivative in two crystalline forms and novel the crystalline forms thereof
US20050032862A1 (en) * 1998-06-24 2005-02-10 Bruno Franc Novel form of irbesartan, processes for obtaining the said and pharmaceutical compositions containing it
WO2005051929A1 (en) * 2003-11-28 2005-06-09 Ranbaxy Laboratories Limited Conversion of aromatic nitriles into tetrazoles
WO2006001026A1 (en) * 2004-06-23 2006-01-05 Hetero Drugs Limited Irbesartan polymorphs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5629331A (en) * 1994-10-19 1997-05-13 Sanofi Process for the preparation of a tetrazole derivative in two crystalline forms and novel the crystalline forms thereof
US20050032862A1 (en) * 1998-06-24 2005-02-10 Bruno Franc Novel form of irbesartan, processes for obtaining the said and pharmaceutical compositions containing it
WO2005051929A1 (en) * 2003-11-28 2005-06-09 Ranbaxy Laboratories Limited Conversion of aromatic nitriles into tetrazoles
WO2006001026A1 (en) * 2004-06-23 2006-01-05 Hetero Drugs Limited Irbesartan polymorphs

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