WO2016142952A1 - Procédé de préparation de vilazodone, et nouveaux intermédiaires de vilazodone - Google Patents

Procédé de préparation de vilazodone, et nouveaux intermédiaires de vilazodone Download PDF

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WO2016142952A1
WO2016142952A1 PCT/IN2015/050034 IN2015050034W WO2016142952A1 WO 2016142952 A1 WO2016142952 A1 WO 2016142952A1 IN 2015050034 W IN2015050034 W IN 2015050034W WO 2016142952 A1 WO2016142952 A1 WO 2016142952A1
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acid
formula
ammonium
dioxolane
solvents
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PCT/IN2015/050034
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Satyanarayana Reddy BHEMIREDDY
Venkat Reddy YARAPATHI
V. Vara Prasada Reddy Paidimarla
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Nosch Labs Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms

Definitions

  • the invention relates to a process for preparation of Vilazodone.
  • the invention also relates to novel intermediates for synthesis of Vilazodone.
  • Vilazodone is a benzofuran-2-carboxamide derivative, chemically known as 5-(4-[4-(5- cyano-lH-indol- 3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide. It is represented by the structure of Formula-XI as shown below-
  • CN 103304547 A discloses a rocess for Vilazodone as shown in below Scheme-2:
  • CN103570697 discloses various routes for synthesis of Vilazodone.
  • 5- (piperazin-l-yl) benzofuran-2-carboxamide reacts with 4-bromo-l-butene to give an intermediate 5- (4- (3- butenyl) piperazin-l-yl) benzofuran-2-carboxamide, which further reacts with 3- iodo-l-tosyl-indole-5- carbonitrile to give 5- (4- (4- (5-cyano-l- tosyl-indol-3-yl) -3-butenyl) piperazin -1- yl) benzofuran -2-carboxamide.
  • X halogen F, CI, Br, I; preferably Br
  • the primary object of the invention is to provide a novel process for the preparation of Vilazodone.
  • Another object of the invention is to provide novel intermediates for the synthesis of Vilazodone.
  • the present invention provides a process for preparation of Vilazodone and novel intermediates for synthesis of Vilazodone.
  • the invention provides a process for preparation of Vilazodone comprising the steps of:
  • Ts Tosyl
  • X represents a leaving group selected from halogen (CI, Br and I), O-tosyl, O- mesyl, O-benzenesulfonyl, O-trifluoromethane sulfonyl; preferably X is halogen, more preferably CI.
  • Y is either oxygen (O) or sulfur (S); preferably Y is O.
  • R 2 is selected from CI to C5 alkyl chain or substituted derivatives like isopropyl, Bis(2,2,2-trichloroethyl), diacetyl etc; and for cyclic ketals R 2 is selected from CI to C5 alkyl chain individually or its substituted derivatives like 4-bromomethyl-l,3-dioxolane, 4-(3-butenyl)- 1,3- dioxolane, 4-(4-methoxyphenyl)-l,3-dioxolane, 4-(2-nitrophenyl)-l,3- dioxolane, 4-trimethylsilylmethyl- 1 ,3-dioxolane, (4R,5R)-diphenyl- 1 ,3- dioxolane, 4,5-dimethyl-l,3-dioxolane, trans- 1,2-cyclohexanediol ketal, trans- 4,6-d
  • R 2 is selected from CI to C5 alkyl chain or substituted derivatives like diphenyl, dibenzyl, diacetyl etc, and for cyclic thioketals R 2 is selected from CI to C5 alkyl chain individually or its substituted derivatives like l,5-dihydro-3H-2,4-dibenzodithiepin.
  • R 3 represents either NH 2 or C1-C4 alkoxy group selected from methoxy, ethoxy, propoxy and butoxy; preferably R 3 is methoxy (-OMe) or ethoxy (-OEt).
  • CH 2 CHCH 2 CH 2 CHOHCH 2 OH
  • Step-(a) is performed with or without presence of catalyst.
  • Suitable catalyst in step-(a) may be selected from organic acids such as succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzenesulfonic acid, citric acid, camphorsulfonic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids” such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid; preferably hydrochloric acid or sulfuric acid.
  • organic acids such as succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzenesul
  • Suitable solvent used in step-(a) may be selected from “alcoholic solvents” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n- pentane and the like, “chloro solvents” such as methylene chloride, ethylene dichloride, carbon te
  • the suitable bases in step-(b) are acid binding agents, which may be selected from an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or alkali metal or alkali earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate or calcium carbonate or alkali metal or alkaline earth metal salt of a week acid, preferably a potassium, sodium or calcium salt, or an organic bases such as triethylamine, dimethylaniline, pyridine or quinoline and the like or the mixtures thereof; preferably triethylamine.
