Sacubitril, WO 2016180275, New patent, SUZHOU PENGXU PHARMATECH CO., LTD

Sacubitril, WO 2016180275, New patent, SUZHOU PENGXU PHARMATECH CO., LTD

AHU-377 INTERMEDIATES AND METHOD FOR PREPARING AHU-377 AND AHU-377 INTERMEDIATES PATENT

WO2016180275, new patent, SUZHOU PENGXU PHARMATECH CO., LTD. [CN/CN]; 3rd Floor Building 7, 2358 Chang An Road, Wujiang Suzhou, Jiangsu 215200 (CN)

WANG, Peng; (CN).

LI, Pixu; (CN).

GU, Xiangyong; (CN)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016180275&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Heart failure is a very high mortality syndrome, for patients with heart failure, so far no drug can significantly improve mortality and morbidity, and thus a new type of therapy is necessary. AHU-377 (CAS No. 149709-62-6) is an enkephalinase inhibitor, which is a prodrug ester groups can be lost through hydrolysis, converted to pharmaceutically active LBQ657, inhibit endorphin enzyme (NEP) the role of the main biological effects of NEP is to natriuretic peptides, bradykinin and other vasoactive peptide degradation failure. AHU-377 and angiotensin valsartan composition according to the molar ratio of 1 LCZ696. LCZ696 is an angiotensin receptor enkephalinase inhibitors, which can lower blood pressure, treat heart failure may become a new drug. Clinical data show, LCZ696 is more effective for the treatment of hypertension than valsartan alone.

 

Patents US 5,217,996 and US 5,354,892 reported the first synthesis of AHU-377, the synthetic route is as follows:

 

 

 

 

Reaction with unnatural D-tyrosine derivative as a substrate, more expensive, while the second step in the synthesis is necessary to use Pd-catalyzed Suzuki coupling reaction, whereby preparative route costs than the AHU-377 high.

 

 

Patent US 8,115,016 above routes also reported the departure from the pyroglutamate, through multi-step process for preparing a reaction AHU-377, which is more difficult methylation reaction, and the yield is not high. Patent US 8,580,974 also reported a carbonyl group of the a- introducing N, N- dimethyl enamine is converted to methyl, however, there are some problems in the route for constructing methyl chiral centers, are not suitable for scale-up synthesis route as follows:

 

 

 

 

About the latest AHU377 synthesis intermediates, Patent WO2014032627A1 reported using a Grignard reagent to react with epichlorohydrin, a quicker been important intermediates, synthetic route Compound AHU377 synthesized as follows:

 

However, the second step of the synthetic route use succinimide nitrogen atoms introduced by Mitsunobu reaction with hydrochloric acid hydrolysis to remove, then converted to Boc protected at the end of the synthesis process AHU377 Boc will have to take off protection, then any connection with succinic anhydride reaction product introduced into the structure of succinic acid portion, so that this method of atom economy and the economy of the steps are low.

 

Example 1

 

Synthesis of Compound 2

 

 

In inert atmosphere, a solution of three 500mL flask was added compound 1 (10g, 1eq), dissolved after 90mL THF, was added CuI (4.814g, 0.1eq), the system moves to the low temperature in the cooling bath to -20 ℃ when, biphenyl magnesium bromide dropwise addition, the internal temperature was controlled not higher than -10 ℃. Bi closed refrigeration drop, return to room temperature overnight. Completion of the reaction, the reaction solution was poured into saturated the NH ₄ of Cl (10vol, 100 mL) was stirred at room temperature for 0.5h. Suction filtered, the filter cake was rinsed with a small amount of EA, and the filtrate was transferred to a separatory funnel carved, and the aqueous phase was extracted with EA (10vol × 2,100mL × 2) and the combined organic phases with saturated NaHC [theta] ₃ , the NH ₄ of Cl, each Brine 150mL (15vol) washed once, dried over anhydrous over MgSO ₄ dried, suction filtered, and concentrated to give a white solid. Product obtained was purified by column 15.2g, yield 78%.

 

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.6Hz, 2H), 7.52 (D, J = 8.1Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.38-7.25 (m, 8H), 4.62-4.47 ( m, 2H), 4.09 (dd, J = 6.7,3.5Hz, 1H), 3.54 (dd, J = 9.5,3.5Hz, 1H), 3.43 (dd, J = 9.4 , 6.9Hz, 1H), 2.84 ( d, J = 6.6Hz, 2H), 2.38 (s, 1H).

 

Example 2

 

Synthesis of Compound 3

 

 

In an inert gas, at room temperature was added to the flask 500mL three Ph3P (18.54g, 2eq), 240mL DCM dissolution, butyryl diimide (of 6.44 g), compound 2 (15g), an ice-water bath cooling to 0 ℃ or so, was added dropwise DIAD (14mL) was complete, the reaction go to room temperature.Starting material the reaction was complete, the system was added to water (100 mL) quenched the reaction was stirred for 10min; liquid separation, the aqueous phase was extracted with DCM (100mL × 2), the combined organic phases with saturated Brine 100mL × 2), dried over anhydrous over MgSO ₄ dried , filtration, spin dry to give a white solid; product was purified by column 15.4g, yield 82%.

