WO2008026227A2 - A process for the preparation of atomoxetine hydrochloride - Google Patents

A process for the preparation of atomoxetine hydrochloride Download PDF

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Publication number
WO2008026227A2
WO2008026227A2 PCT/IN2007/000408 IN2007000408W WO2008026227A2 WO 2008026227 A2 WO2008026227 A2 WO 2008026227A2 IN 2007000408 W IN2007000408 W IN 2007000408W WO 2008026227 A2 WO2008026227 A2 WO 2008026227A2
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Prior art keywords
tolyloxy
methyl
phenylpropylamine
ethyl acetate
hydrochloride
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PCT/IN2007/000408
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French (fr)
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WO2008026227A3 (en
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Gorantla Seeta Ramanjaneyulu
Chavakula Ramdas
Konudula Babu Rao
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Matrix Laboratories Ltd
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Publication of WO2008026227A3 publication Critical patent/WO2008026227A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10Separation; Purification; Stabilisation; Use of additives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/50Ethers of hydroxy amines of undetermined structure, e.g. obtained by reactions of epoxides with hydroxy amines
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical isomers

Definitions

  • the present invention relates to the process for the preparation of crystalline Atomoxetine hydrochloride
  • Atomoxetine hydrochloride (R)(-)-N-methyl-3-(o-tolyloxy)-3- phenylpropyl amine hydrochloride has the formula as shown below
  • Atomoxetine is the (R)-(-)enantiomer of Tamoxetine, is an aryloxyphenyl propyl-amine, a selective norepinephrine reuptake inhibitor, marketed as hydrochloride salt under the name of STRATTERA ® used for the treatment of Attention Deficit/Hyperactivity Disorder (ADHD).
  • ADHD Attention Deficit/Hyperactivity Disorder
  • US 4,314,081 discloses a process for preparation of N-methyl 3-(o-tolyloxy)-3- phenylpropylamine hydrochloride along with other compounds.
  • One of the disclosed process for preparation of N-methyl 3-(o-tolyloxy)-3-phenylpropylamine involves the reaction of N,N-dimethyl 3-phenyl-3-chloro propyl amine hydrochloride with sodium salt of the corresponding phenol in methanol followed by demethylation using cyanogens bromide.
  • the reaction of N, N-dimethyl 3-phenyl-3-halopropyl amine hydrochloride with sodium salt of the corresponding phenol in methanol is a time consuming process, requires about five days for completion of reaction.
  • the alternate process disclosed involves the bromination of 3-phenylchloropropyl amine with N-Bromosuccinimide, condensation with o-cresol followed by animation with methyl amine. The process requires the dry sodium salt of phenol.
  • EP 052492 discloses the process for preparation of Atomoxetine hydrochloride from N- methyl 3-(o-tolyloxy)-3-phenylpro ⁇ ylamine by crystallization as (R)-(-) N-methyl 3-(o- tolyloxy)-3-phenylpropylamine (S)-(+)-mandalate, basification in water, extraction with diethyl ether and bubbling the hydrogen chloride gas. .
  • US 5,847,214 discloses a process that involves the reaction of N-methyl-3-phenylpropyl amines with aryl halides; the success of reaction depends on the electron withdrawing group on the benzene ring of the aryl halide.
  • US 6,541,668 discloses a process that involves the reaction of alkoxide of N-methyl-3- phenyi-3 hydroxy propyl amine or a corresponding N-protected derivative with 2-fluoro toluene in presence of solvent.
  • WO 2006/020348 discloses the crystalline polymorphic forms, Form A, Form B and Form C of Atomoxetine hydrochloride. WO 2006/020348 further discloses that the repetition of the processes disclosed in EP 052,492 and US 6,541,668 yielded a crystalline form of Atomoxetine hydrochloride denominated as Form A.
  • the present invention provides a process for preparation of Atomoxetine hydrochloride involves the reaction of N,N-dimethyl 3-phenyl-3-chloro propyl amine acid addition salt with o-Cresol in presence of a phase transfer catalyst followed by demethylation and resolution with (S)-(+)-mandelic acid followed by salification with hydrochloride.
  • the main object of the present invention is to provide a process for the preparation of Atomoxetine and its pharmaceutically acceptable salts.
  • Another object of the present invention is to provide a process for preparation of Atomoxetine hydrochloride.
  • Another object of the present invention is to provide a process for preparation of crystalline Atomoxetine hydrochloride.
  • Another object of the present invention is to provide a process for preparation of
  • Atomoxetine using N, N-dimethyl 3-(o-tolyloxy)-3-phenylpropylamine and its salts thereof.
  • Another object of the present invention is to provide a process for preparation of N, N- dimethyl 3-(o-tolyloxy)-3-phenylpropylamine and its salts thereof.
  • N,N-dimethyl 3-phenyl-3-chloropropyl amine acid addition salt on reaction with o-cresol in presence of a base and phase transfer catalyst yields the N, N-dimethyl 3-(o-tolyloxy)-3-phenylpropylamine, which can be isolated as acid addition salts.
  • Fig: 1 shows the X-ray diffraction pattern of Atomoxetine hydrochloride obtained as per the present invention
  • Atomoxetine hydrochloride is prepared by the following steps;
