* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With pyridine; aluminum (III) chloride In dichloromethane at 0 - 45℃; for 2.5 h;
N, N-diethyl-2-cyano-3- (3-methoxy-4-hydroxy-5-nitrophenyl) acrylamide (20g) (0. 062mole) of the formula 4 where, R=methyl obtained by the process described in step (i) of Example-2 is charged with pyridine 50ml along with dichloromethane 120 ml and stirred and cooled to 0-5 degrees and slowly charged the aluminium chloride 32g (0.239 mole) keeping the temperature below 5 and stirred at 0-5 C for 30 minutes. After maintaining for 30 minutes the reaction mixture was slowly raised to room temperature to 40-45 C and stirred for 2 hours. The reaction mixture quenched in dilute hydrochloric acid and ice water (50ml) after removing the methylene chloride and stirred for 60 minutes. The formed product was filtered and dried. The dried weight is 18g (94. 1 percent) with HPLC purity of about 94.42percent. It was purified using methanol and toluene as a solvent to get the ENTACAPONE as a pure product having HPLC purity of 99.5percent. it is matching with in all respect with the product obtained from the Example-1 (step-2).
With hydrogenchloride In water; isopropyl alcohol at 20 - 30℃;
A dissolution comprising a mixture of water (1200 <n="14"/>ml) and 35 percent aq. HCl is added to a suspension of the piperidine salt of Entacapone obtained in a) (119 g; 305 mmole) in isopropanol (600 ml), keeping the temperature from 20 to 300C(29.8 ml; 335 mmole). The resulting precipitate is cooled at 0-50C, filtered off and washed with isopropanol/water (80 ml: 160 ml), and finally, with water (240 ml). The resulting product is dried at 400C in a vacuum oven to provide 84.8 g (yield= 91.1 percent) of an orange solid (m.p.= 162.4-163.5°C;HPLC purity= 99.8 percent (Z-isomer= 0.05 percent) ) .
Stage #1: With aluminum (III) chloride; triethylamine In dichloromethane at 0 - 5℃; for 3 - 4 h; Heating / reflux Stage #2: With hydrogenchloride In dichloromethane at 0 - 20℃; for 0.5 h;
A round-bottom flask under nitrogen atmosphere is loaded with N,N-diethyl-2-cyano-3-(-3-methoxy-4-hydroxy-5-nitrophenyl-)-acrylamide (134 g, 0.421 mol) dissolved in dichloromethane (0.65 l) and triethylamine (128 g, 1.26 mol). The solution is cooled to 0-5° C. and aluminium trichloride (67.4 g, 0.505 mol) is added in portions. After that, the mixture is refluxed for 3-4 hours, until completion of the conversion. The reaction mixture is cooled to 0-5° C., a 20percent hydrochloric acid solution (0.5 l) is dropped in the mixture, which is left under stirring at room temperature for 30 minutes. The resulting solid is filtered, washing with water (0.1 l.x.3), and dried in a static dryer under reduced pressure at 50° C.; 126 g are obtained. Yield: 98percent.1H-NMR (300 MHz), δ (DMS0) 7.90 (d, 1H); 7.75 (d, 1H); 7.60 (s, 1H); 3.40 (m, 4H); 1.15 (m, 6H).
98%
With aluminum (III) chloride; triethylamine In dichloromethane
Example 2 Preparation of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide (entacapone); (I) A round-bottom flask under nitrogen atmosphere is loaded with N,N-diethyl-2-cyano-3-(-3-methoxy-4-hydroxy-5-nitrophenyl-)-acrylamide (134 g, 0.421 mol) dissolved in dichloromethane (0.65 1) and triethylamine (128 g, 1.26 mol). The solution is cooled to 0-5°C and aluminium trichloride (67.4 g, 0.505 mol) is added in portions. After that, the mixture is refluxed for 3-4 hours, until completion of the conversion. The reaction mixture is cooled to 0-5°C, a 20percent hydrochloric acid solution (0.5 1) is dropped in the mixture, which is left under stirring at room temperature for 30 minutes. The resulting solid is filtered, washing with water (0.1 I x 3), and dried in a static dryer under reduced pressure at 50°C; 126 g are obtained. Yield: 98percent. 1H-NMR (300 MHz), δ (DMSO): 7.90 (d, 1 H); 7.75 (d, 1 H); 7.60 (s, 1 H); 3.40 (m, 4H); 1.15 (m, 6H).
92%
Stage #1: With aluminum (III) chloride; triethylamine In tetrahydrofuran at 0℃; Reflux Stage #2: With hydrogenchloride In tetrahydrofuran; water for 6 h; Cooling
(E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5- nitrophenyl)acrylamide (32 g) and tetrahydrofuran (250 mL) were added to a 500 mL flask at room temperature to form a reaction mixture. The mixture was cooled toO °C. After anhydrous aluminum chloride (16.0 g) was added to the reaction mixture, triethylamine (41.6 mL) was added dropwise to the reaction mixture. The reaction mixture was heated under reflux and then cooled. The cooled mixture was dropwise added to dilute hydrochloric acid (10percent) followed by adding 314 mL of water. It was allowed to maintain at the same temperature for 6 hours for crystallization and was centrifuged and dried to obtain 28.0 g of (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitrophenyl) acrylamide (entacapone). The yield was 92percent. The HPLC purity of the E-isomer was 99.92percent.
76%
Stage #1: With aluminum (III) chloride In N,N-dimethyl-formamide at 5 - 80℃; for 16 h; Stage #2: With hydrogenchloride; water In N,N-dimethyl-formamide at 5 - 30℃; for 2 h;
Method B; AlCl3 (1.25 eq) was added portionwise to a solution of E-2-cyano-3-(3-methoxy-4-hydroxy-5-nitrophenyl)-N,N-diethylacrylamide (1.0 eq) in N,N-dimethylformamide (8.6 mL/g) at 5 °C under a nitrogen atmosphere. The mixture was heated to 80 °C and stirred for 16 h. The resulting red solution was cooled to 10 °C and 35percent aqueous HCl solution (5 eq) was added, followed by addition of H2O (10 mL/g) at 30 °C. The suspension was stirred at 5 °C for 2 h. The solid was filtered off, washed with cold water and dried under reduced pressure to give E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide.
61%
Stage #1: With pyridine; aluminum (III) chloride In N,N-dimethyl-formamide at 5 - 90℃; for 15 h; Stage #2: With hydrogenchloride; water In N,N-dimethyl-formamide at 5 - 30℃; for 1 - 3 h;
Method A; AlCl3 (1.25 eq) and pyridine (3.0 eq) were added to a solution of E-2-cyano-3-(3-methoxy-4-hydroxy-5-nitrophenyl)-N,N-diethylacrylamide (1.0 eq) in N,N-dimethylformamide (8.6 mL/g) at 5 °C under a nitrogen atmosphere. The mixture was heated to 80 °C- 90 °C and stirred for 15 h. The resulting red solution was cooled to 10-30 °C and 35percent aqueous HCI solution (5 eq) and H2O (10 mL/g) were added. Stirring was continued for 1-3 h at 5 °C and the precipitated solid was collected by filtration, washed with cold water and dried under reduced pressure to give E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide.
56.1%
With pyridine; aluminum (III) chloride In chloroform at 0 - 5℃; Heating / reflux
(iii) Preparation of N1,N1-diethyl-(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenamide (entacapone); A reactor vessel is charged with dry chloroform (30 L), N1,N1-diethyl-(E)-2-cyano-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-propenamide (1.083 kg, 3.392 mol) and aluminium chloride (0.498 kg, 3.731 mol). The suspension is agitated and cooled down to 0-5° C. Dry pyridine (1.180 kg, 14.923 mol), dissolved in dry chloroform (3 L) is transferred to a dropping funnel and added carefully, drop wise to the suspension. After complete addition, the reaction mixture is agitated and heated to reflux until an in process control indicates the ether cleavage to be complete. Most of the chloroform is distilled out of the reaction mixture. Water (7 L) is added and the residual chloroform is removed out of the two phase mixture by aceotropic distillation. The distilled water is transferred back to the reactor together with ethylacetate (25 L). The mixture is cooled down to 0-5° C. and 25percent HCl (20 L) is added. The two phase mixture is agitated at ambient temperature for 30 minutes. After phase separation the watery layer is extracted twice with ethylacetate (2.x.12 L). The combined organic layers are distilled down to a final volume of 5 L. The product is precipitated by the addition of hexanes (10 L). After agitating for 1 hour the resulting solid is collected on a 20 L Buchner funnel by vacuum filtration. The filtercake is washed with water, transferred to trays and dried in a vacuum oven at 30° C. under reduced pressure, to gain the pure product as a green solid (0.581 kg, 56.1percent)Mp.: 161.05° C. HPLC: 99.37percent E-Entacapone+0.19percent Z-Entacapone. API/MS: [M+H]+ 306.17, [M+H]+-H2O=288.11, [M+H]+-Et=278.17, [M+H]+-NEt2=233.
0.9 g
With pyridine; aluminum (III) chloride In dichloromethane at 0 - 45℃;
(E)-2-Cyano-N,N-diethyl-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylamide 10(1.0 g, 0.0031 mol) was added to a solution of dichloromethane (6.0 ml) and pyridine(2.5 ml) at 0–5 °C. Aluminium chloride (1.58 g, 0.0118 mol) was added at 0–5 °C overa period of 15–20 min and maintained for 30 min. Reaction mass temperature wasraised to RT and maintained for 2–3 h at 40–45 °C. After completion of the reaction,the reaction mass was quenched into dilute hydrochloric acid and ice water (3.0 ml).The organic layer was separated and the solvent distilled off to get the pure entacapone1 (0.9 g).1H NMR (400 MHz, CDCl3): δ 1.30 (s, 1H), 3.50 (s, 4H), 6.22 (s, 1H), 7.57 (s,1H), 7.88 (s, 1H), 8.12 (s, 1H), 10.93 (s, 1H). 13 C NMR (100 MHz, CDCl3): δ 12.53,13.55, 40.87, 43.32, 107.92, 115.33, 118.44,120.73, 124.41, 133.44, 145.19, 147.09,148.17, 162.59; MS (ESI) m/z: 304.5 [M-1].
