WO2008132759A2 - Industrially advantageous process for the production of lisinopril dihydrate - Google Patents
Industrially advantageous process for the production of lisinopril dihydrate Download PDFInfo
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- WO2008132759A2 WO2008132759A2 PCT/IN2008/000259 IN2008000259W WO2008132759A2 WO 2008132759 A2 WO2008132759 A2 WO 2008132759A2 IN 2008000259 W IN2008000259 W IN 2008000259W WO 2008132759 A2 WO2008132759 A2 WO 2008132759A2
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- lisinopril
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- dihydrate
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- lisinopril dihydrate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06086—Dipeptides with the first amino acid being basic
Definitions
- the present invention relates to an industrially advantageous process for the production of lisinopril dihydrate which is selective and does not involve column chromatographic techniques. Also the process is economically advantageous and saves the time consumed in cumbersome column methods.
- Present invention also discloses a novel method of condensing NH-protected L-lysine and carboxy protected L-proline in the preparation of lisinopril dihydrate.
- Lisinopril is a drug of the angiotensin converting enzyme (ACE) inhibitor class that is primarily used in treatment of hypertension, congestive heart failure, heart attacks and also in preventing renal and retinal complications.
- ACE angiotensin converting enzyme
- Lisinopril was the third ACE inhibitor after captopril and enalapril and was introduced into therapy in the early ⁇ 990s(Nature 288 (5788): 280-3).
- Lisinopril has a number of properties that distinguish it from other ACE inhibitors as it is hydrophilic, has long half life and tissue penetration and is not metabolized by the liver.
- Lisinopril is the lysine-analog of enalapril.
- lisinopril is not a prodrug and is excreted unchanged in the urine. In cases of overdosage, it can be removed from circulation by dialysis.
- US 4,374,829 discloses the process wherein crude lisinopril is adsorbed on strong acid ion exchange resin to remove salts and is eluted with a solvent which is further purified by gel filtration chromatography.
- the disadvantage of using column is the limitations in batch sizes and the amount and quality of water used in removing the salts. Sulfate ash and inorganic salts contamination in the final product is another critical aspect with columns.
- EP 0168769 A2 discloses the process wherein the lisinopril along with salts is adsorbed on strong acid ion exchange resins and washed with water to remove salts. The product was then eluted from the ion exchange resin using a solvent and further purified and crystallised to get lisinopril dihydrate.
- US 6,271,393 discloses the process of preparation of lisinopril wherein protected lisinopril is subjected to hydrolysis followed by separation using water miscible organic solvent particularly ethanol.
- the disadvantage of the process is, to eliminate the inorganic salts the dilution/concentration procedure has to be repeated more number of times which is industrially cumbersome.
- the solvent ethanol is water miscible organic solvent and the process is carried out in aqueous medium, the neutral inorganic salts contamination in the final product depends on the operation concentration,temperature , pH and procedure.
- the present invention discloses a process which is industrially feasibleness cumbersome and gives high yields with more purity.
- lisinopril dihydrate which minimizes the sulphate ash, inorganic salts in the final product and also is time saving.
- the present invention provides the process for the preparation of compounds of formula I which is lisinopril dihydrate comprising the following steps:
- step 2 (b) Deprotecting the compound obtained from step 1 in presence of reducing agents like Pd/C, in C 1 -C 4 alkanols under hydrogen atmosphere.
- step 2 Reductive alkylating the compound obtained from step 2 to form protected lisinopril in presence of reducing agents in Ci-C 4 alkanols under hydrogen atmosphere.
- the present invention provides the process for preparing compounds of formula I without using the columns for purification which method is industrially disadvantageous compare to the solvent purification.
- R is a C 1 -C 4 alkyl group, preferably ethyl group.
- condensation between NH protected lysine with carboxy protected L-proline is carried out in presence of acid chlorides like pivaloyl chloride phenylchloroformate, substituted phenylchloroformate like 4- nitrophenylchloroformate inpresence of organic bases like triethylamine, N-methyl morpholine, 4-dimethylaminopyridine or pyridine.