  • an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide
  • sodium carbonate, potassium carbonate or calcium carbonate or alkali metal or alkaline earth metal salt of a week acid preferably a potassium, sodium or calcium salt
  • organic bases such as triethylamine, dimethylaniline, pyr
  • the solvent used in step-(b) may be selected from triethylamine (TEA), toluene, diglyme, acetone, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran (THF), dioxane, water, dimethylformamide (DMF), dimethylacetamide, N-methylpyrrolidone, acetonitrile or mixtures thereof; preferably triethylamine (TEA).
  • the suitable activating agents in step-(b) may be metal halides and/or phase transfer catalysts. Step-(b) is performed with or without presence of metal halides and with or without presence of phase transfer catalyst.
  • the metal halides in step-(b) may be selected from iodide and bromide of alkali metal or alkali earth metal; preferably sodium iodide or potassium iodide.
  • the phase transfer catalyst in step-(b) may be selected from tetra butyl ammonium bromide (TBAB), tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide and ethyl triphenyl phosphonium bromide; preferably TBAB.
  • TBAB tetra butyl ammonium bromide
  • the suitable amidation agent in step-(c) may be selected from ammonia, formamide, ammonia gas, ammonium carbamate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate, ammonium citrate, ammonium chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartarate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate, alkyl or aryl amines, magnesium
  • Suitable solvent in step-(c) may be selected from water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof.
  • Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol, glycerol, propylene glycol; polyglycols such as polyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol 400; pyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone; glycol ethers such as propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and diethylene glycol ethyl ether, ⁇ , ⁇ -dimethyl acetamide, PEG 300, propylene glycol; chloro solvents like methylene chloride, chloroform and ethylene chloride; hydrocarbon solvents like to toluene, xylene, heptane, cyclohexane and hexane; preferably the solvent selected from methanol or ethanol.
  • Step-(d) is performed in presence of suitable reagents/catalysts.
  • the suitable reagents used in step-(d) for deprotection ketals may be selected from Si0 2 , TMSI,TIC1 4 , LiBF 4 , Amberlyst, H 2 0 2 , BF 3 Et 2 0/TEAI, SiH 2 I 2 , M0 2 (acac) 2 , AcCl/SmCl 3 , SnCl 2 /graphite, DDQ, HM-zeolite, ISiCl 3 , ZnCl 2 /Me 2 S, Na 2 S 2 0 4 , montimorillonite, Me 2 BBr, Zn, alumina/silica gel, pyridinium tosylate(PPTS), MgS0 4 , Ph3CBF 4 , NaTeSH, CuS0 4 , DDQ, PPh 3 /CBr 4 , SmCl
  • the suitable reagents used in step-(d) for deprotection of thioketals may be selected from AgN0 3 /Ag 2 0, AgC10 4 , HgCl 2 /CdC0 3 /CaC0 3 , Me 2 CH(CH 2 ) 2 ONO, T1(N0 3 ) 3 , S0 2 Cl 2 /Si0 2 , I2/NaHC0 3 , H 2 0 2 , NaI0 4 , CuCl/CuO, HgO, mCPBA, PhsCClCVPhsCOMe/NaHCOs, DDQ, GaCl 3 , clay supported NH 4 N0 3 , NaOMe/Si0 2 , Hg(C10 4 ) 2 /CaC0 3 , NCS, Tl(OCOCF 3 ) 3 , p-MeC 6 H 4 S0 2 N(Cl)Na, (PhSeO) 2 0, Me 2 (CH 2
  • the catalysts may be acid catalysts selected from organic acids such as trifluoroacetic acid, formic acid, perchloric acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzene sulfonic acid, citric acid, camphorsulfonic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids” such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid and phosphoric acid; preferably the acid used is hydrochloric acid (HC1), more preferably aqueous hydrochloric acid.
  • organic acids such as trifluoroacetic acid, formic acid, perchloric acid
  • the solvent used in step-(d) may be selected from "alcoholic solvents” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; "ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; "ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n- pentane and the like; "chloro solvents” such as methylene chloride, ethylene dichloride, carbon tet
  • the suitable reducing agent in step-(e) may be used alone or in combination of suitable reagents selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithium borohydride, NaBH 3 CN, sodium borohydride/BF 3 -etherate, vitride, sodiumborohydride/aluminium chloride, borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN, acetic acid /sodiumborohydride, trifluoroacetic acid (TFA)/sodiumborohydride, Et 3 SiH/TFA, Zn-Hg and sodiumborohydride/tosylhydrazone; preferably combination of trifluoroacetic acid with sodiumborohydride is used.
