WO2015063795A2 - Novel process for preparation of optically pure norephedrine and its derivatives - Google Patents

Novel process for preparation of optically pure norephedrine and its derivatives Download PDF

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WO2015063795A2
WO2015063795A2 PCT/IN2014/000699 IN2014000699W WO2015063795A2 WO 2015063795 A2 WO2015063795 A2 WO 2015063795A2 IN 2014000699 W IN2014000699 W IN 2014000699W WO 2015063795 A2 WO2015063795 A2 WO 2015063795A2
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acid
pyrrolidinyl
process according
norephedrine
tartaric acid
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PCT/IN2014/000699
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English (en)
French (fr)
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WO2015063795A3 (en
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Satyanarayana Chava
Seeta Rama Anjaneyulu GORANTLA
Venkata Sunil Kumar Indukuri
Narasimha Rao Ketavarapu
Veeraiah Chowdary GORANTLA
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Laurus Labs Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain

Definitions

  • the present invention relates to a novel process for preparation of norephedrine and its derivatives, particularly norephedrine, pyrrolidinyl norephedrine and the like with high chiral purity; a chiral auxiliary useful in the preparations of anti retroviral drugs like efavirenz.
  • the present invention also relates to a process for separation of individual isomers of norephedrine and its derivatives using suitable chiral resoluting agents.
  • Chiral amine derivatives like pyrrolidinyl norephedrine play an important role in the pharmaceutical and chemical industry. Chiral amine derivatives in general are frequently used as a resolving agents or intermediates or synthons for the preparation of various physiologically, for instance pharmaceutically active substances. In a great number of the various applications of chiral amine derivatives, only one particular optically active form has the desired physiological activity. Thus, there is a clear need to - provide processes for the preparation of chiral amine derivatives in an optically active form.
  • Pyrrolidinyl norephedrine is a pyrrolidine derivative of Norephedrine, chemically known as l-phenyl-2-(pyrrolidin-l-yl) propan-l-ol, represented by the following structural Formula:
  • Norephedrine and its derivatives exhibits optical isomerism and have chiral centers, giving rise to four stereoisomers.
  • the pair of enantiomers with the stereochemistry (1R, 2S and IS, 2R) is designated norephedrine derivatives, while the pair of enantiomers with the stereochemistry (1R, 2R and IS, 2S) is called norpseudoephedrine derivatives.
  • the optical isomers of Pyrrolidinyl norephedrine is use as a resolving agents.
  • the four enantiomers are represented by the following structural formula: -
  • U.S. Patent No. 5,856,492 discloses a process for the preparation of pyrrolidinyl norephedrine by reacting (1R, 2S) - norephedrine with 1,4-dibromobutane as mentioned i he below scheme:
  • PCT Publication No..2013/0244543 discloses a method of production of active chiral amines from alpha hydroxyl ketone using enzyme transaminase as the biocatalyst.
  • the reported literature disclose the use of norephedrine as intermediate or starting material, which is a controlled substance and thus having certain limitations when using in commercial scale operations and further the reported literature involves enzymatic reactions, which are not viable in commercial scale operations.
  • the present invention provides a process for the preparation of norephedrine and its derivatives, particularly norephedrine, pyrrolidinyl norephedrine and the like with simple and commercially available starting materials that avoids controlled substances and enzymatic reactions.
  • the present invention encompasses to a novel process for preparation of norephedrine and its derivatives with high chiral purity.
  • the present invention relates to a novel process for preparation of norephedrine with high chiral purity.
  • the present invention also relates to a novel process for preparation of pyrrolidinyl norephedrine with high chiral purity.
  • the present invention also relates to a process for separation of individual isomers of norephedrine and its derivatives using suitable chiral resoluting agents.
  • the present invention provides a process for the preparation of norephedrine and its derivatives of Formula I,
  • Rl and R2 independently represent hydrogen or Rl and R2 combine to form a cyclic ring; comprising: a) reacting propiophenone of Formula TV
  • 'X' is a halogen selected from CI, Br or I;
  • Rl and R2 independently represents hydrogen or a formyl group; or Rl and R2 combine to form a cyclic ring; to obtain a keto compound Formula II;
  • Rl and R2 independently represent hydrogen or Rl and R2 combine to form a cyclic ring
  • the present invention provides a process for the preparation of pyrrolidinyl norephedrine of Formula IA, comprising:
  • 'X' is a halogen selected from CI, Br or I;
  • the present invention provides a process for the preparation of optically pure pyrrolidinyl norephedrine of Formula IA, comprising: a) reacting propiophenone of Formula ⁇ with a suitable halogenating agent to obtain halopropiophenone of Formula III, wherein 'X' is a halogen selected from CI, Br or I;
  • the present invention provides a process for the preparation optically pure pyrrolidinyl norephedrine, comprising:
  • the present invention provides a process for the preparation of optically pure pyrrolidinyl norephedrine, comprising:
  • halogen is Chloro or Bromo
  • the suitable reducing agent is selected from the group comprising sodium borohydride, lithium aluminum hydride, vitride (Sodium bis(2- methoxyethoxy)aluminum hydride), DIBAL-H and the like;
  • the metal salt is represented by the formula MX 2 , wherein the 'M' represents a metal cation selected from zinc, beryllium, magnesium, calcium, cerium, strontium, manganese, copper and barium; 'X' represents halide, acetate or trifluoromethane sulfonate;
  • the suitable chiral acid is selected from the group comprising P(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, L(+)-tartaric acid, L(+)-malic acid, L(+)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l,l'-binaphthalene-2,2'- dihydrogen phosphate and the like.
  • the present invention provides a process for the preparation of optically pure (1R, 2S) - pyrrolidinyl norephedrine, comprising: treating either any ratio of optical isomers of pyrrolidinyl norephedrine or its mixture with optical isomers of pyrrolidinyl norpseudoephedrine with a suitable chiral acid in an appropriate solvent to obtain (1R, 2S) - pyrrolidinyl norephedrine.
  • the present invention provides a process for the preparation of optically pure (1R, 2S) - pyrrolidinyl norephedrine, comprising: treating either any ratio of optical isomers of pyrrolidinyl norephedrine or its mixture with optical isomers of pyrrolidinyl norpseudoephedrine with a suitable chiral acid in an appropriate solvent to obtain (1R, 2S) - pyrrolidinyl norephedrine; wherein the suitable chiral acid is selected from the group comprising: D(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S-hydratropic acid, (S)-2- methoxy phenyl
  • the present invention provides a process for the preparation of (1R, 2S) - pyrrolidinyl norephedrine, comprising:
  • the present invention provides a process for the isomer separation of (1R, 2S) - pyrrolidinyl norephedrine, comprising: a) providing a solution of racemic mixture comprising optical isomers of pyrrolidinyl' norephedrine and optical isomers of pyrrolidinyl norpseudoephedrine;
  • suitable chiral acid of step b) is selected from the group comprising L(+)- tartaric acid, L(+)-malic acid, L(+)-lactic acid and the like and suitable chiral acid of step d) is selected from the group comprising D(-)-tartaric acid, D(-)-malic acid, D(-)- lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl- D-tartaric acid, camphor sulfonic acid, naproxen, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, Di-p-anisoyl-D- tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l,l'-binaphthalene- 2,2'-
  • the present invention provides a chiral acid salt compound of Formula I,
  • Rl and R2 independently represent hydrogen or Rl and R2 combine to form a cyclic ring
  • chiral acid is selected from the group comprising: D(-)-tartaric acid, D(-)- malic acid, D(-)-lactic acid, L(+)-tartaric acid, L(+)-malic acid, L(+)-lactic acid, S(+)- mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfomc acid, naproxen, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l,l'-binaphthalene-2,2'- dihydrogen phosphate and the like.
  • the present invention provides a chiral acid salt of pyrrolidinyl norephedrine; wherein the chiral acid is selected from the group comprising: D(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, L(+)-tartaric acid, L(+)- malic acid, L(+)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l,l'- bin
  • the present invention provides a process for isomer enrichment of optical purity of (1R, 2S) - pyrrolidinyl norephedrine or a salt thereof, comprising:
  • the present invention provides a process for the preparation of optically pure (IS, 2R) - pyrrolidinyl norephedrine, comprising: treating a mixture of (1 S, 2R) and (IR, 2S) optical isomers of pyrrolidinyl norephedrine, with a suitable chiral acid in an appropriate solvent to obtain (IS, 2R) - pyrrolidinyl norephedrine;
  • the suitable resoluting agent is selected from the group comprising: D(-)- tartaric acid, D(-)-malic acid, D(-)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S- hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l,l'-binaphthalene-2,2'-d ydrogen phosphate and the like.
