Patent Application
20080171885
The present invention relates to process for manufacturing trandolapril of formula I of high enantiomeric purity.
Trandolapril [CAS Reg. No. [87679-37-6]], chemically known as N-(1(S)-carboethoxy-3-phenylpropyl)-S-alanyl-(2S, 3aR, 7aS)-octahydroindole-2-carboxylic acid, was first disclosed in U.S. Pat. No. 4,933,361. Trandolapril is a well-known antihypertensive agent due to its Angiotensin Converting Enzyme (ACE) inhibitory activity.
U.S. Pat. No. 4,933,361 describes the synthesis of trandolapril that employs racemic (2S, 3aR, 7aS)-trans-octahydro-1H-indole-2-carboxylic acid (Ia) and (2R, 3aS, 7aR)-trans-octahydro-1H-indole-2-carboxylic acid (Ib) as intermediate.
U.S. Pat. No. 4,933,361 discloses several methods for the preparation of the above mentioned octahydro-1H-indole-2-carboxylic acids (Ia-h). Such methods for preparation of trans octahydro-1H-indole-2-carboxylic acids (Ia-d) employ the reduction of the mixture of enamine of the formula (A) and imine of formula (B) by catalytic hydrogenation using Raney Nickel, or Pt/C in glacial acetic acid or reduction with complex borohydrides or borane-amine complexes. However these methods are commercially non-viable since the undesired cis isomers (Ie-h) are produced in major amount (i.e. more than 60%).
In copending application No. 1033/MUM/2003 there is disclosed and claimed an improved method for the production of desired racemic trans octahydroindole-1H-2-carboxylic acids (Ia and Ib) by the reduction of mixture of enamine compound formula (A) and imine compound of formula (B) using Rh/C under alkaline condition in presence of water and water miscible organic solvent.
This method provided diastereomeric mixture of octahydroindole-1H-2-carboxylic acids (Ia-h) in which the ratio of trans acids (Ia-Ih) to cis acids (Ie-Ih) was greater than or equal to 1:1. In the subsequent process the mixture of acids (Ia-h) was enriched to >94% racemate of trans octahydroindole-1H-2-carboxylic acids (Ia and Ib) by selective fractional crystallization initially from isopropanol and then from methanol. The resulting racemate of trans exo amino acids (Ia and Ib) was >94% containing <1% of the trans endo isomers (Ic and Id); and <5% of the cis isomers (Ie-h). The composition of cis and trans acids in the mixture was determined by converting the mixture to benzyl esters (IIa-h) and then checking the purity of benzyl ester by HPLC method.
The synthesis described in U.S. Pat. No. 4,933,361 is shown in scheme 1 which involves conversion of racemic trans acids Ia and Ib to corresponding mixture of hydrochloride salts IIa.HCl and IIb.HCl with benzyl alcohol and thionyl chloride. The mixture of hydrochloride salts IIa.HCl and IIb.HCl was neutralised with N-methyl morpholine in dimethyl formamide to give racemic mixture of free benzyl esters IIa and IIb which was condensed with N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanine (NEPA, IIIb) by using 1-hydroxybenzotriazole and dicyclohexylcarbodiimide to obtain a diastereomeric mixture of trandolapril benzyl esters IVa and IVb.
The diastereomers IVa and IVb were separated by column chromatographic method to obtain pure isomer IVa which was then subjected to hydrogenolysis with 10% Pd/C in ethanol to afford trandolapril as a foamy material.
