WO 2016147120, AZILSARTAN, NEW PATENT, SMILAX Laboratories Ltd

WO-2016147120, AZILSARTAN, NEW PATENT, SMILAX Laboratories Ltd

SMILAX LABORATORIES LIMITED [IN/IN]; Plot No. 12/A, Phase - III, I.D.A. Jeedimetla, Hyderabad 500 055 (IN).

The present invention relates to an improved process for the preparation of substantially pure compound of 2-Ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol- 3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan) of Formula I, with a reduced content of desethyl impurity less than 0.1% and an efficient, commercially viable process for the preparation of pure intermediates of Azilsartan.

KOTAGIRI, Vijaya Kumar; (IN).
YENUMULA, Raghavendra Rao; (IN).
BANDARI, Mohan; (IN).
SURYADEVARA, Murali Krishna; (IN)

(WO2016147120) AN IMPROVED PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE AZILSARTAN

Azilsartan (I) is an angiotensin receptor II antagonist used in the treatment of hypertension. Angiotensin II causes vasoconstriction via an angiotensin II receptor on the cell membrane and elevates blood pressure.

Azilsartan medoxomil i.e. (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid is developed by Takeda pharmaceuticals and is marketed under the trade name Edarbi. It was approved by USFDA on 25 Feb, 2011 and EMEA on 7 Dec 2011 for the treatment of high blood pressure in adults.

Azilsartan medoxomil and its salts thereof are imbibed with properties such as strong and long lasting angiotensin II antagonistic activity and hypotensive action which has an insulin sensitizing activity useful for the treatment of metabolic diseases such as diabetes and the like., and a useful agent for the prophylaxis or treatment of circulatory diseases such as hypertension, cardiac diseases, nephritis and stroke. Azilsartan medoxomil is the prodrug of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan).

Methods of preparing benzimidazole derivative useful as an angiotensin II receptor antagonist such as Azilsartan Medoxomil and salts thereof are disclosed by Takeda in US 5,243,054 (herein after referred as US '054 patent). The US'054 patent describes several synthetic routes for preparing Azilsartan. According to one of the synthetic process, the compound of formula II is reacted with hydroxylamine hydrochloride in a conventional organic solvent and sodium methoxide in methanol to give the amidoxime compound of formula III which on further reaction with ethyl chloroformate in presence of triethylamine base in refluxing xylene undergoes cyclization to provide a compound of formula IV. Azilsartan was prepared by hydrolysis of compound of formula IV in presence of lithium hydroxide by adjusting the pH with HC1. The process is as depicted below in Scheme A:

However, the amidoxime compound of formula III obtained by the above process contains about 50% of amide imputiy along with desired product, owing to the strong reaction conditions which impairs the quality and loss of yield. The pH adjustment with HC1 in the hydrolysis step of compound IV results in the formation of an undesired desethyl impurity of formula V due to acid sensitive nature of the ether linkage in the benzimidazole moiety of Azilsartan.

Formula V

According to another method disclosed in US'054 for the preparation of Azilsartan comprises by reacting ethoxycarboimidoyl biphenyl benzimidazole derivative of compound with ethyl chloroformate to give N-methoxycarbonyl ethoxycarboimidoyl biphenyl benzimidazole derivative, which is further converted to compound of formula IV and then to Azilsartan of formula I by hydrolysis.

According to one another embodiment method for the preparation of Azilsartan disclosed in US '054, cyanobiphenyl aminobenzoate derivative compound reacts with hydroxylamine hydrochloride in presence of triethylamine subsequently followed by addition of ethyl chlorocarbonate results in the formation of compound of formula IV which is further hydrolyzed to obtain Azilsartan of formula I.

J. Med. Chem. Vol. 39, No. 26, 5230-5237 (1996) describes the use of triethylamine as base during the conversion of compound of formula II to amidoxime compound of formula III and use of 2-ethylhexylchloroformate instead of ethylchloroformate as cyclizing agent.

Processes for the preparation of Azilsartan medoxomil and its potassium salt are described in US 7,157,584 which comprises reacting Azilsartan with 4-hydroxymethyl-5-methyl-l,3-dioxol-2-one in presence of dimethylacetamide, p-toluoyl sulfonylchloride, 4-dimethylaminopyridine and potassium carbonate.