  • N,N-dimethyl 3-phenyl-3-chloropropyl amine acid addition salt is added to a mixture of o-cresol, acid addition salt is selected from hydrochloride, hyrobromide, sulphate, phosphate, nitrate or acetate.
  • the preferred acid addition salt is hydrochloride, base such as sodium hydroxide, potassium hydroxide and a phase transfer catalyst such as tertiary ammonium salts, selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, triethyl benzyl ammonium chloride, tributyl benzyl ammonium chloride and mixtures thereof; phosphonium salts; crown ethers in water and a halogenated hydrocarbon such as methylene chloride, ethylene dichloride, chloroform at a temperature of about O 0 C to about 5O 0 C preferably at about 15 to 35 0 C.
  • a phase transfer catalyst such as tertiary ammonium salts, selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, triethyl benzyl ammonium chloride, tributyl benzyl ammonium chloride and mixtures thereof
  • Reaction mass is maintained for about 6 hrs to 24 hrs, preferably for about 12 hrs to 16 hrs at a temperature of O 0 C to 5O 0 C preferably at 15 0 C to 35 0 C.
  • an additional quantity of same phase transfer catalyst as 2 nd lot can be introduced into the reaction mass after initial maintenance of 2 hrs to 6hrs.
  • Reaction mass is allowed to settle and separated the layers.
  • Aqueous layer is extracted with same halogenated hydrocarbon, washed the combined organic layer with sodium hydroxide solution, water and brine solution.
  • Solvent is removed from the organic layer preferably under vacuum at temperature below 6O 0 C affords the N,N-dimethyl 3-(o-tolyloxy)-3-phenylpropyl amine.
  • N,N-dimethyl 3-(o- tolyloxy)-3-phenylpropyl amine is dissolved in an alkyl ester such as ethyl acetate, isopropyl acetate and treated with an acid such as hydrochloric acid, oxalic acid at a temperature of 1O 0 C to 5O 0 C, preferably at 2O 0 C to 4O 0 C for about 30 min to 4hrs followed by cooling to a temperature of O 0 C to 2O 0 C 5 maintained for 15min to 4 hrs followed by isolation and drying afforded the N,N-dimethyl 3-(o-tolyloxy)-3- phenylpropylamine acid addition salts.
  • an alkyl ester such as ethyl acetate, isopropyl acetate and treated with an acid such as hydrochloric acid, oxalic acid at a temperature of 1O 0 C to 5O 0 C, preferably at 2O 0 C to 4O
  • N,N-dimethyl 3-(o-tolyloxy)-3-phenylpropylamine acid addition salt/s is basif ⁇ ed with ammonia solution in toluene, separated the layers, treated the organic layer with phenyl chloroformate in presence of diisopropyl ethyl amine at a temperature of about 40 0 C to 65 0 C for about 12 to 4 hrs.
  • Sodium bicarbonate solution is added to the reaction mass, stirred and settled.
  • the organic layer is separated and washed with dilute hydrochloric acid, sodium bicarbonate solution.
  • the organic layer is concentrated to afford residue.
  • the obtained residue is dissolved in DMSO, treated with aqueous sodium hydroxide at 3O 0 C to 6O 0 C 5 preferably at 4O 0 C to 5O 0 C for about 8 hrs.
  • the reaction mass is transferred into to chilled water, adjusted the pH 5.0 to 6.0 with acetic acid and washed the reaction mass with n-hexane. Again pH is adjusted 10.5 to 11.5 with sodium hydroxide.
  • Toluene layer is washed with water, optionally treated the organic layer with activated carbon. pH of the Toluene layer is adjusted to below 2.0 by addition of hydrochloric acid.
  • Toluene is removed by vacuum distillation preferably at temperature below 6O 0 C.
  • ethyl acetate is added and stripped off below 55 0 C.
  • the obtained residue is dissolved in ethyl acetate, maintained the mass for about 2 hrs at temperature of 15 to 25 0 C, followed by cooling and maintained at temperature of O 0 C to 5 0 C for about 1 hr.
  • the precipitated N-methyl 3-(o-tolyloxy)-3- phenylpropylamine hydrochloride is isolated and dried.
  • N-methyl 3-(o-tolyloxy)-3-phenylpro ⁇ ylamine hydrochloride is suspended in a mixture of water and toluene.
  • the reaction mass is basified with a base such as sodium hydroxide, ammonia solution and allowed for settling.
  • Toluene layer is separated and the aqueous layer is extracted with toluene.
  • the combined toluene layer is washed with water. Toluene is removed under vacuum at temperature below 75 0 C affords the N-methyl 3-(o- tolyloxy)-3-phenylpropylamine as a residue.
  • the residue is dissolved in a mixture of toluene, ethyl acetate in a ratio of 1 :3, treated with (S)-(+)-mandalic acid at a temperature of 20 0 C to 5O 0 C preferably 35 0 C to 45 0 C for 30 min to 4hrs.
  • the reaction mass is cooled and maintained at a temperature of 25 0 C to 35 0 C for 3 to 6 hrs, further cooled to a temperature of O 0 C to 1O 0 C.
  • the precipitated product is isolated and dried to get (R)-(-) N-methyl 3-(o-tolyloxy)-3-phenylpropylarnine (S)-(+)-mandalate.
  • the (S)-(+)-mandalate salt can be optionally purified in ethyl acetate to get an enantiomeric purity > 99.0%.
  • (R)-(-)N-methyl 3-(o-tolyloxy)-3-phenylpropylamine (S)-(+)-mandalate is neutralized with a base such as alkali hydroxides like sodium hydroxide, potassium hydroxide, alkali carbonates, ammonia solution, preferably sodium hydroxide in water and extracted with water immiscible solvent such as ethyl acetate.
  • the organic layer is separated and the aqueous layer is extracted with same solvent. Combined organic layer is with brine solution and treated with activated carbon.
