WO2004043921A1 - Nouveau procede de preparation de 4-aryl-3-hydroxymethyl-1-methylpiperidines - Google Patents

Nouveau procede de preparation de 4-aryl-3-hydroxymethyl-1-methylpiperidines Download PDF

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WO2004043921A1
WO2004043921A1 PCT/IN2003/000356 IN0300356W WO2004043921A1 WO 2004043921 A1 WO2004043921 A1 WO 2004043921A1 IN 0300356 W IN0300356 W IN 0300356W WO 2004043921 A1 WO2004043921 A1 WO 2004043921A1
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formula
compound
ome
toluene
methyl
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Muddasani Pulla Reddy
Nannapaneni Venkaiah Chowdary
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Natco Pharma Limited
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    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
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    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
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    • C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
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    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/48—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
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    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic 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
    • C07D211/08—Heterocyclic 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
    • C07D211/18—Heterocyclic 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
    • C07D211/20—Heterocyclic 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
    • C07D211/22—Heterocyclic 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 an improved process for the preparation of ( ⁇ )-trans-4- aryl-3 -hyroxymethyl- 1 -methylpiperidines.
  • the compound of the formula-I wherein b represents fluorine is a key intermediate used in the synthesis of (-)-trans-4-p-fluorophenyl-3-(3',4'-methylenedioxyphenoxymethyl)- piperidine, a compound also known as paroxetine of the formula- ⁇ .
  • Paroxetine commercially available in the market as an anti-depressant inhibits 5-hydroxytryptamine (5-HT) re-uptake.
  • Scheme-II Compound of the formula-I where b represents fluorine was also prepared (Scheme-Ill) by reducing trans-4-p-fluorophenyl-6-oxopiperidine-3-carboxilic acid esters of the formula- V, wherein R is alkyl and subsequent N-methylation or by N-methylation of compound ofthe formula-V and subsequent reduction (as disclosed in EP 802,185, ES 96 00,369, EP 812827, and WO 98 53,824).
  • the secondary amine of the formula-XIII can be reacted with acrylic acid esters to give the corresponding ⁇ -alkylated derivative ofthe formula-XIV.
  • the compound of the formula-XVI can be prepared by generation of an anion ⁇ to the ester carbon present in compound ofthe formula-XV and cyclizing through displacement ofthe leaving group X.
  • the ester group present in compound ofthe formula-XVI can be reduced with a simple reagent like sodium borohydride to get the desired compound of the formula-I where X has the meanings given earlier.
  • the reaction can be carried out in a polar alcoholic or aqueous solvent.
  • the secondary amine can be employed in the form of its inorganic or organic salt or as a free base.
  • the suitable inorganic or organic are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid, oxalic acid, fumaric acid, tartaric acid, -adipic acid, etc.
  • the amine is used in free base form at least one equivalent of organic or inorganic acid is used along with the solvent.
  • the known dimethylamine derived Mannich salt (compound of the formula-XVIII) is converted to the known hydroxy compound of formula-XIX by known processes.
  • the hydroxy compound thus obtained can be de-methylated using methyl or ethyl chloroformate to get the corresponding urethane derivative of the formula-XX.
  • the urethane derivative can be hydrolyzed using alkali to get the secondary amine of the formula-XIII.
  • the Mannich salt obtained from N-benzylmethylamine (compound ofthe formula-XXI), can be neutralized and reduced in situ with sodium borohydride to get the hydroxy compound ofthe formula-XXII.
  • the reduction can be done in alcoholic solvent.
  • This can be converted to the secondary amine of formula-XIII by direct hydrogenation in the presence of a metal catalyst under mild hydrogenation.
  • the hydrogenation can be done in an alcoholic solvent like methanol, ethanol, isopropanol, etc.
