FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine oxalate of Formula I.

The present invention further relates to an improved process for the preparation an acid addition salt of N,N-dimethyl-3-chloropropylamine of formula (II).

BACKGROUND OF THE INVENTION

Atomoxetine hydrochloride is chemically known as (-)-N-methyl-3-phenyl-3-(o-tolyloxy)propylamine hydrochloride. Atomoxetine is a selective norepinephrine reuptake inhibitor. A norepinephrine reuptake inhibitor (NRI, NERI) is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore an increase in adrenergic neurotransmission. Atomoxetine hydrochloride is used for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) and is marketed as the free acid under the trade name STRATTERA®. US Patent No. 4,314,081 disclosed racemic Atomoxetine and its pharmaceutically acceptable salts.

us 081 also discloses the process for the preparation of N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine oxalate (I) by reacting N,N-dimethyl-3-phenyl-3-hydroxypropylamine (IV) with SOCI2 in the presence of HCl and chloroform to produce N,N-dimethyl-3-chloropropylamine hydrochloride (Ila), which is condensed with o-cresol in the presence of methanol and sodium hydroxide to produce N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine (la), followed by treatment with oxalic acid in the presence of ethyl acetate to produce N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine oxalate (I). The process is as shown in Scheme-I below:

The major disadvantage with the above process is the use of class-I solvent like chloroform and excess use of SOCI2, which is environmentally hazardous and unwanted impurities are formed and that leads to lower yield.

EP 0 052 492 specifically disclosed Atomoxetine and its pharmaceutically acceptable salts.
EP '492, discloses the process for the preparation of Atomoxetine hydrochloride by reacting N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine (la) with phenyl
chloroformate in the presence of toluene to form carbamate intermediate of formula (V) and hydrolyzing the intermediate with sodium hydroxide in the presence of propylene glycol to form racemic Atomoxetine (VI), which is then resolved using (S)-(+)-mandelic acid to produce Atomoxetine (Ilia), followed by treating with hydrogen chloride gas to produce Atomoxetine hydrochloride (III). The process is as shown in Scheme-II below:

The present invention is directed towards a process for the preparation of N,N-dimethyl-3-(o-toIyloxy)-3-phenylpropylamine oxalate (I) with high purity and good yield by treating N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine (la) with oxalic acid in an alcoholic solvent.

The present invention further directed to the use of aromatic hydrocarbon solvent in the reaction of N,N-dimethyl-3-phenyl-3-hydroxypropylamine (IV) with SOCI2 to produce an acid addition salt of N,N-dimethyl-3-chloropropylamine (II) with good yield and high purity.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and cost-effective process for the preparation of N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine oxalate (I) and an acid addition salt of N,N-dimethyl-3-chloropropylamine (II) of high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the preparation an acid addition sah of N,N-dimethyl-3-chloropropylamine of formula (II),

wherein, the acid is selected from hydrochloric acid, hydrobromic acid, methane sulfonic acid, para toluene sulfonic acid, which comprises:

(i) reacting N,N-dimethyl-3 -phenyl-3 -hydroxypropylamine of Formula (IV),

with a chlorinating agent in the presence of an acid in an aromatic hydrocarbon solvent,

(ii) isolating the compound of formula (II).

In another embodiment, the present invention provides a process for the preparation of N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine oxalate (I).

which comprises; (i) condensing N,N-dimethyl-3-chloropropylamine of formula (II) or its salt with o-cresol in the presence of a base in a solvent to produce N,N-dimethyl-3-(o-
tolyloxy)-3 -phenylpropylamine (la), (ii) treating the compound of formula (la) of step-(i) with oxalic acid in an alcoholic solvent to produce N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine oxalate (I), (iii) isolating compound of formula (I).

In another embodiment, the present invention provides the use of N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine oxalate (I) prepared by the present invention in the preparation of Atomoxetine hydrochloride of formula (III).
In another embodiment, the present invention provides the use of N,N-dimethyl-3-chloropropylamine of formula (II) prepared by the present invention in the preparation of Atomoxetine hydrochloride of formula (III).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of N,N-dimethyl-3-chloropropylamine of formula (II).