 

NMR data for the product are as follows:

 

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.56 (D, J = 7.4Hz, 2H), 7.49 (D, J = 8.0Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.37-7.30 (m, 3H), 7.27 ( d, J = 6.7Hz, 3H), 7.22 (d, J = 8.0Hz, 2H), 4.75 (s, 1H), 4.56 (d, J = 12.0Hz, 1H), 4.45 (d, J = 12.0Hz, 1H ), 4.06 (t, J = 9.6Hz, 1H), 3.70 (dd, J = 10.0,5.2Hz, 1H), 3.23 (dd, J = 13.8,10.3Hz, 1H) , 3.14-3.00 (m, 1H), 2.48 (d, J = 4.0Hz.4H).

 

Example 3

 

Synthesis of Compound 4

 

 

Protection of inert gas, at room temperature was added to the flask 1L three compound 3 (18.81g), 470mL EtOH was dissolved, was added Pd / C, replaced the H ₂ three times, move heated on an oil bath at 60 ℃ reaction. Raw reaction was complete, the system was removed from the oil bath, the reaction solution was suction filtered through Celite and concentrated to give the crude product. It was purified by column pure 11.8g, a yield of 81.2%.

 

NMR data for the product are as follows:

 

₁ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.8Hz, 2H), 7.51 (D, J = 7.8Hz, 2H), 7.42 (T, J = 7.5Hz, 2H), 7.33 (T , J = 7.2Hz, 1H), 7.26 (d, J = 7.2Hz, 2H), 4.55 (d, J = 5.2Hz, 1H), 4.06-3.97 (m, 1H), 3.86 (dd, J = 12.0, 3.1Hz, 1H), 3.16 (dd , J = 8.1,2.9Hz, 2H), 2.58 (t, J = 7.0Hz, 4H), 1.26 (s, 2H).

Example 4

 

Synthesis of Compound 7

 

Protection of inert gas, at room temperature to a 25mL flask was added three Dess-Martin oxidant (767.7mg), 10mL DCM was dissolved, the system was cooled down to -10 deg.] C, was added 4 (500mg). Starting material the reaction was complete, to the system was added saturated NaHCO3 and Na2S2O3 each 5mL, quench the reaction stirred for 10min; aqueous phase was extracted with DCM (10mL × 3) and the combined organic phases with saturated NaHCO3, Brine 30mL each wash, dried over anhydrous MgSO4, filtration, spin dried to give the crude product used directly in the next reaction cast.

Example 5

 

Synthesis of Compound 8

Inert gas, at room temperature for three to 500mL flask 7 (497.5mg), 10mL DCM to dissolve an ice water bath to cool, added phosphorus ylide reagent (880.6mg), the system was removed from the ice water bath at room temperature. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. Liquid separation, the aqueous phase was extracted with DCM (10mL × 2), organic phases were combined, washed with saturated Brine 20mL × 2, dried over anhydrous MgSO4, filtration, spin crude done. Product obtained was purified by column 563mg, 90% yield.

 

NMR data for the product are as follows:

 

¹ the H NMR (400MHz, CDCl ₃ ) δ7.60-7.53 (m, 2H), 7.51 (D, J = 8.1Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.33 (D, J = 7.3Hz, 1H), 7.23 (d , J = 8.1Hz, 2H), 7.13 (dd, J = 9.2,1.5Hz, 1H), 5.26 (td, J = 9.5,6.9Hz, 1H), 4.25-4.05 ( m, 2H), 3.40 (dd , J = 13.7,9.7Hz, 1H), 3.13 (dd, J = 13.8,6.7Hz, 1H), 2.53 (d, J = 2.2Hz, 4H), 1.85 (d, J = 1.4Hz, 3H), 1.30 ( t, J = 7.1Hz, 3H).

Example 6

 

Synthesis of Compound 9

 

Protection of inert gas, at room temperature to a 50mL flask was added three 8 (365mg, 1eq), 9mL of ethanol and stirred to dissolve, the system was replaced with hydrogen three times, was added Pd / C (25% w / w) at room temperature. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. The reaction mixture was suction filtered through Celite and concentrated to give the crude product. Product was purified by column, yield 80.2%, purity 97.2%.

Example 7

 

Synthesis of Compound 10

Equipped with Compound 9 (100mg) acetic acid A reaction flask (9mL), hydrochloric acid (1mL). The reaction was heated oil bath at 80 deg.] C. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. After saturated NaHCO3 and extracted with EA and concentrated to give crude product. Product obtained was purified by column 90mg, yield 84%.

 

NMR data for the product are as follows:

 

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.54 (m, 2H), 7.53-7.48 (m, 2H), 7.41 (dd, J = 10.5,4.9Hz, 2H), 7.31 (dd, J = 8.3 , 6.4Hz, 1H), 7.22 ( d, J = 8.2Hz, 2H), 5.93 (t, J = 9.7Hz, 1H), 4.34-4.00 (m, 3H), 2.91-2.71 (m, 2H), 2.68 -2.57 (m, 2H), 2.55 (ddd, J = 9.4,7.0,4.3Hz, 1H), 2.42 (dt, J = 13.3,6.8Hz, 2H), 1.97-1.74 (m, 1H), 1.64-1.46 (m, 1H), 1.23 ( td, J = 7.1,3.3Hz, 3H), 1.14 (dd, J = 7.1,3.9Hz, 3H)

Example 8

Synthesis of Compound 5

 

 

Example 8-1: The reaction flask was added compound 4 (1eq) was added water (2VOL), concentrated hydrochloric acid (2VOL), 110 ℃ reaction was heated in an oil bath overnight, complete conversion of starting material, the HPLC peak area 97%. 10% NaOH solution was added to adjust the pH to about 10, filtration products. Yield 85%.

