WO2006009884A1

WO2006009884A1 - 3-aryloxy-3-arylpropylamine synthesis

Info

Publication number: WO2006009884A1
Application number: PCT/US2005/021554
Authority: WO
Inventors: Sundaram Venkataraman; Vijayavitthal Thippannachar Mathad; Mahesh Reddy Ghanta; Shanmugam Govindan; Prabhakar Macharla; Venu Nalivela
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2004-06-17
Filing date: 2005-06-17
Publication date: 2006-01-26

Abstract

A process for preparing a 3-aryloxy-3-arylpropylamine comprises reacting a 3-hydroxy-3-arylpropylamine with a substituted aryl compound, in a solvent comprising N-N-dimethylacetamide or hexamethylphosphorous triamide.

Description

3-ARYLOXY-3-ARYLPROPYLAMINE SYNTHESIS

INTRODUCTION TO THE INVENTION

The present invention relates to an improved process for the synthesis of 3- aryloxy-3-arylpropylamines.

(-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, or (-)-/V-methyl-3- phenyl-3-(o-tolyloxy)-propylamine hydrochloride, known by its adopted name "atomoxetine." It is represented as shown in Formula 1 and is a selective norepinephrine reuptake inhibitor. A commercial product is sold as STRATTERA™ in the form of capsules containing 10, 18, 25, 40, or 60 mg of atomoxetine, for treating attention-deficit/hyperactivity disorder.

Formula 1

U.S. Patent No. 4,314,081 describes 3-Aryloxy-3-phenyl propylamines, which possess central nervous system activity. The patent describes the process for preparing atomoxetine and related compounds in two different ways as depicted below in Scheme 1 and Scheme 2. Scheme 1

Atomoxetine Scheme 2

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. Though the process appears to be very simple, it involves the following drawbacks:

(i) N-bromosuccinimide is a corrosive and sensitive chemical, so its usage demands special care;

(ii) the workup of the compound having formula 7 involves high vacuum distillation at 135-145°C (0.03 torr), which is a tedious and cumbersome process to carry out at the plant level; and

(iii) the reaction conditions involved in some of the steps are harsh; for example, the amination reaction is conducted at 140⁰C at a pressure of 10 kg for 12 hours in an autoclave.

All of the above points make the process not viable for commercial scale- up.

On the other hand, 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. As can be clearly understood the process is associated with the following problems:

(i) the usage of costly reagents such as diborane make the process uneconomical.

(ii) the passage of dry HCI gas followed by thionyl chloride addition is very cumbersome and is not advisable in the plant. (iii) time taking process, involves a reaction which demands five days for its completion.

(iv) usage of cyanogen bromide, which is highly toxic. All the above-quoted drawbacks make the process unfriendly to both the plant as well as the environment. Further, J. Org. Chem., 53, 2916-2920 (1988); Tet. Let, 30, 5207-5210

(1989); U.S. Patent No. 4,868,344; J. Org. Chem., 53, 4081-4084 (1988); Tet. Let, 31, 7101 (1990) and U.S. Patent No. 4,950,791 disclose stereospecific methods for the preparation of 3-aryloxy-3-phenylpropylamines; the enantiomers of 3-hydroxy-3-phenylpropylamines are prepared by the stereo specific reduction of the corresponding ketone. The thus obtained (S)-3-hdroxy-3-phenyl propylamines are subjected to condensation with the aryl alcohols using the Mitsunobo reaction. This is shown in the following Scheme 3:

Diisopinocamphenyl chloroborane

OH

.CH₃

DEAD/ triphenyl phosphine

As can be seen in Scheme 3 the reaction involves two critical steps, the first being the asymmetric reduction of the ketone to its corresponding alcohol. The second critical step involves the condensation of the obtained enantiomeric alcohol with the corresponding aryl alcohol. The process suffers from the following disadvantages:

(i) the reagent used for the asymmetric reduction of the ketone is very expensive;

(ii) the reagent diethyl azodicarboxylate (DEAD) is expensive; (iii) the DEAD reagent is known to be highly carcinogenic, thus creating problems in handling; and

(iv) the 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.

The foregoing process does not have commercial applicability due to the above noted drawbacks.

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. As can be seen, 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:

where 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.

SUMMARY OF THE INVENTION

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.

In one aspect, 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 (-)-Λ/-methyl-3-phenyl-3-(o-tolyloxy)-propylamine or a salt thereof.

DETAILED DESCRIPTION

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.

In an embodiment, 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.

Formula 2 Formula 3 Formula 4

In an embodiment of the invention, the process provides an improved, simple method for the production R-(-)-N-methyl-3-(2-methylphenoxy)-3-phenyl- propylamine of Formula 1. In general, 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. The following reaction Scheme 5, where Ar and An are as defined below, summarizes the process of an embodiment of the invention.

