Improved Process for Pure Duloxetine Hydrochloride

Priority Claim
This application claims the priority of our earlier application No: 30/CHE/2006, filed on 6th January 2006.
Field of Invention
The present invention relates to an improved process for the preparation of pure Duloxetine hydrochloride substantially free of (+)-N-methyl-3-(l-napthalenyIoxy)-3(3-thineyl) propanamine impurity. Duloxetine hydrochloride is chemically known as (+)-N-methyI-3-(I-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride compound of formula-1 represented as follows

Duloxetine and related class of compounds like fluoxetine, tomoxetine etc., are important for treating psychiatric disorders. Fluoxetine is selective inhibitor of serotonin in serotonergic neurons; tomoxetine and nisoxetine are selective inhibitors of norepinephrine in noradrenergic neurons while duloxetine is a dual inhibitor of serotonin and norepinephrine reuptake and thus have a better pharmacological profile as an antidepressant drug.
Serotonin and norepinephrine neuro transmitters are intimately involved in a number of physiological and behavioral processes, suggesting that duloxetine (ability to produce robust increase of extra cellular serotonin and norepinephrine levels) is not only a highly efficient antidepressant agent for treating psychiatric disorders but also can be used for treating other symptoms like alcoholism, urinary incontinence, fatigue, stroke, intestinal cystitis, obsessive compulsive disorder, panic disorder, hyperactivity disorder, sleep disorder, sexual dysfunction etc. It is commercially available as CYMBALTA.
Background of the Invention:
Duloxetine, as well as the process for its preparation is disclosed in few available literatures such as U.S. patent No. 5023269, US 5362886, E.P. patent No. 457559 etc.

Like any chemical compound, duloxetine hydrochloride can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in duloxetine hydrochloride or any active pharmaceutical ingredient are undesirable, and in extreme cases, might even be harmful to a patient being treating with a dosage form of the active pharmaceutical ingredient in which a sufficient amount of impurities is present. Furthermore, the undesired enantiomeric impurities reduce the sufficient level of active pharmaceutical ingredient present in the pharmaceutical composition.
It is also known in the art that impurities in an active pharmaceutical ingredient may arise from degradation of the active pharmaceutical ingredient itself, which is related to the stability of the pure active pharmaceutical ingredient during storage, and the manufacturing process, including chemical synthesis. Process impurities which include unreacted starting materials, chemical derivatives of impurities contained in the starting materials, synthetic by-products, and degradation products.
In addition to stability, which is factor in the shelf life of the active pharmaceutical ingredient, the purity of the active pharmaceutical ingredient in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the ICH Q7A guidance for active pharmaceutical ingredient manufacturers requires that process impurities be maintained below set limits by specifying the quality raw materials, controlling process parameters, such as temperature, pressure, time and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during the preparation process, it should be analyzed for the purity by HPLC or TLC analysis to determine if it is desirable for continue the process or need to purified further to continue the process especially for use

in a pharmaceutical product. The active pharmaceutical ingredient need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainably. Rather the purity standards are set with the intension of ensuring that an active pharmaceutical ingredient is as free of impurities as possible, and thus, is as safe as possible for clinical use.
Duloxetine hydrochloride prepared as per the prior art process containing the isomer impurity (+)-N-methyl-3(l-naphtalenyloxy)-3-(3-thienyl) propanamine, referred to herein as “DU-I”, and represented as follows

The impurity “DIM” is formed due to the carry over of isomer, i.e., 3-acetyl thiophene compound of formula 21 as an impurity present in 2-acetyl thiophene compound of formula 2, the formation of isomer “DLM” during the preparation of duloxetine hydrochloride schematically represented in scheme-1, in which the Formula-41. 51, 61 and 81 represents the corresponding derivatives of isomer impurity formation in each stage.
The international patent publication WO 2006/099433 disclosed the process for the purification of duloxetine hydrochloride to reduce the (+)-N-methyl-3-( 1 -napthalenyloxy)-3(3-thineyl) propanamine isomer impurity i.e. UDU-F\ The said patent disclosed the process for the purification of Duloxetine hydrochloride to reduce the level of said isomer content. Generally purification at the final stage of any compound leads to loss of material which increases cost of production which is not recommended for commercial scale-up.


