WO2011161646A2 - Process for the preparation of alvimopan or its pharmaceutically acceptable salt or solvate thereof - Google Patents

Process for the preparation of alvimopan or its pharmaceutically acceptable salt or solvate thereof Download PDF

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WO2011161646A2
WO2011161646A2 PCT/IB2011/052764 IB2011052764W WO2011161646A2 WO 2011161646 A2 WO2011161646 A2 WO 2011161646A2 IB 2011052764 W IB2011052764 W IB 2011052764W WO 2011161646 A2 WO2011161646 A2 WO 2011161646A2
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formula
ethyl
process according
glycinate
benzyl
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PCT/IB2011/052764
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French (fr)
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WO2011161646A3 (en
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Anand Prakash Tiwari
Shyam Sunder Verma
Shravan Kumar Singh
Kaptan Singh
Mohan Prasad
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Ranbaxy Laboratories Limited
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63Esters of sulfonic acids
    • C07C309/72Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • the present invention relates to novel intermediates, ethyl N-[(25 -2-benzyl-3- hydroxypropanoyl]glycinate and ethyl N-[(2S)-2-benzyl-3- ⁇ [(4-bromophenyl)sulfonyl] oxy ⁇ propanoyl]glycinate, and processes for their preparation.
  • the present invention also relates to a process for producing alvimopan or its pharmaceutically acceptable salt or solvate thereof using these novel intermediates.
  • trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines derivatives are an important class of compounds that exhibit opioid antagonist activity.
  • Alvimopan of Formula A shown below represents an example of this class of opioid antagonists.
  • U.S. Patent No. 5,250,542 provides a process for the preparation of alvimopan which involves multiple steps; namely the chromatographic separation of a mixture of sterioisomeric products to isolate the desired stereoisomer of [[2-[[4-(3-hydroxyphenyl)- 3 ,4-dimethyl- 1 -piperidinyl] methyl] - 1 -oxo-3 -phenylpropyl] amino] acetic acid.
  • 5,434,171 provides crystalline dihydrate of alvimopan and a process for its preparation which involves treating (2S,3R,4R)[[2-[[4-(3- hydroxyphenyl)-3 ,4-dimethyl- 1 -piperidinyljmethyl] - 1 -oxo-3 -phenylpropyl] - amino] acetic acid 2-methylpropyl ester with an aqueous solution of sodium hydroxide in water and ethanol.
  • U.S. Patent No. 6,794,510 provides a process for the preparation of alvimopan through a variety of synthetic methods.
  • alvimopan is prepared by treating [[2(S/R)-[[4(R)-(3-acetoxyphenyl)-3(R),4-dimethyl-l-piperidinyl]methyl]-l-oxo-3- phenylpropyl]amino]acetic acid ethyl ester with sodium hydroxide in tetrahydrofuran at room temperature followed by separation of diasteriomers to give alvimopan.
  • Patent No. 100383121 provides a process for the preparation of benzyl ester of alvimopan by the reaction of (+)-3R,4R-(3 -hydroxy phenyl)3 ,4-dimethyl- 1-piperidine and (2S)-benzyl-N-[(2S)-2-benzyl-3 ⁇ [(4bromophenyl)sulfonyl]oxy ⁇
  • propanoyljglycinate in the presence of potasium carbonate and potassium iodide in isopropanol.
  • U.S. Patent No. 6,031,121 provides a process for the preparation of N-(S-2- hydroxymethyl-1 -oxo-3 -phenylpropyl)glycine benzyl ester by reacting S-2- hydroxymethyl-3-phenylpropionic acid with glycine benzyl ester p-toluene sulfonic acid salt in the presence of a base, such as triethylamine and a condensation agent, such as diclclohexylcarbodiamide.
  • a base such as triethylamine
  • a condensation agent such as diclclohexylcarbodiamide.
  • It also provides a process for the preparation of N-(S-2-(p- toluenesulfonyl)methyl-l -oxo-3 -phenylpropyl)-glycine benzyl ester by treating N-(S-2- hydroxymethyl-1 -oxo-3 -phenylpropyl)-glycine benzyl ester with p-toluenesulfonyl chloride in the presence of a base, such as pyridine, in a suitable solvent, such as dichloromethane at ambient temperature.
  • a base such as pyridine
  • alvimopan as a peripherally acting ⁇ -opioid antagonist, there is a need for a novel and efficient synthetic route for its preparation of alvimopan that provides good yields and high enantiomeric purity.
  • the present invention provides for ethyl N-[(2S)-2-benzyl- 3-hydroxypropanoyl]glycinate of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides for ethyl-N-[(2S)-2- benzyl-3- ⁇ [(4-bromophenyl)sulfonyl]oxy ⁇ propanoyl]glycinate of Formula 2, or a pharmaceutically acceptable salt thereof;
  • Bs is a /7-bromobenzene sulfonyl group.
  • the present invention provides for a process for the preparation of ethyl N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate of Formula 1 or a pharmaceutically acceptable salt thereof,
  • the process includes:
  • Embodiments of this aspect may include one or more of the following features.
  • step a) may be carried out in one or more solvents.
  • Step a) may also be carried out with a coupling agent in the presence of one or more bases.
  • Step a) may also be carried out at a temperature of 0°C to 50°C.
  • the solvents may be water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the coupling agent may be selected from the group of ⁇ , ⁇ '-dicyclohexylcarbodimide diisopropyl carbodiimide, a water soluble carbodiimide, carbonyldiimidazole, or diphenylphosphorylazide.
  • the base may selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
  • the present invention provides for a process for the preparation of ethyl-N-[(2S)-2-benzyl-3- ⁇ [(4-bromophenyl)
  • Bs is a j9-bromobenzene sulfonyl group
  • Bs is a j9-bromobenzenesulfonyl group.
  • Embodiments of this aspect may include one or more of the following features.
  • step a) may be carried out in one or more solvents.
  • Step a) may also be carried out in the presence of one or more bases and a catalyst.
  • the solvents may be water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the catalyst may be N,N-Dimethyl amino pyridine.
  • the base may be selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
  • the present invention provides for a process for the preparation of ethyl N- ⁇ (25 -2-benzyl-3-[(3i?,4i?)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-l-yl]propanoyl ⁇ glycinate of Formula 3 or a pharmaceutically acceptable salt thereof, the process includes: a) treating the ethyl-N-[(2S)-2-benzyl-3- ⁇ [(4-bromophenyl)sulfonyl]- oxy ⁇ propanoyl] glycinate of Formula 2 with trans-(+)-(3R,4R)-4-(3- hydroxyphenyl)-3 ,4-dimethylpiperidine; and
  • Embodiments of this aspect may include one or more of the following features.
  • step a) may be performed in one or more solvents in the presence of one or more bases.
  • Step a) may also be conducted at a temperature between about 40°C to reflux temperature.
  • the solvents may be water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents or mixtures thereof.
  • the base may be selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
  • the present invention provides for a process for the preparation of alvimopan of Formula A,
  • Bs is a />-bromobenzene sulfonyl group
  • Embodiments of this aspect may include one or more of the following features.
  • step a) may be carried out in one or more solvents.
  • Step a) may be carried out with a coupling agent in the presence of one or more bases.
  • Step b) may be carried out in one or more solvents.
  • Step b) may be carried out in the presence of one or more bases and a catalyst.
  • Step c) may be performed in one or more solvents in presence of base.
  • Step d) may be carried out in a mixture of ethanol and water.
  • the present invention provides for preparation of alvimopan of Formula A,
  • Embodiments of this aspect may include one or more of the following features.
  • step a) may be performed in one or more solvents in presence of base.
  • Step b) may be carried out in the presence of sodium hydroxide solution.
  • Step b) may be carried out in a mixture of ethanol and water.
  • Step b) may also be carried out at a temperature of 15°C to 40°C.
  • the solvents may be water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the bases may be selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
  • the present invention is directed to a method for the preparation of alvimopan or its pharmaceutically acceptable salt or solvate thereof using novel intermediates with the objective of developing efficient, economical and commercially viable process that employs cheap and easily available raw materials.
  • pharmaceutically acceptable salt means acid addition or basic addition salts.
  • Pharmaceutically acceptable salt are well known in the art. For example, S.M Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66, p. 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base with a suitable organic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including ammonium,
  • Trans-(3R,4R-dimethyl-4-piperidinyl)phenol employed in the preparation of alvimopan can be synthesized by the methods known in the art, for example, U.S. Patent No. 5,250,542.
  • Optically active (S)-3-Hydroxy-2-phenylmethylpropanoicacid can be synthesized by the methods known in the art, for example, U.S. Patent No. 6,031,121.
