* 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.
General procedure: Followed previous procedures: 1a mixture of 2-aminobenzonitrile (0.02 mol) and ammonium iodide (0.02 mol) were dissolved in acetic acid (50 mL), and then 30percent aqueous hydrogen peroxide solution (0.13 mol) was slowly added at room temperature and stirred for 12 h. After reaction completion, the reaction solution was treated with aqueous sodium thiosulfate solution 40 mL (0.03 mol) and basified to about pH~8 by the addition of 20percent sodium hydroxide. The reaction mixture was stirred at room temperature for 0.5 h. The desired product, which was partially precipitated during this step, was isolated by vacuum filtration to afford A as silvery white flake solid (yield 92.6percent).
84.9%
at 20℃; for 3 h;
The 2.0g (16.9mmol) 2- aminobenzonitrile (Compound of Formula II) was dissolved in 20mL glacial acetic acid; was slowly added dropwise 2.8g (17.2 mmol) 10mL glacial acetic acid solution of iodine monochloride dropwise was completed, the reaction mixture was stirred 3H at room temperature; the reaction mixture was poured into 150mL ice water, Suction filtered, the filter cake was washed with water, dried with cyclohexane - toluene: Recrystallization (9 1, v / v), to give 2-amino-5-iodobenzonitrile (formula III Compound) (3.5g, molar yield of 84.9percent, HPLC purity 98.7percent),
48%
With ammonium iodide; dihydrogen peroxide; acetic acid In water at 20℃; for 12 h;
[612] Preparation 52: Synthesis of 2-amino-5-iodo-benzonitrile [613] [614] 2-Amino-benzonitrile (10g, 0.085mol) and ammonium iodide (13.5g, 0.094mol) were dissolved in acetic acid (200mL). 30percent aqueous hydrogen peroxide solution (5.3mL, 0.094mL) was slowly added at room temperature and stirred for 12 h. After completion of the reaction, the reaction solution was filtered through celite. The filtrate was treated with aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The solid obtained using dichloromethane (10mL) and hexane (200mL) was filtered and dried under nitrogen gas to give the title compound (10g, Yield 48percent). [615] NMR: 1H-NMR(CDCl3) δ 7.64 (1H, d), 7.56 (1H, dd), 6.35 (1H, d), 4.44 (2H, br s) [616] Mass(EI) 245 (M++1) [617]
Reference：
[1] Acta Crystallographica Section C: Crystal Structure Communications, 2007, vol. 63, # 7, p. o408-o410
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 7, p. 1584 - 1587
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4309 - 4313
[4] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 7, p. 2637 - 2649
[5] Patent: CN103896889, 2016, B, . Location in patent: Paragraph 0041-0043
[6] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # 10, p. 959 - 964
[7] European Journal of Medicinal Chemistry, 1992, vol. 27, # 1, p. 7 - 18
[8] Journal of Organic Chemistry, 2001, vol. 66, # 22, p. 7522 - 7526
[9] Patent: WO2011/43568, 2011, A2, . Location in patent: Page/Page column 46
[10] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # SUPPL. 1, p. S539-S540
[11] Journal of Labelled Compounds and Radiopharmaceuticals, 1997, vol. 40, p. 83 - 84
[12] Tetrahedron Letters, 2007, vol. 48, # 35, p. 6124 - 6128
[13] Patent: WO2010/61400, 2010, A1, . Location in patent: Page/Page column 14
[14] Patent: WO2011/39759, 2011, A1, . Location in patent: Page/Page column 13
2
[ 516-12-1 ]
[ 1885-29-6 ]
[ 132131-24-9 ]
Yield
Reaction Conditions
Operation in experiment
73%
at 20℃; for 18 h;
N-iodosuccinimide (11.35 g, 50.4 mmol) was added in several portions at room temperature to a solution of anthranilonitrile (Aldrich, 5.87 g, 49.7 mmol) in DMF (80 mL) and stirred under N2 for 18 h. The reaction mixture was concentrated to [1/4] volume and diluted with [H20] (200 mL) and [CH2C12.] The phases were separated. The organic phase was washed with H2O, dried [(NA2SO4),] and concentrated in vacuo to give 14 g of dark liquid that was dissolved in hot ethanol and diluted with ca. 100 mL of hot H2O. The solution was cooled to room temperature overnight. The crystallized mixture was filtered and the pink mica-like sheets were washed with [H20] and dried in a vacuum oven at [40 C] to give 8. 85 g (73percent) of product; mp [76-78 C] : MS (EI) [INTO] (rel. intensity) 244 (M+, 99), 245 (12), 127 (9), 118 (9), 117 (72), 90 (75), 84 (11), 64 (14), 63 (42), 62 (13).
