* 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.
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6270 - 6282
[2] Synthetic Communications, 1992, vol. 22, # 14, p. 2077 - 2102
2
[ 16732-73-3 ]
[ 40047-23-2 ]
Reference：
[1] ChemMedChem, 2018, vol. 13, # 23, p. 2522 - 2529
[2] Letters in Organic Chemistry, 2011, vol. 8, # 1, p. 48 - 52
3
[ 15050-04-1 ]
[ 16732-73-3 ]
Yield
Reaction Conditions
Operation in experiment
4.6 g
With water; lithium hydroxide In tetrahydrofuran at 20℃; for 16 h;
6-Methoxy-1H-indole-2-carboxylic acid ethyl ester (5.0 g) was treated with lithium hydroxide (2.33 g) in THF (90 mL) followed by water (30 mL) and stirred at ambient temperature for 16 h. The solution was acidified with 10percent hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 6-Methoxy-1H-indole-2-carboxylic acid (4.60 g). This material (4.64 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.60 g) in dichloromethane (200 mL) were treated with N-methylpiperazine (3.23 mL) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (200 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10percent 2M ammonia in methanol/dichloromethane) to give (6-Methoxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (6.60 g). This material (0.16 g) was dissolved in dichloromethane (10 mL). At room temperature, 1 M boron tribromide (1.5 mL) was added dropwise. The reaction mixture was heated to reflux overnight, and then cooled, quenched with saturated sodium hydrogencarbonate solution, and extracted with dichloromethane. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (0-10percent 2M ammonia in methanol/dichloromethane) to give the title compound
1.2 g
With sodium hydroxide In ethanol; water at 70℃; for 1 h;
A suspension of ethyl 6-methoxy-1H-indole-2-carboxylate (1.5 g6.84 mmol) in ethanol (80 mL) was treated with a 1 mol/L aqueous NaOH solution (14 mL) and heated at 70°C for 1 h. After the reaction, the solvent was evaporated in vacuo and 100 mL water was added. The solution then was washed by CH2Cl2 (100 mL×3) and the water phase was acidified with 2 mol/L HCl and the precipitate formed was isolated by filtration, and washed with water to give 1.2 g white solid. LC-MS: m/z= 189.1 [M-H]-. m.p. 203-205°C.
1.2 g
at 70℃; for 1 h;
To a 100 mL eggplant flask was added ethyl 6-methoxy-1H-indole-2-carboxylate (1.5 g, 6.84 mmol)1mol / L aqueous sodium hydroxide solution 14mL,70 reflux 1h,Stop the reaction.Methanol was distilled off,Add 100mL water,The aqueous layer was washed with dichloromethane (100 mL × 3)PH adjusted to 2 with 2N hydrochloric acid,Precipitation,Stirring,Suction filtration,Washed,The filter cake was dried to give 6-methoxy-1H-indole-2-carboxylic acid (1.2 g) as a white solid.The product was separated and purified directly to the next reaction.
Reference：
[1] Patent: US2003/207893, 2003, A1,
[2] Patent: WO2004/22061, 2004, A1, . Location in patent: Page/Page column 71
[3] Patent: EP1373204, 2016, B1, . Location in patent: Paragraph 0216
[4] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1943 - 1948
[5] Patent: CN106478606, 2017, A, . Location in patent: Paragraph 0122; 0123; 0128; 0129
4
[ 98081-83-5 ]
[ 16732-73-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6270 - 6282
[2] Synthetic Communications, 1992, vol. 22, # 14, p. 2077 - 2102
[3] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 5, p. 483 - 486
[4] Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1849 - 1860
[5] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 3, p. 950 - 954
5
[ 143702-29-8 ]
[ 16732-73-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6270 - 6282
[2] Synthetic Communications, 1992, vol. 22, # 14, p. 2077 - 2102
6
[ 123-11-5 ]
[ 16732-73-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1740 - 1742
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1943 - 1948
[3] Patent: CN106478606, 2017, A,
7
[ 3189-13-7 ]
[ 124-38-9 ]
[ 16732-73-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 13, p. 2003 - 2010
8
[ 98081-75-5 ]
[ 16732-73-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1740 - 1742
9
[ 536-90-3 ]
[ 16732-73-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 3, p. 950 - 954
10
[ 15384-39-1 ]