  • suitable reagents selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithium borohydride, NaBH 3 CN, sodium borohydride/BF 3 -etherate, vitride, sodiumborohydride/aluminium chloride, bo
  • the solvent used in step-(e) may be selected from "alcoholic solvents” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; "ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; "ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, n- pentane and the like; "chloro solvents” such as methylene chloride, ethylene dichloride, carbon tet
  • the suitable base used in step-(f) may be selected from an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal or alkaline earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate and calcium carbonate; or alkali metal or alkaline earth salt of weak acid, preferably a potassium, sodium or calcium salt; or an organic base such as triethylamine, dimethylaniline, pyridine or quinoline and the like; ammonia or mixtures thereof; preferably the base is sodium hydroxide (NaOH) and potassium hydroxide (KOH); more preferably the base used is NaOH.
  • an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide
  • alkali metal or alkaline earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate and calcium carbonate
  • alkali metal or alkaline earth salt of weak acid preferably a potassium, sodium or calcium salt
  • Suitable solvent used in step-(f) may be selected from “alcoholic solvents” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, n- pentane and the like; “chloro solvents” such as methylene chloride, ethylene dichloride, carbon te
  • the invention provides a process for preparation of Vilazodone comprising the steps of:
  • -Ts represents a tosyl group
  • R 3 represents either NH 2 or C1-C4 alkoxy group selected from methoxy, ethoxy, propoxy and butoxy; preferably R 3 is methoxy (-OMe) or ethoxy (-OEt) and, Et represents ethyl (-C 2 Hs).
  • the present invention provides a process for preparation of Vilazodone of Formula- XL
  • the invention provides a process for preparation of Vilazodone as shown below in Scheme- A (Path- A):
  • Ri is p-toluene
  • Z is tosyl group (Ts).
  • - X represents a leaving group selected from halogen (CI, Br and I), O-tosyl, O- mesyl, O-benzenesulfonyl, 0-trifluoromethane sulfonyl; preferably X is halogen, more preferably CI.
  • Y is either oxygen (O) or sulfur (S); preferably Y is O.
  • R 2 is selected from CI to C5 alkyl chain or substituted derivatives like isopropyl, Bis(2,2,2-trichloroethyl), diacetyl etc; and for cyclic ketals R 2 is selected from CI to C5 alkyl chain individually or its substituted derivatives like 4-bro mo methyl- 1,3 -dioxolane, 4-(3-butenyl)- 1,3- dioxolane, 4-(4-methoxyphenyl)-l,3-dioxolane, 4-(2-nitrophenyl)-l,3- dioxolane, 4-trimethylsilylmethyl- 1 ,3-dioxolane, (4R,5R)-diphenyl- 1 ,3- dioxolane, 4,5-dimethyl-l,3-dioxolane, trans- 1,2-cyclohexanediol ketal, trans- 4,6-d
  • R 2 is selected from CI to C5 akyl chain or substituted derivatives like diphenyl, dibenzyl, diacetyl etc, and for cyclic ketals R 2 is selected from CI to C5 alkyl chain individually or its substituted derivatives like l,5-dihydro-3H-2,4-dibenzodithiepinect; preferably when Y is S, R 2 is CI to C5 alkyl chain, more preferably methyl or ethyl.
  • R 3 represents either NH 2 or C1-C4 alkoxy group selected from methoxy, ethoxy, propoxy and butoxy; preferably R 3 is methoxy (-OMe) or ethoxy (-OEt).
  • the invention provides a process for preparation of Vilazodone comprising the steps of:
  • Step-(a) of the process in Scheme-A comprises a process for the preparation of a novel intermediate compound of Formula-II starting from a compound of Formula-I as shown below:
  • CH 2 CHCH 2 CH 2 CHOHCH 2 OH
  • TMS protected glycerol trans- 1,2- cyclohexanediol/z ' -prOTMS
  • 2,4-pentane diol/Sc(OTf) 3 4,5-dimethoxymethyl-l,3- diol.
  • the suitable reagents are trimethylorthoformate or Triethyl Orthoformate.
  • the suitable reagent is methane thiol or ethane thiol.
  • the reaction of Formula-I with suitable reagent in above step-(a) is performed with or without suitable catalyst and/ or a suitable solvent.
  • the suitable catalyst used in the above step-(a) of the process may be selected from organic acids such as succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzenesulfonic acid, citric aicd, camphorsulfonic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids” such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric aicd and phosphoric acid.
  • the catalyst used is hydrochloric acid or sulfuric acid.
  • the suitable solvent used in the above step-(a) of the process may be selected from "alcoholic solvents” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso- butanol, ethylene glycol and the like; "ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butyl ether, 1,4- dioxane and the like; "hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane and the like, "chloro solvents” such as methylene chloride, ethylene dichloride, carbon
  • X is -CI; Ri is p-toluene, Y is O and R 2 is ethyl (Et).
  • Ri is p-toluene, Z represents a tosyl group (Ts).
  • Ts represents tosyl group.