  • the secondary amine derivative of the formula-XIII is reacted with an alkyl ester of acrylic acid to get the corresponding tertiary amine derivative of the formula-XIV.
  • the reaction can be done in an aromatic solvent (benzene, toluene, xylene, etc.), in a hydrocarbon solvent (hexane, heptane, cyclohexane, etc.), or in an ether solvent (dimethyl ether, diisopropyl ether, methyl isobutyl ether, methyl tert-butyl ether, etc.).
  • the hydroxy group present in compound of the formula-XIN can be converted to its mesylate or tosylate. Alternatively, it can be reacted with thionyl chloride or excess mineral acid (HBr or HCl) to get the corresponding halide as the hydrogen halide salt.
  • the sulfonate derivatives or the halide salts of compound of the formula-XN can be reacted with a strong base ( ⁇ aH, n-butyl lithium, lithium diisopropyl amide, etc.) in a dipolar aprotic solvent to get the cyclic derivative of the formula-XV.
  • a strong base ⁇ aH, n-butyl lithium, lithium diisopropyl amide, etc.
  • at least two equivalents of base is used to carryout the cyclization step.
  • the cyclized compound of the formula-XV can be reduced using sodium borohydride under various conditions (sodium borohydride/borontrifluoride-etherate, sodium borohydride/t-butanol/methanol, reflux; t-butanol/acetic acid, etc.), vitride, sodium/ethanol, lithium tris-(t-butoxy)aluminum hydride, lithium aluminum hydride, etc., to get the required compound of the formula-I where X has the meanings given earlier.
  • the medium of the reaction can be an alcoholic solvent (for sodium borohydride), aromatic solvent for vitride, and an ether solvent for lithium reagents.
  • the invention provides novel compounds ofthe formula-XX,
  • the alkyl/aryl chloroformate used for the N-demethylation of the compound of the formula-XIX may be selected from methyl, ethyl, or phenyl chloroformate .
  • the invention also provides novel compounds ofthe formula-XIII,
  • the invention also provides a process for the preparation of novel compounds ofthe formula-XIII, which comprises:
  • the alkyl chloroformate used for the N-demethylation of the compound of the formula- XIX in step (i) may be selected from methyl, ethyl, and phenyl chloroformate.
  • the alkali used in step (ii) may be selected from sodium or potassium hydroxide preferably potassium hydroxide in aqueous DMSO at 60-140°C, preferably 100-120°C.
  • the present invention also provides novel compounds of formula-XXI,
  • the invention also provides a process for the preparation of novel compounds ofthe formula-XXI,
  • the present invention also provides novel compounds ofthe formula-XXII,
  • X F, Me, OMe
  • HX' is inorganic or organic acid with a base in alcoholic medium
  • the base used in step (i) may- be selected from sodium or potassium hydroxide, carbonate, bicarbonate and the like.
  • the alcoholic medium used in reduction may be selected from methanol, ethanol, isopropanol, sec-butanol, etc., with or without water.
  • the base used in step (i) may be selected from sodium or potassium hydroxide, carbonate, bicarbonate and the like.
  • the alcoholic medium used in reduction may be selected from methanol, ethanol, isopropanol, sec-butanol, etc., with or without water.
  • the metal catalyst used in debenzylation step may be selected from Raney nickel, 2-10% palladium-on-carbon, 2-5% platinum-on-carbon and the like.
  • the invention also provides novel compounds ofthe formula-XIV.
  • Michael addition product ofthe formula-XIV The reaction can be done in solvents such as benzene, toluene, xylene, hexane, heptane, cyclohexane, methylene chloride, acetonitrile, preferably toluene, cyclohexane, heptane.
  • the temperature ofthe reaction can be in the range of 25-100°C, preferably 40-70°C.
  • the invention also provides novel compounds ofthe formula-XV.
  • the N-alkylation reaction can be done in solvents such as benzene, toluene, xylene, hexane, heptane, cyclohexane, methylene chloride, acetonitrile, preferably toluene, cyclohexane, heptane.
  • the temperature of the reaction can be in the range of 25-100°C, preferably 40-70°C.
  • the conversion of hydroxy group present in compound of formula-XIV into a leaving group X' is done by treating the compound of formula-XIV with a base and the required sulfonyl chloride in the presence of a solvent at a temperature in the range of -30 to 30°C.
  • the base used in the reaction can be selected from inorganic base like sodium or potassium carbonate, bicarbonate, or an organic base such as pyridine, triethylamine, etc., preferably triethylamine.
