NEW PATENT WO2015188782, METHOD FOR PREPARING SOFOSBUVIR

 

SOFOSBUVIR

NEW PATENT WO2015188782,

 (WO2015188782) METHOD FOR PREPARING SOFOSBUVIR

CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD [CN/CN]; No. 8 Julong North Rd., Xinpu District Lianyungang, Jiangsu 222006 (CN)
 




Sofosbuvir synthesis routes currently used include the following two methods:



https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015188782&redirectedID=true

 

Preparation Example 1 sofosbuvir implementation

[0067]

[0068]

Step (a):

[0069]

At 0 ℃, dichloro-phenyl phosphate (6.0g, 28.4mmol) in dry dichloromethane (30ml) and stirred added alanine isopropyl ester hydrochloride (4.8g, 28.4mmol), the mixture After stirring and cooling to -55 ℃, was slowly added dropwise triethylamine (6.5g, 64mmol) and dichloromethane (30ml) mixed solution, keeping the temperature during at -55 ℃, dropping was completed, stirring was continued for 60 minutes, after liters to -5 ℃ stirred for 2 hours, TLC monitored the reaction was complete. To remove triethylamine hydrochloride was filtered and the filtrate evaporated under reduced pressure to give compound 3-1 as a colorless oil (Sp / Rp = 1/1).

[0070]

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ as internal standard): δ8.25 & 7.94 (1: 1);

[0071]

¹ HNMR (CDCl ₃ , 300 MHz): δ7.39-7.34 (m, 2H), 7.27-7.18 (m, 3H), 5.10-5.02 (m, 1H), 4.51 (br, 1H), 4.11 (m, 1H ), 1.49 (d, 3H), 1.29-1.24 (m, 6H);

[0072]

¹³ C NMR (CDCl ₃ , 300 MHz): δ172.1 (Rp), 196.3 (Sp), 129.8,129.6 (d), 125.9,120.5 (d), 69.7 (d), 50.7 (d), 21.6 (d), 20.4 (d).

[0073]

Step (b):

[0074]

At 5 ℃, the compound of formula 2 (5.20g, 20.0mmol) in dry THF (30ml) and stirred at t-butyl chloride (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise the compound 3-1 (approximately 28.4mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 4: 1). Toluene was added (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (2.6g, yield 25%, HPLC purity measured 98.8%).

[0075]

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ as internal standard): δ3.54ppm;

[0076]

¹³ C NMR (CDCl ₃ , 300 Hz): δ173.1 (d), 162.7 (s), 150.2 (d), 139.3 (d), 129.6 (q);

[0077]

MS (M + H): 530.1.

[0078]

Preparation of compounds of formula 2 shown in Example 3-2

[0079]

[0080]

(1) a nucleophilic reagent as NaSCN, the phase transfer catalyst is TBAB

[0081]

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added dropwise It was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

[0082]

¹ HNMR (CDCl ₃ , 500Hz): δ7.32-7.13 (m, 3H), 7.08-7.02 (m, 2H), 5.0-4.9 (m, 1H), 3.92 (m, 1H), 1.49 (m, 3H ), 1.23-1.17 (m, 6H);

[0083]

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ-18.16 / -18.26.

[0084]

(2) nucleophile NaSCN, phase transfer catalyst is 18-crown-6 ether

[0085]

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in ethyl acetate (20ml) was added 18-crown -6 (2.8mmol), the NaSCN (35mmol) was added to the above the reaction mixture. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

[0086]

(3) nucleophile NaSCN, phase transfer catalyst is TBAB and 18-crown-6

[0087]

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol) and 18-crown -6 (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

[0088]

(4) nucleophile as NaN ₃ , phase transfer catalyst is TBAB

[0089]

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaN ₃ (35 mmol) in water (2.0ml) solution of was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = N ₃ ).

[0090]

¹ HNMR (CDCl ₃ , 500Hz): δ7.30-7.33 (m, 2H), 7.27-7.21 (m, 3H), 5.10-5.05 (m, 1H), 4.12-4.00 (m, 1H), 1.43 (d , 3H), 1.28-1.17 (m, 6H);

[0091]

³¹ PNMR- (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ2.04 / 2.19.

[0092]

(5) the nucleophilic reagent is KCN, the phase transfer catalyst is TBAB

[0093]

The compound was dissolved in methylene chloride as in formula 3-1 (20ml), was added TBAB (2.8mmol), the KCN (35mmol) in water (2.0ml) was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give a compound as shown in Formula 3-2 (where X = CN).

[0094]

¹ HNMR (CDCl ₃ , 300 Hz): δ7.22-7.13 (m, 3H), 7.09-7.02 (m, 2H), 5.01-4.95 (m, 1H), 4.08-3.93 (m, 1H), 1.43-1.35 (m, 3H), 1.20-1.17 (m, 6H);

[0095]

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ-2.71 / -2.93.

[0096]

Preparation Example 3 sofosbuvir implementation

[0097]

[0098]

(1) X is SCN

[0099]

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 (Preparation Example 2 28.4 mmol, obtained) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. After dropping was completed, the mixture was stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (3.6g, yield 34%, HPLC purity measured 98.7%).