PCT publication WO 2012/107814 discloses process for the preparation of Azilsartan or its esters or salts by reacting amidoxime compound of formula III with carbonyl source such as carbodiimides, dialkyl carbonate and phosgene equivalents in presence of a suitable base to obtain compound of formula IV which is further converted to Azilsartan and its pharmaceutically acceptable salts. The process for the preparation of Azilsartan is as depicted in Scheme B:

Scheme - B

This publication also discloses that use of a carbonyl source reduces the formation of the content of desethyl impurity during cyclization.

Polymorphs of Azilsartan and its salts are disclosed in WO 2013/044816 and WO 2013/186792.

All the above prior art methods for the preparation of Azilsartan have inherent disadvantages such as the usage of unsafe reagents, high boiling solvents, extreme reaction conditions invariably resulting in the formation of low pure intermediates as well as Azilsartan having a considerably higher content of desethyl impurity. Accordingly, there remains a need for the industrial preparation of substantially pure Azilsartan which is free of impurities with high yield.

Examples

Example-1: Preparation of Methyl-2-ethoxy-l-[[2'- ((hydroxycarbamimidoyl)biphenyl)-4-yl]methyl]-lH-benzimidazole-7-carboxylate (Formula-Ill):

To a stirred solution of DMSO (1500.0 mL), Hydroxylamine hydrochloride ( 126.7g 1.83mol) and Dipotassium hydrogen phosphate (634.9g 3.65mol) was added Methyl l-[[2'-cyanobiphenyl-4-yl]methyl]-2-ethoxybenzimidazole-7-carboxylate (lOO.Og 0.243mol) at 25-30°C. The reaction mass temperature was raised to 80-85°C and maintained for 30-40 hours. Reaction completion was monitored by TLC. Upon completion of reaction, reaction mass was cooled to 10- 15°C, and was poured into water (3000.0 mL), stirred for 45min at 20-25°C. and was filtered. The filtered wet solid was washed with water and dried at 65°C to get crude Methyl-2-ethoxy-l-[[(2'-(hydroxycarbarmrmdoyl)biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylate. The wet material was slurried in Acetone (optional) at reflux and filtered at room temperature to obtain pure compound.

Yield: 79.92 g, 74.0%; HPLC Purity: 97.78%; Desethyl impurity: 0.318%; Amide impurity: 1.42%.

Example-2: Preparation of Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (Formula-IV) :

To the pre cooled solution of Methylene dichloride (375.0 mL) and Methyl-2-ethoxy-1 -[[2' -((hydroxycarbamimidoyl)biphenyl)-4-yl] methyl]- lH-benzimidazole-7-carboxylate (75.0g, 0.168mol) was added ethyl chloroformate ( 18.3g 0.168mol)

followed by addition of triethylamine (18.75g 0.185mol). The reaction mass was maintained at 0-5 °C for about 1 hour. Upon completion of the reaction, reaction mass was poured into water (200.0 mL), organic layer was separated and washed with 5% NaHC03 solution (150.0 mL) and then with water (150.0 mL). The organic layer was dried over sodium sulfate and distilled to obtain the crude material (optionally be isolated using cyclohexane solvent). To this obtained crude material, ethyl acetate (750.0mL) and potassium carbonate (112.5g 0.814mol) were added and heated to reflux for 6 to 8 hours. The contents were cooled, filtered and wet solid was slurried in water. Wet material so obtained was slurried in ethyl acetate at reflux and filtered at room temperature and dried at 60-65°C to give Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

Yield: 64.27 g, 81.0 %; HPLC Purity: 99.80%; Desethyl impurity: 0.085%.

Example-3: Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (395.8 mL) and Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (25. Og) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (125.0mL). pH of the separated aqueous product layer was adjusted to 4.0 to 5.0 using dilute acetic acid at 0-5 °C. The obtained solid material was filtered and washed with water (lOO.OmL). This material was dried to obtain the title product.

Yield: 20.0 g, 82.47%; HPLC Purity : 99.80%; Desethyl impurity: 0.10%.

Example-4: Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (633.33 mL) and Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (40.0g) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (200.0mL). pH of the separated aqueous product layer was adjusted to 4.0 to 4.5 using acetic acid at 10-15°C. The obtained solid material was filtered and washed with water (lOO.OmL). This material was dried to obtain the title product.