N-iodosuccinimide (11.35 g, 50.4 mmol) was added in several portions at room temperature to a solution of anthranilonitrile (Aldrich, 5.87 g, 49.7 mmol) in DMF (80 mL) and stirred under N2 for 18 h. The reaction mixture was concentrated to [1/4] volume and diluted with [H20] (200 mL) and [CH2C12.] The phases were separated. The organic phase was washed with H2O, dried [(NA2SO4),] and concentrated in vacuo to give 14 g of dark liquid that was dissolved in hot ethanol and diluted with ca. 100 mL of hot H2O. The solution was cooled to room temperature overnight. The crystallized mixture was filtered and the pink mica-like sheets were washed with [H20] and dried in a vacuum oven at [40 C] to give 8. 85 g (73%) of product; mp [76-78 C] : MS (EI) [INTO] (rel. intensity) 244 (M+, 99), 245 (12), 127 (9), 118 (9), 117 (72), 90 (75), 84 (11), 64 (14), 63 (42), 62 (13).
In N,N-dimethyl acetamide; at 110℃; for 2h;Heating / reflux;Product distribution / selectivity;
Alternative Synthesis of iV-(4-moipholinophenyl)-6-(4-(4-morphoIinophenyIamino)quinazolin-6-yl)quinazolin-4-amine; N'-(2-Cyano-4-iodo~phenyl)-N,N-dimethyl-formamidine:2-Amino-5-iodo-benzonitrile (5g, 20.5mmol) was heated to reflux in DMF-DMA (20ml) for 2h. On cooling and concentrating to dryness in vacuo the residue was filtered through silica (2Og, SiO2) eluting with dichloromethane to afford a brown oil (6.15g, 100%)1H NMR (CDCl3) delta 7.71 ( IH, d), 7.58 ( IH, dd), 7.505 ( IH, s), 6.64 (IH, d), 3.01 (6H, s)LC-MS rt 3.46 m/z 299 MH+; Example 2; N*4*-(4-Morpholin-4-yI-phenyl)-N*4*-phenyl-[6,6']biquinazolinyl-4,4'- diamine; N'-(2-Cyano-4-iodo-phenyl)-N,N-dimethyl-formamidine; 2-Amino-5-iodo-benzonitrile (5g) in DMF-DMA ( 10ml) was heated to 110 for 2h. The cooled reaction mixture was diluted with water (100ml) and extracted into ethyl acetate (3xl00ml). The combined organic phases were dried (MgSO4) and concentrated to give a viscous brown oil (~ quantitative) which was used without further purification.1H NMR (CDCl3) delta 7.77 (IH, m), 7.65 (IH, dm, J8.85Hz), 7.57 (IH, s), 6.70 ( IH, d,J8.85Hz), 3.012 (6H, s)LC-MS rt 3.46 m/z 299.78
at 70 - 75℃; for 2h;
(ii) Preparation of N'-(2-cyano-4-iodo-phenyl)-N,N-dimethyIformamidine (8): Into a 500 ml 3 necked round bottomed flask, N, N-dimethylforamide (100 ml), 2- amino-5-iodobenzonitrile (50g) obtained by the process given in the above step (i) and Nu,Nu-dimethyl formamide dimethyl acetate (51.3 g) were charged. The reaction mass was maintained at 70-75 C for about 2 Hrs. The completion of the reaction was monitored by TLC. The reaction mass was cooled to 25-35 C and quenched into ice water and maintained for about 2 Hrs. at 0-5 C. The product was filtered and dried under vacuum at 25-35 C to get 58 g of N'-(2-cyano-4-iodo-phenyl)-N,N- dimethylforrnamidine as a pale yellow coloured amorphous powder. Melting range: 53-55 CHPLC purity: 99.8%
EXAMPLE 166 The same procedures as described in Example 165 were repeated except that 3.5 g of 7-iodoanthranilonitrile was employed instead of the 3.5 g of <strong>[132131-24-9]5-iodoanthranilonitrile</strong>. As a result, 2.12 g of 3-amino-7-iodoindazole having the following analytical values was obtained in a yield of 57%. IR absorption spectrum (numax, cm-1): 3390, 3270, 2960 and 1620. NMR spectrum [delta, D6 -DMSO]: 7.01(d, 1H), 7.32(d, 1H) and 7.69(d, 1H). Mass spectrum (m/e): 259(M+), 242(M-17), 228(M-31), 149(M-110) and 131(M-128).