Stage #1: With piperidine In 1,2-dimethoxyethane; n-heptane for 15 - 25 h; Heating / reflux Stage #2: at 25 - 35℃; for 24 h;
Example- 1:Preparation of (2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (Entacapone).3,4-Dihydroxy-5-nitrobenzaldehyde (50 g), N,N-diethyl cyanoacetamide (76.5 g), piperidine (19.2 g), are charged to a reaction vessel containing a mixture of dimethoxy ethane (200 ml) and heptane (200 ml). The reaction mixture is refluxed for 15-25 hours till the starting material is <n="7"/>disappeared (monitored by HPLC). The solvent was removed by distillation under high vacuum at 70-80°C. Then cooled to 25-35°C. To the crude mass in the flask was added methylene chloride (1.0 lit) at 25°C-35°C. The mixture was stirred for 24 hours at that temperature. It is then filtered and dried and charged to reaction flask containing methanol. The mixture is charcolised, filtered and concentrated to give title compound in 75percent yield (HPLC 99.78percent, Z- isomer content <0.1percent).
75.5%
With piperidine In isopropyl alcohol for 12 - 15 h; Heating / reflux
Example 1 Crystallographically pure (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide Form C 3,4-Dihydroxy-5-nitrobenzaldehyde (10.0 gm, 54.6 mmol), N,N-diethyl-cyanoacetamide (15.5 gm, 11.06 mmol) and piperidine (15.0 gm, 170.3 mmol) is charged to isopropanol (200 ml). The reaction mixture is heated at reflux for 12 to 15 hours until the starting material is disappeared. After the reaction is complete, the reaction mixture is cooled to room temperature and acetic acid glacial (15 ml) is added. The reaction mixture is concentrated, followed by dilution with ethyl alcohol (50 ml). The mixture is stirred overnight and filtered. The isolated product is dried under vacuum to provide crystallographically pure Form C of crystalline (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide with melting point of 156-160° C. The title product is obtained as a crystalline solid in 75.5percent yield. HPLC Purity=99.45percent (Z-isomer 0.24percent). Mass Spectra=m+1 306.1 (100percent).
59.63%
Stage #1: With piperidine; acetic acid In ethanol for 6 h; Heating / reflux Stage #2: at 65℃; for 0.5 h;
Example 1; A mixture of 3,4-dihydroxy-5-nitro benzaldehyde (50Og), N,N-diethyl cyano acetamide(575ml), acetic acid (375ml) and piperidine (500ml) in ethanol (4.51) were refluxed for 6 hrs. Ethanol was distilled off under vacuum and 1.5 1 of formic acid was added to the residue at65° C and stirred for 30 mins at 65° C. The reaction mixture was cooled to R T and charged with methylene dichloride. The organic layer was separated and washed twice with 2 x 3.5 1 water. Methylene dichloride was distilled off under vacuum from the organic layer and the residue was treated with ethyl acetate 1.25 1. The yellow solid was filtered out from the solvent, washed with 1.25 1 ethyl acetate and dried in an electric oven at 60-70° C to obtain crude N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl) acrylamide.Yield of crude entacapone 495g (59.63 percent), Purity 99.2++Z- isomer 0.5percent
13%
With 1-methyl-piperazine In methanol at 20℃; for 20 h;
General procedure: A solution of arylaldehyde (1 equiv), 2-cyanoacetamide or derivative (1.0-1.5 equiv) and N-methylpiperazine (0.05-1.05 equiv) in methanol (2-10 ml) was stirred at room temperature overnight. After addition of an equivalent volume of water/methanol (1:1) or 1 N HCl/methanol (1:1) for acidic products, the precipitate was collected by filtration and washed with water/methanol (1:1). If precipitation did not occur, the mixture was evaporated and the residue was purified by flash chromatography.
99.80 % de
Stage #1: With piperidine In cyclohexane; toluene at 20 - 94℃; Stage #2: With acetic acid In cyclohexane; toluene at 25 - 30℃;
Example 3; Preparation of Entacapone; 3,4-dihydroxy 5-nitrobenzaldehyde (17 gm) and diethylcyanoacetamide (16.9 gm) was charged in a solution of toluene (85 ml) and cyclohexane (85 ml ml) at rt followed by addition of piperidine (0.78 gm). The reaction temperature was raised to reflux (88-94° C.) and removed water azeotrophically from the reaction. After completion of reaction glacial acetic acid (34 ml) was added to reaction mixture followed by cooling at 25° C. to 30° C. The reaction mixture was stirred and filtered. The residue was washed with toluene and water. The residue was dried under vacuum at 50-55° C. to get Entacapone (22.7 gm).HPLC Purity: E-isomer 99.42percent and Z isomer content 0.10percent.
2.1 g
Stage #1: at 108 - 112℃; Dean-Stark Stage #2: at 90 - 95℃; for 1 h;
A round bottomed flask equipped with a stirrer, thermowell, and a dean-Stark condenser was charged with 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 1.54 g of N,N-diethyl-2-cyano acetamide, 150 mg of IRA 120 resin, and 15 mL of toluene. The mixture was refiuxed at 108 - 112 °C and the formed water was removed azeotropically until the starting material was consumed (approximately 12-16 hours). The resin was removed by filtration and the reaction mass was concentrated by distilling the solvent completely under vacuum. A mixture of geometric isomers was formed with the ratio of E/Z isomers being approximately 70:30. The concentrated mass was treated with a solution of 1percent HBr in acetic acid and maintained under stirring at 90-95 °C for 1 hour. The reaction mixture was cooled to room temperature and stirred for 20-24 hours. The reaction mixture was filtered and the precipitate recrystallized from alcohol to afford 2.1 g of Pure (E)-entacapone. The melting point of the resulting compound was 163.3 - 164.9 °C.
Stage #1: With piperidine In isopropyl alcohol for 12 - 15 h; Heating / reflux Stage #2: With acetic acid In isopropyl alcohol at 20℃;
EXAMPLE 1; Crystallographically pure (E)-N, N-Diethyl-2-cyano-3-(3, 4dihydroxy-5-nitrophenyl)- acrylamide Form C; 3,4-Dihydroxy-5-nitrobenzaldehyde (10.0 gm), N, N-Diethylcyanoacetamide (15.5 gm) and piperidine (15.0 gm) is charged to isopropanol (200 ml). The reaction mixture is refluxed for 12 to 15 hours till the starting material is disappeared. The solution is slowly cooled to room temperature and acetic acid glacial (15 ml) is added to it thereafter reaction mixture is concentrated followed by dilution with ethyl alcohol (50 ml). The mixture is stirred overnight and filtered. Isolated product thus obtained is dried under vacuum to afford crystallographically pure Form C of crystalline (E)-N, N-Diethyl-2-cyano-3- (3, 4-dihydroxy- 5-nitrophenyl) acrylamide with melting point between 156-160 °C. The title product is obtained as crystalline solid in 75.5 percent yield. HPLC Purity = 99.45percent (Z-isomer 0.24percent). Mass Spectra = m+1 306.1 (100percent).
41.99 % de
Stage #1: at 75 - 80℃; Stage #2: With ammonium acetate In ethanol for 24 h;
1: Preparation of racemic 2-cvano-3-(3,4-dihvdroxy-5-nitrophenyl)-N,N-diethylprop-2~ en amide3,4-dihydroxy-5-nitro-benzaldehyde (5Og) and N,N-diethyl-2-cyano acetamide (99.4g) were taken together in dry ethanol (100OmL) and refluxed at 75-8O0C for 15-20min. followed by the addition of ammonium acetate (27g) lot-wise over a period of 24hrs at every 2 hours of interval. After completion of reaction the content was cooled to room temperature and the ethanol was distilled off under vacuum. The residue was taken in dichloromethane (100OmL) and stirred for 15min at 25-300C followed by the addition of purified water (100OmL) and stirred at 25-3O0C for 1 hr. The layer if not cleared was filtered through hyflobed and washed with methylene chloride. The organic layer was separated and the aqueous layer was washed with dichloromethane twice. The organic layer were combined and treated with dilute hydrochloric acid 30OmL (1:1 ratio of HCl and water). The organic layer was separated and treated with purified water to remove any undissolved impurities, the water treatment was repeated two to three times and further the organic layer was treated with activated carbon at 25-30 ° C and filtered. The filtrate distilled off under vacuum at 600C and the residue was taken in ethyl alcohol at 25-3O0C, stirred for 15- 20min. and distilled off under vacuum at 350C. To the residue was added purified water and the <n="9"/>stirred for 2 hrs at 25-300C3 filtered and washed with water and dried to obtain racemic 2-cyano- 3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide.(Dry Weight : 6Og (72.20percent), HPLC purity : 98.32percent, E isomer (69.80percent) and Z isomer (28.52percent)
40 % de
With IRA 120 resin In toluene at 108 - 112℃; Dean-Stark
A round bottomed flask equipped with a stirrer, thermowell, and a dean-Stark condenser was charged with 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 1.54 g of N,N-diethyl-2-cyano acetamide, 150 mg of IRA 120 resin, and 15 mL of toluene. The mixture was refiuxed at 108 - 112 °C and the formed water was removed azeotropically until the starting material was consumed (approximately 12-16 hours). The resin was removed by filtration and the reaction mass was concentrated by distilling the solvent completely under vacuum. A mixture of geometric isomers was formed with the ratio of E/Z isomers being approximately 70:30. The concentrated mass was treated with a solution of 1percent HBr in acetic acid and maintained under stirring at 90-95 °C for 1 hour. The reaction mixture was cooled to room temperature and stirred for 20-24 hours. The reaction mixture was filtered and the precipitate recrystallized from alcohol to afford 2.1 g of Pure (E)-entacapone. The melting point of the resulting compound was 163.3 - 164.9 °C.