  • the present invention provides a process for the preparation of (1 S, 2S) - pyrrolidinyl norpseudoephedrine, comprising:
  • step b) separating the optical isomers of pyrrolidinyl norpseudoephedrine from the resulting mixture of step a) using a column chromatography with a suitable eluent,
  • the present invention provides a process for the preparation of (IS, 2S) - pyrrolidinyl norpseudoephedrine, comprising:
  • step b) separating the optical isomers of pyrrolidinyl norpseudoephedrine from the resulting mixture of step a) using a column chromatography with a suitable eluent,
  • the suitable chiral acid is selected from the group comprising: D(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p- toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S- hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2- trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D- tartaric acid monodimethyl amide, S(+)-l, -binaphthalene-2,2'-dihydrogen phosphate and the like.
  • the present invention provides a process for enrichment of. optical purity of (IS, 2S) - pyrrolidinyl norpseudoephedrine, comprising:
  • the present invention provides a process for the preparation of (1R, 2R) - pyrrolidinyl norpseudoephedrine, comprising:
  • the present invention provides a process for the preparation of optically pure (1R, 2R) - pyrrolidinyl norpseudoephedrine, comprising: treating a mixture of (IS, 2S) and (1R, 2R) optical isomers of pyrrolidinyl norpseudoephedrine, with a suitable chiral acid in an appropriate solvent to obtain (1R, 2R) - pyrrolidinyl norpseudoephedrine;
  • the suitable chiral acid is selected from the group comprising: D(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p- toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S- hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifiuoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l, -binaphthalene-2,2'-dihydrogen phosphate and the like.
  • the present invention provides a process for the preparation of norephedrine of Formula IB, comprising:
  • 'X' is a halogen selected from CI, Br or I;
  • Rl and R2 independently represent hydrogen or a formyl group; to obtain a keto compound Formula IIB;
  • the present invention provides a process for the preparation of (1R, 2S) - norephedrine, comprising:
  • halogen is chloro or Bromo
  • the suitable reducing agent is selected from the group comprising sodium borohydride, lithium aluminum hydride, vitride (Sodium bis(2- methoxyethoxy)aluminum hydride), DIBAL-H and the like;
  • the metal salt is represented by the formula MX 2 , wherein the 'M' represents a metal cation selected from zinc, beryllium, magnesium, calcium, cerium, strontium, manganese, copper and barium; 'X' ' represents halide, acetate or trifluoromethane sulfonate;
  • the suitable chiral acid is selected from the group comprising D(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l, -binaphthalene-2,2'-dihydrogen phosphate and the like.
  • the present invention encompasses to a novel process for preparation of norephedrine and its derivatives such as norephedrine, pyrrolidinyl norephedrine and the like with high chiral purity. - .
  • the present invention also relates to a process for separation of individual isomers of norephedrine and its derivatives using suitable chiral acids.
  • the present invention provides a process for the preparation of norephedrine and its derivatives of Formula I,
  • Rl and R2 independently represent hydrogen or Rl and R2 combine to form a cyclic ring; comprising: a) reacting propiophenone of Formula TV
  • Rl and R2 independently represents hydrogen or a formyl group; or Rl and R2 combine to form a cyclic ring; Formula II;
  • Rl and R2 independently represents hydrogen or Rl and R2 combine to form a cyclic ring
  • the present invention provides a process for the preparation of norephedrine arid its derivatives of Formula I, wherein Rl and R2 independently represents hydrogen or Rl and R2 combine to form a cyclic ring such as pyrrolidine and the like.
  • the present invention provides a process for the preparation of pyrrolidinyl norephedrine of Formula IA, comprising:
  • 'X' is a halogen selected from CI, Br or I; preferably CI, or Br;
  • Step a) of foregoing process may be carried out by reacting propiophenone of Formula ⁇ with a suitable halogenating agent in a suitable solvent to obtain halopropiophenone of Formula III.
  • the suitable halogenating agent includes, but are not limited to bromine, N-halo succinimide such as N-bromo succinimide, N-chloro succinimide and the like; sulfuryl chloride, thionyl chloride, thionyl bromide, phosphorous trichloride, phosphorous tribromide and the like and mixtures thereof; preferably bromine or sulfuryl chloride.
  • the suitable solvent includes, but are not limited to halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and the like; ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-Dixoane and the like and mixtures thereof; preferably methylene chloride, chloroform, toluene and mixtures thereof.
  • halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and the like
  • ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-Dixoane and the like and mixtures thereof
  • THF tetrahydrofuran
  • the reaction temperature should be sufficient to effect halogenation.
  • the reaction temperature may be from about ambient temperature to about reflux temperature.
  • the reaction temperature is about 25°C to about 80°C; more preferably about 30°C to about 45°C.
  • Step b) of the foregoing process involves reaction of halopropiophenone of step a) with pyrrolidine in a suitable solvent in presence of a base to obtain a keto compound of Formula IIA.
  • the suitable solvent used herein for step b) is selected form the group consisting of halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and the like; ethers such as diethyl ether, methyl, tert-butyl ether, diisopropyl ether, THF, 1,4-Dixoane and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; esters such as ethyl acetate, isopropyl acetate and the like; Nitriles such as acetonitrile, propionitrile, benzonitrile and the like; aromatic hydrocarbons such as toluene, xylene and the like and mixtures thereof; preferably methylene chloride, chloroform, toluene and the like and mixtures thereof.
  • halogenated hydrocarbons such as methylene chloride
  • the suitable base used herein for step b) is selected form the group consisting of alkali or alkaline metal hydroxides, carbonates, bicarbonates and the like; preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like and mixtures thereof; more preferably potassium carbonate.
  • the reaction temperature should be sufficient to effect step b) reaction. Typically the reaction temperature may be from about ambient temperature to about reflux temperature. Preferably the reaction temperature is about 25°C to about 90°C; more preferably about 55° to about 85°C.
  • Step c) of the foregoing process is carried out by treating sufficient amount of a suitable reducing agent to the resultant product in order to carrying keto reduction in a solvent.
  • the suitable reducing agent in the foregoing process may be selected from the group comprising of sodium borohydride, lithium aluminum hydride, vitride (Sodium bis(2- methoxyethoxy)aluminum hydride), DIBAL-H and the like; preferably sodium borohydride.
  • the solvent for keto reduction includes, but is not limited to alcohols, ethers, halogenated hydrocarbons, nitriles, aromatic hydrocarbons and the like and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, n- propanol, t-butanol and the like and mixtures thereof;
  • halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and the like and mixtures thereof;
  • ethers include, but are not limited to dimethyl ether, diethyl ether, methyl ethyl ether, diisopropyl ether, methyl tertiary butyl ether, THF, 1 ,4-dioxane and the like and mixtures thereof;
  • nitriles include, but are not limited to acetonitrile, propionitrile and the like and
  • the organic solvent is selected from the group consisting of methanol, ethanol, methylene chloride, chloroform, tetrahydrofuran, diisopropyl ether, methyl ethyl ether, methyl tertiary butyl ether, toluene and mixtures thereof; more preferably methanol, methylene chloride, chloroform, toluene and mixtures thereof.
  • the reaction temperature should be sufficient to effect reduction of keto to alcohol.
  • the reaction temperature may be from about ambient temperature to about reflux temperature.
  • the reaction temperature is about -10°C to about 60°C; preferably about -5°C to about 10°C.
  • the reaction may take from about 15 minutes to about 20 hours depending upon the reducing agent, solvent and temperature chosen, preferably about 30 minutes to about 6 hours.
  • pyrrolidinyl norephedrine recovered using the process of the present invention having a chiral purity of about 10-35% each of four optical isomers i.e. pyrrolidinyl norephedrine isomers [(1R, 2S) and (IS, 2R)] and pyrrolidinyl norpseudoephedrine isomers [(IS, 2S) and (1R, 2R)].
  • norephedrine and its derivatives such as norephedrine, pyrrolidinyl norephedrine and the like with high chiral selectivity may be obtained by incorporating the process modifications such as use of a metal salt along with a suitable reducing agent in the keto reduction, yielding a product containing substantially higher selectivity of the optical isomers of norephedrines.
  • the keto reduction of step c) may be advantageously carried out with a suitable reducing agent and a metal salt.
  • the metal salt in the foregoing process may be represented by the following formula MX 2 , wherein the 'M' represents a metal cation selected from the group comprising zinc, beryllium, magnesium, calcium, cerium, strontium, manganese, copper and barium; ' ⁇ ' represents halide, acetate, sulfate, bisulfate, carbonate;, bicarbonate or trifluoromethane sulfonate.
