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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; |
A suspension of <strong>[771-50-6]indole-3-carboxylic acid</strong> (2.90 g, 18.0 mmol) in CH2Cl2 (75 ml) was treated with oxalyl chloride (1.84 ml, 20.7 mmol) and DMF (1 drop) and the mixture was stirred at room temperature for 2 h, then concentrated in vacuo to leave the acid chloride as a yellow solid. This was dissolved in a mixture of CH2CI2 (30 ml) and THF (10 ml) and added dropwise (30 min) to a stirred solution of 4- (4-hydroxymethyl-piperidin-l-yl) butyric acid 2, 2 , 2-trichloroethyl ester (from Example 11) (4.98 g, 15.0 mmol) and NEt3 (1.82 g, 18.0 mmol) in CH2Cl2 (30 ml) . The reaction mixture was stirred at room temperature overnight, treated with an aqueous satd. NaCl solution (25 ml) and 10% aqueous NaHCO3 solution (25 ml) . The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to a brown viscous oil. The residue was separated with flash chromatography (SiO2, EtOAc) . The product was obtained as a pale yellow solid (1.83 g, 25.6%). Conversion to the hydrochloride salt was effected using etheral HCl.1H-NMR (300 MHz, CDCl3) :delta 9.02 (br S, 1 H) , 8.22-8.18 (m,l H), 7.92 (d, 1 H), 7.48-7.41 (m, 1 H), 7.35-7.28 EPO <DP n="27"/>(m, 2 H), 4.77 (s, 2 H), 4.24 (d, 2 H) 3.03 (d, 2 H), 2.59-2.44 (q, 5 H), 2.13-1.85 (m, 7 H), 1.60-1.43 (m, 2 H)13C-EMR (75 MHz, CDCl3) : delta 171.7, 165.5, 136.2, 131.5, 125.7, 122.8, 121.7, 121.0, 111.7, 108.0, 94.8, 73.7, 67.9, 57.5, 53.1, 35.4, 31.7, 28.8, 21.8MS(ES) : 477.1 [M + H]+ |
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With thionyl chloride; for 0.5h;Heating / reflux; |
EXAMPLE 14 1H-Indole-3-carboxylic acid (1-benzoyl-pyrrolidin-3-yl)-methyl-amide The procedure is the same as the following one, which was described in Blair et. al. PCT WO 00/76521 indole 3-carboxylic acid, (2.0 g) was dissolved in 5 ml of SOCl2.The mixture was heated to reflux for 30 minutes.Removal of excess of SOCl2 under vaccum provided intermediate 9, indole 3-carbonyl chloride, which was carried to the next step without further purification. A mixture of indole 3-carbonyl chloride, intermediate 9 (50 mg), N-Benzoyl-3-methylamino-pyrrolidine, intermediate 10, (57 mg), pyridine (44 mg) in THF (5 ml) was stirred at room temperature for 10 hours.Solvents were removed under vaccum, and the residue was purified using a Shimadzu automated preparative HPLC System to give 78 mg of the compound of example 14, N-Benzoyl-3-[N-(indol-3-yl-carbonyl)-N-methyl]amino-pyrrolidine: MS m/z: (M+H)+ calcd for C21H19FN3O3: 348.17; found 348.22. HPLC retention time: 1.40 p minutes (column A). |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; |
Example 3 Synthesis of lH-<strong>[771-50-6]indole-3-carboxylic acid</strong> 1- [3- (2, 2, 2-trichloroethyl- ethoxycarbonyl)-propyl]-piperidine-4-ylmethyl ester A suspension of <strong>[771-50-6]indole-3-carboxylic acid</strong> (2.90 g, 18.0 mmol) in CH2Cl2 (75 ml) was treated with oxalyl chloride (1.84 ml, 20.7 mmol) and DMF (1 drop) and the mixture stirred at room temperature for 2 h, then concentrated in vacuo to leave the acid chloride as a yellow solid. This was dissolved in a mixture of CH2C12 (30 ml) and THF (10 ml) and added dropwise (30 min) to a stirred solution of 4- (4-hydroxymethyl-piperidin-1-yl) butyric acid 2,2, 2-trichloroethyl ester (from example 2) (4.98 g, 15.0 mmol) and NEt3 (1.82 g, 18.0 mmol) in CH2CI2 (30 ml). The reaction mixture was stirred at room temperature overnight, treated with an aqueous satd. NaCl solution (25 ml) and 10 % aqueous NaHCO3 solution (25 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to a brown viscous oil. The residue was separated with flash chromatography (SiOz, EtOAc). The product was obtained as a pale yellow solid (1.83 g, 25.6 %). Conversion to the hydrochloride salt was effected using etheral HCI. 1H-NMR (300 MHz, CDCl3):No. 9.02 (br s, 1 H), 8.22-8. 