WO2011161690A1 - Procédés pour la préparation de (+)-n,n-diméthyl-2-[1-(naphtalényloxy)éthyl]benzène-méthanamine et intermédiaires de celle-ci - Google Patents

Procédés pour la préparation de (+)-n,n-diméthyl-2-[1-(naphtalényloxy)éthyl]benzène-méthanamine et intermédiaires de celle-ci Download PDF

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WO2011161690A1
WO2011161690A1 PCT/IN2011/000116 IN2011000116W WO2011161690A1 WO 2011161690 A1 WO2011161690 A1 WO 2011161690A1 IN 2011000116 W IN2011000116 W IN 2011000116W WO 2011161690 A1 WO2011161690 A1 WO 2011161690A1
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acid
formula
compound
dapoxetine
hplc
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PCT/IN2011/000116
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English (en)
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Dodda Mohan Rao
Pingili Krishna Reddy
Aadepu Jithender
Bingi Venugopal
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Symed Labs Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to processes for the preparation of S(+)-N,N-dimethyl-2- [l-(naphthalenyloxy)ethyl]benzene methanamine and intermediates thereof.
  • Dapoxetine hydrochloride is the potent selective serotonin reuptake inhibitors (SSRIs) the most advanced agent under review in US and approved in some of the European countries for premature ejaculation. Dapoxetine is structurally related to the antidepressant fluoxetine (Prozac) is enantiomerically pure and one of the important drug as a serotonin reuptake inhibitor. Dapoxetine hydrochloride is available under the brand name PRILIGYTM in Europe.
  • Dapoxetine hydrochloride is chemically known as S(+)-N,N-dimethyl-2-[l-(naphthalenyloxy)- ethyl]benzene methanamine hydrochloride (here after referred by its generic name dapoxetine) and represented by the formula (I).
  • the processes of present invention has advantages as they uses optical pure intermediates for the preparation of dapoxetine and the unwanted isomers can be racemised and the wanted isomers can be recycled thus giving the final compounds with high yield and purities and most cost effective, industrially applicable.
  • the process of the invention makes it possible to obtain the target enantiomer of the compound of formula (la) in an excellent enantiomeric excess, with high productivity and in an excellent yield.
  • the present invention relates to processes for the preparation of S(+)-N,N-dimethyl-2- [l-(naphthalenyloxy)ethyl]benzene methanamine and intermediates thereof.
  • the present invention relates to a process for preparing the intermediate compound of formula (Ilia),
  • Rl and R2 are independently H or methyl
  • Rl, R2 are independently H or methyl and R 3 is H or Ci-Cg alkyl straight chain or branched, aryl alkyl.
  • the present invention relates to a process for preparing the intermediate compound of formula (Ha),
  • Rl, R2 are independently H or methyl
  • Rl, R2 are independently H or methyl and R 3 is H or Ci-C 8 alkyl straight chain or branched, aryl alkyl.
  • the present invention relates to a process for preparing the intermediate compound 3(S)-(+)-N,N-dimeth lamino-3-phenyl propanol of formula (V),
  • the present invention rovides the compound of formula (IV)
  • X is chiral acid or derivative thereof, preferably (+)-Dibenzoyl-D-tartaric acid or L-(+) tartaric acid
  • the present invention relates to racemisation process for the conversion of (+) or (-) 3-N,N-dimethylamino-3-phenyl propanol into the racemic compound of formula III comprising :
  • the present invention relates to a process for the preparation f S
  • X is a leaving group like halogen (CI, Br, F, I), S0 3 H, etc
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound 3-amino-3-phenyl propanol of formula (lb)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound 3-N,N-dimethylamino-3-phenyl propanol of formula (III)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (S)-(+)-3-N,N-dimethylamino-3-phenyl propanol of formula (V)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (+)-2,3-Dibenzoyl-D-tartaric acid of formula (VIII)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound naphthalene derivative of formula (VII)
  • X is a leaving group like halogen (CI, Br, F, I), S0 3 H,
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound 1-naphthol of formula (Vila)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound N-desmethyl dapoxetine of formula (IX)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound ⁇ , ⁇ -didesmethyl dapoxetine of formula (IXa)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (-)-N,N-dimethyl-l-phenyl-3-(l- naphthalenyloxy)propanamine (R-(- -Dapoxetine) of formula (IXb)
  • the present invention relates to processes for the preparation of S(+)-N,N-dimethyl-2- [l-(naphthalenyloxy)ethyl]benzene methanamine and intermediates thereof.