- acid chlorides like pivaloyl chloride phenylchloroformate, substituted phenylchloroformate like 4- nitrophenylchloroformate inpresence of organic bases like triethylamine, N-methyl morpholine, 4-dimethylaminopyridine or pyridine.
- Isolation of lisinopril dihydrate from protected lisinopril is carried out by first hydrolyzing with inorganic bases.
- the reaction mixture obtained after hydrolysis is neutralized using a strong inorganic acid to pH about 5.0 to 6.0 and given washing with water immiscible organic solvent to remove organic impurities.
- the reaction mixture pH is adjusted to below 4.0 preferably to 2.5 to 4.0 with dilute inorganic acid.
- the lisinopril acid salts formed are more soluble in organic phase and are extracted with, partially water miscible solvent at a temperature range of about 0-80°C, optionally of about 15-30 0 C and inorganic salts remains in water.
- the organic layer pH is adjusted to about 5.0 to 6.0 with a base to get lisinopril and the reaction mass is further concentrated. To this solution water is added. pH of the solution is maintained at about 5.0 to 6.0 and crude lisinopril dihydrate is crystallized .
- the lisinopril dihydrate thus obtained does not have organic as well as inorganic impurities . This process avoids using column, to remove inorganic impurities which are industrially very cumbersome to remove.
- inorganic bases used for hydrolysis are selected from but not restricted to hydroxides and carbonates of alkali and alkaline earthmetals such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, magnecium hydroxide, calcium hydroxide or mixtures thereof. These bases are used as aqueous solutions and may be added successively or all at once so that pH may be maintained at a selective value during hydrolysis.
- Inorganic acids that are used are selected from but not limited to strong acids, preferably hydrochloric and sulphuric acids. The amount of inorganic acid used, mainly depends on the amount of inorganic base used for hydrolysis.
- the organic impurities are generally removed by washing with water immiscible solvent which is selected from dichloromethane, ethyl acetate and like.
- water immiscible solvent which is selected from dichloromethane, ethyl acetate and like.
- the inorganic salts formed from inorganic base and inorganic acid are removed by selective extraction of the compound into partially water miscible solvent like n-butanol and leaving the inorganic salts in aqueous phase.
- the acids and the bases are used for maintaining certain pH and these are hot selective as per the examples.
- the advantage of the present invention is removal of column techniques in isolating the compound from inorganic salts and also during purification process .
- Inorganic salts are removed through selective separation by using partially water miscible solvents thus reducing the inorganic salts impurity in the final product and also sulphated ash impurities which are critical when using columns, is bypassed.
- the inorganic salts formed from inorganic base and inorganic acid are removed by using more water soluble organic or inorganic salts like ammonium chloride, triethylamine hydrochloride which expedite the process of precipitation of inorganic salts formed due to neutralization from inorganic base and inorganic acid .
- the organic solvent used for dilution in this process is a poor solvent for the inorganic salt i.e the percentage of elimination of the inorganic salt increases with increased percentage of organic solvent.
- More preferable organic solvents are C 1 -C 4 alkanols, acetone, tetrahydrofuran, acetonitrile and like. Water content of the organic solvent having lisinopril, is adjusted to about 8.5 to 12% w/w and crystallized lisinopril dihydrate using lisinopril seeding.
- Purification of lisinopril dihydrate is carried out by giving carbon treatment to crude compound solution in water and further crystallization from Ci-C 4 alkanols preferably ethanol with lisinopril seeding.
- the present invention is advantageous as regards to the solvent system which is suitable for selective separation of organic and inorganic salts after neutralization step thereby simplifying the process and in turn minimizing the possible adverse effects in the case of presence of inorganic salts in trace amounts in the final product.
- Another aspect of the present invention is to expedite the precipitation of inorganic salts formed due to neutralization by using more water soluble salts and isolating lisinopril dihydrate by using organic solvents.
- Example 1 Preparation of crude Lisinopril dihydrate.