The method described in U.S. Pat. No. 4,933,361 suffers from the several drawbacks such as:
U.S. Pat. No. 6,335,453 assigned to Kaneka Corporation discloses a general method for preparation of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl-amino acids (IIIc) having low content of diketopiperazine (IIId) which involve reaction of corresponding amino acid with NEPA-NCA (IIIa) under basic condition at pH 9-12 in aqueous medium or in biphasic medium consisting mixture of organic solvent and water in the ratio 96:4 to 0:100. In this method at least 2 molar equivalent of amino acid is used. Moreover, we found that trandolapril prepared by following this method was contaminated with NEPA (IIIb) which was formed presumably by hydrolysis of NEPA-NCA (IIIa). Thus, the method disclosed in U.S. Pat. No. 6,335,453 B1 suffers from the following disadvantages:
The resolution of the racemic benzyl esters IIIa and IIb is disclosed in Drug Design and Discovery, 1992, vol 9, pp 11-28 by using DBTA. The DBTA precipitates the salt of benzyl (2S, 3aR, 7aS)-trans-octahydro-1H-indole-2-carboxylate (IIa.DBTA) which is the required one for synthesis of trandolapril. As described in this publication, the resolution is achieved by treating the racemic benzyl esters IIa and IIb with DBTA in absolute ethanol followed by crystallization of crude solid from ethanol. It was found that by following this method of preparation of pure enantiomer IIa, transesterification of the benzyl ester takes place leading to the formation of undesired ethyl ester (IIj). The formation of salt IIj.DBTA was revealed from the mass spectrum which showed a peak at m/z 197 amu (M+1) arising from ethyl ester IIj. It was also found that when resolution and crystallization was carried out in methanol as solvent then the transesterification of the benzyl ester leading to the formation of undesired methyl ester (IIi) occurs.
This was evident from the fact that trandolapril manufactured from enantiomer IIa obtained by following the method of resolution as described in above publication had the contamination of the trandolapril ethyl ester (IVj) as indicated by peak at m/z 459.3 amu (M+1) (when ethanol was used for resolution and recrystallization). Similarly, trandolapril methyl ester (IVi) as indicated by peak at m/z 445 amu (M+1) was formed when methanol was used as solvent for resolution and recrystallization. These impurities were detected by their mass spectra were formed in the range of 5-12% as per HPLC analysis. The removal of these trandolapril methyl ester (IVi) or trandolapril ethyl ester (IVj) impurities from trandolapril resulted in significant loss in yield.
Thus, the resolution method described in Drug Design and Discovery, 1992, vol 9, pp 11-28 suffers from the disadvantage of undergoing side reaction i.e. transesterification of benzyl ester which complicates the subsequent steps and finally leads to contamination of impurities in the trandolapril that are arising from the transesterification products.
It is an object of the present invention to solve the problem of transesterification and provide a process for the preparation of highly pure trandolapril of Formula I which is simple and industrially suitable process and which can provide trandolapril in very high purity (i.e. >99%).
It is a further object of the present invention to provide a process for preparation of highly pure trandolapril of Formula I which is cost effective and also easy to operate on plant scale.
The applicants have found that the problem of transesterification may be solved by carrying out the resolution of racemic benzyl esters IIa and IIb in aprotic solvent selected from dimethyl formamide, dimethyl sulphoxide, acetonitrile or a mixture thereof.
A process for the preparation of highly pure trandolapril of Formula I
comprising the steps of:
According to a preferred aspect of the invention there is provided a process for the preparation of highly pure trandolapril of Formula I comprising the following steps:
According to a further preferred aspect there is provided step of resolution comprises the following steps:
According to still further aspect of the invention the step of recrystallization of crude trandolapril comprises of the following steps:
The present invention has four parts as shown below in scheme 2.
Racemic trans octahydroindole-1H-2-carboxylic acids (Ia and Ib) were prepared as per process described in the copending application No. 1033/MUM/2003 by the reduction of mixture of enamine compound formula (A) and imine compound of formula (B) using Rh/C under alkaline condition in presence of water and water miscible organic solvent. The purity of racemate of trans exo amino acids (Ia and Ib) was >94% and it contain <1% of the trans endo isomers (Ic and Id); and <5% of the cis isomers (Ie-h). The purification of trans exo acids (Ia and Ib) up to 99% was achieved after repeatedly crystallization from methanol but the yield was poor and hence this method of purification was not commercially feasible.
