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

WO 2016027283, New patent, Indacaterol, Reddy-Cheminor Inc

Beta 2 adrenoceptor agonist

Chronic obstructive pulmonary disease

WO 2016027283, New patent, Indacaterol, Reddy-Cheminor Inc

A process for preparing indacaterol and salts thereof

REDDY, G Pratap; (IN).
SUNKU, Venkataiah; (IN).
BABU, Sunkaraneni Suresh; (IN)

The present invention relates to a process for preparing indacaterol or salts thereof. The process comprises of forming compound of Formula 1 by reacting compound of Formula 2 and compound of Formula 3 in the presence of a solvent to Form compound of Formula 4, 5 which on removal of the protecting groups forms compound of Formula 1.

Indacaterol maleate is a beta-selective adrenoceptor agonist with potent bronchodilator activity. Indacaterol is chemically known as 5-[(R)-2-(5, 6-diethyl-indan-2- yl amino)-l-hydroxy-ethyl ]-8-hydroxy-(lH)-quinolin-2-one.

US7534890 claims a process to prepare 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)- 1 -hydroxy-ethyl] -8-hydroxy-(l H)-quinolin-2-one salt. One of the key steps in the process is reacting an epoxide, such as 8-substituted oxy-5-(R)- oxiranyl-(lH)-quinoline-2-one [Formula (I)] with an amine, such as 2-amino-(5,6-diethyl)-indan to form an intermediate 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l -hydroxy-ethyl]-8- substituted oxy-(lH)-quinolin-2-one [Formula (Ha)].

The drawback of this process is opening of epoxide ring is not regioselective and thereby resulting, in formation of substantial quantities of impurities as by products, Formula (lib) and Formula (lie) resulting in overall lower yields. The quantity of 2- amino-(5,6-diethyl)-indan used in this step is also large excess than theoretical amounts. Subsequent improvements also did not address this problem effectively.

WO 2013/132514 discloses a process to prepare Indacaterol involving the steps of treating a compound of Formula (III), wherein L is a leaving group, with the amine, 2-amino-(5,6-diethyl)-indan or its acid addition salts to obtain a compound of Formula (IV) or its acid addition salts.

Though higher yields have been claimed, the process has not overcome completely all the problems mentioned earlier.

There is a need for developing a more efficient process for preparing Indacaterol or salts thereof especially for large scale production with higher yields.

 

The reaction scheme of synthesis of compound of Formula 3 is represented below.

Formula 3 Formula 13 Formula 12

xample 1

Process to prepare 5-[ (R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-( lH)-quinolin-2-one

2-Chloro-5,6-diethylindan (4.2g) was added to a solution of 5-[(R)-(2-amino-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one (6g) in dimethylformamide (20ml) followed by addition of N,N-diisopropyl-N-ethylamine (3.6 g) and sodium iodide (lg) at room temperature and stirred for 10 minutes. The reaction mixture was heated to 90° C and the temperature was maintained at 90 °C till the completion of reaction. The reaction mass was cooled to room temperature and diluted with dichloromethane (100ml) and water (100 ml) and stirred for 30 minutes. The organic phase was separated and the aqueous layer was extracted with dichloromethane. Combined organic layer was washed with water, dried and concentrated. The resulting residue was dissolved in isopropyl alcohol under reflux and cooled slowly to obtain 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-phenylmethoxy -(lH)-quinolin-2-one, which was isolated by filtration and dried under vacuum (7.4 g). Yield: 79.3 %. Purity of the product is >95 % (HPLC).

Example 2

Process to prepare 5-[(R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-( lH)-quinolin-2-one

Solution of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-phenylmethoxy-(lH)-quinolin-2-one (lOg) in methanol (100ml) and acetic acid (20ml) was hydrogenated using palladium on charcoal 5% (1.5g) until completion of the reaction. The mixture was filtered over celite and the filtrate was concentrated at 55°C under vacuum. The residue obtained was dissolved in hot methanol to precipitate 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-! -hydroxy-ethyl]-8-hydroxy-(lH)-quinolin-2-one.