  • One aspect of the present invention provides optically active ethyl N-[2-benzyl- 3-hydroxypropanoyl]glycinate represented by a compound of Formula 1 or a
  • Formula 1 Another aspect the present invention provides a process for the preparation of ethyl N-[(25)-2-benzyl-3-hydroxypropanoyl] glycinate represented by a compound of Formula 1 or a pharmaceutically acceptable salt
  • Treating optically active 3-Hydroxy-2-methylphenylpropanoic acid with ethyl glycinate or its salt can be carried out in one or more solvents; optionally with a coupling agent in the presence of one or more bases.
  • the bases can be selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like;
  • primary, secondary, and tertiary amines such as, pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; and ammonia and ammonium salts.
  • the salt of ethyl glycinate can be any acid addition salt which may be inorganic or organic acids selected from the group of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid.
  • the most preferable salt of ethyl glycinate is hydrochloric acid which is available commercially.
  • the optically active 3-Hydroxy-2-methylphenyl propanoic acid can be the S- isomer.
  • solvents includes any solvent or solvent mixture, including for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • Preferable solvents employed for the preparation of ethyl N-[(2S)-2-benzyl-3- hydroxypropanoyl] glycinate are dimethylformamide, dichloromethane,
  • dichloromethane ethylacetate or their mixture thereof.
  • the most preferred solvent is dichloromethane.
  • the coupling agent can be selected from the group of N, N'- dicyclohexylcarbodimide and diisopropyl carbodiimide, a water soluble carbodiimide, carbonyldiimidazole, diphenylphosphorylazide and optionally, a catalyst, for example, 1-hydroxybenzotriazole, N-hydroxy succinimide.
  • Treating optically active 3-Hydroxy-2-methylphenylpropanoic acid with ethyl glycinate or its salt can be carried out preferably at a temperature of 0°C to 50°C for a time period sufficient to complete the reaction, preferably for about 30 minutes to 20 hours.
  • Step b) of the isolation of ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate involves common isolation technique, such a,s one or more of washing, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the preferred method of isolation of ethyl-N-[(2S)-2-benzyl-3- hydroxypropanoyl] glycinate may involve filtration of the reaction mass obtained in step a) to remove the dicyclohexylcarbodiimide urea present in the reaction mass followed by one or more washings with IN HCl solution at a temperature of about 20°C to 40°C.
  • the reaction mass may further be washed with a saturated sodium bicarbonate solution and 30% sodium chloride solution.
  • the isolated ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate may be further purified by salt formation, crystallization, chromatographic methods, or a combination thereof.
  • the present invention also provides for ethyl N-[(2S)-2-benzyl-3- ⁇ [(4- bromophenyl)sulfonyl]oxy ⁇ propanoyl]glycinate represented by compound of Formula 2 or a pharmaceutically acceptable salt
  • Bs is -bromobenzene sulfonyl group.
  • the present invention also provides for a process for the preparation of ethyl-N- [(2S)-2-benzyl-3- ⁇ [(4-bromophenyl)sulfonyl]oxy ⁇ propanoyl]glycinate represented by compound of Formula 2
  • Bs is /?-bromobenzene sulfonyl group
  • the process includes:
  • Bs is /)-bromobenzenesulfonyl group.
  • Treating ethyl -N-[(25)-2-benzy 1-3 -hydroxypropanoyl] glycinate with p- bromobenzenesulfonylchloride can be preferably carried out in one or more solvents; optionally in the presence of one or more bases and a catalyst.
  • the bases can be selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as, pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; ammonia and ammonium salts.
  • alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like
  • primary, secondary, and tertiary amines such as, pyridine, piperidine, triethylamine, diisoprop
  • solvents includes any solvent or solvent mixture, including for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • Preferable solvents employed for the preparation of ethyl N-[(2S)-2-benzyl-3- hydroxypropanoyljglycinate are dimethylformamide, dichloromethane,
  • dichloromethane dichloroethane, chloroform, carbontetrachloride ethylacetate, or their mixture thereof.
  • the most preferred solvent to carry out the reaction efficiently is dichloromethane.
  • the optional catalyst employed in step b) may be ⁇ , ⁇ -Dimethyl amino pyridine.
  • Treating ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate with p- bromobenzenesulfonylchloride can be preferably carried out at a temperature of about 0°C to 50°C for a time period sufficient to complete the reaction, preferably for about 30 minutes to 20 hours.
  • Step b) of isolation of ethyl-N-[(2S)-2-benzyl-3- ⁇ [(4-bromophenyl)sulfonyl]oxy ⁇ propanoyljglycinate involves common isolation technique, such as, one or more of washing, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • ⁇ [(4bromophenyl)sulfonyl]oxy ⁇ propanoyl]glycinate involves one or more washings with IN HC1 and a saturated solution of sodium carbonate followed by the precipitation of ethyl-N-[(2S)-2-benzyl-3- ⁇ [(4 bromophenyl)sulfonyl]oxy ⁇ propanoyl]glycinate by the removal of the solvents.
  • To remove the solvents one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum may be used.
  • the isolated ethyl-N-[(2S)-2-benzyl-3- ⁇ [(4 bromophenyl)sulfonyl]oxy ⁇ propanoyl]glycinate may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
  • Yet another aspect of the present invention provides for a process for the preparation of ethyl N- ⁇ (25)-2-benzyl-3-[(3/?,4i?)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-l-yl]propanoyl ⁇ glycinate represented by the compound of Formula 3, or a pharmaceutically acceptable salt.
  • the process includes:
  • Treating the ethyl-N-[(2S)-2-benzyl-3- ⁇ [(4-bromophenyl)sulfonyl]- oxy ⁇ propanoyl] glycinate represented by compound of Formula 2 with trans-(+)- (3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine can be performed in one or more solvents in the presence of base.
  • the bases can be selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium
  • bicarbonate sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; ammonia and ammonium salts; and pyridine.
  • the most suitable base is a bicarbonate of alkaline metals that may be optionally selected from the group comprising of sodium bicarbonate, potassium bicarbonate, or a mixture thereof.
  • solvents includes any solvent or solvent mixture, including water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanes.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, 1 ,2-dimethoxy ethane, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • the preferred solvent is 1 ,2-dimethoxyethane.
  • the reaction can be preferably conducted at a temperature of between about
  • Step b) of isolation of ethyl N- ⁇ (2S)-2-benzyl-3-[(3i?,4i?)-4-(3-hydroxyphenyl)- 3,4-dimethylpiperidin-l-yl]propanoyl ⁇ glycinate involves common isolation techniques, such as, one or more of washing, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the ethyl-N- ⁇ (2S)-2-benzyl-3-[(3i?,4i?)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-l-yl]propanoyl ⁇ glycinate can be isolated preferably by cooling the mixture obtained in step b) to 20°C to 30°C followed by filtration to remove the unwanted salts.
  • the filtrate may be evaporated preferably under vacuum at a temperature of about 40°C to 50°C to obtain ethyl-N- ⁇ (2S)-2-benzyl-3-[(3i?,4i?)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidin-l-yl]propanoyl ⁇ glycinate.
  • the present invention also provides for a process for the preparation of alvimopan of Formula A
  • the process includes:
  • Treating optically active 3-Hydroxy-2-methylphenylpropanoic acid with ethyl glycinate or its salt can be carried out in one or more solvents, optionally with a coupling agent, in the presence of one or more bases.
  • the bases can be selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium
  • bicarbonate sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as, pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; and/or ammonia and ammonium salts.
  • the salt of ethyl glycinate can be any acid addition salt which may be inorganic or organic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, p-toluenesulfonicacid, methanesulfonicacid.
  • the most preferable salt of ethyl glycinate is hydrochloricacid which is available commercially.
  • the optically active 3-Hydroxy-2-methylphenyl propanoic acid can be the S-isomer.
  • solvents includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide,
  • Preferable solvents employed for the preparation of ethyl N-[(2S)-2-benzyl-3- hydroxypropanoyl] glycinate are dimethylformamide, dichloromethane,
  • dichloromethane ethylacetate, or their mixture thereof.
  • the most preferred solvent to carry out the reaction efficiently is dichloromethane.
  • the coupling agent can be selected from the group of N, N'- dicyclohexylcarbodimide and diisopropyl carbodiimide, a water soluble carbodiimide, carbonyldiimidazole, diphenylphosphorylazide and optionally, a catalyst, for example, 1 -hydroxybenzotriazole, N-hydroxy succinimide
  • Treating optically active 3-Hydroxy-2-methylphenylpropanoic acid with ethyl glycinate or its salt can be carried out preferably at a temperature of between 0°C to 50°C for a time period sufficient to complete the reaction, preferably for about 30 minutes to 20 hours.
  • Treating ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate with p- bromobenzenesulfonylchloride can be preferably carried out in one or more solvents in the presence of one or more bases and a catalyst.
  • Suitable bases can be selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; ammonia and ammonium salts.
  • alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like
  • primary, secondary, and tertiary amines such as pyridine, piperidine, triethylamine, diisopropyle
  • solvents includes any solvent or solvent mixture, including for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, and the like.
  • a suitable polar aprotic solvent includes one or more of ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide,
  • Preferable solvents employed for the preparation of ethyl N-[(2S)-2-benzyl-3- hydroxypropanoyljglycinate are dimethylformamide, dichloromethane,
  • dichloromethane dichloroethane, chloroform, carbontetrachloride or a mixture thereof ethylacetate, or their mixture thereof.
  • the preferred solvent to carry out the reaction efficiently is dichloromethane
  • the catalyst employed in step b) may be ⁇ , ⁇ -Dimethyl amino pyridine.
  • Treating ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate with p- bromobenzenesulfonylchloride can be preferably carried out at a temperature of between about 0°C to 50°C for a time period sufficient to complete the reaction; preferably for about 30 minutes to 20 hours.
  • Treating ethyl-N-[(2S)-2-benzyl-3- ⁇ [(4-bromophenyl)sulfonyl]-oxy ⁇ propanoyl] glycinate represented by compound of Formula 2 with trans-(+)-(3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidine can be performed in one or more solvents in the presence of base.
  • the base can be selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides for example, potassium
  • bicarbonate sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; ammonia and ammonium salts; and pyridine.
  • the most suitable base is bicarbonate of alkaline metals that can be optionally selected from the group of sodium bicarbonate, potassium bicarbonate, or a mixture thereof.
  • solvents includes any solvent or solvent mixture, including water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanes.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, and the like.
  • a suitable polar aprotic solvent includes one or more of ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • the preferred solvent is 1 ,2-dimethoxyethane.
  • the reaction can be preferably conducted between about 40°C to reflux temperature for a time period of 1 hour to 24 hours.
  • the product is optionally isolated from the reaction mass by known techniques, such as, one or more of washing, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof, or the reaction mass is carried to step d) with out isolation.
  • step d) the compound of Formula 3 is hydrolyzed to alvimopan.
  • the compound of Formula 3 is hydrolyzed under basic condition in presence of a sodium hydroxide solution.
  • the hydrolysis is carried out in a mixture of ethanol and water as solvent at suitable temperature.
  • the hydrolysis is carried out at 15°C to 40°C.
  • step d) the hydrolysis of compounds of Formula III can be carried out in a solvent, for example, an alcoholic solvent, for example, methanol, ethanol or
  • the hydrolysis can be preferably performed at a temperature of 15°C to 60°C.
  • the hydrolysis of a compound of Formula III can be carried out in the presence of an inorganic base, for example, sodium hydroxide, potassium hydroxide or mixture(s) thereof.
  • the hydrolysis may be performed for a time period of 15 minutes to 12 hours.
  • the product is isolated from the reaction mass by known techniques, such as, one or more of washing, crystallization, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the preferable method of isolation of the product involves crystallizing the product from the reaction mass by adjusting the pH of the reaction mass to 3-6.5 using concentrated hydrochloricacid.
  • the reaction mass may be optionally seeded to effect the crystallization of the product.
  • the alvimopan thus obtained may be further converted to pharmaceutically acceptable salt, hydrate or solvate thereof as desired by the techniques available in the literature.
  • the present invention also provides for a process for preparation of alvimopan of Formula A
  • the process includes:
  • Treating ethyl-N-[(2S)-2-benzyl-3- ⁇ [(4-bromophenyl)sulfonyl]-oxy ⁇ propanoyl] glycinate represented by compound of Formula 2 with trans-(+)-(3R,4R)-4-(3- hydroxyphenyl)-3 ,4-dimethylpiperidine can be performed in one or more solvents in presence of base.
  • the base can be selected from the group of alkali metal and alkaline earth metal carbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine and the like; ammonia and ammonium salts; and pyridine.
  • alkali metal and alkaline earth metal carbonates or hydroxides for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like
  • primary, secondary, and tertiary amines such as piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine and the like
  • the most suitable base is a bicarbonate of an alkaline metal that can be optionally selected from the group of sodium bicarbonate, potassium bicarbonate, or a mixture thereof.
  • solvents includes any solvent or solvent mixture, including water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • the esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanes.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone, methyl ethyl ketone, and the like.
  • ethers include diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and the like.
  • a suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
  • the preferred solvent is 1,2-dimethoxyethane.
  • the reaction can be preferably conducted at a temperature of between about 40°C to reflux for a time period of 1 hour to 24 hours.
  • step b) the compound of Formula 3 is hydrolyzed to alvimopan.
  • the compound of Formula 3 is hydrolyzed under basic condition in presence of sodium hydroxide solution.
  • the hydrolysis is carried out in a mixture of ethanol and water as the solvent at a temperature of between 15° to 40°C.
  • step b) the hydrolysis of the compounds of Formula 3 can be carried out in a solvent, for example, an alcoholic solvent, such as, methanol, ethanol or isopropanol, water or mixture(s) thereof at a temperature of between about 15°C to 60°C.
  • a solvent for example, an alcoholic solvent, such as, methanol, ethanol or isopropanol, water or mixture(s) thereof at a temperature of between about 15°C to 60°C.
  • the hydrolysis of a compound of Formula III can be carried out in the presence of an inorganic base, for example, sodium hydroxide, potassium hydroxide, or mixture(s) thereof.
  • the hydrolysis may be performed for a time period of 15 minutes to 12 hours.
  • the product is isolated from the reaction mass by known techniques, such as one or more of washing, crystallization, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the preferable method of isolation of the product involves crystallizing the product from the reaction mass by adjusting the pH of the reaction mass to 3-6.5 using concentrated hydrochloric acid.
  • the reaction mass may be optionally seeded to effect the crystallization of the product.
  • the alvimopan obtained may be further converted to pharmaceutically acceptable salt, hydrates or solvate thereof as desired by the techniques available in the literature.
  • the product at each step can be optionally carried to the next step without isolation.
  • Ethyl glycinate hydrochloride (4.07 g) was charged in a four neck round bottom flask at 25°C to32°C under nitrogen.
  • Dichloromethane 50 ml was charged at 25°C to 32°C.
  • the reaction mass was cooled to 10°C to 15°C.
  • Triethylamine (2.95 g) was added drop by drop at 10°C to 15°C in 10 minutes.
  • the resulting reaction mass was stirred at 10°C to 15°C for 15 minutes to 20 minutes.
  • the reaction mass was cooled further to 0°C to 5°C.
  • Chiral 3-Hydroxy-2-methylphenyl propanoic acid (5.0 g) was charged to the reaction mass.
  • a solution of dicyclohexylcarbodimide (6.9 g) in 25 ml dichloromethane was prepared in a separate flask at 25°C to 32°C. This solution was slowly added to the reaction mass at 0°C to 5°C and stirred for 1 hour at 0°C to 5°C. The temperature of the reaction mass was raised to 25°C to 32°C and stirred for 15 hours. After 15 hours, the reaction mass was cooled to 0°C to 5°C and stirred for 1 hour at 0°C to 5°C.
  • the reaction mass was filtered at 0°C to 5°C to remove DCC urea.
  • the filtrate was collected and washed with lN-hydrochloric acid (25 ml) solution at 25°C to 32°C.
  • the dichloromethane layer was separated and washed with saturated sodium bicarbonate solution (25 ml) at 25°C to 32°C.
  • the dichloromethane layer was separated and washed finally with a 30% sodium chloride solution at 25°C to 32°C.
  • the dichloromethane was recovered completely under vacuum below 45°C. Traces of dichloromethane were completely removed to obtain the title compound.
  • a solution of 4-Bromo benzene sulfonyl chloride (6.4 g) in dichloromethane (45 ml) was prepared in a separate flask at 25°C to 32°C.
  • the solution of 4-Bromo benzene sulfonyl chloride in dichloromethane was then added to reaction mass at 0°C to 5°C.
  • the reaction mass stirred at 0°C to 5°C for 3 hours to 4 hours. After 2 hours, the reaction mass was washed with lN-hydrochloricacid (45 ml) solution at 25°C to 32°C.
  • the layers were separated and the dichloromethane layer was washed further with a saturated sodium carbonate solution (45 ml) at 25°C to 32°C.
  • the dichloromethane layers were separated and the dichloromethane was recovered completely under vacuum below 45 °C to obtain the title compound.
  • the reaction mass obtained was stirred and heated to a temperature of 80°C to 85°C to reflux.
  • the reaction mass was stirred at reflux for 16 hours to 18 hours.
  • the reaction mass was cooled to 25°C to 32°C and filtered to remove unwanted salts.
  • the filtrate was collected and concentrated under vacuum to below a temperature of 45°C. Traces of solvents were completely removed to obtain the title compound.