The process comprises, reacting N,N-dimethyl-3-phenyl-3-hydroxypropylamine of Formula (IV) with a chlorinating agent selected from thionyl chloride, phosphorus oxy chloride and phosphorus trichloride in the presence of an acid selected from hydrochloric acid, hydrobromic acid, methane sulfonic acid, para toluene sulfonic acid in an aromatic hydrocarbon solvent selected from toluene, o-xylene, w-xylene, p-xylene, n-hexane, cyclohexane, n-heptane, n-octane to produce the acid addition salt of N,N-dimethyl-3-chloropropylamine of formula (II).

The reaction is carried out at a temperature of about 0 to 50°C for a period of about 1 to 10 hrs, preferably 3 to 4 hrs. The reaction is carried out by adding chlorinating agent in portion wise to the mixture of N,N-dimethyl-3-phenyl-3-hydroxypropylamine of Formula (IV) in a solvent and acid and slowly raise the temperature of the reaction after addition of the chlorinating agent. The reaction is optionally carried out by addition of second solvent selected from polar aprotic solvent such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), A'iA'^-dimethylacetamide (DMA), A-methyl-2-pyrrolidone (NMT) before addition of chlorinating agent.

After completion of the reaction, as ascertained by the known techniques such as HPLC, solvent is removed from the reaction mass under reduced pressure, followed by stirring the reaction mass, filtered and dried to produce acid addition salt of N,N-dimethyl-3-chloropropylamine of formula (II).

In another embodiment, the present invention also relates to the use of acid addition salt of N,N-dimethyl-3-chloropropylamine of formula (II), prepared by the present invention in the preparation of Atomoxetine hydrochloride (III) by the process disclosed in US 4,314,081 and EP 0 052 492 Bl.

In another embodiment, the present invention relates to a process for the preparation of N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine oxalate (I).

The process comprises, condensing N,N-dimethyl-3-chloropropylamine or salt of formula (II) with o-cresol in the presence of a base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate in a solvent selected from Ci-C6-alkanols such as methanol, ethanol, isopropanol, butanol and mixtures there of, to produce N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine (la).

The reaction is carried out at a temperature of about 30 to 100°C for a period of about 1 to 10 hrs, preferably 3 to 4 hrs. The reaction is carried out by addition of base in portion wise or in lots to the reaction mass containing compound (II), and then heated the resulting reaction mass to 30 to 100°C.

After completion of the reaction, as ascertained by the known techniques such as HPLC, the solvent is distilled off from the reaction mass under reduced pressure. The residue containing compound (la) is extracted with a solvent selected from toluene, ethyl acetate, methylene chloride, xylenes, ethers, followed by treating the organic layer with aqueous base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the separated organic layer is concentrated to oily residual mass containing N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine (la).

The reaction is carried out at a temperature of about 30 to 100°C for a period of about 1 to 3 hrs, preferably 1 to 2 hrs. The reaction is carried out by addition of N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine (la) to solution containing oxalic acid in a solvent selected from Ci-Ce alkanol such as methanol, ethanol, isopropanol, butanol and lower alkyl ester of acetic acid and propionic acid or mixtures there of, then stirred the reaction mass for 1 to 2 hours, followed by cooling the reaction mass to 20 to 30°C and filtered, dried to produce pure N,N-dimethyl-3-(o-tolyIoxy)-3-phenylpropylamine oxalate (1).

In another embodiment, the present invention also relates to the use of N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine oxalate (I) prepared by the present invention in the preparation of Atomoxetine hydrochloride (III) by the process disclosed in EP 0 052 492 Bl.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES

EXAMPLE1

Step-(i): Preparation of N,N-dimethyl-3-phenyl-3-chloro propylamine hydrochloride (Ila):

Method-1;