- Step I Preparation of N-carbobenzyloxy-N-trifluoroacetyl-L-Iysine-proline benzyl ester :
- L-proline benzyl ester was prepared from 61.0 g of L-proline benzyl ester hydrochloride in 150 ml of ethyl acetate using ammonia solution at 0-5 0 C at pH 9-9.5 which was reacted with 100.0 g of N-Carbobenzyloxy-N-trifiuoroacetyl-L-lysine in presence of 28.2 g of triethyl amine and 32.0 g of pivaloyl chloride at -15 to -20 0 C in 600 ml of ethyl acetate for about 1-2 hr.
- the resulting reaction mixture was diluted with HCl solution (11.4 ml (35%) in 88.0 ml water) and separated the organic layer.
- the organic layer was washed with 100 ml of water, 2x100 of 10% ammonia solution to give N-Carbobenzyloxy-N-trifiuoroacetyl-L-lysine- proline benzyl ester.
- Step II Preparation of N-trifluoroacetyl-L-lysine-Proline: Ethyl acetate was distilled off from the above solution and the residue was dissolved in 400 ml of methanol. The resulting solution was treated with 3.5 g of 5% Pd/C in 100 ml methanol at 40 psi of hydrogen pressure for 3 hrs. After completion of the reaction the catalyst was filtered and the solution was taken to the next step without isolation or isolation also can be done with n-butanol and diisopropyl ether.
- Step III Preparation of Preparation of N-trifluoroacetyl-N- [(S)-I -Ethoxycarbony 1-3- phenylpropyl]-l-lysine-l-proline :
- the above solution / solid (80.0 g) was reductive alkylated with ethyl-2-oxo-4-phenyl butanoate in presence of Raney nickel (40 g) and 225 g of molecular sieves at 40 psi of hydrogen pressure for 4-8 hrs, which was filtered and methanol was removed completely from the filtrate.
- the resulting viscous mass was dissolved in 375 ml of water using 15 g of sodium carbonate in 150 ml of water.
- the aq. Layer was washed with 3x200 ml of toluene.
- the aq.layer pH was adjusted to 4.1-4.3 with 1 :1 dilute hydrochloric acid solution.
- the resulting mass was extracted with 2x300 ml of MDC, concentrated to yield protected lisinopril (viscous liquid).
- Method I Isolation of crude Lisinopril dihydrate: 50.0 g of protected Lisnopril was reacted with aq sodium hydroxide solution (13.2 g of NaOH in 330 ml of water) at 40- 45 C for about 2-4 hrs. The resulted deprotected lisinopril solution was cooled and the pH was adjusted to 5.0-5.3 with dilute (1:1) HCl solution and washed with 125.0 ml of
- reaction mass pH was further adjusted to below 4.0 (preferably 3.0-4.0) with dilute (1:1) HCl solution.
- the resulted solution was extracted with 350.0 ml of n-Butanol at 20-25 0 C.
- the Organic layer pH was adjusted to 5.0-5.3 with Con. ammonia solution.
- Example-3 Preparation of pure Lisinopril dihydrate.
- Lisinopril dihydrate 40.0 g was dissolved in 240 ml of water and treated with 4.0 g of activated carbon and distilled the water under vacuum. The resulted solution water content was about 60-70% and Lisinopril dihydrate was crystallized using 20.0ml ethanol and lisinopril seeding (0.5g). The suspension was maintained for 12 hrs, diluted with 180 ml of ethanol and filtered to give 30 g of pure lisinopril dihydrate.
Abstract
The present invention relates to an Industrially advantageous process for the production of lisinopril dihydrate which is selective and does not involve column chromatographic techniques. Also the process is economically advantageous and saves the time consumed in cumbersome extraction methods. Present invention also discloses a novel method of condensing NH-protected L-lysine and carboxy protected L-proline in the preparation of lisinopril dihydrate.
Description
INDUSTRIALLY ADVANTAGEOUS PROCESS FOR THE PRODUCTION OF LISINOPRIL DIHYDRATE
Field of invention: The present invention relates to an industrially advantageous process for the production of lisinopril dihydrate which is selective and does not involve column chromatographic techniques. Also the process is economically advantageous and saves the time consumed in cumbersome column methods.Present invention also discloses a novel method of condensing NH-protected L-lysine and carboxy protected L-proline in the preparation of lisinopril dihydrate.