 

Example 8-2: The reaction flask was added compound 4 (1eq) was added ethanol (5 vol), water (5 vol), potassium hydroxide (8 eq), was heated in an oil bath overnight at 110 ℃ reaction, complete conversion of the starting material, the HPLC peak area 99%. Water was added (5Vol), filtered to obtain the product. Yield 95%. Product was dissolved in toluene, was added ethanolic hydrochloric acid, the precipitated hydrochloride Compound 5.

NMR data for the product are as follows:

 

¹ the H NMR (400MHz, of DMSO) [delta] 8.31 (S, 3H), 7.70-7.61 (m, 4H), 7.47 (T, J = 7.6Hz, 2H), 7.42-7.31 (m, 3H), 4.09 (the dq- , J = 42.6,7.1Hz, 1H), 3.62-3.51 (m, 1H), 3.50-3.41 (m, 1H), 3.11-3.00 (m, 1H), 2.95-2.84 (m, 1H), 1.30-1.10 (m, 1H).

 

EXAMPLE 9

Synthesis of Compound 6

 

To the reactor was added compound 5, was added absolute ethanol (3vol). Temperature of the outer set 30 ℃ heating, stirring was continued after the temperature reached 25 ℃ 20min. Was added 30% NaOH aqueous solution (1.1eq). External temperature 65 ℃ heating provided, after the internal temperature reached 60 deg.] C was slowly added (of Boc) ₂ O (1.1 eq). Stirring 0.5h, reaction monitoring. After completion of the reaction, water was added slowly dropwise (8vol), turn off the heating and natural cooling. The system temperature was lowered to 25 deg.] C and continue stirring for 2h. Filter cake at 50 ℃ blast oven drying to obtain the product.

 

NMR data of the product are as follows:

 

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.50 (m, 4H), 7.61-7.50 (m, 4H), 7.46-7.39 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.23 (m, 3H), 7.37-7.26 ( m, 3H), 4.82 (d, J = 7.9Hz, 1H), 4.82 (d, J = 7.9Hz, 1H), 3.91 (s, 1H), 3.70 (d, J = 11.0Hz, 1H), 3.77-3.54 (m, 2H), 3.65-3.47 (m, 1H), 2.88 (d, J = 7.0Hz, 2H), 2.88 (d, J = 7.0Hz, 2H), 2.51 (s, 1H), 2.51 (s, 1H), 1.42 (s, 9H), 1.42 (s, 9H).

 

Synthesis of Intermediate Compound 6 to Compound 10, i.e., the AHU-377, a synthetic route in the background of the present invention, the cited patent application WO2014032627A1 loaded in detail, not in this repeat.

 

Example 10

Synthesis of Compound 2

 

 

Benzyl glycidyl ether preparation (50g) in THF (200mL) was added. Under inert gas protection, the biphenyl magnesium bromide (365mmol) was added to THF (1020mL) was added the reaction flask is placed in a low temperature bath -40 ℃ cooling. Cuprous iodide (O.leq) when the internal temperature dropped to -9 ℃. Continued to decrease the temperature of -23 ℃ dropwise addition of benzyl glycidyl ether in THF was added dropwise to control the internal temperature process of not higher than -15 deg.] C, 47 min when used, the addition was completed the cooling off the reaction was stirred overnight. The cooling system to -20 ℃ quenched with 1N HCl aqueous solution, <10 ℃ Go stirred 30min at room temperature. Liquid separation, the aqueous phase was extracted with THF, the combined THF phases. Respectively saturated ammonium chloride (250mL), saturated brine (250mL) washed. Rotary evaporation to remove THF, and water (200 mL) Continue rotary evaporation 1h, cool to precipitate a solid. Suction crude. Crude n-heptane was added 2Vol beating, suction filtration to obtain the product in a yield of 90 ~ 95%, HPLC peak area 94%. In another column purification was pure, columned yield 88.6%, HPLC 99.1%.

 

Example 11

 

Synthesis of Compound 3

 

Preparation Example 9, said compound taking the embodiment 2 (5g) added to the reaction flask, the reaction flask was added toluene (80mL), phthalimide (2.55 g of) and triphenylphosphine (5.35g of), the nitrogen was replaced protection. An ice-salt bath cooling to -5 deg.] C, was added dropwise DIAD (4.12g), dropwise addition was exothermic, the temperature was raised to 5 ℃. The reaction was continued 1h sampling HPLC test material substantially complete reaction. Join 12g silica spin column done to collect the product (including DIEA derivative).

 

Example 12

Synthesis of Compound 11

 

 

Compound 3 (3g) was added to the reaction flask embodiment taken in Preparation Example 10, was added ethanol (30 mL), with stirring. Was added hydrazine hydrate (2g) was heated in an oil bath reflux 1h, when supplemented with 20mL ethanol was stirred difficulties, the reaction was continued to 2.5h, HPLC showed the starting material the reaction was complete. Add EA / H2O 100mL each liquid separation, the EA phase was washed with water (100mL) and the combined organic phases were washed with water (100mL) and saturated brine (100mL) washed. Anhydrous magnesium sulfate and filtered spin column was done product 1.88g, yield 88%, HPLC 94%.