Stage #1: With aluminum (III) chloride In N,N-dimethyl-formamide at 5 - 80℃; for 15 h; Stage #2: With hydrogenchloride; water In N,N-dimethyl-formamide at 5 - 30℃; for 2.5 h;
Example 10: Preparation of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide using AlCl3 (compound of formula (I)); AlCl3 (75.0 g, 0.56 mol) was added portionwise to a solution of E-2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N,N-diethylacrylamide (150.0 g, 0.45 mmol) in N,N-dimethylformamide (1290 mL) at 5 °C under a nitrogen atmosphere. The mixture was heated to 80 °C and stirred for 15 h. The resulting red solution was cooled to 10 °C and 35percent aqueous HCl solution (200 mL) was added, followed by the slow addition of H2O (1500 mL) at 30 °C. The suspension was stirred at 5 °C for 2.5 h. The solid was filtered off, washed with cold water and dried under reduced pressure to give 126.3 g (92percent yield) of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide. Light yellow solid. 1H-RMN (400 MHz, CDCl3) δ 7.92 (1 H, d, J = 2.2), 7.73 (1 H, d, J = 2.2), 7.62 (1 H, s), 3.40 (4H, broad q), 1.14 (6H, broad t). Purity by HPLC: 99.7percent, (Z)-isomer: 0.2percent.
80%
Stage #1: With pyridine; aluminum (III) chloride In N,N-dimethyl-formamide at 5 - 80℃; for 15 h; Stage #2: With hydrogenchloride; water In N,N-dimethyl-formamide at 5 - 30℃; for 2 h;
Example 9: Preparation of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide using AlCl3 / pyridine (compound of formula (I)); AlCl3 (371 mg, 2.78 mmol) and pyridine (0.54 mL, 6.69 mmol) were added portionwise to a solution of E-2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N,N-diethylacrylamide (742 mg, 2.23 mmol) in N,N-dimethylformamide (6.4 mL) at 5 °C under a nitrogen atmosphere. The mixture was heated to 80 °C and stirred for 15 h. The resulting red solution was cooled to 10 °C and 35percent aqueous HCl solution (1.0 mL) was added, followed by the addition of H2O (7.4 mL) at 30 °C. Stirring was continued for 2 h at 5 °C and the precipitated solid was collected by filtration, washed with cold water and dried under reduced pressure to give 541 mg (80percent yield) of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide. HPLC purity: 96.0percent, (Z)-isomer: 0.4percent.
74%
Stage #1: With boron tribromide In dichloromethane at -15 - 20℃; Stage #2: With water In dichloromethane for 0.5 h;
Example 8: Preparation of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide using BBr3 (compound of formula (I)); A 1.0 M solution of BBr3 in CH2Cl2(1.62 ml, 1.62 mmol) was added dropwise to a solution of E-2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N,N-diethylacrylamide (154 mg, 0.46 mmol) in CH2Cl2 (0.5 mL) at -15 °C under a nitrogen atmosphere. The resulting red suspension was stirred for 1 h at -15 °C and allowed to warm to room temperature overnight. The reaction was quenched by the addition of H2O (4 mL) and stirred for 30 min. The aqueous phase was extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with saturated brine (20 mL) and dried (Na2SO4). The solvent was eliminated under reduced pressure to give 105 mg (74percent yield) of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide.
With hydrogenchloride In water; toluene at 7 - 20℃; for 4 h; Heating / reflux
Mother liquors, containing mainly isomer (Z), were concentrated under vacuum, treated with 100ml of toluene and a catalytic amount of hydrochloric acid (2ml), and stirred under reflux for 4 hours, with the aim of conversion of isomer (Z) ((Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide) into isomer (E) (Entacapone). After cooling down to room temperature, 50ml 4.5percent HCl was added dropwise and the obtained suspension was stirred at 7-100C for 1 hour. A second batch of crude 2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide (a mixture of (E) and (Z) isomers) was filtered off, washed with 2x10ml toluene and dried at 400C. Crystallization from methanol gave 2.4g (14percent) of pure Entacapone as polymorph form A.
With hydrogenchloride; In water; toluene; at 7 - 20℃; for 4h;Heating / reflux;
Mother liquors, containing mainly isomer (Z), were concentrated under vacuum, treated with 100ml of toluene and a catalytic amount of hydrochloric acid (2ml), and stirred under reflux for 4 hours, with the aim of conversion of isomer (Z) ((Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide) into isomer (E) (Entacapone). After cooling down to room temperature, 50ml 4.5% HCl was added dropwise and the obtained suspension was stirred at 7-100C for 1 hour. A second batch of crude 2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide (a mixture of (E) and (Z) isomers) was filtered off, washed with 2x10ml toluene and dried at 400C. Crystallization from methanol gave 2.4g (14%) of pure Entacapone as polymorph form A.
Example- 1:Preparation of (2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (Entacapone).3,4-Dihydroxy-5-nitrobenzaldehyde (50 g), N,N-diethyl cyanoacetamide (76.5 g), piperidine (19.2 g), are charged to a reaction vessel containing a mixture of dimethoxy ethane (200 ml) and heptane (200 ml). The reaction mixture is refluxed for 15-25 hours till the starting material is <n="7"/>disappeared (monitored by HPLC). The solvent was removed by distillation under high vacuum at 70-80C. Then cooled to 25-35C. To the crude mass in the flask was added methylene chloride (1.0 lit) at 25C-35C. The mixture was stirred for 24 hours at that temperature. It is then filtered and dried and charged to reaction flask containing methanol. The mixture is charcolised, filtered and concentrated to give title compound in 75% yield (HPLC 99.78%, Z- isomer content <0.1%).
75.5%
With piperidine; In isopropyl alcohol; for 12 - 15h;Heating / reflux;
Example 1 Crystallographically pure (E)-N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide Form C 3,4-Dihydroxy-5-nitrobenzaldehyde (10.0 gm, 54.6 mmol), <strong>[26391-06-0]N,N-diethyl-cyanoacetamide</strong> (15.5 gm, 11.06 mmol) and piperidine (15.0 gm, 170.3 mmol) is charged to isopropanol (200 ml). The reaction mixture is heated at reflux for 12 to 15 hours until the starting material is disappeared. After the reaction is complete, the reaction mixture is cooled to room temperature and acetic acid glacial (15 ml) is added. The reaction mixture is concentrated, followed by dilution with ethyl alcohol (50 ml). The mixture is stirred overnight and filtered. The isolated product is dried under vacuum to provide crystallographically pure Form C of crystalline (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide with melting point of 156-160 C. The title product is obtained as a crystalline solid in 75.5% yield. HPLC Purity=99.45% (Z-isomer 0.24%). Mass Spectra=m+1 306.1 (100%).
59.63%
Example 1; A mixture of 3,4-dihydroxy-5-nitro benzaldehyde (50Og), N,N-diethyl cyano acetamide(575ml), acetic acid (375ml) and piperidine (500ml) in ethanol (4.51) were refluxed for 6 hrs. Ethanol was distilled off under vacuum and 1.5 1 of formic acid was added to the residue at65 C and stirred for 30 mins at 65 C. The reaction mixture was cooled to R T and charged with methylene dichloride. The organic layer was separated and washed twice with 2 x 3.5 1 water. Methylene dichloride was distilled off under vacuum from the organic layer and the residue was treated with ethyl acetate 1.25 1. The yellow solid was filtered out from the solvent, washed with 1.25 1 ethyl acetate and dried in an electric oven at 60-70 C to obtain crude N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl) acrylamide.Yield of crude entacapone 495g (59.63 %), Purity 99.2++Z- isomer 0.5%
13%
With 1-methyl-piperazine; In methanol; at 20℃; for 20h;
General procedure: A solution of arylaldehyde (1 equiv), 2-cyanoacetamide or derivative (1.0-1.5 equiv) and N-methylpiperazine (0.05-1.05 equiv) in methanol (2-10 ml) was stirred at room temperature overnight. After addition of an equivalent volume of water/methanol (1:1) or 1 N HCl/methanol (1:1) for acidic products, the precipitate was collected by filtration and washed with water/methanol (1:1). If precipitation did not occur, the mixture was evaporated and the residue was purified by flash chromatography.
piperidine; In isopropyl alcohol; for 10 - 15h;Heating / reflux;
EXAMPLE 1 (E)-N, N-Diethyl-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl) acrylamide 3, 4-Dihydroxy-5-nitrobenzaldehyde (5.0 gm, 27.3 mmol), N, N-Diethyl cyanoacetamide (7.65 gm, 54.57 mmol) and piperidine (7.50 gm, 85.15 mmol) is charged to isopropanol (50 ml). The reaction mixture is refluxed for 10 to 15 hours till the disappearance of stating material. After the reaction is over it is cooled to room temperature. The reaction mixture is poured slowly into a mixture of cold water and ethyl acetate followed by adjusting pH between about 3.5 to about 4.0 with acetic acid. Organic layer is separated, charcolized and concentrated to afford crystalline (E)-N, N-Diethyl-2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) acrylamide. The title product is filtered and dried to get the desired product in 99.7 % HPLC purity. Mass spectra = (m + 1) 306 (100 %). (Z)-Entacapone is observed in less than 0.1 %.
Example-2;3,4-Dihydroxy-5-nitrobenzaldehyde (25 g), N,N-diethyl cyanoacetamide (38.25 g), dibutylamine (10 g), are charged to in a mixture of dimethoxy ethane (100 ml) and heptane (100 ml). The reaction mixture is refluxed for 15-25 hours till the starting material is disappeared (monitored by HPLC). The solvent was removed by distillation under high vacuum at 70-800C. Then cooled to 25-350C. To the crude mass in the flask was added methylene chloride (500 ml) at 25C-35C. The mixture was stirred for 24 hours at that temperature. It is then filtered, washed with water, dried and is charged to reaction flask containing acetonitrile. The mixture is charcolised, filtered and concentrated to give title compound (HPLC 99.7%, Z-isomer content <0.1%).
Example 1 :Preparation of (E) N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro) acrylamide [Entacapone]Charge 3,4-dihydroxy-5-nitro benzaldehdye 100 Kg, followed by N.N-diethyl-2-cyano acetamide 92 Kg in to solvent Toluene. Charge piperidine acetate prepared from 30 kg <n="9"/>piperidine and 35 Kg acetic acid . Reaction mass was heated to reflux ( 108-112 0C), maintained at reflux with azeotropic distillation ( 108-112 0C) for 6 Hours and water was collected. After reaction completion Toluene was removed completely under vacuum below 80 C. Mass was cooled to 50-55 0C methanol ( 500 Its) was charged in to the above mass under stirring. To this clear solution carbon was added maintained at 55-60 c for 1 hour. Mass was filtered through hyflow bed in hot condition. Filtrate was cooled to 10 0C, pH of the filtrate adjusted to 1.0 to 2.0 with Con HCl. Mass was cooled to 5-10 C and product (E) -entacapone with Z-isomer content NMT 0.20% is isolated, dried at 70-80C was found to be stable polymorph A with melting point 162-164 0 C.
