WO2006134612A1 - A process for the preparation of saquinavir using novel intermediate - Google Patents

A process for the preparation of saquinavir using novel intermediate Download PDF

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Publication number
WO2006134612A1
WO2006134612A1 PCT/IN2005/000204 IN2005000204W WO2006134612A1 WO 2006134612 A1 WO2006134612 A1 WO 2006134612A1 IN 2005000204 W IN2005000204 W IN 2005000204W WO 2006134612 A1 WO2006134612 A1 WO 2006134612A1
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Prior art keywords
acid
formula
saquinavir
reaction
pharmaceutically acceptable
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PCT/IN2005/000204
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French (fr)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dandamudi Satish Kumar
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Hetero Drugs Limited
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Priority to PCT/IN2005/000204 priority Critical patent/WO2006134612A1/en
Priority to ARP050104036A priority patent/AR051302A1/en
Publication of WO2006134612A1 publication Critical patent/WO2006134612A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention provides a commercially viable process for preparing saquinavir and pharmaceutically acceptable acid addition salts thereof using novel intermediate.
  • U.S. Patent No. 5,196,438 disclosed benzyloxycarbonyl- and 2- quinolylcarbonyl- amino acid derivatives and pharmaceutically acceptable acid addition salts thereof. These compounds are antiviral agents. Among them saquinavir, chemically (2S)-N'-[(1S,2R)-3-[(3S,4aS,8aS)-3-[[(1 ,1-dimethylethyl) amino]carbonyl]octahydro-2(1 H)-isoquinolinyl]-2-hydroxy-1-(phenylmethyl) propyl]-2-[(2-quinolinylcarbonyl)amino]butanediamide is a selective HIV protease inhibitor and can be used as medicaments for the treatment of prophylaxis of viral infections in mammals, humans or non-humans. Saquinavir is represented by the following structure:
  • saquinavir is prepared by reacting N-(2-quinoIylcabonyI)-L- asparagine with 2-[3(S)-amin ⁇ 2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-deca hydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in tetrahydrofuran in presence of 3-hydroxy-1 ,2,3-benzotriazin-4(3H)-one and dicyclohexylcarbodiimide to give saquinavir.
  • This process involves the direct condensation of N-(2-quinolylcabonyl)-L- asparagine and 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-deca hydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, which requires longer time to complete the reaction and the yield obtained is not satisfactory and purity is very low.
  • the present invention is an improved, commercially viable process solving the aforesaid problem associated with process described in the prior art.
  • One object of the present invention is to provide a novel process for preparing saquinavir and pharmaceutically acceptable acid addition salts of saquinavir; in high purity and in high yield using a novel intermediate.
  • saquinavir of formula I and optionally converting saquinavir formed into a pharmaceutically acceptable acid addition salts of saquinavir.
  • Preferable organic base used in step-(a) is selected from the group consisting of triethyl amine, trimethyl amine, tributyl amine and n-butyl amine. More preferable base is triethyl amine.
  • the reaction in step (a) is carried out at about 0 - 30 0 C, more preferably at about 0 - 10 0 C and still more preferably at about 0 - 5 0 C.