We. the present inventors found the origin of isomer impurity formation “DU-I” (represented in scheme-1), which is due to the 3-acetyl impurity present in the starting material 2-acetyI compound of formula-2.
When we were working to eliminate the “DU-l” impurity in the origin itself, surprisingly found that by employing purification in the first stage, i.e. purification of compound of formula-4, then usage of this pure intermediate in the preparation of Duloxetine hydrochloride gives high pure Duloxetine hydrochloride which is free from the said isomer impurity. By employing purification at the initial stages instead of final stage avoids the usage of high inputs of raw materials, which avoids increase in cost of production.
The main objective of the present invention is to provide an improved process for the preparation of high pure Duloxetine hydrochloride substantially free of (+)-N-methyi-3-( 1 -naptha!enyloxy)-3(3-thineyl) propanamine impurityO’DLM”).
Brief description of the invention
Accordingly the present invention provides an improved process for the preparation of high pure Duloxetine hydrochloride substantially free of (+)-N-methyl-3-(I -napthalenyloxy)-3(3-thineyl) propanamine impurity, Duloxetine hydrochloride

chemically known as (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine hydrochloride compound of formula-1 represented as below

The present invention comprises of the following steps
a) Reacting l-(thiophen-2-yI)ethanone compound of formuIa-2 with dimethylamine hydrochloride compound of formula-3 in presence of paraformaldehyde in a suitable solvent gives the compound of formula-4,
b) Purifying the compound of formula-4 in a suitable solvents and/or mixtures thereof to give the pure compound of formula-4 ,
c) Reducing the compound of formula-4 with an alkali metal borohydrides in a suitable solvent gives the compound of formula-5,
d) Resolving the compound of formula-5 with chiral acid in a suitable solvent and further treating the obtained compound with weak inorganic base in a suitable chloro solvents or ester solvents gives the compound of formula-6,
e) Reacting the compound of formula-6 with the compound of formula-7 in presence of an alkali base and in a suitable polar aprotic solvent, which in situ demethylation and converting into oxalate salt of compound of formula-8,
f) Converting the Duloxetine oxalate salt into its hydrochloride salt compound of formula-1 using suitable alcoholic HC1 or ester HC1 in a suitable solvent like alcoholic solvents or ester solvents.

? Removing of (+)-N-methyl-3-(l-napthalenyIoxy)-3(3-thineyl) propanamine impurity by purification at the initial stage of the process avoids the usage of high inputs of raw materials which avoids increase in cost of production.
? Cost effective, eco-friendly process and commercially scalable process
Detailed description of the Invention
The present invention provides an improved process for the preparation of high pure Duloxetine hydrochloride substantially free of (+)-N-methyi-3-(l-napthalenyIoxy)-3(3-thineyl) propanamine impurity, Duloxetine hydrochloride chemically known as (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine hydrochloride compound of formula-1 represented as below

The present invention comprises of the following steps
a) Reacting l-(thiophen-2-yl)ethanone compound of formula-2

with dimethylamine hydrochloride compound of formula-3 in presence of paraformaldehyde in a suitable solvent selected from alcohol, preferably isopropyl alcohol gives the compound of formula-4,


b) Purifying the compound of formula-4 to eliminate corresponding derivative of “DU-I” impurity, in a suitable solvent selected from alcohols like methanol, ethanol, isopropyl alcohol, with or without combination of water and/or ketones like acetone, methylisobutyl ketone with or without combination of water and/or mixtures thereof, preferably mixture of isopropyl alcohol and water to get the high pure compound of formula-4,
c) Reducing the compound of formula-4 with an alkali metal borohydrides like sodium borohydride, potassium borohydride preferably sodium borohydride in a suitable solvent selected from C1-C4 alcoholic solvents, preferably methanol gives the compound of formula-5,

d) Resolving the compound of formula-5 with chiral acid like mandelic acid, tartaric acid, di-p-tolyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid, preferably mandelic acid in a suitable solvent selected from ester solvents like ethyl acetate, propyiacetate, preferably ethyl acetate and further treating the obtained compound with weak inorganic base like sodium carbonate, sodium bicarbonate in suitable chloro solvents or ester solvents, preferably chloro solvents more preferably methylene chloride gives the compound of formula-6,

e) Reacting the compound of formula-6 with the compound of formula-7


in presence of an alkali base like sodium hydroxide, potassium hydroxide preferably sodium hydroxide and in a suitable polar aprotic solvent like dimethylsulfoxide, dimethylformamide, which in situ demethylation and converting into oxalate salt compound of formula-8,