Example 2 :Preparation of (E) N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro) acrylamide [Entacapone]Charge 3,4-dihydroxy-5-nitro benzaldehdye 100 gms, followed by N.N-diethyl-2-cyano acetamide 95 gms in to solvent Toluene. Charge piperidine acetate prepared from 30 gm piperidine and 35 gm acetic acid . Reaction mass was heated to reflux ( 108-1120C), maintained at reflux with azeotropic distillation ( 108-112 0C) for 6 Hours and water was collected. After reaction completion 10 ml aqueous HBr ( 48%) is added and maintained at reflux temperature. Toluene was removed completely under vacuum below 80 0C. Mass was cooled to 50-55 0C methanol (500 Its) was charged in to the above mass under stirring. To this clear solution carbon was added maintained at 55-60 0C for 1 hour. Mass was filtered through hyflow bed in hot condition. Filtrate was concentrated by vacuum distillation . Mass was cooled to 10 0C, Con HCl is added and further cooled to -5 0C. Precipitated mass was maintained at 0 to -5 C for 2 hours and 150 gms product mixture of (E) and Z-isomer is isolated, dried at 70 to 80 0C . This mixture of E and Z isomer is re- crystallized in methanol or ethyl acetate resulting E -entacapone with Z-isomer NMT 0.20%, polymorph A.
With piperidine; acetic acid; In isopropyl alcohol; for 37 - 49h;
Example 2: Preparation of Form D of entacapone3, 4-dihydroxy-5-nitrobenzaIdehyde (500 gm) was added to a mixture of 2-cyano- N,N-diethylacetamide (640 gm), piperidine (620 gm) and acetic acid (400 gm) in isopropyl alcohol (5 L) and stirred. The reaction mixture was refluxed for about 15-24 hours. After completion of the reaction, the reaction mixture was concentrated and the concentrated mass treated with a mixture of isopropyl alcohol (700 mL) and acetic acid (640 mL). The reaction mixture was further stirred for about 22-25 hours. The product so precipitated was filtered and washed with a mixture of water (90%) -acetic acid (10%). The product was dried to get the Form D of entacapone. Yield: 449 gm. Purity (by HPLC): 99.31%.
Example 3; Preparation of Entacapone; 3,4-dihydroxy 5-nitrobenzaldehyde (17 gm) and diethylcyanoacetamide (16.9 gm) was charged in a solution of toluene (85 ml) and cyclohexane (85 ml ml) at rt followed by addition of piperidine (0.78 gm). The reaction temperature was raised to reflux (88-94 C.) and removed water azeotrophically from the reaction. After completion of reaction glacial acetic acid (34 ml) was added to reaction mixture followed by cooling at 25 C. to 30 C. The reaction mixture was stirred and filtered. The residue was washed with toluene and water. The residue was dried under vacuum at 50-55 C. to get Entacapone (22.7 gm).HPLC Purity: E-isomer 99.42% and Z isomer content 0.10%.
2.1 g
A round bottomed flask equipped with a stirrer, thermowell, and a dean-Stark condenser was charged with 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 1.54 g of N,N-diethyl-2-cyano acetamide, 150 mg of IRA 120 resin, and 15 mL of toluene. The mixture was refiuxed at 108 - 112 C and the formed water was removed azeotropically until the starting material was consumed (approximately 12-16 hours). The resin was removed by filtration and the reaction mass was concentrated by distilling the solvent completely under vacuum. A mixture of geometric isomers was formed with the ratio of E/Z isomers being approximately 70:30. The concentrated mass was treated with a solution of 1% HBr in acetic acid and maintained under stirring at 90-95 C for 1 hour. The reaction mixture was cooled to room temperature and stirred for 20-24 hours. The reaction mixture was filtered and the precipitate recrystallized from alcohol to afford 2.1 g of Pure (E)-entacapone. The melting point of the resulting compound was 163.3 - 164.9 C.
EXAMPLE 1; Crystallographically pure (E)-N, N-Diethyl-2-cyano-3-(3, 4dihydroxy-5-nitrophenyl)- acrylamide Form C; 3,4-Dihydroxy-5-nitrobenzaldehyde (10.0 gm), N, N-Diethylcyanoacetamide (15.5 gm) and piperidine (15.0 gm) is charged to isopropanol (200 ml). The reaction mixture is refluxed for 12 to 15 hours till the starting material is disappeared. The solution is slowly cooled to room temperature and acetic acid glacial (15 ml) is added to it thereafter reaction mixture is concentrated followed by dilution with ethyl alcohol (50 ml). The mixture is stirred overnight and filtered. Isolated product thus obtained is dried under vacuum to afford crystallographically pure Form C of crystalline (E)-N, N-Diethyl-2-cyano-3- (3, 4-dihydroxy- 5-nitrophenyl) acrylamide with melting point between 156-160 C. The title product is obtained as crystalline solid in 75.5 % yield. HPLC Purity = 99.45% (Z-isomer 0.24%). Mass Spectra = m+1 306.1 (100%).
piperidine; methylamine hydrochloride; In butan-1-ol; at 82℃; for 4 - 5h;Product distribution / selectivity;
Example 1; Mixture of the E and Z isomers of N,N-diethyl-2-cvano-3-(3,4-dihydroxy-5- nitrophenvDacrylamide[0031 ] A vessel is charged with 240 ml of n-butanol, 120 g of 3,4-dihydroxy-5- nitrobenzaldehyde, 4.8 g of methylamine hydrochloride, 122 g of N5N- diethylcyanoacetamide and 7.2 ml of piperidine. The temperature is raised using water <n="11"/>separation under vacuum to about 82 0C and the reaction mixture is boiled at this temperature using water separation for 4 hours. The reaction is followed using HPLC.[0032] After completing the reaction 240 ml of hot water is added to the reaction mixture and 2.4 ml of strong sulphuric acid is added.[0033] The reaction mixture is cooled to a temperature of 75 C and seeded with crude N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (comprises 70 % by weight of the E- isomer). After seeding the mixture is cooled to about 28 C within 3 hours, during which time the E isomer crystallizes.[0034] The reaction mixture is seeded with a mixture of the E and Z isomers of N9N- diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (comprises about 30 % by weight of the Z- isomer) and mixed at about 28 C for two hours. Thereafter the mixture is cooled slowly to 0 0C during which time the Z isomer crystallizes.[0035] The mixture is filtered and washed twice with 60 ml of cold water and the filtering cake is dried. The yield is about 90 % and the purity over 99.5 %.Example 2 Mixture of the E and Z isomers of N,N-diethyl-2-cvano-3-(3,4-dihvdroxy-5- nitrophenvDacrylamide[0036] A vessel is charged with 180 ml of n-butanol, 120 g of 3,4-dihydroxy-5- nitrobenzaldehyde, 2.9 g of methylamine hydrochloride, HO g of N9N- diethylcyanoacetamide and 4.3 ml of piperidine. The temperature is raised using water separation under vacuum to about 82 0C and the reaction mixture is boiled at this temperature using water separation for 5 hours. The reaction is followed using HPLC.[0037] After completing the reaction 180 ml of hot water is added to the reaction mixture and 12 ml of strong sulphuric acid is added.[0038] The reaction mixture is cooled to a temperature of 75 0C and seeded with crude N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (comprises 70 % <n="12"/>by weight of the E- isomer). After seeding the mixture is cooled to about 28 0C within 2 hours, during which time the E isomer crystallizes.[0039] The reaction mixture is seeded with a mixture of the E and Z isomers of N5N- diethyl-2-cyano-3-(3,4-dihydroxy-5-m'trophenyl)acrylamide (comprises about 30 % by weight of the Z- isomer) and mixed at about 28 C for two hours. Thereafter the mixture is cooled slowly to 0 0C during which time the Z isomer crystallizes.[0040] The mixture is filtered and washed twice with 100 ml of cold water and the filtering cake is dried. The yield is about 96% and the purity over 99.5 %.
piperidine; methylamine hydrochloride; In i-Amyl alcohol; at 89 - 90℃; for 3h;Product distribution / selectivity;
Example 3; Mixture of the E and Z isomers of N,N-diethyl-2-cvano-3-(3,4-dihvdroxy-5- nitrophenypacrylamide[0041] A vessel is charged with 100 ml of isoamylalcohol (3-methyl-butanol), 50 g of 3,4-dihyroxy-5-nitrobenzaldehyde, 2 g of methylamine hydrochloride, 5O g of N,N- diethylcyanoacetamide and 3 ml of piperidine. The temperature is raised using water separation under vacuum to about 90 C and the reaction mixture is boiled at this temperature using water separation for 3 hours. The reaction is followed using HPLC.[0042] After completing the reaction 220 ml of hot water is added to the reaction mixture and 1 ml of strong sulphuric acid is added.[0043] The reaction mixture is cooled to a temperature of 75 C and seeded with crude N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (comprises 70 % by weight of the E- isomer). After seeding the mixture is cooled to about 28 C within 2 hours, during which time the E isomer crystallizes.[0044] The reaction mixture is seeded with a mixture of the E and Z isomers of N5N- diethyl-2-cyano-3-(354-dihydroxy-5-nitrophenyl)acrylamide (comprises about 30 % by weight of the Z- isomer) and mixed at about 28 C for two hours. Thereafter the mixture is cooled to 0 0C during which time the Z isomer crystallizes. <n="13"/>[0045] The mixture is filtered and washed with 120 ml of cold water and the filtering cake is dried. The yield is 77.58 g ( 93.1 % of the theoretical yield). HPLC purity of the product is over 99 %.Example 4 Mixture of the E and Z isomers of N,N-diethyl-2-cvano-3-(3,4-dihydroxy-5- mtrophenvDacrylamide[0046] A vessel is charged with 100 ml of isoamylalcohol (3-methyl-butanol), 50 g of 3,4-dihyroxy-5-nitrobenzaldehyde, 2 g of methylamine hydrochloride, 50 g of N5N- diethylcyanoacetamide and 3 ml of piperidine. The temperature is raised using water separation under vacuum to about 89 C and the reaction mixture is boiled at this temperature using water separation for 3 hours. The reaction is followed using HPLC.[0047] After completing the reaction 220 ml of hot water is added to the reaction mixture and 1 ml of strong sulphuric acid is added.[0048] The reaction mixture is cooled to a temperature of 75 C and seeded with crude N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (comprises 70 % by weight of the E- isomer). After seeding the mixture is cooled to about 28 0C within 2 hours, during which time the E isomer crystallizes.[0049] The reaction mixture is seeded with a mixture of the E and Z isomers of N5N- diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (comprises about 30 % by weight of the Z- isomer) and mixed at about 28 C for two hours. Thereafter the mixture is cooled to 0 C during which time the Z isomer crystallizes.[0050] The mixture is filtered and washed with 120 ml of cold water and the filtering cake is dried. The yield is 79.0 g (94.8 % of the theoretical yield). HPLC purity of the product is over 99 %.
