* 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 chloroform at 0℃; for 16 h; Reflux
Compound 104 (10 g, 50.76 mmol) was added to a stirred suspension of AICI3 (7.44 g, 55.83 mmol) in dry chloroform (150 mL) at 0°C. Pyridine (18.0 mL, 223.35 mmol) was dropwise added to the resulting mixture, and the mixture was refluxed for 16h. The mixture was cooled to room temperature and poured into ice water. The solid was filtered, and the residue was purified by silica gel column chromatography to give the title compound 105 (8.0 g, 86percent) . 1HNMR (400 MHz, DMSO-d6) : δ 10.91 (br s, 2H) , 9.81 (s, 1H) , 7.98 (d, J= 2.0 Hz, 1H) , 7.46 (d, J = 2.0Hz, 1H) .
73%
With 1-N-ferrocenylmethyl benzimidazole tagged polymer In N,N-dimethyl-formamideReflux
General procedure: A mixture of aryl methyl ether (1 mmol) and [FemMerBenz]Al2Cl7 (200 mg, 0.96 mol percent) in DMF (5 mL) was refluxed in an oil bath. After completion of the reaction as monitored by the TLC, the reaction mixture was cooled and filtered. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (3 20 mL). The combined organic layers were dried over Na2SO4. Evaporation of the solvent followed by column chromatography over silica gel using ethyl acetate/ petroleum ether (1:4 v/v) afforded pure O-demethylated product, which was characterized by spectral methods.
71%
With pyridine; aluminium(III) iodide In acetonitrile at 80℃; for 18 h;
General procedure: To a solution of AlI3 (36.6 mmol, 1.1 equiv) in MeCN (100 mL)was added dropwise a solution of pyridine (12.2 g, 154.2 mmol,4.6 equiv) and eugenol (5.4 g, 33.0 mmol). The mixture wasstirred at 80 °C for 18 h. After cooling to room temperature, themixture was quenched with aq HCl (2 mol/L, 50 mL), and wasextracted with EtOAc (4 × 50 mL). The combined organic phaseswere washed with brine and dried by MgSO4. After evaporationof solvents by a rotary evaporator, the residue was purifiedthrough flash column chromatography to afford 5 as a whitesolid (4.9 g, 99percent).
71%
Stage #1: With pyridine; iodine; aluminium In acetonitrile for 18 h; Reflux Stage #2: With hydrogenchloride In water; acetonitrile at 20℃;
To a 100 ml eggplant flask were added iodine (2.095 g), aluminum powder (0.368 g) and acetonitrile (40 ml), heated toReflux, stir for 2 hours to the purple red of iodine disappears. Pyridine (1.597 g) and 5-nitro vanillin (0.986 g) were added and the reaction was continuedThe reaction was carried out for 18 hours. After stirring, the mixture was cooled to room temperature and then 2 mol / L dilute hydrochloric acid (10 ml) was added to the reaction solution,Ester (50 ml x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was evaporated to dryness with a rotary evaporator and the residue was removedPurification by flash column chromatography (mobile phase ethyl acetate: petroleum ether = 1: 3, volume ratio) gave 3,4-dihydroxy-5-nitroBenzaldehyde (yellow solid, 0.650 g, 71percent yield).
50%
With hydrogen bromide In water for 4 h; Reflux
A solution of 94 (3.5 g, 17.8 mmol) in hydrobromic acid (48percent, 32 ml) was refluxed for 4 h. After cooling to room temperature and addition of water and ice, the precipitate was filtered off and washed with cold water, to give compound 95 as a brown solid (1.62 g, 50percent). 1H NMR (300 MHz, DMSO-d6): δ = 7.46 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 1.9 Hz, 1H), 9.79 (s, 1H), 10.52 (br m, 2H) ppm; 13C NMR (75 MHz, DMSO-d6): δ = 115.8, 119.6, 127.0, 137.2, 147.2, 148.3, 190.5 ppm; HRMS (ESI): m/z [M-H]- calcd for C7H4NO5: 182.0059, found: 182.0088.