Background of invention: Lisinopril is a drug of the angiotensin converting enzyme (ACE) inhibitor class that is primarily used in treatment of hypertension, congestive heart failure, heart attacks and also in preventing renal and retinal complications.Lisinopril was the third ACE inhibitor after captopril and enalapril and was introduced into therapy in the early \990s(Nature 288 (5788): 280-3). Lisinopril has a number of properties that distinguish it from other ACE inhibitors as it is hydrophilic, has long half life and tissue penetration and is not metabolized by the liver. Lisinopril is the lysine-analog of enalapril. Unlike other ACE inhibitors, lisinopril is not a prodrug and is excreted unchanged in the urine. In cases of overdosage, it can be removed from circulation by dialysis.
US 4,374,829 discloses the process wherein crude lisinopril is adsorbed on strong acid ion exchange resin to remove salts and is eluted with a solvent which is further purified by gel filtration chromatography.The disadvantage of using column is the limitations in batch sizes and the amount and quality of water used in removing the salts. Sulfate ash and inorganic salts contamination in the final product is another critical aspect with columns.
EP 0168769 A2 discloses the process wherein the lisinopril along with salts is adsorbed on strong acid ion exchange resins and washed with water to remove salts.The product was then eluted from the ion exchange resin using a solvent and further purified and crystallised to get lisinopril dihydrate.
US 6,271,393 discloses the process of preparation of lisinopril wherein protected lisinopril is subjected to hydrolysis followed by separation using water miscible organic solvent particularly ethanol. The disadvantage of the process is, to eliminate the inorganic salts the dilution/concentration procedure has to be repeated more number of times which is industrially cumbersome. During the recovery of lisinopril by crystallisation after neutralisation ,further neutralisation is necessary and the salt formed at that step may contaminate the desired crystals or may worsen the crystallisability of the desired product. As the solvent ethanol is water miscible organic solvent and the process is carried out in aqueous medium, the neutral inorganic salts contamination in the final product depends on the operation concentration,temperature , pH and procedure.
To overcome the disadvantages of prior disclosed art the present invention discloses a process which is industrially feasibleness cumbersome and gives high yields with more purity.
Summary of the invention:
It is the principle aspect of the present invention to provide an improved and industrially feasible process for making compound of formula I
known as lisinopril dihydrate which minimizes the sulphate ash, inorganic salts in the final product and also is time saving.
In accordance with the preffered embodiment, the present invention provides the process for the preparation of compounds of formula I which is lisinopril dihydrate comprising the following steps:
(a) Condensing NH-protected lysine with carboxy protected proline in presence of acid chlorides like pivaloyl chloride, phenylchloroformate, substituted phenylchloroformate like 4-nitrophenylchloroformate in presence of organic bases like triethylamine,N-methyl morpholine ,4-dimethylaminopyridine,pyridine.
(b) Deprotecting the compound obtained from step 1 in presence of reducing agents like Pd/C, in C1-C4 alkanols under hydrogen atmosphere.
(c) Reductive alkylating the compound obtained from step 2 to form protected lisinopril in presence of reducing agents in Ci-C4 alkanols under hydrogen atmosphere.
(d) Isolating lisinopril dihydrate from protected lisinopril by using either
> Partially water immiscible organic solvent (or)
> more water soluble salts
(e) Optionally crystallising lisinopril dihydrate
In accordance with another preferred embodiment the present invention provides the process for preparing compounds of formula I without using the columns for purification which method is industrially disadvantageous compare to the solvent purification.
Detailed description of the invention:
Thus in accordance with the present invention in one embodiment the process for the preparation of lisinopril of the following structure II
is prepared from N2-(l(S)-alkoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl L-lysyl-L- proline of general formula III
where R is a C1-C4 alkyl group, preferably ethyl group.
In another embodiment of the present invention the condensation between NH protected lysine with carboxy protected L-proline is carried out in presence of acid chlorides like pivaloyl chloride phenylchloroformate, substituted phenylchloroformate like 4-
nitrophenylchloroformate inpresence of organic bases like triethylamine, N-methyl morpholine, 4-dimethylaminopyridine or pyridine.
