New patent, WO 2016042573, Acitretin, Emcure Pharmaceuticals Ltd

Acitretin

PDT PATENT US4105681

WO-2016042573

Process for preparation of acitretin

Emcure Pharmaceuticals Ltd

EMCURE PHARMACEUTICALS LIMITED [IN/IN]; an Indian company at EMCURE HOUSE, T-184, MIDC., Bhosari, Pune - 411 026 Maharashtra (IN)

GURJAR MUKUND KESHAV; (IN).
JOSHI SHASHIKANT GANGARAM; (IN).
BADHE SACHIN ARVIND; (IN).
KAMBLE MANGESH GORAKHANATH; (IN).
MEHTA SAMIT SATISH; (IN)

The present invention Provides a process for preparation of {(2E, 4E, 6E, 8E) -9- (4-methoxy-2,3,6-trimethyl) phenyl-3,7-dimethyl-nona-2,4,6 , 8} tetraenoate, acitretin year intermediate of formula (VI) with trans isomer ≥97%, comprenant of Reacting 3-formyl-Crotonic acid butyl ester of formula (V) Substantially free of impurities, with 5- (4-methoxy- 2,3,6-trimethylphenyl) -3-methyl-penta-2,4-diene-l-triphenyl phosphonium bromide of formula (IV) and isolating resulting compound of formula (VI) Treating the filtrate with iodine for isomerization of the Undesired cis intermediate and finally Obtaining acitretin (I), with trans isomer Desired ≥97%.

Samit Satish Mehta holds the position of the President - Research & Development

Acitretin of formula (I), chemically known as (2E,4E,6E,8E)-9-(4-methoxy-2,3,6- trimethyl)phenyl-3,7-dimethyl-nona-2,4,6,8-tetraenoic acid, is a second generation retinoid a roved by USFDA in 1996, for the treatment of psoriasis.

Acitretin (I)

The process for preparation of acitretin (I) was first disclosed in US 4,105,681 wherein the intermediate, 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l-triphenyl phosphonium bromide was reacted with 3-formyl-crotonic acid butyl ester in presence of sodium hydride as base and dimethylformamide as solvent. The resultant ester derivative was obtained with a trans is (E/Z) ratio of around 55:45 which was subjected to hydrolysis in presence of potassium hydroxide and ethyl alcohol to obtain acitretin.

Use of hazardous, highly pyrophoric and moisture sensitive reagent like sodium hydride, along with cumbersome work-up and successive crystallizations to obtain the desired isomer rendered the process unviable for commercial scale.

Indian patent application 729/MUM/2012 discloses use of organic bases such as triethyl amine or pyridine for the reaction of 3-formyl-crotonic acid butyl ester and 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l -triphenyl phosphonium bromide for the synthesis of acitretin. The process utilizes a large excess of the organic base (2.85:1.0) with respect to the reactant phosphonium bromide derivative. Further, there is no mention of the ratio of cis and trans geometric isomers of the product thus obtained either at the intermediate or final stage. The trans: cis (E/Z) ratio of the intermediate significantly impacts the final yield and purity of the product as several purifications and crystallizations are required to obtain the desired trans isomer.

The present inventors have experimentally observed that use of organic base in such large quantities severely hampers the removal of the undesired side product triphenyl phosphonium oxide formed in significant amounts. Also, the intermediate is obtained with a very modest trans: cis (E/Z) ratio.

WO2012/155796 discloses another method wherein alkali metal alkoxides are used as bases in the reaction of 5-(4-methoxy-2,3,6-trimethylphenyl)-3 -methyl -penta-2,4-diene-l -triphenyl phosphonium bromide with 3-formyl-crotonic acid. The obtained reaction mass, after adjusting pH to 7-8 with acid, is directly subjected to catalytic isomerization using catalysts such as Pd(OAc)₂ or Pd(NH₃)₂Cl_2. The reaction mixture so obtained is quenched with water, neutralized and filtered to get the desired product, which is further recrystallized from ethyl acetate. Although this procedure avoids the hydrolysis step and attempts in-situ isomerization, however the use of expensive, soluble palladium catalyst which cannot be recycled from the reaction mass coupled with lengthy reaction time of 25-30 hours and large solvent volumes make the process unviable.

It may be noted that in the synthesis of acitretin, the key reaction of 5-(4-methoxy-2,3,6-trimethylphenyl)-3 -methyl-penta-2 ,4-diene- 1 -triphenylphosphoniumbromide with 3 -formyl crotonic acid or its ester in presence of either strong inorganic bases such as sodium hydride, alkali metal alkoxides or organic bases like triethylamine is common to almost all synthetic routes disclosed in the prior art. Hence, all these routes suffer from the inherent problems of formation of undesired impurities including cis-isomeric compounds and their separation from the desired all-trans product which necessitates various purification methods ranging from column chromatography, multiple crystallizations etc.

Thus, there still exists a need for a convenient, easy-to-scale up process for synthesis of acitretin (I) which avoids use of pyrophoric strong bases and provides a robust method which affords acitretin having desired isomeric purity in high yield.