  • the solvent used in the reaction can be selected hexane, heptane, cyclohexane, toluene, methylene chloride, chloroform, ethylene dichloride, diethyl ether, diisopropyl ether, THF, 1,4-dioxane, etc, preferably toluene, methylene chloride or THF.
  • the conversion of hydroxy group present in compound of formula-XIV into a leaving group X' (OAc) is done by treating the compound of formula-XIV with acetic anhydride/acetyl chloride in the present of a solvent.
  • the solvent used in the reaction can be selected hexane, heptane, cyclohexane, toluene, methylene chloride, chloroform, ethylene di chloride, diethyl ether, diisopropyl ether, THF, 1,4-dioxane, etc, preferably toluene, methylene chloride or THF.
  • the conversion of hydroxy group present in compound of formula-XIV into a leaving group X' (CI) is done by treating the compound of formula-XIV with excess thionyl chloride in a solvent at elevated temperature.
  • the solvent used in the reaction can be selected hexane, heptane, cyclohexane, toluene, methylene chloride, chloroform, ethylene dichloride, diethyl ether, diisopropyl ether, THF, 1,4-dioxane, etc, preferably toluene, methylene chloride or THF.
  • the temperature of the reaction can be in the range of 10- 60°C.
  • the invention also provides novel compounds ofthe formula-XVI
  • the base used in the reaction is selected from lithium diisopropylamide, sodium hydride, potassium t-butoxide, etc.
  • the ether solvent used in the reaction is selected from THF, diethyl ether.
  • the dipolar aprotic solvent used in the reaction is selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc.
  • the temperature of the reaction is in the range of -15 to 25°C.
  • the invention also provides novel compounds ofthe formula-I,
  • the invention also provides a process for the preparation of novel compounds of the formula-I
  • the invention also provides a novel process for the preparation of compounds of the formula-I
  • step (iv) Reducing the ester group present in the compound of the formula-XVI with a reducing agent to get the hydroxy compound of formula-I where X has the meanings given earlier
  • the acrylate ester used in step (i) is selected from methyl or ethyl acrylate and the like.
  • the solvent such as toluene, cyclohexane, heptane, xylene, acetonitrile, and the like preferably, toluene or cyclohexane is used in step (i).
  • the temperature employed in step (i) is in the range of 60 to70°C.
  • the reagents used in step (ii) for the conversion of the hydroxy group are selected from thionyl chloride, thionyl bromide, phosphorous trichloride, phosphorous tribromide, hydrochloric acid, hydrobromic acid, methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, acetyl chloride, benzoyl chloride, trifluoromethanesulfonyl chloride, etc., preferably thionyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride or trifluoromethanesulfonyl chloride, more preferably thionyl chloride or methanesulfonyl chloride.
  • the solvent used in step (ii) is methylene chloride, ethylene dichloride, toluene, cylcohexane, heptane, etc., preferably, methylene chloride, toluene or heptane and the reaction temperature is in the range of -20 to 25°C, preferably -5 to 15°C.
  • the base used in step (ii) is triethylamine, pyridine, lutidine, sodium or potassium carbonate, or bicarbonate, etc., preferably, pyridine or triethylamine.
  • the strong base used in step (iii) is selected from sodium hydride, butyl lithium, hexyl lithium, lithium diisopropylamide, sodium t-butoxide, potassium t-butoxide, sodium sec- amyloxide, sodium amide, lithium amide, sodium methoxide, and the like, preferably sodium hydride lithium diisopropylamide.
  • the solvent used in step (iii) is selected from N,N-dimethylformamide, N,N- dimethylacetamide, pyridine, dimethylsulfoxide, tetrahydrofuran, dioxane, toluene, xylene, diisopropyl ether, etc., preferably N,N-dimethylformamide, dimethylsulfoxide, pyridine, tetrahydrofuran, more preferably N,N-dimethylformamide, tetrahydrofuran.
  • the temperature of reaction in step (iii) is between -10 to 45°C, preferably -5 to 25°C.
  • the mole ratio of base to substrate in step (iii) is 1:1.1 to 1:2.0, preferably 1:1.25.
  • the reducing agent used in step (iv) is selected from sodium borohydride/t- butanol/methanol, sodium borohydride in the presence of an acid catalyst like boron trifluoride-etherate, sulfuric acid, etc.; vitride, lithium aluminum hydride, lithium tris-(t- butoxy)aluminum hydride, sodium/ethanol, and the like, preferably, sodium borohydide/t-butanol/methanol, vitride, lithium aluminum hydride.