  • Organic layer is concentrated preferably under vacuum and again fresh solvent is added.
  • Reaction mass is cooled to a temperature of O 0 C to 1O 0 C and the pH is adjusted below 2.0 by passing the hydrogen chloride gas at temperature of -1O 0 C to 2O 0 C, preferably at O 0 C to 1O 0 C. After pH adjustment the reaction mass is maintained for 30 min to 3 hrs at the same temperature.
  • the precipitated product is isolated and dried to get Atomoxetine hydrochloride.
  • Atomoxetine hydrochloride is dissolved in an alkanol such as methanol, ethanol, isopropanol and mixtures thereof, preferably methanol at temperature of 2O 0 C to 5O 0 C.
  • the obtained solution is optionally treated with activated carbon and the solvent is removed at temperature below 6O 0 C preferably under vacuum.
  • a second solvent such as alkyl ester like ethyl acetate, isopropyl acetate is added at temperature of 15 0 C to 45 0 C and maintained for 30 min to 2 hrs.
  • the reaction mass is further cooled and maintained at temperature of -1O 0 C to 2O 0 C preferably O 0 C to 1O 0 C for 30 min to 3 hrs.
  • the precipitated product is isolate and dried at temperature of 4O 0 C to 6O 0 C preferably under vacuum afforded the crystalline Atomoxetine hydrochloride.
  • the prepared and purified Atomoxetine hydrochloride is identified as crystalline Atomoxetine hydrochloride polymorphic form-A based on the PXRD.
  • Example-1 Preparation of N,N-DimethyI-3-(toIyIoxy)-3-phenyl propyl amine oxalate.
  • O-Cresol (152.5 Gms) is added to aqueous sodium hydroxide (86.5 Gms in 1400 ml) at temperature of 30 to 35°C over 30 minutes. The reaction mixture is stirred for 30 minutes at 30 to 35°C, Triethyl benzyl ammonium chloride (13.25 Gms) and methylene dichloride (1400 ml) are added 30 to 35°C. N,N-Dimethyl 3- ⁇ henyl-3-chloropropyl amine hydrochloride is added to the reaction mixture at a temperature of 25 to 30°C over 1-1 1 A hours. The reaction mass is maintained at a temperature of 25 to 30°C for 4 hrs.
  • Triethyl benzyl ammonium chloride (13.0 Gms) is added at 25-30°C and maintained the reaction mass at temperature of 25 to 30 0 C for 8 hours. Reaction completion is checked by HPLC and allowed the reaction mass to settle. Organic layer is separated and the aqueous layer is extracted with dichloromethane (175 ml). The combined organic layer is washed with 10% Sodium hydroxide solution (175 ml), DM Water (2X175 ml), 10% sodium chloride solution (175 ml) and finally with DM Water (175 ml) successively. MDC is distilled off till temperature reaches to 55°C and finally under vacuum to remove traces of MDC at temperature below 55°C.
  • the obtained residue is dissolved in Ethyl acetate (175 ml) and distilled off under vacuum at temperature below 55 0 C.
  • the obtained residue is dissolved in ethyl acetate (1000 ml) and treated with activated carbon (17.5 gm). Filtered the mass through hyflow bed and washed the bed with ethyl acetate (400 ml). Combined the filtrate and ethyl acetate washings.
  • Oxalic acid (103 gm) is added to the ethyl acetate layer lot wise at temperature of 25 to 35°C over 1 to 2 hours. The reaction mass is maintained for 1 hour at temperature of 25 to 35°C.
  • reaction mass is cooled to 0°C and maintained for 1 hr at 0 to 5°C. Filter the mass and washed the wet cake with chilled ethyl acetate (175 ml). The wet cake is dried at room temperature and then at temperature of 50-55°C till constant weight.
  • the dry weight of N,N-Dimethy 1-3 -(tolyloxy)-3 -phenyl propyl amine oxalate is 230 Gms
  • reaction mass is raised to 40 0 C and slowly added Sodium hydroxide solution (62.6 g sodium hydroxide + 395 ml of DM Water) at 40-45 0 C. Maintained the reaction mass at 40-50 0 C for 8 hrs. Checked the reaction completion by TLC and cooled the reaction mass to 18 - 25°C.
  • Step-1 (R) (-) N-Methyl-3-(2-methylphenoxy)-3-phenyIpropylamine(S)-(+) mandelate
  • N-Methyl-3-(2-methyl phenoxy)-3 -phenyl propyl amine hydrochloride (100 Gms) is added to a mixture of DM water (400ml) and Toluene (400 ml) at 25-35°C. Temperature is raised to 40-45°. Slowly added ammonia solution (110 ml) at 40-45°C and maintained for 30 min at 40 - 45 0 C. Allowed the reaction mass to settle for 30 min and separated the layers. Organic layer is separated and the aqueous layer is extracted with toluene (100 ml). Combined the organic layer and washed with DM water (2 X 100 ml).
  • Toluene is distilled of under vacuum at 60-65°C and to the obtained residue toluene (90 ml) and Ethyl acetate (270 ml) are added.
  • Charged S(+)-Mandelic acid (26 gm) at 28- 32°C and maintained for 30 minutes at 25-30°C Slowly raised the temperature to 40- 45°C over a period of 1.0 hour and maintained the mass at 40 - 45°C for 2.0 hours.
  • Atomoxetine hydrochloride 60 gm is dissolved in methanol (120 ml) at 40 - 45 0 C and treated with activated Carbon (6.0 gm). Filtered the reaction mass through Hyflow bed and washed the bed with methanol (60 ml). Methanol is distilled off below 45 0 C under vacuum and cooled the reaction mass to 25 to 35°C. Ethyl acetate (600 ml) is charged and maintained the reaction mass at 25-35 0 C for one hour. The reaction mass is cooled to 0-5 0 C and maintained for one hour at 0-5 0 C. Filtered the material and washed the wet cake with chilled ethyl acetate (60 ml). The wet material is dried at room temperature for 2.0 hours followed by at 45-55°C under vacuum till LOD is less than 0.5%.