18 (m, l H), 7.92 (d, 1 H), 7.48-7. 41 (m, 1 H), 7.35-7. 28 (m, 2 H), 4.77 (s, 2 H), 4.24 (d, 2 H) 3.03 (d, 2 H), 2.59-2. 44 (q, 5 H), 2.13-1. 85 (m, 7 H), 1.60-1. 43 (m, 2 H) 13C-NMR (75 MHz, CDCl3) : 5 171.7, 165.5, 136.2, 131.5, 125.7, 122.8, 121.7, 121.0, 111.7, 108.0, 94.8, 73.7, 67.9, 57.5, 53.1, 35.4, 31.7, 28.8, 21.8 MS (ES): 477.1 [M + H] + |
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With oxalyl dichloride; In 1,2-dichloro-ethane; at 0 - 20℃; for 1h; |
Example 13 trans-4-((2S,4S)-1-{2,5-Dichloro-4-[(indol-3-yl)carboxamido]phenyl}acetyl-4-methoxypyrrolidin-2-yl)methoxycyclohexane-1-carboxylic acid ethyl ester (29) Oxalyl chloride (0.106 mL, 1.21 mmol) in 1,2-dichloroethane (3 mL) was added to <strong>[771-50-6]indole-3-carboxylic acid</strong> (172 mg, 1.07 mmol) in 1,2-dichloroethane (3 mL) under stirring at 0C. The reaction mixture was stirred for 1 hour at room temperature and concentrated to dryness under reduced pressure. The residue was dissolved in 1,2-dichloroethane (3 mL), and the solution was added to trans-4-[(2S,4S)-1-(4-amino-2,5-dichlorophenyl)acetyl-4-methoxypyrrolidin-2-yl]methoxycyclohexane-1-carboxylic acid ethyl ester (348 mg, 0.714 mmol) in 1,2-dichloroethane (15 mL) under stirring at 0C. The reaction mixture was stirred for 10 hours under reflux conditions. The reaction mixture was cooled to room temperature, and water (20 mL) was added thereto, followed by extraction with 1,2-dichloroethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified through silica gel column chromatography, and, from a fraction obtained through use of chloroform:ethyl acetate (9:1 to 3:1, v/v), the title compound (29) was obtained as a crystalline powder (340 mg, 76%). Melting point: 188-197C. 1H-NMR(CDCl3)delta: 1.21-1.31(5H,m), 1.44-1.51(2H,m), 1.97-2.36(7H,m), 3.27(1H,m), 3.34 and 3.36(3H,each s), 3.50-4.35(11H,series of m), 7.26-7.30(3H,m), 7.41(1H,m), 7.69(1H,m), 8.06(1H,m), 8.17(1H,m), 8.62(1H,m), 9.54(1H,m). Element analysis: Calcd for C32H37Cl2N3O6: C, 60.95; H, 5.91; N,6.60. Found: C,60.75; H,5.83; N,6.60. |
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With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 23℃; for 0.333333h; |
[0246] Next, a solution of indole-3-carbonyl chloride was prepared. A well-stirred suspension of <strong>[771-50-6]indole-3-carboxylic acid</strong> (67.7 mg, 0.42 mmol) in dry DCM (2 ml) containing a small amount of dimethylformamide (DMF) (20 mu?) was treated with oxalyl chloride (0.84 mmol, 107 mg, 72 mu ) at 0 C. Following addition to the oxalyl chloride, the mixture was stirred for 20 minutes at 23 C, producing a clear, slightly yellow solution. This solution was evaporated to dryness in vacuo at 0.1 Torr to ensure removal of excess oxalyl chloride, and was subsequently re-dissolved in 2 ml of dry DCM. |
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With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃;Inert atmosphere; |