  • the present invention provides a process for preparing the intermediate compound of formula (Ilia),
  • Rl and R2 are independently H or, methyl
  • Rl, R2 are independently H or methyl and R 3 is H or Ci-C 8 alkyl straight chain or branched, aryl alkyl.
  • the suitable reducing agent that can be used is selected from the group consisting of sodium borohydride, lithium aluminum hydride, vitride and the like; preferably sodium borohydride in the presence of an acid is being used.
  • the acid that can be used include but are not limited to organic acid or inorganic acid.
  • Organic acids such as phosphonic acid, para toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid, formic acid, maleic acid, acetic acid, succinic acid, and the like;
  • Inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid; sulfuric acid, phosphoric acid and the like, and their aqueous mixtures thereof, preferably methane sulfonic acid is being used.
  • the molar equivalents of acid and the reducing agent used can be from about 0.5 to about 5 moles on the weight of the starting compound Illb taken.
  • the organic solvent that can be used is selected from the group consisting of ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide, N-methyl pyrolidone (NMP) or mixtures thereof.
  • ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like
  • hydrocarbons such as toluene, xylene, cyclohexane and the like
  • aprotic polar solvents such as ⁇ , ⁇ -dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide, N-methyl pyrolidone (NMP) or mixtures thereof.
  • the reaction temperature and time should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products.
  • the reaction is carried out at temperature from about 25°C to about 100°C or boiling point of the solvents used. Preferably from about 25°C to about 50°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent(s) employed. The time period is from about 1 hour to about 45 hours, preferably from about 1 hour to fO hours.
  • the present invention provides a process for preparing the intermediate compound of formula (Ila),
  • Rl , R2 are independently H or methyl
  • Rl, R2 are independently H or methyl and R 3 is H or C)-C 8 alkyl straight chain or branched, aryl alkyl.
  • the suitable reducing agent, acid, organic solvent and reaction temperature, time are same as applicable as mentioned in the above embodiment.
  • X is a chiral acid or a derivative thereof.
  • the suitable resolving agent that can be used is selected from the group consisting of L(+) mandelic acid, L(+) tartaric acid, (+) di-p-toluyl D-tartaric acid, (+)-Dibenzoyl-D-tartaric acid, (+) diethyl D-tartrate, (+) diisopropyl D-tartrate, camphor sulfonic acid, 2- chloromandelic acid or their enantiomers and the like, preferably (+)-Dibenzoyl-D-tartaric acid or L(+) tartaric acid is being used.
  • the solvent that can be used in step a) include but are not limited to water, alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol and the like; ketones such as acetone, methylisobutylketone, methyl ethyl ketone and the like; esters such as ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate and the like; or mixtures of thereof.
  • alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol and the like
  • ketones such as acetone, methylisobutylketone, methyl ethyl ketone and the like
  • esters such as ethyl acetate, isopropyl acetate, n-butyl
  • the reaction temperature can range from about 25 °C to about boiling point of the solvents used, preferably at boiling point of the solvents used.
  • the time period can be range from about 30 minutes to about 5 hours, preferably 1 hour.
  • the solution obtained is optionally filtered through celite or diatamous earth to separate the extraneous matter present or formed in the solution by using conventional filtration technique known in the art.
  • the precipitation of solid is achieved but not limited to evaporation, cooling, drying, by adding antisolvent and the like. Preferably by cooling.
  • the temperature for the precipitation of solid can be from about -10 °C to about 30°C, preferably about 30°C.