Abstract

Provided is the process for the preparation of Atomoxetine hydrochloride by the condensation of N,N-dimethyl 3-phenyl-3-chloropropyl amine acid addition salt with o- cresol in presence of a phase transfer catalyst and base followed by demethylation and resolution. Also provided preparation of crystalline Atomoxetine hydrochloride.

Description

Title: A Process for the preparation of Atomoxetine hydrochloride
Field of the Invention:
The present invention relates to the process for the preparation of crystalline Atomoxetine hydrochloride
Background of the Invention:
Atomoxetine hydrochloride, (R)(-)-N-methyl-3-(o-tolyloxy)-3- phenylpropyl amine hydrochloride has the formula as shown below
Figure imgf000002_0001
Atomoxetine hydrochloride
Atomoxetine is the (R)-(-)enantiomer of Tamoxetine, is an aryloxyphenyl propyl-amine, a selective norepinephrine reuptake inhibitor, marketed as hydrochloride salt under the name of STRATTERA® used for the treatment of Attention Deficit/Hyperactivity Disorder (ADHD).
US 4,314,081 discloses a process for preparation of N-methyl 3-(o-tolyloxy)-3- phenylpropylamine hydrochloride along with other compounds. One of the disclosed process for preparation of N-methyl 3-(o-tolyloxy)-3-phenylpropylamine involves the reaction of N,N-dimethyl 3-phenyl-3-chloro propyl amine hydrochloride with sodium salt of the corresponding phenol in methanol followed by demethylation using cyanogens bromide. The reaction of N, N-dimethyl 3-phenyl-3-halopropyl amine hydrochloride with sodium salt of the corresponding phenol in methanol is a time consuming process, requires about five days for completion of reaction. The alternate process disclosed involves the bromination of 3-phenylchloropropyl amine with N-Bromosuccinimide, condensation with o-cresol followed by animation with methyl amine. The process requires the dry sodium salt of phenol.
EP 052492 discloses the process for preparation of Atomoxetine hydrochloride from N- methyl 3-(o-tolyloxy)-3-phenylproρylamine by crystallization as (R)-(-) N-methyl 3-(o- tolyloxy)-3-phenylpropylamine (S)-(+)-mandalate, basification in water, extraction with diethyl ether and bubbling the hydrogen chloride gas. .
US 4,950,791 discloses a process that involves the condensation of (S)-3-hydroxy-3- phenylpropyl amine with aroyl alkanols using the Mitsunobo reaction which requires the use of reagent diethyl azodicarboxylate, known to be highly carcinogenic and expensive.
US 5,847,214 discloses a process that involves the reaction of N-methyl-3-phenylpropyl amines with aryl halides; the success of reaction depends on the electron withdrawing group on the benzene ring of the aryl halide.
US 6,541,668 discloses a process that involves the reaction of alkoxide of N-methyl-3- phenyi-3 hydroxy propyl amine or a corresponding N-protected derivative with 2-fluoro toluene in presence of solvent.
WO 2006/020348 discloses the crystalline polymorphic forms, Form A, Form B and Form C of Atomoxetine hydrochloride. WO 2006/020348 further discloses that the repetition of the processes disclosed in EP 052,492 and US 6,541,668 yielded a crystalline form of Atomoxetine hydrochloride denominated as Form A.
None of the prior art methods reported the use of phase transfer catalysts for the condensation of aryl alkanols or their alkali salts with aryl 3-halopropyl amine or amine protected derivatives. The present invention provides a process for preparation of Atomoxetine hydrochloride involves the reaction of N,N-dimethyl 3-phenyl-3-chloro propyl amine acid addition salt with o-Cresol in presence of a phase transfer catalyst followed by demethylation and resolution with (S)-(+)-mandelic acid followed by salification with hydrochloride. Summary of the Invention:
The main object of the present invention is to provide a process for the preparation of Atomoxetine and its pharmaceutically acceptable salts.
Another object of the present invention is to provide a process for preparation of Atomoxetine hydrochloride.
Another object of the present invention is to provide a process for preparation of crystalline Atomoxetine hydrochloride.
Another object of the present invention is to provide a process for preparation of
Atomoxetine using N, N-dimethyl 3-(o-tolyloxy)-3-phenylpropylamine and its salts thereof.
Another object of the present invention is to provide a process for preparation of N, N- dimethyl 3-(o-tolyloxy)-3-phenylpropylamine and its salts thereof.
Accordingly in the present invention N,N-dimethyl 3-phenyl-3-chloropropyl amine acid addition salt on reaction with o-cresol in presence of a base and phase transfer catalyst yields the N, N-dimethyl 3-(o-tolyloxy)-3-phenylpropylamine, which can be isolated as acid addition salts. Demethylation of N,N-dimethyl 3 -(o-tolyloxy)-3 -phenyl propylamine on with phenyl chloroformate in presence of diisopropyl ethyl amine and sodium hydroxide in DMSO affords the N-methyl 3-(o-tolyloxy)-3-phenylpropylamine (Tomoxetine), which on treatment with (S)-(+)-mandelic acid in a mixture of toluene and ethyl acetate gives the (R)-(-) N-methyl 3-(o-tolyloxy)-3-phenylpropylamine (S)-(+)- mandalate. Basifϊcation of (R)-(-) N-methyl 3-(o-tolyloxy)-3-phenylpropylamine (S)-(+)- mandalate in presence of water followed by extraction with solvent and treatment with hydrogen chloride affords the Atomoxetine hydrochloride, can be purified by dissolution in an alkanol, treatment with carbon followed by removal of solvent and addition of a second solvent affords the Atomoxetine hydrochloride.