Yield: 32.35 g, 83.37%; HPLC Purity: 99.45%; Desethyl impurity: 0.12%.

Example-5: Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (791.66 mL) and Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (50.0g) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (250.0mL). pH of the separated aqueous product layer was adjusted to 3.0 to 4.0 using citric acid at 10-15°C. The obtained solid material was filtered and washed with water (125.0mL). This material was dried to obtain the title product.

Yield: 37.0 g, 76.28%; HPLC Purity: 99.69%; Desethyl impurity: 0.083%.

Example-6: Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (395.83 mL) and Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (25. Og) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (lOO.OmL). pH of the separated aqueous product layer was adjusted to 3.0 to 4.0

using hydrochloric acid at 10-15°C. The obtained solid material was filtered and washed with water (72.5 mL). This material was dried to obtain the title product. Yield: 20.22 g, 83.37%; HPLC Purity: 99.45%; Desethyl impurity: 0.217%.

Example-7: Purification of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

Charged 2-Ethoxy- 1 - [[2' -(2,5-dihydro-5-oxo- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (lOO.Og), methanol (600.0ml) and methylene dichloride (600.0ml) and were stirred for 10 min at 25-30°C to get a clear solution. Above solution was treated with Activated carbon (lO.Og) and stirred for 10.0 min at 25-30°C. Reaction mixture was passed through a hyflow bed and washed with a mixture of (1: 1) ratio of 200.0ml methanol and methylene dichloride. The solvent mixture was distilled out at below 50°C till the solid formation was observed. Reaction mixture is stirred for 30.0min at 30°C, then the solid was filtered and washed with 200.0ml of methylene dichloride. To the obtained solid, methanol (450.0 ml) was charged at 25-30°C, heated to 45°C, stirred for 30 min at 45°C and then cooled to 30°C. After cooling, the solid was filtered and washed with methanol (90.0ml) which was further dried at 50-55°C for 12 hours.

Yield: 80.0 g, 80.0%; HPLC Purity: 99.96%; Desethyl impurity : 0.012%.

Smilax Managing Director, S. Murali Krishna received the award from Hon’ble Chief Minister of Andhra Pradesh Shri. N. Kiran Kumar Reddy.

//////////WO 2016147120, AZILSARTAN, NEW PATENT, SMILAX Laboratories Ltd

Duloxetine Hydrochloride, MSN, PATENT, US. 8362279

US. 8362279

http://www.google.co.in/patents/US8362279

Inventors	Manne Satyanarayana Reddy, Muppa Kishore Kumar, Srinivasan Thirumalai Rajan,Durgadas Shyla Prasad,
Original Assignee	Msn Laboratories Limited

Synthesis of duloxetine is described in detail in EP-A-273 658, EP-A-457 559 and EP-A-650965, starting from 2-acetylthiophene, an aminomethylation with dimethylamine and formaldehyde (Mannich reaction) is carried out in step-A. The 3-dimethylamino-1-(2-thienyl)-1-propanone formed is reduced to the corresponding alcohol 1-hydroxy-1-(2-thenyl)-3-dimethylaminopropane by means of complex hydrides in step B. The alcohol is then converted in step C with an alkali metal hydride and 1-fluoro-naphthalene, optionally in the presence of a potassium compound (cf. EP-A-650 965), to the naphthyl derivative, N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine. In the final step D, the amino group is then demethylated by reaction with a chloroformic acid ester, preferably phenyl chloroformate or trichloroethyl chloroformate, optionally in the presence of a mixture of zinc and formic acid (EP-A-457 559), followed by alkaline hydrolysis of the carbamate to give N-methyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine.

The EP patent 457559 described the process for the preparation of duloxetine comprises of using alkali metal hydride like sodium hydride, which is commercially not recommendable.

The U.S. Pat. No. 5,362,886 described the process for the preparation of (+)Duloxetine hydrochloride by isolating the (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine phosphoric acid salt and preparation of hydrochloride salt using aqueous hydrochloric acid and ethyl acetate as a solvent.

The U.S. Pat. No. 5,023,269 claims Duloxetine and its pharmaceutically acceptable salts and method of treating anxiety and obesity. The patent also discloses the processes for the preparation of Duloxetine and its pharmaceutically acceptable salts, however the patent not disclosed the process for the preparation of hydrochloride salt.