(E)-N'-(2-cyano-4-iodophenyl)-N,N-dimethylformamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
at 120℃; for 2h;
Intermediate 2 : N'-(2-Cyano-4-iodo-phenyI)-N,N-dimethyl-formamidineA solution of <strong>[132131-24-9]2-ammo-5-iodobenzonitrile</strong> (50g, 0.2mol) in DMF-DMA ( 2.5eq, 68ml) heated to 120 for 2h. The excess DMF-DMA was removed by concentration in vacuo to leave the title compound as a viscous brown oil (6 Ig, quant)1H NMR (CDCl3) delta 7.79 (IH, d, J =1.9Hz), 7.65 (IH, dd, J 1.9, 8.5Hz), 7.57 (IH, s),6.70 (IH, d, J 8.2Hz), 3.08 (6H, s)LC-MS rt 2.1 M/z 300 ES+
98%
at 90℃; for 1h;
<strong>[132131-24-9]2-cyano-4-iodoaniline</strong> (1g,4.1mmol) was suspended in 1,1-dimethoxy-N,N-dimethylmethylamine (2mL), the reaction solution was stirred at 90Cfor 1 hour, then evaporated to dryness under reduced pressure to give 1.2g brown oil with a yield of 98%.
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 4h;
Intermediate 3: 2-Amino-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaboroIan-2-yl)- benzonitrileA mixture of Pd Cl2(dppf) (3.35g), potassium acetate ( 12.07g) and bis(pinacolato)boron (12.48g) in dry DMF (80ml) was treated with intermediate 1 (1Og) and heated to 80deg for 4h. The cooled mixture was partitioned between water (400ml) and CH2Cl2 (400ml). The aqueous phase was further extracted with CH2Cl2 (2x100ml) and the combined organic phases dried and concentrated in vacuo. The residue was purified by chromatography on Silica gel (9Og, retrieve) with 10-30% ethyl acetate in petrol as eluant. Concentration of fractions containing product and trituration with further petrol gave the desired product as a white solid (6.9 Ig, 69%)1H NMR(CDCl3) delta 7.87 (IH, s), 7.72 (2H5 d, J 8.21), 6.7 (IH, d, J 8.2Hz), 4.57 (2H, br s), 1.31 (12H, s)LC-MS rt 2.84m/z 244 ES+
69%
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 80℃; for 4h;
A mixture of Pd Cl2 (dppf) (3.35 g), potassium acetate (12.07 g) and bis(pinacolato)boron (12.48 g) in dry DMF (80 ml) was treated with Intermediate 1 (10 <n="28"/>g) and heated to 80 for 4 h. The cooled mixture was partitioned between water (400 ml) and DCM (400 ml). The aqueous phase was further extracted with DCM (2 x 100 ml) and the combined organic phases dried and concentrated. The residue was purified by chromatography on silica gel (90 g, MPLC) with 10-30 % EtOAc in petrol as eluant. Concentration of fractions containing product and trituration with further petrol gave the desired product as a white solid (6.91 g, 69 %)1H NMR(CDCl3) delta 7.87 (IH5 s), 7.72 (2H, d, J 8.21), 6.7 (IH, d, J 8.2Hz), 4.57 (2H, br s), 1.31 (12H, s); LC-MS rt 2.84 m/z 244 ES+.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 16h;
Example 3: Preparation of [6-(3,4-Dimethoxy-phenyI)-quinazolin-4-yI]-(4- morpholin-4-yl-phenyI)-ammeStep 1: 4-Amino-3',4'-dimethoxy-biphenyl-3-carbonitrileA mixture of 3,4-dimethoxyboronic acid (956mg, 2eq), intermediate 1 ( 640mg, leq), tetrakis (triphenylphosphine) palladium (0) (10%, 303mg) in DME / 2M aq sodium carbonate ( 2:1, 21ml) was heated to 80 for 16h.The cooled reaction mixture was diluted with ethyl acetate and washed with further aq sodium carbonate then water. The dried organic phase was concentrated to a dark red gum which was dissolved in CH2Cl2 and loaded onto a SPE cartridge ( Si5 2Og) and eluted with CH2Cl2. The major fractions containing product were combined and concentrated to a semi-solid which was triturated with diethyl ether and the desired compound isolated by filtration as a light brown solid (296mg5 44%) EPO <DP n="20"/>LC-MS rt 2.73 no ion observed1H (DMSO) 57.77 (IH, s), 7.71 (IH, d), 7.2 (IH5 s), 7.17 (IH5 d), 7.03 (IH, d), 6.91(IH5 d). 6.17 (2H5 br s), 3.89 (3H5 s), 3.83 (3H5 s)