43%
With aluminium(III) iodide; diisopropyl-carbodiimide In acetonitrile at 80℃; for 18 h;
General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in hot CH3CN (40 mL) were added sequentially DIC (0.379 g, 3 mmol, 0.6 equiv) and eugenol (1, 0.821 g, 5.0 mmol). The mixture was stirred for 18 h at 80 °C, and then it was cooled to r.t., acidified with HCl (2 mol/L, 10 mL), and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with sat. aq Na2S2O3 (10 mL) and brine (10 mL), and was dried (MgSO4). The solvent was removed on a rotary evaporator and the residue was purified by flash column chromatography (PE/EtOAc, 4:1) to afford 2 (0.750 g, 99percent) as a white solid
43%
With aluminium(III) iodide; diisopropyl-carbodiimide In acetonitrile at 80℃; for 18 h;
To a 100 ml eggplant flask were added aluminum triiodide (2.248 g), acetonitrile (40 ml) Heated to reflux, followed by the addition of DIC (0.378 g) and 5-nitro vanillin (0.986 g), heated to 80 ° C, After stirring for 18 hours, the mixture was stirred, cooled to room temperature and then acidified with 2 mol / L dilute hydrochloric acid (10 ml) And extracted with ethyl acetate (50 ml X). The combined organic phases were washed first with a saturated aqueous solution of sodium thiosulfate (10 ml), washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated Instrument evaporated, The residue was purified by flash column chromatography (eluent: ethyl acetate / petroleum ether = 2: 3, volume ratio) To give 0.395 g of 3,4-dihydroxy-5-nitrobenzaldehyde (yellow solid in 43percent yield)
39.5%
at 90℃; for 17 h;
00455] Intermediate 45 : Synthesis of 8-nitro-2,3-dihydrobenzo[b][l,4]dioxine-6- carbaldehyde:[00456] Step 1: Synthesis of 3,4-dihydroxy-5-nitrobenzaldehyde: To a solution of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (3 g, 15.2 mmol) in acetic acid (3.1 mL) was added 40percent hydrobromic acid (9.24 mL). The mixture was heated at 90°C for 17 h. Reaction mixture was cooled and poured into ice water (100 mL), followed by a standardaqueous/EtOAc workup and purified by column chromatography on silica gel (petroleum ether/ethyl acetate =5: 1) to give 3,4-dihydroxy-5-nitrobenzaldehyde (1.1 g, yield 39.5percent).
14%
With aluminium(III) iodide; calcium oxide In acetonitrile at 80℃; for 18 h;
To a 100 ml eggplant flask was added aluminum triiodide (2.242 g, 5.5 mmol), acetonitrile (40 ml),CaO (0.421 g, 7.5 mmol) and 5-nitro vanillin (0.985 g, 5.0 mmol) were heated to 80 °C,After 18 hours of reaction, stirring was stopped. After cooling to room temperature, 2 mol/L dilute hydrochloric acid (10 ml) was acidified in an eggplant-shaped flask.Extract with ethyl acetate (50ml x 3) and combine the organic phases and wash first with saturated aqueous sodium thiosulfate (10ml).It was washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness on a rotary evaporator.The residue was purified by flash column chromatography (eluent: ethyl acetate/petroleum ether=1:3, volume ratio).0.131 g of 3,4-dihydroxy-5-nitrobenzaldehyde (yellow solid, yield 14percent) was obtained.