  • step-(a) Formula-la is treated with Triethyl Orthoformate in presence of sulfuric acid and ethanol to give novel intermediate compound of Formula-IIa as shown below:
  • Step-(b) of the process in Scheme-A comprises a process for the preparation of novel intermediate of Formula- IV by coupling of the compound of Formula-II with a compound of Formula-Ill as shown below: wherein,
  • step-(b) The coupling of Formula-II and Formula-Ill in step-(b) is performed in presence of suitable bases/reagents in suitable solvents.
  • the suitable bases in step-(b) are acid binding agents, which may be selected from an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or alkali metal or alkali earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate or calcium carbonate or alkali metal or alkaline earth metal salt of a week acid, preferably a potassium, sodium or calcium salt, or an organic base such as triethylamine, dimethylaniline, pyridine or quinoline and the like or the mixtures thereof.
  • the acid binding agent selected is triethylamine.
  • the solvent used in step-(b) may be selected from triethylamine (TEA), toluene, diglyme, acetone, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran (THF), dioxane, water, dimethylformamide (DMF), dimethylacetamide, N-methylpyrrolidone, acetonitrile or mixtures thereof.
  • TFA triethylamine
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • N-methylpyrrolidone acetonitrile or mixtures thereof.
  • the solvent used in step- (b) is triethylamine (TEA).
  • the suitable reagents may be metal halides and phase transfer catalysts.
  • the coupling reaction can be performed with or without metal halides.
  • Formula-II in step-(b) Formula-II is condensed with Formula-Ill in presence of metal halides selected from iodide and bromide of alkali metal or alkali earth metal; preferably sodium iodide or potassium iodide.
  • the metal halide used in step-(b) is potassium iodide (KI).
  • the coupling reaction can be performed with or without phase transfer catalysts.
  • the phase transfer catalysts in step-(b) may be selected from tetra butyl ammonium bromide (TBAB), tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide and ethyl triphenyl phosphonium bromide.
  • TBAB tetra butyl ammonium bromide
  • tributyl benzyl ammonium bromide tetraoctyl ammonium bromide
  • step-(b) Formula-II is condensed with Formula-Ill in the presence of phase transfer catalyst tetra butyl ammonium bromide (TBAB).
  • phase transfer catalyst tetra butyl ammonium bromide
  • X is -CI; Ri is p-toluene, Y is O and R 2 is ethyl (Et) and R 3 is ethoxy (OEt).
  • Ri is p-toluene
  • Z represents a tosyl group (Ts).
  • Formula- IVa As shown below:
  • Formula-IVa wherein Ts represents tosyl group.
  • Formula-IVa wherein Ts represents tosyl group.
  • Formula-IVa wherein Ts represents tosyl group.
  • Formula-IVa wherein Ts represents tosyl group.
  • Formula-IVa wherein Ts represents tosyl group.
  • step-(b) Formula- Ila is condensed with Formula-IIIa (when R 3 in Formula-Ill is ethoxy (OEt)) in presence of potassium iodide (KI) and catalyst TBAB in solvent TEA to give the novel intermediate compound of Formula- IVa as shown below:
  • Step-(c) of the process in Scheme-A (Path-A) comprises amidation of intermediate compound of Formula-IV obtained in above step-(b) by treating with an suitable amidation agent in presence of suitable solvent to give novel intermediate compound of
  • Z, Y, R 2 and R 3 represent the same meanings as defined in Scheme-A (Path-A).
  • R 3 is NH 2 this amidation step is not required and Formula- IV becomes Formula- V.
  • R 3 is ethoxy (OEt).
  • the amidation agent is the source of ammonia.
  • the suitable amidation agent used in step-(c) may be selected from ammonia, formamide, ammonia gas, ammonium carbamate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate, ammonium citrate, ammonium chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartarate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate or t- butyl carb
  • Source of ammonia is selected from ammonia gas, liquid ammonia, aqueous ammonia, ammonium hydroxide, magnesium nitride and formamide with base; more preferably the source of ammonia is ammonia gas.
  • the amidation reaction in step-(c) is advantageously carried out using ammonia gas under pressure of about 1 Kg/Cm 2 to about 10 Kg/ Cm 2 , and specifically about 3 Kg/ Cm 2 .
  • Suitable solvent in step-(c) may be selected from water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof.
  • Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol, glycerol, propylene glycol; polyglycols such as polyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol 400; pyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone; glycol ethers such as propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and diethylene glycol ethyl ether, ⁇ , ⁇ -dimethyl acetamide, PEG 300, propylene glycol; chloro solvents like methylene chloride, chloroform and ethylene chloride; hydrocarbon solvents like to toluene, xylene, heptane, cyclohexane and hexane.
  • the solvent selected in step-(c) is alcohol; more
  • X is -CI; Ri is p-toluene, Y is O and R 2 is ethyl (Et) and R 3 is ethoxy (OEt).