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 2h;Heating / reflux;
Example 1 : {6-[4-(2-MorphoIin-4-yl-ethoxy)-phenyl]-quinazoIin-4-yI}-(4- morphoIin-4-yI-phenyI)-amine Step 1: 4-Amino-4'-(2-morphoIin-4-yl-ethoxy)-biphenyl-3-carbonitriIeA mixture of intermediate 1 ( 0.5g) 4-hydroxyphenylboronic acid (565mg) and tetrakis (triphenylphosphine) palladium (0) (290mg) in DME / 2M aqueous sodium carbonate (2:1, 15ml) was heated at reflux for 2hr. The cooled mixture was diluted with ethyl EPO <DP n="18"/>acetate and washed with further aqueous base. The organic phase was dried (MgSO4) and reduced onto silica gel. Flash chromatography with CH2Cl2 to 5% methanol in CH2Cl2 as eluant gave the coupling product, slightly contaminated with triphenylphosphine oxide by NMR. This material (340mg) was heated with 2- chloroethyl morpholine hydrochloride (330mg) and potassium carbonate (670mg) in acetone (20ml) at reflux overnight. The cooled reaction was partitioned between CH2Cl2 and 2M hydrochloric acid (aq). The acid phase was separated, basified and extracted with CH2Cl2 (2x),. These organic washes were concentrated to give the title compound as a brown solid (342mg) LC-MS rt 2.15 M+ 3241H NMR delta 7.55 (2H, m) ,7.38 (2H, d, J 8.21Hz), 6.95 ( 2H, d, J 8.21Hz), 6.78 (IH, m), 4.24 ( 2H, br s) 4.14 (2H, t, J 6.3Hz), 3.72 (4H, m), 2.82 (2H, m), 2.59 (4H5 m)
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 3h;
Example 5: Preparation of {6-[3-FIuoro-4-(2-morpholin-4-yl-ethoxy)-phenyI]- quinazoline-4-yl}-(4-morphoIin-4-yl-phenyI)-amineA mixture of intermediate 1 (lOOmg), 4-hydroxy-3 -fluorophenyl boronic acid (128mg) and tetrakis(triphenylphosphine)palladium (0) (47mg) in DME (3ml) and aq 2M sodium carbonate (ImI) were heated for 80 for 3h. The cooled mixture was diluted with ethyl acetate and washed with water. The organic phase was dried, concentrated and purified by column chromatography with CH2Cl2/Et0H/ NH3 (300:8:1) to give the desired biphenyl compound (70mg, LC-MS rt 2.29 m/z 227 ES-) which was dissolved in acetone (2ml) and treated with chloroethylmorpholine hydrochloride (63mg) and potassium carbonate (128mg) and heated to reflux for 16h. After concentration, the residue was taken up in CH2Cl2 and washed with water. The organic phase was dried and concentrated to a brown solid (79mg) which was partially purified by chromatography on silica gel with CH2Cl2/Et0H/ NH3 (300:8:1) to give material (69mg, LC-MS rt 1.95 m/z 342 ES+) which was heated in DMF-DMA (ImI) for 2h at 80 . The solvent was removed in vacuo and the residue (74mg, LC-MS rt 1.85 m/z 397 ES+) heated with 4-morpholinoaniline (68mg) in acetic acid (ImI) at 80 for 4h. The cooled mixture was diluted with water and basified with 2M NaOH before being extracted with ethyl acetate . The combined organics were dried and concentrated to a dark solid that was purified by chromatography on silica with CH2Cl2/Et0H/ NH3 (300:8:1 to 100:8:1) as eluant. This gave the title compound (31.5mg, 31%) 1H NMR (DMSO) delta 9.79 (IH, s), 8.76 (IH, s), 8.15 (IH5 d, J 8.5Hz), 7.8 (2H5 m), 7.66 (3H, m), 7.35 (IH5 t, J 8.85Hz)5 6.99 (2H5 d5 J 8.85Hz)5 4.25 (2H, t, J 5.7Hz)5 3.76 (4H5 m), 3.59 (4H, m), 3.11 (4H5 m), 2.75 (2H5 1, J 5.69Hz) LC-MS rt 2.01 m/z 530 ES+