Example 1 - Preparation of (epsilon)-2-cvano-3-(3,4-dihvdroxy-5-nitrophenyl)-N,N-diethyl-2- propenamide, Entacapone <n="10"/>A solution containing 10.0Og of 3,4-dihydroxy-5-nitrobenzaldehyde, 8.42g of N,N-diethyl-2- cyanoacetamide and 0.84g of piperidine acetate in 150ml of toluene was refluxed for 3.5 hours with water removal by azeotropic distillation. The content of the reactor was cooled to room temperature and 10ml of methanol was added. 100ml 4.5% HCl was added dropwise to obtain a yellow-green solid and the mixture was stirred at 7-100C for 1 hour. Crude 2-cyano- 3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide being a mixture of (E) and (Z) isomers was filtered off, washed with 2x15ml toluene and dried to a constant mass. Yield: 15.7g (94 %). The product was purified by crystallization from methanol to obtain 8.2g (49%) of pure Entacapone as polymorph form A.
1: Preparation of racemic 2-cvano-3-(3,4-dihvdroxy-5-nitrophenyl)-N,N-diethylprop-2~ en amide3,4-dihydroxy-5-nitro-benzaldehyde (5Og) and N,N-diethyl-2-cyano acetamide (99.4g) were taken together in dry ethanol (100OmL) and refluxed at 75-8O0C for 15-20min. followed by the addition of ammonium acetate (27g) lot-wise over a period of 24hrs at every 2 hours of interval. After completion of reaction the content was cooled to room temperature and the ethanol was distilled off under vacuum. The residue was taken in dichloromethane (100OmL) and stirred for 15min at 25-300C followed by the addition of purified water (100OmL) and stirred at 25-3O0C for 1 hr. The layer if not cleared was filtered through hyflobed and washed with methylene chloride. The organic layer was separated and the aqueous layer was washed with dichloromethane twice. The organic layer were combined and treated with dilute hydrochloric acid 30OmL (1:1 ratio of HCl and water). The organic layer was separated and treated with purified water to remove any undissolved impurities, the water treatment was repeated two to three times and further the organic layer was treated with activated carbon at 25-30 C and filtered. The filtrate distilled off under vacuum at 600C and the residue was taken in ethyl alcohol at 25-3O0C, stirred for 15- 20min. and distilled off under vacuum at 350C. To the residue was added purified water and the <n="9"/>stirred for 2 hrs at 25-300C3 filtered and washed with water and dried to obtain racemic 2-cyano- 3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide.(Dry Weight : 6Og (72.20%), HPLC purity : 98.32%, E isomer (69.80%) and Z isomer (28.52%)
With IRA 120 resin; In toluene; at 108 - 112℃;Dean-Stark;
A round bottomed flask equipped with a stirrer, thermowell, and a dean-Stark condenser was charged with 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 1.54 g of N,N-diethyl-2-cyano acetamide, 150 mg of IRA 120 resin, and 15 mL of toluene. The mixture was refiuxed at 108 - 112 C and the formed water was removed azeotropically until the starting material was consumed (approximately 12-16 hours). The resin was removed by filtration and the reaction mass was concentrated by distilling the solvent completely under vacuum. A mixture of geometric isomers was formed with the ratio of E/Z isomers being approximately 70:30. The concentrated mass was treated with a solution of 1% HBr in acetic acid and maintained under stirring at 90-95 C for 1 hour. The reaction mixture was cooled to room temperature and stirred for 20-24 hours. The reaction mixture was filtered and the precipitate recrystallized from alcohol to afford 2.1 g of Pure (E)-entacapone. The melting point of the resulting compound was 163.3 - 164.9 C.
N,N-diethyl-2-cyano-3-(3-ethoxy-4-hydroxy-5-nitrophenyl)acrylamide[ No CAS ]
[ 130929-57-6 ]
Yield
Reaction Conditions
Operation in experiment
87.3%
With pyridine; aluminum (III) chloride; In dichloromethane; at 0 - 45℃; for 50h;
N, N-diethyl-2-cyano-3- (3-ethoxy-4-hydroxy-nitrophenyl) acrylamide 5g (0.0150 mole) of the formula 4 where, R= ethyl obtained by the process described in step (i) above is charged with pyridine 12. 5ml along with dichloromethane 50 ml and stirred and cooled to 0-5 degrees and slowly charged the aluminium chloride 10g (0. 751m) keeping the temperature below 5 and stirred at 0-5 for 30 minutes. After maintaining for 30 minutes the reaction mixture was slowly raised to 40-45 C and stirred at that temperature for 50 hours. After reaction completion the solvent is removed to get a residual volume of 10 ml and quenched in to dilute hydrochloric acid and chilled water (50ml) and stirred for 30 minutes. The formed product was filtered and dried. The dried weight is 4g (87.3%) (with HPLC purity of about 93.25%. it was purified using methanol and toluene as a solvent to get the ENTACAPONE as a pure product having HPLC purity of 99.5% and the IR matching with the reported spectrum. MR= 162-163 C HPLC = 99.76% PMR = 200MHz (DMSO-d6): 8 value; 1.26 (m, 6H), 3.49 ( q, 4H), 7.50 (s, 1H,), 7.905 (d, 1H, J=0.01), 7.99 ( in, J=0.01). MS = M/Z = 306.4 (M+1)
With pyridine; aluminum (III) chloride; In dichloromethane; at 0 - 45℃; for 2.5h;
N, N-diethyl-2-cyano-3- (3-methoxy-4-hydroxy-5-nitrophenyl) acrylamide (20g) (0. 062mole) of the formula 4 where, R=methyl obtained by the process described in step (i) of Example-2 is charged with pyridine 50ml along with dichloromethane 120 ml and stirred and cooled to 0-5 degrees and slowly charged the aluminium chloride 32g (0.239 mole) keeping the temperature below 5 and stirred at 0-5 C for 30 minutes. After maintaining for 30 minutes the reaction mixture was slowly raised to room temperature to 40-45 C and stirred for 2 hours. The reaction mixture quenched in dilute hydrochloric acid and ice water (50ml) after removing the methylene chloride and stirred for 60 minutes. The formed product was filtered and dried. The dried weight is 18g (94. 1 %) with HPLC purity of about 94.42%. It was purified using methanol and toluene as a solvent to get the ENTACAPONE as a pure product having HPLC purity of 99.5%. it is matching with in all respect with the product obtained from the Example-1 (step-2).
A round-bottom flask under nitrogen atmosphere is loaded with N,N-diethyl-2-cyano-3-(-3-methoxy-4-hydroxy-5-nitrophenyl-)-acrylamide (134 g, 0.421 mol) dissolved in dichloromethane (0.65 l) and triethylamine (128 g, 1.26 mol). The solution is cooled to 0-5 C. and aluminium trichloride (67.4 g, 0.505 mol) is added in portions. After that, the mixture is refluxed for 3-4 hours, until completion of the conversion. The reaction mixture is cooled to 0-5 C., a 20% hydrochloric acid solution (0.5 l) is dropped in the mixture, which is left under stirring at room temperature for 30 minutes. The resulting solid is filtered, washing with water (0.1 l×3), and dried in a static dryer under reduced pressure at 50 C.; 126 g are obtained. Yield: 98%.1H-NMR (300 MHz), delta (DMS0) 7.90 (d, 1H); 7.75 (d, 1H); 7.60 (s, 1H); 3.40 (m, 4H); 1.15 (m, 6H).
98%
With aluminum (III) chloride; triethylamine; In dichloromethane;
Example 2 Preparation of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide (entacapone); (I) A round-bottom flask under nitrogen atmosphere is loaded with N,N-diethyl-2-cyano-3-(-3-methoxy-4-hydroxy-5-nitrophenyl-)-acrylamide (134 g, 0.421 mol) dissolved in dichloromethane (0.65 1) and triethylamine (128 g, 1.26 mol). The solution is cooled to 0-5C and aluminium trichloride (67.4 g, 0.505 mol) is added in portions. After that, the mixture is refluxed for 3-4 hours, until completion of the conversion. The reaction mixture is cooled to 0-5C, a 20% hydrochloric acid solution (0.5 1) is dropped in the mixture, which is left under stirring at room temperature for 30 minutes. The resulting solid is filtered, washing with water (0.1 I x 3), and dried in a static dryer under reduced pressure at 50C; 126 g are obtained. Yield: 98%. 1H-NMR (300 MHz), delta (DMSO): 7.90 (d, 1 H); 7.75 (d, 1 H); 7.60 (s, 1 H); 3.40 (m, 4H); 1.15 (m, 6H).
92%
(E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5- nitrophenyl)acrylamide (32 g) and tetrahydrofuran (250 mL) were added to a 500 mL flask at room temperature to form a reaction mixture. The mixture was cooled toO C. After anhydrous aluminum chloride (16.0 g) was added to the reaction mixture, triethylamine (41.6 mL) was added dropwise to the reaction mixture. The reaction mixture was heated under reflux and then cooled. The cooled mixture was dropwise added to dilute hydrochloric acid (10%) followed by adding 314 mL of water. It was allowed to maintain at the same temperature for 6 hours for crystallization and was centrifuged and dried to obtain 28.0 g of (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitrophenyl) acrylamide (entacapone). The yield was 92%. The HPLC purity of the E-isomer was 99.92%.