Brief description of the drawings:
Fig: 1 shows the X-ray diffraction pattern of Atomoxetine hydrochloride obtained as per the present invention
Detailed description of the invention:
Thus in accordance with the present invention Atomoxetine hydrochloride is prepared by the following steps;
• Adding N,N-dimethyl 3-phenyl-3-chloropropyl amine acid addition salt slowly to a suspension of o-cresol, sodium hydroxide and a phase transfer catalyst in a mixture of water and a halogenated hydrocarbon
• Maintaining the reaction mass for the complete conversion of N, N-dimethyl 3-phenyl-3-chloropropyl amine hydrochloride to N, N-dimethyl 3-(o- tolyloxy)-3 -phenylpropylamine • Isolating the obtained N,N-dimethyl 3-(o-tolyloxy)-3-phenylpropylamine
• Demethylating N,N-dimethyl 3-(o-tolyloxy)-3-phenylpropyl amine with phenyl chloroformate in presence of diisopropyl ethyl amine to get N-methyl 3 -(o-tolyloxy)-3 -phenylpropylamine
• Treating N-methyl 3-(o-tolyloxy)-3-phenylproρylamine with (S)-(+)-mandelic acid in a mixture of toluene and ethyl acetate
• Crystallizing and isolating (R )-(-) N-methyl 3-(o-tolyloxy)-3-phenylpropyl amine (S)-(+)-mandalate
• Basifying (R )-(-) N-methyl 3-(o-tolyloxy)-3-phenylpropylamine (S)-(+)- mandalate and extracting the liberated (R )-(-) N-methyl 3-(o-tolyloxy)-3- phenylpropylamine with an water immiscible solvent
• Salification with hydrogen chloride to get Atomoxetine hydrogen chloride • Dissolution of Atomoxetine hydrochloride in an alkanol
• Optionally treating the solution with activated carbon
• Removing the solvent from the solution
• Adding a second solvent and Isolating Atomoxetine hydrochloride
N,N-dimethyl 3-phenyl-3-chloropropyl amine acid addition salt is added to a mixture of o-cresol, acid addition salt is selected from hydrochloride, hyrobromide, sulphate, phosphate, nitrate or acetate. The preferred acid addition salt is hydrochloride, base such as sodium hydroxide, potassium hydroxide and a phase transfer catalyst such as tertiary ammonium salts, selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, triethyl benzyl ammonium chloride, tributyl benzyl ammonium chloride and mixtures thereof; phosphonium salts; crown ethers in water and a halogenated hydrocarbon such as methylene chloride, ethylene dichloride, chloroform at a temperature of about O0C to about 5O0C preferably at about 15 to 350C. Reaction mass is maintained for about 6 hrs to 24 hrs, preferably for about 12 hrs to 16 hrs at a temperature of O0C to 5O0C preferably at 150C to 350C. Optionally an additional quantity of same phase transfer catalyst as 2nd lot can be introduced into the reaction mass after initial maintenance of 2 hrs to 6hrs. Reaction mass is allowed to settle and separated the layers. Aqueous layer is extracted with same halogenated hydrocarbon, washed the combined organic layer with sodium hydroxide solution, water and brine solution. Solvent is removed from the organic layer preferably under vacuum at temperature below 6O0C affords the N,N-dimethyl 3-(o-tolyloxy)-3-phenylpropyl amine. N,N-dimethyl 3-(o- tolyloxy)-3-phenylpropyl amine is dissolved in an alkyl ester such as ethyl acetate, isopropyl acetate and treated with an acid such as hydrochloric acid, oxalic acid at a temperature of 1O0C to 5O0C, preferably at 2O0C to 4O0C for about 30 min to 4hrs followed by cooling to a temperature of O0C to 2O0C5 maintained for 15min to 4 hrs followed by isolation and drying afforded the N,N-dimethyl 3-(o-tolyloxy)-3- phenylpropylamine acid addition salts.
N,N-dimethyl 3-(o-tolyloxy)-3-phenylpropylamine acid addition salt/s is basifϊed with ammonia solution in toluene, separated the layers, treated the organic layer with phenyl chloroformate in presence of diisopropyl ethyl amine at a temperature of about 400C to 650C for about 12 to 4 hrs. Sodium bicarbonate solution is added to the reaction mass, stirred and settled. The organic layer is separated and washed with dilute hydrochloric acid, sodium bicarbonate solution. The organic layer is concentrated to afford residue. The obtained residue is dissolved in DMSO, treated with aqueous sodium hydroxide at 3O0C to 6O0C5 preferably at 4O0C to 5O0C for about 8 hrs. The reaction mass is transferred into to chilled water, adjusted the pH 5.0 to 6.0 with acetic acid and washed the reaction mass with n-hexane. Again pH is adjusted 10.5 to 11.5 with sodium hydroxide. Extracted the reaction mass with toluene. Toluene layer is washed with water, optionally treated the organic layer with activated carbon. pH of the Toluene layer is adjusted to below 2.0 by addition of hydrochloric acid. Toluene is removed by vacuum distillation preferably at temperature below 6O0C. To the obtained residue ethyl acetate is added and stripped off below 550C. The obtained residue is dissolved in ethyl acetate, maintained the mass for about 2 hrs at temperature of 15 to 250C, followed by cooling and maintained at temperature of O0C to 50C for about 1 hr. The precipitated N-methyl 3-(o-tolyloxy)-3- phenylpropylamine hydrochloride is isolated and dried.