  • the reaction mass was then stirred for 3 to 4 hours at 25°C to 32°C. After 4 hours, the pH of the reaction mass was adjusted to 5.8-6.2 using concentrate hydrochloric acid at 25°C to 32°C. The reaction mass was seeded at 25°C to 32°C at pH 5.8-6.2. After a few minutes, the product starts crystallizing at 25°C to 32°C. The reaction mass was stirred at 25°C to 32°C for 3 to 4 hours. The solid was filtered at 25°C to 32°C. The wet cake was washed with ethanol (15 ml) at 25°C to 32°C. The wet cake was slurry washed with deionized water at 25°C to 32°C. The wet cake was air dried at 30°C to 35°C under vacuum until constant weight of alvimopan was obtained.

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Abstract

The present invention relates to novel intermediates, ethyl N-[(2S)-2 -benzyl-3- hydroxypropanoyl]glycinate and ethyl N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl] oxy}propanoyl]glycinate, and processes for their preparation. The present invention also relates to a process for producing alvimopan or its pharmaceutically acceptable salt or solvate thereof using these novel intermediates.(A).

Description

PROCESS FOR THE PREPARATION OF ALVIMOPAN OR ITS PHARMACEUTICALLY ACCEPTABLE SALT OR SOLVATE THEREOF
Field of the Invention
The present invention relates to novel intermediates, ethyl N-[(25 -2-benzyl-3- hydroxypropanoyl]glycinate and ethyl N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl] oxy}propanoyl]glycinate, and processes for their preparation. The present invention also relates to a process for producing alvimopan or its pharmaceutically acceptable salt or solvate thereof using these novel intermediates.
Background of the Invention
The trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines derivatives are an important class of compounds that exhibit opioid antagonist activity. Alvimopan of Formula A shown below represents an example of this class of opioid antagonists.
Figure imgf000003_0001
Formula A
Alvimopan dihydrate, chemically known as [[2(S)-[[4(i?)-(3-hydroxyphenyl)-
3 (R), 4 -dimethyl- 1 -piperidinyl]methyl] - 1 -oxo-3 -phenylpropyl]amino] acetic acid dihydrate is indicated to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.
U.S. Patent No. 5,250,542 provides a process for the preparation of alvimopan which involves multiple steps; namely the chromatographic separation of a mixture of sterioisomeric products to isolate the desired stereoisomer of [[2-[[4-(3-hydroxyphenyl)- 3 ,4-dimethyl- 1 -piperidinyl] methyl] - 1 -oxo-3 -phenylpropyl] amino] acetic acid. U.S. Patent No. 5,434,171 provides crystalline dihydrate of alvimopan and a process for its preparation which involves treating (2S,3R,4R)[[2-[[4-(3- hydroxyphenyl)-3 ,4-dimethyl- 1 -piperidinyljmethyl] - 1 -oxo-3 -phenylpropyl] - amino] acetic acid 2-methylpropyl ester with an aqueous solution of sodium hydroxide in water and ethanol.
U.S. Patent No. 6,794,510 provides a process for the preparation of alvimopan through a variety of synthetic methods. In one method alvimopan is prepared by treating [[2(S/R)-[[4(R)-(3-acetoxyphenyl)-3(R),4-dimethyl-l-piperidinyl]methyl]-l-oxo-3- phenylpropyl]amino]acetic acid ethyl ester with sodium hydroxide in tetrahydrofuran at room temperature followed by separation of diasteriomers to give alvimopan.
CN Patent No. 100383121 provides a process for the preparation of benzyl ester of alvimopan by the reaction of (+)-3R,4R-(3 -hydroxy phenyl)3 ,4-dimethyl- 1-piperidine and (2S)-benzyl-N-[(2S)-2-benzyl-3 {[(4bromophenyl)sulfonyl]oxy}
propanoyljglycinate in the presence of potasium carbonate and potassium iodide in isopropanol.
U.S. Patent No. 6,031,121 provides a process for the preparation of N-(S-2- hydroxymethyl-1 -oxo-3 -phenylpropyl)glycine benzyl ester by reacting S-2- hydroxymethyl-3-phenylpropionic acid with glycine benzyl ester p-toluene sulfonic acid salt in the presence of a base, such as triethylamine and a condensation agent, such as diclclohexylcarbodiamide. It also provides a process for the preparation of N-(S-2-(p- toluenesulfonyl)methyl-l -oxo-3 -phenylpropyl)-glycine benzyl ester by treating N-(S-2- hydroxymethyl-1 -oxo-3 -phenylpropyl)-glycine benzyl ester with p-toluenesulfonyl chloride in the presence of a base, such as pyridine, in a suitable solvent, such as dichloromethane at ambient temperature.
U.S. Patent Nos. 7,381,721 and 6,992,090 provide processes for the preparation of alvimopan analogs.
Most of the prior-art processes for the preparation of alvimopan suffer from one or more disadvantages, such as the use of expensive and inaccessible raw materials, time consuming multi-step reaction sequences, lengthy procedures for the separation of isomeric mixtures involving column chromatographic purification, or isolation of intermediates at every stage resulting in low yields of the desired product.
In view of the importance of alvimopan as a peripherally acting μ-opioid antagonist, there is a need for a novel and efficient synthetic route for its preparation of alvimopan that provides good yields and high enantiomeric purity.
Summary of the Invention
In one general aspect, the present invention provides for ethyl N-[(2S)-2-benzyl- 3-hydroxypropanoyl]glycinate of Formula 1 or a pharmaceutically acceptable salt thereof.
Figure imgf000005_0001
Formula 1
In another general aspect, the present invention provides for ethyl-N-[(2S)-2- benzyl-3-{[(4-bromophenyl)sulfonyl]oxy}propanoyl]glycinate of Formula 2, or a pharmaceutically acceptable salt thereof;
Figure imgf000005_0002
Formula 2
wherein, Bs is a /7-bromobenzene sulfonyl group.
In another general aspect, the present invention provides for a process for the preparation of ethyl N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate of Formula 1 or a pharmaceutically acceptable salt thereof,
Figure imgf000006_0001
Formula 1
the process includes:
a) treating optically active 3-Hydroxy-2-methylphenyl propanoic acid with ethyl glycinate or its salt; and
b) isolating ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl] glycinate of
Formula 1 or a pharmaceutically acceptable salt thereof.
Embodiments of this aspect may include one or more of the following features. For example, step a) may be carried out in one or more solvents. Step a) may also be carried out with a coupling agent in the presence of one or more bases. Step a) may also be carried out at a temperature of 0°C to 50°C.
The solvents may be water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. The coupling agent may be selected from the group of Ν,Ν'-dicyclohexylcarbodimide diisopropyl carbodiimide, a water soluble carbodiimide, carbonyldiimidazole, or diphenylphosphorylazide. The base may selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
In another general aspect, the present invention provides for a process for the preparation of ethyl-N-[(2S)-2-benzyl-3-{[(4-bromophenyl)
sulfonyl]oxy}propanoyl]glycinate of Formula 2,
Figure imgf000006_0002
Formula 2 wherein, Bs is a j9-bromobenzene sulfonyl group;
or a pharmaceutically acceptable salt thereof, the process includes:
a) treating ethyl -N-[(25 -2-benzyl-3 hydroxypropanoyl]glycinate of Formula 1
Figure imgf000007_0001
Formula 1
with j9-bromobenzenesulfonylchloride; and
b) isolating ethyl-N-[(2S)-2-benzyl-3-{[(4- bromophenyl)sulfonyl]oxy}propanoyl] glycinate of Formula 2
Figure imgf000007_0002
Formula 2
wherein, Bs is a j9-bromobenzenesulfonyl group.
Embodiments of this aspect may include one or more of the following features. For example, step a) may be carried out in one or more solvents. Step a) may also be carried out in the presence of one or more bases and a catalyst.
The solvents may be water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. The catalyst may be N,N-Dimethyl amino pyridine. The base may be selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
In another general aspect, the present invention provides for a process for the preparation of ethyl N-{(25 -2-benzyl-3-[(3i?,4i?)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-l-yl]propanoyl}glycinate of Formula 3 or a pharmaceutically acceptable salt thereof, the process includes: a) treating the ethyl-N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl]- oxy}propanoyl] glycinate of Formula 2 with trans-(+)-(3R,4R)-4-(3- hydroxyphenyl)-3 ,4-dimethylpiperidine; and
b) isolating ethyl N-{(2S)-2-benzyl-3-[(3 ?,4i?)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-l-yl]propanoyl} glycinate of Formula 3.
Figure imgf000008_0001
Formula 3
Embodiments of this aspect may include one or more of the following features. For example, step a) may be performed in one or more solvents in the presence of one or more bases. Step a) may also be conducted at a temperature between about 40°C to reflux temperature.