  • the reaction in step (a) is carried out in a solvent selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane, n-heptane and cyclohexane; and a mixture thereof. More preferable solvent is methylene chloride or n-heptane.
  • the reaction in step (b) is carried out in a solvent selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane, n-heptane and cyclohexane; and a mixture thereof. More preferable solvent is methylene chloride or n-heptane.
  • chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform
  • hydrocarbon solvents such as n-hexane, n-heptane and cyclohexane
  • More preferable solvent is methylene chloride or n-heptane.
  • Preferable pharmaceutically acceptable acid addition salts are selected from salts obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, maleic acid, fumaric acid and tartaric acid. More preferable pharmaceutically acceptable acid addition salt is methanesulfonic acid.
  • N 2 -(2-QuinoIinylcarbonyl)-L-asparagine (44.7 gm) is suspended in methylene chloride (500 ml) at 25 - 35 0 C under N 2 atmosphere, the suspension is cooled to 0 - 5 0 C and then triethylamine (15.1 gm) is slowly added for 15 minutes. Then the contents are stirred for 10 minutes at 0 - 5 0 C to form a clear solution.
  • pivaloyl chloride (17.2 gm) is added as fast as possible under vigorous stirring and then stirred for 2 minutes at 0 - 5 0 C to obtain pivaloyl N 2 -(2-quinolinylcarbonyl)-L- asparaginate as dark red colour residual mass (it is an exothermic addition so, the temperature of the mass should be maintain at 0 - 5 0 C).
  • Step-ll [3S,4aS,8aS]-2-(3S-amino-2F?-hydroxy-4 ⁇ phenylbutyl)-N-(1 , 1 -dimethyl ethyl)decahydro-3-isoquinoline carboxamide (50 gm) is added to the pivaloyl N 2 - (2-quinolinylcarbonyl)-L-asparaginate (obtained in step-l) under vigorous stirring and then stirred for 15 minutes to form a almost dark red colour clear solution. Water (200 ml) is.added to the solution, stirred for 10 minutes and separated the layers.
  • the pH of the organic layer is adjusted to 7.8 - 8.2 with 10% aqueous sodium bicarbonate solution (500 ml) and stirred for 30 minutes.
  • the organic layer is further washed with 10% aqueous sodium bicarbonate solution, stirred for 30 minutes, washed with water (250 ml) and then separated the layers.
  • the resulting organic layer is concentrated at 35 - 45 0 C under reduced pressure until completely distilled off the solvent.
  • Methanol 100 ml is added to the mass distilled off the solvent at 35 - 45 0 C under reduced pressure to obtain an oily residue.
  • the precipitated product is filtered, washed two times with methanol (each time 50 ml) and dried at 35 - 45 0 C under reduced pressure to give 75 gm of saquinavir mesylate crude (HPLC purity: 98.0%).
  • the crude saquinavir mesylate is purified by acid/base treatment to give 60 gm of 99.5% pure saquinavir mesylate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention provides a commercially viable process for preparing saquinavir and pharmaceutically acceptable acid addition salts thereof using novel intermediate. Thus, for example, N2-(2-quinolinylcarbonyl)-L-asparagine is reacted with pivaloyl chloride in methylene chloride in presence of triethyl amine to give pivaloyl N2-(2-quinolinylcarbonyl)-L-asparaginate, which is then condensed with [3S,4aS,8aS]-2-(3S-amino-2R-hydroxy-4-phenylbutyl)-N-(1,1-dimethylethyl)decahydro-3-isoquinoline carboxamide to give saquinavir, followed by treatment with methanesulfonic acid to give saquinavir mesylate.