76%
Method B; AlCl3 (1.25 eq) was added portionwise to a solution of E-2-cyano-3-(3-methoxy-4-hydroxy-5-nitrophenyl)-N,N-diethylacrylamide (1.0 eq) in N,N-dimethylformamide (8.6 mL/g) at 5 C under a nitrogen atmosphere. The mixture was heated to 80 C and stirred for 16 h. The resulting red solution was cooled to 10 C and 35% aqueous HCl solution (5 eq) was added, followed by addition of H2O (10 mL/g) at 30 C. The suspension was stirred at 5 C for 2 h. The solid was filtered off, washed with cold water and dried under reduced pressure to give E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide.
61 - 85%
Method A; AlCl3 (1.25 eq) and pyridine (3.0 eq) were added to a solution of E-2-cyano-3-(3-methoxy-4-hydroxy-5-nitrophenyl)-N,N-diethylacrylamide (1.0 eq) in N,N-dimethylformamide (8.6 mL/g) at 5 C under a nitrogen atmosphere. The mixture was heated to 80 C- 90 C and stirred for 15 h. The resulting red solution was cooled to 10-30 C and 35% aqueous HCI solution (5 eq) and H2O (10 mL/g) were added. Stirring was continued for 1-3 h at 5 C and the precipitated solid was collected by filtration, washed with cold water and dried under reduced pressure to give E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide.
56.1%
With pyridine; aluminum (III) chloride; In chloroform; at 0 - 5℃;Heating / reflux;
(iii) Preparation of N1,N1-diethyl-(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenamide (entacapone); A reactor vessel is charged with dry chloroform (30 L), N1,N1-diethyl-(E)-2-cyano-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-propenamide (1.083 kg, 3.392 mol) and aluminium chloride (0.498 kg, 3.731 mol). The suspension is agitated and cooled down to 0-5 C. Dry pyridine (1.180 kg, 14.923 mol), dissolved in dry chloroform (3 L) is transferred to a dropping funnel and added carefully, drop wise to the suspension. After complete addition, the reaction mixture is agitated and heated to reflux until an in process control indicates the ether cleavage to be complete. Most of the chloroform is distilled out of the reaction mixture. Water (7 L) is added and the residual chloroform is removed out of the two phase mixture by aceotropic distillation. The distilled water is transferred back to the reactor together with ethylacetate (25 L). The mixture is cooled down to 0-5 C. and 25% HCl (20 L) is added. The two phase mixture is agitated at ambient temperature for 30 minutes. After phase separation the watery layer is extracted twice with ethylacetate (2×12 L). The combined organic layers are distilled down to a final volume of 5 L. The product is precipitated by the addition of hexanes (10 L). After agitating for 1 hour the resulting solid is collected on a 20 L Buchner funnel by vacuum filtration. The filtercake is washed with water, transferred to trays and dried in a vacuum oven at 30 C. under reduced pressure, to gain the pure product as a green solid (0.581 kg, 56.1%)Mp.: 161.05 C. HPLC: 99.37% E-Entacapone+0.19% Z-Entacapone. API/MS: [M+H]+ 306.17, [M+H]+-H2O=288.11, [M+H]+-Et=278.17, [M+H]+-NEt2=233.
31.9 g (0.1 moles) of (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro- phenyl)-acrylamide and 250 ml of N-methyl-pyrrolidone are weighed into a flask equipped with a stirrer, a thermometer and a reflux condenser. 15.6 g (0.12 moles) EPO <DP n="9"/>of aluminium chloride are added to the solution in portions under external cooling, and then still under cooling 24 ml of dry pyridine are dropped into the mixture. The reaction mixture is heated to 1000C and stirred at this temperature for 1.5 hours. After cooling to room temperature 56 ml of concentrated hydrochloric acid are added to the mixture under cooling, followed with 320 ml of water. After 2 hours of stirring the product is filtered off, washed with water, and dried at 5O0C under reduced pressure. 28.8 g of the title compound are obtained.
31 :9 g (0.1 moles) of (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro- phenyl)-acrylamide and 200 ml of N,N-dimethyl formamide are weighed into a flask equipped with a stirrer, a thermometer and a reflux condenser. 15.6 g (0.12 moles) of aluminium chloride are added to the solution in portions under externa. cooling, and then still under cooling 24 ml of dry pyridine are dropped into the mixture. The -reaction mixture is heated to 1000C and stirred at this temperature for 1 hour. After cooling to room temperature 56 ml of concentrated, hydrochloric acid are added to the mixture under cooling, followed with 320 ml of water. After 2 hours of stirring the product is filtered off, washed with water, and dried at 500C under reduced pressure. 29.8 g of the title compound are obtained.
0.9 g
With pyridine; aluminum (III) chloride; In dichloromethane; at 0 - 45℃;
(E)-2-Cyano-N,N-diethyl-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylamide 10(1.0 g, 0.0031 mol) was added to a solution of dichloromethane (6.0 ml) and pyridine(2.5 ml) at 0-5 C. Aluminium chloride (1.58 g, 0.0118 mol) was added at 0-5 C overa period of 15-20 min and maintained for 30 min. Reaction mass temperature wasraised to RT and maintained for 2-3 h at 40-45 C. After completion of the reaction,the reaction mass was quenched into dilute hydrochloric acid and ice water (3.0 ml).The organic layer was separated and the solvent distilled off to get the pure entacapone1 (0.9 g).1H NMR (400 MHz, CDCl3): delta 1.30 (s, 1H), 3.50 (s, 4H), 6.22 (s, 1H), 7.57 (s,1H), 7.88 (s, 1H), 8.12 (s, 1H), 10.93 (s, 1H). 13 C NMR (100 MHz, CDCl3): delta 12.53,13.55, 40.87, 43.32, 107.92, 115.33, 118.44,120.73, 124.41, 133.44, 145.19, 147.09,148.17, 162.59; MS (ESI) m/z: 304.5 [M-1].
29.8 g of the title compound, prepared as described in Example 6, are dissolved in 450 ml of hot isopropanol, the hot solution is decolourized with 2 g of EPO <DP n="10"/>activated carbon, and then carbon is removed by filtration. The solution is allowed to cool and then kept at 10-200C for 3 hours. The separated product is filtered off, washed with cold isopropanol and dried in air. The resulting 26.4 g of product are dissolved at 6O0C in a mixture of 100 ml of acetone and 8 ml of glacial acetic acid, the solution is decolourized with 2 g of activated carbon, the carbon is removed by filtration, and the filtrate is kept at 10-200C for 3 hours. The separated crystalline ? product is filtered off, washed with cold acetone, and dried in air. 23 g of the title compound are obtained with a purity grade of 99.9 % as determined by HPLC; m.p.: 164-1650C. X-ray diffraction pattern shows that this product consists solely of the stable polymorphic form.
With hydrogenchloride; water; at 37℃; for 12h;pH 1;Reactivity (does not react);
ib) Stability at Different pH-Values, t1/2 [h]The stability of compounds of the present invention is tested at pH 1 and at pH 7.4. The testing is carried out by the following HPLC method:Chemical hydrolysis rates t1/2 [h] of selected compounds of formula I are determined in 0.1 N HCl (pH 1) and PBS buffer (pH 7.4) solution. Solutions are prepared by dissolving an appropriate amount of compound in 0.1 N HCl and PBS buffer solution. Samples were withdrawn at designated time intervals and analysed for remaining prodrug by HPLC at 37 C. over 12 h.Reversed phase gradient HPLC method, column YMC Pro C8, 50 mm×4.0 mm, 3 mum, Eluent A: Water:trifluoroacetic acid (100:0.5 (v/v)), Eluent B: Acetonitrile:trifluoroacetic:acid (100:0.5 (v/v)). Column temperature 30 C., Flow rate 3.0 mL/min, Detection wavelength: 220 nmFor evaluation, the peak area of the respective compound from the first injection is defined as 100% relative concentration. The peak areas of all other subsequent injections are calculated in percentage relating to this standard. (relative concentration in %). The relative concentrations are plotted in a logarithmic scale (ln) against the injection times. Based on the assumption of a first order kinetic, the rate constant and half life times (t1/2 [h]) can be calculated.The results of the study are summarized in Table 2.
With water; at 37℃; for 12h;pH 7.4;PBS buffer;Reactivity (does not react);
ib) Stability at Different pH-Values, t1/2 [h]The stability of compounds of the present invention is tested at pH 1 and at pH 7.4. The testing is carried out by the following HPLC method:Chemical hydrolysis rates t1/2 [h] of selected compounds of formula I are determined in 0.1 N HCl (pH 1) and PBS buffer (pH 7.4) solution. Solutions are prepared by dissolving an appropriate amount of compound in 0.1 N HCl and PBS buffer solution. Samples were withdrawn at designated time intervals and analysed for remaining prodrug by HPLC at 37 C. over 12 h.Reversed phase gradient HPLC method, column YMC Pro C8, 50 mm×4.0 mm, 3 mum, Eluent A: Water:trifluoroacetic acid (100:0.5 (v/v)), Eluent B: Acetonitrile:trifluoroacetic:acid (100:0.5 (v/v)). Column temperature 30 C., Flow rate 3.0 mL/min, Detection wavelength: 220 nmFor evaluation, the peak area of the respective compound from the first injection is defined as 100% relative concentration. The peak areas of all other subsequent injections are calculated in percentage relating to this standard. (relative concentration in %). The relative concentrations are plotted in a logarithmic scale (ln) against the injection times. Based on the assumption of a first order kinetic, the rate constant and half life times (t1/2 [h]) can be calculated.The results of the study are summarized in Table 2.
In isopropyl alcohol; at 25 - 85℃;Purification / work up;
3: Purification of Crude (2E)-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2- enamide polymorphic form AThe compound (4Og) obtained from the example 2 above was taken in isopropyl alcohol (20OmL) and heated to reflux at 80-850C for 2 hrs. The reaction contents was cooled to 25-3O0C and stirred for 1 hr at 25-3O0C, filtered and washed with isopropanol and dried. To this dried compound (38g) was charged ethyl acetate (115mL) and the content were refluxed at 72-780C for 2 hrs, cooled and stirred at 25-3O0C for 1 hr, filtered and dried under vacuum at 50-550C to give 30 g of pure (2E)-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide polymorphic form A or (E) <strong>[130929-57-6]Entacapone</strong> polymorphic form A. Dry Weight : 36g (90.0%) and single individual impurity of 0.04%.