The solvents may be water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents or mixtures thereof. The base may be selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
In another general aspect, the present invention provides for a process for the preparation of alvimopan of Formula A,
Figure imgf000009_0001
Formula A
rmaceutically acceptable salt or solvate thereof, the process includes:
a) treating optically active 3-Hydroxy-2-methylphenyl propanoic acid with ethyl glycinate or its salt to obtain optically active ethyl N-[(2S)-2-benzyl-3 hydroxypropanoyl] glycinate of Formula 1 ;
Figure imgf000009_0002
Formula 1
b) treating the compound of Formula 1 with /j-bromobenzenesulfonylchloride to obtain ethyl-N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl]
oxy}propanoyl] glycinate of Formula 2,
Figure imgf000009_0003
Formula 2
wherein, Bs is a />-bromobenzene sulfonyl group;
c) treating ethyl-N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl]- oxy}propanoyl] glycinate of Formula 2 with trans-(+)-(3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidine to obtain ethyl N-{(2S)-2-benzyl-3- [(3i?,4i?)-4-(3 -hydroxyphenyl)-3 ,4-dimethylpiperidin- 1 yl]propanoyl } glycinate of Formula 3; and
Figure imgf000010_0001
Formula 3
d) hydro lyzing the compound of Formula 3 to obtain alvimopan or a
pharmaceutically acceptable salt, or solvate thereof.
Embodiments of this aspect may include one or more of the following features. For example, step a) may be carried out in one or more solvents. Step a) may be carried out with a coupling agent in the presence of one or more bases. Step b) may be carried out in one or more solvents. Step b) may be carried out in the presence of one or more bases and a catalyst. Step c) may be performed in one or more solvents in presence of base. Step d) may be carried out in a mixture of ethanol and water.
In yet another general aspect, the present invention provides for preparation of alvimopan of Formula A,
Figure imgf000010_0002
Formula A
larmaceutically acceptable salt or solvate thereof, the process includes:
a) treating the compound of Formula 2 with trans-(+)-(3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidine to obtain ethyl -N- {(2S)-2-benzy 1-3- [(3J?, ft)-4-(3 -hydroxyphenyl)-3 ,4-dimethylpiperidin- 1 - yl]propanoyl}glycinate of Formula 3; and
Figure imgf000011_0001
Formula 3
b) hydrolyzing the compound of Formula 3 to obtain alvimopan or a
pharmaceutically acceptable salt or solvate thereof.
Embodiments of this aspect may include one or more of the following features. For example, step a) may be performed in one or more solvents in presence of base. Step b) may be carried out in the presence of sodium hydroxide solution. Step b) may be carried out in a mixture of ethanol and water. Step b) may also be carried out at a temperature of 15°C to 40°C.
The solvents may be water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. The bases may be selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
Detailed Description of the Invention
The present invention is directed to a method for the preparation of alvimopan or its pharmaceutically acceptable salt or solvate thereof using novel intermediates with the objective of developing efficient, economical and commercially viable process that employs cheap and easily available raw materials.
The term "pharmaceutically acceptable salt", as used herein, means acid addition or basic addition salts. Pharmaceutically acceptable salt are well known in the art. For example, S.M Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66, p. 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including ammonium,
tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,
trimethylamine, triethylamine, ethylamine, and the like.
Trans-(3R,4R-dimethyl-4-piperidinyl)phenol employed in the preparation of alvimopan can be synthesized by the methods known in the art, for example, U.S. Patent No. 5,250,542. Optically active (S)-3-Hydroxy-2-phenylmethylpropanoicacid can be synthesized by the methods known in the art, for example, U.S. Patent No. 6,031,121.
One aspect of the present invention provides optically active ethyl N-[2-benzyl- 3-hydroxypropanoyl]glycinate represented by a compound of Formula 1 or a
pharmaceutically acceptable salt.
Figure imgf000012_0001
Formula 1 Another aspect the present invention provides a process for the preparation of ethyl N-[(25)-2-benzyl-3-hydroxypropanoyl] glycinate represented by a compound of Formula 1 or a pharmaceutically acceptable salt
Figure imgf000013_0001
Formula 1
which includes:
a) treating optically active 3-Hydroxy-2-methylphenylpropanoic acid with ethyl glycinate or its salt; and
b) isolating ethyl-N-[(25)-2-benzyl-3-hydroxypropanoyl]glycinate represented compound of Formula 1 or a pharmaceutically acceptable salt.
Treating optically active 3-Hydroxy-2-methylphenylpropanoic acid with ethyl glycinate or its salt can be carried out in one or more solvents; optionally with a coupling agent in the presence of one or more bases.
The bases can be selected from the group of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like;
primary, secondary, and tertiary amines, such as, pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; and ammonia and ammonium salts.
The salt of ethyl glycinate can be any acid addition salt which may be inorganic or organic acids selected from the group of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid. The most preferable salt of ethyl glycinate is hydrochloric acid which is available commercially.
The optically active 3-Hydroxy-2-methylphenyl propanoic acid can be the S- isomer. The term "solvents" includes any solvent or solvent mixture, including for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
Preferable solvents employed for the preparation of ethyl N-[(2S)-2-benzyl-3- hydroxypropanoyl] glycinate are dimethylformamide, dichloromethane,
dichloromethane, ethylacetate or their mixture thereof. The most preferred solvent is dichloromethane.
The coupling agent can be selected from the group of N, N'- dicyclohexylcarbodimide and diisopropyl carbodiimide, a water soluble carbodiimide, carbonyldiimidazole, diphenylphosphorylazide and optionally, a catalyst, for example, 1-hydroxybenzotriazole, N-hydroxy succinimide.
Treating optically active 3-Hydroxy-2-methylphenylpropanoic acid with ethyl glycinate or its salt can be carried out preferably at a temperature of 0°C to 50°C for a time period sufficient to complete the reaction, preferably for about 30 minutes to 20 hours.
Step b) of the isolation of ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate involves common isolation technique, such a,s one or more of washing, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The preferred method of isolation of ethyl-N-[(2S)-2-benzyl-3- hydroxypropanoyl] glycinate may involve filtration of the reaction mass obtained in step a) to remove the dicyclohexylcarbodiimide urea present in the reaction mass followed by one or more washings with IN HCl solution at a temperature of about 20°C to 40°C. The reaction mass may further be washed with a saturated sodium bicarbonate solution and 30% sodium chloride solution.
The isolated ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate may be further purified by salt formation, crystallization, chromatographic methods, or a combination thereof.
The present invention also provides for ethyl N-[(2S)-2-benzyl-3-{[(4- bromophenyl)sulfonyl]oxy}propanoyl]glycinate represented by compound of Formula 2 or a pharmaceutically acceptable salt
Figure imgf000015_0001
Formula 2
wherein, Bs is -bromobenzene sulfonyl group.
The present invention also provides for a process for the preparation of ethyl-N- [(2S)-2-benzyl-3-{ [(4-bromophenyl)sulfonyl]oxy}propanoyl]glycinate represented by compound of Formula 2
Figure imgf000015_0002
Formula 2
wherein, Bs is /?-bromobenzene sulfonyl group;
or a pharmaceutically acceptable salt thereof. The process includes:
a) treating ethyl-N-[(2S)-2-benzyl-3 hydroxypropanoyl]glycinate represented by the compound of Formula 1
Figure imgf000016_0001
Formula 1
with /)-bromobenzenesulfonylchloride; and
b) isolating ethyl-N-[(2S)-2-benzyl-3-{ [(4-bromophenyl)sulfonyl]
oxy}propanoyl] glycinate represented by compound of Formula 2
Figure imgf000016_0002
Formula 2
wherein, Bs is /)-bromobenzenesulfonyl group.
Treating ethyl -N-[(25)-2-benzy 1-3 -hydroxypropanoyl] glycinate with p- bromobenzenesulfonylchloride can be preferably carried out in one or more solvents; optionally in the presence of one or more bases and a catalyst.
The bases can be selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as, pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; ammonia and ammonium salts.
The term "solvents" includes any solvent or solvent mixture, including for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
Preferable solvents employed for the preparation of ethyl N-[(2S)-2-benzyl-3- hydroxypropanoyljglycinate are dimethylformamide, dichloromethane,
dichloromethane, dichloroethane, chloroform, carbontetrachloride ethylacetate, or their mixture thereof. The most preferred solvent to carry out the reaction efficiently is dichloromethane.
The optional catalyst employed in step b) may be Ν,Ν-Dimethyl amino pyridine.
Treating ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate with p- bromobenzenesulfonylchloride can be preferably carried out at a temperature of about 0°C to 50°C for a time period sufficient to complete the reaction, preferably for about 30 minutes to 20 hours.