  • the halide includes, but is ndt limited to fluoro, bromo, chloro, iodo and the like.
  • the metal salt is selected from the group consisting of zinc chloride, zinc bromide, zinc sulfate, zinc acetate, zinc trifluoromethane sulfonate, magnesium chloride, magnesium acetate, manganese chloride, calcium chloride, cerium chloride and the like.
  • the suitable reducing agent, organic solvent and the reaction temperature used for the keto reduction with a suitable reducing agent as described above can also be same as for the process of keto reduction with a suitable reducing agent along with a metal salt.
  • the norephedrines such as pyrrolidinyl norephedrine recovered using the process of the present invention having a chiral purity of about 20-45% of each of (1R, 2S) and (IS, 2R) isomers.
  • the high selectivity of optical isomers of (1R, 2S) and (IS, 2R) enantiomers in the reduction stage may be obtained due to the presence of metal salt in the reduction stage.
  • the enantioselectivity of pyrrolidinyl norephedrine can be further improved by resolving pyrrolidinyl- norephedrine obtained by the above procedure using a suitable resoluting agent such as suitable chiral acid.
  • the present invention provides a process for the preparation of optically pure pyrrolidinyl norephedrine, comprising:
  • the keto reduction of step c) may be advantageously carried out with a suitable reducing agent and a metal salt.
  • Starting mixture of optical isomers of pyrrolidinyl norephedrine and optical isomers pyrrolidinyl norpseudoephedrine of step d) is obtained by process of steps a) to c) as process described as above and then treating with a suitable chiral acid.
  • any ratio of optical isomers of pyrrolidinyl norephedrine and pyrrolidinyl norpseudoephedrine as defined above or the same may be obtained by any known process can be used as starting material for the resolution.
  • the present invention provides a process for the preparation of optically pure (1R, 2S) - pyrrolidinyl norephedrine, comprising: treating either any ratio of optical isomers of pyrrolidinyl norephedrine or its mixture with optical isomers pyrrolidinyl norpseudoephedrine with a suitable chiral acid in an -appropriate solvent to obtain (1R, 2S) - pyrrolidinyl norephedrine.
  • the resolution step of the present invention involves conversion of mixture of optical isomers of pyrrolidinyl norephedrine and pyrrolidinyl norpseudoephedrine to its corresponding pyrrolidinyl norephedrine chiral acid salt and then neutralizing the chiral acid salt.
  • the suitable chiral acid may be selected from the group comprising: D(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, L(+)-tartaric acid, L(+)-malic acid, L(+)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l,l'-binaphthalene-2,2'- dihydrogen phosphate and the like.
  • chiral acid resolving agents may be determined by testing and the use thereof in a process as described above falls within the scope of the present invention.
  • the appropriate solvent may be selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, n-propanol and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; halogenated solvents such as methylene chloride, ethylene chloride, chloroform and the like; esters such as ethyl acetate, n-propyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, dimethyl ether, tetrahydrofuran, methyl tertiary butyl ether and the like; hydrocarbon solvents such as toluene, xylene, n- hexane, n-heptane, cyclohexane and the like; amides such as dimethyl formamide,
  • the resolution may be carried out at a temperature ranging from about 0°C to reflux temperature of the solvent used.
  • the reaction time may range from about 30 minutes to about 30 hours, or longer, depending on the conditions chosen.
  • the obtained chiral salt of compound of pyrrolidinyl norephedrine (which is generally optically enriched as a single enantiomer) may be isolated by techniques, such as centrifugation, gravity filtration, or vacuum filtration or other techniques known in the art for the separation of solids; for example gravity filtration.
  • the solvent from the reaction mass may be removed completely or partially by distillation techniques such as atmospheric distillation, distillation under vacuum or evaporation before isolation.
  • the chiral acid salt of pyrrolidinyl norephedrine thus obtained may be further purified to remove impurities, reaction byproducts, and the like by slurrying or crystallizing from a suitable solvent.
  • the chiral salt of pyrrolidinyl norephedrine recovered using the process of the present invention having a chiral purity of greater than about 95%, about 4% of (1R, 2S), (IS, 2R) respectively and about 0.5% each of (IS, 2S) and (1R, 2R) isomers.
  • the enantioselectivity of (1R, 2S) enantiomer can be further improved by purifying the pyrrolidinyl norephedrine chiral acid salt obtained by the above procedure using a suitable solvent.
  • the suitable solvent includes, but is not limited to alcohols, esters, ethers, halogenated solvents, hydrocarbon solvents, water and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol and the like; esters include, but are not limited to ethyl acetate, isopropyl acetate and the like; ethers include, but are not limited to tetrahydrofuran, diisopropyl ether, diethyl ether and the like; halogenated solvents include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbon solvents include, but are not limited to toluene, xylene, hexane, heptane, cyclohexane and the like; preferably methanol, ethanol, ethyl acetate, toluene and the like and mixtures thereof.
  • the solvent may be heated to obtain a solution at a temperature of from about ambient temperature to about reflux temperature.
  • the reaction solution may be cooled at a temperature from about 20°C or less such that chiral acid salt of (1R, 2S) - pyrrolidinyl norephedrine can be isolated by conventional techniques.
  • optically pure chiral acid salt of (1R, 2S) - pyrrolidinyl norephedrine may be neutralized to obtain free base of optically pure (1R, 2S) - pyrrolidinyl norephedrine.
  • the neutralization step may be carried out by any known procedure; for example optically pure chiral acid salt of (1R, 2S) - pyrrolidinyl norephedrine may be combined with water and a water immiscible organic solvent such as toluene, methylene chloride, ethyl acetate, chloroform, ethyl acetate and the like. Then the solution pH may be adjusted to basic with a suitable base such as sodium hydroxide and the like. The product containing organic layer may be separated and isolating the (1R, 2S)- pyrrolidinyl norephedrine free base by conventional methods such as evaporation, solvent crystallization or both.
  • a water immiscible organic solvent such as toluene, methylene chloride, ethyl acetate, chloroform, ethyl acetate and the like.
  • a suitable base such as sodium hydroxide and the like.
  • the product containing organic layer
  • the present invention provides a process for the preparation of (1R, 2S) - pyrrolidinyl norephedrine, comprising:
  • the present invention provides a process for the isomer separation of (1R, 2S) - pyrrolidinyl norephedrine, comprising:
  • Starting compound of racemic mixture comprising optical isomers of pyrrolidinyl norephedrine and optical isomers of pyrrolidinyl norpseudoephedrine is obtained by process of steps a) to c) as process described as above and then treating with a suitable chiral acid.
  • any ratio of optical isomers of pyrrolidinyl norephedrine and optical isomers pyrrolidinyl norpseudoephedrine as defined above or the same may be obtained by any known process can be used as starting material for the resolution.
  • the present invention provides a process for the preparation of optically pure (1R, 2S) - pyrrolidinyl norephedrine, comprising: treating either any ratio of optical isomers of pyrrolidinyl norephedrine or its mixture with pyrrolidinyl norpseudoephedrine with a suitable chiral acid in an appropriate solvent to obtain (IS, 2R) - pyrrolidinyl norephedrine and converting the mother liquors containing mixture of (1R, 2S)-pyrrolidinyl norephedrine and optical isomers of pyrrolidinyl norpseudoephedrine in to pure (1R, 2S) - pyrrolidinyl norephedrine by treating it with another suitable chiral acid.
  • the resolution step of the present invention involves conversion of mixture of optical isomers of pyrrolidinyl norephedrine and optical isomers of pyrrolidinyl norpseudoephedrine to its corresponding pyrrolidinyl norephedrine chiral acid salt and then neutralizing the chiral acid salt.
  • the suitable chiral acid for step b) is selected from the group comprising L(+)-tartaric acid, L(+)-malic acid, L(+)-lactic acid and the like; preferably L(+)-tartaric acid.
  • Other suitable chiral acid resolving agents may be determined by testing and the use thereof in a process as described above falls within the scope of the present invention.
  • the appropriate solvent for resolution of racemic mixtures of pyrrolidinyl norephedrine may be selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, n-propanol and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; halogenated solvents such as methylene chloride, ethylene chloride, chloroform and the like; esters such as ethyl acetate, n-propyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, dimethyl ether, tetrahydrofuran, methyl tertiary butyl ether and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane,
  • the resolution may be carried out at a temperature ranging from about 0°C to reflux temperature of the solvent used.