In acetone; toluene;Reflux;Purification / work up;
Example 1 - purification of trans-<strong>[130929-57-6]Entacapone</strong> (inventive method) A flask is charged with 76.7 g of crude <strong>[130929-57-6]Entacapone</strong> (of purity 99,7% and containing 1,0% of cis-<strong>[130929-57-6]Entacapone</strong>) in 383.5 ml of toluene and 536.9 ml of acetone and the mixture is heated at reflux until complete dissolution. 7.7 g of Acticarbon are then added and the mixture is stirred at reflux for 30 minutes, is filtered while still hot and the filter cake is washed with 3x38.4 ml of acetone. The filtrate is added to the <strong>[130929-57-6]Entacapone</strong> mixture, which is heated again until dissolution. Then, 375.83 ml of acetone are distilled off with Dean-Stark under atmospheric pressure, until an internal temperature of 75-80C is reached. Heating is switched off and the mixture is kept hot (hot oil bath) until the product starts to precipitate. After 1 hour under stirring the oil bath is removed and the mixture is allowed to cool to 20C. After 1 hour at 20C under stirring, the mixture is colled to 0C and is stirred for additional 3 hours, then it is filtered and the solid cake is washed with a cool mixture of 38.4 ml toluene and 19 ml acetone. The product so obtained is dried in an oven at 45C for 10-12 hours, to give trans-<strong>[130929-57-6]Entacapone</strong> in a yield of 84% and with a purity of 99.88%. Cis-<strong>[130929-57-6]Entacapone</strong> was not detected (lower than 0,02%) and major impurity 0,04%.
26
[ 686349-59-7 ]
[ 130929-57-6 ]
Yield
Reaction Conditions
Operation in experiment
iodine; In ethyl acetate; for 10 - 12h;Heating / reflux; Isomerisation;Product distribution / selectivity;
A mixture of 3,4-dihydroxy-5-nitrobenzaldehyde (100 gm), N,N-diethyl-2-cyanoacetamide (92.0 gm), piperidine (18.58 gm), acetic acid (13.0 gm) at 20-25 C. in toluene (1000 ml) was refluxed to remove water azeotrophically. After completion of reaction, acetonitrile (1000 ml) was added to clear the reaction mass and charcoalization treatment has been given. Solvent was evaporated and ethyl acetate (1200 ml) was added in the residue then iodine (5 gm) was added to it. Reactions mass was refluxed for 10-12 hrs and cooled to room temperature. Ethyl acetate (2500 ml) was added to reaction mass followed by addition of methanol (1050 ml). Organic layer washed with 4% Sodium thiosulphate solution (600 ml) and water (500 ml). Solvent was evaporated under vacuum till 250 ml of volume remaining in reaction mixture. n-Hexane (1500 ml) was added to the reaction mass and stirred 2 hrs at room temperature. The product filtered and washed with n-hexane (2×150 ml). The product was dried in vacuum to obtain E-isomer of Entacapone. Yield: 72.28% Purity: 99%; EXAMPLE 2 Preparation of Entacapone A mixture of 3,4-dihydroxy-5-nitrobenzaldehyde (100 gm), N,N-diethyl-2-cyanoacetamide (92.0 gm), piperidine (18.58 g) acetic acid (13.0 g) at 20-25 C. in ethylacetate (1000 ml) was refluxed to remove water azeotrophically. After completion of reaction, iodine (5 gm) was added to it and further stirred the reaction mixture for another 10-12 hrs. The reaction mass is concentrated and cooled and filtered the material. The wet material was suspended in sodium thiosulfate solution in water and filtered, washed with water to get the wet material. Finally it was dried to get the E-isomer of Entacapone. Yield: 84% Purity: 99%
With hydrogen bromide; acetic acid; In water; at 15 - 90℃; for 23 - 26h;
STEP 3 . Preparation of N,N-DIETHYL-2-CYANO-3-(3,4-DIHYDROXY-5-NITRO PHENYL)ACRYL AMIDE . (PURE E- ENTACAPO N E).; A mixture containing 140.0 gm of the crude product obtained according to step-2 in 420.0 ml of acetic acid was heated to 85-900C and 9.8 ml hydrogen <n="17"/>bromide is added and cooled to 20-250C. The reaction mixture was stirred for 18-20 hrs at 20-250C and for 5-6 hrs at 15-180C. The precipitated product was filtered and washed with a mixture of toluene and acetic acid (14.0 ml each) and finally with toluene (28.0 ml) .The product was dried at 50-550C. The dried weight is 104.0 gm with HPLC purity of 99.88%. It was further purified using methanol as solvent to get 95.0 gm of the E-Entacapone of polymorphic form A as a pure product having HPLC purity of 99.91% Melting 163.6-164.9 and matching in all repect with the reported E-Entacapone of polymorph form A.
EXAMPLE 100 N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide The procedure described in Example 99 was repeated using 1.83 g of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> and 1.5 g of N,N-Hydrochloric diethylcyanoacetamide. Yield 2.23 g (73%), m.p. 153-156 C.
With acetic acid; In methanol; for 1h;Heating / reflux;Purification / work up;
The crude product (495 g), methanol (3960ml) and acetic acid (990ml) were refluxed for lhr.The clear solution was filtered and the product was precipitated by gradually cooling the filtrate to 10-15 C. The solid was filtered out, washed twice with cold ethyl acetate(2 x 990 ml) at 15C_and dried in an electric oven at 60-70 C.Yield of entacapone based on the crude product 445.5g (90 %). Purity 99.8%.Z-isomer 0.02 %
With IRA 96 resin; In toluene;Reflux;
General procedure: To a solution of N, N-diethylcyanoacetamide (0.1 mol) in toluene was added 0.2 g IRA 96 resin and an aromatic aldehyde (0.1 mol). The reaction mass was heated to reflux under azeotrope for 5-6 hours. After completion of the reaction, the mixture was filtered hot. The filtrate was evaporated completely under vacuum and the residue was purified in ethanol to afford the pure compounds. The melting points for the compounds are shown in Table 1.
29
[ 146698-91-1 ]
[ 130929-57-6 ]
[ 145195-63-7 ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; aluminum (III) chloride; In dichloromethane; at 0 - 55℃; for 3.08333 - 4.25h;
STEP 2.; Preparation of N,N-DIETHYL-2-CYAN.O-3-(3,4-DIHYDROXY-5- NITRO PHENYL)ACRYL AMIDE( CRUDE ENTACAPONE (3); The product N,N-Diethyl-2-cyano-3-(3-mefhoxy-4-hydroxy-5-nitro phenyl) acryl amide of the formula (7) 160.0 gm (0.50 mole) obtained from step-1 and 960 ml of dichloromethane and 400 ml pyridine were cooled to 0-50C and slowly charged 200.4gm (1.50 mole, 3.0 equiv.) of aluminium chloride in lot keeping the temperature below 50C in 35-45 min. The resulting reaction mixture was stirred for 30 min. at 0-50C and slowly heated to 45-50 degrees and maintained that temperature with stirring for 2-3 hrs. After completion of the reaction dichloromethane evaporated and resulting reaction mixture is added to Ice water containing little hydrochloric acid and stirred for 2-3 hrs. The precipitated product was filtered and dried to get 140.0 gm (94.6%) of title product of the formula (3) as crystalline solid with total HPLC purity 99.49% having 68.74% of E- isomer and 30.75% of Z-isomer.
In isopropyl alcohol; at 20℃; for 2h;Product distribution / selectivity;
Piperidine (6.26 g; 73.5 mmole) is added to a suspension of <strong>[130929-57-6]Entacapone</strong> (E-isomer= 75 %; Z-isomer= 25 %)(12.5 g; 40.9 mmole) in isopropanol (150 ml) at room temperature. The mixture is stirred for approximately 2 hours, obtaining an abundant precipitate. Finally, it is cooled at 0-50C for approximately 2 hours and the resulting precipitate is filtered off and washed with cold isopropanol(20 ml) . The resulting product is dried at 400C in a vacuum oven to provide 14.2 g (yield= 88.8%) of an orange solid (m.p.=152-4C (decomp.); (Z-isomer= 1.3 %) ) .
30 % aq. NaOH is added to a suspension of <strong>[130929-57-6]Entacapone</strong>(E-isomer= 69%; Z-isomer= 31%) (15.15 g; 40.9 mmole) in ethanol (100 ml) at room temperature (8.73 g; 65.5 mmole).The mixture is stirred at room temperature and the resulting precipitate is kept in stirring at this temperature overnight. Finally, it is cooled at 0-50C for approximately 2 hours and filtered off and washed with cold ethanol (20 ml) . The resulting product is dried at 400C in a vacuum oven to provide 14.13 g (yield= 87.1%) of a red solid (m.p.= 260-4C (decomp. ) ; (Z-isomer= 1.80%) ) .
With hydrogenchloride; In water; isopropyl alcohol; at 20 - 30℃;
A dissolution comprising a mixture of water (1200 <n="14"/>ml) and 35 % aq. HCl is added to a suspension of the piperidine salt of Entacapone obtained in a) (119 g; 305 mmole) in isopropanol (600 ml), keeping the temperature from 20 to 300C(29.8 ml; 335 mmole). The resulting precipitate is cooled at 0-50C, filtered off and washed with isopropanol/water (80 ml: 160 ml), and finally, with water (240 ml). The resulting product is dried at 400C in a vacuum oven to provide 84.8 g (yield= 91.1 %) of an orange solid (m.p.= 162.4-163.5C;HPLC purity= 99.8 % (Z-isomer= 0.05 %) ) .
Example 10: Preparation of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide using AlCl3 (compound of formula (I)); AlCl3 (75.0 g, 0.56 mol) was added portionwise to a solution of E-2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N,N-diethylacrylamide (150.0 g, 0.45 mmol) in N,N-dimethylformamide (1290 mL) at 5 C under a nitrogen atmosphere. The mixture was heated to 80 C and stirred for 15 h. The resulting red solution was cooled to 10 C and 35% aqueous HCl solution (200 mL) was added, followed by the slow addition of H2O (1500 mL) at 30 C. The suspension was stirred at 5 C for 2.5 h. The solid was filtered off, washed with cold water and dried under reduced pressure to give 126.3 g (92% yield) of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide. Light yellow solid. 1H-RMN (400 MHz, CDCl3) delta 7.92 (1 H, d, J = 2.2), 7.73 (1 H, d, J = 2.2), 7.62 (1 H, s), 3.40 (4H, broad q), 1.14 (6H, broad t). Purity by HPLC: 99.7%, (Z)-isomer: 0.2%.