 

NMR data of the product are as follows:

 

¹ the H NMR (400MHz, of DMSO) [delta] 7.64 (D, J = 7.2Hz, 2H), 7.57 (D, J = 8.1Hz, 2H), 7.45 (T, J = 7.6Hz, 2H), 7.39-7.32 ( m, 5H), 7.29 (d , J = 8.1Hz, 3H), 4.55-4.43 (m, 2H), 3.38-3.23 (m, 3H), 3.18-3.10 (m, 1H), 2.82-2.74 (m, 1H), 2.61-2.52 (m, 1H ).

 

Example 13

 

Synthesis of Compound 11

 

To the toluene solution of the compound 2 was added phthalimide (1.1 eq), triphenylphosphine (1.3 eq) with stirring. External bath set -10 ℃, to cool the system, the internal temperature dropped to 0 ~ 5 ℃, start dropping DIAD (1.3eq), control the internal temperature -5 ~ 5 ℃. Completion of the dropwise addition, the cooling bath was turned off outside the reaction was stirred at room temperature. The reaction was stirred for 1 to 4 hours. The reaction solution to give compound 3, administered directly in the next reaction. To the above reaction mixture was added hydrazine hydrate (6 eq), heated to 70 ~ 80 ℃, to complete the reaction, filtered hot, the filtrate. Aqueous sodium hydroxide solution (20vol 10%) was stirred for 0.5h, allowed to stand for liquid separation from toluene phase. Water was added (20vol) was stirred for 0.5h, allowed to stand for liquid separation from toluene phase. The toluene phase was added hydrochloric acid (20vol, 3N), stirred for 0.5h, to form a solid precipitate. Filtration and drying to obtain a product, i.e. compound 11, the hydrochloride salt, yield 60% in two steps.

NMR data of the product are as follows:

 

¹ the H NMR (400MHz, of DMSO) [delta] 8.46 (S, 3H), 7.63 (dd, J = 16.4,7.7Hz, 4H), 7.47 (T, J = 7.6Hz, 2H), 7.42-7.22 (m, 8H ), 4.56 (d, J = 12.1Hz, 1H), 4.48 (d, J = 12.1Hz, 1H), 3.58 (d, J = 7.9Hz, 2H), 3.47 (dd, J = 10.9,6.3Hz, 1H ), 3.11 (dd, J = 13.5,4.9Hz, 1H), 2.92 (dd, J = 13.4,9.1Hz, 1H).

Example 14

 

Synthesis of Compound 12

 

 

Weigh Compound 11 (1.38g) was added to the reaction flask. To the reaction flask plus DCM (14ml) and Et3N (462mg, 0.73ml). Weighed (of Boc) ₂O (1.23 g of) was added to DCM (5ml) was dissolved. Room temperature (8 ℃), a solution (of Boc) ₂ DCM solution O was added dropwise to the reaction, (2ml) rinsed with DCM. The reaction mixture was stirred at room temperature, detected by HPLC, the reaction ends 4h. Reaction mixture was washed (15ml) 3 times with Brine (15ml) The reaction solution was washed 1 times. Inorganic sulfate, concentrated and purified by column PE:EA = 15:1 give product 560mg, yield 30.8%, HPLC 99.92%.

NMR data of the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.6Hz, 2H), 7.49 (D, J = 7.4Hz, 2H), 7.43 (T, J = 7.3Hz, 2H), 7.39-7.28 (m, 5H), 7.24 ( d, J = 9.0Hz, 3H), 5.00-4.80 (br, 1H), 4.51 (q, J = 11.8Hz, 2H), 4.08-3.85 (br, 1H), 3.43 ( d, J = 2.9Hz, 2H) , 3.02-2.77 (m, 2H), 1.42 (s, 9H).

Example 15

Synthesis of Compound 6

 

 

Weigh Compound 12 (250mg) and methanol (9ml) was added to the reaction flask. Added Pd / C (138mg, 1 / 4w / w, water content 55%). The H ₂replaced 3 times, 50 ℃ stirred and heated. HPLC detection reaction, the reaction end 30h. Filtered off Pd / C, 40 ℃ concentrated under reduced pressure to remove methanol. PE:EA = 3:1 florisil column to give the product 196mg, 100% yield, 99.34% purity.

 

NMR data of the product are as follows:

 

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.50 (m, 4H), 7.61-7.50 (m, 4H), 7.46-7.39 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.23 (m, 3H), 7.37-7.26 ( m, 3H), 4.82 (d, J = 7.9Hz, 1H), 4.82 (d, J = 7.9Hz, 1H), 3.91 (s, 1H), 3.70 (d, J = 11.0Hz, 1H), 3.77-3.54 (m, 2H), 3.65-3.47 (m, 1H), 2.88 (d, J = 7.0Hz, 2H), 2.88 (d, J = 7.0Hz, 2H), 2.51 (s, 1H), 2.51 (s, 1H), 1.42 (s, 9H), 1.42 (s, 9H).