  • Ri is p-toluene
  • Z represents a tosyl group (Ts).
  • Formula-V becomes Formula- Va as shown below:
  • step-(c) Formula- IVa is treated with ammonia under pressure in presence of solvent ethanol to give a novel intermediate compound of Formula- Va as shown below:
  • Step-(d) of the process in Scheme-A comprises deprotection of ketals or thioketals by treating intermediate compound of Formula-V with an suitable reagent in presence of a solvent to give intermediate compound of Formula- VI;
  • Step-(d) is performed in presence of suitable reagents/catalysts.
  • the reagents used in step-(d) for deprotection of ketals may be selected from Si0 2 , TMSI,TIC1 4 , LiBF 4 , Amberlyst, H 2 0 2 , BF 3 Et 2 0/TEAI, SiH 2 I 2 , M0 2 (acac) 2 , AcCl/SmCl 3 , SnCl 2 /graphite, DDQ, HM-zeolite, ISiCl 3 , ZnCl 2 /Me 2 S, Na 2 S 2 0 4 , montimorillonite, Me 2 BBr, Zn, alumina/silica gel, pyridinium tosylate(PPTS), MgS0 4 , Ph3CBF 4 , NaTeSH, CuS0 4 , DDQ, PPh 3 /CBr 4 , SmCl TMSCl, 2,4,6-triphenyl tetrafluoroborate, NaI/C
  • the reagents used for deprotection thioketals may be selected from AgN0 3 /Ag 2 0, AgC10 4 , HgCl 2 /CdC0 3 /CaC0 3 , Me 2 CH(CH 2 ) 2 ONO, T1(N0 3 ) 3 , S0 2 Cl 2 /Si0 2 , I2/NaHC0 3 , H 2 0 2 , NaI0 4 , CuCl/CuO, HgO, mCPBA, Ph 3 CC10 4 /Ph 3 COMe/NaHC0 3 , DDQ, GaCl 3 , clay supported NH 4 N0 3 , NaOMe/Si0 2 , Hg(C10 4 ) 2 /CaC0 3 , NCS, Tl(OCOCF 3 ) 3 , p-MeC 6 H 4 S0 2 N(Cl)Na, (PhSeO) 2 0, Me 2 (CH 2 ) 2 O
  • Chlorobezotrizole Ce(NH 4 ) 2 (N0 3 ) 6 , MeOS0 2 F, Mel, Et 3 OBF 4 , Ac 2 0/TEA, PyHBr/Br 2 , TBAB, CuCl 2 /Si0 2 , TMSOTf/0 2 NC 6 H 4 CHO, Se0 2 , H 5 IO 5 , DDQ, SbCls/N 2 , GaCl 3 , Amberlyst, Dowex 50W/paraformaldehyde, oxone/wetalumina, Fe(N0 3 ) 3 .
  • the catalyst used for deprotection of ketals in step-(d) is an acid, which may be selected from organic acids such as trifluoroacetic acid, formic acid, perchloric acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzene sulfonic acid, citric acid, camphorsulfonic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids” such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid and phosphoric acid.
  • the acid used in step-(d) is hydrochloric acid (HCl), more preferably aqueous hydrochloric acid (
  • the solvent used in step-(d) may be selected from "alcoholic solvents” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; "ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; "ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n- pentane and the like; "chloro solvents” such as methylene chloride, ethylene dichloride, carbon tet
  • Formula- VI becomes Formula- Via as shown below:
  • step-(d) Formula- Va is treated with aqueous hydrochloric acid (aq. HCl) in presence of solvent methanol to give novel intermediate compound of Formula-VIa as shown below:
  • Step-(e) of the process in Scheme-A comprises reduction of ketone group by treating Formula-VI with reducing agents in presence of suitable solvent to give intermediate compound of Formula- VII as shown below:
  • the reducing agents in step-(e) may be used alone or in combination of suitable reagent.
  • the reducing agents used in step-(e) may be selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithium borohydride, NaBH 3 CN, sodium borohydride/BF 3 -etherate, vitride, sodiumborohydride/aluminium chloride, borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN, acetic acid/sodiumborohydride, trifluoroacetic acid (TFA)/sodiumborohydride, Et 3 SiH/TFA, Zn-Hg and sodiumborohydride/tosylhydrazone.
  • DIBAL-H lithium aluminiumhydride
  • sodiumborohydride lithium borohydride
  • NaBH 3 CN sodium borohydride/BF 3 -etherate
  • vitride sodiumborohydride/aluminium chloride
  • borane/aluminium chloride sodiumborohydride
  • the reducing agent used in step-(e) of the process is in combination with an acid.
  • the reducing agent used in step-(e) of the process is combination of trifluoroacetic acid with sodiumborohydride.