N-methyl 3-(o-tolyloxy)-3-phenylproρylamine hydrochloride is suspended in a mixture of water and toluene. The reaction mass is basified with a base such as sodium hydroxide, ammonia solution and allowed for settling. Toluene layer is separated and the aqueous layer is extracted with toluene. The combined toluene layer is washed with water. Toluene is removed under vacuum at temperature below 750C affords the N-methyl 3-(o- tolyloxy)-3-phenylpropylamine as a residue. The residue is dissolved in a mixture of toluene, ethyl acetate in a ratio of 1 :3, treated with (S)-(+)-mandalic acid at a temperature of 200C to 5O0C preferably 350C to 450C for 30 min to 4hrs. The reaction mass is cooled and maintained at a temperature of 250C to 350C for 3 to 6 hrs, further cooled to a temperature of O0C to 1O0C. The precipitated product is isolated and dried to get (R)-(-) N-methyl 3-(o-tolyloxy)-3-phenylpropylarnine (S)-(+)-mandalate. The (S)-(+)-mandalate salt can be optionally purified in ethyl acetate to get an enantiomeric purity > 99.0%. (R)-(-)N-methyl 3-(o-tolyloxy)-3-phenylpropylamine (S)-(+)-mandalate is neutralized with a base such as alkali hydroxides like sodium hydroxide, potassium hydroxide, alkali carbonates, ammonia solution, preferably sodium hydroxide in water and extracted with water immiscible solvent such as ethyl acetate. The organic layer is separated and the aqueous layer is extracted with same solvent. Combined organic layer is with brine solution and treated with activated carbon. Organic layer is concentrated preferably under vacuum and again fresh solvent is added. Reaction mass is cooled to a temperature of O0C to 1O0C and the pH is adjusted below 2.0 by passing the hydrogen chloride gas at temperature of -1O0C to 2O0C, preferably at O0C to 1O0C. After pH adjustment the reaction mass is maintained for 30 min to 3 hrs at the same temperature. The precipitated product is isolated and dried to get Atomoxetine hydrochloride.
Atomoxetine hydrochloride is dissolved in an alkanol such as methanol, ethanol, isopropanol and mixtures thereof, preferably methanol at temperature of 2O0C to 5O0C. The obtained solution is optionally treated with activated carbon and the solvent is removed at temperature below 6O0C preferably under vacuum. After distillation a second solvent such as alkyl ester like ethyl acetate, isopropyl acetate is added at temperature of 150C to 450C and maintained for 30 min to 2 hrs. The reaction mass is further cooled and maintained at temperature of -1O0C to 2O0C preferably O0C to 1O0C for 30 min to 3 hrs. The precipitated product is isolate and dried at temperature of 4O0C to 6O0C preferably under vacuum afforded the crystalline Atomoxetine hydrochloride.
The prepared and purified Atomoxetine hydrochloride is identified as crystalline Atomoxetine hydrochloride polymorphic form-A based on the PXRD.
The invention is further illustrated with a few non-limiting examples.
Example-1: Preparation of N,N-DimethyI-3-(toIyIoxy)-3-phenyl propyl amine oxalate.
O-Cresol (152.5 Gms) is added to aqueous sodium hydroxide (86.5 Gms in 1400 ml) at temperature of 30 to 35°C over 30 minutes. The reaction mixture is stirred for 30 minutes at 30 to 35°C, Triethyl benzyl ammonium chloride (13.25 Gms) and methylene dichloride (1400 ml) are added 30 to 35°C. N,N-Dimethyl 3-ρhenyl-3-chloropropyl amine hydrochloride is added to the reaction mixture at a temperature of 25 to 30°C over 1-11A hours. The reaction mass is maintained at a temperature of 25 to 30°C for 4 hrs. Triethyl benzyl ammonium chloride (13.0 Gms) is added at 25-30°C and maintained the reaction mass at temperature of 25 to 300C for 8 hours. Reaction completion is checked by HPLC and allowed the reaction mass to settle. Organic layer is separated and the aqueous layer is extracted with dichloromethane (175 ml). The combined organic layer is washed with 10% Sodium hydroxide solution (175 ml), DM Water (2X175 ml), 10% sodium chloride solution (175 ml) and finally with DM Water (175 ml) successively. MDC is distilled off till temperature reaches to 55°C and finally under vacuum to remove traces of MDC at temperature below 55°C. The obtained residue is dissolved in Ethyl acetate (175 ml) and distilled off under vacuum at temperature below 550C. The obtained residue is dissolved in ethyl acetate (1000 ml) and treated with activated carbon (17.5 gm). Filtered the mass through hyflow bed and washed the bed with ethyl acetate (400 ml). Combined the filtrate and ethyl acetate washings. Oxalic acid (103 gm) is added to the ethyl acetate layer lot wise at temperature of 25 to 35°C over 1 to 2 hours. The reaction mass is maintained for 1 hour at temperature of 25 to 35°C. The reaction mass is cooled to 0°C and maintained for 1 hr at 0 to 5°C. Filter the mass and washed the wet cake with chilled ethyl acetate (175 ml). The wet cake is dried at room temperature and then at temperature of 50-55°C till constant weight.
The dry weight of N,N-Dimethy 1-3 -(tolyloxy)-3 -phenyl propyl amine oxalate is 230 Gms
Example-2: Preparation of N-Methyl-3-(2-methyI phenoxy)-3-phenyI propyl amine hydrochloride
Charged toluene (1000 ml), N,N-Dimethyl-3 -(to lyloxy)-3 -phenyl propyl amine oxalate (200 gm) and DM Water (1000 ml) at 25-350C. Raised the temperature to 40 - 45°C, Ammonia solution (260 ml) is added at 40-450C and maintained for 30 min. Reaction mass allowed to settle. Organic layer is separated and the aqueous layer is extracted with toluene (200 ml) at 30-40°C. Combined the organic layer, and washed with DM water (2 X 200 ml) at 30-35°C. Distilled off toluene (200 - 250 ml) azeotropically to remove the water and make up final volume to 1200 ml with fresh toluene. Cooled the reaction mass to 35 - 40°C and added Diisopropyl ethyl amine (8.4 gm). Raised the reaction mass temperature to 50-55°C. Slowly added Phenylchloroformate (90.4 gms) at 50 - 550C over 1 Vz - 2hrs. Maintained the reaction mass at 50-600C for 11A hours. Checked the reaction completion by TLC. Cooled the reaction mass to 30-35°C and washed the reaction mass with 1% Sodium bicarbonate solution (2000 ml), 0.5 N HCl (2 X 100 ml) and 1% Sodium bicarbonate solution (1500 ml) at 25-35°C. Toluene is distilled off under vacuum below 65°C. DMSO (2000 ml) is added to the residue and maintained for 5- 10 min to get clear solution. Reaction mass temperature is raised to 400C and slowly added Sodium hydroxide solution (62.6 g sodium hydroxide + 395 ml of DM Water) at 40-450C. Maintained the reaction mass at 40-500C for 8 hrs. Checked the reaction completion by TLC and cooled the reaction mass to 18 - 25°C.