g) Converting the Duloxetine oxalate salt compound of formula-8 into its hydrochloride salt compound of formula-1 using ethylacetate HCI, methanolic HC1, isopropyl alcohol HCI, preferably ethylacetate HCI in a suitable solvent like alcoholic solvents or ester solvents, preferably ester solvents more preferably ethyl acetate.
Related substances by HPLC of Duloxetine hydrochloride is carried out using a liquid chromatograph is equipped with variable wavelength UV-Detector, symmetry C8, 250x4.6 mm, 5jxm or equivalent column, 1.0 ml/min flow rate at 215 nm, ambient temperature, and the buffer is used 1.38 grams of sodium dihydrogen phosphate monohydrate in 300 ml water, dilute with water to 1000 ml, add 1.0 ml of TEA and pH is adjusted to 2.5 with phosphoric acid. Mobile phase A (degassed phosphate buffer), Mobile phase B (Acetonitrile: water in the ratio of 90:10 V/V)
R-Isomer content by Chiral HPLC is carried out using a liquid chromatograph is equipped with variable wavelength UV-Detector, Chiralcel OJ-H, 250X4.6 mm column. 1.0 ml flow rate at 230 nm and 40°C temperature, mobile phase is a mixture of 90 volumes of n-Hexane, 10 volumes of ethanol, and 0.1 volumes of diethyl amine.

The present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples
Example-l:
Preparation of 3-(dimethyIamino)-l-(thiophen-2-yl) propan-1-one hydrochloride
Added 3.8 Kgs. of hydrochloric acid to a solution of 100 Kgs. of 2-acetyl thiophene, 81.5 Kgs. of dimethylamine hydrochloride, 35.4 Kgs. parafomaldehyde in 250 liters of isopropyl alcohol. Heated the reaction mixture to 75-80°C. Stirred the reaction mixture for 6 hours at 75-80°C. Cooled the reaction mixture to 0-5°C. Stirred the reaction mixture for 2 hours at 0-5°C. Filtered the solid and washed with isopropyl alcohol. M.R: 174-176°C
Purification: Added 1500 liters of isopropyl alcohol and 45 liters of water to the above obtained wet material. Stirred the reaction mixture for 15 minutes at 25-30°C. Heated the reaction mixture to reflux. Stirred the reaction mixture for 2 hours at reflux. Cooled the reaction mixture slowly to 25-30°C. Stirred the reaction mixture for 4 hours at 25-30°C. Filtered the solid and washed with isopropyl alcohol. Dried the material at 25-30°C for 2 hours followed by drying at 50-55°C for 6 hours to get the pure title compound. Yield 144 Kgs. M.R: 185-190°C.
Example-2:
Preparation of 3-(dimethylamino)-l-(thiophen-2-yl) propan-1-one hydrochloride
Added 3.8 Kgs. of hydrochloric acid to a solution of 100 Kgs. of 2-acetyl thiophene, 81.5 Kgs. of dimethylamine hydrochloride, 35.4 Kgs. parafomaldehyde in 250 liters of isopropyl alcohol. Heated the reaction mixture to 75-80°C. Stirred the reaction mixture for 6 hours at 75-80°C. Cooled the reaction mixture to 0-5°C. Stirred the reaction mixture for 3 hours at 0-5°C. Filtered the solid and washed with isopropyl alcohol. M.R: 174-176°C

Purification: Added 1500 liters of acetone and 45 liters of water to the above obtained wet material. Stirred the reaction mixture for 15 minutes at 25-30°C. Heated the reaction mixture to reflux. Stirred the reaction mixture for 2 hours at reflux. Cooled the reaction mixture slowly to 25-30°C. Stirred the reaction mixture for 4 hours at 25-30°C. Filtered the solid and washed with acetone. Dried the material at 25-30°C for 2 hours followed by drying at50-55°C for 6 hours to get the pure title compound. Yield 142 Kgs. MR: 185-190°C.
Example-3:
Preparation of 3-(dimethyIamino)-l-(thiophen-2-yl) propan-1-ol
Added 50 liters of 20% sodium hydroxide solution to a cooled solution of 100 Kgs. of 3-(dimethylamino)-l-(thiophen-2-yl) propan-1-one hydrochloride, 100 liters of methanol and 25 liters of water at 0-5°C. Added a solution of 10 Kgs. of sodium borohydride in 50 liters of 20% sodium hydroxide to the above reaction mixture slowly at 0-5°C in 5 hours. Allowed the reaction mixture temperature to 25-30°C. Stirred the reaction mixture for 6 hours at 25-30°C. Extracted the reaction mixture with methylene chloride. Separated the organic and aqueous layers. Extracted the aqueous layer with methylene chloride. Washed the organic layer with 10% brine solution. Distilled the solvent completely under reduced pressure at below 40°C. Added 25 liters of hexanes to the above reaction mixture. Distilled the solvent completely under reduced pressure at below 40°C. Added 100 liters of hexanes to the above reaction mixture. Heated the reaction mixture to reflux. Stirred the reaction mixture for 60 minutes. Cooled the reaction mixture to 0-5°C and stirred the reaction mixture for 3 hours. Filtered the precipitated solid and washed with chilled hexanes. Dried the material at 50-55°C for 6 hours to get the title compound. Yield 75 Kgs. MR: 70-80°C.