  • the suitable base that can be used in step c) can include organic base or, inorganic base.
  • Organic bases such as triethylamine, pyridine, diisopropylamine, diisopropylethylamine and the like;
  • Inorganic bases such as ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like or mixtures thereof, preferably sodium hydroxide or ammonia is being used.
  • the organic solvent that can be used include but are not limited to hydrocarbons such as n-hexane, n-heptane, cyclohexane, toluene, xylene and the like; halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, dichlorobenzene and the like; esters such as ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate and the like; or mixtures of thereof.
  • methylene chloride is being used.
  • the reaction temperature can range from about 25 °C to about 40°C, preferably about
  • the product obtained by the process described above can have high enantiomeric excess.
  • the amount of R-enantiomer is less than about 10% as measured. by area percentage HPLC, more preferably less than about 5%, and most preferably less than about 0.5%.
  • the present invention provides the compound of formula IV
  • X is chiral acid or derivative thereof, preferably (+)-Dibenzoyl-D-tartaric acid or L-(+) tartaric acid
  • the compound of formula IV may be a crystalline or amorphous form or mixture thereof.
  • the base that can be used in step a) include organic base or inorganic base.
  • Inorganic bases such as ammonia, sodium hydroxide, potassium hydroxide, potassium tertiary butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate and the like;
  • Organic bases such as triethylamine, pyridine, diisopropylamine, diisopropylethylamine and the like or mixtures thereof.
  • potassium tertiary butoxide or potassium hydroxide is being used.
  • the solvent that can be used optionally include but are not limited to hydrocarbons such as toluene, xylene, and the like; aprotic polar solvents such as dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), or mixtures thereof. Preferably dimethyl sulfoxide (DMSO) is being used.
  • hydrocarbons such as toluene, xylene, and the like
  • aprotic polar solvents such as dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), or mixtures thereof.
  • DMSO dimethyl sulfoxide
  • the reaction temperature can range from about 30°C to about 100°C, or reflux temperature of the solvents used. Preferably about 90°C.
  • the pH of the reaction can be adjusted in step b) from about 0.1 to about 6, preferably
  • the acid that can be used in step b) include but are not limited to inorganic acid that can be used include, but are not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and their aqueous mixtures thereof, preferably hydrochloric acid is being used.
  • the pH of the reaction in step c) can be adjusted from about 7 to about 12, preferably about 9.
  • the solvents that can be used for extraction of the product include, but are not limited to halogenated solvents such as dichloromethane, ethylene dichloride , chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbons such as toluene, xylene and the like; and mixtures thereof.
  • halogenated solvents such as dichloromethane, ethylene dichloride , chloroform and the like
  • esters such as ethyl acetate, isopropyl acetate and the like
  • hydrocarbons such as toluene, xylene and the like
  • mixtures thereof Preferably dichloromethane is being used.
  • the present invention provides a process for the preparation of S(+)-N,N-dimethyl-2-[l-(naphthalenyloxy)ethyl]benzene methanamine of formula (la) or a pharmaceutically acceptable salt thereof .
  • X is a leaving group like halogen (CI, Br, F, I) S0 3 H etc
  • the base that can be used include inorganic or organic base.
  • Inorganic bases such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, ammonia and the like; and organic bases such as triethylamine, tripropylamine, pyridine, dimethyl amino pyridine, diisopropylamine, diisopropylethylamine and the like or mixtures thereof, preferably potassium carbonate or sodium hydroxide is being used.
  • the molar equivalent of base used can be from about 0.5 to about 10 on the weight of the compound of formula II taken. Preferably 5 molar equivalents.
  • the solvents that can be used is selected from the group consisting of water, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran (THF), 2-methyl tetrahydrofuran and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide, N-methyl pyrrolidone (NMP) or mixtures thereof.
  • reaction temperature and time should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products, the reaction temperature can be from about 25°C to about 100°C or boiling point of the solvents used. Preferably from about 50°C to about 100 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent(s) employed. The time period is from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours.