Charged DM Water (2000 ml) in another flask and cooled to 18-25°C. Slowly transfered the above reaction mass to cold water at temperature of 18-25°C. Adjusted the pH of the reaction mass to 5.6 - 6.0 with Acetic acid at 18-25°C. Washed the reaction mass with n- Hexane (2 X 150 ml). Adjusted the pH of reaction mass to 10.5 - 11.5 with 50% w/w Sodium hydroxide solution and stirred for 15 minutes at 20-250C. Added toluene (1000 ml) and maintained for 15 - 30 min at 20 - 250C. Reaction mass is allowed to settle and separated the organic layer. Extracted the aqueous layer with toluene (200 ml). Combined toluene layer is washed with DM water (3 x 200ml) and treated with activated carbon (20 Gms). Stirred for 30 min. at<25-35°C and filtered through hyflow bed. Washed the bed with toluene (100 ml). Adjusted the pH of the toluene layer to below 2.0 with CP HCl at 25-300C. Stirred for 30 min. at 25-300C. Toluene is distilled off completely under vacuum at 50-55°. Charged ethyl acetate (100 ml) to the residue and distilled off completely under vacuum at 50-550C. Added ethyl acetate (600 ml) to the above residue and maintained at 15 - 2O0C for 2 hrs. Cooled the reaction mass to 0-20C and maintained for 60 min at 0-50C. Filtered the mass and washed the wet cake with chilled ethyl acetate (200 ml). Dried the material at 50-550C till constant weight.
Output : 110 Gms Example 3: Preparation of Atomoxitine HCl
Step-1: (R) (-) N-Methyl-3-(2-methylphenoxy)-3-phenyIpropylamine(S)-(+) mandelate
N-Methyl-3-(2-methyl phenoxy)-3 -phenyl propyl amine hydrochloride (100 Gms) is added to a mixture of DM water (400ml) and Toluene (400 ml) at 25-35°C. Temperature is raised to 40-45°. Slowly added ammonia solution (110 ml) at 40-45°C and maintained for 30 min at 40 - 450C. Allowed the reaction mass to settle for 30 min and separated the layers. Organic layer is separated and the aqueous layer is extracted with toluene (100 ml). Combined the organic layer and washed with DM water (2 X 100 ml). Toluene is distilled of under vacuum at 60-65°C and to the obtained residue toluene (90 ml) and Ethyl acetate (270 ml) are added. Charged S(+)-Mandelic acid (26 gm) at 28- 32°C and maintained for 30 minutes at 25-30°C Slowly raised the temperature to 40- 45°C over a period of 1.0 hour and maintained the mass at 40 - 45°C for 2.0 hours. Slowly cooled the mass to 28-32°C over a period of 1.0 hr and maintained at 28-32°C for 4-5 hrs. Again cooled the reaction mass to 0-5°C and maintained at 0-5°C for 1.0 hr. filtered the material and washed the wet cake with chilled ethyl acetate (100 ml). Dried the material at 40-45°C for 1.0 hour.
Output: 60 Gms
Suspended the above obtained material in Ethyl acetate (270 ml) and raised the reaction mass to reflux for dissolution. Maintained at reflux for 20 - 30 minutes. Cooled the reaction mass to 25-30°C and maintained for 1.0 hour at 25-30°C. Filtered the product and washed the wet cake with Ethyl acetate (60 ml). Dried the material at 40- 450C till constant weight.
Output: 55 Gms : Step-2: Preparation of Atomoxetine hydrochloride
(R)(-)N-Methyl-3-(2-methylphenoxy)-3-phenylpropylamine(S)-(+) mandelate (100 gm) is suspended in DM water (500ml) at room temperature. 10% Sodium Hydroxide solution (15gms Sodium hydroxide in 150 ml DM Water) is added at 25-35°C in 30 - 40 min and pH is checked. The reaction mixture is extracted with ethyl acetate (500 ml + 200 ml). Combined ethyl acetate layer is washed with 10% sodium chloride solution (2 x 200 ml) and treated with activated carbon (10 gm) for 30 min at 25-35°C. Filtered the mass through hyflow bed and washed the bed with ethyl acetate (100 ml). Ethyl acetate is distilled under vacuum below 45°C to get residue. The obtained residue is dissolved in ethyl acetate (310 ml) and HCl gas is passed slowly to the reaction mass till pH becomes below 2.0. The reaction mass is cooled to 0-5°C and maintained for one hour at 0-5°C. The product is filtered and washed the wet cake with chilled ethyl acetate (100 ml) and dried the material at 40-450C under vacuum till LOD becomes below 1.0%.
Output: 60 Gms
Step-3: Purification of Atomoxetine hydrochloride
Atomoxetine hydrochloride (60 gm) is dissolved in methanol (120 ml) at 40 - 450C and treated with activated Carbon (6.0 gm). Filtered the reaction mass through Hyflow bed and washed the bed with methanol (60 ml). Methanol is distilled off below 450C under vacuum and cooled the reaction mass to 25 to 35°C. Ethyl acetate (600 ml) is charged and maintained the reaction mass at 25-350C for one hour. The reaction mass is cooled to 0-50C and maintained for one hour at 0-50C. Filtered the material and washed the wet cake with chilled ethyl acetate (60 ml). The wet material is dried at room temperature for 2.0 hours followed by at 45-55°C under vacuum till LOD is less than 0.5%.
Output: 57 Gm