Scheme 5

Accordingly, 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 24 wherein Ar is as defined above and R is H or CH₃, with the substituted toluene of formula 25:

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. In one embodiment, the present invention relates to a process for preparing atomoxetine and its pharmaceutically acceptable addition salts comprising the following steps: i. reacting N-methyl-3-phenyl-3-hydroxy propylamine represented by the following formula

with 2-flourotoluene in the presence of N-N-dimethylacetamide or hexamethylphosphorous triamide as a solvent; ii. stirring the contents of the reaction mass in step (i) at temperatures in the range of 80-140⁰C, preferably 110-130⁰C, 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 120⁰C; iv. adding methanol and sodium hydroxide and heating to a temperature about 80-14O⁰C₁ 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. cooling the reaction mass in step (vi) to 0-5⁰C; 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. 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.

It frequently is not necessary to isolate the atomoxetine free base. The conversion of step xv can be performed in situ by adding the desired acid for salt formation.

The following reaction Scheme 6 summarizes the process of an embodiment of the invention.

Formula - 1 R-(-)-N-Methyl-3-ρhenyl-3-(o-me thylphenoxy) propylamineS-(+)- mandelic acid salt

Scheme 6

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 process of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the claimed invention.

EXAMPLE 1

To a solution of N-methy-3-phenyl-3-hydroxy phenylpropylamine (25 g, 0.15 mole) in N,N-dimethylacetamide and potassium tertiary butoxide (19 g, 0.17 mole) at 50-60⁰C was charged 2-flourotoluene (50 g, 0.45 mole) and the mixture was heated to 105-110⁰C and maintained for 7-9 hours. After the completion of the reaction (as monitored by TLC) there were charged water (250 ml) followed by dichloromethane (250 ml) and the mixture was stirred for 10-15 minutes. 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 0-5⁰C. 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%.

EXAMPLE 2

250 milliliters of N,N-dimethylacetamide was taken into round bottom flask to which 115.3 grams of potassium tertiary butoxide, 100 grams of N-Methyl-3- phenyl-3-(o-tolyloxy)propylamine and 100 grams of 2-fluorotoulene were added, followed by heating to 120 to 130⁰C for about 12 to 14 hours. Solvent was distilled from the above reaction mass under vacuum below 118 to 122°C, followed by the addition of 500 milliliters of methanol and 300 milliliters of a 45-50 percent by weight sodium hydroxide solution. The reaction mass was transferred into an autoclave and then heated to a temperature of 105 to 110⁰C for about 6 to 7 hours. The solvent was totally distilled off under vacuum at a temperature below 80⁰C, then 1 liter of demineralised water and 1 liter of toluene were added, followed by cooling to 0 to 5⁰C 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 60⁰C for 4 to 5 hours under vacuum to afford atomoxetine oxalate.

EXAMPLE 3

To a solution of N-methy-3-phenyl-3-hydroxy phenylpropylamine (25 g, 0.15 mole) in hexamethylphosphorous triamide and potassium tertiary butoxide (19 g, 0.17 mole) at 50-60°C was charged 2-flourotoluene (50 g, 0.45 mole) and the contents of the reaction were heated to 105-110⁰C. The reaction was maintained for 19-20 hours. After the completion of the reaction (checked by TLC) there were charged water (250 ml) followed by toluene (250 ml) and the mixture was stirred for 10-15 minutes. The aqueous and organic layers were separated, then the aqueous layer was extracted with toluene (2*75 ml). The combined organic layer was washed with water (3*75 ml) and then subjected to distillation to obtain a thick residue. The residue was dissolved in acetone (150 ml) followed by adding oxalic acid and isopropyl ether (200 ml) and the mixture was stirred for 1-1.5 hours at 0-5⁰C, then the obtained solid was separated by filtration and washing with isopropyl ether (100 ml) resulting in the oxalate of atomoxetine. Yield 62.4% and HPLC purity 95.4%.

EXAMPLE 4

Atomoxetine oxalate (35 grams), dichloromethane (350 ml), water (350 ml), and sodium hydroxide (17.5 grams) were mixed and stirred for 10 minutes. 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 50-55⁰C for about one hour. Petroleum ether (50 ml) was added and the mixture was cooled to 30-35⁰C. The separated solid was isolated by filtration and washed with petroleum ether (30 ml), then dried at 50-55⁰C under reduced pressure to get the mandelic acid salt of atomoxetine.