  • the suitable solvent used in step-(e) may be selected from "alcoholic solvents” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; "ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; "ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents” such as toluene, xylene,
  • step-(e) the ketone group of Formula- Via is reduced to give intermediate compound of Formula- Vila by treating Formula- Via with reducing agents TFA/sodiumborohydride in presence of solvent methylene dichloride (DCM) as shown below:
  • Step-(f) of the process in Scheme-A comprises deprotection of protecting group (Z) of Formula-VII to provide Vilazodone free base as shown below:
  • the deprotection of protecting group of nitrogen in step-(f) of the process involves basic hydrolysis of Formula- VII (when Z is not H) using bases.
  • the suitable bases used in step-(f) may be selected from an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal or alkaline earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate and calcium carbonate; or alkali metal or alkaline earth salt of weak acid, preferably a potassium, sodium or calcium salt; or an organic base such as triethylamine, dimethylaniline, pyridine or quinoline and the like; ammonia or mixtures thereof.
  • the bases selected in step-(f) are alkali and alkaline earth metal hydroxides, more preferably NaOH and KOH.
  • the base used in step- (f) is NaOH.
  • the suitable solvent used in step-(f) may be selected from "alcoholic solvents” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; "ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; "ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, n- pentane and the like; "chloro solvents” such as methylene chloride, ethylene dichloride, carbon te
  • alcoholic solvents like C1-C5 alkyl chain or branched alkyl chain is used. More preferably the solvent used in step-(f) is alcoholic solvent such as methanol or ethanol; more preferably methanol is used.
  • alcoholic solvent such as methanol or ethanol
  • methanol is used.
  • Z is Ts; in step-(f) compound of Formula- Vila is treated with NaOH in presence of solvent methanol to give Vilazodone free base as shown below:
  • the invention provides a process for preparation of Vilazodone as shown below in general reaction scheme Scheme-B (Path-B):
  • R 3 is NH 2
  • the amidation step-(d) is not required and Formula- VIII becomes Formula-IX.
  • R 3 is ethoxy (OEt) or Methoxy (-OMe).
  • Z is H
  • the deprotection step-(c) is not required.
  • Z is Ts (tosyl).
  • Step-(c) of the process in Scheme-B involves deprotection of nitrogen protecting group (Z) of Formula- IV to give novel intermediate compound of Formula- VIII as shown in below:
  • Z is H
  • this deprotection step is not required.
  • Z is Ts (tosyl).
  • the deprotection of protecting group of nitrogen in step-(c) of the process comprises basic hydrolysis of general Formula- IV (when Z is not H) using bases.
  • the bases used in step-(c) may be selected from an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal or alkaline earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate and calcium carbonate; or alkali metal or alkaline earth salt of weak acid, preferably a potassium, sodium or calcium salt; or an organic base such as triethylamine, dimethylaniline, pyridine or quinoline and the like; ammonia or mixtures thereof.
  • the bases selected in step-(c) are alkali and alkaline earth metal hydroxides, more preferably NaOH and KOH.
  • the base used in step- (c) is NaOH.
  • the suitable solvent used in step-(c) may be selected from "alcoholic solvents” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; "ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; "ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents” such as toluene, xylene, cyclohex
  • Formula- VIII becomes Formula- Villa as shown below:
  • step-(c) compound of Formula- IVa is treated with NaOH in presence of solvent ethanol to give novel intermediate compound of Formula- Villa as shown below:
  • Step-(d) of present process in Scheme-B involves amidation of intermediate compound of Formula- VIII obtained in above step-(c) by treating with suitable amidation agent in presence of suitable solvent to give novel intermediate compound of Formula- IX as shown in below: Formcla-IX
  • R 3 is NH 2i this amidation step-(d) is not required and Formula- VIII becomes Formula-IX.
  • R 3 is ethoxy (OEt).
  • the amidation agent is the source of ammonia.
  • the suitable amidation agent used in step-(d) may be selected from ammonia, formamide, ammonia gas, ammonium carbamate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate, ammonium citrate, ammonium chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartarate, ammonium triflate, ammonium thiocyanate,
  • Source of ammonia is selected from ammonia gas, liquid ammonia, aqueous ammonia, ammonium hydroxide, magnesium nitride and formamide with base; more preferably the source of ammonia is ammonia gas.
  • the amidation reaction in step-(d) is advantageously carried out using ammonia gas under pressure of about 1 Kg/Cm 2 to about 10 Kg/ Cm 2 , and specifically about 3 Kg/ Cm 2 .
  • Suitable solvent in step-(d) is selected from water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof.
  • Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol, glycerol, propylene glycol; polyglycols such as polyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol 400; pyrrolidones such as N-methyl pyrrolidone and 2- pyrrolidone; glycol ethers such as propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and diethylene glycol ethyl ether, ⁇ , ⁇ -dimethyl acetamide, PEG 300, propylene glycol; chloro solvents like methylene chloride, chloroform and ethylene chloride; hydrocarbon solvents like to toluene, xylene, heptane, cyclohexane and hexane.
  • alcohols such as methanol, ethanol, propan
  • the solvent selected in step-(d) is alcohol; more preferably ethanol (EtOH) or Methanol (MeOH).
  • EtOH ethanol
  • MeOH Methanol
  • Step-(e) of present process in Scheme-B comprises deprotection of ketals or thioketals of intermediate compound of Formula- IX obtained in above step-(d) with an suitable reagents which are selected from Scheme-A (path- A) step-d in presence of a suitable solvent to give intermediate compound of Formula-X as shown in below:
  • the acid used for deprotection of ketals in step-(e) may be selected from trifluoroacetic acid, formic acid, perchloric acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzene sulfonic acid, citric acid, camphorsulfonic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids” such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid and phosphoric acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid and phosphoric acid.
  • the acid used in step-(e) is hydrochloric acid (HC1), more preferably aqueous hydrochloric acid.
  • the solvent used in step-(e) may be selected from "alcoholic solvents” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; "ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; "ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptan
  • step-(e) Formula- IXa is treated with aqueous hydrochloric acid (aq. HC1) in presence of solvent methanol to give intermediate compound of Formula-X as shown below:
  • Step-(f) of the process in Scheme-B involves reduction of ketone group of Formula-X obtained in above step-(e) by treating with reducing agents in presence of suitable solvent to provide Vilazodone free base (Formula-XI) as shown in below:
  • the reducing agents in step-(f) may be used alone or in combination of acids.
  • the reducing agents used in step-(f) may be selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithium borohydride, NaBH 3 CN, sodium borohydride/BF 3 -etherate, vitride, sodiumborohydride/aluminium chloride, borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN, acetic acid/sodiumborohydride, trifluoroacetic acid (TFA)/sodiumborohydride, Et 3 SiH/TFA, Zn-Hg and sodiumborohydride/tosylhydrazone.
  • the reducing agent used is in combination with an acid.
  • the reducing agent used in step-(f) of the process is combination of trifluoroacetic acid with sodiumborohydride.
  • the suitable solvent used in step-(f) may be selected from "alcoholic solvents” such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; "ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; "ether solvents” such as tetrahydrofuran, diethylether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, n- pentane and the like; "chloro solvents” such as methylene chloride, ethylene dichloride, carbon te
  • the invention provides novel intermediates for the preparation of Vilazodone.
  • the present invention provides novel intermediate compounds of general Formula- II Formula- IV, Formula- V and Formula- VI as shown below:
  • Trifluoromethyl benzyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3- aminophenyl, 4-aminophenyl, 4-methylphenyl, 1-napthalene, 2-napthalene.
  • X represents a leaving group selected from halogen (CI, Br and I), O-tosyl, O- mesyl, O-benzenesulfonyl, O-trifluoromethane sulfonyl.
  • Y is either oxygen (O) or sulfur (S). when Y is O, for acyclic ketals; R 2 is selected from CI to C5 akyl chain or substituted derivatieves like isopropyl, Bis(2,2,2-trichloroethyl), diacetyl etc; and for cyclic ketals R 2 is selected from CI to C5 akyl chain individually or its substituted derivatieves like 4-bromomethyl-l,3-dioxolane, 4-(3-butenyl)- 1,3- dioxolane, 4-(4-methoxyphenyl)-l,3-dioxolane, 4-(2-nitrophenyl)-l,3- dioxolane, 4-trimethylsilylmethyl- 1 ,3-dioxolane, (4R,5R)-diphenyl- 1 ,3- dioxolane, 4,5-dimethyl-l,3-dioxolane,
  • R 2 when Y is S, for acyclic thioketals R 2 is selected from CI to C5 akyl chain or substituted derivatives like diphenyl, Dibenzyl, Diacetyl etc, and for cyclic thioketals R 2 is selected from CI to C5 akyl chain individually or its substituted derivatives like l,5-dihydro-3H-2,4-dibenzodithiepin.
  • R 3 represents either NH 2 or C1-C4 alkoxy group selected from methoxy, ethoxy, propoxy and butoxy; preferably R 3 is ethoxy (-OEt).
  • -Ts represents a tosyl group
  • R 3 represents either NH 2 or C1-C4 alkoxy group selected from methoxy, ethoxy, propoxy and butoxy; preferably R 3 is methoxy (-OMe) or ethoxy (-OEt) and;
  • Example-1 Preparation of intermediate compound of Formula-IIa (Path-A, Step-(a)) To a solution of Formula-la (5 g, 12 mmol) and triethyl orthoformate (55g, 375 mmol) in 50 mL of Ethanol, Cone, sulfuric acid (2.15 g, 21 mmol) was added drop wise for 30 min at room temperature. The total reaction mixture was heated to 50-55°C for lhr. Reaction was monitored by the TLC. After completion of the reaction, the reaction mass cooled to RT, then poured in to the 35 mL of chilled saturated NaHC0 3 solution. Aqueous layer extracted with ethyl acetate (2x15 mL).