Description

A PROCESS FOR THE PREPARATION OF SAQUINAVIR USING NOVEL
INTERMEDIATE
FIELD OF THE INVENTION The present invention provides a commercially viable process for preparing saquinavir and pharmaceutically acceptable acid addition salts thereof using novel intermediate.
BACKGROUND OF THE INVENTION
U.S. Patent No. 5,196,438 disclosed benzyloxycarbonyl- and 2- quinolylcarbonyl- amino acid derivatives and pharmaceutically acceptable acid addition salts thereof. These compounds are antiviral agents. Among them saquinavir, chemically (2S)-N'-[(1S,2R)-3-[(3S,4aS,8aS)-3-[[(1 ,1-dimethylethyl) amino]carbonyl]octahydro-2(1 H)-isoquinolinyl]-2-hydroxy-1-(phenylmethyl) propyl]-2-[(2-quinolinylcarbonyl)amino]butanediamide is a selective HIV protease inhibitor and can be used as medicaments for the treatment of prophylaxis of viral infections in mammals, humans or non-humans. Saquinavir is represented by the following structure:
Figure imgf000002_0001
Processes for the preparations of saquinavir and related compounds were disclosed in U.S. Patent No. 5,196,438. According to U.S. Patent No.
5,196,438, saquinavir is prepared by reacting N-(2-quinoIylcabonyI)-L- asparagine with 2-[3(S)-aminθτ2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-deca hydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in tetrahydrofuran in presence of 3-hydroxy-1 ,2,3-benzotriazin-4(3H)-one and dicyclohexylcarbodiimide to give saquinavir.
This process involves the direct condensation of N-(2-quinolylcabonyl)-L- asparagine and 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-deca hydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, which requires longer time to complete the reaction and the yield obtained is not satisfactory and purity is very low.
The present invention is an improved, commercially viable process solving the aforesaid problem associated with process described in the prior art.
One object of the present invention is to provide a novel process for preparing saquinavir and pharmaceutically acceptable acid addition salts of saquinavir; in high purity and in high yield using a novel intermediate. DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided a novel process for preparing saquinavir of formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof: which comprises: a) reacting N?-(2-quinolinylcarbonyI)-L-asparagine of formula
Figure imgf000003_0002
with pivaloyl chloride of formula III
Figure imgf000003_0003
in presence of an organic base to give mixed anhydride of formula IV:
Figure imgf000004_0001
b) reacting the mixed anhydride of formula IV with [3S,4aS,8aS]-2-(3(S)-amino- 2(f?J-hydroxy-4-phenylbutyI)-N-(1 , 1 -dimethylethyl)decahydro-3-isoquinoline carboxamide of formula V:
Figure imgf000004_0002
to give saquinavir of formula I and optionally converting saquinavir formed into a pharmaceutically acceptable acid addition salts of saquinavir.
Mixed anhydride of the formula IV is novel and forms part of the invention. Preferable organic base used in step-(a) is selected from the group consisting of triethyl amine, trimethyl amine, tributyl amine and n-butyl amine. More preferable base is triethyl amine.
The reaction in step (a) is carried out at about 0 - 300C, more preferably at about 0 - 100C and still more preferably at about 0 - 50C. Preferably the reaction in step (a) is carried out in a solvent selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane, n-heptane and cyclohexane; and a mixture thereof. More preferable solvent is methylene chloride or n-heptane. Preferably the reaction in step (b) is carried out in a solvent selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane, n-heptane and cyclohexane; and a mixture thereof. More preferable solvent is methylene chloride or n-heptane.
Preferable pharmaceutically acceptable acid addition salts are selected from salts obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, maleic acid, fumaric acid and tartaric acid. More preferable pharmaceutically acceptable acid addition salt is methanesulfonic acid.
The invention will now be further described by the following example, which is illustrative rather than limiting.
Example Step-I:
N2-(2-QuinoIinylcarbonyl)-L-asparagine (44.7 gm) is suspended in methylene chloride (500 ml) at 25 - 350C under N2 atmosphere, the suspension is cooled to 0 - 50C and then triethylamine (15.1 gm) is slowly added for 15 minutes. Then the contents are stirred for 10 minutes at 0 - 50C to form a clear solution. To the solution 3,5-lutidine (2.5 gm) is added, immediately pivaloyl chloride (17.2 gm) is added as fast as possible under vigorous stirring and then stirred for 2 minutes at 0 - 50C to obtain pivaloyl N2-(2-quinolinylcarbonyl)-L- asparaginate as dark red colour residual mass (it is an exothermic addition so, the temperature of the mass should be maintain at 0 - 50C).
Step-ll: [3S,4aS,8aS]-2-(3S-amino-2F?-hydroxy-4~phenylbutyl)-N-(1 , 1 -dimethyl ethyl)decahydro-3-isoquinoline carboxamide (50 gm) is added to the pivaloyl N2- (2-quinolinylcarbonyl)-L-asparaginate (obtained in step-l) under vigorous stirring and then stirred for 15 minutes to form a almost dark red colour clear solution. Water (200 ml) is.added to the solution, stirred for 10 minutes and separated the layers. The pH of the organic layer is adjusted to 7.8 - 8.2 with 10% aqueous sodium bicarbonate solution (500 ml) and stirred for 30 minutes. The organic layer is further washed with 10% aqueous sodium bicarbonate solution, stirred for 30 minutes, washed with water (250 ml) and then separated the layers. The resulting organic layer is concentrated at 35 - 450C under reduced pressure until completely distilled off the solvent. Methanol (100 ml) is added to the mass distilled off the solvent at 35 - 450C under reduced pressure to obtain an oily residue.
To the residue methanol (210 ml) is added, heated to 40 - 450C, carbon eno anticromos (5.0 gm) is added and stirred for 15 minutes at 40 - 450C. The carbon is filtered through hi-flo and washed with hot methanol (70 ml). Then the filtrate is cooled to 20 - 250C, methane sulfonic acid (12 gm) is added drop wise for 15 minutes and stirred for 12 hours at 20 - 250C. The precipitated product is filtered, washed two times with methanol (each time 50 ml) and dried at 35 - 450C under reduced pressure to give 75 gm of saquinavir mesylate crude (HPLC purity: 98.0%).
The crude saquinavir mesylate is purified by acid/base treatment to give 60 gm of 99.5% pure saquinavir mesylate.