Step b) of isolation of ethyl-N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl]oxy} propanoyljglycinate involves common isolation technique, such as, one or more of washing, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof. The preferred method of isolation of the ethyl-N-[(2S)-2-benzyl-3-
{[(4bromophenyl)sulfonyl]oxy}propanoyl]glycinate involves one or more washings with IN HC1 and a saturated solution of sodium carbonate followed by the precipitation of ethyl-N-[(2S)-2-benzyl-3-{[(4 bromophenyl)sulfonyl]oxy}propanoyl]glycinate by the removal of the solvents. To remove the solvents one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum may be used. The isolated ethyl-N-[(2S)-2-benzyl-3-{ [(4 bromophenyl)sulfonyl]oxy}propanoyl]glycinate may be further purified by salt formation, crystallization or chromatographic methods, or a combination thereof.
Yet another aspect of the present invention provides for a process for the preparation of ethyl N-{(25)-2-benzyl-3-[(3/?,4i?)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-l-yl]propanoyl}glycinate represented by the compound of Formula 3, or a pharmaceutically acceptable salt. The process includes:
a) treating the ethyI-N-[(2S)-2-benzyl-3-{ [(4-bromophenyl)sulfonyl]- oxy}propanoyl] glycinate represented by compound of Formula 2 with trans-(+)-(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine; and b) isolating ethyl N-{(25)-2-benzyl-3-[(3J?,4/?)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-l-yl]propanoyl} glycinate represented by the compound of Formula 3
Figure imgf000018_0001
Formula 3
Treating the ethyl-N-[(2S)-2-benzyl-3-{ [(4-bromophenyl)sulfonyl]- oxy}propanoyl] glycinate represented by compound of Formula 2 with trans-(+)- (3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine can be performed in one or more solvents in the presence of base.
The bases can be selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium
bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; ammonia and ammonium salts; and pyridine.
The most suitable base is a bicarbonate of alkaline metals that may be optionally selected from the group comprising of sodium bicarbonate, potassium bicarbonate, or a mixture thereof.
The term "solvents" includes any solvent or solvent mixture, including water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanes. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, 1 ,2-dimethoxy ethane, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone. The preferred solvent is 1 ,2-dimethoxyethane.
The reaction can be preferably conducted at a temperature of between about
40°C to reflux for a time period of 1 hour to 24 hours.
Step b) of isolation of ethyl N-{(2S)-2-benzyl-3-[(3i?,4i?)-4-(3-hydroxyphenyl)- 3,4-dimethylpiperidin-l-yl]propanoyl}glycinate involves common isolation techniques, such as, one or more of washing, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The ethyl-N-{(2S)-2-benzyl-3-[(3i?,4i?)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-l-yl]propanoyl}glycinate can be isolated preferably by cooling the mixture obtained in step b) to 20°C to 30°C followed by filtration to remove the unwanted salts. The filtrate may be evaporated preferably under vacuum at a temperature of about 40°C to 50°C to obtain ethyl-N-{(2S)-2-benzyl-3-[(3i?,4i?)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidin-l-yl]propanoyl}glycinate.
The present invention also provides for a process for the preparation of alvimopan of Formula A
Figure imgf000020_0001
Formula A
or a pharmaceutically acceptable salt or solvate thereof. The process includes:
a) treating optically active 3-Hydroxy-2-methylphenyl propanoic acid with ethyl glycinate or its salt to obtain optically active ethyl N-[(2S)-2-benzyl-3 hydroxypropanoyl ] glycinate represented by a compound of Formula 1 ;
Figure imgf000020_0002
Formula 1
b) treating the compound of Formula 1 with p-bromobenzenesulfonylchloride to obtain ethyl N-[(2S)-2-benzyl-3-{[(4- bromophenyl)sulfonyl]oxy}propanoyl]glycinate represented by compound of Formula 2
Figure imgf000020_0003
Formula 2 wherein, Bs is >-bromobenzene sulfonyl group;
c) treating the ethyl-N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl]- oxy}propanoyl] glycinate represented by compound of Formula 2 with trans-(+)-(3R,4R)-4-(3-hydroxyphenyl)-3 ,4-dimethylpiperidine to obtain ethyl N-{(25 -2-benzyl-3-[(3^,4^)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-1 yljpropanoyl} glycinate represented by the compound of Formula 3; and
Figure imgf000021_0001
Formula 3
d) hydrolyzing the compound of Formula 3 to obtain alvimopan or a
pharmaceutically acceptable salts or solvate thereof
Treating optically active 3-Hydroxy-2-methylphenylpropanoic acid with ethyl glycinate or its salt can be carried out in one or more solvents, optionally with a coupling agent, in the presence of one or more bases.
The bases can be selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium
bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as, pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; and/or ammonia and ammonium salts.
The salt of ethyl glycinate can be any acid addition salt which may be inorganic or organic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, p-toluenesulfonicacid, methanesulfonicacid. The most preferable salt of ethyl glycinate is hydrochloricacid which is available commercially. The optically active 3-Hydroxy-2-methylphenyl propanoic acid can be the S-isomer.
The term "solvents" includes any solvent or solvent mixture, including, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide,
dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
Preferable solvents employed for the preparation of ethyl N-[(2S)-2-benzyl-3- hydroxypropanoyl] glycinate are dimethylformamide, dichloromethane,
dichloromethane, ethylacetate, or their mixture thereof. The most preferred solvent to carry out the reaction efficiently is dichloromethane.
The coupling agent can be selected from the group of N, N'- dicyclohexylcarbodimide and diisopropyl carbodiimide, a water soluble carbodiimide, carbonyldiimidazole, diphenylphosphorylazide and optionally, a catalyst, for example, 1 -hydroxybenzotriazole, N-hydroxy succinimide
Treating optically active 3-Hydroxy-2-methylphenylpropanoic acid with ethyl glycinate or its salt can be carried out preferably at a temperature of between 0°C to 50°C for a time period sufficient to complete the reaction, preferably for about 30 minutes to 20 hours.
Treating ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate with p- bromobenzenesulfonylchloride can be preferably carried out in one or more solvents in the presence of one or more bases and a catalyst. Suitable bases can be selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as pyridine, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; ammonia and ammonium salts.
The term "solvents" includes any solvent or solvent mixture, including for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one or more of Ν,Ν-dimethylformamide, N,N-dimethylacetamide,
dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
Preferable solvents employed for the preparation of ethyl N-[(2S)-2-benzyl-3- hydroxypropanoyljglycinate are dimethylformamide, dichloromethane,
dichloromethane, dichloroethane, chloroform, carbontetrachloride or a mixture thereof ethylacetate, or their mixture thereof. The preferred solvent to carry out the reaction efficiently is dichloromethane
The catalyst employed in step b) may be Ν,Ν-Dimethyl amino pyridine.
Treating ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate with p- bromobenzenesulfonylchloride can be preferably carried out at a temperature of between about 0°C to 50°C for a time period sufficient to complete the reaction; preferably for about 30 minutes to 20 hours. Treating ethyl-N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl]-oxy}propanoyl] glycinate represented by compound of Formula 2 with trans-(+)-(3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidine can be performed in one or more solvents in the presence of base. The base can be selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides for example, potassium
bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines, such as, piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like; ammonia and ammonium salts; and pyridine.
The most suitable base is bicarbonate of alkaline metals that can be optionally selected from the group of sodium bicarbonate, potassium bicarbonate, or a mixture thereof.
The term "solvents" includes any solvent or solvent mixture, including water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanes. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, and the like. A suitable polar aprotic solvent includes one or more of Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone. The preferred solvent is 1 ,2-dimethoxyethane.
The reaction can be preferably conducted between about 40°C to reflux temperature for a time period of 1 hour to 24 hours. After the reaction, the product is optionally isolated from the reaction mass by known techniques, such as, one or more of washing, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof, or the reaction mass is carried to step d) with out isolation.
In step d) the compound of Formula 3 is hydrolyzed to alvimopan. The compound of Formula 3 is hydrolyzed under basic condition in presence of a sodium hydroxide solution. The hydrolysis is carried out in a mixture of ethanol and water as solvent at suitable temperature. The hydrolysis is carried out at 15°C to 40°C.
In step d) the hydrolysis of compounds of Formula III can be carried out in a solvent, for example, an alcoholic solvent, for example, methanol, ethanol or
isopropanol, water or mixture(s) thereof at a suitable temperature. The hydrolysis can be preferably performed at a temperature of 15°C to 60°C. The hydrolysis of a compound of Formula III can be carried out in the presence of an inorganic base, for example, sodium hydroxide, potassium hydroxide or mixture(s) thereof. The hydrolysis may be performed for a time period of 15 minutes to 12 hours.
After the reaction the product is isolated from the reaction mass by known techniques, such as, one or more of washing, crystallization, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The preferable method of isolation of the product involves crystallizing the product from the reaction mass by adjusting the pH of the reaction mass to 3-6.5 using concentrated hydrochloricacid. The reaction mass may be optionally seeded to effect the crystallization of the product. The alvimopan thus obtained may be further converted to pharmaceutically acceptable salt, hydrate or solvate thereof as desired by the techniques available in the literature.