  • the reaction time may range from about 30 minutes to about 30 hours, or longer, depending on the conditions chosen.
  • the obtained (IS, 2R) - pyrrolidinyl norephedrine chiral salt of compound of pyrrolidinyl norephedrine may be isolated by techniques, such as centrifugation, gravity filtration, or vacuum filtration or other techniques known in the art for the separation of solids; for example gravity filtration.
  • Step c) of the foregoing process involves neutralizing the mother liquors obtained from step b) containing a salt of (lR,2S)-pyrrolidinyl norephedrine and salt of optical isomers of pyrrolidinyl norpseudoephedrine to obtain (1R, 2S) - pyrrolidinyl norephedrine and optical isomers of pyrrolidinyl norpseudoephedrine.
  • the neutralization step c) may be carried out by removing the solvent form the mother liquors obtained from step b) under vacuum at ambient temperature to about 80°C obtain a residue, then adding water and water immiscible organic solvent to the ⁇ residue and adjusting the pH to basic of about 10 with a suitable base such as sddium hydroxide, potassium hydroxide and the like.
  • the organic layer may be separated and removing the water immiscible organic solvent completely under vacuum to obtain a residue containing free base of mixture of (1R, 2S) - pyrrolidinyl norephedrine and optical isomers of pyrrolidinyl norpseudoephedrine.
  • the water immiscible organic solvent used herein for step c) is. selected from the group consisting of toluene, ethyl acetate, methylene chloride, chloroform and the like, preferably toluene.
  • the neutralization step c) can be carried out by adding water to the mother liquors obtained from step b), if the solvent used in the step b) is water immiscible organic solvent, and ' adjusting the pH to basic of about 10 with a suitable base such as sodium hydroxide, potassium hydroxide and the like.
  • a suitable base such as sodium hydroxide, potassium hydroxide and the like.
  • Step d) of the foregoing process involves treating the resultant mixture of step c) with a suitable cbiral acid in a suitable solvent to obtain a salt of (1R, 2S) - pyrrolidinyl norephedrine.
  • the suitable chiral acid used herein for step f) is selected from the group comprising D(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2- trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l,l'-binaphthalene-2,2'-dihydrogen phosphate and the like; preferably D(-)-tartaric acid.
  • the suitable solvent used herein for step d) is selected from the group comprising alcohols such as methanol, ethanol, isopropanol, n-propanol and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; halogenated solvents such as methylene chloride, ethylene chloride, chloroform and the like; esters such as ethyl acetate, n-propyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, dimethyl ether, tetrahydrofuran, methyl tertiary butyl ether and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; amides such as
  • the resolution may be carried out at a temperature ranging from about 0°C to reflux temperature of the solvent used.
  • the reaction time may range from about 30 minutes to about 30 hours, or longer, depending on the conditions chosen.
  • the obtained chiral acid salt of (lR,2S)-pyrrolidinyl norephedrine can be isolated by techniques known in the art, such as centrifugation, gravity filtration, or vacuum filtration or other techniques known in the art for the separation of solids; for example gravity filtration.
  • the solvent from the reaction mass may be removed completely or partially by distillation techniques such as atmospheric distillation, distillation under vacuum or evaporation before isolation.
  • the chiral acid salt of (lR,2S)-pyrrolidinyl norephedrine thus obtained may be further purified to remove impurities, reaction byproducts, and the like by slurrying or crystallizing from a suitable solvent.
  • the present invention provides a process for isomer enrichment of (lR,2S)-pyrrolidinyl norephedrine or a salt thereof, comprising:
  • the suitable solvent includes, but is not limited to alcohols, esters, ethers, halogenated solvents, hydrocarbon solvents, water and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol and the like; esters include, but are not limited to ethyl acetate, isopropyl acetate and the like; ethers include, but are not limited to tetrahydrofuran, diisopropyl ether, diethyl ether and the like; halogenated solvents include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbon solvents include, but are not limited to toluene, xylene, hexane, heptane, cyclohexane and the like; preferably methanol, ethanol, ethyl acetate, toluene and the like and mixtures thereof; more preferably methanol, ethanol, toluene and mixtures thereof.
  • the solvent may be heated to obtain a solution at a temperature of from about ambient temperature to about reflux temperature, preferably about 35°C to 85°C.
  • the reaction solution may be cooled at a temperature from about 20°C or less such that chiral acid salt of (1R, 2S) - pyrrolidinyl norephedrine can be isolated by conventional techniques, for example filtration.
  • optically pure chiral acid salt of (IR, 2S) - pyrrolidinyl norephedrine may be neutralized to obtain free base of optically pure (IR, 2S) - pyrrolidinyl norephedrine.
  • the neutralization step may be carried out by any known procedure; for example optically pure chiral acid salt of (IR, 2S) - pyrrolidinyl norephedrine may be combined with water and a water immiscible organic solvent such as toluene, methylene chloride, ethyl acetate, chloroform, ethyl acetate and the like. Then the solution pH may be adjusted to basic with a suitable base such as sodium hydroxide and the like. The product containing organic layer may be separated and isolating the (1R-, 2S)- pyrrolidinyl norephedrine free base by conventional methods such as evaporation, solvent crystallization or both.
  • a water immiscible organic solvent such as toluene, methylene chloride, ethyl acetate, chloroform, ethyl acetate and the like.
  • a suitable base such as sodium hydroxide and the like.
  • the present invention provides a (IR, 2S)-pyrrolidinyl norephedrine, obtained by the process described herein, having a chiral purity of at least about 98%, as measured by HPLC, preferably at least about 99% as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC; contains less than about 1% of (IS, 2R)- enantiomer, as measured by HPLC, preferably less than about 0.5%, as measured by HPLC, more preferably less than about 0.2%, as measured by HPLC; and substantially free of enantiomers of norpseudoephedrine such as (IS, 2S) and (IR, 2R), wherein the word "substantially free” refers to (IR, 2S)-pyrrolidinyl norephedrine having less than about 0.1%) of (IS, 2S) and (IR, 2R)-enantiomers, as measured by HPLC; more preferably less than about 0.05% of (IS,
  • the present invention provides a chiral acid salt compound of Formula I,
  • Rl and R2 independently represent hydrogen or Rl and R2 combine to form a cyclic ring
  • chiral acid is selected from the group comprising: D(-)-tartaric acid, D(-)- malic acid, D(-)-lactic acid, L(+)-tartaric acid, L(+)-malic acid, L(+)-lactic acid, S(+)- mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l,l'-binaphthalene-2,2'- dihydrogen phosphate and the like.
  • the present invention provides a chiral acid salt of pyrrolidinyl norephedrine; wherein the chiral acid is selected from the group comprising: D(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, L(+)-tartaric acid, L(+)- malic acid, L(+)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l,l'- binaphthalen
  • the present invention provides (IS, 2R)-pyrrolidinyl norephedrine L(+)-tartaric acid salt. In a preferred embodiment, the present invention provides (1R, 2S)-pyrrolidinyl norephedrine D(-)-tartaric acid salt.
  • the present invention provides (IS, 2S)-pyrrolidinyl norpseudoephedrine S(+)-mandelic acid salt.
  • the present invention provides (IS, 2S)-pyrrolidinyl norpseudoephedrine dibenzoyl-d-tartaric acid salt.
  • the present invention provides a process for the preparation of (1R, 2S) - pyrrolidinyl norephedrine, . comprising recycling the mother liquors containing unwanted optical isomers of pyrrolidinyl norephedrine as obtained by the process described above or may be obtained by any known process, as a starting material by means of oxidation to obtain keto compound of Formula IIA and converting the compound of Formula IIA into optically pure (1R, 2S)- pyrrolidinyl norephedrine.
  • the present invention provides a process for the preparation of (1R, 2S) - pyrrolidinyl norephedrine, comprising: a) providing mother liquors containing either any ratio of optical isomers of pyrrolidinyl norephedrine or its mixture with pyrrolidinyl norpseudoephedrine, b) evaporating the solvent from the mother liquors to obtain a residue,
  • the starting mother liquors containing mixed enantiomers of pyrrolidinyl norephedrine and pyrrolidinyl norpseudoephedrine such as (1R, 2S), (IS, 2R), (IS, 2S) and (1R, 2R) obtained by the process described above or may be obtained by any known process may be evaporated to remove solvent completely under reduced pressure to obtain a residue.
  • the residue may be taken into an appropriate solvent such as water and treating with an oxidizing agent to obtain a ketopyrrolidine compound of Formula IIA, which is further converted into optically pure (1R, 2S) - pyrrolidinyl norephedrine by the process of keto reduction and then chiral resolution process as described herein as above.
