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WO2006009884A1 - Synthèse de 3-aryloxy-3-arylpropylamine - Google Patents

Synthèse de 3-aryloxy-3-arylpropylamine Download PDF

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Publication number
WO2006009884A1
WO2006009884A1 PCT/US2005/021554 US2005021554W WO2006009884A1 WO 2006009884 A1 WO2006009884 A1 WO 2006009884A1 US 2005021554 W US2005021554 W US 2005021554W WO 2006009884 A1 WO2006009884 A1 WO 2006009884A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
methyl
acid
followed
reaction
Prior art date
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Ceased
Application number
PCT/US2005/021554
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English (en)
Inventor
Sundaram Venkataraman
Vijayavitthal Thippannachar Mathad
Mahesh Reddy Ghanta
Shanmugam Govindan
Prabhakar Macharla
Venu Nalivela
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Original Assignee
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr Reddys Laboratories Ltd, Dr Reddys Laboratories Inc filed Critical Dr Reddys Laboratories Ltd
Publication of WO2006009884A1 publication Critical patent/WO2006009884A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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 an improved process for the synthesis of 3- aryloxy-3-arylpropylamines.
  • the process illustrated in Scheme 1 involves the preparation of atomoxetine using 3-phenyl chloropropyl amine (Formula 5) as a starting material.
  • the process involves bromination of said starting compound (Formula 5) by using N-bromosuccinimide. Further the bromo derivative is condensed with o-cresol to result in to a compound of Formula 7, which is then subjected to amination using methylamine.
  • the process appears to be very simple, it involves the following drawbacks:
  • N-bromosuccinimide is a corrosive and sensitive chemical, so its usage demands special care;
  • reaction conditions involved in some of the steps are harsh; for example, the amination reaction is conducted at 140 0 C at a pressure of 10 kg for 12 hours in an autoclave.
  • Scheme 2 describes the preparation of atomoxetine using /?-dimethylamino propiophenone produced by a Mannich reaction; which is reduced to the hydroxy derivative having Formula 9 using diborane; further, the hydroxy compound (Formula 9) is converted to the corresponding chloro derivative of Formula 10 using dry HCI gas and thionyl chloride, and this is followed by condensation with o-cresol.
  • the reaction is carried out in methanol at reflux for duration of five days to achieve the compound of formula 11 , and is followed by demethylation using cyanogen bromide to end up with atomoxetine.
  • the process is associated with the following problems:
  • DEAD diethyl azodicarboxylate
  • reaction involves the usage of triphenyphosphine and DEAD and the byproducts formed in the reaction, such as phosphine oxide and hydrazine derivatives, are very difficult to remove.
  • Patent Publication No. WO 00/58262 relates to a stereospecific process for the preparation of atomoxetine using nucleophilic aromatic displacement.
  • the aromatic ring having a functional group that may be converted to a methyl group.
  • the process is very lengthy and involves many steps and is thus not commercially beneficial.
  • U.S. Patent No. 5,847,214 describes a nucleophilic aromatic displacement reaction of 3-hydroxy-3-arylpropylamines with activated aryl halides, for example the reaction of N-methyl-3-phenyl-3-hydroxypropylamine with 4-triflouromethyl-1- chlorobenzene has been reported; the success of this reaction is mainly due to an electron withdrawing group on benzene ring of the aryl halides.
  • U.S. Patent No. 6,541 ,668 describes a process for the preparation of atomoxetine and its pharmaceutically acceptable addition salts which comprises reacting an alkoxide of N-Methyl-3-phenyl-3-hydroxypropylamine or an N- protected derivative thereof, with 2-flourotoIuene, in the presence of 1 ,3-dimethyl- 2-imidazoIidinone or N-methylpyrrolidinone as the solvent.
  • the process disclosed in the patent can be shown as the following Scheme-4:
  • M is an alkali metal
  • the process of present invention has an advantage over these others in that it avoids the usage of expensive or harmful chemicals involved in the previous processes and reduces the number of steps. Also, the conditions used in the process of the present invention are safe, plant friendly and highly cost effective.
  • a process for preparing a 3-aryloxy-3-arylpropylamine comprises reacting a 3-hydroxy-3-arylpropylamine with a halogen-substituted aryl compound, in a solvent comprising N-N-dimethylacetamide or hexamethylphosphorous triamide.
  • N-methyl-3-phenyl-3-hydroxypropylamine is reacted with 2- fluorotoluene, and the product is subjected to further steps including resolution of enantiomers, to produce pure (-)- ⁇ /-methyl-3-phenyl-3-(o-tolyloxy)-propylamine or a salt thereof.
  • the present invention includes in one aspect the condensation of 2- fluorotoluene and related haloaromatics with a 3-hydroxy-3-aryl propylamine in the medium of polar aprotic solvents, particularly N,N-dimethylacetamide (“DMAC”) or hexamethylphosphorous triamide.
  • DMAC N,N-dimethylacetamide