5-(4-methoxy,2,3,6 trimethylphenyl)- 3-formyl crotonic acid butyl glyoxalate L(+) tartaric acid

3-methyl-penta-2,4-dien-1-triphenyl butyl ester (V) dibutyl ester

phosphonium bromide (IV)

Acitretin (I)

Satish Mehta,CEO, Above and here Inspiring the participants

EXAMPLES

Example 1: Preparation of 4-(4-methoxy-2,3,6-trimethylphenyl)-but-3-en-2-one (II)

Acetone (6000 ml) was added to 4-methoxy-2,3,6 trimethyl benzaldehyde (500.3 g) and the mixture was stirred at 20-30°C. Aqueous solution of sodium hydroxide (134.8 g in 500 ml water) was gradually added to it and the resulting mixture was heated to 45-50°C with continued stirring. After completion of the reaction, as monitored by HPLC, the reaction mass was cooled and acetic acid was added till pH 4.5 to 5.5. Distillation of acetone, followed by addition of cyclohexane to the residue, followed by washing with water, separation and concentration of the organic layer gave 4-(4-methoxy-2,3,6 trimethylphenyl)-but-3-en-2-one of formula (II).

Yield: 80-84%

Example 2: Preparation of 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene- 1-triphenyl phosphonium bromide (IV)

4-(4-Methoxy-2,3,6-trimethylphenyl)-but-3-en-2-one (II; 500 g) dissolved in toluene (2000 ml) was gradually added to a mixture of vinyl magnesium bromide (3500 ml; 1 molar solution in THF) and lithium chloride (4.8 g) and stirred at 20-30 C till completion of the reaction as monitored by HPLC. The reaction mixture was quenched with water and concentrated hydrochloric acid was added till the pH was between 3 and 4. The organic layer was separated and concentrated to give residue containing 5-(4-methoxy-2,3,6 trimethylphenyl)-3 -methyl -penta l,4-dien-3-ol (III). Methyl isobutyl ketone (3500 ml) was added to the residue, followed by gradual addition of triphenyl phosphine hydrobromide (745.3 g) at room temperature. The reaction mixture was heated to 50-60°C till completion of the reaction. The reaction mixture was cooled and filtered to give 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l-triphenyl phosphonium bromide of formula (IV).

Yield: 1000 g (76%)

Example 3: Preparation of 3-formyl crotonic acid butyl ester (V)

Dibutyl-L- tartrate (500 g) was dissolved in isopropanol (3500 ml) at room temperature, and water (750 ml) was added to it. The reaction mixture was cooled to 15-25°C and sodium metaperiodate (448.5 g) was gradually added to it with stirring. The reaction was continued at 20-30°C till completion of the reaction based on GC analysis. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was dissolved in toluene (1000 ml), stirred and filtered to obtain the filtrate containing butyl glyoxylate. Propionaldehyde (221.0 g) was added to the filtrate and heated to around 60°C, followed by gradual addition of piperidine (26.4 g, dissolved in toluene). The reaction mixture was further heated and stirred at 110-120°C till completion of the reaction, as monitored by GC. After completion, the reaction mass was cooled, washed with aqueous sulfuric acid, water and finally with aqueous sodium bicarbonate solution. The organic layer was concentrated and the residue was distilled to give 3-formyl crotonic acid butyl ester (V)

Yield: 230-280 g (35-43%)

Example 4. Preparation of butyI{(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethyl) phenyl-3,7-dimethyl-nona-2,4,6,8}tetraenoate (VI)

Sodium carbonate (297. lg), was added to the mixture of 5-(4-Methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l-triphenyl-phosphoniumbromide (IV; 1000 g) in toluene (5000 ml) followed by gradual addition of 3-formyl crotonic acid butyl ester (330 g) at room temperature. The stirred reaction mixture was heated to 60-70°C till completion of the reaction as monitored by HPLC. The reaction mass was cooled, quenched with water. The organic layer was separated, concentrated and n-heptane was added to the residue. The mass was stirred, filtered and 40% aqueous methanol (2000 ml) was added to it with stirring. Layer separation, concentration of the organic layer, and crystallization of the resulting residue from isopropyl alcohol, optionally with seeding followed by filtration gave crop I of butyl {{(2E,4E,6E,8E)— 9-(4-methoxy-2,3,6 trimethyl)phenyl-3,7 dimethyl -nona-2,4,6,8} tetraenoate (VI),.

Yield: 45-50%;

Cis: Trans isomer ratio (2.0:98.0)

The filtrate was concentrated, the residue was dissolved in toluene (2000 ml) and treated with iodine (4.5 g) at room temperature. After completion of the reaction, as monitored by HPLC, the reaction mixture was stirred with aqueous sodium thiosulfate solution. Separation and concentration of the organic layer and crystallization of the resulting residue from isopropyl alcohol, optionally with seeding, gave crop II of butyl {{(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethyl)phenyl-3,7-dimethyl-nona-2,4,6,8} tetraenoate (VI).

Yield (crop II): 15 to 20%.

Cis: Trans isomer ratio (2.0:98.0)

Total yield (crop I+II): 60-70%.