  • the suitable oxidizing agent in the foregoing process may be selected from the group consisting of chromium trioxide, sodium dichromate, potassium dichromate, potassium permanganate, pyridinium chlorochromate, dess-martin periodinane, pyridinium dichromate, magnesium dioxide, manganese (IV) oxide, dichromate (VI), chromium (VI) oxide and the like; preferably sodium dichromate.
  • the present invention provides a process for the preparation of optically pure (IS, 2R) - pyrrolidinyl norephedrine, comprising: treating a mixture of (IS, 2R) and (1R, 2S) optical isomers of pyrrolidinyl norephedrine, with a suitable resoluting agent in an appropriate solvent to obtain (IS, 2R) - pyrrolidinyl norephedrine; wherein the suitable resoluting agent is selected from the group comprising: D(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p-toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-
  • the starting mixture of (IS, 2R) and (1R, 2S) optical isomers of pyrrolidinyl norephedrine contains excess of (IS, 2R) isomer ⁇
  • the starting mixture of (IS, 2R) and (1R, 2S) optical isomers of pyrrolidinyl norephedrine may be obtained by the process described as above or may be obtained by any known process.
  • mother liquors containing mixture of (IS, 2R) and (1R, 2S) optical isomers of pyrrolidinyl norephedrine, wherein the content of (IS, 2R) isomer is greater than the other isomer may be evaporated to remove solvent completely under reduced pressure to obtain a residue. Then, the residue may be taken into an appropriate solvent and treating with a suitable resoluting agent to obtain optically pure (IS, 2R) - pyrrolidinyl norephedrine.
  • the appropriate solvent may be selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, n-propanol and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; halogenated solvents such as methylene chloride, ethylene chloride and the like; esters such as ethyl acetate, n-propyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, dimethyl ether, tetrahydrofuran, methyl tertiary butyl ether and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; amides such as dimethyl formamide, dimethyl acet
  • the enantioselectivity of the obtained (IS, 2R) enantiomer can be further improved by purifying the pyrrolidinyl norephedrine chiral acid salt obtained by the above procedure using a suitable solvent for example, a purification process as described for (1R, 2S) enantiomer.
  • the obtained optically pure chiral acid salt of (IS, 2R) - pyrrolidinyl norephedrine may be neutralized to obtain free base of optically pure (IS, 2R) - pyrrolidinyl norephedrine.
  • the neutralization step may be carried out any known procedure; for example neutralization process as described above for the process of (1R, 2S) - pyrrolidinyl norephedrine.
  • the (IS, 2R)- pyrrolidinyl norephedrine recovered using the process of the present invention having a chiral purity of at least about 98%, as measured by HPLC, preferably at least about 99% as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC; contains less than about 1% of (1R, 2S)-enantiomer, as measured by HPLC, preferably less than about 0.5%, as measured by HPLC, more preferably less than about 0.2%, as measured by HPLC.
  • the present invention provides a process for the preparation of (IS, 2S) - pyrrolidinyl norpseudoephedrine, comprising: a) reducing a keto compound of Formula IIA with a suitable reducing agent optionally in presence of a metal salt to obtain a mixture of optical isomers of pyrrolidinyl norephedrine and pyrrolidinyl norpseudoephedrine;
  • step b) separating the optical isomers of pyrrolidinyl norpseudoephedrine from the resulting mixture of step a) using a column chromatography with a suitable eluent,
  • keto compound of Formula IIA may be carried out by adding sufficient amount of a suitable reducing agent to the keto compound of Formula IIA in order to carrying keto reduction in an organic solvent.
  • Suitable reducing agent, organic solvent and the reaction temperature for the keto reduction with a suitable reducing agent optionally in presence of a metal salt can also be the same as the process of keto reduction described as above.
  • pyrrolidinyl norephedrine recovered using the process of the present invention having a chiral purity of about 10-35% each of four optical isomers i.e. pyrrolidinyl norephedrine isomers [(1R, 2S) and (IS, 2R)] and pyrrolidinyl norpseudoephedrine isomers [(IS, 2S) and (1R, 2R)].
  • the step b) of foregoing process involves separating the optical isomers of pyrrolidinyl norpseudoephedrine from the resulting mixture of step a) using a column chromatography with a suitable eluent.
  • the suitable eluent is selected from the group consisting of halogenated solvents such as methylene chloride, chloroform and the like; alcohols such as methanol, ethanol and the like and mixtures thereof.
  • the fractions contaming mixture of pyrrolidinyl norpseudoephedrine isomers [(IS, 2S) and (1R, 2R)] are separated first and then other isomers pyrrolidinyl norephedrines [(1R, 2S) and (IS, 2R)]. Then the solvent fractions containing mixture of (IS, 2S) and (1R, 2R) isomers are evaporated under reduced pressure to obtain a residue.
  • step c) of foregoing process involves resolution of pyrrolidinyl norpseudoephedrine isomers obtained from step b) using a suitable resoluting agent in a suitable solvent to obtain pure (IS, 2S) - pyrrolidinyl norpseudoephedrine.
  • the suitable resoluting agent may be selected from the group comprising: D(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p- toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S- hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l, -binaphthalene-2,2'-dihydrogen phosphate and the like; preferably S(+)-mandelic acid or dibenzoyl-D-tartaric acid.
  • the suitable solvent may be selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, n-propanol and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; halogenated solvents such as methylene chloride, ethylene chloride and the like; esters such as ethyl acetate, n-propyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, dimethyl ether, tetrahydrofuran, methyl tertiary butyl ether and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; amides such as dimethyl formamide, dimethyl acet
  • the obtained (IS, 2S) - pyrrolidinyl norpseudoephedrine chiral salt may be isolated by techniques known in the art, such as centrifugation, filtration, or vacuum filtration or other techniques known in the art for the separation of solids; for example filtration.
  • the (IS, 2S) - pyrrolidinyl norpseudoephedrine chiral salt recovered using the process of the present invention having a chiral purity of about 97% and 3% of (IS, 2S) and (1R, 2R) respectively.
  • the enantioselectivity of (IS, 2S) enantiomer can be further improved by purifying the (IS, 2S)-pyrrolidinyl norpseudoephedrine chiral acid salt obtained by the above procedure using a suitable solvent.
  • the present invention provides a process for isomer enrichment of optical purity of (IS, 2S) - pyrrolidinyl norpseudoephedrine, comprising:
  • the suitable solvent includes, but is not limited to alcohols, esters, ethers, halogenated solvents, hydrocarbon solvents, water and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol and the like; esters include, but are not limited to ethyl acetate, isopropyl acetate and the like; ethers include, but are not limited to tetrahydrofuran, diisopropyl ether, diethyl ether and the like; halogenated solvents include, but are not limited to methylene chloride, ethylene chloride and the like; hydrocarbon solvents include, but are not limited to toluene, xylene, hexane, heptane, cyclohexane and the like; preferably ethanol, isopropanol, ethyl acetate and mixtures thereof; more preferably ethanol.
  • the solvent may be heated to obtain a solution at a temperature of from about ambient temperature to about reflux temperature.
  • the reaction solution may be cooled at a temperature from about 20°C or less such that chiral acid salt of (I S, 2S) - pyrrolidinyl norpseudoephedrine can be isolated by conventional techniques.
  • optically pure chiral acid salt of (IS, 2S) - pyrrolidinyl norpseudoephedrine may be neutralized as per the procedure known in the art to obtain free base of optically pure (IS, 2S) - pyrrolidinyl norpseudoephedrine.
  • the (I S, 2S)- pyrrolidinyl norpseudoephedrine recovered using the process of the present invention having a chiral purity of at least about 98%, as measured by HPLC, preferably at least about 99% as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC; contains less than about 1% of (1R, 2R)-enantiomer, as measured by HPLC, preferably less than about 0.5%, as measured by HPLC, more preferably less than about 0.2%, as measured by HPLC.
  • the present invention provides a process for the preparation of (1R, 2R) - pyrrolidinyl norpseudoephedrine, comprising:
  • the step a) of starting mother liquors containing mixed enantiomers of pyrrolidinyl norpseudoephedrine such as (I S, 2S) and (1R, 2R) obtained by the process described above or may be obtained by any known process may be evaporated to remove solvent completely under reduced pressure to obtain a residue.
  • the residue may be taken into water and a water immiscible organic solvent such as toluene and then adjusting the pH to basic with a suitable base such as sodium hydroxide and the like.