 

Method for preparing the AHU-377, characterized by comprising the steps of: (a) Compound (1) S- benzyl glycidyl ether and biphenyl Grignard reagent produced by the reaction of the compound (2) in an organic solvent; ( b) compound (2) with a succinimide or phthalimide Mitsunobu reaction occurs in an organic solvent to form a compound (3); (C) compound (3) in an organic solvent in the role of a catalyst under removal debenzylation protected form compound (4); (D) compound (4) with an oxidizing agent oxidation reaction occurs in an organic solvent to form a compound (7); (E) compound (7) with a phosphorus ylide reagent in an organic solvent to give the compound (8); (F.) compound (8) in an organic solvent in the selective catalytic hydrogenation of the compound (9); and (g) of the compound (9) in an organic solvent in the hydrolysis reaction of the amide compound occurs in the presence of an acid ( 10), i.e., AHU-377;

LUPIN LIMITED, WO 2016181313, NEW PATENT, SOFOSBUVIR

WO2016181313,  A PROCESS FOR THE PREPARATION OF SOFOSBUVIR INTERMEDIATES & ITS POLYMORPH

LUPIN LIMITED [IN/IN]; Kalpataru Inspire 3rd Floor, Off Western Express Highway Santacruz (East) Mumbai 400 055 (IN)

SINGH, Girij, Pal; (IN).
SRIVASTAVA, Dhananjai; (IN).
MEHARE, Kishor, Gulabrao; (IN).
MALIK, Vineet; (IN).
DEOKAR, Sharad, Chandrabhan; (IN).
DANGE, Abhijeet, Avinash; (IN)

SUCCESS QUOTIENT: Lupin chairman DB Gupta (sitting) with managing director Kamal K Sharma (centre), directors Vinita Gupta (right) and Nilesh Gupta.

The present invention provides a novel process for preparation N-[(2,3,4,5,6- Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester (formula 2) and resolving the formula 2 in the presence base to form N-[(S)-(2,3,4,5,6- Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester (formula 2').

Sofosbuvir is chemically named as (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4- dioxo3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran- 2yl)methoxy)-(phenoxy)phosphorylamino)propanoate and is represented by the following chemical structure:

Formula 1

PCT publications WO2011123645 and WO2010135569 describes process for preparation of compound of formula 2' by reacting isopropyl (chloro(phenoxy)phosphoryl)-L-alaninate and pentaflurophenol in the presence of base.

Formula 2'

Example-1:

Preparation of sodium 2,3,4,5,6-pentaflurophenolate using sodium hydride

10.2g of sodium hydride was dissolved in 100 ml anhydrous THF. This solution was slowly added to a solution of pentafluorophenol (50g) in THF (100ml), Reaction mass was stirred for 60-120 min at 25-30°C. Reaction mass was distilled under reduced pressure, obtained solid was dried under vacuum at 45-50°C (yield=55g, confirmed by IR)

Example-2:

Preparation of sodium 2,3,4,5,6-pentaflurophenolate using sodium methoxide

2,3,4,5, 6-pentafluorophenol (lOg) was dissolved in methanol (100ml), solution was cooled to 5-10°C. To this was added a solution of sodium methoxide in methanol. The reaction mass was stirred for 60-120 min at 25-30°C. Reaction mass was distilled under reduced pressure, obtained residue was striped with toluene. Obtained solid was dried under vacuum at 45-50°C (yield=l lg)

Example 3:

Preparation of sodium 2,3,4,5,6-pentaflurophenolate using sodium hydroxide

2,3,4,5, 6-pentafluorophenol (lOOg) dissolved in methanol (—ml), solution was cooled to 5-10°C. To this was added a solution of sodium hydroxide (— g) in methanol. The reaction mass was stirred for 60-120 min at 25-30°C. Reaction mass was distilled under reduced pressure, obtained residue was striped with dichloromethane. Obtained solid was dried under vacuum at 45-50°C (yield=— g)

Example 4:

Preparation of (2S)-isopropyl-2-((chloro(phenoxy)posphoryl)amino)propanoate:

phenyl phosphodichloridate (30.6g) was dissolved in dichloromethane , to this was added a solution of 1-alanine isopropyl ester free base (19.16g) in dichloromethane at-60°C under nitrogen. Solution of triethylamine (20.7ml) was added to above reaction mass. Reaction mass was stirredat -60°C for 30 min and then temperature was raised to 25 °C. Reaction mass was stirred at 20-25 °C for 60 min & filtered and washed with dichloromethane. Clear filtrate was distilled under reduced pressure obtained residue was stirred with diisopropyl ether & filtered. Clear filtrate was distilled under reduced pressure to get (2S)-isopropyl-2-((chloro(phenoxy)posphoryl)amino)propanoate compound.