The process for enriching the p-toluene sulphonic acid salts of IIa and IIb to >99% purity is achieved by the present invention. The octahydroindole-1H-2-carboxylic acid (Ia-h) containing >94% of the trans racemate Ia and Ib; <1% of the trans isomers (Ic) and (Id); and <5% of the cis-diasteromers (Ie-h) was converted to its corresponding benzyl ester p-toluene sulphonate salts (IIa-h.p-TsOH) by treatment with benzyl alcohol and p-toluene sulphonic acid monohydrate by refluxing in cyclohexane and simultaneously removing the water formed during reaction by azeotropic distillation. The mixture of p-toluene sulphonic acid salts of benzyl esters (IIa-IIj). p-TsOH was then purified by crystallization from various solvents selected from cyclohexane, dichloromethane, ethyl acetate and diisopropyl ether or mixtures thereof, preferably from a mixture of dichloromethane-cyclohexane dichloromethane-diisopropyl ether or ethyl acetate-diisopropyl ether. A comparison of purity and yield obtained by using various solvents for crystallization is indicated in Table 1.
The invention involves the appropriate selection of solvent for purification and to provide a process for obtaining the mixture of p-toluene sulphonic acid salts of benzyl esters IIa and IIb in a purity >99%.
The conversion of salts IIa.p-TsOH and IIb.p-TsOH to free esters (IIa and IIb) has been achieved by treatment with inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide etc in biphasic mixture containing water immiscible organic solvent such as ethyl acetate, dichloromethane and water at lower temperature such as 0-10° C., preferably 0-5° C.
The resolution of the racemic mixture of benzyl esters IIa and IIb with DBTA was accomplished in various solvents such as ethanol, methanol, acetonitrile, ethyl acetate, acetone mixture of dimethyl sulphoxide and acetonitrile, mixture of dimethyl formamide and acetonitrile. The chiral purity and yield obtained in different solvents is indicated in Table 2. The preferred solvent for resolution is mixture of dimethyl formamide-acetonitrile or dimethyl sulphoxide-acetonitrile. The most preferred solvent is mixture of dimethyl formamide-acetonitrile.
In a preferred aspect the resolution of the racemic mixture of benzyl esters IIa and IIb was carried out with DBTA in a mixture of dimethyl formamide and acetonitrile at temperature between 15° C. to 35° C. When resolution was carried out at 25-35° C. impurity formation was up to 2-3.6%. In a further preferred aspect the resolution carried out at 15-20° C. in which the unknown impurity formation was controlled below 2%. The effect of variation in ratio of dimethyl formamide to acetonitrile is shown in table 3.
The conversion of salt IIa.DBTA to free benzyl ester (IIa) has been achieved by treatment with inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide etc in biphasic mixture containing water immiscible organic solvent such as ethyl acetate, dichloromethane and water at lower temperature such as 0-10° C., preferably 0-5° C.
The optically pure enantiomer benzyl ester IIa is converted to trandolapril benzyl ester (IVa) by treating with NEPA-NCA (IIIb) in dichloromethane which on deprotection of the benzyl group by catalytic hydrogenation over Pd/C in ethanol furnished crude trandolapril.
The crude trandolapril is purified by recrystallization from solvents such as ethanol, mixture of ethanol-diisopropyl ether, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane and dimethoxy propane. Among these preferred is a mixture of ethanol and diisopropyl ether. In a preferred embodiment the ratio 3:5 and 2:5 of ethanol and diisopropyl ether was studied. The preferred ratio is 2:5 in which purity >99.5% and yield >70% (from crude trandolapril) was obtained. The crystallization from ethanol-diisopropyl ether minimizes the formation of diketopiperazine impurity. Also it resulted in reduction of trandolapril analogues below 0.1% which were arising from cis endo ester (II) and unknown impurity formed by epimerisation in resolution. The results of crystallization of crude trandolapril are shown in table 4.
The infrared spectrum of crystallized trandolapril obtained by the process of the present invention is given in
Though in the example 42 (c) of the product U.S. Pat. No. 4,933,361 the nature of trandolapril is mentioned as foam, it was found that while repeating the same procedure and evaporating the solvent under reduced pressure (2-4 mm Hg) for longer time (20 hours) trandolapril as solid was obtained.
The infra red spectrum and X-ray powder diffraction pattern of trandolapril solid obtained by practicing the process disclosed in product U.S. Pat. No. 4,933,361 is given in
The infrared spectrum crystallized trandolapril obtained by the process of the present invention (
The powder XRD of crystallized trandolapril obtained by the process of the present invention (
The invention is further illustrated by the following non-limiting examples.