  • isolation of the desired compound from the reaction mixture can be carried out by common operation, but in consideration of the physical properties of the desired compound, crystallization, extraction, washing, column chromatography, etc. can be combined.
  • the intermediate compounds can be optionally purified by recrystallisation, using a solvent or mixture of solvents; or by converting into their corresponding pharmaceutically acceptable salts and then processed back to the original compounds.
  • the process of present invention provides the intermediates with higher yields and purities leading to higher yields and purities of final product.
  • the processes of present invention provides substantially pure S- enantiomer that will be free from R-enantiomer as an impurity both in the precursor intermediate compounds used herein and also the final product dapoxetine or pharmaceutically acceptable salt thereof resulting in high yield greater than about 90% with chemical purity greater than 99.5% by HPLC and preferably greater than about 99.8% by chiral HPLC.
  • (+) dapoxetine is commonly called as dapoxetine thus can be referred here in either way.
  • racemic mixture may include mixtures of enantiomers in ratios other than, as well as, a 50:50 mixture of R:S enantiomers (for example from 99: 1 to 1 :99).
  • a particular process of the invention begins with a 50:50 mixture of enantiomers. The process may involve differing mixtures of enantiomers at various stages (including, but not limited to 50:50 mixtures).
  • racemisation covers the conversion of an unresolved enantiomer into a mixture containing the enantiomer to be resolved.
  • the process of present invention provides the intermediates in higher yields and purities which further results in higher yields and purities of final product.
  • (+) dapoxetine is commonly called as dapoxetine thus can be referred here in either way.
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound 3 -amino-3 -phenyl propanol of formula (lb)
  • the present invention provides dapoxetine or pharmaceutically acceptable salt thereof having the compound 3-N,N-dimethylamino-3-phen propanol of formula (III)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (S)-(+)-3-N,N-dimethylamino- 3-phenyl propanol of formula (V)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (+)-2,3-Dibenzoyl-D-tartaric acid of formula (VIII) (VIII)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound naphthalene derivative of formula (VII)
  • X is a leaving group like halogen (CI, Br, F, I), S0 3 H etc.
  • the present invention provides dapoxetine or pharmaceutically acceptable salt thereof having the compound 1-naphthol of formula (Vila)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound N-desmethyl dapoxetine of formula (IX)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound ⁇ , ⁇ -didesmethyl dapoxetine of formula (IXa)
  • the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (-)-N,N-dimethyl-l-phenyl-3- (l-naphthalenyloxy)propanamine (R-(-)-Dapoxetine) of formula (IXb)
  • the crystal particles of dapoxetine or a pharmaceutically acceptable salt preferably hydrochloride obtained by the by the processes of present invention has a mean particle size less than about 500 ⁇ , more preferably less than about 200 ⁇ , most preferably less than about 100 ⁇ .
  • the present invention provides dapoxetine hydrochloride particles obtained by the processes described above having a mean particle size ranging from about 5 ⁇ to about 200 ⁇ .
  • ⁇ refers to "micrometer” which is lxl0 ⁇ 6 meter.
  • crystalline particles means any combination of single crystals, aggregates and agglomerates.
  • the phrase "mean particle size distribution, i.e., d (0.5)" means the median of said particle size distribution.
  • dapoxetine or its pharmaceutically acceptable salts obtained by the process described above has residual organic solvents or organic volatile impurities comprises less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; less than about 2000 ppm of methanol, ethanol, tetrahydrofuran (THF), ethyl acetate, dimethyl sulfoxide (DMSO) and less than about 500ppm of dichloromethane, toluene.
  • THF tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • the present invention provides simple, ecofriendly, inexpensive, reproducible, robust processes for preparation intermediates of dapoxetine, which forthwith are viably adaptable on a commercial scale.
  • Residue wt 47.5gms.