ExampIe-4:
Preparation of (S) 3-(dimethylamino)-l-(thiophen-2-yl) propan-l-ol Mandelate salt
Added 35 Kgs. of L(+)-mandelic acid to a solution of 70 Kgs. of 3-(dimethylamino)-I-(thiophen-2-yl) propan-l-ol in 700 liters of ethyl acetate at 25-30°C. Stirred the reaction mixture for 90 minutes at 25-35°C. Heated the reaction mixture to 70-75°C Stirred the reaction mixture for 3 hours at 70-75°C. Cooled the reaction mixture to 25-35°C. Stirred the reaction mixture for 10 hours at 25-35°C. Filtered the precipitated solid and washed with ethyl acetate. Added 350 liters of ethyl acetate to the obtained solid. Heated the reaction mixture to 60-65°C. Stirred the reaction mixture for 60 minutes. Cooled the reaction mixture to 25-35°C. Stirred the reaction mixture for 90 minutes. Filtered the precipitated solid and washed with ethyl acetate. Dried the material at 60-65°C for 5 hours to get the title compound. Yield: 62 Kgs. MR: I 13-1 15°C
Example-5:
Preparation of (S) 3-(dimethylamino)-l-(thiophen-2-yl) propan-l-ol
A solution of 75 Kgs. of mandelate salt of (S)-3-(dimethylamino)-l-(thiophen-2-yl) propan-l-ol, 150 liters of water and 450 liters of methylene chloride is cooled to 0-5°C. Adjusted the pH of the reaction mixture to 9.8 with 10% sodium carbonate solution at 0-5°C. Stirred the reaction mixture for 20 minutes at 0-5°C. Separated the organic and aqueous layers. Extracted the aqueous layer with methylene chloride. Washed the organic layer twice with 10% brine solution. Distilled the solvent completely under reduced pressure at below 35°C. Added 19 liters of cyclohexane to the above reaction mixture. Distilled the solvent completely under reduced pressure at below 35°C. Added 150 liters of cyclohexane to the above reaction mixture. Heated the reaction mixture to 40-45°C and stirred for 60 minutes. Cooled the reaction mixture to 0-5°C. Filtered the precipitated solid and washed with cyclohexane. Dried the material at 40-45°C for 6 hours to get the title compound. Yield: 40 Kgs. MR: 70-80°C

Example-6:
Preparation of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyI) propanamine
oxalate.
Heated a solution of 125 liters of dimethyl sulfoxide and 27 Kgs. of sodium hydroxide to 50-55°C and Stirred for 45 minutes. Added 25 Kgs. of (S)-3-(dimethylamino)-l-(thiophen-2-yl) propan-I-ol, 2.5 Kgs. of tertiarybutylammonium bromide and 30 Kgs. of 1-fluronapthalene in 25 liters of dimethyl sulfoxide to the above reaction mixture at 50-55°C. Stirred the reaction mixture for 50 hours at 60-65°C. Cooled the reaction mixture to 15-20°C. Quenched the reaction mixture with water at 15-20°C. Extracted the reaction mixture with toluene. Separated the organic and aqueous layer. Washed the organic layer twice with water. Dried the organic layer with sodium sulphate. Added 27.5 Kgs. of diisopropylethylamine to the above reaction mixture at 25-35°C. Heated the reaction mixture to 43-48°C. Added 36 Kgs. of phenylchloroformate slowly to the reaction mixture at 43-45°C. Stirred the reaction mixture for 4 hours at 43-48°C. Cooled the reaction mixture to 20-25°C. Quenched the reaction mixture with water. Separated the organic and aqueous layers. Organic layer washed with acetic acid solution followed by oxalic acid and sodium bicarbonate solution. Distilled the solvent completely under reduced pressure at below 45°C. Added 500 liters of dimethylsulfoxide to the above obtained crude and heated to 40-45°C. Added sodium hydroxide solution (25 Kgs. in 100 liters of water) to the above reaction mixture at 40-45°C for 3 hours. Further heated the reaction mixture to 50-55°C. Stirred the reaction mixture for 30 hours at 50-55°C. Cooled the reaction mixture to 15-20°C and quenched the reaction mixture with water. Extracted the reaction mixture thrice with toluene and washed the organic layer twice with water. Added 17.5 Kgs. of oxalic acid to the above organic layer at 25-30°C. Stirred the reaction mixture for 4 hours at 25-30°C. Filtered the precipitated solid and washed with toluene. Dried the material at 40-45°C to get the title compound. Yield: 160 Kgs. MR: 126-130°C.