The EP patent 0650965 B1 discloses the process for the preparation of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine an intermediate of Duloxetine which was isolated as a phosphoric acid salt and disclosed the process for the preparation of Duloxetine hydrochloride using aqueous hydrochloric acid and ethyl acetate as a solvent.

The U.S. Pat. No. 5,491,243 and U.S. Pat. No. 5,362,886 discloses the stereospecific process for the synthesis of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine and claimed the same. In both the patents the above said compound isolated as a phosphoric acid salt.

Duloxetine hydrochloride prepared as per the prior art process containing the isomer impurity (+)-N-methyl-3(1-naphtalenyloxy)-3-(3-thienyl) propanamine, referred to herein as “DU-I” (represented below) and other undesired isomer i.e., R-isomer of Duloxetine hydrochloride.

The impurity “DU-I” is formed due to the carry over of isomer, i.e., 3-acetyl thiophene compound of formula 2I as an impurity present in 2-acetyl thiophene compound of formula 2. The formation of isomer “DU-I” during the preparation of duloxetine hydrochloride schematically represented in scheme-1, in which the Formula-4I, 5I, 6I and 8I 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. “DU-I”. 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 (“DU-I”) formation (represented in scheme-1) is due to the presence of 3-acetyl impurity in the starting material 2-acetyl compound of formula-2.

When we were working to eliminate the “DU-I” impurity in the origin itself, surprisingly found that the purity of Duloxetine hydrochloride has been increased by employing purification at first stage. The 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. Purification of mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol in a suitable solvent to eliminate the corresponding derivative of R-isomer in an early stage. 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 from impurities such as (+)-N-methyl-3-(1-napthalenyloxy)-3(3-thineyl) propanamine impurity (“DU-I”) and undesired (R)-isomer of Duloxetine hydrochloride.

DISADVANTAGEOUS OF THE PRIOR ART PROCESSES

• • The EP patent 457559 uses alkali metal hydride like sodium hydride in the preparation of duloxetine, which is commercially not recommended.
  • Duloxetine hydrochloride prepared as per the prior art process having high level of impurities like DU-I and R-isomer of duloxetine hydrochloride.
  • The U.S. Pat. No. 5,362,886 describes the process for the preparation of (+) Duloxetine hydrochloride by isolating the (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2 thienyl)propanamine as phosphoric acid salt leads to one more step and preparation of hydrochloride salt of Duloxetine using aqueous hydrochloric acid and ethyl acetate as a solvent leads to degradation of the obtained compound as shown below.

The present invention schematically represented as follows

 

Example-1 Preparation of 3-(dimethylamino)-1-(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 and 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 0-5C. Stirred the reaction mixture for 2 hours at 0-5° C. Filtered the solid and washed with isopropyl alcohol.

Yield: 151 Kgs

M.R: 174-176° C.

Example-2 Purification of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-one hydrochloride

Added 1500 liters of isopropyl alcohol and 45 liters of water to 151 Kgs of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-one hydrochloride. 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-3 Purification of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-one hydrochloride

Added 1500 liters of acetone and 45 liters of water to 151 Kgs of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-one hydrochloride. 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 at 50-55° C. for 6 hours to get the pure title compound.

Yield: 142 Kgs.

M.R: 185-190° C.

Example-4 Preparation of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol

Added 50 liters of 20% sodium hydroxide solution to a cooled solution of 100 Kgs. of 3-(dimethylamino)-1-(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% sodium chloride 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.

Example-5 Preparation of (S) 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol

Added 35 Kgs. of L(+)-mandelic acid to a solution of 70 Kgs. of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol and 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 mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol compound and washed with ethyl acetate. Added 350 liters of ethyl acetate to the obtained mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol compound. 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 compound and washed with ethyl acetate. Dried the mandelate salt compound at 60-65° C. for 5 hours to get the pure mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol compound free from corresponding derivative of R-isomer.

Yield: 62 Kgs.

• Before Purification: MR: 113-115° C.; SOR: (+) 31° (C=1; Methanol) Corresponding derivative of R-isomer by Chiral HPLC: 7.0%
• After Purification: MR: 121-124° C.; SOR: (+) 33° (C=1; Methanol) Corresponding derivative of R-isomer by Chiral HPLC: Nil

A mixture of 62 Kgs. of mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol, 125 liters of water and 375 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% sodium chloride 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 125 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: 33 Kgs.