  • Recrystallization 39 grams of (+) 3(S)-N,N-dimethylamino-3-phenyl propanol -Dibenzoyl D-tartarate, 78 ml of ethanol and 546 ml of water were taken and heated to reflux for about 20 minutes to make homogenous solution. The resultant solution was cooled to about 30°C. Separated solid was filtered and washed with 400ml of water to afford 28 gms of pure (+) 3(S)- N,N-dimethylamino-3-phenyl propanol -Dibenzoyl D-tartarate.
  • the aqueous layer was basified to a pH of about 9 with 10% caustic lye solution followed by extraction with 3x150 ml of ethyl acetate. Organic and aqueous layers were separated and the organic layer was distilled completely at about 55°C under vacuum to afford racemic mixture 3-N,N-dimethyl-amino-3-phenyl propanol.
  • reaction mass was washed with toluene (2x20ml).Aqueous layer was separated and cooled to 10- 15°C.Aqueous layer was basified with 20% sodium carbonate solution to a pH of 9-10. Organic layer was separated and 30ml. of chloroform was added. The total organic layer was washed with water (2x30ml.).Then chloroform layer was separated and distilled under vacuum to provide the title compound.
  • Step-a 190gr. of (+)-p-ditoluyl tartaric acid and 400ml. of ethyl acetate were charged into a clean and dry 1 lit. 4 neck RB Flask and stirred for about 15min. l00gr. of methyl-3- ⁇ , ⁇ - dimethylamino-3-phenyl propanoate was added and stirred for about lOmin.Then the resulted solution was heated to reflux and maintained for about Ali Cup. The resultant reaction mass was cooled to about 30°C and stirred for about Jackpot. The reaction mass was filtered to obtain the of (+)-methyl-3-N,N-dimethylamino-3-phenyl propanoate p-ditoluyl tartaric acid salt.
  • Step-b 2.5 gr. of pure (+)-methyl-3-N,N-dimethylamino-3-phenyl propionate p-ditoluyl tartarate salt, 30ml. of water and 20ml. of 20%w/v sodium carbonate solution were charged into a clean and dry 250 ml. 4 neck RB Flask and stirred for about 5 min.Then extracted with dichloromethane (2 x 80ml). The organic layers were combined and washed with 80ml. of water. The organic layer was separated and treated with 0.5gr. of charcoal carbon and distilled completely under vacuum to provide the title compound.
  • Example-16 Preparation of 3-N,N-dimethyl amino-3-phenyl propanol Same procedure as described in Ex. 1 but using 50 g. of 3-N,N-dimethyl amino-3- phenyl propanoic acid hydrochloride, 750 ml of tetrahydrofuran (THF), 24.6 g. of sodium borohydride and 87.08 g. of methane sulfonic acid to provide the title compound to provide the title compound. Wt: 30-32gr. (%Yield: 82.26%); Purity by HPLC: 96%.
  • Second Recrystallization Taken 17.5gr. of the recrystallized compound,87.5ml. of ethanol and 5ml. of distilled water at ambient temperature and heated to dissolve and stirred for 30min. at the same temperature. Then the reaction mass was cooled to ambient temperature. Added 100ml. of acetone at ambient temperature stirred for 30min. and filtered.
  • Step b Taken 12gr. the compound obtained above, 96ml. of distilled water at room temperature and stirred for 5min.Then added 3.5ml. of caustic lye at room temperature and stirred for lOmin.Then the reaction mass was extracted with (40ml.x3 times) of
  • dichloromethane The dichloromethane layer was washed with (60ml.x2 times) of distilled water. Finally the dichloromethane was distilled under vacuum to provide the residue.
  • Residue wt: 5gr. : SOR (+) 43.66 0 (0.6% CHC1 3 ); Purity by HPLC : 99.01%.
  • Step-a lOOgr. of racemic 3-N,N-dimethylamino-3 -phenyl propanol, 102.5gr. of (+)- Dibenzoyl-D-tartaric acid (DBTA), 80gr. of citric acid, 200ml. of ethyl alcohol and 1000ml. of water in a clean and dry 2 lit. 4 neck RBFlask.