  • the present invention provides a process for the preparation of atomoxetine of Formula 1 , which eliminates use of hazardous reagents and is safe and suitable for industrial scale-up.
  • the present invention provides an improved, cost-effective, plant friendly and simple process for the preparation of 3-aryloxy-3-arylpropylamines, more specifically, the R-(-)-N-methyl-3-(2-methylphenoxy)-3-phenyl-propylamine of Formula 1.
  • An embodiment of an improved process of the present invention comprises condensation of 3-hydroxy-3-phenylpropylamine of Formula 2 and a halo aromatic compound of Formula 3, followed by resolution of the obtained racemic compound of Formula 4.
  • the process provides an improved, simple method for the production R-(-)-N-methyl-3-(2-methylphenoxy)-3-phenyl- propylamine of Formula 1.
  • the process comprises reacting N-methyl- 3-phenyl-3-hydroxypropylamine with 2-flurotoluene to obtain the compound of interest. Further the obtained compound is subjected to resolution to obtain the enantiomerically pure compound.
  • reaction Scheme 5 where Ar and An are as defined below, summarizes the process of an embodiment of the invention.
  • an aspect of the present invention relates to an improved process for preparing 3-aryloxy-3-arylpropylamines of the following formula, wherein Ar is phenyl and An is 2-methoxy phenyl or 2-methyl phenyl, and more specifically, to preparing R-(-)-N-methyl-3-(2-methylphenoxy)-3-phenyl- propylamine, and pharmaceutically acceptable salts thereof, comprising the following steps a. reacting a 3-hydroxy-3-aryl propylamine of the formula 24:
  • Formula 25 wherein A is methoxy or methyl and X is a halogen; b. resolution of the formed 3-aryloxy-3-aryl propylamine to give the specific isomer of the same; and c. optional formation of an acid addition salt using a pharmaceutically acceptable organic acid such as glutaric acid, lactic acid, citric acid, malic acid, fumaric acid and the like or an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid and the like, in a suitable solvent such as: a halo solvent such as dichloromethane or chloroform; an ether solvent such as diethyl ether, methyl tertiary butyl ether, or methyl ethyl ether; an alcoholic solvent such as isopropyl alcohol or ethanol; and an ester solvent such as ethyl acetate.
  • the present invention relates to a process for preparing atomoxetine and its
  • step (i) stirring the contents of the reaction mass in step (i) at temperatures in the range of 80-140 0 C, preferably 110-130 0 C, until the reaction is complete, such as for a duration of 7-20 hours; iii. removing the solvent by distillation under vacuum at temperatures less than about 120 0 C; iv. adding methanol and sodium hydroxide and heating to a temperature about 80-14O 0 C 1 preferably about 100-110°C; v. removing the solvent by distillation under vacuum at temperatures below about 80°C; vi. adding water and toluene; vii.
  • step (vi) cooling the reaction mass in step (vi) to 0-5 0 C; viii. adjusting the pH to a value between 8 and 9 with dilute hydrochloride acid ix. separating the aqueous and the organic layers from the reaction mass of step (viii); x. washing the organic layer of step (ix) with water; xi. subjecting the organic layer of step (x) to evaporation under reduced pressure to remove solvent; xii.
  • step (xi) purifying the residue from step (xi) by forming a salt with an acid such as an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, and the like, or an organic acid such as glutaric acid, lactic acid, citric acid, malic acid, fumaric acid, oxalic acid, and the like; xiii. subjecting the salt formed in step (xii) to hydrolysis in the presence of a base and dissolving the free base in organic solvent, followed resolution of the compound by treating with an optically pure mandelic acid; xiv. hydrolyzing the mandelate salt compound from step (xiii) in the presence of a base; and xv. converting atomoxetine free base formed in step (xiv) to the corresponding acid addition salt and isolating a pure enantiomeric salt compound in a suitable solvent like isopropyl alcohol.
  • an acid such as
  • step xv can be performed in situ by adding the desired acid for salt formation.
  • Reaction of the amine with the substituted toluene is facilitated by a prior alkoxide formation at the hydroxyl group of the amine.
  • This can be accomplished by adding at least a stoichiometric equivalent amount of an alkali metal hydride, hydroxide, or alkoxide, or a mixture thereof, to the amine in a solvent, prior to the addition of the substituted toluene. It is not necessary to isolate the formed alkoxide.
  • Representative alkali metal compounds that can be used include, without limitation thereto, sodium or potassium hydride, sodium or potassium hydroxide, and sodium or potassium propoxide or butoxide. Potassium f-butoxide is used in the following examples, but it can readily be replaced by any of numerous other compounds, as will be appreciated by those skilled in the art.
  • the organic layer was separated from the aqueous layer, and the aqueous layer was extracted with dichloromethane (2x50 ml). The combined organic layer was subjected to distillation to obtain a thick residue. The obtained residue was further purified by preparing its oxalate salt.