MR: 70-80° C.; SOR: (−) 6.20 (C=1; Methanol).

Example-7 Preparation of (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl) 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 a mixture of 25 Kgs. of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol, 2.5 Kgs. of tertiarybutylammonium bromide and 30 Kgs. of 1-fluoronapthalene and 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, oxalic acid followed by 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: 36 Kgs.; M.R: 126-130° C.

Example-8 Preparation of (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride

A solution of 100 Kgs. of (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-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 2.0 with ethyl acetate HCl. 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.

Undesired R-isomer content by Chiral HPLC: 0.13%

HPLC Purity: 99.80%, 0.07% (“DU-I” impurity)

Example-9 Purification of Duloxetine Hydrochloride

Added 500 ml of ethyl acetate and 100 ml of methanol to 100 gr of Duloxetine hydrochloride. Heated the reaction mixture to 55-60° C. and stirred the reaction mixture at 55-60° C. for 90 minutes. Cooled the reaction mixture to 20-25° C. Stirred the reaction mixture for 4 hours at 20-25° C. Filtered the solid and washed with ethyl acetate. Dried the material at 55-60° C.

Yield: 70gr;

MR: 164-166° C.;

SOR: (+) 118° (C=1; Methanol);

Particle size: (d, 90): below 100 microns; Micronized material: (d, 90): below 25 microns;

Undesired R-isomer content by Chiral HPLC: 0.02%; HPLC Purity: 99.80% 0.02% (“DU-I” impurity).

A RECAP

US. 8362279

http://www.google.co.in/patents/US8362279

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MSN Laboratories Limited, Andhra Pradesh, Hyderabad, India

 

Process for Pure Duloxetine Hydrochloride

 

 

 

Duloxetine, 126, is used to treat mild depression and is available as the HCl salt under the name Cymbalta. The current patent points out that alternative processes for the preparation of 126produce a material that contains the impurity 127 as well as the unwanted R-enantiomer. Earlier patents covering the removal of 127 and the synthesis of 126 have been reviewed ( Org. Process Res. Dev. 2009, 13, 829). This patent discloses a method for preparing pure 126 by removing the precursor to 127 during the synthesis. Scheme 39 shows the first step in the synthesis of 126 that starts by reaction of the thiophene 122 with Me2NH and paraformaldehyde to form 124 that is subsequently converted to 126. However, 122 contains the isomer 123 as an impurity, and in the reaction with Me2NH and HCHO, compound 125 is formed that eventually forms impurity 127. Alternative processes that use this reaction sequence generally remove 127at the end of the synthetic procedure. The current patent removes 125 after this first step, and it is claimed that this produces a higher-quality final product. This initial reaction produces the HCl salts of 124 and 125, and the crude solid mixture is heated in refluxing PriOH or Me2CO containing H2O. The purified salt 124·HCl is then recovered from the cooled mixture by filtration, and although the product purity is not reported, the example describes the preparation of >140 kg of the salt.

Scheme 39. a

aReagents and conditions: (a) (i) Concd HCl, PriOH, 80 °C, 6 h; (ii) cool <5 °C, 2 h; (iii) filter. (b) See Scheme 40.

The purified salt is then used to prepare 126 by the reaction sequence shown in Scheme 40. The salt is first treated with NaOH to give the free base 124 that is not isolated but is reduced in situ using NaBH4 to form the racemic alcohol 128. This is resolved using L-mandelic acid, and the enantiomer S-128 is recovered containing no R-enantiomer, and then the L-mandelate salt that is converted to S-128 by treatment with aq Na2CO3. The overall yield of the free base is 47%. In the next stage S-128 is reacted with 129 in the presence of an alkaline base and a PTC. This stage of the reaction takes 50 h and is followed by a demethylation step using ClCO2Ph to give 126 that is recovered as the oxalate salt, and this step takes more than 30 h. In the final step the oxalate salt is converted to the HCl salt of 126 using a solution of HCl in EtOAc. Alternative processes use aq HCl for this step that is said to lead to degradation of 126 by hydrolysis of the ether bond. The HCl salt is isolated with a purity of 99.8% containing 0.13% of the R-enantiomer and 0.07% of impurity 127.