General procedure: Under inert atmosphere, a mixture of carboxylic acid 21-31 ( Scheme 1 ) (1 equiv), thionyl chloride (1.5 equiv) and DMF (3-5 drops) in dichloromethane was stirred at rt until the complete consumption of the carboxylic acid (1H NMR control). The pale yellow solution was concentrated in vacuo to give the crude acid chloride 32-42 ( Scheme 1 ) as a yellow pale solid in quantitative yield |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; |
General procedure: General procedure (15): To a suspension of the carboxylic acid (1.0 equiv) in dichloromethane (10 mL for 0.838 mmol of starting material), oxalyl chloride 2.0 M solution in dichloromethane (approximately 1.5 mL) was added, followed by one drop of DMF. The reaction was stirred at room temperature for 2 h. The solution was evaporated under vacuum to afford the crude acid chloride. Dichloromethane was added to the crude acid chloride and evaporated under vacuum again for 2 times. The acid chloride was then re-dissolved in THF and added slowly to a solution of the amine derivative (1.2 equiv) and triethylamine (2.5 equiv) in THF. The reaction was stirred at room temperature for 16 h. The mixture was poured into water and extracted with ethyl acetate 3 times. The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, concentrated in vacuo and purified by flash silica gel column chromatography to afford the amide product. Chemical Example 29 (Compound 29) ia2191 V-(isoquinolin-5-yl)-1H-indole-3-carboxamide Compound 29 [a219] (101 mg, 0.352 mmol) was prepared as a brown solid from 1/-/-indole- 3-carboxylic acid (135 mg, 0.838 mmol) and 5-aminoisoquinoline (145 mg, 1.006 mmol) according to general procedure (15) using 9:1 ethyl acetate/methanol as eluent for flash silica gel column chromatography and subsequent recrystallization from methanol. Yield: 42%. 1H NMR (400 MHz, DMSO) delta: 11.80 (s, 1 H), 9.98 (s, 1 H), 9.35 (d, J = 0.7 Hz, 1 H), 8.53 (d, J = 6.0 Hz, 1 H), 8.44 (s, 1 H), 8.20 - 8.14 (m, 1 H), 7.99 (t, J = 7.0 Hz, 2H), 7.94 (d, J = 6.0 Hz, 1 H), 7.72 (t, J = 7.8 Hz, 1 H), 7.53 - 7.47 (m, 1 H), 7.22 - 7.13 (m, 2H). 13C NMR (100 MHz, DMSO) delta: 163.86, 152.45, 142.51 , 136.24, 133.55, 131.11 , 129.15, 128.87, 127.17, 126.48, 126.43, 124.59, 122.16, 121.02, 120.71 , 116.41 , 111.96, 109.97. LC-MS (ESI): m/z 288.1 [M + H]+. |
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With thionyl chloride; In dichloromethane; at 0 - 20℃; for 2h; |
The reaction (I) (50 g, 0.31 mol), methylene chloride (300 mL) was added to the reaction flask,Cooling to 0 or so,Thionyl chloride (27 mL, 0.37 mol) was added dropwise to the above reaction flask,Bi completed,Warmed to room temperature and stirred for 2h,TLC monitoring process,After the reaction is complete,The reaction system was concentrated to dryness under reduced pressure at room temperature,A yellow solid (II) was obtained,Excluding weight and yield,Add tetrahydrofuran (400mL) dissolved,Directly used for the next reaction; |
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With thionyl chloride; for 5h;Reflux; |
General procedure: Thionylchloride (8 mL) was added dropwise to a solution of 4a (2.5 mmol) and the mixture was refluxed for 5 h to afford 9. After removal of the solvent in vacuum, the solid was dissolved in CH2Cl2 (20 mL) and 8a-8d (2.5 mmol) in Et3N was added to the mixture at 0C. The reaction mixture was stirred for 18 h at 30C. The solid residue was collected by filtration. The crude product was recrystallized from absolute ethanol. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 0℃; for 1.5h;Inert atmosphere; |