  • the crude residue was charged into acetone (240 ml) followed by the addition of oxalic acid, petroleum ether (240 ml) was charged, and the mixture was stirred for 1-5 hours at 0-5 0 C. Filtering the obtained solid and washing with a mixture of acetone and petroleum ether in a 1 :1 ratio (100 ml) resulted in the recovery of atomoxetine oxalate. Yield 55% and HPLC purity 98.35%.
  • the solvent was totally distilled off under vacuum at a temperature below 80 0 C, then 1 liter of demineralised water and 1 liter of toluene were added, followed by cooling to 0 to 5 0 C and adjusting the pH to a value between 8 and 9 with dilute hydrochloric acid.
  • the above reaction mass was stirred for about 15 to 30 minutes to separate the organic and aqueous layers and the aqueous layer was extracted with 400 milliliters of toluene followed by stirring for about 5 to 10 minutes. Organic and aqueous layers were separated and the combined organic layers were washed with 400 milliliters of dimineralised water.
  • the organic layer was taken into a round bottom flask followed by complete distillation under vacuum below 80°C and then cooled to 25 to 35°C.
  • 1.3 liters of acetone and 64.2 grams of oxalic acid were added to the round bottom flask followed by stirring for about 45 to 60 minutes.
  • the solid mass that was obtained was filtered and washed with 520 milliliters of acetone, and then slurried in 700 milliliters of acetonitrile in a round bottom flask and stirred for about 30 to 45 minutes.
  • the solid mass was isolated by filtration and washed with 200 milliliters of acetonitrile, followed by drying at 50 to 60 0 C for 4 to 5 hours under vacuum to afford atomoxetine oxalate.
  • Atomoxetine oxalate 35 grams
  • dichloromethane 350 ml
  • water 350 ml
  • sodium hydroxide 17.5 grams
  • the aqueous layer was separated and extracted with dichloromethane (100 ml).
  • Combined organic layer was washed with 5% sodium hydroxide solution followed by water (100 ml).
  • the organic solvent was removed by distillation under reduced pressure.
  • To the residue was added ethyl acetate (50 ml) followed by mandelic acid (2.9 grams) and the mixture was heated to 50-55 0 C for about one hour.
  • Petroleum ether 50 ml
  • the separated solid was isolated by filtration and washed with petroleum ether (30 ml), then dried at 50-55 0 C under reduced pressure to get the mandelic acid salt of atomoxetine.
  • the material that was obtained from filtration was taken into a round bottom flask along with 125 milliliters of isopropyl alcohol followed by heating at a temperature of 75 to 8O 0 C until a clear solution was obtained.
  • the solution was kept at 75 to 80 0 C for about 15 to 30 minutes and then cooled to 0 to 5°C for about 45 to 60 minutes for crystallization.
  • the solid was separated by filtration and washed with 55 milliliters of isopropyl alcohol, followed by drying at 50 to 55°C for about 4 to 5 hours under vacuum to get the mandelic acid salt of atomoxetine.
  • the mandelic acid salt of atomoxetine (5.5 grams), dichloromethane (50 ml), and water (50 ml) were mixed and stirred for 10 minutes at 25-35 0 C. A 5 % sodium hydroxide solution was added and the mixture was stirred for 10 minutes at 25-35 0 C. The aqueous layer and organic layer were separated and the aqueous layer was extracted with dichloromethane (25 ml). Combined organic layer was washed with 5% sodium hydroxide solution (25 ml) followed by washing with water (25 ml). Then the organic layer was separated and solvent was removed by distillation under reduced pressure.
  • 3-(o-tolyloxy)propylamine-S-(+)-mandelic acid salt and 250 milliliters of toluene were taken in a round bottom flask and cooled to 10 to 15 0 C followed by adjusting the pH to a value between 10.5 and 11.5 with the addition of a sodium hydroxide solution.
  • the reaction mixture was stirred for about 10 to 15 minutes to separate the organic and aqueous layers followed by the extraction of the aqueous layer with 100 milliliters of toluene and the organic layer was washed with 100 milliliters of demineralised water.
  • the solvent was distilled off completely under vacuum at a temperature below 60 to 65 0 C and the residue was taken into a round bottom flask along with 50 milliliters of isopropyl alcohol, followed by cooling to 0 to 5 0 C.
  • An equal volume of an 18% by weight solution of hydrochloric acid in isopropyl alcohol was added slowly over about 30 to 45 minutes to the mixture at a temperature of 0 to 5°C with stirring, then the mixture was refluxed for about 30 to 45 minutes until a clear solution was obtained.
  • the above solution was cooled to 0 to 5°C to produce a precipitate, and 145 milliliters cyclohexane were added and the mixture was maintained for about 45 to 60 minutes at a temperature of 0 to 5°C.
  • Atomoxetine hydrochloride thus obtained has a purity of 99.9% by weight.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Le processus de préparation d'une 3-aryloxy-3-arylpropylamine comprend la mise en réaction d'une 3-hydroxy-3-arylpropylamine avec un composé substitué d'aryle dans un solvant comprenant une acétamide diméthylique-N-N ou une triamide hexaméthylphosphorique.
PCT/US2005/021554 2004-06-17 2005-06-17 Synthèse de 3-aryloxy-3-arylpropylamine Ceased WO2006009884A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US58050304P 2004-06-17 2004-06-17
US60/580,503 2004-06-17