[0100]

¹ HNMR (CDCl ₃ , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl'-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH ₃ ) ₂ ) , 4.57-4.41 (m, 2H, C5'-H2), 4.12-4.09 (d, 1H, C3'-H), 4.06-3.79 (m, 3H, C3'-OH, C4'-H, Ala-CH -CH ₃ ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2'-H3), 1.36-1.34 (d, 3H, Ala-CH ₃ ), 1.25-1.23 (t, 6H, CH- (CH ₃ ) ₂ );

[0101]

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

[0102]

(2) X is N ₃

[0103]

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. Was added lithium chloride (21.0mmol), was slowly added dropwise after the compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 7: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.2g, yield 40%, HPLC purity measured 98.8%).

[0104]

¹ HNMR (CDCl ₃ , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl'-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH ₃ ) ₂ ) , 4.57-4.41 (m, 2H, C5'-H2), 4.12-4.09 (d, 1H, C3'-H), 4.06-3.79 (m, 3H, C3'-OH, C4'-H, Ala-CH -CH ₃ ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2'-H3), 1.36-1.34 (d, 3H, Ala-CH ₃ ), 1.25-1.23 (t, 6H, CH- (CH ₃ ) ₂ );

[0105]

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

[0106]

(3) X is CN

[0107]

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.02g, yield 40%, HPLC purity measured 98.8%).

[0108]

¹ HNMR (CDCl ₃ , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl'-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH ₃ ) ₂ ) , 4.57-4.41 (m, 2H, C5'-H2), 4.12-4.09 (d, 1H, C3'-H), 4.06-3.79 (m, 3H, C3'-OH, C4'-H, Ala-CH -CH ₃ ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2'-H3), 1.36-1.34 (d, 3H, Ala-CH ₃ ), 1.25-1.23 (t, 6H, CH- (CH ₃ ) ₂ );

[0109]

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

 

 
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WO 2015186065 NEW PATENT RELATED TO AFATINIB FROM SUN PHARMACEUTICALS, INDIA

Afatinib

439081-18-2

850140-73-7 dimaleate

Tovok, BIBW2992, Tomtovok

Boehringer Ingelheim Int,

An irreversible EGFR/HER2 inhibitor

Molecular Weight:	485.94
Molecular Formula:	C24H25ClFN5O3

N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide

4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4 - (N, N-dimethylamino)-1-oxo-2-buten-1-yl] - amino} -7 - ((S )-tetrahydrofuran-3-yloxy)-quinazoline

(E)-4-Dimethylamino-but-2-enoic acid {4-(3-chloro-4-fluoro- phenylanimo)-7-[(S)-(tetrahydro-furan-3-yl) oxy]-quinazolin-6-yl} -amide

 4 - [(3_ chloro-4 - fluorophenyl) amino] -6 - {[4_ (N, N-dimethylamino)-buten-1-oxo-_2_ - yl] amino}-7 - ((S) - tetrahydrofuran-3 - yloxy) - quinazoline

EMA:Link, US FDA:link

See photos

Sun Pharmaceutical Industries Ltd.  
Website
Directions
Pharmaceutical Company
Address: Sun House, CTS No. 201 B/1, Western Express Highway, Goregaon East, Mumbai, Maharashtra 400063

PATENT

WO2015186065

 PROCESS FOR THE PREPARATION OF 4-DIMETHYLAMINOCROTONIC ACID

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

VERMA, Shyam Sunder; (IN).
SINGH, Shravan Kumar; (IN).
SINGH, Kaptan; (IN).
PRASAD, Mohan; (IN)

Afatinib is a tyrosine kinase inhibitor disclosed in U.S. Patent Nos. RE43,431 and

6,251,912. Afatinib is depicted by Formula la:

Formula la

Afatinib is presented as the dimaleate salt and is chemically designated as 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(35)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2£)-,(2Z)-2-butenedioate (1 :2) having the structure depicted by Formula I:

Formula I

Processes for the preparation of 4-dimethylaminocrotonic acid or its salts are disclosed in U.S. Patent No. 7,126,025 and U.S. Publication No. 2012/0046494.

U.S. Patent No. 7,126,025 discloses a process for the preparation of 4-dimethylaminocrotonic acid or its salts by reacting but-2-enoic acid with

chlorotrimethylsilane in pyridine to obtain trimethylsilylcrotonate, which is brominated with a brominating agent under free radical conditions and in the presence of methylene chloride, acetonitrile, 1,2-dichloroethane, carbon tetrachloride, or ethyl acetate to give trimethylsilyl-4-bromocrotonate. The bromocrotonate compound is treated with dimethylamine in tetrahydrofuran to provide the 4-dimethylaminocrotonic acid.

U.S. Patent No. 7,126,025 also discloses a process for the preparation of 4-dimethylaminocrotonic acid by treating methyl or ethyl 4-bromocrotonate with dimethylamine to provide methyl or ethyl 4-dimethylaminocrotonate, which is hydrolyzed to provide the 4-dimethylaminocrotonic acid.