Example 5: Preparation of acitretin (I)

Aqueous solution of potassium hydroxide (155.2 g in 600 ml water) was added to a solution of butyl {(2E,4E,6E,8E)-9-(4-methoxy-2,3 ,6-trimethyl) phenyl-3 ,7-dimethyl-nona- 2,4,6,8}tetraenoate, VI (300.0 g) in ethanol (1800 ml) at 25-30°C and the reaction mixture was stirred at reflux temperature till completion of the reaction. After completion, as monitored by HPLC, the reaction mixture was quenched with water, and hydrochloric acid was added till pH was between 2.5 and 3.5. The mass was heated at 70°C, stirred, cooled to 40-50°C and filtered. Recrystallization of the resulting solid from tetrahydrofuran gave acitretin (I).

Yield: 154.0 g (60%)

Desired trans isomer: > 98%

India's hockey stars Sardara Singh and Sandeep Singh with Emcure Pharmaceuticals COO, Arun Khanna

HE Dr. Kenneth Kaunda, First President of Zambia interacting with Mr. A. K. Khanna, COO & ED, Emcure at Emcure booth at AIDS 2012 conference, Washington

Mr. Sunil Mehta is an Executive Director and Senior Director (Projects)

Arun Khanna is the Chief Operating Officer and Executive Director on the Board of Emcure Pharmaceuticals Limited.

//////New patent, WO 2016042573,  Acitretin,   Emcure Pharmaceuticals Ltd

WO 2016042441, Mankind Research Centre, Silodosin, New patent

WO 2016042441, Mankind Research Centre, Silodosin, New patent

WO-2016042441

Mankind Research Centre

MANKIND RESEARCH CENTRE [IN/IN]; 191-E, Sector 4-II, IMT-Manesar, Haryana 122050 (IN)

A novel process for the preparation of considerably pure silodosin

GANGWAR, Kuldeep Singh; (IN).
KUMAR, Anil; (IN).
BHASHKAR, Bhuwan; (IN)

The present invention relates to a novel, improved, commercially viable and industrially advantageous process for the preparation of Silodosin of Formula (I), its pharmaceutically acceptable salts or solvates thereof. The invention relates to the preparation of considerably pure Silodosin with high yield.

Silodosin, l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide of Formula (I) is an indoline antidysuric which has a selectively inhibitory effect against urethra smooth muscle constriction, and decreases urethra internal pressure without great influence on blood pressure. Silodosin is available under trade names RAPAFLO^® or UROREC^®. Silodosin was first disclosed in EP 0600675 as a therapeutic agent for the treatment of dysuria associated with benign prostatic hyperplasia, where a process for producing the compound is also disclosed.

Formula (I)

Since, Silodosin is an optically active compound having a complex chemical structure; its synthesis is relatively complex and requires a sequence of multiple steps.

US patent no. 6,310,086, discloses a process for preparing Silodosin analogue compound from reaction of (R)-3-{5-(2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl} propylbenzoate with 2-(2-ethoxyphenoxy)ethyl methanesulfonate and finally isolated as a crude compound which is purified by column chromatography. The said process has a major disadvantage of using column chromatography which is not feasible at plant scale production.

PCT application no. WO 2012147019, discloses the preparation of Silodosin as shown in scheme- 1, wherein the Ν,Ν-dialkyl impurity of Formula (Ila) formed during condensation of 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate of Formula (III) with 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate of Formula (IV); is removed through preparation of monotartarate salt to give compound of Formula (VI). The compound of Formula (VI) is base hydrolyzed followed by cyano hydrolysis to give crude Silodosin of Formula (VIII) which is then further purified by crystallization to get desired pure Silodosin.

Scheme- 1:

Major drawback of above said reaction process is that multiple isolations and crystallizations are required to get pure Silodosin.

Similarly, US 7,834,193 discloses monooxalate salt represented by Formula Via having 0.9% of dialkyl impurity represented by Formula Ila. The oxalate salt so obtained is subjected to alkaline hydrolysis followed by transformation of the nitrile to an amide.

Formula (Ila)

Similarly, PCT application no. WO 2012147107, discloses the method wherein Silodosin is prepared by condensation of 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl} propyl benzoate with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate in solvent using base and phase transfer catalyst wherein, dialkyl impurity is formed up to 11%, followed by hydroxyl deprotection in protic solvent using base and phase transfer catalyst which is then subjected to purification to remove N,N-dialkyl impurity represented by Formula (lib) up to 0.6% through the preparation of acetate salt. This process suffers from a serious drawback i.e., accountable formation of dialkyl impurity and even after purification the impurity is reduced to only up to 0.6%. Secondly, the process requires multiple isolations and purifications ensuing into time engulfing workups and purifications and hence incurring solvent wastage. This makes process lengthy, uneconomical and tedious to be performed at plant scale.

Another PCT application no. WO 2012131710, discloses the preparation of Silodosin in which the chiral compound (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) is reacted with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate in isopropyl alcohol using sodium carbonate as base. The reaction is completed in 40-50h and about 9-11% of dimer is formed during condensation. After completion of reaction, it is subjected to hydroxyl deprotection and the crude compound so obtained is purified to remove the Ν,Ν-dialkyl impurity of Formula (lib). The pure compound is then reacted with hydrogen peroxide in dimethyl sulfoxide to give Silodosin. The major drawback of this process is that the process is a multistep process wherein the condensation reaction is long-drawn-out resulting into countable amount of dimer formation during the process.