Publications (1)

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WO2006009884A1 true WO2006009884A1 (fr) 2006-01-26

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1794112A4 (fr) * 2004-09-27 2009-11-04 Reddys Lab Ltd Dr Synthese d'hydrochlorure d'atomoxetine
EP2348120A1 (fr) 2009-12-30 2011-07-27 Universität Wien Réduction enzymatique de 1-phénylpropanone et dérivés associés
US8299305B2 (en) 2010-06-29 2012-10-30 Sci Pharmtech, Inc. Method for preparing atomoxetine
WO2015001565A3 (fr) * 2013-07-02 2015-04-09 Zcl Chemicals Limited "procédé amélioré pour la préparation de 3-aryloxy-3- phénylpropylamine et son sel"
CN108929236A (zh) * 2017-05-26 2018-12-04 万特制药(海南)有限公司 盐酸托莫西汀的制备

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5225585A (en) * 1991-08-27 1993-07-06 Teva Pharmaceutical Industries Ltd. Production of fluoxetine and new intermediates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5225585A (en) * 1991-08-27 1993-07-06 Teva Pharmaceutical Industries Ltd. Production of fluoxetine and new intermediates

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1794112A4 (fr) * 2004-09-27 2009-11-04 Reddys Lab Ltd Dr Synthese d'hydrochlorure d'atomoxetine
EP2348120A1 (fr) 2009-12-30 2011-07-27 Universität Wien Réduction enzymatique de 1-phénylpropanone et dérivés associés
US8299305B2 (en) 2010-06-29 2012-10-30 Sci Pharmtech, Inc. Method for preparing atomoxetine
WO2015001565A3 (fr) * 2013-07-02 2015-04-09 Zcl Chemicals Limited "procédé amélioré pour la préparation de 3-aryloxy-3- phénylpropylamine et son sel"
US20160107983A1 (en) * 2013-07-02 2016-04-21 Zcl Chemicals Limited An improved process for the preparation of 3-aryloxy-3-phenylpropylamine and salt thereof
US9604906B2 (en) 2013-07-02 2017-03-28 Zcl Chemicals Limited Process for the preparation of 3-aryloxy-3-phenylpropylamine and salt thereof
CN108929236A (zh) * 2017-05-26 2018-12-04 万特制药(海南)有限公司 盐酸托莫西汀的制备

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