Example 5:

Preparation of isopropyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (formula 2):

(Formula 2)

Obtained (2S)-isopropyl-2-((chloro(phenoxy)phosphoryl)amino)propanoate (1.2 mol eq.) was dissolved in dichloromethane and cooled to 0-5°C under nitrogen atmosphere. To this was added solution of sodium 2,3,4,5,6-pentaflurophemolate (1 mol eq.) in tetrahydrofuran . Temperature of reaction mass was raised to 25°C and reaction mass was stirred for 3 hrs. After completion of reaction, reaction mass was distilled under reduced pressure & obtained residue was dissolved I ethyl acetate. Ethyl acetate layer was washed with water, dried over sodium sulfate & distilled off under reduced pressure. Diisopropyl ether was added to obtained residue and stirred for 60 min at 25 °C, obtained mass was filtered & washed with diisopropyl ether. Solid product was dried under vacuum at 40-45 °C .(yield=20g, enantiomer purity=93.45%)

Example 6:

Preparation of (S)-isopropyl 2-(((S)- (perfluorophenoxy)phenoxy)phosphoyl)amino)propanoate (Formula 2'):

Formula 2'

(2S)-isopropyl-2-((chloro(phenoxy)phosphoryl)amino)propanoate (1.2 mol eq.) was dissolved in tetrahydrofuran (3.5 volumes). The reaction mass was cooled to -10°C. Solution of sodium salt of pentafluorophenol (1 mol eq.) in tetrahydrofuran (3.5 volumes) was added dropwise to the reaction mass at -10°C. After completion of the reaction solvent was distilled off. Ethyl acetate and water were added to the reaction mass. Reaction mass was stirred, ethyl acetate layer was separated and washed with sodium bicarbonate solution and brine. Ethyl acetate layer was concentrated under reduced pressure. Reaction mass was stripped with n-hepatane to get crude product. Crude product was dissolved in Methyl tert-butyl ether and n-heptane (1 : 1 ratio). The pH of reaction mass was adjusted to pH 8 by using triethylamine. Reaction mass was stirred overnight. Solid mass was filtered and washed with a mixture of methyl tertiary-butyl ether: n-heptane (1 : 1). The obtained product was dissolved in ethyl-acetate and washed with water and 20% brine solution. Ethyl acetate layer was separated; solvent was distilled off under reduced pressure. Reaction mass was stripped with diisopropyl ether. Di-isopropyl ether was added to the reaction mass. Reaction mass was stirred at 45-50°C. Reaction mass was cooled to 5-10°C and stirred. The titled compound was isolated by filtration and washed with di-isopropyl ether. The titled compound was dried under reduced pressure at 40°C. Yield 66.81%.

Vinita Gupta, CEO, Lupin Pharmaceuticals Inc

Desh Bhandu Gupta- Founder and chairman of Lupin Limited

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SUVEN LIFE SCIENCES LTD, WO 2016178064, POLYMORPH OF NINTEDANIB ETHANESULPHONATE, NEW PATENT

NINTEDANIB ETHANESULPHONATE

NEW PATENT

WO2016178064, CLICK FOR PATENT

POLYMORPH OF NINTEDANIB ETHANESULPHONATE, PROCESSES AND INTERMEDIATES THEREOF

SUVEN LIFE SCIENCES LIMITED [IN/IN]; 5th floor, Serene Chamber, Road No.5, Off Avenue No. 7, Banjara Hills, Telangana Hyderabad 500034 (IN)

ARAVA, Veera Reddy; (IN).
GOGIREDDY, Surendra Reddy; (IN).
JASTI, Venkateswarlu; (IN)

DR VEERA ARAVA REDDY

Veerareddy Arava

Vice President

Suven Life Sciences Limited, Hyderabad · Research and Development

Surendra Reddy Gogireddy, Sr.Research Associate

Suven Life Sciences Limited, Hyderabad · Research and Development

 

 

JASTI, Venkateswarlu

 

The present invention provides novel crystalline Form of Nintedanib and process for its preparation. The present invention also provides to a novel process for the preparation of Nintedanib. The present invention further provides to novel intermediates used in the preparation of Nintedanib and process for their preparation.

Nintedanib inhibits multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs).The chemical name of Nintedanib is lH-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl-(4-methyl-l-iperazinyl)acetyl]amino]phenyl]amino]phenylmethylene] -2-oxo-,methylester, (3Z)-, ethanesulfonate (1 : 1) and is structurally represented by compound of Formula I.

Formula I

Nintedanib is marketed in the United States under the trade name OFEV and is indicated for the treatment of Idiopathic Pulmonary Fibrosis (IPF).

Nintedanib was first described and claimed in U.S. Pat.No. 6,762, 180 and EP 1224 170. These patents disclose a process for the preparation of Nintedanib as depicted in scheme I given below:

U.S.Pat.No. 8,067,617 discloses a process for the preparation of Nintedanib intermediate Enolindole derivative), which is shown in the scheme-II given below:

Scheme-II

U.S.Pat. No. 7,119,093 discloses Nintedanib monoethanesulphonate in crystalline form characterised by X-ray powder diffraction pattern having 2Θ values at 7.70, 8.78, 9.47, 9.82, 11.59, 11.93, 13.15, 13.69, 14.17, 16.32, 16.72, 16.92, 17.43, 17.77, 18.58, 18.81, 19.03, 19.73, 19.87, 20.03, 20.61, 20.83, 21.26, 21.76, 22.05, 22.19, 22.57, 23.10, 23.81, 24.69, 24.78, 24.91, 25.42, 26.24, 26.91, 27.19, 27.61, 27.95, 28.71, 29.25.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint and solid state NMR spectrum. One polymorph may give rise to thermal behaviour different from that of another polymorph. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermo gravimetric analysis ("TGA") and differential scanning calorimetry ("DSC"), which have been used to distinguish polymorphic forms.