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 5, p. 1969 - 1989
[2] Journal of Organic Chemistry, 2000, vol. 65, # 23, p. 8001 - 8010
[3] Journal of the American Chemical Society, 2000, vol. 122, # 44, p. 10781 - 10787
[4] Organic Letters, 2008, vol. 10, # 7, p. 1369 - 1372
[5] Patent: WO2016/199943, 2016, A1, . Location in patent: Paragraph 0402
[6] Synthetic Communications, 2002, vol. 32, # 4, p. 641 - 649
[7] Tetrahedron Letters, 2012, vol. 53, # 47, p. 6361 - 6366,6
[8] Synlett, 2017, vol. 28, # 1, p. 138 - 142
[9] Patent: CN106278825, 2017, A, . Location in patent: Paragraph 0080; 0081; 0082; 0083
[10] Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4584 - 4588
[11] Journal of Medicinal Chemistry, 2010, vol. 53, # 8, p. 3396 - 3411
[12] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 24, p. 7318 - 7337
[13] Synthesis (Germany), 2017, vol. 49, # 12, p. 2721 - 2726
[14] Patent: CN106866377, 2017, A, . Location in patent: Paragraph 0179-0181
[15] Patent: WO2011/38204, 2011, A1, . Location in patent: Page/Page column 149
[16] Patent: CN107473916, 2017, A, . Location in patent: Paragraph 0105-0107
[17] Chemische Berichte, 1903, vol. 36, p. 2935
[18] Patent: WO2005/63695, 2005, A1, . Location in patent: Page/Page column 10
[19] Patent: US5236952, 1993, A,
[20] Synthetic Communications, 2008, vol. 38, # 15, p. 2507 - 2520
[21] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6553 - 6557
[22] Patent: US2010/234632, 2010, A1, . Location in patent: Page/Page column 3-4
[23] Patent: WO2015/69110, 2015, A1, . Location in patent: Page/Page column 70; 71
2
[ 6635-20-7 ]
[ 7440-44-0 ]
[ 116313-85-0 ]
Yield
Reaction Conditions
Operation in experiment
80%
With acetic acid In conc. hydrobromic acid; water
EXAMPLE 111 3,4-Dihydroxy-5-nitrobenzaldehyde A solution containing 8.0 kg of 5-nitrovanillin and 8.7 kg of acetic acid in 35 kg of conc. hydrobromic acid was refluxed for 20 h. 0.6 kg of charcoal was added and the mixture was filtered. 32 kg of water was added with stirring and the solution was cooled to -10° C. and stirring was continued for 2 h more. The crystalline product was filtered and washed with water. Yield 5.66 kg (80percent), m.p. 135°-137° C.
Reference：
[1] Patent: US4963590, 1990, A,
3
[ 121-33-5 ]
[ 116313-85-0 ]
Reference：
[1] Chemische Berichte, 1903, vol. 36, p. 2935
[2] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 24, p. 7318 - 7337
4
[ 621-59-0 ]
[ 116313-85-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4367 - 4371
5
[ 80547-69-9 ]
[ 116313-85-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4367 - 4371
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.
EXAMPLE 104 3,4-Dihydroxy-5-nitrobenzylalcohol To a solution containing 6.0 g of sodium borohydride in 50 ml of water 9.15 g of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> was gradually added with stirring at room temperature. The mixture was stirred for 1 h more after which it was acidified with hydrochloric acid. The solution was filtered to remove tarry impurities and extracted 4 times with ether. The ether extract was dried over anhydrous sodium sulfate, filtered and concentrated to a volume of about 100 ml. The crystalline solid was filtered. Yield 6.0 g (65%), m.p. 100 C. (decomp.).
With hydroxylamine hydrochloride; In formic acid; water;
EXAMPLE 112 3,4-Dihydroxy-5-nitrobenzonitrile A solution containing 0.92 g of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> and 0.49 g of hydroxylamine hydrochloride in 5.0 ml of formic acid was refluxed for 1 h. 50 ml of water was added and the product was filtered and washed with water. Yield 0.3 g (33%), m.p. 175-178 C.