A solution of <strong>[132131-24-9]2-amino-5-iodobenzonitrile</strong> (50g, 0.2mol) in DMF-DMA (2.5 eq, 6 ml) was heated to 120 for 2 h. The excess DMF-DMA was removed by <n="27"/>concentration to leave the title compound as a viscous brown oil (61 g, quant). Solidifies on standing at 4 .1H NMR (CDCl3) delta 7.79 (IH, d, J 1.9Hz), 7.65 (IH, dd, J 1.9, 8.5Hz), 7.57 (IH3 s), 6.70 (IH, d, J 8.2Hz), 3.08 (6H, s); LC-MS rt 2.1 M/z 300 ES+
100%
at 120℃; for 2h;
Intermediate 2: N'-(2-Cyano-4-iodo-phenyl)-N,N-dimethyl-formamidine; A solution of <strong>[132131-24-9]2-amino-5-iodobenzonitrile</strong> (50 g, 0.2 mol) in DMF-DMA (2.5 eq, 68 ml) was heated to 120 0C for 2h. The excess DMF-DMA was removed by concentration to leave the title compound as a viscous brown oil (61 g, 100%) which solidified on standing at 40C to a brown solid.1HNMR(CDCl3) delta 7.79 (IH, d, J 1.9Hz), 7.65 (IH, dd, J 1.9, 8.5Hz), 7.57 (IH, s), 6.70 (IH, d, J 8.2Hz), 3.08 (6H, s); LC-MS rt 2.1 min, m/z 300 ES+.
89.3%
With acetic acid; In toluene; at 35℃; for 0.5h;
A mixture of <strong>[132131-24-9]2-amino-5-iodobenzonitrile</strong> (A) (0.01 mol), toluene (20 mL), and DMF-DMA (0.02 mol) were heated up to 35 C and acetic acid (0.25 mL) was added. 0.5 h later, the resultant mixture was cooled to approximately 25 C. Toluene was completely stripped off .The mixture was added to water and basified to about pH~13 by the addition of 20% sodium hydroxide. The mixture was extracted with methylene chloride (CH2Cl2 2 × 30 mL) and the combined organic extracts were washed with water (2 × 200 mL) and brine (1 × 200 mL), dried over Mg2SO4. The organic solvent was evaporated to give B as yellow solid (yield 89.3%).
N-(2-CYANO-4-IODOPHENYL)-7-(PHENYLSULFONYL)-1H-INDOLE-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
A mixture of [7- (phenylsulfonyl)-1H-indolE-2-CARBOXYLIC] acid (0.80 g, 2.67 mmol) and oxalyl chloride (10 mL) in [CH2C12] (10 mL) was treated at room temperature with DMF (10 L). The mixture was stirred at room temperature for 3 [H.] The solution was concentrated in vacuo to give a crude acid chloride that was suspended in [CH2C12] (2 mL) and added slowly to a solution of <strong>[132131-24-9]2-amino-5-iodobenzonitrile</strong> (0.65 g, 2.67 mmol) in dry pyridine (6 mL) at room temperature. The mixture was stirred overnight and then concentrated. The residue was partitioned with CH2C12 and aqueous 1N [HC1.] The phases were separated. The aqueous phase was extracted again with [CH2C12] - CHCl3 mixture. The combined organic extracts were concentrated in vacuo to give a brown residue that was digested in boiling ethanol. The cooled mixture was filtered and the solid was washed with ethanol and dried to give 0.92 g (65%) of tan solid.MS (EI) [M/Z] (rel. intensity) 527 (M+, 59), 285 (52), 284 (99), 190 (31), 165 (25), 143 (27), 142 [(50),] 115 (26), 114 (24), 77 (27).HRMS (FAB) calcd for [C22H14IN303S] [+HI] 527.9880, found 527.9877.