  • the water immiscible organic solvent layer may be separated and evaporating under reduced pressure to obtain a mixture of (IS, 2S) and (1R, 2R) isomers as residue, which is further treating with a suitable reso luting agent in a suitable solvent to obtain (1R, 2R) - pyrrolidinyl norpseudoephedrine.
  • step f) involves conversion of mixture of optical isomers of (IS, 2S) and (1R, 2R) - pyrrolidinyl norpseudoephedrine to its corresponding chiral acid salt and then neutralizing the chiral acid salt.
  • the suitable resoluting agent may be selected from the group comprising: D(-)-tartaric acid, D(-)-malic acid, D(-)-lactic acid, S(+)-mandelic acid, pyroglutamic acid, di-p- toluyl tartaric acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, naproxen, S- hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-mefhoxy-2-trifluoromethyl phenylacetic acid, Di-p-anisoyl-D-tartaric acid, Dibenzoyl-D-tartaric acid monodimethyl amide, S(+)-l, -binaphthalene-2,2'-dihydrogen phosphate and the like; preferably S(+)-mandelic acid.
  • the suitable solvent may be selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, n-propanol and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; halogenated solvents such as methylene chloride, ethylene chloride and the like; esters such as ethyl acetate, n-propyl acetate, isobutyl acetate and the like; ethers such as diethyl ether, dimethyl ether, tetrahydrofuran, methyl tertiary butyl ether, and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; amides such as dimethyl formamide, dimethyl ace
  • the resolution may be carried out at a temperature ranging from about 0°C to reflux temperature of the solvent used.
  • the reaction time may range from about 30 minutes to about 30 hours, or longer, depending on the conditions chosen.
  • the obtained chiral acid salt of compound of (1R, 2R)-pyrrolidinyl norpseudoephedrine may be isolated by techniques known in the art, such as centrifugation, filtration, or vacuum filtration or other techniques known in the art for the separation of solids; for example filtration.
  • the chiral acid salt of (1R, 2R)-pyrrolidinyl norpseudoephedrine recovered using the process of the present invention having a chiral purity of about 97% and 3% of (1R, 2R) and (I S, 2S) respectively.
  • the enantioselectivity of (1R, 2R) enantiomer can be further improved by purifying the pyrrolidinyl norpseudoephedrine chiral acid salt obtained by the above procedure using a suitable solvent system as per the procedure described for (I S, 2S) enantiomer.
  • the purification process may provide a high chiral purity level of the resulting chiral acid salt of (1R, 2R) - pyrrolidinyl norpseudoephedrine from the corresponding crude chiral acid salt, e.g., content of (1R, 2R) enantiomer of at least about 99% and other (I S, 2S) enantiomer is of less than about 1%.
  • optically pure chiral acid salt of (1R, 2R) - pyrrolidinyl norpseudoephedrine may be neutralized as per the procedure known in the art to obtain free base of optically pure (1R, 2R) - pyrrolidinyl norpseudoephedrine.
  • the (1R, 2R)- pyrrolidinyl norpseudoephedrine recovered using the process of the present invention having a chiral purity of at least about 98%, as measured by HPLC, preferably at least about 99% as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC; contains less than about 1% of (I S, 2S)-enantiomer, as measured by HPLC, preferably less than about 0.5%, as measured by HPLC, more preferably less than about 0.2%, as measured by HPLC.
  • the present invention provides a process for the preparation of norephedrine of Formula IB, comprising:
  • 'X' is a halogen selected from CI, Br or I;
  • Rl and R2 independently represents hydrogen or a formyl group; to obtain a keto compound Formula IIB;
  • Formula IIB c) reducing the keto compound of Formula IIB with a suitable reducing agent to obtain norephedrine of Formula IB.
  • the step a) of lialogenation of propioplienone of Formula TV is earned out with a suitable halogenating agent as process described above for pyrrolidinyl norephedrine.
  • step b) of the foregoing process may involve reaction of halopropiophenone of step a) with a suitable amine source of Formula:
  • Rl and R2 independently represent hydrogen or a formyl group; preferably the suitable amine source can be selected from ammonia, diformylimide and the like; in a suitable solvent to obtain a keto compound of Formula IIB.
  • the suitable solvent may be selected form the group consisting of halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and the like; ethers such as ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, THF, 1,4-Dioxane and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; esters such as ethyl acetate, isopropyl acetate and the like; Nitriles such as acetonitrile, propionitrile, benzonitrile and the like; aromatic hydrocarbons such as to
  • the step c) of foregoing process may be carried out by adding sufficient amount of a suitable reducing agent and optionally in presence of a metal salt to the resultant product in order to carrying keto reduction in an organic solvent.
  • Suitable reducing agent, organic solvent and the reaction temperature for the keto reduction with a suitable reducing agent optionally in presence of a metal salt can also be the same as the process of keto reduction described as above for pyrrolidinyl norephedrine.
  • norephedrine of Formula IB recovered using the process of the present invention having a chiral purity of about 10-35% of each four optical isomers i.e. norephedrine isomers [(1R, 2S) and (IS, 2R)] and norpseudoephedrine isomers [(IS, 2S) and (1R, 2R)].
  • optical isomers of norephedrine (1R, 2S) and (IS, 2R)] and norpseudoephedrine isomers [(IS, 2S) and (1R, 2R)] may be separated by resolution process using a suitable resoluting .agents as per the process described above for separation of optical isomers of its corresponding pyrrolidine derivative.
  • the present invention provides norephedrine and its derivatives, obtained by the process described herein, as analyzed using the chiral high performance liquid chromatography ("chiral HPLC”) with the conditions described below:
  • the enantiomerically pure norephedrine and its derivatives obtained by the process of the present invention can be used in the preparation of many pharmaceutically active medicaments, for example as chiral auxiliary in the preparation of anti retroviral drugs like efavirenz.
  • the present invention provides a method for preparing pharmaceutically active medicaments, for example anti retroviral agent such as Efavirenz with high enantiomeric purity from (1R, 2S)-enantiomer of pyrrolidinyl norephedrine, obtained by the process of the present invention.
  • the processes of the invention allow for economical synthesis, shorter reaction times, and yields of high purity.
  • Example 1 Preparation of l-phenyl-2-(pyrrolidin-l-yl)propan-l -one.
  • the reaction mass was heated to about 25°C to 30°C and stirred for about 12 hours at same temperature and reaction completion was monitored by TLC.
  • the reaction mass pH was adjusted to about 4 with dilute HCl (210 ml) and the reaction mass was concentrated under vacuum at below 60°C to obtain residue.
  • the residue was allowed to cool to 30°C to 35°C, water (900 ml) was charged and adjusted pH to about 2 with dilute HCl (10 ml) then heated to about 50°C.
  • the reaction mass was washed with toluene (200 ml) and the aqueous layer pH was adjusted to about 10 with aqueous sodium hydroxide (290 ml) and then extracted the product with toluene (2*300 ml).
  • the organic layer was washed with 10% sodium chloride solution and the organic layer was concentrated under vacuum at below 60°C to obtain the title compound as residue (Yield: 92 gms)
  • Example 3 Preparation of pyrrolidinyl norephedrine using sodium borohydride and zinc bromide.
  • a I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged ethanol (350 ml) and Zinc bromide (27.6 gms) at a temperature of about 25°C to 35°C.
  • the reaction mixture was allowed to cool to about 0°C to 5°C and sodium borohydride (22.45 gms) was added at same temperature and stirred for 1 minutes.
  • reaction mass To the reaction mass, solution of l-phenyl-2-(pyrrolidin-l-yl) propan-l-one (100 gms in 350 ml ethanol) was added at 0°C to 5°C and stirred for about 5 hours at same temperature and reaction completion was monitored by TLC.
  • the reaction mass pH was adjusted to about 4 with dilute HCl (210 ml) and the reaction mass was concentrated under vacuum at below 60°C to obtain residue. The residue was allowed to cool to 30°C to 35°C, water (900 ml) was charged and adjusted pH to about 2 with dilute HCl (10 ml) then heated to about 50°C.
  • reaction mass was washed with toluene (200 ml) and the aqueous layer pH was adjusted to about 10 with aqueous sodium hydroxide (290 ml) and then extracted the product with toluene (2x300 ml).
  • the organic layer was washed with 10% sodium chloride solution and the organic layer was concentrated under vacuum at below 60°C to obtain the title compound as residue (Yield: 94 gms).
  • Example 4 Preparation of pyrrolidinyl norephedrine using sodium borohydride and zinc acetate.
  • reaction mass raised the reaction mass to 25°C to 30°C and maintained for 18 hrs and the reaction completion was monitored by TLC.