Thus, the prior art methods of preparing Silodosin require multiple and repeated purifications to synthesize DMF (Drug Master File) grade Silodosin. None of the prior art produces compound of Formula (VI) or (VII) with Ν,Ν-dialkyl impurity of Formula (Ila) or (lib) in an amount less than 0.6% to 0.5% even after purification. Therefore to prepare highly pure Silodosin, there is a need to explore new synthetic schemes that could be more economical and scalable. The present invention provides a novel, improved, commercially viable and industrially advantageous process for the synthesis of Silodosin and its pharmaceutically acceptable salts or solvates thereof. The present invention focus on preparation of highly pure Silodosin in appreciable yields with minimal use of solvents wherein the Silodosin is isolated with purity >99.5% having Ν,Ν-dialkyl impurity less than 0.03% and other individual impurities below 0.1%.

Ramesh Juneja (seated), founder of Mankind Pharma, with brother Rajeev, who is senior director (marketing & sales)

Mankind Pharma Chairman and Founder RC Juneja

In accordance to one embodiment of the present invention, the process of the preparation of Silodosin represented by Formula (I)

comprises the steps of:

a) condensing chiral compound represented by Formula (III)

Formula (III)

wherein, Bz represents to Benzoyl group with compound represented by Formula (IV)

Formula (IV)

wherein, Ms represents to Methanesulfonyl group in presence of base and phase transfer catalyst in an organic solvent to give intermediate represented by Formula (V)

Formula (V)

wherein, n is an integer of 1 and 2 and Bz is as defined above, wherein the compound having n=2 is formed in an amount of less than 5%;

b) optionally isolating compound of Formula (V),

c) without purification converting it to de-protected compound represented by Formula (IX) in an organic solvent;

Formula (IX)

wherein, n is as defined above;

d) optionally isolating compound of Formula (IX), and

e) without purification converting it to compound represented by Formula (X)

Formula (X)

wherein n is as defined above;

f) subjecting compound of Formula (X) to purification by converting to acid salt for removal of Ν,Ν-dialkyl impurity represented by Formula (lie);

Formula (He)

g) hydrolysis of the said acid salt to get Silodosin of Formula (I) with purity >99.5%.

Examples

The invention is explained in detail in the following examples which are given solely for the purpose of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1

Preparation of Crude Silodosin:

Method A:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of toluene was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Cooled the reaction mass, added de-mineralized water and separated the toluene layer followed by distillation to get crude viscous mass. Added 110ml of dimethyl sulfoxide and a solution of 1.51g (0.0415 mol) of sodium hydroxide dissolved in 8.52ml of water followed by addition of 6.42g (0.0567 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at 20-25°C till completion and added sodium sulfite solution. Extracted the compound in ethylacetate, washed the organic layer with brine solution and concentrated to get 10.2g of crude Silodosin.

Ν,Ν-dialkyl impurity is 3.2% as per HPLC.

Method B:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of toluene was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added solution of 4.4g of sodium hydroxide dissolved in 10ml of water and stirred the reaction at ambient temperature till completion. Quenched the reaction mass with water and separated the layers. Washed the toluene layer with brine and concentrated under reduced pressure to get crude mass. Dissolved the crude mass so obtained in 110ml of dimethyl sulfoxide and added a solution of 1.95g (0.0488 mol) of sodium hydroxide dissolved in 7.95ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 10. lg of crude Silodosin.

Ν,Ν-dialkyl impurity is 3.0% as per HPLC

Method C:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of dimethyl sulfoxide was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 2-3h. Added 100ml of water and 50ml of toluene and stirred the reaction mass at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure. To the crude mass so obtained was added 110ml of dimethyl sulfoxide and a solution of 4.4g of sodium hydroxide dissolved in 10ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 9.8 g of crude Silodosin.

Ν,Ν-dialkyl impurity is 2.1% as per HPLC

Method D:

To the solution of 20g (0.055 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 200ml of toluene was added 28.6g (0.165 mol) of dipotassium hydrogen phosphate and 16.4g (0.0522 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate followed by addition of 4.0g (0.11 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added de-mineralized water and stirred at room temperature for half an hour. Separated the toluene layer to which was added a solution of 8.8g of sodium hydroxide dissolved in 20ml of water and stirred the reaction at ambient temperature till completion. Quenched the reaction mass with water and separated the layers. Washed the toluene layer with brine and concentrated under reduced pressure to get crude mass. Dissolved the crude mass so obtained in 200ml of dimethyl sulfoxide and added a solution of 3.9g (0.0976 mol) of sodium hydroxide dissolved in 16ml of water followed by addition of 15g (0.132 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 400ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 21. Og of crude Silodosin.