N,N-Dimethyl-3-phenyl-3-hydroxypropylamine (50 g) was dissolved in toluene (500 ml) at 25±2°C, and the resulting solution was cooled to 0-5°C. Dry hydrogen chloride gas (10.2 g) was purged through the reaction solution over a period of 45-60 min at 0-5°C. Thionyl chloride (39.88 g) was added at 0-5°C over a period of 10-15 min, the temperature was slowly raised to 25±2°C and maintained for 2h at the same temperature. Completion of reaction was checked with HPLC. Toluene (75 ml) was distilled under reduced pressure at 25±2°C, the resulting reaction mass was cooled to 0-5°C and stirred for 30±5 min at 0-5°C. The product was filtered and washed with toluene (50 ml, 0-5°C). Finally product was slurry washed with acetone (3 x 75 ml), suck dried and dried under reduced pressure at 60-65°C. Yield = 57.7 g Chromatographic purity (by HPLC): 98.26%

Method-2:

N,N-Dimethyl-3-phenyl-3-hydroxypropylamine (100 g) was dissolved in toluene (1000 ml) at 25-30°C and the resulting solution was cooled to 0-5°C. Dry hydrogen chloride gas (20.4 g) was passed through the reaction at 0-5°C. N,N-Dimethylformamide (2 ml) was added at 0-5°C and thionyl chloride (83.1 g) was added slowly over a period of 10-15 min at 0-5°C. The reaction mixture was stirred for 1 h at 6±1°C and the temperature was slowly raised to 25±2°C over a period of 30-40 min. Nitrogen gas was purged through the reaction mass at 25±2°C for 30±5 min. Toluene (150 ml) was distilled under reduced pressure at 25-30°C, then cooled to 0-5°C and stirred for 30±5 min. The product was filtered and washed with toluene (100 ml, 0-5°C). Finally slurry washed with acetone (3 x 150 ml), suck dried and dried under reduced pressure at 60-65°C. Yield =117 g Chromatographic purity (by HPLC): 98.86%

Method-3;

N,N-Dimethyl-3-phenyl-3-hydroxypropylamine (100 g) was dissolved in toluene (1000 ml) at 25-30°C, and the resulting solution was cooled to 0-5°C. Dry hydrogen chloride gas (23.85 g) was passed through the reaction mass at 0-5°C over a period of 1 h. DMF (2 ml) was added to the reaction mass at 0-5°C, then, thionyl chloride (83.1 g) was added at 0-5°C over a period of 15-20 min and stirred for 1 h at 5°C. The sample was analyzed by HPLC. The temperature was slowly raised to 25±2°C and nitrogen passed through the reaction mass over a period of 30-60 min at 25±2°C. Toluene (-130 ml) was distilled under reduced pressure at 25-30°C. The product slurry was cooled to 0-5°C and stirred for 30±5 min at 0-5°C. The product was filtered and washed with toluene (100 ml, 0-5°C). Finally slurry washed with acetone (3 x 200 ml), dried under suction for 10 min and dried under reduced pressure at 60-65°C. Yield =117 g Chromatographic purity (by HPLC): 99%

Step-(ii): Preparation of N,N-diniethyl-3-(o-tolyIoxy)-3-phenylpropylainine oxalate
(I)

Method-1;

o-Cresol (48.44 g) was diluted with isopropyl alcohol (250 ml) at 25-30°C, followed by sodium hydroxide flakes (17.90 g) were added and stirred for 10-15 min. N,N-dimethyl-3-phenyl-3-chloropropylamine hydrochloride (50 g) was added in a single lot at 30-35°C, and the reaction mixture was slowly heated to 60-65°C, stirred for 1 h and the reaction progress was monitored by HPLC. Isopropyl alcohol was completely distilled under reduced pressure at 45-50°C. Toluene (500 ml) was added followed by DM water (50 ml) and 20% w/w aqueous sodium hydroxide (50 ml) at 25-30°C, then vigorously stirred for 10±1 min at 25-30°C and the organic layer was separated. The organic layer was washed with 20% w/w aqueous sodium hydroxide solution (2 x 50 ml) at 25±2°C. Finally the organic layer was washed with DM water (3 x 100 ml) at 25±2°C. Organic layer was completely concentrated under reduced pressure at 45-50°C to produce N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine as an oily mass.