Example-7:
Preparation of (S)-(+)-N-methyI-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine
hydrochloride.
A solution of 100 Kgs. of (S)-(+)-N-methyl-3-(l-naphthalenyioxy)-3-(2-thienyl) propanamine oxalate, 400 liters of water and 400 liters of methylene chloride is cooled to 0-5°C. Adjusted the pH of the reaction mixture 8.8 with aqueous ammonia. Stirred the reaction mixture for 15 minutes. Separated the organic layer and washed the organic phase with water. Distilled the solvent completely under reduced pressure at below 40°C. Added 400 liters of ethyl acetate to the above obtained crude. Cooled the reaction mixture to 0-5°C. Adjusted the pH of the reaction mixture to 3.8 with ethyl acetate HC1. Stirred the reaction mixture for 2 hours. Filtered the precipitated solid and washed with ethyl acetate. Dried the material at 45-50°C to get the title compound. Yield: 45 Kgs. MR: 164-166°C
Chiral Purity: 99.80%, 0.07% (R- isomer); HPLC Purity: 99.80%, 0.05%(DU-I impurity)

We Claims:
1. An improved process for the preparation of Duloxetine hydrochloride compound of formula-1 substantially free of (+)-N-methyl-3-(l-napthalenyloxy)-3(3-thineyl) propanamine impurity,

Which comprises of the following steps
a) Reacting l-(thiophen-2-yl)ethanone compound of formula-2

with dimethylamine hydrochloride compound of formula-3 in presence of paraformaldehyde in a suitable solvent selected from alcohol, preferably isopropyl alcohol gives the compound of formula-4,

b) Purifying the compound of formula-4 to eliminate corresponding derivative of ‘‘DU-r impurity, in a suitable solvent selected from alcohols like methanol, ethanol, isopropyl alcohol, with or without combination of water and/or ketones like acetone, methylisobutyl ketone with or without combination of water and/or mixtures thereof, preferably mixture of isopropyl alcohol and water to get the high pure compound of formula-4,

c) Reducing the compound of formula-4 with an alkali metal borohydrides like sodium borohydride, potassium borohydride preferably sodium borohydride in a suitable solvent selected from CrC4 alcoholic solvents, preferably methanol gives the compound of formula-5,

d) Resolving the compound of formula-5 with chirai acid like mandelic acid, tartaric acid, di-p-tolyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid, preferably mandelic acid in a suitable solvent selected from ester solvents like ethyl acetate, propylacetate. preferably ethyl acetate and further treating the obtained compound with weak inorganic base like sodium carbonate, sodium bicarbonate in suitable chloro solvents or ester solvents, preferably chloro solvents more preferably methylene chloride gives the compound of formula-6,

e) Reacting the compound of formula-6 with the compound of formula-7

in presence of an alkali base like sodium hydroxide, potassium hydroxide preferably sodium hydroxide and in a suitable polar aprotic solvent like dimethylsulfoxide. dirnethylformamide, which in situ demethylation and converting into oxalate salt compound of formula-8,


t) Converting the Duloxetine oxalate salt compound of formuIa-8 into its hydrochloride salt compound of formula-1 using ethylacetate HCI, methanolic HCI, isopropyl alcohol HCI, preferably ethylacetate HCI in a suitable solvent like alcoholic solvents or ester solvents, preferably ester solvents more preferably ethyl acetate.
2. Process for the purification of 3-(dimethyIamino)-l-(thiophen-2-yl) propan-1-ol compound of formula-4, which comprises of the following
a) Heating a compound of formula-4 in a suitable solvent selected from alcohols like methanol, ethanol, isopropyl alcohol, with or without combination of water and/or ketones like acetone, methylisobutyl ketone with or without combination of water and/or mixtures thereof to reflux,
b) Cooling the reaction mixture,
c) Isolated pure compound of formula-4 by filtration.

3. Process according to claim 2 a), wherein the solvent used is selected from alcohols with or without combination of water and/or ketones with or without combination of water.
4. Process according to claim 2 a) wherein the solvent used is selected from alcohols like methanol, ethanol, isopropyl alcohol, with or without combination of water and/or ketones like acetone, methylisobutyl ketone with or without combination of water.
5. Process according to claim 2 a) wherein the solvent used is selected from ketones like acetone, methylisobutyl ketone with or without combination of water.

6. Process according to claim 2 a) wherein the solvent used is mixture of solvents isopropyl alcohol and water.
7. Process according to claim 2 a) wherein the solvent used is mixture of solvents acetone and water.