Example 3

Process to prepare 5-[(R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-(lH)-quinolin-2-one maleate

Crude 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l -hydroxy-ethyl]-8-hydroxy-(lH)-quinolin-2-one prepared by the process of Example 2 was added to a solution of maleic acid (2.6g) in methanol and the resulting clear solution was slowly cooled to 5° C and stirred for 2 hours at the same temperature. The slurry was filtered, washed with cold methanol and dried to obtain 5-[(R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-(lH)-quinolin-2-one maleate (8.8g). Yield: 83.5 %. Purity of the product is >99%. E.e. >99 %.

Example 4

Process for preparing 5-[(R)-(2-phthalimido-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one

Diisopropylethylamine (6g) was added to a solution of phthalimide (6g) in dimethylformamide (30 ml) at room temperature. To this solution, 8-(phenylmethoxy)-5-[(R)-2-bromo-l-hydroxy-ethyl]-(lH)-quinoline-2-one (11 gm) was added slowly followed by sodium iodide (1 g). The resulting mass was heated to 90°C and stirred till the completion of reaction as monitored by TLC. The reaction mass was diluted with water (200 ml) and the crude product was isolated by filtration. The wet filter cake was suspended in water (60 ml), stirred for 1 hour, filtered, washed with water to obtain 5-[(R)-(2-phthalimido-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one (10.4 gm) after drying. Yield: 80.7 %.

Method A- Process for preparing 5-[(R)-(2-amino-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one

To a solution of 5-[(R)-(2-phthalimido-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one ( 13.2 g) in a mixture of isopropanol (86 ml) and water (14 ml) sodium borohydride (4.6 g) was added slowly at room temperature and stirred overnight. Thereafter, the pH of the reaction mass was lowered to 5.5 with acetic acid, and then the reaction mass was heated to reflux for two hours. Isopropanol was distilled out under reduced pressure. The residue was diluted with ethyl acetate (120 ml) and concentrated hydrochloric acid (8 ml) was added and stirred for 15 minutes for the salts to precipitate out. The reaction mass was filtered and the salt was washed with ethyl acetate. To the clear filtrate concentrated hydrochloric acid (10 ml) was added and stirred at 5° C for 30 minutes for 5-[(R)-(2-amino-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one to separate out as hydrochloride salt. The product was isolated by filtration and dried under vacuum (8.2 g). The hydrochloride salt was dissolved in minimum amount of water and basified with sodium hydroxide solution. The product was isolated as free amine by concentrating the solution under reduced pressure and extracting the residue with isopropyl alcohol and distilling out the solvent (7.45 g). Yield 80 %.

1H-NMR (CDC13) ppm: 2.56-2.70 (m, 2H), 3.35 (s, br, 2H, exchangeable), 4.89 (m, 1H), 5.29 (s, 2H), 5.76 (s, 1H, exchangeable), 6.53 (d, 1H), 7.11-7.19 (dd, 2H), 7.29-7.36 (dd, 1H), 7.39 (d, 2H), 7.57 (d, 2H), 8.21 (d, 1H), 10.7 (s, br, 1H, exchangeable).

Method B- Process for preparing 5-[(R)-(2-amino-l-hydroxy-ethyl)-8-phenylmethoxy-( lH)-quinolin-2-one

To a solution of 5-[(R)-(2-phthalimido-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one ( 10 g) in ethanol (60 ml) hydrazine hydrate (4.8 g) was added and refluxed the mixture for about 6 hours. The solvent was distilled out under reduced pressure. To the residue, concentrated hydrochloric acid (16 ml) was added and heated to about 80°C and maintained till the completion of the reaction. The reaction mass was cooled to room temperature and filtered. The clear filtrate was basified and concentrated under reduced pressure. The product was isolated as free amine (5.8 g) by extracting with isopropyl alcohol and distilling out the solvent. Yield: 83%.