Isolation of lisinopril dihydrate from protected lisinopril is carried out by first hydrolyzing with inorganic bases. In the second step the reaction mixture obtained after hydrolysis is neutralized using a strong inorganic acid to pH about 5.0 to 6.0 and given washing with water immiscible organic solvent to remove organic impurities. Further the reaction mixture pH is adjusted to below 4.0 preferably to 2.5 to 4.0 with dilute inorganic acid. At this pH the lisinopril acid salts formed are more soluble in organic phase and are extracted with, partially water miscible solvent at a temperature range of about 0-80°C, optionally of about 15-300C and inorganic salts remains in water. The organic layer pH is adjusted to about 5.0 to 6.0 with a base to get lisinopril and the reaction mass is further concentrated. To this solution water is added. pH of the solution is maintained at about 5.0 to 6.0 and crude lisinopril dihydrate is crystallized .The lisinopril dihydrate thus obtained does not have organic as well as inorganic impurities .This process avoids using column, to remove inorganic impurities which are industrially very cumbersome to remove.
In the present invention inorganic bases used for hydrolysis are selected from but not restricted to hydroxides and carbonates of alkali and alkaline earthmetals such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, magnecium hydroxide, calcium hydroxide or mixtures thereof. These bases are used as aqueous solutions and may be added successively or all at once so that pH may be maintained at a selective value during hydrolysis. Inorganic acids that are used are selected from but not limited to strong acids, preferably hydrochloric and sulphuric acids. The amount of inorganic acid used, mainly depends on the amount of inorganic base used for hydrolysis. After the neutralization step the organic impurities are generally removed by washing with water immiscible solvent which is selected from dichloromethane, ethyl acetate and like. The inorganic salts formed from inorganic base
and inorganic acid are removed by selective extraction of the compound into partially water miscible solvent like n-butanol and leaving the inorganic salts in aqueous phase. Thus the inorganic salts impurity can be controlled at this stage which is industrially advantageous and time saving. The acids and the bases are used for maintaining certain pH and these are hot selective as per the examples.
The advantage of the present invention is removal of column techniques in isolating the compound from inorganic salts and also during purification process .Inorganic salts are removed through selective separation by using partially water miscible solvents thus reducing the inorganic salts impurity in the final product and also sulphated ash impurities which are critical when using columns, is bypassed.
Also in another embodiment of the present invention the inorganic salts formed from inorganic base and inorganic acid are removed by using more water soluble organic or inorganic salts like ammonium chloride, triethylamine hydrochloride which expedite the process of precipitation of inorganic salts formed due to neutralization from inorganic base and inorganic acid .The organic solvent used for dilution in this process is a poor solvent for the inorganic salt i.e the percentage of elimination of the inorganic salt increases with increased percentage of organic solvent. More preferable organic solvents are C1-C4 alkanols, acetone, tetrahydrofuran, acetonitrile and like. Water content of the organic solvent having lisinopril, is adjusted to about 8.5 to 12% w/w and crystallized lisinopril dihydrate using lisinopril seeding.
Purification of lisinopril dihydrate is carried out by giving carbon treatment to crude compound solution in water and further crystallization from Ci-C4 alkanols preferably ethanol with lisinopril seeding.
The present invention is advantageous as regards to the solvent system which is suitable for selective separation of organic and inorganic salts after neutralization step thereby
simplifying the process and in turn minimizing the possible adverse effects in the case of presence of inorganic salts in trace amounts in the final product.
Another aspect of the present invention is to expedite the precipitation of inorganic salts formed due to neutralization by using more water soluble salts and isolating lisinopril dihydrate by using organic solvents.
The following specific examples illustrate the present invention in detail and do not limit the scope of the invention.
Example 1: Preparation of crude Lisinopril dihydrate.