  • Example-5 Preparation of intermediate compound of Formula- Vila (Path-A, Step-(e)): To a mixture of TFA (23.48 g, 206 mmol) and 50 mL of DCM, sodiumborohydride (2.6 g, 68.7 mmol) was added portion wise for 1 hr at 10-15 °C. After completion of the addition reaction mixture was stirred for additional 2 hrs at same temperature. Now the solution of Formula- Via (10 g, 16.4 mmol) in 100 mL of DCM was added drop wise to the above reaction mixture for 1 hr at same temperature. Now temperature was slowly raised to 40-45 °C and stirred for 15 hrs at same temperature.
  • Example-10 Preparation of crude Vilazodone free base (Path-B, Step-(f)): To a mixture of TFA (33.9 g, 298 mmol) and 105 mL of DCM, sodiumborohydride (3.6 g, 96 mmol) was added portion wise for 1 hr at 10-15 °C. After completion of the addition reaction mixture was stirred for additional 2 hrs at same temperature. Now the solution of Formula-X (10.5 g, 23 mmol) in 100 mL of DCM was added drop wise to the above reaction mixture for 1 hr at same temperature. Now temperature was slowly raised to 40-45 °C and stirred for 15 hrs at same temperature.
  • reaction mixture cooled to 10 °C and 200 mL of water was added drop wise and solution P was adjusted to 10 using 10% K 2 C0 3 at same temperature.
  • Bottom organic layer was separated and aqueous layer again extracted with DCM (2x100 mL). Combined organic layer was washed with 50 mL of water and 100 mL of brine solution. Organic layer was dried with Na 2 S0 4 and distil out completely under reduced pressure to get solid of crude Vilazodone base. Weight 8.3 g, yield 82.5%, purity by HPLC 95%.

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Abstract

L'invention concerne un procédé de préparation de vilazodone et de nouveaux intermédiaires pour la synthèse de vilazodone.
PCT/IN2015/050034 2015-03-10 2015-05-08 Procédé de préparation de vilazodone, et nouveaux intermédiaires de vilazodone WO2016142952A1 (fr)

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CN108164552A (zh) * 2017-12-10 2018-06-15 常州市雄图纺织有限公司 一种脲酶抑制剂的制备方法
CN108530390A (zh) * 2017-03-06 2018-09-14 西南化工研究设计院有限公司 一种4-羟基二苯甲酮的烷基化方法
CN109627237A (zh) * 2017-10-09 2019-04-16 北京济美堂医药研究有限公司 一种维拉唑酮盐酸盐的制备方法
CN110037052A (zh) * 2019-04-11 2019-07-23 浙江工商大学 一种光催化杀菌剂及其制备方法和应用
CN112175173A (zh) * 2020-10-09 2021-01-05 中国科学技术大学 一种烯烃插入率可控的可降解聚α-烯烃材料的制备方法

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CN103304547A (zh) * 2012-03-13 2013-09-18 中国药科大学 一种抗抑郁药维拉唑酮的制备方法

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US5532241A (en) * 1993-09-30 1996-07-02 Merck Patent Gesellschaft Mit Beschrankter Haftung Piperidines and piperazines
CN103304547A (zh) * 2012-03-13 2013-09-18 中国药科大学 一种抗抑郁药维拉唑酮的制备方法

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CN108530390A (zh) * 2017-03-06 2018-09-14 西南化工研究设计院有限公司 一种4-羟基二苯甲酮的烷基化方法
CN108530390B (zh) * 2017-03-06 2020-04-21 西南化工研究设计院有限公司 一种4-羟基二苯甲酮的烷基化方法
CN109627237A (zh) * 2017-10-09 2019-04-16 北京济美堂医药研究有限公司 一种维拉唑酮盐酸盐的制备方法
CN108164552A (zh) * 2017-12-10 2018-06-15 常州市雄图纺织有限公司 一种脲酶抑制剂的制备方法
CN110037052A (zh) * 2019-04-11 2019-07-23 浙江工商大学 一种光催化杀菌剂及其制备方法和应用
CN112175173A (zh) * 2020-10-09 2021-01-05 中国科学技术大学 一种烯烃插入率可控的可降解聚α-烯烃材料的制备方法
CN112175173B (zh) * 2020-10-09 2022-04-19 中国科学技术大学 一种烯烃插入率可控的可降解聚α-烯烃材料的制备方法

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