Ν,Ν-dialkyl impurity is 2.8% as per HPLC

Method E:

To the solution of 2g (0.0055 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 20ml of was dimethyl sulfoxide was added 2.87g (0.0165 mol) of dipotassium hydrogen phosphate and 1.64g (0.0052 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 0.29g (0.0011 mol) of 16-crown ether and stirred the reaction mass at 85-90°C for 10-12h. Added a solution of 0.88g of sodium hydroxide dissolved in 2ml of water and stirred the reaction at ambient temperature till completion. Added de-mineralized water and toluene and stirred at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure and to the solid mass so obtained were added 20ml of dimethyl sulfoxide and a solution of 0.38g (0.0231 mol) of sodium hydroxide dissolved in 1.6ml of water followed by addition of 1.5g (0.0132 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 2.1g of crude Silodosin.

Ν,Ν-dialkyl impurity is 2.2% as per HPLC

Method F:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of was acetonitrile was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetra butyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added a solution of 4.4g of sodium hydroxide dissolved in 10ml of water and stirred the reaction at ambient temperature till completion. Added de-mineralized water and toluene and stirred at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure and to the solid mass so obtained were added 110ml of dimethyl sulfoxide and a solution of 1.95g (0.0488 mol) of sodium hydroxide dissolved in 7.95ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 9.5g of crude Silodosin.

Ν,Ν-dialkyl impurity is 3.1% as per HPLC

Method G:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of was Dimethyl sulfoxide was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 4.0g (0.0055 mol) of tetra butyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added a solution of 4.4g of sodium hydroxide dissolved in 10ml of water and stirred the reaction at ambient temperature till completion. Added de-mineralized water and toluene and stirred at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure and to the solid mass so obtained were added 110ml of dimethyl sulfoxide and a solution of 1.95g (0.0488 mol) of sodium hydroxide dissolved in 7.95ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 10.4g of crude Silodosin.

Ν,Ν-dialkyl impurity is 1.83% as per HPLC

Example 2

Purification of Crude Silodosin:

To the lOg (0.0080 mol) of crude mass of Silodosin was added 110ml of isopropyl alcohol followed by addition of 1.75g of oxalic acid at ambient temperature. Stirred the solution 6-8h and filtered the precipitates. Added ethyl acetate and water in the ratio of 1: 1 to the above solid followed by addition of 5ml of liquor ammonia. Stirred the reaction mass at ambient temperature for 15 min and separated the layers. Concentrated the organic layer to ¼ of its volume and left undisturbed overnight. Filtered the precipitates and recrystallized with ethyl acetate followed by drying under reduced pressure to get 5.1g of pure Silodosin. The amount of impurities and the percent impurity of the Silodosin obtained was as follows:

Ν,Ν-dialkyl impurity: undetectable amount

Other impurities: 0.03 to 0.09%

Silodosin purity: 99.65% (HPLC)

////WO 2016042441, Mankind Research Centre, Silodosin, New patent

Mehta Api Pvt Ltd, Cinacalcet hydrochloride, New patent, WO 2016027211

Mehta Api Pvt Ltd, Cinacalcet hydrochloride, New patent, WO 2016027211

Mehta Api had cinacalcet hydrochloride under development and holds US DMF and European DMF as listed on the company's website. Amgen and Kyowa Hakko Kirin, under license from NPS Pharmaceuticals, have developed and launched cinacalcet.

The present filing represents the first PCT filing from the assignee, which focuses on developing (using green chemistry) manufacturing and marketing of API's- multi step, highly complex, potent, chiral and semi-synthetic, advance intermediates, specialty chemicals and building blocks.

PROCESS FOR THE PREPARATION OF CINACALCET AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

MEHTA API PVT. LTD. [IN/IN]; 203, Centre Point, 2nd Floor, Near Hotel Kohinoor, J.B. Nagar, Andheri-Kurla Road, Andheri (East), Maharashtra, Mumbai 400 059 (IN)

KHAN, Rao, Uwais, Ahmad; (IN).
PATHAK, Rajesh, Harshnath; (IN).
PATIL, Chetan, Vinesh; (IN).
GAIKWAD, Sanjay, Ramrao; (IN).
APAR, Shrikrishna, Motiram; (IN).
LINGE, Govind, Udhavrao; (IN).
SHAIKH, Mohammad, Umar; (IN)

Cinacalcet (N-[l-(R)-(-)-(l-naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-l-aminopropane) of Formula II, belongs to a category of calcimimetics class of compounds. It is useful for the treatment of hyperparathyroidism and the preservation of bone density in patients with kidney failure or hypercalcemia due to cancer. It is marketed under the trade name of Senipar in United States and under the trade name of Mimpara in Europe.

US6211244 and Drugs of the future (2002) 27 (9): 831, discloses a synthesis of Cinacalcet by reductive amination which implies the reaction of (R)-(l-naphthyl) ethylamine of formula (IV) with 3 -[3- (trifluoromethyl) phenyl] propionaldehyde of formula (V) in the presence of titaniumisopropoxide to afford the corresponding cinacalcet imine of formula (III), which is reduced to cinacalcet of formula (II) with NaBH₄CN in ethanol.

WO2012007954 A 1 discloses process for Cinacalcet by reductive amination in presence of titanium Isopropoxide using NaBH₄CN, wherein an ether solvent is used instead of ethanol. Indian patent applications 2268/DEL/2008 and 87/MUM/2011 disclose preparation of Cinacalcet wherein reaction of (R)-(I-naphthyl)ethylamine of formula (IV) with 3-[3-(trifluoromethyl)phenyl] propionaldehyde of formula (V) is carried out in the presence of titaniumisopropoxide to afford the corresponding cinacalcet imine, which is further reduced to cinacalcet with NaBH_4.