General procedure: To the acid (1 eq) in 1 mL of THF and 1 drop of DMF at 0C, oxalyl chloride (1.2 eq) was added. The reaction was stirred under nitrogen for 1.5 hours and then the solution was concentrated. The acid chloride was continued to the next step. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; |
To a suspension of <strong>[771-50-6]1H-<strong>[771-50-6]indole-3-carboxylic acid</strong></strong> (135?mg, 0.838?mmol, 1.0 equiv) in dichloromethane (10?mL), oxalyl chloride 2.0?M solution in dichloromethane (approximately 1.5?mL) was added, followed by one drop of DMF. The reaction was stirred at room temperature for 2?h which turned into a dark yellow solution. The solution was evaporated under vacuum to afford the crude acid chloride. Dichloromethane was added to the crude acid chloride and evaporated under vacuum again for 2 times. The acid chloride was then re-dissolved in THF and added slowly to a solution of 5-aminoisoquinoline (145?mg, 1.006?mmol, 1.2 equiv) and triethylamine (292?muL, 212?mg, 2.096?mmol, 2.5 equiv) in THF. The reaction was stirred at room temp for 16?h. The mixture was poured into water and extracted with ethyl acetate 3 times. The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, concentrated in vacuo and purified by flash silica gel column chromatography (9:1 ethyl acetate/methanol) to yield a yellow oil which was recrystallized with methanol to afford 24 as a brown solid (101?mg, 0.352?mmol). Yield: 42%. HPLC RT 10.79?min; HPLC purity 95.43%. 1H NMR (400?MHz, DMSO-d6) delta: 11.80 (s, 1H), 9.98 (s, 1H), 9.35 (d, J?=?0.7?Hz, 1H), 8.53 (d, J?=?6.0?Hz, 1H), 8.44 (s, 1H), 8.20-8.14 (m, 1H), 7.99 (t, J?=?7.0?Hz, 2H), 7.94 (d, J?=?6.0?Hz, 1H), 7.72 (t, J?=?7.8?Hz, 1H), 7.53-7.47 (m, 1H), 7.22-7.13 (m, 2H). 13C NMR (100?MHz, DMSO-d6) delta: 163.86, 152.45, 142.51, 136.24, 133.55, 131.11, 129.15, 128.87, 127.17, 126.48, 126.43, 124.59, 122.16, 121.02, 120.71, 116.41, 111.96, 109.97. LC-MS (ESI): m/z 288.1 [M + H]+. |
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With thionyl chloride; In dichloromethane; at 60℃; for 2h; |
3. Synthesis of XO-CH151; XO-CH151 was prepared by converting indole-3-caboxylic acid into an acid chloride, amidating it with aqueous ammonia and then, converting to a tetrazole in a similar manner to that of XO-CH150 (the following scheme).; 6. Synthesis of XO-CH151 XO-CH148; Indole-3-carboxylic acid (0.494 g, 3.07 mmol) was suspended in dichloromethane (10 mL), and to the suspension were added thionyl chloride (0.27 mL, 3. 7 mmol) and acetonitrile (5 mL). The mixture was stirred for an hour at 60C, and to the reaction mixture was further added thionyl chloride (0.27 mL, 3.7 mmol). The mixture was stirred for an hour. After the solvent of the reaction mixture was evaporated to dryness, the residue was dissolved in acetonitrile (5 mL). To the solution was added 28% aqueous ammonia (2 mL) in an ice-water bath, and the mixture was stirred for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (twice) and brine and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and dried under reduced pressure to give XO-CH148 as a pale yellow solid (0.252 g, 51% yield). |
| 446 g |
With oxalyl dichloride; In dichloromethane; at 0 - 20℃;Inert atmosphere; |
Oxalyl chloride (473.3 g, 3.73 mol) was added dropwise to a suspension of indol-3 -carboxylic acid (400 g, 2.48 mol) in DCM (4 L) at 0C over 1 h. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated to dryness to afford lif-indole-3 -carbonyl chloride (446.0 g). |
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