Method C

Preparation of 5-(2-benzylamino-l-hydroxy-ethyl)-8-phenylmethoxy-( lH)-quinolin-2-one 5-Acetyl-8-phenylmethoxy-(lH)-quinolin-2-one (30 g) was refluxed with selenium dioxide

(11.5 g) in a mixture of dioxane (350 ml) and water (30 ml) for 16 hours. The reaction mixture was diluted with dioxane (150 ml) and precipitated inorganic salts were removed by filtration. Clear filtrate was concentrated to about 60 ml under vacuum and diluted with methanol (100 ml). The reaction mass was cooled to 15° C and benzylamine (7.5 g) was added slowly over a period of 45 minutes and stirred at the same temperature for two hours.

The reaction mass was further cooled to 0°C and sodium borohydride (2.8 g) was added slowly over a period of one hour. Thereafter, the reaction mass was stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum and diluted with 300 ml water and stirred at 20° C for three hours. The precipitated product was collected by filtration, washed with water followed by isopropyl ether and then dried (28.2 g) to obtain 5-(2-benzylamino-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one.

Example 5

Preparation of 5-acetyl-8-phenylmethoxy-(lH)-quinolin-2-one

To a solution of 5-acetyl-8-hydroxy-(lH)-quinolin-2-one (35 g) in dimethylformamide (175 ml) potassium carbonate (35 g) was added at room temperature and stirred for 10 minutes. To the suspension, benzylbromide (32 g) was slowly added over a period of 30 minutes and stirred for 2 hours at the same temperature for completion of reaction (monitored by TLC). The reaction mass was diluted with water (800 ml) and stirred for 20 minutes for the product to precipitate out. The product was filtered, washed with water and dried under vacuum to get the title product (48 g).

Example 6

Preparation of 5-(2-bromoacetyl)-8-phenylmethoxy-( lH)-quinolin-2-one

Boron trifluoride-diethyletherate (29 ml) was slowly added to a solution of 5-acetyl-8-phenylmethoxy-(lH)-quinolin-2-one (50 g) in dichloromethane (500 ml) at 0° C and stirred for 10 minutes at the same temperature to get a thick precipitate. The reaction mass was heated to reflux temperature and bromine solution was added (29 g in 190 ml dichloromethane) slowly over a period of 2 hours under reflux (the HBr fumes coming from the condenser was scrubbed). Thereafter, the reaction mass was refluxed for further 45 minutes. The solvent was distilled out completely under vacuum and the mass was triturated with 10% aqueous sodium carbonate solution (100 ml). The suspension was filtered, washed with water and the crude product was taken for the next stage reaction.

Example 7

Preparation of 5-(2-phthalimido-l-oxo-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one

Potassium carbonate (33.4 g) was added to a solution of phthalimide (21.73 g) in dimethylformamide (80 ml) at room temperature and stirred for 10 minutes. To this suspension, crude 5-(2-bromoacetyl)-8-phenylmethoxy-(lH)-quinolin-2-one of example 6, dissolved in dimethylformamide (120 ml), was added slowly over a period of 20 minutes. The resulting suspension was stirred at 50° C for about 1 hour for the completion of reaction as monitored by TLC. The mixture was diluted with water (800 ml) and the crude product was isolated by filtration. The wet filter cake was suspended in water (600 ml), stirred for 1 hour, filtered, washed with water and dried under vacuum to get 5-(2- phthalimido-l-oxo-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one (67.4 g). Over all yield

(after two steps): 90%.