Step I: Preparation of N-carbobenzyloxy-N-trifluoroacetyl-L-Iysine-proline benzyl ester : L-proline benzyl ester was prepared from 61.0 g of L-proline benzyl ester hydrochloride in 150 ml of ethyl acetate using ammonia solution at 0-50C at pH 9-9.5 which was reacted with 100.0 g of N-Carbobenzyloxy-N-trifiuoroacetyl-L-lysine in presence of 28.2 g of triethyl amine and 32.0 g of pivaloyl chloride at -15 to -200C in 600 ml of ethyl acetate for about 1-2 hr. The resulting reaction mixture was diluted with HCl solution (11.4 ml (35%) in 88.0 ml water) and separated the organic layer. The organic layer was washed with 100 ml of water, 2x100 of 10% ammonia solution to give N-Carbobenzyloxy-N-trifiuoroacetyl-L-lysine- proline benzyl ester.
Step II: Preparation of N-trifluoroacetyl-L-lysine-Proline: Ethyl acetate was distilled off from the above solution and the residue was dissolved in 400 ml of methanol. The resulting solution was treated with 3.5 g of 5% Pd/C in 100 ml methanol at 40 psi of hydrogen pressure for 3 hrs. After completion of the reaction the catalyst was filtered and the solution was taken to the next step without isolation or isolation also can be done with n-butanol and diisopropyl ether.
Step III: Preparation of Preparation of N-trifluoroacetyl-N- [(S)-I -Ethoxycarbony 1-3- phenylpropyl]-l-lysine-l-proline :The above solution / solid (80.0 g) was reductive alkylated with ethyl-2-oxo-4-phenyl butanoate in presence of Raney nickel (40 g) and 225 g of molecular sieves at 40 psi of hydrogen pressure for 4-8 hrs, which was filtered and methanol was removed completely from the filtrate. The resulting viscous mass was dissolved in 375 ml of water using 15 g of sodium carbonate in 150 ml of water. The aq. Layer was washed with 3x200 ml of toluene. The aq.layer pH was adjusted to 4.1-4.3 with 1 :1 dilute hydrochloric acid solution. The resulting mass was extracted with 2x300 ml of MDC, concentrated to yield protected lisinopril (viscous liquid).
Example-2:
Method I: Isolation of crude Lisinopril dihydrate: 50.0 g of protected Lisnopril was reacted with aq sodium hydroxide solution (13.2 g of NaOH in 330 ml of water) at 40- 45 C for about 2-4 hrs. The resulted deprotected lisinopril solution was cooled and the pH was adjusted to 5.0-5.3 with dilute (1:1) HCl solution and washed with 125.0 ml of
' MDC. Reaction mass pH was further adjusted to below 4.0 (preferably 3.0-4.0) with dilute (1:1) HCl solution. The resulted solution was extracted with 350.0 ml of n-Butanol at 20-250C. The Organic layer pH was adjusted to 5.0-5.3 with Con. ammonia solution.
The reaction mass was concentrated, filtered to remove salts and the residue was dissolved in water (50.0 ml). The aq. layer pH was adjusted to 5.0-5.3 with cone, ammonia solution. The resulted solution moisture, was adjusted to 50-60 % w/w and crude Lisinopril dihydrate was crystallized using isopropyl alcohol (10 V/ 500 ml) and Lisinopril seeding (0.5 g). The crude purity was greater than 95% and yield was 0.5- 0.85% w/w. Crude Lisinopril dihydrate can be obtained either from protected or deprotected lisinopril as a starting material by following the experiment described above.
Method II: Isolation of crude Lisinopril dihydrate: 50.0 g of protected Lisnopril was reacted with aq sodium hydroxide solution (13.2 g of NaOH in 330 ml of water) at 40-
450C for about 2-4 hrs. The resulted deprotected lisinopril solution was cooled and the pH was adjusted to 5.0-5.3 with dilute (1:1) HCl solution and washed with 125.0 ml of
MDC. 7.5 g of Ammonium chloride was added to aq. layer and concentrated to 70-80 ml of mass volume. 400 ml of IPA was added to aq. layer and stirred for 1 hr at 40-450C.
The insolubles were filtered and washed with 50 ml of IPA. The resulted solution water content was adjusted to 9.5-11,0% w/w and crude Lisinopril dihydrate was crystallized using Lisinopril seeding(0.5 g) .
Crude Lisinopril dihydrate can be obtained either from protected or deprotected lisinopril as a starting material by following the experiment described above.
Example-3: Preparation of pure Lisinopril dihydrate.