  • DBTA Dibenzoyl-D-tartaric acid
  • the resultant reaction mixture was heated to dissolve the contents. Dissolution was observed at 85-95°C.Then the reaction mass was stirred for 10-15min. at the same temperature. Then the solution was cooled to about 30 °C and stirred for about lhr. at the same temperature.
  • the separated solid was filtered to obtain of (+)-3-N,N- dimethylamino-3-phenyl propanol dibenzoyl tartaric acid salt.
  • Wet wt 171 gr.

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Abstract

La présente invention concerne des procédés pour la préparation de S(+)-N,N-diméthyl-2-[1-(naphtalényloxy)éthyl]benzène-méthanamine et des intermédiaires de celle-ci. Plus particulièrement, la présente invention concerne la préparation du composé 3(S)-(+)-N,N-diméthylamino-3-phénylpropanol utile en tant qu'intermédiaire dans la synthèse de composés pharmaceutiquement actifs.
PCT/IN2011/000116 2010-06-23 2011-02-25 Procédés pour la préparation de (+)-n,n-diméthyl-2-[1-(naphtalényloxy)éthyl]benzène-méthanamine et intermédiaires de celle-ci WO2011161690A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1770CH2010 2010-06-23
IN1770/CHE/2010 2010-06-23
IN108CH2011 2011-01-13
IN108/CHE/2011 2011-01-13

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CN102942496A (zh) * 2012-11-28 2013-02-27 扬州工业职业技术学院 (s)-n,n-二甲基-3-(萘酚-1-氧基)-1-苯基丙基-1-胺的制备方法
CN103304434A (zh) * 2012-03-16 2013-09-18 湖南欧亚生物有限公司 达泊西汀的一种新型合成方法
CN103373931A (zh) * 2012-04-27 2013-10-30 重庆医药工业研究院有限责任公司 一种达泊西汀及其中间体的工业化制备方法
CN103396320A (zh) * 2013-08-21 2013-11-20 南京海融医药科技有限公司 (s)-3-氯-n,n-二甲基-1-苯基-1-丙胺及一种通过该中间体制备达泊西汀的方法
CN103664659A (zh) * 2013-12-04 2014-03-26 苏州永健生物医药有限公司 一种盐酸达泊西汀晶型及其制备方法
KR101382102B1 (ko) * 2012-01-31 2014-04-04 주식회사 파마코스텍 （ｓ）-다포세틴 염산염의 제조방법
EP2749553A1 (fr) 2012-12-31 2014-07-02 Deva Holding Anonim Sirketi Procédé de préparation de S- (+) -N, N-diméthyl-a- [2- (naphthalenyloxy) éthyl] benzenemethanamine pur
CN104496829A (zh) * 2014-11-28 2015-04-08 重庆华邦制药有限公司 一种盐酸达泊西汀的新晶型及其制备方法与应用
CN105461573A (zh) * 2015-12-02 2016-04-06 重庆康乐制药有限公司 一种(s)-n-脱甲基达泊西汀的制备方法
CN105732445A (zh) * 2014-12-11 2016-07-06 上海医药工业研究院 达泊西汀中间体及其制备方法
CN106397227A (zh) * 2016-08-19 2017-02-15 山东省药学科学院 一种达泊西汀盐酸盐的制备方法
CN106883133A (zh) * 2017-03-10 2017-06-23 南京斯贝源医药科技有限公司 一种盐酸达泊西汀的制备方法