The above disclosed processes require the use of reagents such as NaBH₄CN, titanium isopropoxide, which are extremely toxic and flammable as well as not being environmentally sound. These reagents therefore make the industrial application of the process difficult.

US20110124917A1 and WO2008068625A2 both disclose preparation of Cinacalcet by reductive amination wherein reduction is performed by using sodiumtriacetoxyborohydride as a selective reducing agent for imines.

Sodiumtriacetoxyborohydride is hygroscopic in nature hence demands anhydrous conditions to be maintained rendering it not suitable for use on industrial scale.

WO2012007954 A 1 discloses reaction and work-up in THF followed by salt formation in Di-isopropyl ether and further purification in two solvent system consisting of Water and Methanol or Water and Acetonitrile. US20110124917 discloses reaction in Methanol, Workup in toluene, Salt formation in Ethyl Acetate and purification in Isopropanol. WO2008068625A2 discloses reaction, salt formation and Purification in two solvent system consisting of isobutyl Acetate and n-Heptane. 2268/DEL/2008 discloses reaction in MDC, Salt formation in Ethyl Acetate and Purification in Ethyl Acetate and Di-isopropyl ether. 87/MUM/2011 discloses reaction in THF, work-up in toluene. Salt formation in two solvent system consisting of cyclohexane and MTBE.

All the above prior-art process employs use of different solvents for each unit operation or a two-solvent system for purification, thereby rendering the processes not easily scalable on industrial scale.

1367/MUM/2009 discloses reductive amination using sodium borohydride with 67.6% yield reported. 3068/MUM/2012 discloses reductive amination using sodium borohydride with 86% yield but with less purity. Further 3068/MUM/2012 requires the usage of sulphuric acid for the reaction of (R)-(I-naphthyl)ethylamine of formula (II) with 3-[3-(trifluoromethyl)phenyl] propionaldehyde of formula (III).

Thus the processes disclosed above have one or other drawbacks, ranging from poor yield, purity, use of difficult to handle and toxic reagents or use of different solvents for each unit operation.

In view of the problems occurred in above methods, there remains a need for more economical and efficient industrially scalable process for the preparation of Cinacalcet and its pharmaceutically acceptable salts, which overcomes the drawbacks as disclosed in the prior art.

The present inventors have surprisingly found that when the condensation of [3-(trifluoromethyl)phenyl]propionaldehyde of formula - (V) with (R)-(l- naphthyl)ethylamine formula - (IV) is carried out in the absence of any reagent and water is removed under vacuum by azeotropic distillation at low temperatures in the optional presence of water scavengers, than Cinacalcet.hydrochloride with high purity and yield is obtained. Further the process is also industrially feasible due to the non-usage of hazardous reagents as also due to the reduction in isolation and purification steps.

Example I:

Preparation of Cinacalcet Hydrochloride, Formula (la)

To (1000 ml) toluene in a 4Neck Round Bottom flask along with dean-stark apparatus coupled to a condenser, charge (80gms) (R)-(l- naphthyl) ethylamine of formula - (IV). Cool to 10-15°C. Charge (lOOgms) 3-[(3-Trifluoromethyl)phenyl] propionaldehyde of formula (V). Apply vacuum to the reaction mass through condenser and maintain for 8 hrs simultaneously azeotroping out water generated in the reaction till the reaction complies by thin layer chromatography to give Cinacalcet imine of formula (III) in-situ. Release vacuum after the reaction complies. Water collected after Azeotropic distillation: 7-7.5 ml. Cool the reaction mass to 5-10°C. Charge (35 gms) sodium borohydride in two lots to the reaction mass and raise the temperature to 25-30°C. Maintain the reaction mass for 8 hrs to give Cinacalcet of formula (II) in-situ. After the reaction complies by thin layer chromatography adjust the pH of the reaction mass to about pH 6 using acetic acid. Charge (200 ml) water to the reaction mass and stir for 30 mins. Separate Layers the organic layer and treat with 15% HC1 (150 ml). Stirr the Reaction mass at 40 - 50°C for one hour and separate the layer. Heat the toluene at same temperature. Adjust pH of toluene layer to below pH-2 by treating with 15% HC1 (150 ml) at 40-45 °C. Distill out 500 ml toluene under vacuum below 45 °C. Gradually charge 500 ml water to the reaction mass along with simultaneously distilling out 500 ml toluene approximately. Filter the reaction mass to give crude Cinacalcet Hydrochloride. Dry at 45-50°C for 8 hrs.

Weight: 182 gms

% Yield on theoretical basis: 98.9%

Purity: 97.54%

To (182 gms) of Crude cinacalcet Hydrochloride charge (800 ml) Methyl tert butyl ether and stirr for 60°C for 3 hrs. Cool gradually at 25-30°C and further chill the reaction mass to 0°C -5°C. Maintain the reaction mass at 0-5°C for 2 hrs and filter under vacuum followed by washing to the wet-cake with (100 ml) chilled Methyl tert butyl ether.

Wet cake is dried under vacuum at 40°C.