The present invention also provides for a process for preparation of alvimopan of Formula A
Figure imgf000026_0001
Formula A
or a pharmaceutically acceptable salt or solvate thereof. The process includes:
a) treating the compound of Formula 2 with trans-(+)-(3R,4R)-4-(3- hydroxyphenyl)-3 ,4-dimethylpiperidine to obtain ethyl-N- { (25)-2-benzyl-3 -
[(3i?,4i?)-4-(3 -hydroxyphenyl)-3 ,4-dimethylpiperidin- 1 - yl ]propanoyl}glycinate represented by compound of Formula 3; and
Figure imgf000026_0002
Formula 3
b) hydro lyzing the compound of Formula 3 to obtain alvimopan or a
pharmaceutically acceptable salt or solvate thereof.
Treating ethyl-N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl]-oxy}propanoyl] glycinate represented by compound of Formula 2 with trans-(+)-(3R,4R)-4-(3- hydroxyphenyl)-3 ,4-dimethylpiperidine can be performed in one or more solvents in presence of base.
The base can be selected from the group of alkali metal and alkaline earth metal carbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide, and the like; primary, secondary, and tertiary amines such as piperidine, triethylamine, diisopropylethylamine, N-methylmorpholine and the like; ammonia and ammonium salts; and pyridine.
The most suitable base is a bicarbonate of an alkaline metal that can be optionally selected from the group of sodium bicarbonate, potassium bicarbonate, or a mixture thereof.
The term "solvents" includes any solvent or solvent mixture, including water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanes. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and the like. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone. The preferred solvent is 1,2-dimethoxyethane.
The reaction can be preferably conducted at a temperature of between about 40°C to reflux for a time period of 1 hour to 24 hours.
In step b) the compound of Formula 3 is hydrolyzed to alvimopan. The compound of Formula 3 is hydrolyzed under basic condition in presence of sodium hydroxide solution. The hydrolysis is carried out in a mixture of ethanol and water as the solvent at a temperature of between 15° to 40°C.
In step b) the hydrolysis of the compounds of Formula 3 can be carried out in a solvent, for example, an alcoholic solvent, such as, methanol, ethanol or isopropanol, water or mixture(s) thereof at a temperature of between about 15°C to 60°C. The hydrolysis of a compound of Formula III can be carried out in the presence of an inorganic base, for example, sodium hydroxide, potassium hydroxide, or mixture(s) thereof. The hydrolysis may be performed for a time period of 15 minutes to 12 hours. After the reaction, the product is isolated from the reaction mass by known techniques, such as one or more of washing, crystallization, evaporation of solvent, evaporation of solvent under vacuum, cooling, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The preferable method of isolation of the product involves crystallizing the product from the reaction mass by adjusting the pH of the reaction mass to 3-6.5 using concentrated hydrochloric acid. The reaction mass may be optionally seeded to effect the crystallization of the product.
The alvimopan obtained may be further converted to pharmaceutically acceptable salt, hydrates or solvate thereof as desired by the techniques available in the literature.
After the reaction the product at each step can be optionally carried to the next step without isolation.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1 : Preparation of (2sVEthyl-iV-[2-Benzyl-3-HvdroxypropanoyllGlvcinate
Ethyl glycinate hydrochloride (4.07 g) was charged in a four neck round bottom flask at 25°C to32°C under nitrogen. Dichloromethane (50 ml) was charged at 25°C to 32°C. The reaction mass was cooled to 10°C to 15°C. Triethylamine (2.95 g) was added drop by drop at 10°C to 15°C in 10 minutes. The resulting reaction mass was stirred at 10°C to 15°C for 15 minutes to 20 minutes. The reaction mass was cooled further to 0°C to 5°C. Chiral 3-Hydroxy-2-methylphenyl propanoic acid (5.0 g) was charged to the reaction mass. A solution of dicyclohexylcarbodimide (6.9 g) in 25 ml dichloromethane was prepared in a separate flask at 25°C to 32°C. This solution was slowly added to the reaction mass at 0°C to 5°C and stirred for 1 hour at 0°C to 5°C. The temperature of the reaction mass was raised to 25°C to 32°C and stirred for 15 hours. After 15 hours, the reaction mass was cooled to 0°C to 5°C and stirred for 1 hour at 0°C to 5°C.
The reaction mass was filtered at 0°C to 5°C to remove DCC urea. The filtrate was collected and washed with lN-hydrochloric acid (25 ml) solution at 25°C to 32°C. The dichloromethane layer was separated and washed with saturated sodium bicarbonate solution (25 ml) at 25°C to 32°C. The dichloromethane layer was separated and washed finally with a 30% sodium chloride solution at 25°C to 32°C. The dichloromethane was recovered completely under vacuum below 45°C. Traces of dichloromethane were completely removed to obtain the title compound.
Yield: 6.5 g (88%)
SOR [a]D 25: -48.48° (Methanol, C= 1%)
IR (cm"1, Neat): 3316.1
MASS (M+H): 266.2
'HNMR (CDCI3, 400 M Hz): δ 7.29- 7.18 (m, 5H); 6.54 (bs, 1H); 4.20- 4.06 (m, 3H); 3.84- 3.72 (m, 3H); 3.35 (bs, 1H); 3.03- 2.97 (m, 1H); 2.75-2.74 (m, 1H), 2.69- 2.65 (m, 1H), 1.25 (t, 3 H) ,
13C NMR (CDCI3, 75 MHz): δ 174.9, 170.3, 139.0, 128.8, 128.5, 126.4, 66.1, 61.6, 50.5, 41.4, 34.4, 14.0
Example 2: Preparation of r2s)-Ethyl-N-r('2s)-2-Benzyl-3 (r('4bromophenyl)Sulfonyl1 Oxy I Propano yl] Glycinate
2S-ethyl N-[2-benzyl-3 hydroxypropanoyl] glycinate (9.0 g) was charged in a four neck round bottom flask at 25°C to 32°C under nitrogen containing 90 ml dichloromethane. 4-N,N-dimethyl amino pyridine (0.3 g) was charged at 25°C to 32°C. Triethyl amine (4.1 g) was charged at 25°C to 32°C. The reaction mass was stirred to get clear solution at 25°C to 32°C. The reaction mass was cooled further to 0°C to 5°C. A solution of 4-Bromo benzene sulfonyl chloride (6.4 g) in dichloromethane (45 ml) was prepared in a separate flask at 25°C to 32°C. The solution of 4-Bromo benzene sulfonyl chloride in dichloromethane was then added to reaction mass at 0°C to 5°C. The reaction mass stirred at 0°C to 5°C for 3 hours to 4 hours. After 2 hours, the reaction mass was washed with lN-hydrochloricacid (45 ml) solution at 25°C to 32°C. The layers were separated and the dichloromethane layer was washed further with a saturated sodium carbonate solution (45 ml) at 25°C to 32°C. The dichloromethane layers were separated and the dichloromethane was recovered completely under vacuum below 45 °C to obtain the title compound.
Yield: 13.9 g (85%)
IR (cm"1, Neat): 3310.9, 1747.8
MASS (M+H): 484.2
1HNMR (CDC13, 400 M Hz): δ 7.73- 7.66 (m, 2H); 7.28- 7.1 l(m, 2H); 7.1 1- 7.09(m, 2H); 6.08 (bs, 1H); 4.26- 4.09 (m, 4H); 3.91- 3.82 (m, 2H); 2.89- 2.88 (m, 2H), 2.87- 2.75 (m, 1H), 1.26 (t 3 H)
13C NMR (CDC13, 75 MHz): δ 171.1, 169.3, 137.3, 134.4, 132.6, 129.4, 129.2, 128.7, 128.7, 126.9, 70.3 ,61.5, 48.2, 41.3, 34.8, 14.1
Example 3: Preparation of Ethyl N-iC2 V2-Benzyl-3-rGr.4r -4-(3-Hvdroxyphenyl)-3,4- Dimethylpiperidin-l-Y11Propanoyl}Glvcinate
Ethyl-N-[(2S)-2-benzyl-3-{[(4bromophenyl)sulfonyl]oxy}propanoyl]glycinate (15 g) was charged in a four neck round bottom flask containing 1 ,2-dimethoxy ethane (150 ml) at 25°C to 32°C. The reaction mass was stirred to get clear solution at 25°C to 32°C. Trans-(+)-(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine (6.5 g) was charged to the reaction mass at 25°C to 32°C. Sodium hydrogen carbonate (8.24 g) was charged to the reaction mass at 25°C to 32°C. The reaction mass obtained was stirred and heated to a temperature of 80°C to 85°C to reflux. The reaction mass was stirred at reflux for 16 hours to 18 hours. The reaction mass was cooled to 25°C to 32°C and filtered to remove unwanted salts. The filtrate was collected and concentrated under vacuum to below a temperature of 45°C. Traces of solvents were completely removed to obtain the title compound.