CN108663460A (zh) * 2018-08-03 2018-10-16 安徽省金楠医疗科技有限公司 一种盐酸达泊西汀异构体检测方法
CN108689866A (zh) * 2017-04-06 2018-10-23 成都博腾药业有限公司 一种(r)-3-氨基丁醇的合成方法
CN109369424A (zh) * 2018-07-09 2019-02-22 华控创新（北京）药物研究院有限公司 一种盐酸达泊西汀的纯化方法
CN110078632A (zh) * 2019-04-17 2019-08-02 淮阴工学院 一种达泊西汀中间体的生物合成方法及其中间体
CN111763700A (zh) * 2020-06-23 2020-10-13 南京欧信医药技术有限公司 一种达泊西汀中间体的生物合成方法
CN113880721A (zh) * 2021-08-06 2022-01-04 湖南九典制药股份有限公司 达泊西汀的合成方法

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KR101382102B1 (ko) * 2012-01-31 2014-04-04 주식회사 파마코스텍 （ｓ）-다포세틴 염산염의 제조방법
CN103304434A (zh) * 2012-03-16 2013-09-18 湖南欧亚生物有限公司 达泊西汀的一种新型合成方法
CN103373931A (zh) * 2012-04-27 2013-10-30 重庆医药工业研究院有限责任公司 一种达泊西汀及其中间体的工业化制备方法
CN102942496B (zh) * 2012-11-28 2014-06-11 扬州工业职业技术学院 (s)-n,n-二甲基-3-(萘酚-1-氧基)-1-苯基丙基-1-胺的制备方法
CN102942496A (zh) * 2012-11-28 2013-02-27 扬州工业职业技术学院 (s)-n,n-二甲基-3-(萘酚-1-氧基)-1-苯基丙基-1-胺的制备方法
EP2749553A1 (fr) 2012-12-31 2014-07-02 Deva Holding Anonim Sirketi Procédé de préparation de S- (+) -N, N-diméthyl-a- [2- (naphthalenyloxy) éthyl] benzenemethanamine pur
CN103396320A (zh) * 2013-08-21 2013-11-20 南京海融医药科技有限公司 (s)-3-氯-n,n-二甲基-1-苯基-1-丙胺及一种通过该中间体制备达泊西汀的方法
CN103664659A (zh) * 2013-12-04 2014-03-26 苏州永健生物医药有限公司 一种盐酸达泊西汀晶型及其制备方法
CN103664659B (zh) * 2013-12-04 2016-01-06 苏州永健生物医药有限公司 一种盐酸达泊西汀晶型及其制备方法
CN104496829A (zh) * 2014-11-28 2015-04-08 重庆华邦制药有限公司 一种盐酸达泊西汀的新晶型及其制备方法与应用
CN105732445A (zh) * 2014-12-11 2016-07-06 上海医药工业研究院 达泊西汀中间体及其制备方法
CN105461573A (zh) * 2015-12-02 2016-04-06 重庆康乐制药有限公司 一种(s)-n-脱甲基达泊西汀的制备方法
CN106397227A (zh) * 2016-08-19 2017-02-15 山东省药学科学院 一种达泊西汀盐酸盐的制备方法
CN106883133A (zh) * 2017-03-10 2017-06-23 南京斯贝源医药科技有限公司 一种盐酸达泊西汀的制备方法
CN108689866A (zh) * 2017-04-06 2018-10-23 成都博腾药业有限公司 一种(r)-3-氨基丁醇的合成方法
CN108689866B (zh) * 2017-04-06 2022-05-10 江西博腾药业有限公司 一种(r)-3-氨基丁醇的合成方法
CN109369424A (zh) * 2018-07-09 2019-02-22 华控创新（北京）药物研究院有限公司 一种盐酸达泊西汀的纯化方法
CN108663460A (zh) * 2018-08-03 2018-10-16 安徽省金楠医疗科技有限公司 一种盐酸达泊西汀异构体检测方法
CN110078632A (zh) * 2019-04-17 2019-08-02 淮阴工学院 一种达泊西汀中间体的生物合成方法及其中间体
CN111763700A (zh) * 2020-06-23 2020-10-13 南京欧信医药技术有限公司 一种达泊西汀中间体的生物合成方法
CN111763700B (zh) * 2020-06-23 2023-07-04 南京欧信医药技术有限公司 一种达泊西汀中间体的生物合成方法
CN113880721A (zh) * 2021-08-06 2022-01-04 湖南九典制药股份有限公司 达泊西汀的合成方法
CN113880721B (zh) * 2021-08-06 2024-05-28 湖南九典制药股份有限公司 达泊西汀的合成方法

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