40.0 g of crude Lisinopril dihydrate was dissolved in 240 ml of water and treated with 4.0 g of activated carbon and distilled the water under vacuum. The resulted solution water content was about 60-70% and Lisinopril dihydrate was crystallized using 20.0ml ethanol and lisinopril seeding (0.5g). The suspension was maintained for 12 hrs, diluted with 180 ml of ethanol and filtered to give 30 g of pure lisinopril dihydrate.
Claims
1. A process for the preparation of lisinopril dihydrate comprising the following steps:
(a) condensing NH-protected lysine with carboxy protected proline in presence of acid chlorides like pivaloyl chloride, optionally substituted phenylchloroformate in presence of organic bases like triethylamine, N- methyl morpholine, 4-dimethylaminopyridine, pyridine,
(b) deprotecting the compound obtained from step 1 in presence of reducing agents like Pd/C, in Cj-C4 alkanols under hydrogen atmosphere, (c) reductive alkylating the compound obtained from step 2 to form protected lisinopril in presence of reducing agents in C1-C4 alkanols under hydrogen atmosphere,
(d) isolating lisinopril dihydrate from protected lisinopril by using partially water miscible organic solvent and (e) optionally crystallising lisinopril dihydrate.
2. The process according to claim 1 , wherein condensation of NH-protected lysine with Carboxy protected proline is carried out in presence of pivaloyl chloride.
3. The process according to claim 1, wherein lisinopril dihydrate is isolated from protected lisinopril using partially water miscible organic solvents.
4. The process according to claim 3, wherein the partially water miscible organic solvent is n-butanol.
5. A process for the preparation of lisinopril dihydrate comprising the following steps:
(a) condensing NH-protected lysine with carboxy protected proline in presence of acid chlorides like pivaloyl chloride, optionally substituted phenylchloroformate in presence of organic bases like triethylamine, N- methyl morpholine, 4-dimethylaminopyridine, pyridine, (b) deprotecting the compound obtained from step 1 in presence of reducing agents like PdVC, in Ci-C4 alkanols under hydrogen atmosphere, (c) reductive alkylating the compound obtained from step 2 to form protected lisinopril in presence of reducing agents in Cj-C4 alkanols under hydrogen atmosphere, (d) isolating lisinopril dihydrate from protected lisinopril by using more water soluble salts and (e) optionally crystallising lisinopril dihydrate.
6. The process according to claim 5, wherein isolation of lisinopril dihydrate from protected lisinopril by using more water soluble salts
7. The process according to claim 6, wherein more water soluble salt is ammonium chloride
8. A process for the preparation of lisinopril dihydrate comprising;
(a) condensing NH-protected lysine with Carboxy protected proline in presence of pivaloyl chloride,
(b) deprotecting the compound obtained from step 1 in presence of reducing agents like PdVC, in Cj-C4 alkanols under hydrogen atmosphere, (c) reductive alkylating the compound obtained from step 2 to form protected lisinopril in presence of reducing agents in Ci-C4 alkanols under hydrogen atmosphere and
(d) isolating lisinopril dihydrate from protected lisinopril by using n- butanol.
9. A process for the preparation of lisinopril dihydrate comprising (a) condensing NH-protected lysine with Carboxy protected proline in presence of pivaloyl chloride,
(b) deprotecting the compound obtained from step 1 in presence of reducing agents like Pd/C, in C1-C4 alkanols under hydrogen atmosphere, (c) reductive alkylating the compound obtained from step 2 to form protected lisinopril in presence of reducing agents in C1-C4 alkanols under hydrogen atmosphere and
(d) isolating lisinopril dihydrate from protected lisinopril by using Ammonium chloride.
10. A process for isolating lisinopril dihydrate from protected lisinopril comprising
(a) hydrolysing the protected lisinopril by using inorganic base,
(b) adjusting pH to about 5.0 - 6.0 by adding inorganic acid,
(c) washing with water immiscible organic solvent,
(d) adjusting pH to less than 4.0 by adding inorganic acid, (e) extracting lisinopril with partially water miscible organic solvent,
(f) recovering the lisinipril by adjusting organic layer pH to about 5.0 - 6.0,
(g) adjusting the water content of the organic layer to about 8.5 to 12% w/w and
(h) crystallizing lisinopril dihydrate.