Step 1. Preparation of Benzyl Ester p-toluenesulphonate Salt (IIa-h.p-Ts-OH)
A mixture of racemic amino acid Ia-h (83 gm, 0.491 mole), p-toluenesulphonic acid monohydrate (186.6 gm, 0.982 moles), and benzyl alcohol (265.2 gm, 2.455 moles) in cyclohexane (830 ml), was slowly heated to reflux temperature (79-80° C.) for about 10-12 hours. The cyclohexane was distilled under reduced pressure till thick mobile residue was left. The residue was cooled to 25-30° C. and diisopropyl ether (2490 ml) was added. The white solid separated out was filtered, washed with diisopropyl ether (274 ml). Yield: 323.7 g (wet solid) and HPLC purity 94.9%.
Step 2. Purification of Benzyl Ester p-TsOH Salts (IIa-h.p-TsOH)
A flask was charged with dichloromethane (448.2 ml), wet solid benzyl ester p-TsOH salt (323.7 gm) obtained above in step 1 was added with stirring at 25-30° C. Cyclohexane (747 ml) was added to the slurry at 25-30° C. The reaction mixture was heated further to 50-55° C. Cyclohexane (747 ml) was added to the slurry and heating continued further at for 1 hour. The reaction mixture was then cooled to 25-30° C., filtered and the solid was washed with a mixture of dichloromethane (80 ml) and cyclohexane (280 ml). Solid dried under reduced pressure at 50-55° C. for 4-5 hours Yield: 257.3 gm and HPLC purity 99.1%.
Step 3. Preparation of Racemic Benzyl Ester (IIa+IIb) Free Base
Racemic benzyl ester p-TsOH salt (211.6 gm, 0.491 moles) obtained in step 2 above was added to flask containing dichloromethane (622.5 ml). Cooled to 0° C. A cooled aqueous solution of cold 5% sodium bicarbonate (2905 ml) was added maintaining the temperature below 5° C. Stirred at 2-5° C. for 15-20 minutes to get a clear biphasic mixture. The organic layer was separated and washed twice with 5% sodium bicarbonate solution (581 ml) followed by saturated sodium chloride solution (83 ml). The organic layer was concentrated under reduced pressure to give thick light brownish liquid. Yield 95.68 gm and HPLC purity 98.96%.
Step 4. Resolution of the Racemic Benzyl Esters IIa and IIb
The racemic benzyl ester IIa+IIb (41 gm, 0.158 mole) obtained in step 3 above was charged to flask containing acetonitrile (574 ml). Cooled to 15-20° C. and then dimethyl formamide (246 ml). A solution of (−)-dibenzoyl-L-tartaric acid monohydrate (61.29 gm, 0.163 mole) in mixture of acetonitrile (143.5 ml) and dimethyl formamide (61.5 ml) was slowly added at 15-20° C. Seed of salt IIa.DBTA (0.041 gm) was added. The resulting solution was stirred for 5 hrs at 15-20° C. The dibenzoyl tartarate salt of the benzyl ester IIa (IIa.DBTA) separated as solid was filtered and washed with acetonitrile (20.5). The solid was dried at 50-55° C. under reduced pressure for 10 hrs. Yield of IIa.DBTA was 28.7 gm and chiral purity by HPLC 98.18%.