Scheme 40. a

aReagents and conditions: (a) 20% NaOH, MeOH, H2O, <5 °C. (b) (i) NaBH4, 20% NaOH, <5 °C, 5 h; (ii) 30 °C, 6 h; (iii) L-mandelic acid, EtOAc, 75 °C, 3h; (iv) cool, filter; (v) aq Na2CO3, DCM, 5 °C; (vi) separate, brine wash, evaporate; (vii) cyclohexane, 45 °C, 1 h; (viii) cool, filter, dry. (c) (i) NaOH, Bu4NBr, DMSO, 65 °C, 50 h; (ii) add H2O, <20 °C; (iii) extract in PhMe, H2O wash, dry; (iv) add Pri2NEt, 35 °C; (v) add ClCO2Ph, 48 °C, 4 h; (vi) cool <25 °C, add H2O; (vii) separate, wash in HOAc, wash in (CO2H)2, wash in aq NaHCO3, evaporate; (ix) aq NaOH, DMSO, 45 °C, 3 h; (x) 55 °C, 30 h; (xi) cool, add H2O, extract in PhMe; (xii) add (CO2H)2, 30 °C, 4 h; (xiii) filter, wash, dry. (d) (i) DCM, H2O, NH4OH to pH 8.8, 5 °C, 0.25 h; (ii) separate, H2O wash, evaporate; (iii) HCl/EtOAc, 5 °C, 2 h; (iii) filter, EtOAc wash, dry.

All of the examples in the patent involve large-scale batches with the final step being the production of 45 kg of 126·HCl, thereby indicating the commercial status of the process.

Advantages

The process gives higher-purity product with fewer steps and lower production costs.

Cited Patent	Filing date	Publication date	Applicant	Title
US5023269	27 Mar 1990	11 Jun 1991	Eli Lilly And Company	3-aryloxy-3-substituted propanamines
US5362886	12 Oct 1993	8 Nov 1994	Eli Lilly And Company	Asymmetric synthesis
US5491243	18 Jul 1994	13 Feb 1996	Eli Lilly And Company	Intermediate useful for the asymmetric synthesis of duloxetine
US20050197503	16 Feb 2005	8 Sep 2005	Boehringer Ingelheim International Gmbh	Process for the preparation of N-alkyl-N-methyl-3-hydroxy-3-(2-thienyl)-propylamines
US20080015363 *	21 Feb 2007	17 Jan 2008	Santiago Ini	Process for the preparation of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropananine, a duloxetine intermediate
EP0273658B1	18 Dec 1987	31 Oct 1990	Eli Lilly And Company	3-aryloxy-3-substituted propanamines
EP0457559A2	15 May 1991	21 Nov 1991	Eli Lilly And Company	Chiral synthesis of 1-aryl-3-aminopropan-1-ols
EP0650965B1	7 Oct 1994	7 Feb 2001	Eli Lilly And Company	Asymmetric synthesis of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine an intermediate in the preparation of duloxetine
WO2006099433A1	14 Mar 2006	21 Sep 2006	Teva Pharmaceutical Industries Ltd.	Pure duloxetine hydrochloride

 

Reference
1	*	English translation of Gao et al. (Chinese Journal of New Drugs, vol. 14, No. 1, pp. 74-76). Translated by Schreiber Translations, Inc in Mar. 2012.
2	*	Gao et al. (Chinese Journal of New Drugs, vol. 14, No. 1, pp. 74-76).
3	*	Gao et al. (Chinese Journal of New Drugs, vol. 14, No. 1, pp. 74-76, 2005).
4		Luo, G., et al. "An Improved Synthesis Method of Antidepressant Drug Duloxetine Hydrochloride. Yaouxue J." (2006), 30(4), 181-184, Columbus Ohio, USA: Chemical Abstracts vol. 146, Jun. 21, 2006, the abstract No. 592369.
5		PCT Written Opinion of the International Searching Authority from PCT/IN2007/000003, Dated: Mar. 3, 2008.