11. The process according to claim 10, wherein the hydrolysis is carried out in presence of inorganic base selected from hydroxides and carbonates of alkali and alkaline earthmetals.
12. The process according to claim 1, wherein base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, magnecium hydroxide, calcium hydroxide or mixtures thereof.
13. The process according to claim 10, wherein inorganic acids are selected from strong acids, preferably hydrochloric and sulphuric acids.
14. The process according to claim 10, wherein Partially water miscible organic solvent for extraction of lisinopril is n-butanol.
15. A process for isolating lisinopril dihydrate from protected lisinopril comprising
(a) hydrolysing the protected lisinopril by using inorganic base,
(b) adjusting pH to about 5.0 - 6.0 by adding inorganic acid,
(c) washing with water immiscible organic solvent,
(d) precipitating inorganic salts by adding more water soluble salt, (e) concentrating reaction mass volume,
(f) diluting aqueous layer with organic solvent,
(g) recovering the lisinipril by adjusting water content of the organic layer to about 8.5 to 12% w/w and
(h) crystallizing lisinopril dihydrate.
16. The process according to claim 15, wherein more water soluble salt is ammonium chloride.
17. The process according to claim 15, wherein organic used for dilution solvent is selected from Ci-C4 alkanols, acetone, tetrahydrofuran, acetonitrile.
18. The process according to claim 17, wherein more preferable organic solvent is isopropyl alcohol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN907/CHE/2007 | 2007-04-27 | ||
| IN907CH2007 | 2007-04-27 |
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| WO2008132759A2 true WO2008132759A2 (en) | 2008-11-06 |
| WO2008132759A3 WO2008132759A3 (en) | 2009-04-30 |
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| PCT/IN2008/000259 WO2008132759A2 (en) | 2007-04-27 | 2008-04-24 | Industrially advantageous process for the production of lisinopril dihydrate |
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| Country | Link |
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| WO (1) | WO2008132759A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101985463A (en) * | 2010-10-29 | 2011-03-16 | 浙江昌明药业有限公司 | Method for separating and preparing lysinopril by using membrane separation technology |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4935526A (en) * | 1988-04-06 | 1990-06-19 | Rhone-Poulenc Chimie | Process for the purification of peptides |
| EP0523449B1 (en) * | 1991-07-13 | 1996-05-15 | Degussa Ag | Reductive amination of an aminoacid or an aminoacid derivative with an alpha-keto acid or an alpha-keto acid derivative |
| WO2004000874A1 (en) * | 2002-06-19 | 2003-12-31 | Eos Eczacibasi Ozgun Kimyasal Urunler Sanyi Ve Ti Caret A.S. | Process for the production of lisinopril |
| WO2004031215A2 (en) * | 2002-10-04 | 2004-04-15 | Solvay Sa | Method for synthesizing peptides comprising at least one glycine molecule |
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2008
- 2008-04-24 WO PCT/IN2008/000259 patent/WO2008132759A2/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4935526A (en) * | 1988-04-06 | 1990-06-19 | Rhone-Poulenc Chimie | Process for the purification of peptides |
| EP0523449B1 (en) * | 1991-07-13 | 1996-05-15 | Degussa Ag | Reductive amination of an aminoacid or an aminoacid derivative with an alpha-keto acid or an alpha-keto acid derivative |
| WO2004000874A1 (en) * | 2002-06-19 | 2003-12-31 | Eos Eczacibasi Ozgun Kimyasal Urunler Sanyi Ve Ti Caret A.S. | Process for the production of lisinopril |
| WO2004031215A2 (en) * | 2002-10-04 | 2004-04-15 | Solvay Sa | Method for synthesizing peptides comprising at least one glycine molecule |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101985463A (en) * | 2010-10-29 | 2011-03-16 | 浙江昌明药业有限公司 | Method for separating and preparing lysinopril by using membrane separation technology |
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| Publication number | Publication date |
|---|---|
| WO2008132759A3 (en) | 2009-04-30 |
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