80%
Example 9: Preparation of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide using AlCl3 / pyridine (compound of formula (I)); AlCl3 (371 mg, 2.78 mmol) and pyridine (0.54 mL, 6.69 mmol) were added portionwise to a solution of E-2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N,N-diethylacrylamide (742 mg, 2.23 mmol) in N,N-dimethylformamide (6.4 mL) at 5 C under a nitrogen atmosphere. The mixture was heated to 80 C and stirred for 15 h. The resulting red solution was cooled to 10 C and 35% aqueous HCl solution (1.0 mL) was added, followed by the addition of H2O (7.4 mL) at 30 C. Stirring was continued for 2 h at 5 C and the precipitated solid was collected by filtration, washed with cold water and dried under reduced pressure to give 541 mg (80% yield) of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide. HPLC purity: 96.0%, (Z)-isomer: 0.4%.
74%
Example 8: Preparation of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide using BBr3 (compound of formula (I)); A 1.0 M solution of BBr3 in CH2Cl2(1.62 ml, 1.62 mmol) was added dropwise to a solution of E-2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N,N-diethylacrylamide (154 mg, 0.46 mmol) in CH2Cl2 (0.5 mL) at -15 C under a nitrogen atmosphere. The resulting red suspension was stirred for 1 h at -15 C and allowed to warm to room temperature overnight. The reaction was quenched by the addition of H2O (4 mL) and stirred for 30 min. The aqueous phase was extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with saturated brine (20 mL) and dried (Na2SO4). The solvent was eliminated under reduced pressure to give 105 mg (74% yield) of E-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide.
Method A; The compounds disclosed in table 1, wherein R2 is H are prepared by method A.Method A comprises the formation of a cyclic ester by means of phosgene, followed by selective ring opening via alcoholysis as shown in the specification before.<strong>[130929-57-6]Entacapone</strong> (0.61 g, 2 mmol) is dissolved in dry toluene (20 mL). Pyridine (0.2 mL, 2 mmol) is added at ambient temperature. The reaction mixture is cooled in an ice bath and a 20% toluene solution of phosgene (4.55 g, 5.3 mL, 20 mmol) is added. A further 10 mL toluene was added. The mixture is agitated with an ice cooling for 1.5 h and 2 h at ambient temperature. The precipitate is removed by filtration and the filter cake is washed with a small amount of toluene. The filtrate is evaporated under vacuum. The resulting pale yellow solid is taken up in 20 mL of dichloromethane, and an excess of the appropriate alcohol is added. The reaction mixture is agitated at ambient temperature over night. Inprocess controls are done either by TLC or HCLC. After completion of the reaction, the yellow solution is washed twice with 50 mL portions of 2 N HCl and water, the organic layer dried over sodium sulphate and evaporated under vacuum to gain the crude compound either as a solid or as an oil which in most cases solidifies on standing. Typical yields of crude products are 60 to 80%. Purification is done by recrystallisation with hexane/ethyl acetate or by flash chromatography. The purified compounds are obtained as yellow to orange solids in 10 to 20% yields with purities 95%. The purity and identity is determined by HPLC/ESI-MS.
With human UDP-glucuronosyltransferase1A10; magnesium chloride; at 37℃; for 0.5h;pH 7.4;aq. phosphate buffer; Enzymatic reaction;Kinetics;
General procedure: Glucuronidation rates at a single protein and substrate concentrations ("screening assays") were measured in duplicates (at most 15% difference between duplicates), in a final volume of 100 mul. In addition, the kinetics of pNP, estradiol and EED were determined, and in these assays triplicates were used. The protein concentrations for the screenings and the kinetics were 20-200 mug/ml, depending on the tested substrate and enzyme variant. The screening reaction mixtures contained 50 mM phosphate buffer, pH 7.4, 5 mM MgCl2, 5 mM saccharolactone, 5 mM UDPGA and the following concentrations of the tested substrates: 500 muM in the cases of scopoletin, pNP, <strong>[130929-57-6]entacapone</strong> and estriol, 200 muM of 4-MU, or 100 muM for the screening assays with estradiol, EED and 1-naphthol. Estradiol, EED and estriol were dissolved in DMSO and the final concentration of the solvent in assays with these substrates was either 5% (estradiol and estriol), or 10% (EED). These concentrations of DMSO do not inhibit the activity of recombinant UGTs[29].
General procedure: These were prepared by treating a solution of <strong>[130929-57-6]entacapone</strong> (0.01 mol)in ethanol with the appropriate amine (0.01 mol). The reaction mass was stirred for 25-30 min at 25-30C.When salt formation was complete, the precipitated salt solid was filtered and dried to afford the product.
In ethanol;
To a solution of <strong>[130929-57-6]entacapone</strong> (3.05 g, 0.01 mol) in ethanol was added 0.85 g of piperidine (0.01 mol). The reaction mass was stirred for 25-30 min. After completion of the reaction, the solid was filtered and dried in an air drier. The melting point of the resulting compound was 156.3 - 159.6 C.
2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl)prop-2-eneamide[ No CAS ]
[ 130929-57-6 ]
Yield
Reaction Conditions
Operation in experiment
With ethanol; triethylamine; at 70 - 75℃; for 12h;
To a solution of 6 (3.19g, 0.01 mol) was dissolved in ethanol (30ml) and heated withtriethylamine (3.03g, 0.03mol) at 70-75C for 12hr.The reaction mass wasevaporated to remove ethanol, addition of water to theresidue and acidification with hydrochloric acid. The precipitate wascrystallized from ethyl acetate to give pure 7. Yellow solid, yield: (45%), m.p. 161.2-163.2 C. 1H NMR (400MHz,CDCl3): deltaH 1.20(br s, 6H), 3.43 (br s,4H), 7.44 (s,1H), 7.84 (unresolved doublet, Ar-H), 7.94(unresolved doublet, 1ArH), 9.67(br s, -OH), 10.79 (br s, -OH); 13C NMR ( CDCl3,75MHz) deltaC:162.96,148.56, 148.36, 146.88, 133.81,124.03 120.69, 118.41, 115.62, 107.08, 43.42,40.72, 13.50 and 12.50; MS m/z =304.1(negativemode); IR (NEAT) 3038 (ArC-H), 2980 (C-H), 2216(-CN),1627 (C=O), 1605 (C=C), 1297, 1512 (N=O)
2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl)prop-2-eneamide[ No CAS ]
[ 130929-57-6 ]
Yield
Reaction Conditions
Operation in experiment
55%
Acrylamide13 (3.19, 0.01 mol) was demethylated with triethylamine in ethanol at 70-75C for 12 h. After completion of the reaction, the intermediate salt (2.9 g)was isolated by distilling off the solvent. The salt was dissolved in water, acidified with hydrochloric acid,and the product extracted into ethyl acetate. The dried organic layer was evaporated to get the crude demethylated product. This was purified through silica gel column chromatography using hexane/ethyl acetate as mobile phase to afford pure 1. 45% isolated yield asyellow solid. MR: 162-163C (lit.10:162-163C). 1HNMR(400 MHz, CDCl3): delta 1.20 (br s, 6H), 3.43 (brs,4H), 7.44 (s,1H), 7.84 (unresolved doublet, Ar-H),7.94 (unresolved doublet, 1ArH), 9.67(br s, -OH), 10.79(br s, -OH); 13C-NMR( CDCl3,75MHz) : delta 162.90,148.96, 148.36, 146.88, 133.81,124.03 120.69, 118.41,116.62, 107.08, 43.42, 40.72, 13.50, 12.50; ms: m/z=304.1 (negative mode); HPLC purity >99%. Theyield of 1 was increased to 55% when the reaction timewas extended to 14 h.
General procedure: These were prepared by treating a solution of <strong>[130929-57-6]entacapone</strong> (0.01 mol)in ethanol with the appropriate amine (0.01 mol). The reaction mass was stirred for 25-30 min at 25-30C.When salt formation was complete, the precipitated salt solid was filtered and dried to afford the product.
General procedure: These were prepared by treating a solution of <strong>[130929-57-6]entacapone</strong> (0.01 mol)in ethanol with the appropriate amine (0.01 mol). The reaction mass was stirred for 25-30 min at 25-30C.When salt formation was complete, the precipitated salt solid was filtered and dried to afford the product.
General procedure: These were prepared by treating a solution of <strong>[130929-57-6]entacapone</strong> (0.01 mol)in ethanol with the appropriate amine (0.01 mol). The reaction mass was stirred for 25-30 min at 25-30C.When salt formation was complete, the precipitated salt solid was filtered and dried to afford the product.
General procedure: These were prepared by treating a solution of <strong>[130929-57-6]entacapone</strong> (0.01 mol)in ethanol with the appropriate amine (0.01 mol). The reaction mass was stirred for 25-30 min at 25-30C.When salt formation was complete, the precipitated salt solid was filtered and dried to afford the product.
0.227 g of entacapone (0.744 mmol) and 0.132 g of L-<strong>[3081-61-6]theanine</strong> (0.758 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 13a, while the FTIR spectrum is shown in Figure 13b. The DSC melting endotherm of the product was characterized by a peak maximum at 160C.
With pyridine; aluminum (III) chloride; In chloroform; at 0℃; for 0.5h;Reflux;
The product prepared in Example 4 was 2-cyano-3-(3-methyl-4-hydroxy-5-nitrophenyl)-N,N diethyl acrylamide diethylamine salt (V, R = Methyl) 60.0gMixed with 250ml chloroform,Stir and cool to 0 C,Add 60.0g of aluminum chloride,Add 88.9g of pyridine dropwisea mixture with 150 ml of chloroform,After stirring for 30 min, the reaction was heated to reflux.The reaction was completely detected by TLC, and the reaction liquid was evaporated to dryness under reduced pressure. a mixture of 400 ml of water and 200 ml of concentrated hydrochloric acid was added, and the mixture was stirred for 2 hours, then filtered, washed with water, and dried.46.9 g of a yellow powder was obtained in a yield of 81.10%.HPLC purity 98.40% (including isomers).
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