The differences in the physical properties of different polymorphs results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular Formula yet having distinct advantageous physical properties compared to other polymorphs of the same composition or complex. Hence there remains a need for polymorphic forms which have properties suitable for pharmaceutical processing on a commercial scale.

Considering the importance of Nintedanib, there exists a need to develop an alternate and improved process for the preparation of Nintedanib with better yield. Further, the process involved should be simple, convenient and cost-effective for large scale production. The inventors of the present invention during their continuous efforts also developed a novel high melting stable polymorphic form of Nintedanib ethanesulfonate.

EXAMPLES

Example 1: Process for the preparation of Nintedanib Monoethane Sulfonate:

Step-1: Preparation of methyl-3-(hydroxy(phenyl)methylene)-2-oxoindoline-6-carboxylate: To the suspension of methyl 2-oxoindoline-6-carboxylate (50 gm, 0.261 mol) in IPA (350 ml) was added slowly SMO-powder (33.8 gm, 0.626 mol) and stirred for about 15 min. Benzyl chloride (44 g, 0.313 mol) was added after completion of the reaction at a reaction temperature of -5 to -10°C for about 5hrs. The reaction mixture was quenched into ice-water (700 ml) and acidified with Cone. HC1 (2.0-2.5 ml). Filtered the reaction mixture, washed with water (2X100 ml) and dried the precipitate to obtain crude product which can be recrystallized from acetonitrile (28 ml) to obtain methyl-3-(hydroxy(phenyl)methylene)-2- oxoindoline-6-carboxylate pure crystalline solid (32 gm) (61%) (HPLC purity >97%). The filtrate was evaporated in vacuum to give unreacted methyl 2-oxoindoline-6-carboxylate. MR: 216-223°C; IR (KBr, cm"1): 3178, 1711, 1651; 1H-NMR (400 MHz, DMSO): δ 3.80 (s, 3H), 7.17 (s, 1H), 7.28-7.31 (m, 2H), 7.46-7.50 (m, 3H), 7.72 (d, 2H, J = 6.0 Hz), 9.52 (s, 1H), 11.53 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 22.12, 52.41, 101.13, 111.13, 119.23, 123.06, 126.65, 127.06, 128.65, 129.21, 132.26, 134.47, 136.99, 166.58, 172.52 and 175.80; MS: m/z 294 [M]"1

Step-2: Preparation of methyl-3-(acetoxy(phenyl)methylene)-l-acetyl-2-oxoindoline-6-carboxylate (Acetyl derivative):

To the suspension of methyl-3-(hydroxy(phenyl)methylene)-2-oxoindoline-6-carboxylate (45 gm, 0.1512 mol) in acetic anhydride (300 ml) was added pyridine (4.5g) slowly (drop-wise) and stirred the reaction at temperature of 0-5°C for about30 min. After completion of the reaction raised the temperature of the reaction mass to 75-80°C and stirred for about lhr. Cooled the reaction mass and stirred for about 30 min at 25-28°C, filtered, washed with hexane (100ml) and dried the precipitate to obtain methyl-3-(acetoxy(phenyl)methylene)-l-acetyl-2-oxoindoline-6-carboxylate.

MR: 226-229°C; IR (KBr, cm"1): 3413, 1771, 1743, 1717, 1640; 1H-NMR (400 MHz, CDC13): δ 2.38 (s, 3H), 2.62 (s, 3H), 3.92 (s, 3H), 7.44 (m, 3H), 7.62 (d, 2H, J = 7.004 Hz), 7.68 (d, 1H, J = 8.12 Hz), 7.91 (d, 1H, J = 8.0 Hz), 8.90 (s, 1H); 13C-NMR (100 MHz, CDC13): δ 21.08, 21.38, 26.96, 52.25, 52.34, 115.17, 117.18, 121.33, 122.77, 125.82, 126.19, 126.56, 128.15, 128.87, 129.27, 129.34, 130.81, 130.90, 131.47, 131.82, 132.80, 138.55, 160.85, 165.95, 166.38, 166.42, 167.01, 170.67 and 170.76; MS: m/z 380 [M]+1.

Step-3: Preparation of methyl- l-acetyl-3-(((4-(2-chloro-N-methylacetamido)phenyl)amino) (phenyl)methylene)-2-oxoindoline-6-carboxylate) (Chloroacetyl derivative) :

Suspension of methyl-3-(acetoxy(phenyl)methylene)- l-acetyl-2-oxoindoline-6-carboxylate (Acetyl derivative) (49gm, 0.129mol) and N-(4-aminophenyl)-2-chloro-N-methylacetamide(25.66gm, 0.129 mol) in a mixture of methanol (350 ml) and DMF (88 ml) was heated to 60-65°C stirred for about 12hr at the same temperature. After completion of the reaction cooled the reaction mass to room temperature and stirred for about 30min. Filtered the reaction mixture, washed with methanol (2X50ml) and dried the precipitate to obtainmethyl-l-acetyl-3-(((4-(2-chloro-N-ethylacetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate).