Weight = 58 g; Chromatographic purity (by HPLC): 92.87% Oxalic acid dihydrate (12.63 g) was dissolved in isopropyl alcohol (162 ml) at 40-45°C and the above prepared N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine (28.5 g) in isopropyl alcohol (27 ml) was added over a period of 20-30 min at 40-50°C, stirred for 10±1 min at 45-50°C and cooled to 20-25°C. The product slurry was stirred for 1 h at 20-25°C, filtered and washed with isopropyl alcohol (40.5 ml). The product was suck dried and dried under reduced pressure at 60-65 °C. Yield = 30.7 g Chromatographic purity (by HPLC): 98.07%

Method-2;

o-Cresol (48.44 g) was diluted with isopropyl alcohol (250 ml) at 25-30°C , followed by sodium hydroxide flakes (17.95 g) were added in one lot, and stirred for 10-15 min at 28-33°C. N,N-dimethyl-3-phenyl-3-chloropropylamine hydrochloride (50 g) was added in a single lot at 30-35°C, then heated the reaction slurry to 50-55°C, stirred for 2 h at 50-55°C and monitor the reaction progress by HPLC. Isopropyl alcohol was completely distilled off under reduced pressure at 40-45°C. Toluene (500 ml), DM water (50 ml) and 20% w/w aqueous sodium hydroxide solution (50 ml) were added at 25-30°C and vigorously stirred for 10 min. The toluene layer was separated and washed with 20% w/w aqueous sodium hydroxide solution (2 x 50 ml) followed by DM water (3 x 100 ml) successively at 25±2°C. The toluene layer was concentrated to complete dryness under reduced pressure at 50-55°C to produce N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine as an oily mass. Weight = 48.5 g; Chromatographic purity: 94.81%.

Oxalic acid dihydrate (22.01 g) was dissolved in isopropyl alcohol (282 ml) at 40-45°C and above prepared N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine (47 g) in isopropyl alcohol (47 ml) was added over a period of 25-35 min at 40-50°C. The product was crystallized out and stirred the product slurry for 10±1 min at 45-50°C. The product slurry was cooled to 20-25°C and maintained for 1 h at 20-25°C. The product was filtered and washed it with isopropyl alcohol (70.5 ml, 20-25°C), followed by suck dried and dried the product under reduced pressure at 60-65°C.

Yield = 56.2 g
Chromatographic Purity (by HPLC): 98.75%

We Claim

1. A process for the preparation of an acid addition salt of N,N-dimethyl-3-
chloropropylamine of formula (II),

wherein, the acid is selected from hydrochloric acid, hydrobromic acid, methane sulfonic acid, para toluene sulfonic acid, which comprises:
(i) reacting N,N-dimethyl-3-phenyl-3-hydroxypropylamine of Formula (IV),

with a chlorinating agent in the presence of an acid in an aromatic hydrocarbon solvent; (ii) isolating the compound of formula (II).

2. The process according to claim 1, wherein the chlorinating agent is selected from
thionyl chloride, phosphorus oxy chloride and phosphorus trichloride.

3. The process according to claim 1, wherein the aromatic hydrocarbon is selected from
toluene, o-xylene, m-xylene, p-xylene or mixtures thereof.

4. A process according to claim 1, further comprises conversion of compound of formula II to Atomoxetine and the pharmaceutically acceptable salts.

5. A process for the preparation of N,N-dimethyl-3-(o-tolyloxy)-3-phenylpropylamine
oxalate (I), which comprises:

(i) condensing N,N-dimethyl-3-chloropropylamine of formula (II) or its salt with o-cresol in the presence of a base in a solvent to produce N,N-dimethyl-3-(o-
tolyloxy)-3-phenylpropylamine(Ia);

(ii) treating the compound of formula (la) of step-(i) with oxalic acid in an alcoholic solvent to produce N,N-dimethyl-3-(o-tolyloxy)-3-
phenylpropylamine oxalate (I); (iii) isolating compound of formula (I).

6. The process according to claim 5, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or mixtures thereof

7. The process according to claim 5, wherein the alcoholic solvent is selected from Ci-Ce-alkanols such as methanol, ethanol, isopropanol, butanol or mixtures thereof