///////Duloxetine Hydrochloride, MSN, PATENT, US. 8362279

Diacerein, US 8324411, Laboratorio Chimico Internazionale s.p.A., Milan, Italy, PATENT

Patent US 8324,411

https://www.google.com/patents/US8324411

Inventors	Annibale Salvi, Antonio Nardi, Stefano Maiorana, Mara Sada
Original Assignee	Laboratorio Chimico Internazionale S.P.A.

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Laboratorio Chimico Internazionale s.p.A., Milan, Italy

Diacerein, 20a, is used in the treatment of arthritis, and there are several methods available for its synthesis. The majority of these are said to involve an oxidation step that uses CrO₃, and as a result, extensive purification is required to remove residues of Cr and reaction byproducts. The patent discloses an oxidation procedure in the preparation of 20a that avoids these problems and is claimed to be suitable for industrial production. Scheme 8 shows the route used to prepare 20athat starts with formation of the protected quinone, 19b. Despite the workup of the compound being quite lengthy, 19b is isolated in 74% yield with 98% purity. The next step is oxidation of the protected dihydroxy quinone 19b using TEMPO and an alkaline chlorite plus an alkaline hypochlorite. The chlorite is used in around 2 mol excess of the substrate and the hypochlorite at around 5 mol % of the substrate. After the oxidation the crude product is isolated in 98% yield and then purified by treatment with Et₃N and DMF. The purified 20b is obtained in 76% yield, and then the protection is removed using FeCl₃/Ac₂O. The yield of crude 20a is 92%, and it is said to be purified by known techniques. The Cr content of the purified material is reported as <1 ppm, and genotoxic impurities such as 19a or acetyl derivatives are reported to be <2 ppm.

Scheme 8. ^a

^aReagents and conditions: (a) (i) K₂CO₃, KI, Bu₄NBr, DMF, 60 °C; (ii) 80 °C, 1 h; (iii) BnCl, 50 °C, 1 h; (iv) 80 °C, 1 h; (v) add MeOH at 50 °C; (vi) cool to <25 °C, filter; (vii) evaporate, add THF; (viii) wash at 60 °C with aq NaOH, H₂O, brine; (ix) evaporate, add EtOAc, concentrate; (x) cool <4 °C, 1 h; (xi) filter, wash, dry. (b) (i) TEMPO, aq NaH₂PO₄, aq Na₂HPO₄, MeCN, 35 °C; (ii) add aq NaClO₂, 35 °C, 50 min; (iii) add aq NaOCl, 65 °C, 3 h; (iv) cool rt, add H₂O; (v) add H₃PO₄, pH 3; (vi) filter, H₂O wash, dry; (vii) Et₃N, DMF, EtOAc, 60 °C, 0.5 h; (viii) filter hot; (ix) add H₂O, separate; (x) extract H₂O phase at 60 °C with EtOAc (×6); (xi) cool organic phases to rt, add HCl to pH 2; (xii) cool <5 °C, 1 h; (xiii) filter, H₂O wash, MeCN wash, dry. (c) (i) FeCl₃, Ac₂O, 65 °C, 1.5 h; (ii) cool <4 °C, 1 h; (iii) filter, wash in Ac₂O, EtOAc wash, dry.

Advantages

The process produces the desired product without using heavy-metal oxidising agents; however, the workup procedures are quite lengthy.