Weight: 163 gms

Yield on theoretical basis: 88.58%

Purity: 99.54%

To (163 gms) of MTBE pure Cinacalcet Hydrochloride is charged (400 ml) Isopropanol and heated to 70-75°C to get a clear solution which is then gradually cooled to 25-30°C and further chilled to 0-5 °C. The reaction mass is maintained for 2 hrs at same temperature and filtered under vacuum followed by washing with chilled isopropanol. Wet cake is dried under vacuum at 40°C.

Weight: 157 gms

Yield on theoretical basis: 85.32%

Purity: 99.91%

Example II:

Preparation of Crude Cinacalcet Hydrochloride, Formula (la)

To (1000 ml) toluene in a 4Neck Round Bottom flask, is charged (80gms) (R)-(l-naphthyl)ethylamine of formula (IV). Cooled to 10-15°C. Charged (lOOgms) 3-[(3-Trifluoromethyl)phenyl] propionaldehyde of formula (V) slowly. Charged (1 gm) Calcium Chloride and maintained for 8 hrs till the reaction complies by thin layer chromatography to give Cinacalcet imine of formula (III) in-situ. After the reaction complies, the reaction mass is cooled to 5-10°C. Charged (35 gms) sodium borohydride in two lots to the reaction mass and raised the temperature to 25-30°C.The reaction mass is maintained for 8 hrs to give Cinacalcet Free base of formula (II) in-situ. After the reaction complies by thin layer chromatography pH of the reaction mass is adjusted to about pH 6 using acetic acid. Charged (200 ml) water to the reaction mass and stirred for 30 mins. Layers separated and the organic layer is treated with 15% HC1 (150 ml). Reaction mass is stirred at 40 - 50°C for one hour and layer separated. Toluene layer is water washed at same temperature. pH of toluene layer adjusted to below pH-2 by treating with 15% HC1 (150 ml) at 40-45°C. Distill out 500 ml toluene under vacuum below 45 °C. Gradually charge 500 ml water to the reaction mass along with simultaneously distilling out 500 ml toluene approximately. Filter the reaction mass to give crude Cinacalcet Hydrochloride. Dry at 45-50°C for 8 hrs

Weight: 178 gms

Yield on theoretical basis: 96.73%

Purity: 94.88%

To (178 gms) of Crude cinacalcet Hydrochloride charged (800 ml) Methyl tert butyl ether and stirr for 60°C for 3 hrs. Allowed to cool gradually at 25-30°C and further chilled the reaction mass to 0-5°C. Maintained the reaction mass at 0-5°C for 2 hrs and filtered under vacuum followed by washing to the wet-cake with (100 ml) chilled Methyl tert butyl ether. Wet cake is dried under vacuum at 40°C.

Weight: 159 gms,

% Yield on theoretical basis: 86.40%

Purity: 99.77%

To (159 gms) of MTBE pure Cinacalcet Hydrochloride is charged (400 ml) Isopropanol and heated to 70-75°C to get a clear solution. Gradually cool to 25-30°C and further chill to 0-5 °C. Maintain the reaction mass is for 2 hrs at same temperature and filte under vacuum followed by washing with chilled isopropanol. Wet cake is dried under vacuum at 40°C. Weight: 150 gms

% Yield on theoretical basis: 81.51 %

Purity: 99.91 %

Example III:

Preparation of Cinacalcet Hydrochloride, Formula (la)

To (1000 ml) toluene in a 4Neck Round Bottom flask, charge (80gms) (R)-(l-naphthyl)ethylamine of formula (IV). Cool to 10-15°C. Charge (lOOgms) 3-[(3-Trifluoromethyl)phenyl] propionaldehyde of formula (V). Charge ( 1 gm) Molecular Sieves and maintain the reaction mass for 8 hrs till the reaction complies by thin layer chromatography to give Cinacalcet imine of formula (III) in-situ. After the reaction complies, cool the reaction mass to 5-10°C. Charge (35 gms) sodium borohydride in two lots to the reaction mass and raise the temperature to 25-30°C. Maintain the reaction mass for 8 hrs to give Cinacalcet of formula (II) in-situ. After the reaction complies by thin layer chromatography adjust the pH of the reaction mass to about pH 6 using acetic acid. Charge (200 ml) water to the reaction mass and stir for 30 mins. Separate the layers and treat organic layer with 15% HC1 (150 ml).Stirr Reaction mass is at 40 - 50°C for one hour and separate layers. Water wash toluene layer at same temperature. Adjust pH of toluene layer pH-2 by treating with 15% HC1 (150 ml) at 40-45 °C. Distill and degasse under vacuum below 70°C to give Cinacalcet Hydrochloride

Weight: 172 gms

Yield on theoretical basis: 93.47%

Purity: 97.29%

To (172 gms) of Crude cinacalcet Hydrochloride charge (800 ml) Methyl tert butyl ether and stirr for 60°C for 3 hrs. Cool gradually at 25-30°C and further chill the reaction mass to 0-5 °C. Maintain the reaction mass at 0-5 °C for 2 hrs and filter under vacuum followed by washing to the wet-cake with (100 ml) chilled Methyl tert butyl ether.