Step 5. Preparation of Benzyl Ester IIa
The dibenzoyl tartarate salt IIa.DBTA (26 gm, 0.042 mole) obtained in step 4 above was charged into dichloromethane (130 ml), cooled to 0-2° C. An aqueous solution of cold 5% NaHCO3 (260 ml) was added with maintaining the temperature 2-4° C. The organic layer was separated and washed twice with 5% NaHCO3 (78 ml) followed by saturated sodium chloride solution (13 ml). The organic layer was concentrated under reduced pressure at 35-40° C. to give benzyl ester IIa as a thick gummy mass. Yield 10.87 gm and HPLC purity 98.06%. The ester IIa was converted to its hydrochloride salt and its specific optical rotation [α]D of ester hydrochloride (IIa.HCl) checked which was −41.8° (c=0.5, acetone) [Lit. −43°]
Step 6. Preparation of Trandolapril Benzyl Ester (IVa)
Benzyl ester IIa (10.87 gm, 0.042 moles) obtained in step 5 above was dissolved in dichloromethane (40 ml) and cooled to 0-2° C. N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanine N-carboxy anhydride (NEPA-NCA, IIIa) (13.49 gm, 0.044 mole) was added and stirred at 2-3° C. for 2 hours. Solution of 5% sodium bicarbonate (130 ml) and triethyl amine (0.85 gm) was added and stirred for 19 hours. The layers were separated. The organic layer washed twice with 5% sodium bicarbonate (52 ml) followed by water (13 ml). The organic layer was concentrated under reduced pressure at 40-45° C. to get a gummy solid. Yield was 21.84 gm and HPLC purity 97.8%.
Step 7. Preparation of Crude Trandolapril
The gummy mass of trandolapril benzyl ester IVa (21.84 gm, 0.042 mole) obtained above in step 6 was dissolved in ethanol (410 ml) at 25-30° C. and charged to autoclave. 10% Pd/C (2.184 g) was added under nitrogen at 25-30° C. The reaction mixture was stirred at 25-30° C. for 2 hours maintaining the hydrogen pressure at 50 psi. The contents were filtered off, and catalyst washed with ethanol (60 ml). The combined filtrate was charged into another flask and ethanol was distilled off under reduced pressure at 35-40° C. till solid was left. Yield of crude trandolapril was 16.5 gm.
Step 8. Crystallization of Crude Trandolapril
Mixture of crude trandolapril (16.5 gm) obtained in step 7 above, ethanol (36.4 ml), and diisopropyl ether (91 ml) was refluxed for 10 minutes. Slowly cooled to 25° C. The solid obtained was filtered off, washed with diisopropyl ether (7.8 ml). Yield of pure trandolapril was 11.848 gm and HPLC purity 99.94% on gradient system and assay 99.2% (on gradient system).
M.P.: 122-124° C.,
IR (KBr): 3278.7, 2942.2, 1735.2, 1654.3, 1456.7, 1433.7, 1366.5, 1192.8, 1101.5, 1063.8 and 1023.8 cm−1 (
1H NMR (CD3OD, δ ppm): 7.33 (s, 5H), 4.34 (m, 3H), 3.86 (q, 2H), 3.28-1.46 (m, 17H) and 1.39 (d+t, 6H),
Mass (m/z, amu): 453.5 (M+Na) and 431.7 (M+H)+ molecular ion.
Powder XRD: The (d) spacings and relative intensities (I/Io) are listed below.
The crystalline trandolapril obtained by the above process of the present invention has the characteristic X-ray powder diffraction pattern as given in
The gummy mass of trandolapril benzyl ester IVa (42 gm, 0.0807 mole) was dissolved in ethanol (1482.3 ml) at 23° C. and solution was charged into autoclave. 10% Pd/C (4.94 gm) was added reaction mixture was hydrogenated under normal pressure at 23° C. for 2 hours. The contents were filtered and filtrate was evaporated to give foamy solid.
The resulting foamy solid was further concentrated under reduced pressure (2-4 mm Hg) for 5 hours to remove the traces of solvent. The trandolapril was obtained was further dried under reduced pressure (2-4 mm Hg) for 20 hours. Yield was 17.2 gm and HPLC purity 98.8%.
M.P.: 117.5-118.5° C.,
IR (KBr): 3278.5, 2942.4, 1735.1, 1654.3, 1457.8, 1433.8, 1366.7, 1192.5, 1101.4, 1063.7 and 1023.7 cm−1 (
Powder XRD: The (d) spacing and relative intensities (I/Io) are listed below.
The characteristic X-ray powder diffraction pattern of trandolapril obtained by the above example 2 is given in
| Number | Date | Country | Kind |
|---|---|---|---|
| 155/MUM/2005 | Feb 2005 | IN | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IN2005/000301 | 9/6/2005 | WO | 00 | 8/14/2007 |