Example 1 Preparation of 1,8-dibenzyloxy-3-(hydroxymethyl)anthraquinone (dibenzyl aloe-emodin)483 g (3.5 moles) of potassium carbonate, 16 g (0.1 moles) of potassium iodide and 16 g (0.05 moles) of tetrabutylammonium bromide are added to a solution of 270 g (1 mole) of 1,8-dihydroxy-3-(hydroxymethyl)anthraquinone (aloe-emodin) in 3500 ml of DMF at 60° C.; the reaction mixture is heated at 80° C. for 1 h. It is cooled to 50° C. and 443 g (3.5 moles) of benzyl chloride are added dropwise in approximately one hour. At the end of the dripping, the reaction mixture is brought back to 80° C. and left at that temperature under stirring for 45-60 minutes. It is then cooled to 50° C. and 200 ml of methyl alcohol are added. It is cooled to 20-25° C. and the inorganic salts are removed by filtering. The organic solvent is distilled at 60-70° C. at reduced pressure and the residue is dissolved in 3200 ml of tetrahydrofuran at 60° C. Maintaining the temperature at 50-60° C., the organic phase is washed twice with 1200 ml of 2.5 molar aqueous sodium hydroxide and once with 1000 ml of a saturated solution of sodium chloride in water. The organic phase is concentrated at reduced pressure at 60° C. and the residue is recovered with 2700 ml of ethyl acetate. The suspension thus obtained is concentrated to approximately ⅓ of the initial volume by distillation of the solvent at reduced pressure. It is gradually cooled to 0-4° C. and kept at that temperature for 1 hour. The solid is filtered and washed with ethyl acetate (100 ml×2). The damp product is dried at 45° C. at reduced pressure for 12-14 hours, providing 334 g (yield 74%) of dibenzyl aloe-emodin having a purity of 98% (HPLC).
melting point: 170-171° C.
IR cm⁻¹: 1655, 1612, 1232
Example 2 Synthesis of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid (dibenzylrhein)10 g (0.06 moles) of radical 2,2,6,6-tetramethyl-1-piperidinyl-oxyl (TEMPO) and 1160 ml of an aqueous solution of 120 g (1 mole) of sodium dihydrogen phosphate and 180 g (1 mole) of disodium hydrogen phosphate are added in sequence to a suspension of 333 g (0.74 moles) of 1,8-dibenzyloxy-3-(hydroxymethyl)anthraquinone in 1660 ml of acetonitrile. The reaction mixture is heated to 35° C. and a solution of 167 g (1.5 moles) of sodium chlorite 80% in 513 ml of water is added dropwise in 40-50 minutes, maintaining the temperature around 35-40° C. 20 ml of aqueous sodium hypochlorite 10-12% are then dripped in and the reaction is heated to 60-65° C. for three hours. It is cooled to room temperature and 1400 ml of water are added. Phosphoric acid 85% is dripped in until reaching a pH of 2.8-3.2. The solid obtained is filtered and washed with water (350 ml×2). The damp product is dried at 50° C. at reduced pressure for 14-16 hours, providing 337 g (yield 98%) of crude dibenzylrhein.
Example 3 Purification of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid (dibenzylrhein)337 g (0.72 moles) of crude 1,8-dibenzyloxyanthraquinone-3-carboxylic acid are dissolved in a solution of 134 ml of triethylamine in 900 ml of dimethylformamide DMF and 1800 ml of ethyl acetate, heating to 60° C. for 20-30 min. Any undissolved elements are removed by hot filtering and 2700 ml of water are added. The organic phase is separated and the aqueous phase is washed 6 times with 800 ml of ethyl acetate each time, maintaining the temperature at 60° C. The organic phase is cooled to room temperature and acidified with hydrochloric acid 33% until pH 2 is reached; the suspension thus obtained is cooled to 0-5° C. for approximately 1 hour. The product is filtered, washing it thoroughly with water (1200 ml) and then with 200 ml of acetonitrile. After drying at 50° C. at reduced pressure for 14-16 hours, 256 g of dibenzylrhein are obtained with a yield of 76%.
melting point: 250-251° C.
IR cm⁻¹: 1666, 1621, 1587, 1524
Example 4 Synthesis of 1,8-diacetoxy-3-carboxyanthraquinone (diacerein)45 g (0.28 moles) of anhydrous iron trichloride are added in portions to a suspension of 255 g (0.55 moles) of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid in 1300 ml of acetic anhydride. The reaction mixture is heated to 65° C. for one hour and thirty minutes. It is gradually cooled to 2-4° C. and maintained at that temperature for 1 hour. The solid obtained is filtered and washed with 150 ml of acetic anhydride and then with 400 ml of ethyl acetate. The damp product is dried at 50° C. at reduced pressure for 14-16 hours, providing 186 g of crude diacerein (yield 92%). The crude diacerein is purified according to the known techniques.
¹H NMR (d6-DMSO) δ: 2.4 (6H, s); 7.6 (1H, dd); 7.9 (1H, t); 8.0 (1H, d); 8.1 (1H, dd); 8.5 (1H, d).
IR cm⁻¹: 1763, 1729, 1655, 1619, 1591, 1183.
Chromium: not detectable (<1 ppm)
Genotoxic impurities (aloe emodin and acetyl derivatives)≦2 ppm.
/////////Diacerein, US 8324411, PATENT