Wet cake is dried under vacuum at 40°C.

Weight: 155 gms

% Yield on theoretical basis: 84.23%

Purity: 99.57%

To (155 gms) of MTBE pure Cinacalcet Hydrochloride charge (400 ml) Isopropanol and heat to 70-75°C to get a clear solution which is then gradually cooled to 25-30°C and further chill to 0-5 °C. Maintain the reaction mass i for 2 hrs at same temperature and filter under vacuum followed by washing with chilled isopropanol. Wet cake is dried under vacuum at 40°C.

Weight: 146 gms

% Yield on theoretical basis: 79.34%

Purity: 99.83%

Mehta API Pvt. Ltd.  

Pharmaceutical Company

 

Address: 203, Center Point, J.B. Next To Kohinoor,, J B Nagar, Andheri East, Mumbai, Maharashtra 400059

MR HARSHADRAI P MEHTA

Chairman & Managing Director

He is the founder of Mehta Group. With over five decades of dedicated work and a wealth of experience in the API Manufacturing field. He is the driving force behind MAPL’s success.

Devendra Mehta

Chief Executive Officer at MEHTA API PVT LTD

////////Mehta Api Pvt Ltd, Cinacalcet hydrochloride, New patent, WO-2016027211, WO 2016027211














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Afatinib dimaleate, Dr Reddy's, New patent, WO 2016027243

Afatinib dimaleate, Dr Reddy's, New patent,  WO-2016027243, 

WO 2016027243

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara Hills, Hyderabad, Telangana, India - 500034. Hyderabad 500034 (IN)

RAMAKRISHNAN, Srividya; (IN).
PEDDY, Vishweshwar; (IN).
MAHAPATRA, Sudarshan; (IN).
KANNIAH, Sundara Lakshmi; (IN).
CHENNURU, Ramanaiah; (IN).
JOSE, Jithin; (IN).
DHAGE, Yogesh Mohanrao; (IN).
PEDDIREDDY, Subba Reddy; (IN).
YARRAGUNTLA, Sesha Reddy; (IN).
RAGHUVEER, Sherial; (IN).
KOLLA, Srinivasa Rao; (IN).
ANIL KSHIRSAGAR, Shivani; (IN).
JAFAR SHAIKH, Latif; (IN).
BANDARU, Srinivasulu; (IN)

The drug compound having the adopted name afatinib dimaleate, has a chemical name N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1 :2), and is represented by structure of formula I

Formula I

Afatinib dimaleate is an anticancer protein kinase inhibitor indicated for treatment of non-small-cell lung cancer. Process for preparation of afatinib, afatinib dimaleate and intermediates useful in preparation of afatinib dimaleate are described in US Patent Nos. 7,019,012; 8,426,586 and 7,960,546.

US Patent No. 8,426,586 discloses crystalline Form A of afatinib dimaleate salt and processes for preparation thereof. US Patent Application Publication No. 20140051713 discloses crystalline Form B of afatinib dimaleate salt and processes for preparation thereof. PCT Application Publication No. 2013052157 discloses crystalline Form C, Form D and Form E of afatinib dimaleate salt and processes for preparation thereof. The PCT publication also discloses crystalline Form A, B, C and Form D of afatinib base.

Polymorphism, the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Discovering new polymorphic forms, hydrates and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid state forms of Afatinib di-maleate.

SUMMARY

The present application provides novel solid state forms of Afatinib di-maleate, processes for preparing them, and pharmaceutical compositions containing them.

The present application also encompasses the use of novel solid state forms of Afatinib di-maleate provided herein, for the preparation of other afatinib salts, other solid state forms of afatinib dimaleate, and formulations thereof.

The present application also encompasses the use of any one of the novel solid state forms of Afatinib di-maleate disclosed herein for the preparation of a medicament, preferably for the treatment of cancer, particularly for the treatment of cancers mediated by epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases, e.g., solid tumors including NSCLC, breast, head and neck cancer, and a variety of other cancers mediated by EGFR or HER2 tyrosine kinases. The present invention further provides a pharmaceutical composition comprising any one of the Afatinib di-maleate crystalline forms of the present invention and at least one pharmaceutically acceptable excipient.

The present application also provides a method of treating cancer, comprising administering a therapeutically effective amount of at least one of the Afatinib di-

maleate novel solid state forms of the present application, or at least one of the above pharmaceutical compositions to a person suffering from cancer, particularly a person suffering from a cancer mediated by epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases, e.g., solid tumors including but not limited to NSCLC, breast, head and neck cancer, and a variety of other cancers mediated by EGFR or HER2 tyrosine kinases.

Example 1 : Preparation of amorphous form of afatinib dimaleate.

2.0 g of afatinib dimaleate was dissolved in 80 mL of a mixture of methanol and acetone (3:1 ) at 26°C and stirred for 15 min. The solution was filtered to remove the undissolved particles and the filtrate was distilled under reduced pressure at 50°C. After distillation the solid was dried under vacuum at 45°C to get 1 .29 g of amorphous afatinib dimaleate. PXRD pattern: Fig. 1 .

///////Afatinib dimaleate, Dr Reddy's, New patent,  WO-2016027243, WO 2016027243