acetic acid 7-benzyloxy-5-benzyloxymethyl-9-hydroxy-8-hydroxymethyl-1a,8,9,9a-tetrahydro-2<i>H</i>-1-oxa-3-aza-benzo[<i>a</i>]cyclopropa[<i>e</i>]cycloocten-3-yl ester[ No CAS ]
acetic acid 7-benzyloxy-8-(<i>tert</i>-butyl-dimethyl-silanyloxymethyl)-9-hydroxy-5-hydroxymethyl-1a,8,9,9a-tetrahydro-2<i>H</i>-1-oxa-3-aza-benzo[<i>a</i>]cyclopropa[<i>e</i>]cycloocten-3-yl ester[ No CAS ]
acetic acid 7-benzyloxy-5-benzyloxymethyl-8-(<i>tert</i>-butyl-dimethyl-silanyloxymethyl)-9-hydroxy-1a,8,9,9a-tetrahydro-2<i>H</i>-1-oxa-3-aza-benzo[<i>a</i>]cyclopropa[<i>e</i>]cycloocten-3-yl ester[ No CAS ]
acetic acid 7-benzyloxy-8-(<i>tert</i>-butyl-dimethyl-silanyloxymethyl)-9-hydroxy-5-(4-methoxy-phenoxymethyl)-1a,8,9,9a-tetrahydro-2<i>H</i>-1-oxa-3-aza-benzo[<i>a</i>]cyclopropa[<i>e</i>]cycloocten-3-yl ester[ No CAS ]
(5S*,6R*)-7-Benzyloxy-9-benzyloxymethyl-5-hydroxy-6-(4-methoxy-benzyloxymethyl)-5,6-dihydro-2H-benzo[b]azocine-1-carboxylic acid tert-butyl ester[ No CAS ]
acetic acid 7-benzyloxy-5-benzyloxymethyl-9-hydroxy-8-(4-methoxy-benzyloxymethyl)-1a,8,9,9a-tetrahydro-2<i>H</i>-1-oxa-3-aza-benzo[<i>a</i>]cyclopropa[<i>e</i>]cycloocten-3-yl ester[ No CAS ]
(5S*,6R*)-7-benzyloxy-9-benzyloxymethyl-5-hydroxy-6-(4-methoxy-benzyloxymethyl)-5,6-dihydro-2H-benzo[b]azocine-1-carboxylic acid 2,2,2-trichloro-ethyl ester[ No CAS ]
allyl-{3-benzyloxy-5-benzyloxymethyl-2-[(1R,2S)-2-hydroxy-1-(4-methoxy-benzyloxymethyl)-but-3-enyl]-phenyl}-carbamic acid 2,2,2-trichloro-ethyl ester[ No CAS ]
(5S*,6R*)-7-Benzyloxy-9-benzyloxymethyl-5-(tert-butyl-dimethyl-silanyloxy)-6-(4-methoxy-benzyloxymethyl)-5,6-dihydro-2H-benzo[b]azocine-1-carboxylic acid tert-butyl ester[ No CAS ]
(1R*,2S*)-allyl-{3-benzyloxy-5-benzyloxymethyl-2-[2-(tert-butyl-dimethyl-silanyloxy)-1-(4-methoxy-benzyloxymethyl)-but-3-enyl]-phenyl}-carbamic acid tert-butyl ester[ No CAS ]
(5S*,6R*)-7-benzyloxy-9-benzyloxymethyl-5-hydroxy-6-(4-methoxy-benzyloxymethyl)-5-(toluene-4-sulfonyl)carbamoyloxy-6-hydro-2H-benzo[b]azocine-1-carboxylic acid 2,2,2-trichloro-ethyl ester[ No CAS ]
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.
EXAMPLE 42 0.875 ml of pyrrolidine in 35 ml of tetrahydrofuran is treated at 5 with 0.605 ml of acetic acid and subsequently with 1.73 g of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> and 2.87 g of 6-oxo-4'-(trifluoromethyl)-heptananilide and stirred at 23 under argon for 56 hours. The residue obtained after evaporating the reaction mixture is partitioned between ethyl acetate and 1N sodium hydroxide solution. The combined sodium hydroxide extracts are made acid with conc. hydrochloric acid, extracted with ethyl acetate, the combined ethyl acetate extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, evaporated and the residue is chromatographed on 120 g of silica gel with methylene chloride/methanol (91:9). After recrystallization from ethyl acetate/petroleum ether there is obtained (E)-8-(3,4-dihydroxy-5-nitrophenyl)-6-oxo-4'-(trifluoromethyl)-7-octenanilide of m.p. 194-197.