Claims

We claim:
1. A process for preparation saquinavir of formula I:
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof: which comprises: a) reacting N2-(2-quinoIinylcarbonyl)-L-asparagine of formula II:
Figure imgf000007_0002
with pivaloyl chloride of formula
Figure imgf000007_0003
in presence of an organic base to give mixed anhydride of formula IV:
Figure imgf000007_0004
b) reacting the mixed anhydride of formula IV with [3S,4aS,8aS]-2-(3(Sj- amino-2(f?J-hydroxy-4-phenylbutyl)-N-(1 ,1-dimethylethyl)decahydro-3- isoquinoline carboxamide of formula V:
Figure imgf000008_0001
to give saquinavir of formula I and optionally converting saquinavir formed into a pharmaceutically acceptable acid addition salts of saquinavir.
2. The process as claimed in claim 1 , wherein the organic base is selected from the group consisting of triethyl amine, trimethyl amine, tributyl amine and n-butyl amine.
3. The process as claimed in claim 2, wherein the organic base is triethyl amine.
4. The process as claimed in claim 1 , wherein the reaction in step (a) is carried out at about 0 - 300C.
5. The process as claimed in claim 4, wherein the reaction is carried out at about 0 - 100C.
6. The process as claimed in claim 5, wherein the reaction is carried out at about 0 - 50C.
7. The process as claimed in claim 1 , wherein the reaction in step (a) is carried out in a solvent selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane, n-heptane and cyclohexane; and a mixture thereof.
8. The process as claimed in claim 7, wherein the solvent is methylene chloride or n-heptane.
9. The process as claimed in claim 1 , wherein the reaction in step (b) is carried out in a solvent selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane, n-heptane and cyclohexane; and a mixture thereof.
10. The process as claimed in claim 9, wherein the solvent is methylene chloride or n-heptane.
11. The process as claimed in claim 1 , wherein the pharmaceutically acceptable acid addition salt is selected from salts obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, maleic acid, fumaric acid and tartaric acid.
12. The process as claimed in claim 11 , wherein the pharmaceutically acceptable acid addition salt is methanesulfonic acid.
13. Compound of formula IV:
Figure imgf000009_0001
PCT/IN2005/000204 2005-06-16 2005-06-16 A process for the preparation of saquinavir using novel intermediate WO2006134612A1 (en)

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ARP050104036A AR051302A1 (en) 2005-06-16 2005-09-26 A PROCEDURE TO PREPARE SAQUINAVIR USING AN INTERMEDIARY

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010095142A2 (en) * 2009-02-17 2010-08-26 Hetero Research Foundation Novel polymorphs of saquinavir
CN102260243A (en) * 2011-06-09 2011-11-30 沈阳亿灵医药科技有限公司 Saquinavir succinic acid half ester salt and its preparation
CN111013309A (en) * 2019-12-17 2020-04-17 南通市天时化工有限公司 Method for purifying tail gas and recovering materials in pivaloyl chloride production process

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5196438A (en) * 1989-12-11 1993-03-23 Hoffmann-La Roche Inc. Amino acid derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5196438A (en) * 1989-12-11 1993-03-23 Hoffmann-La Roche Inc. Amino acid derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GOEHRING W. ET AL.: "Synthesis of the HIV-proteinase inhibitor saquinavir. A challenge for process research", CHIMIA, vol. 50, no. 11, 1996, pages 532 - 537, XP000889687 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010095142A2 (en) * 2009-02-17 2010-08-26 Hetero Research Foundation Novel polymorphs of saquinavir
WO2010095142A3 (en) * 2009-02-17 2011-12-15 Hetero Research Foundation Novel polymorphs of saquinavir
CN102260243A (en) * 2011-06-09 2011-11-30 沈阳亿灵医药科技有限公司 Saquinavir succinic acid half ester salt and its preparation
CN111013309A (en) * 2019-12-17 2020-04-17 南通市天时化工有限公司 Method for purifying tail gas and recovering materials in pivaloyl chloride production process
CN111013309B (en) * 2019-12-17 2022-01-14 南通市天时化工有限公司 Method for purifying tail gas and recovering materials in pivaloyl chloride production process

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