  • the temperature of reaction in step (iv) is -50°C to 70°C, preferably -20°C to 20°C.
  • the strong base used is selected from sodium hydride, butyl lithium, hexyl lithium, lithium diisopropylamide, sodium t-butoxide, potassium t-butoxide, sodium sec- amyloxide, sodium amide, lithium amide, sodium methoxide, and the like, preferably sodium hydride lithium diisopropylamide.
  • isopropanol 150ml
  • N- methylbenzylamine 80gr
  • the reaction mixture was cooled to 15-20°C and treated with IPA-HC1 (192gr, 13.64% HCl content).
  • reaction mixture maintained at same temperature for 4hrs.
  • Sodium hydride (6.5gr, 50%) was added to the reaction mixture in lots over a period of lhr at - 15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 10ml of methanol.
  • the reaction mass was poured into ice water and the product extracted toluene (2 x 100ml).
  • Product was extracted from toluene layer into aqueous acetic acid (10%, 150ml).
  • Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 100ml).
  • reaction mixture was maintained at same temperature for 4hrs.
  • Sodium hydride (12gr, 50%) was added to the reaction mixture in lots over a period of lhr at - 10°C to -15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 5ml of ethanol.
  • the reaction mass was poured into ice water and the product extracted toluene (2 x 100ml).
  • Product was extracted from toluene layer into aqueous acetic acid (10%, 150ml).
  • Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 75ml).
  • reaction mixture was cooled to -15°C and charged triethylamine (l lgr).
  • a solution of benzenesulfonyl chloride (16gr) in THF (30ml) was added to the reaction mixture slowly over a period of 2hrs at -15°C.
  • the reaction mixture maintained at same temperature for lOhrs.
  • Sodium hydride (lOgr, 50%) was added to the reaction mixture in lots over a period of lhr at -15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 10ml of methanol.
  • the reaction mass was poured into ice water and the product extracted toluene (2 x 75ml).
  • IR (KBr): 3126, 3026, 2946, 2858, 2814, 2731, 1732, 1516, 1471, 1458, 1435, 1416, 1402, 1372, 1324, 1199, 1174, 1144, 1109, 1067, 1015, 942, 904, 862, 825, 798, 761, 723, 704, and 562cm "1 .
  • 1H-NMR 300MHz, CDC1 3 ): 7.11-7.27 (m, 4H, ar.H); 5.30 (br.s, exch.
  • reaction mixture was cooled to -5 to 0°C and triethylamine (7.2gr) was added.
  • a solution of methanesulfonyl chloride (5.6gr) in methylene chloride (25ml) was added to the reaction mixture slowly over a period of lhr and kept under maintenance for additional 6hrs.
  • the reaction mixture was poured into 50ml of chilled water and extracted product into methylene chloride. Aqueous layer was extracted with 2 x 50ml of methylene chloride. Combined methylene chloride layer was washed with water and dried over sodium sulfate. Distillation of methylene chloride gave the crude compound of the formula-XV as syrup (6gr). This was found to be sufficiently pure enough for further conversion.
  • reaction mixture was cooled to -5 to 0°C and triethylamine (5gr) was added.
  • a solution of methanesulfonyl chloride (4gr) in methylene chloride (15ml) was added to the reaction mixture slowly over a period of lhr and kept under maintenance for additional 6hrs.
  • the reaction mixture was poured into 50ml of chilled water and extracted product into methylene chloride.
  • Aqueous layer was extracted with 2 x 50ml of methylene chloride.
  • Combined methylene chloride layer was washed with water and dried over sodium sulfate. Distillation of methylene chloride gave the crude compound ofthe formula-XV as syrup (7gr). This was found to be sufficiently pure enough for further conversion.
  • Into a 250ml three-necked RB flask was charged 30ml of dry toluene and 2gr of thionyl chloride.
  • a solution of ( ⁇ )-methyl 3-[N-methyl-N-(3-hydroxy-3-(4-methylphenyl)- propyl)] aminopropionate (3gr) in toluene (10ml) was slowly added to the reaction mixture at RT.
  • the process ofthe present invention has the advantages over the processes ofthe prior art that the piperidine ring is formed without involving any piperidone derivative, and no lithium aluminum hydride is used. No hazardous reactions are involved in the synthesis Therefore, the process simple, cheap, safe and environmentally friendly. In addition the raw materials employed are readily available.