MR: 247-250°C; IR (KBr, cm"1): 3432, 1712, 1675, 1591; 1H-NMR (400 MHz, DMSO): δ 2.74 (s, 3H), 3.11 (s, 3H), 3.78(s, 3H), 3.87 (s, 2H), 5.75 (d, 1H, J = 8.08 Hz), 7.01 (d, 2H, J = 7.96 Hz), 7.22 (d, 2H, J = 6.08Hz), 7.36 (d, 1H, J = 8.48 Hz), 7.46 (d, 2H, J = 7.24 Hz), 7.54-7.64 (m, 3H), 8.74 (s, 1H0, 11.92 (s, 1H), 13C-NMR (100MHz, DMSO): δ 27.17, 37.76, 42.48, 52.40, 96.38, 116.17, 117.59, 124.80, 125.33, 125.68, 128.09, 129.00, 130.10, 131.35, 131.97, 134.05, 160.93, 165.63, 166.68, 168.49 and 171.28; MS: m/z 518 [M]+1 and 520 [M]+1.

Step-4: Preparation of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-lyl)acetamide) phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (Nintedanib free base):

Suspension of methyl- l-acetyl-3-(((4-(2-chloro-N-methylacetamido)phenyl)amino) (phenyl)methylene)-2-oxoindoline-6-carboxylate)(40 gm, 0.077ml) and N-methylpiperidine (23.24 gm, 0.232 mol) in a mixture of DMF (160 ml) was heated to a reaction temperature of 45-50°C for about l-2hrs. The reaction mixture was quenched into ice-water (1.6 Lt) and stirred for about lhr at 15-20°C. Filtered the reaction mixture mass washed with water and dried the precipitate to obtain crystalline crude solid (36 gm). Purified with acetonitrile to obtain Nintedanib free base (34 gm) as a yellow crystals (93.74%) (HPLC purity: >98%). MR: 240-246°C; IR (KBr, cm"1): 3559, 3455, 2940, 2810, 1711, 1657; 1H-NMR (400 MHz, DMSO): δ 2.09 (s, 3H), 2.17 (s, 8H), 2.68 (s, 2H), 3.05 (s, 3H), 3.76 (s, 3H), 5.80 (d, 1H, J = 7.56 Hz), 6.86 (d, 2H, J = 6.72 Hz), 7.11 (d, 1H, J = 6.48 Hz), 7.17 (d, 2H, J = 7.68 Hz), 7.42-7.57 (m, 6H), 10.98 (s, 1H), 12.23 (s, 1H) ; 13C-NMR (100MHz, DMSO): δ 37.17, 46.18, 52.24, 52.79, 55.05, 59.68, 98.10, 109.94, 117.75, 121.96, 124.29, 124.52, 128.06, 128.90, 129.40, 129.92, 130.91, 132.50, 136.72, 140.66, 158.81, 166.84, 169.04 and 170.66; MS: m/z 540 [M]+1.

Step-5: Preparation of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-lyl)acetamide) phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate ethane sulfonate salt:

Suspension of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamide)phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (36 gm, 0.066 mol) in methanol (237 ml) and water (2.88 ml)was heated to 60-65°C and aq. ethane sulfonic acid was added to the reaction mixture. The resulting solution was cooled to 50°C, seeds diluted with isopropanol (237 ml) was added. The reaction mixture was cooled at 0°C for lhr. Filtered the precipitate, washed with mixture of methanol and isopropanol (50 ml), dried to obtain crude Nintedanib monoethane sulfonate (36.6 gm) and crystallized from methanol (5 Vol) to

obtained pure Nintedanib monoethane sulfonate salt as yellow crystals (33 gm) (80%) (HPLC purity >99%).

DSC: 298°C; IR (KBr, cm-1): 3321, 3273, 1710, 1652, 1615, 1515, 1435, 1378, 1289, 1209, 1161, 1087; 1H-NMR (400 MHz, DMSO): δ 1.08 (t, 3H, J = 7.31 Hz), 2.41-2.47 (q, 2H), 2.50-3.16 (broad m, 13H), 3.37 (s, 3H), 3.76 (s, 3H), 5.82 (d, 1H, J = 7.88Hz), 6.87 (d, 2H, J = 7.36 Hz), 7.14-7.20 (m, 3H), 7.49 (s, 1H), 7.49 (d, 2H, J = 6.68 Hz), 7.56-7.63 (m, 3H), 9.45 (s, 1H), 10.99 (s, 1H), 12.25 (s, 1H), 13C-NMR (100 MHz, DMSO): δ 37.15, 42.79, 45.65, 49.40, 52.26, 53.10, 58.04, 98.25, 110.01, 117.78, 121.97, 124.32, 124.59, 128.27, 128.90, 129.36, 130.00, 131.00, 132.52, 136.79, 137.93, 140.00, 158.66, 166.85, 168.47 and 170.65; MS: m/z 540[M]+1.

Example 2: Process for the preparation of Polymorph Form S of Nintedanib monoethanesulf onate :

Crude Nintedanib monoethane sulfonate was dissolved in methanol and heated to 60-64°C for about 15 min. After completion of the reaction cooled to room temperature for about lhr. Filtered the precipitate, washed with mixture of methanol (20ml) and isopropanol (30 ml) and dried to obtain pure crystalline solid (28 gm) (yield: 93.3%) with HPLC purity 99.72% and individual impurities 0.09%, 0.02% and 0.04%.

SUVEN, Chief executive and chairman Venkat Jasti

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