EXAMPLE 5

500 milliliters of demineralized water, 50 grams of N-Methyl-3-phenyl-3-(o- tolyloxy)propylamine oxalate and 500 milliliters of toluene were taken into a round bottom flask and the pH of the reaction mixture was adjusted to a value between 11.5 to 12.5 with the addition of sodium hydroxide solution, followed by stirring for about 10 to 15 minutes. The reaction mixture was heated to a temperature of 50 to 60⁰C for 10 to 15 minutes followed by extraction of the reaction mass with toluene, and then the organic layer was washed with 200 milliliters of demineralized water. The solvent in the organic layer was completely distilled off and the residue was taken into a round bottom flask along with the addition of 11 grams of L-(+)-mandelic acid and 175 grams of ethyl acetate. The above reaction mixture was stirred for 5 to 10 minutes at a temperature of 25 to 35°C and the reaction mass was checked for precipitation, then 315 milliliters of n- heptane was added followed by cooling the reaction mass to 0 to 5⁰C and then stirring for about 45 to 60 minutes at 0 to 5°C. The solid was filtered and washed with a mixture of 75 milliliters of ethyl acetate and n-heptane in the ratio of 1 :2. 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 8O⁰C until a clear solution was obtained. The solution was kept at 75 to 80⁰C 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.

EXAMPLE 6

The mandelic acid salt of atomoxetine (5.5 grams), dichloromethane (50 ml), and water (50 ml) were mixed and stirred for 10 minutes at 25-35⁰C. A 5 % sodium hydroxide solution was added and the mixture was stirred for 10 minutes at 25-35⁰C. 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. The residue was dissolved in methyl tertiary butyl ether followed and isopropyl alcohol was added, then the mixture was stirred for 15 minutes. Hydrochloric acid was added to the solution with stirring and stirring was continued for one hour. Solid was separated and washed with methyl tertiary butyl ether, then dried at 50-55⁰C to get the final atomoxetine product. Yield 73.5%, purity 99.5%.

EXAMPLE 7

250 milliliters of demineralised water, 25 grams of R-(-)-N-Methyl-3-phenyl-

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 15⁰C 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 65⁰C and the residue was taken into a round bottom flask along with 50 milliliters of isopropyl alcohol, followed by cooling to 0 to 5⁰C. 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. Solids were removed by filtration and washed with 500 milliliters of cyclohexane, and then taken into a round bottom flask to which 50 milliliters of isopropyl alcohol was added, and then refluxed at temperatures of 70 to 75°C for about 30 to 45 minutes and cooled to 0 to 5°C for crystallization. The crystals were filtered and washed with 25 milliliters of isopropyl alcohol followed by drying at 45 to 50⁰C for about 6 to 8 hours under vacuum to get atomoxetine hydrochloride. Atomoxetine hydrochloride thus obtained has a purity of 99.9% by weight.

Claims

CLAIMS:

1. A process for preparing a 3-aryloxy-3-arylpropylamine, comprising reacting a 3-hydroxy-3-arylpropylamine with a halogen-substituted aryl compound, in a solvent comprising N-N-dimethylacetamide or hexamethylphosphorous triamide.

2. The process according to claim 1 , wherein the solvent comprises N-N- dimethylacetamide.

3. The process according to claim 1 , wherein the solvent comprises hexamethylphosphorous triamide.

4. The process according to claim 1 , wherein N-methyl-3-phenyl-3- hydroxypropylamine is reacted with 2-fluorotoluene.

5. The process according to claim 1 , wherein N,N-dimethyl-3-phenyl-3- hydroxypropylamine is reacted with 2-fluorotoluene.

6. The process according to claim 1 , wherein N-methyl-3-phenyl-3- hydroxypropylamine is reacted with 2-fluorotoluene and the solvent comprises N,N-dimethylacetamide.

7. The process according to claim 1 , wherein N-methyl-3-phenyl-3- hydroxypropylamine is reacted with 2-fluorotoluene and the solvent comprises hexamethylphosphorous triamide.

8. The process according to claim 1 , wherein N-methyl-3-phenyl-3- hydroxypropylamine is reacted with 2-fluorotoluene and the solvent comprises N,N-dimethylacetamide, further comprising the step of resolving an enantiomer of the 3-aryloxy-3-arylpropylamine.

9. The process according to claim 9, wherein the enantiomer is (-)-Λ/-methyl- 3-phenyl-3-(o-tolyloxy)-propylamine.

10. The process according to claim 1 , wherein N-methyl-3-phenyl-3- hydroxypropylamine is reacted with 2-fluorotoluene and the solvent comprises hexamethylphosphorous triamide, further comprising the step of resolving an enantiomer of the 3-aryloxy-3-arylpropylamine.

11. The process according to claim 10, wherein the enantiomer is (-)-Λ/-methyl- 3-phenyl-3-(o-tolyloxy)-propyIamine.