Example 8

Preparation of 5-[(R)-(2-phthalimido-l-hydroxy-ethyl)-8-phenylmethoxy-(lH)-q inolin-2-one

To a solution of (R)-2-methyl-CBS-oxazaborolidine (1M in toluene, 4.2 ml) in dry

tetrahydrofuran (THF, 50 ml) Borane-diethylaniline (19 ml) was added slowly at - 10° C

and the contents were stirred at the same temperature for 15 minutes. A solution of 5-(2-

Phthalimido-l-oxo-ethyl)-8-phenylmethoxy-(lH)-quinolin-2-one ( 8.3 g), of example 7, in

a mixture of dry THF (50 ml) and dichloromethane (50 ml), was added slowly to the

reaction mass at - 10° C. The reaction mass was further stirred for 2 hours and then

methanol was added and the temperature was slowly raised to room temperature. Dilute

sulfuric acid (6N, 10 ml) was added to the reaction mixture and stirred for 15 minutes. The

reaction mixture was concentrated under vacuum and the crude mass was extracted with

ethyl acetate. The organic phase was washed with dilute sulfuric acid and then water. The

solvent was distilled out completely under vacuum and triturated with hexane. The

compound was isolated by filtration and dried (7.6 g). Yield: 91.1%. e.e.. >97%.

Example 9

Process of preparing 2-chloroindan

2-hydroxy indan (lOOg) was dissolved in 1, 2-dichloroethane (400 ml) and added to thionyl

chloride (125 g) slowly over a period of an hour. Temperature was maintained at less than

10° C. Thereafter, the reaction mass was slowly heated and refluxed till the completion of the reaction. The reaction was monitored by TLC. The reaction mass was cooled to room temperature and poured in to ice water, stirred for 1 hour and organic layer was separated. The aqueous layer was extracted with dichloroethane. Organic layers were combined and washed with water, sodium bicarbonate solution and dried over anhydrous sodium sulphate. Solvent was distilled out completely and the crude product was distilled under vacuum to obtain 2-chloroindan as a colorless liquid (118 g).

Example 10

Process for preparing 5-acetyl-2-chloroindan

Aluminium chloride (146 g) was added in small lots to nitromethane (500 ml) and the solution was cooled to 5° C under inert atmosphere while stirring. Acetyl chloride (84 g) was slowly added keeping the temperature at 5° C. Solution of 2-chloroindan (118 g) was slowly added in acetyl chloride (84 g) keeping temperature at 5° C. After completion of reaction, monitored by TLC, the reaction mass was poured into cold IN HC1 (2000 ml) solution and stirred for 30 minutes. The product was extracted into di-isopropyl ether. The combined organic layer was washed with water, bicarbonate solution, brine and dried over anhydrous sodium sulphate. The solvent was completely distilled out to obtain 5-acetyl-2-chloroindan as yellow waxy solid (130 g).

Example 11

Process for preparing 2-chloro-5-ethylindan

1 Liter hydrogenation vessel was charged with 50 grams of 5-acetyl-2-chloroindan, 400 ml of methanol and 10 ml of acetic acid. Palladium on charcoal 5% (5 g) was added and the reaction mass was hydrogenated until complete conversion to 2-chloro-5-ethylindan. The mixture was filtered over a bed of celite. The filtrate was concentrated under reduced pressure to obtain 2-chloro-5-ethylindan as an oily mass (42 g).

Example 12

Process for preparing 5-acetyl-2-chloro-6-ethylindan

5-acetyl-2-chloro-6-ethylindan was prepared from 2-chloro-5-ethylindan (20 g) in accordance with the procedure followed in Example 10.

Example 13

Process for preparing 2-chloro-5, 6-diethylindan

Hydrogenation of 5-acetyl-2-chloro-6-ethylindan using Palladium on charcoal adopting the procedure as reported in Example 11, gave 2-chloro-5, 6-diethylindan as a liquid. The crude product was distilled under vacuum to get colorless liquid.

1H-NMR (CDC13) ppm: 1.19-1.29 (t, 6H), 2.61-2.66 (q, 4H), 3.13-3.18 (dd, 2H), 3.36-3.41 (dd, 2H), 4.66-4.72 (m, 1H), 7.05 (s, 2H).

////////////WO 2016027283, New patent, Indacaterol, Reddy-Cheminor Inc