U.S. Publication No. 2012/0046494 discloses a process for the preparation of 4-dimethylaminocrotonic acid or its salts by converting alkyl 4-chloro-3 -hydroxy butyrate to alkyl 4-hydroxy crotonate, which is brominated to obtain alkyl 4-bromo crotonate. The alkyl 4-bromo crotonate is treated with dimethyl amine to provide alkyl 4-dimethylaminocrotonate, which is hydrolyzed to get the 4-dimethylaminocrotonic acid.

The use of pyridine or carbon tetrachloride is toxic to humans and therefore their use for the manufacture of a drug substance is not advisable. The bromocrotonate compounds, being lachrymatory in nature, are difficult to handle on an industrial scale.

The present invention provides a faster, more efficient, and industrially feasible process for the preparation of 4-dimethylaminocrotonic acid of Formula II, which is used as an intermediate for the preparation of afatinib or its salts.

A first aspect of the present invention provides a process for the preparation of 4-dimethylaminocrotonic acid of Formula II or its salts,

Formula II

comprising the steps of:

i) converting 2,2-diethoxy-N,N-dimethylethanamine of Formula III

Formula III

to ethyl-4-(dimethylamino)crotonate of Formula IV; and

Formula IV

ii) hydrolyzing the ethyl-4-(dimethylamino)crotonate of Formula IV.

A second aspect of the present invention provides a process for the preparation of afatinib of Formula la or its salts,

Formula la

comprising the steps of:

i) converting 2,2-diethoxy-N,N-dimethylethanamine of Formula III

Formula III

to ethyl-4-(dimethylamino)crotonate of Formula IV;

Formula IV

ii) hydrolyzing the ethyl -4-(dimethylamino)crotonate of Formula IV to obtain 4- dimethylaminocrotonic acid of Formula II or its salts; and

Formula II

iii) converting the 4-dimethylaminocrotonic acid of Formula II or its salts to afatinib of Formula la or its salts.

EXAMPLES

Example 1 : Preparation of ethyl-4-(dimethylamino)crotonate (Formula IV)

In a round bottom flask, 2,2-diethoxy-N,N-dimethylethanamine (Formula III, 200 g) and deionized water (100 mL) were added at about 20°C to about 25°C. To the solution, concentrated hydrochloric acid (240 mL) was added at about 25°C to about 50°C. The temperature of the reaction mixture was raised to about 70°C. The reaction mixture was stirred at about 60°C to about 70°C for about 12 hours. The reaction mixture was cooled to about 0°C. To the reaction mixture, about 200 mL of aqueous potassium hydroxide (240 g in 250 mL water) was added at about 0°C to about 10°C to attain a pH of 9.0. To the reaction mixture, ethyl(diethoxyphosphoryl) acetate (200 g) and 2-methyltetrahydrofuran (600 mL) were added at about 0°C to about 5°C. Further, 50 mL of aqueous potassium hydroxide was added to the reaction mixture at about -5°C to about 0°C to attain a pH of about 13.5. The reaction mixture was stirred at about -5°C to about 0°C for about 1 hour. The reaction mixture was filtered, and then the filtrate was recovered under vacuum at about 45°C to about 50°C to obtain ethyl-4-(dimethylamino)crotonate as an oily mass.

Yield: 89%

Example 2: Preparation of 4-dimethylaminocrotonic acid hydrochloride (Formula ID

In a round bottom flask, ethyl -4-(dimethylamino)crotonate (Formula IV, 120 g) and ethanol (480 mL) were added at about 25°C to about 35°C. To the solution, aqueous sodium hydroxide (30.5 g in 60 mL water) was added at about 10°C to about 20°C. The temperature of the reaction mixture was raised to about 50°C. The reaction mixture was stirred at about 50°C to about 55°C for about 1 hour. The reaction mixture was cooled to about 5°C. To the reaction mixture, concentrated hydrochloric acid (120 mL) was added to attain a pH of 1.5. The reaction mixture was filtered on Celite^® and washed with ethanol (50 mL). The filtrate was recovered under vacuum at about 55°C to about 60°C to obtain a crude mass. Ethanol (240 mL) was added to the crude mass, and then the reaction mixture was stirred at about 55°C to about 60°C for about 15 minutes to obtain a solution. In the solution, sodium chloride was obtained as a byproduct. The solution was filtered to discard sodium chloride. The filtrate was recovered under vacuum at about 55°C to about 60°C to obtain a residue. To the residue, isopropanol (400 mL) was added, and then the reaction mixture was stirred at about 55°C to about 60°C to obtain a clear solution. The solution was gradually cooled to about 25°C to about 30°C. The solution was further stirred at the same temperature for about 2 hours. The solid obtained was filtered, and then washed with isopropanol (50 mL). The solid was dried under vacuum at about 55°C to about 60°C to provide 4-dimethylaminocrotonic acid hydrochloride.

Yield: 63%

Sun Pharma managing director Dilip Shanghvi.


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