Abstract

L'invention concerne un nouveau procédé général amélioré de préparation de 4-aryl-3-hydroxyméthyl-1-méthylpipéridines. La 4-(4-fluorophényl)-3-hydroxyméthyl-1-méthylpipéridine est un intermédiaire connu dans la fabrication de l'antidépresseur paroxetine ((-)-trans-4-p-fluorophényl-3-(3',4'-méthylènedioxy-phénoxyméthyl)pipéridine). De nouvelles N-méthyl-N-[3-(4-substitué-phényl-(F, Me, OMe))-3-hydroxy]propylamines sont préparées par des procédés classiques à partir de sels de Mannich tels que des 3-diméthylamino- ou 3-(N-méthyl-N-benzylamino)-4'-substituée-(F, Me, OMe)-propiophénone-hydrochlorures. Les N-méthyl-N-[3-(4-substitué-phényl-(H, F, Me, OMe))-3-hydroxy]propylamines ainsi obtenues sont mises en réaction avec de l'acrylate d'éthyle ou de méthyle pour former les produits d'addition de type Michael correspondants. Le groupe hydroxy présent dans les produits d'addition de type Michael est converti en un groupe mobile et traité avec une base forte pour former des 4-aryl-N-méthylpipéridine-3-carboxylates par cyclisation intramoléculaire avec de bons rendements. Par réduction du groupe ester présent dans ces pipéridine-3-carboxylates, on obtient les composés selon l'invention sous forme de solides cristallins. Le procédé selon l'invention peut être facilement mis en oeuvre pour la préparation commerciale de l'intermédiaire de la paroxetine (4-(4-fluorophényl)-3-hydroxyméthyl-1-méthylpipéridine).
PCT/IN2003/000356 2002-11-11 2003-11-06 Nouveau procede de preparation de 4-aryl-3-hydroxymethyl-1-methylpiperidines WO2004043921A1 (fr)

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AU2003282379A AU2003282379A1 (en) 2002-11-11 2003-11-06 Novel process for the preparation of 4-aryl-3-hydroxymethyl-1-methylpiperidines.

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IN830CH2002 2002-11-11
IN830/MAS/2002 2002-11-11

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WO2005063707A1 (fr) * 2003-12-26 2005-07-14 Natco Pharma Limited Procede enantiospecifique permettant de preparer un intermediaire de paroxetine

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Publication number Priority date Publication date Assignee Title
WO2005063707A1 (fr) * 2003-12-26 2005-07-14 Natco Pharma Limited Procede enantiospecifique permettant de preparer un intermediaire de paroxetine

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