  • the reaction mass pH was adjusted to about 4 with dilute HCl (11 ml) and the reaction mass was concentrated under vacuum at below 60°C to obtain residue.
  • the residue was allowed to cool to 30°C to 35°C, water (45 ml) was charged and adjusted pH to about 2 with dilute HCl (0.5 ml) then heated to about 50°C.
  • the reaction mass was washed with toluene (10 ml) and the aqueous layer pH was adjusted to about 10 with aqueous sodium hydroxide (15 ml) and then extracted the product with toluene (2x25 ml).
  • the organic layer was washed with 10% sodium chloride solution and the organic layer was concentrated under vacuum at below 60°C to obtain the title compound as residue (Yield: 3.7 gms).
  • Example 5 Preparation of pyrrolidinyl norephedrine using sodium borohydride and manganese chloride.
  • reaction mass pH was adjusted to about 4 with dilute HC1 (20 ml) and the reaction mass was concentrated under vacuum at below 60°C to obtain residue.
  • the residue was allowed to cool to 30°C to 35°C, water (90 ml) was charged and adjusted pH to about 2 with dilute HC1 (1 ml).
  • the reaction mass was washed with toluene (20 ml) and the aqueous layer pH was adjusted to about 10 with aqueous sodium hydroxide (26 ml) and then extracted the product with toluene (2x30 ml).
  • the organic layer was washed with 10% sodium chloride solution and the organic layer was concentrated under vacuum at below 60°C to obtain the title compound as residue. Yield: 8.2 gms.
  • Example 6 preparation of pyrrolidinyl norephedrine D(-)-tartaric acid.
  • Example 7 purification of pyrrolidinyl norephedrine D(-)-tartaric acid.
  • a I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged ethanol (550 ml) and wet material at a temperature of about 25 °C to 35°C.
  • the reaction mass was heated to reflux to get a clear solution and stirred for 30 minutes at same temperature.
  • the resultant solution was allowed to cool to 0°C to 5°C and stirred for 30 minutes at same temperature.
  • the precipitated solids was filtered and washed with chilled ethanol (50 ml).
  • the wet product was dried at 50°C to 55°C under reduced pressure to provide the title compound. Yield: 43 gms.
  • Example 9 Preparation of l-phenyl-2-(pyrrolidin-l-yl) propan-l-one from pyrrolidinyl norephedrine.
  • a 3 L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged 1700 ml of ethanol mother liquors obtained from Example -6 & 7 were concentrated under reduced pressure to obtain a residue (120 gms).
  • a I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged toluene (100 ml), water (100 ml) and the above residue (120 gms) at a temperature of about 25°C to 35°C.
  • the reaction mass pH was adjusted to about 10 with 10% aqueous sodium hydroxide solution (250 ml) at 25°C to 35°C.
  • the layers were separated and the aqueous layer was extracted with toluene.
  • the combined organic layer was concentrated under vacuum at below 60°C and degassed for 30 minutes to obtain racemate of pyrrolidinyl norephedrine as residue. (Yield: 57 gms).
  • a IL round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged DM Water (150 ml) and pyrrolidinyl norephedrine residue (57 gms) at a temperature of about 25°C to 35°C.
  • the reaction mass was allowed to cool to 20°C to 25°C and sulphuric acid (63.9 gms) was added at 20°C to 25°C and stirred for 10 rnin. at same temperature.
  • Sodium dichromate solution (72.6 gm of sodium dichromate was pre-dissolved in 73 ml of DM Water) was added to the reaction mass at 20°C to 25°C and the reaction mass was stirred for 6 hrs at same temperature.
  • Reaction completion was monitored by TLC and after completion of reaction; DM water (50 ml) & Toluene (125 ml) were charged into the reaction mass and was cooled to 0°C to 5°C. The reaction mass pH was adjusted to about 10-11 with 50%» sodium hydroxide solution (95 ml) at 0°C to 5°C. The reaction mass was stirred for 30 min. and undissolved dichromate salts were filtered and washed with Toluene (50ml). The layers were separated and the organic layer was washed with DM Water (100ml). The organic layer was concentrated under vacuum at below 60°C and degassed for 30 minutes to obtain the title compound. Yield: 50 gms.
  • reaction mass pH was adjusted to about 4 with dilute HCl (105 ml) and the reaction mass was concentrated under vacuum at below 60°C to obtain residue.
  • the residue was allowed to cool to 30°C to 35°C, water (450 ml) was charged and adjusted pH to about 2 with dilute HCl (5 ml).
  • the reaction mass was washed with toluene (100 ml) and the aqueous layer pH was adjusted to about 10 with aqueous sodium hydroxide (145 ml) and then extracted the product with toluene (2x 150 ml).
  • the organic layer was washed with 10% sodium chloride solution and the organic layer was concentrated under vacuum at below 60°C to obtain the title compound as residue (Yield: 44 gms).
  • Example 11 Preparation of pyrrolidinyl norephedrine using sodium borohydride.
  • a 3.0L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged methanol (600 ml) and l-phenyl-2-(pyrrolidin-l-yl) propan-l-one (100 gms) at a temperature of about 25°C to 35°C.
  • the reaction mixture was allowed to cool to about 0°C to 5°C and sodium borohydride (18.6 gms pre- dissolved in 56 ml of 0.2N sodium hydroxide solution) was added at same temperature and stirred for 15 minutes.
  • the reaction mass was heated to 20-25°C and stirred for about 4 hours at same temperature and reaction completion was monitored by TLC.
  • the reaction mass pH was adjusted to about 4 with dilute HCl (210 ml) and the reaction mass was concentrated under vacuum at below 60°C to obtain residue.
  • the residue was allowed to cool to 30°C to 35°C, water (900 ml) was charged and adjusted pH to about 2 with dilute HCl (10 ml).
  • the reaction mass was washed with toluene (200 ml) and the aqueous layer pH was adjusted to about 10 with aqueous sodium hydroxide (290 ml) and then extracted the product with toluene (2x300 ml).
  • the organic layer was washed with 10% sodium chloride solution and the organic layer was concentrated under vacuum at below 60°C to obtain the title compound as residue (Yield: 96 gms).
  • Example 12 Separation of mixture of (1R,2S) & (1S,2R) isomers of pyrrolidinyl norephedrine & mixture of (1S,2S) & (1R,2R) isomers of pyrrolidinyl norpseudoephedrine.
  • a 2 Feet length and 3" diameter glass column was loaded with silica gel (500 gms) using methylene chloride. Pyrrolidinyl norephedrine (95 gms pre adsorbed on 47.5 gms of silica gel using methylene chloride) was loaded. The column was eluted with methylene chloride using 0.5% methanol concentration. The fractions were combined and distilled out the solvent under vacuum to obtain mixture of (IS, 2S) & (1R, 2R) isomers as residue (35 gms).
  • Example 14 purification of (IS, 2S)-pyrrolidinyl norpseudoephedrine S(+)-mandelic acid.
  • reaction mass pH was adjusted to about 10 with 10% aqueous sodium hydroxide solution (7.5 ml) at 25°C to 35°C.
  • the layers were separated and the aqueous layer was extracted with toluene (10 ml).
  • the combined organic layer was concentrated under vacuum at below 60°C and degassed for 30 minutes to obtain the title compound. Yield: 1.73 gms.
  • Example .16 preparation of (IS, 2S)-pyrrolidinyl norpseudoephedrine dibenzoyl-d- tartaric acid.
  • Example 17 purification of (IS, 2S)-pyrrolidinyl norpseudoephedrine dibenzoyl-d- tartaric acid.
  • Example 18 purification of (IS, 2S)-pyrrolidinyl norpseudoephedrine free base.
  • Example 19 Preparation of mixture of (IS, 2S) & (1R, 2R) isomers of pyrrolidinyl norpseudoephedrine.
  • Example 21 purification of (1R, 2R)-pyrrolidinyl norpseudoephedrine S(+) Mandalic acid.
  • Example 23 preparation of (lR,2S)-pyrrolidinyl norephedrine D(-)-tartaric acid.
  • Example 25 preparation of (lR,2S)-pyrrolidinyl norephedrine free base.
  • the reaction mass pH was adjusted to about 10 with 10% aqueous sodium hydroxide solution (100 ml) at 25°C to 35°C.
  • the layers were separated and the aqueous layer was extracted with toluene (5 ml).
  • the combined organic layer was concentrated under vacuum at below 60°C and degassed for 30 minutes to obtain the title compound. Yield: 2.3 gms
  • Example 26 Preparation of mixture of (1R,2S) & (IS, 2R) isomers of pyrrolidinyl norephedrine.