b) a solution of 1.7 g of hydroxylamine O-sulfonic acid in 6 ml of water is added to a solution of 1.83 g of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> in 25 ml of water, subsequently stirred at 65 for 3.5 hours, cooled, the separated precipitate is filtered off under suction and taken up in ethyl acetate. The organic phase is dried over sodium sulfate and evaporated in a water-jet vacuum. The crystals obtained are recrystallized from ethyl acetate/n-hexane. There is obtained 3,4-dihydroxy-5-nitrobenzonitrile in the form of yellow crystals of m.p. 194-195.
5-[(3,4-dihydroxy-5-nitrophenyl)-methylidene]-2-thioxothiazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.0 g (89%)
In acetic acid;
EXAMPLE 2 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2 -thioxothiazolidin-4-one A solution containing 2.1 g (0.0157 mol) of rhodanine, 2.76 g (0.0151 mol) of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> and 0.15 ml of piperidine in 10 ml of acetic acid was heated for 7-8 h at 100 C. After cooling the crystalis were filtered and washed with 2-propanol. Yield 4.0 g (89%), mp>350 C. (decomp.).
5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-3-methyl-2-thioxothiazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.87 g (56%)
In acetic acid;
EXAMPLE 6 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-3-methyl-2-thioxothiazolidin-4-one A solution containing 0.74 g (0,005 mol) of 3-methyl -2-thioxothiazolidin-4-one, 0.92 g (0.005 mol) of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong>, 0.05 ml of piperidine in 10 ml of acetic acid was heated for 8 h at 100 C. The product was filtered and washed with 2-propanol. Yield 0.87 g (56%), mp 274-276 C.
4-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-2-thioxoimidazolidin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.0 g (71%)
In acetic acid;
EXAMPLE 1 4-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2 -thioxoimidazolidin-5-one A solution containing 2.9 g (0.025 mol) of 2-thiohydantoin, 4.6 g (0.025 mol) of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> and 0.25 ml of piperidine in 50 ml of acetic acid was heated for 7-8 h at 100 C. The crystalls were filtered and washed with 2-propanol. Yield 5.0 g (71%), mp>350 C. (decom.).
5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-4-thioxothiazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.14 g (76.5%)
EXAMPLE 5 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-4 -thioxothiazolidin-2-one A solution containing 0.67 g (0.005 mol) of 4-thioxothiazolidin-2-one, 0.92 g (0.005 mol) of 3,4-dihydroxy -5-nitrobenzaldehyde and 0.05 ml of piperidine in 10 ml of acetic was heated for 8 h at 100 C. The product was filtered and washed with 2-propanol. Yield 1.14 g (76.5%), mp>350 C. (decomp.).
5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-2-aminothiazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.2 g (86%)
In acetic acid;
EXAMPLE 4 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2-aminothiazolidin-4-one A solution containing 0.58 g (0.005 mol) of 2-aminothiazolidin-4-one, 0.92 g (0.005 mol) of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 24 h at 100 C. The product was filtered and washed with ethanol. Yield 1.2 g (86%), mp 250 C. (decomp.).
5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-thiazolidin-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.0 g (72%)
In acetic acid;
EXAMPLE 3 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-thiazolidin-2,4-dione A solution containing 0.59 g (0.005 mol) of thiazolidine-2,4-dione, 0.92 g (0.005 mol) of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 7-8 h at 80 C. The crystalls were filtered and washed with ethanol. Yield 1.0 g (72%), mp 295-298 C.