Yield: 11.1 g (80%) Example 4: Preparation of rr2fSVr4(RV(3-Hvdroxyphenvn-3(R,).4-Dimethyl-l- PiperidinyllMethyll-l-Oxo-3- PhenylpropyniAminolAcetic Acid Dihydrate (Alvimopan)
[2(S)- [4(R)-(3 -hydroxyphenyl)-3(R),4-dimethyl- 1 -piperidinyl]methyl] - 1 -oxo-3 - (phenylpropyl)] amino] acetic acid ethyl ester (14 g) was charged to a four neck round bottom flask containing ethanol (353 ml) at 25°C to 32°C and stirred to a clear solution. Deionized water (78 ml) was charged to the reaction mass at 25°C to 32°C. lN-sodium hydroxide (93 ml) solution was added to the reaction mass at 25°C to 32°C. The reaction mass was then stirred for 3 to 4 hours at 25°C to 32°C. After 4 hours, the pH of the reaction mass was adjusted to 5.8-6.2 using concentrate hydrochloric acid at 25°C to 32°C. The reaction mass was seeded at 25°C to 32°C at pH 5.8-6.2. After a few minutes, the product starts crystallizing at 25°C to 32°C. The reaction mass was stirred at 25°C to 32°C for 3 to 4 hours. The solid was filtered at 25°C to 32°C. The wet cake was washed with ethanol (15 ml) at 25°C to 32°C. The wet cake was slurry washed with deionized water at 25°C to 32°C. The wet cake was air dried at 30°C to 35°C under vacuum until constant weight of alvimopan was obtained.
Yield: 8.0 g (53%)

Claims

We claim:
1. Ethyl N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate of Formula 1 or a
pharmaceutically acceptable salt thereof.
Figure imgf000032_0001
Formula 1
2. Ethyl-N-[(2S)-2-benzyl-3-{ [(4-bromophenyl)sulfonyl]oxy}propanoyl]glycinate of Formula 2, or a pharmaceutically acceptable salt thereof;
Figure imgf000032_0002
Formula 2
wherein, Bs is a 7-bromobenzene sulfonyl group.
3. A process for the preparation of ethyl N-[(2S)-2-benzyl-3- hydroxypropanoyl]glycinate of Formula 1 or a pharmaceutically acceptable salt thereof,
Figure imgf000032_0003
Formula 1
the process comprising:
a) treating optically active 3-Hydroxy-2-methylphenyl propanoic acid with ethyl glycinate or its salt; and
b) isolating ethyl-N-[(2S)-2-benzyl-3-hydroxypropanoyl]glycinate of Formula 1 or a pharmaceutically acceptable salt thereof.
4. The process according to claim 3, wherein step a) is carried out in one or more solvents.
5. The process according to claim 3, wherein step a) is carried out with a coupling agent in the presence of one or more bases.
6. The process according to claim 4, wherein the solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
7. The process according to claim 5, wherein the coupling agent is selected from the group consisting of Ν,Ν'-dicyclohexylcarbodimide diisopropyl carbodiimide, a water soluble carbodiimide, carbonyldiimidazole, or diphenylphosphorylazide.
8. The process according to claim 5, wherein the base is selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
9. The process according to claim 3, wherein step a) is carried out at a temperature of O°C to 50°C.
10. A process for the preparation of ethyl-N-[(2S)-2-benzyl-3-{[(4-bromophenyl) sulfonyljoxy} propanoyl]glycinate of Formula 2,
Figure imgf000033_0001
Bscr
Formula 2
wherein, Bs is a p-bromobenzene sulfonyl group;
or a pharmaceutically acceptable salt thereof, the process comprising:
a) treating ethyl- V-[(2S)-2-benzyl-3 hydroxypropanoyljglycinate of Formula 1
Figure imgf000034_0001
Formula 1
with -bromobenzenesulfonylchloride; and
b) isolating ethyl-N-[(2S)-2-benzyl-3-{[(4- bromophenyl)sulfonyl]oxy}propanoyl] glycinate of Formula 2
Figure imgf000034_0002
Formula 2
wherein, Bs is a -bromobenzenesulfonyl group.
11. The process according to claim 10, wherein step a) is carried out in one or more solvents.
12. The process according to claim 10, wherein step a) is carried out in the presence of one or more bases and a catalyst.
13. The process according to claim 11, wherein solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
14. The process according to claim 12, wherein the catalyst is N,N -Dimethyl amino pyridine.
15. The process according to claim 12, wherein the base is selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
16. A process for the preparation of ethyl N-{(25)-2-benzyl-3-[(3i?,4i?)-4-(3- hydroxyphenyl)-3 ,4-dimethylpiperidin- 1 -yl]propanoyl } glycinate of Formula 3 or a pharmaceutically acceptable salt thereof the process comprising: a) treating the ethyl-N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl]- oxy}propanoyl] glycinate of Formula 2 with trans-(+)-(3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidine; and
b) isolating ethyl N-{(25)-2-benzyl-3-[(3i?,4i?)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-l-yl]propanoyl} glycinate of Formula 3.
Figure imgf000035_0001
Formula 3
17. The process according to claim 16, wherein step a) is performed in one or more solvents in the presence of one or more bases.
18. The process according to claim 17, wherein the solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents or mixtures thereof.
19. The process according to claim 17, wherein the base is selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
20. The process according to claim 16, wherein step a) is conducted at a temperature between about 40°C to reflux temperature.
21. A process for the preparation of alvimopan of Formula A,
Figure imgf000036_0001
Formula A
or a pharmaceutically acceptable salt or solvate thereof, the process comprising: a) treating optically active 3-Hydroxy-2-methylphenyl propanoic acid with ethyl glycinate or its salt to obtain optically active ethyl N-[(2S)-2-benzyl-3 hydroxypropanoyl] glycinate of Formula 1 ;
Figure imgf000036_0002
Formula 1
b) treating the compound of Formula 1 with -bromobenzenesulfonylchloride to obtain ethyl-N-[(2S)-2-benzyl-3-{ [(4-bromophenyl)sulfonyl]
oxy}propanoyl] glycinate of Formula 2,
Figure imgf000036_0003
Formula 2
wherein, Bs is a -bromobenzene sulfonyl group;
c) treating ethyl-N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl]- oxy}propanoyl] glycinate of Formula 2 with trans-(+)-(3R,4R)-4-(3- hydroxyphenyl)-3 ,4-dimethylpiperidine to obtain ethyl N- { (2S)-2-benzyl-3 - [(3Z?,4i?)-4-(3 -hydroxyphenyl)-3 ,4-dimethylpiperidin- 1 yl]propanoyl } glycinate of Formula 3; and
Figure imgf000037_0001
Formula 3
d) hydrolyzing the compound of Formula 3 to obtain alvimopan or a
pharmaceutically acceptable salt, or solvate thereof.
22. The process according to claim 21 , wherein step a) is carried out in one or more solvents.
23. The process according to claim 21 , wherein step a) is carried out with a coupling agent in the presence of one or more bases.
24. The process according to claim 21 , wherein step b) is carried out in one or more solvents.
25. The process according to claim 21 , wherein step b) is carried out in the presence of one or more bases and a catalyst.
26. The process according to claim 21 , wherein step c) is performed in one or more solvents in presence of base.
27. The process according to claim 21 , wherein step d) is carried out in a mixture of ethanol and water.
28. A process for preparation of alvimopan of Formula A
Figure imgf000038_0001
Formula A
or a pharmaceutically acceptable salt or solvate thereof, the process comprising: a) treating the compound of Formula 2 with trans-(+)-(3R,4R)-4-(3 - hydroxyphenyl)-3,4-dimethylpiperidine to obtain ethyl-N-{(2S)-2-benzyl-3- [(3i?,4i?)-4-(3 -hydroxyphenyl)-3 ,4-dimethylpiperidin- 1 - yl]propanoyl}glycinate of Formula 3; and
Figure imgf000038_0002
Formula 3
b) hydrolyzing the compound of Formula 3 to obtain alvimopan or a
pharmaceutically acceptable salt or solvate thereof.
29. The process according to claim 28, wherein step a) is performed in one or more solvents in presence of base.
30. The process according to claim 29, wherein the solvents comprise water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
31. The process according to claim 29, wherein the bases are selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, primary, secondary, and tertiary amines, ammonia and ammonium salts.
32. The process according to claim 28, wherein step b) is carried out in the presence of sodium hydroxide solution.
33. The process according to claim 28, wherein step b) is carried out in a mixture of ethanol and water.
34. The process according to claim 28, wherein step b) is carried out at a temperature of 15°C to 40°C.
PCT/IB2011/052764 2010-06-25 2011-06-23 Process for the preparation of alvimopan or its pharmaceutically acceptable salt or solvate thereof WO2011161646A2 (en)

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