Claims

We claim;
1. A process for the preparation of Atomoxetine hydrochloride comprising the steps;
• Reacting N,N-dimethyl 3-ρhenyl-3-chloropropyl amine acid addition salt with o-cresol in presence of phase transfer catalyst and base to get N3N- dimethyl 3-(o-tolyloxy)-3-phenylpropylamine,
• Demethylating N,N-dimethyl 3-(o-tolyloxy)-3-phenylpropylamine to get N- methyl 3-(o4olyloxy)-3-phenylpropylamine,
• Treating N-methyl 3-(o-tolyloxy)-3-phenylpropylamine with (S)-(+)-mandelic acid in a mixture of toluene and ethyl acetate to get (S)-(+)-mandalate,
• Isolating (R)-(-) N-methyl 3-(o-tolyloxy)-3-phenylpropyl amine (S)-(+)- mandalate,
• Basifying (R)-(-) N-methyl 3-(o-tolyloxy)-3-phenylpropylamine (S)-(+)- mandalate and extracting the liberated (R)-(-) N-methyl 3-(o-tolyloxy)-3- phenylpropylamine with an water immiscible solvent and
• Salification with hydrochloric acid to get Atomoxetine hydrochloride.
2. The process as claimed in claim 1, wherein acid addition salt is selected from hydrochloride, hydrobromide, sulphate, phosphate, nitrate or acetate.
3. The process as claimed in claim 1, wherein the phase transfer catalyst is selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, triethyl benzyl ammonium chloride, tributyl benzyl ammonium chloride and mixtures thereof.
4. The process as claimed in claim 1, wherein the phase transfer catalyst is selected from phosphonium salts and crown ethers.
5. The process as claimed in claim 1, wherein the base is selected from alkali hydroxides, carbonates like sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
6. The process as claimed in claim 1, wherein condensation reaction of 3-phenyl-3- chloropropyl amine acid addition salt with o-cresol is carried out in a mixture of water and a halogenated hydrocarbon.
7. The process as claimed in claim 1, wherein demethylation takes place with phenyl chloroformate in the presence of diisopropyl ethyl amine.
8. The process as claimed in claim 1, wherein the isolated (R)-(-) N-methyl 3-(o- tolyloxy) -3-phenylpropyl amine (S)-(+)-mandalate is further purified in ethyl acetate.
9. The process as claimed in claim 1, wherein the salification of Atomoxetine is carried out in Ethyl acetate.
10. A process for preparation of crystalline Atomoxetine hydrochloride comprising the steps:
• Dissolving Atomoxetine hydrochloride in a lower alkanol
• Optionally treating the solution with activated carbon
• Removing the solvent from the solution • Adding a second solvent and Isolating Atomoxetine hydrochloride
11. The process as claimed in claim 10, wherein the preferable lower alkanol is selected from methanol, ethanol, isopropanol and mixtures thereof.
12. The process as claimed in claim 11, wherein the second solvent is selected from ethyl acetate, isopropyl acetate and mixture thereof.
PCT/IN2007/000408 2006-08-28 2007-08-24 A process for the preparation of atomoxetine hydrochloride WO2008026227A2 (en)

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EP2348120A1 (en) 2009-12-30 2011-07-27 Universität Wien Enzymatic reduction of 1-phenylpropanone and derivatives thereof
CN102516100A (en) * 2011-12-14 2012-06-27 华宝食用香精香料(上海)有限公司 N-[2-(methoxymethoxy)-2-propenyl]-4,4-diethoxy butylamine compound and preparation method and application thereof
CN114621101A (en) * 2020-12-11 2022-06-14 李冰坚 Refining method of 3, 5-dimethyl-1, 2-phenylenediamine dihydrochloride

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US4950791A (en) * 1988-03-30 1990-08-21 Brown Herbert C Novel process of producing phenyl or substituted phenylalkylamine pharmaceutical agents and novel chiral intermediates of high enantiomeric purity useful therein
WO2000058262A1 (en) * 1999-03-29 2000-10-05 Eli Lilly And Company Stereospecific method for preparing tomoxetine and intermediates thereof
WO2006020348A2 (en) * 2004-07-22 2006-02-23 Teva Pharmaceutical Fine Chemicals S.R.L. Polymorphs of atomoxetine hydrochloride
WO2006037055A1 (en) * 2004-09-27 2006-04-06 Dr. Reddy's Laboratories Ltd. Synthesis of atomoxetine hydrochloride

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US4314081A (en) * 1974-01-10 1982-02-02 Eli Lilly And Company Arloxyphenylpropylamines
US4950791A (en) * 1988-03-30 1990-08-21 Brown Herbert C Novel process of producing phenyl or substituted phenylalkylamine pharmaceutical agents and novel chiral intermediates of high enantiomeric purity useful therein
WO2000058262A1 (en) * 1999-03-29 2000-10-05 Eli Lilly And Company Stereospecific method for preparing tomoxetine and intermediates thereof
WO2006020348A2 (en) * 2004-07-22 2006-02-23 Teva Pharmaceutical Fine Chemicals S.R.L. Polymorphs of atomoxetine hydrochloride
WO2006037055A1 (en) * 2004-09-27 2006-04-06 Dr. Reddy's Laboratories Ltd. Synthesis of atomoxetine hydrochloride

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2348120A1 (en) 2009-12-30 2011-07-27 Universität Wien Enzymatic reduction of 1-phenylpropanone and derivatives thereof
CN102516100A (en) * 2011-12-14 2012-06-27 华宝食用香精香料(上海)有限公司 N-[2-(methoxymethoxy)-2-propenyl]-4,4-diethoxy butylamine compound and preparation method and application thereof
CN102516100B (en) * 2011-12-14 2013-12-18 华宝食用香精香料(上海)有限公司 N-[2-(methoxymethoxy)-2-propenyl]-4,4-diethoxy butylamine compound and preparation method and application thereof
CN114621101A (en) * 2020-12-11 2022-06-14 李冰坚 Refining method of 3, 5-dimethyl-1, 2-phenylenediamine dihydrochloride

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