  • Example 27 preparation of (1S,2R)- pyrrolidinyl norephedrine D(-) tartaric acid.
  • Example 28 purification of (lS,2R)-pyrrolidinyl norephedrine D(-)-tartaric acid.
  • Example 29 preparation of (lS,2R)-pyrrolidinyl norephedrine free base.
  • Example 30 Preparation of pyrrolidinyl norephedrine using a procedure analogous to that employed in Example 2 with using sodium borohydride and different metal salts as described in the following table:
  • Example 31 Preparation of (1R, 2S)- pyrrolidinyl norephedrine D(-)-tartaric acid.
  • the organic and aqueous layer was separated and then the aqueous layer pH was adjusted to 10-10.5 with aqueous sodium hydroxide solution at 25°C to 35°C.
  • Chloroform ((300 ml) was added to the reaction mass and stirred for 15 mins at 25°C to 35°C and organic layer was separated. The organic layer was heated and water was removed by azeotrope distillation and the reaction mass was allowed to cool to 25°C to 35°C.
  • Chloroform (260 ml) and methanol (44 ml) was added to the reaction mass and was heated to 40°C to 45°C.
  • L(+)-tartaric acid 64 gms was added to the reaction mass at 40°C and stirred for 30 mins at 40°C to 45°C.
  • seed crystals of (IS, 2R)- pyrrolidinyl norephedrine L-(+)-tartaric acid salt 0.1 gm was added and the reaction mass was allowed to cool to 25°C to 35°C and stirred for 2 hours at same temperature.
  • the precipitated solid was filtered, washed with chloroform and suck dried for 30 mins. The filtrate was taken in to RBF and water was added to it at 25°C to 35°C then stirred for 15 mins.
  • reaction mass pH was adjusted to 9.5-10.5 with aqueous sodium hydroxide solution at 25°C to 30°C.
  • the aqueous and organic layer was separated and the organic layer was allowed to cool to 40°C to 45°C.
  • D(-)-tartaric acid 51 gms was added to the reaction mass at 40°C to 45°C and stirred for 30 mins.
  • the reaction mass was allowed to cool to 25°C to 35°C and stirred for 2 hours.
  • the solid formed was filtered off, washed with chloroform and dried the compound at 50°C to 55°C for 4 hours to obtain the title compound.
  • reaction mass was stirred at reflux for 30 mins and toluene (500 ml) was added to it at 60-65°C.
  • the reaction mass was cooled to 45°C to 50°C and seed crystals of (1R, 2S)-pyrrolidinyl norephedrine D-(-)-tartaric acid salt (0.1 gm) was added and stirred for 30 mins at 45°C to 50°C.
  • the reaction mass was allowed to cool to 33-37°C and stirred for 60 mins.
  • the reaction mass was further allowed to cool to 10°C to 15°C and stirred for 60 mins.
  • the precipitated solid was filtered off, washed with a mixture of methanol and toluene and then dried at 50°C to 60°C to obtain the title compound.
  • Example-34 Preparation of (1R, 2S)- pyrrolidinyl norephedrine D(-)-tartaric acid.
  • a round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was charged with propiophenone (100 gms) and methylene chloride (300 ml) at 25°C to 35°C.
  • the reaction mass was allowed to cool to 20°C to 25°C and sulfuryl chloride (110.65 gms) was added to the reaction mass.
  • the reaction mass was heated to 30°C to 35°C and stirred for 2 hours.
  • chilled water 200 ml was added to the reaction mass and stirred for 15 mins at 25°C to 35°C.
  • reaction mass was allowed to cool to 25 °C to 35°C and water (400 ml) was added to it.
  • the reaction mass pH was adjusted to 2-2.5 with aqueous hydrochloric acid solution at 25°C to 35°C and stirred for 15 mins.
  • the aqueous and organic layer was separated and the organic layer was extracted with water (100 ml).
  • sodium hydroxide solution was added to adjust the pH to 9-9.5 at 25°C to 35°C followed by Toluene (300 ml) was added to the reaction mass and stirred for 15 mins.
  • the organic layer was separated and the aqueous layer was extracted with toluene (150 ml).
  • the combined organic layer was washed with water and the organic layer was concentrated under vacuum till 5 vol remains in the flask.
  • the reaction mass was allowed to cool to 0°C to 5°C and Zinc bromide (38.7 gms) was added at 0°C to 5°C and stirred for 15 mins.
  • Sodium borohydride (33.8 gms) was added to the reaction mass at 0-5°C and stirred for 15 mins.
  • Methanol (280 ml) was added to the reaction mass and stirred for 2 hours at 0-5°C.
  • the reaction mass pH was adjusted to 2-2.5 with aqueous hydrochloric acid at 0-5°C and then Water (980 ml) was added to the reaction mass.
  • the reaction mass was heated to 45°C to 50°C and stirred for 15 mins and organic and aqueous layer was separated.
  • Water (140 ml) was added to the organic layer at 45 °C to 50°C, stirred and the aqueous layer was separated.
  • the aqueous layers were combined and pH was adjusted to 10-10.5 with sodium hydroxide solution at 45°C to 50°C and extracted the product with Toluene (2x420 ml) at 45°C to 50°C.
  • the organic layer was washed with sodium chloride solution and the organic layer was concentrated under vacuum at below 60°C to obtain a residue.
  • the residue was dissolved in ethanol and was further concentrated under vacuum at below 60°C to obtain a residue (130 gms).
  • the filtrate was distilled off the solvent completely under vacuum at below 50°C and the obtained residue was allowed to cool to 40°C to 50°C.
  • Water (100 ml) and toluene (300 ml) was added to the residue and stirred for 15 mins.
  • the reaction mass pH was adjusted to 9.5-10 with aqueous sodium hydroxide solution and stirred for 15 mins at 25-30°C.
  • the organic and aqueous layer was separated and aqueous layer was extracted with toluene (100 ml). Organic layer were combined and was washed with 5% sodium chloride solution at 25-30°C.
  • the organic layer was concentrated under vacuum at below 60°C to obtain a residue.

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CN104805148A (zh) * 2015-04-30 2015-07-29 苏州汉酶生物技术有限公司 一种(1r,2s)-n-吡咯烷基去甲麻黄碱的生物制备方法
CN105523984A (zh) * 2015-09-07 2016-04-27 赤峰艾克制药科技股份有限公司 （1r，2s）-1-苯基-2-（1-吡咯烷基）-1-丙醇的制备方法
CN109134335A (zh) * 2017-06-27 2019-01-04 苏州引航生物科技有限公司 一种制备手性(1r,2s)-1-苯基-2-(1-吡咯烷基)丙烷-1-醇的方法
CN110655496A (zh) * 2018-12-18 2020-01-07 安徽贝克联合制药有限公司 手性化合物的合成方法
CN113866289A (zh) * 2021-09-03 2021-12-31 上海凌凯医药科技有限公司 2,3-二苯甲酰氧基-4-二甲基氨基-4-氧代丁酸的手性分离检测方法

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WO2007077140A1 (de) * 2006-01-06 2007-07-12 Basf Aktiengesellschaft Hydroxy-norephedrin-derivate und verfahren zu ihrer herstellung

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CN104805148A (zh) * 2015-04-30 2015-07-29 苏州汉酶生物技术有限公司 一种(1r,2s)-n-吡咯烷基去甲麻黄碱的生物制备方法
CN104805148B (zh) * 2015-04-30 2019-02-01 苏州汉酶生物技术有限公司 一种(1r,2s)-n-吡咯烷基去甲麻黄碱的生物制备方法
CN105523984A (zh) * 2015-09-07 2016-04-27 赤峰艾克制药科技股份有限公司 （1r，2s）-1-苯基-2-（1-吡咯烷基）-1-丙醇的制备方法
CN109134335A (zh) * 2017-06-27 2019-01-04 苏州引航生物科技有限公司 一种制备手性(1r,2s)-1-苯基-2-(1-吡咯烷基)丙烷-1-醇的方法
CN109134335B (zh) * 2017-06-27 2022-05-17 苏州引航生物科技有限公司 一种制备手性(1r,2s)-1-苯基-2-(1-吡咯烷基)丙烷-1-醇的方法
CN110655496A (zh) * 2018-12-18 2020-01-07 安徽贝克联合制药有限公司 手性化合物的合成方法
CN113866289A (zh) * 2021-09-03 2021-12-31 上海凌凯医药科技有限公司 2,3-二苯甲酰氧基-4-二甲基氨基-4-氧代丁酸的手性分离检测方法

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