4-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-2,5-imidazolidindione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.56 g (42%)
With ammonium acetate; In acetic acid;
EXAMPLE 8 4- [(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2,5-imidazolidindione A solution containing 0.65 g of hydantoin, 0.92 g of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> and 0.15 g of ammonium acetate in 15 ml of acetic acid was refluxed overnight. The product was filtered and washed with acetic acid and 2-propanol. Yield 0.56 g (42%), mp>350 C.
5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-2,4,6(1H,3H,5H)-pyrimidinetrione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.28 g (44%)
With thionyl chloride; In isopropyl alcohol;
EXAMPLE 7 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2,4,6(1H,3H,5H)-pyrimidinetrione. To a solution containing 1.28 g (0.01 mol) of barbituric acid and 1.83 g (0.01 mol) of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> in 20 ml of 2-propanol was gradually added 5.0 ml of thionyl chloride. The mixture was stirred for 100 h at room tempererature. The product was filtered, washed with 2-propanol and recrystallized from acetic acid. Yield 1.28 g (44%), mp 269-272 C.
With acetic acid;piperidine; In toluene; at 20 - 25℃;Heating / reflux;Product distribution / selectivity;
A mixture of 3,4-dihydroxy-5-nitrobenzaldehyde (100 gm), <strong>[26391-06-0]N,N-diethyl-2-cyanoacetamide</strong> (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%
With acetic acid;piperidine; In ethyl acetate; at 20 - 25℃;Heating / reflux;Product distribution / selectivity;
A mixture of 3,4-dihydroxy-5-nitrobenzaldehyde (100 gm), <strong>[26391-06-0]N,N-diethyl-2-cyanoacetamide</strong> (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 xanthin; for 20.0h;pH 7.4;Enzymatic reaction;
Reaction of XO and DHNB [0084] To determine how DHNB inhibits XO enzyme activity, 30 muM DHNB was incubated with 15 mU/ml (or 30 nM) XO in phosphate buffer (pH 7.4) and xanthine was then added to initiate the reaction as discussed above. The inhibition of DHNB on XO activity lasted up to 20 h. After that, the enzymatic activity of XO was recovered. The optical spectral change of DHNB was measured in a system without xanthine, i.e., 30 muM DHNB with 15 mU/ml (or 30 nM) XO in phosphate buffer. The absorption of DHNB at 327 nm decreased with time and a new peak appeared at 270 nm (see FIG. 6A). The decay rate was in the range of 10-10 mol/L/s and was pH dependent, i.e., the higher the pH value, the faster DHNB decayed (see FIG. 6B). Without XO, however, DHNB itself was very stable. At room temperature, DHNB was converted by XO enzyme to a product which has no inhibitory effect on XO and thus recovered the XO activity as the concentration of DHNB decreased. The UV-VIS spectrum of the product was different from that of DHNB. HPLC analysis of DHNB/XO showed a new peak which was more polar than DHNB (see FIG. 6C). Mass spectrometric analysis of the product gave a molecular ion (EM-HI) peak at m/z 198 in the EI mass spectrum, while DHNB showed EM-Fir peak at m/z 182 (see FIG. 6D, E). The MS/MS of m/z 182 of DHNB gave several typical fragments such as m/z 165 ([M-H-OH]-), 152 ([M-H-CHO-H]-) and 135 (m/z 152-OH). However, the MS/MS of molecular ion at m/z 198 of the product gave a first main fragment at m/z 154, a mass difference of 44 indicating a loss of CO2, which further loses a -OH to give a fragment at m/z 137. Based on the mass spectrum, the product is 3,4-dihydroxy-5-nitrobenzoic acid, implying that DHNB is oxidized to the acid by the enzyme.
The crude mixture (25 g) was treated with 500 mL toluene and 50 mL of acetic acid and heated to reflux for 4 hours. The reaction mixture was then cooled to 5 C over the period of 3-5 hours and filtered to separate the insoluble solid and filtrate. The filtrate was concentrated and also co-evaporated with n-hexane to afford 7.5g Z-entacapone. The melting point of the resulting compound was 139.2 - 141.1 C.
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