(ii) Preparation of N-[3-chloro-4-[(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolin amine (3)Into a one liter four-necked round bottomed flask, 50OmL of xylene, 50.0 g of N'-^-chloro- 4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine obtained by the process given in example-(l), 40 g of <strong>[132131-24-9]2-amino-5-iodobenzonitrile</strong> obtained by the process given in above step (i) and 25 mL of acetic acid were charged under stirring. The reaction was maintained at reflux condition for 10 hours and the completion of the reaction was monitored by TLC. The solvent was distilled off completely under vacuum and cooled to room temperature. 100 mL of isopropylalcohol was added and adjusted the pH to basic (about 10) with aqueous ammonia solution. The mass was maintained at that temperature for about lhr. The mass was cooled to room temperature and filtered and dried to get 70.0 g of N-[3-chloro-4-[(3- fluorobenzyloxy)phenyl]-6-iodo-quinazolinamine as a pale yellow coloured crystalline powder.Purity: 99.43% by HPLC Melting point range: 222-225 C
With acetic acid; In xylene; for 10h;Reflux;
(ii) Preparation of N-[3-chloro-4-[(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolin amine (3)Into a one liter four-necked round bottomed flask, 500 mL of xylene, 50.0 g of N1-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine obtained by the process given in example-(1), 40 g of <strong>[132131-24-9]2-amino-5-iodobenzonitrile</strong> obtained by the process given in above step (i) and 25 mL of acetic acid were charged under stirring. The reaction was maintained at reflux condition for 10 hours and the completion of the reaction was monitored by TLC. The solvent was distilled off completely under vacuum and cooled to room temperature. 100 mL of isopropylalcohol was added and adjusted the pH to basic (about 10) with aqueous ammonia solution. The mass was maintained at that temperature for about 1 hr. The mass was cooled to room temperature and filtered and dried to get 70.0 g of N-[3-chloro-4-[(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolinamine as a pale yellow coloured crystalline powder.Purity: 99.43% by HPLCMelting point range: 222-225 C.
With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; potassium carbonate; In toluene; for 24h;Reflux;
Preparation 53: Synthesis of 1-(4-amino-3-cyano-phenyl)-pyrazole-4-carboxylic acid ethyl ester [619] [620] 2-Amino-5-iodo-benzonitrile (5g, 20mmol) obtained in Preparation 52 was dissolved in toluene (40mL). At room temperature, 1H-pyrazole-4-carboxylic acid ethyl ester (2.3g, 16.7mmol), cupper iodide (0.323g, 1.7mmol), potassium carbonate (4.9g, 36mmol) and N,N-dimethyl-ethane-1,2-diamine (0.37mL, 3.4mmol) were added and refluxed for 24 h. The solution was filtered through celite using ethyl acetate, and the solvent was distilled off. The solid obtained using dichloromethane and methanol was filtered and dried under nitrogen gas to give the title compound (2.95g, Yield 56%). [621] NMR: 1H-NMR(CDCl3) delta 8.25 (1H, s), 8.05 (1H, s), 7.72 (1H, d), 7.71-7.57 (2H, m), 6.84 (1H, d), 4.55 (2H, br s), 4.35-4.30 (2H, q), 1.37 (3H, t) [622] Mass(EI) 257 (M++1)
pyrographite; In hexane; toluene; at 25 - 30℃; for 1h;Purification / work up;
Purification: Into a two liter four necked round bottomed flask, 275 mL of toluene and 55 g of crude 2-aminobenzonitrile as obtained above were charged. The mass was stirred for 30 min and clarified with activated carbon (5g) and filtered. To the filtrate 825 mL of hexane was added and stirred for 1 hr. at 25-30 C to crystallize out the product. The product was filtered and dried under vacuum at 30-40 C to get 46.5 g of 2-amino-5- iodobenzonitrile as a pinkish coloured crystalline powder.Melting -range: 85 to 87 CPurity : 99.89% by HPLC
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