[ 16732-73-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 3, p. 950 - 954
11
[ 24513-03-9 ]
[ 16732-73-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1943 - 1948
12
[ 16792-46-4 ]
[ 16732-73-3 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 1612[2] Journal of the Chemical Society, 1922, vol. 121, p. 1872
13
[ 2042-14-0 ]
[ 16732-73-3 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 1612[2] Journal of the Chemical Society, 1922, vol. 121, p. 1872
14
[ 17484-36-5 ]
[ 16732-73-3 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 1612[2] Journal of the Chemical Society, 1922, vol. 121, p. 1872
15
[ 67-56-1 ]
[ 16732-73-3 ]
[ 98081-83-5 ]
Yield
Reaction Conditions
Operation in experiment
328 mg
at 65℃; Inert atmosphere
6-Methoxy-lH-indole-2-carboxylic acid acid (1 g, 5.23 mmol, commercially available from, for example, Amfinecom Inc.) was dissolved in methanol (16 mL), to this solution HC1 (12.39 M, 1.689 mL, 20.92 mmol) was added. The reaction was stirred at 65 °C under nitrogen for 3 h. The reaction was left stirring at 65 °C under nitrogen overnight, LCMS showed 43percent) conversion to desired product. The reaction was left stirring at 65 °C under nitrogen for a further 4.5 h. The solution was then allowed to cool and taken to pH14 using NaOH (2 M). The desired product was filtered off to give the desired product (328 mg) a brown solid.LCMS (Method B): Rt = 0.92 min, MH+ = 442.1.
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 30, p. 8809 - 8813[2] Angew. Chem., 2015, vol. 127, # 30, p. 8933 - 8937,5
[3] Patent: WO2016/185279, 2016, A1, . Location in patent: Page/Page column 198
[4] Journal of Enzyme Inhibition and Medicinal Chemistry, 2018, vol. 33, # 1, p. 1225 - 1238
With ammonium hydroxide; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 8h;
The solution of 25% ammonium hydroxide (0.21 g, 1.5 mmol) was added to the solution of <strong>[16732-73-3]6-methoxy-1H-indole-2-carboxylic acid</strong> (0.2 g, 1.0 mmol), HOBt (0.16 g,1.2 mmol), EDCI (0.23 g, 1.2 mmol) and diisopropylethylamine (0.15 g, 1.2 mmol) in anhydrous THF (30 mL) at 0C. Then the reaction mixture was stirred at room temperature for 8 h. When the reaction was completion, the THF was evaporated and 100 mL water was added. The solution was extracted with ethyl acetate twice (80 mL*2). The organic layer was separated and washed with water and brine and dried over anhydrous sodium sulfate. Filtration and removal of solvent in vacuo provided the crude product 0.2 g, which was then used directly without further purification. LC-MS: m/z= 191.2 [M+H]+.
To a 100 mL eggplant flask was added 6-methoxy-lH-indole-2-carboxylic acid (0.2 g, 1.0 mmol)Anhydrous tetrahydrofuran 30mL,Adjust the pH to 8 with DIEA,HOBt (0.16 g, 1.2 mmol) was added at 0 C,EDCI (0.23 g, 1.2 mmol) for 30 min,Aqueous 25% (w%) ammonia (0.21 g, 1.5 mmol)Transferred to room temperature reaction 8h,Stop the reaction.The solvent was evaporated,Add 100mL water,100 mL of ethyl acetate,The organic layer was washed with water (100 mL × 3)Saturated sodium chloride solution to wash it again,The organic layer was dried over anhydrous sodium sulfate,Suction filtration,Dry the filtrate,Have a pale yellow solid 6-methoxy-1H-indole-2-carboxamide (0.2 g), Crude without purification directly to the next reaction.
(6-methoxy-1H-indol-2-yl)-(4-methylpiperazin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;
6-Methoxy-1 H-indole-2-carboxylic acid ethyl ester (5.0 g) was treated with lithium hydroxide (2.33 g) in THF (90 mL) followed by water (30 mL) and stirred at ambient temperature for 16 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 6-Methoxy-1 H-indole-2-carboxylic acid (4.60 g). This material (4.64 g) and [1- (3-DIMETHYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE] hydrochloride (5.60 g) in dichloromethane (200 mL) were treated with N- methylpiperazine (3.23 mL) and stirred at ambient temperature for 16 h. The reaction mixture was poured into [DICHLOROMETHANE] (200 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% 2M ammonia in methanol/dichloromethane) to give [(6-METHOXY-1] [H-INDOL-2-YL)- (4-METHYL-] piperazin-1-yl)-methanone (6.60 g). This material (0.16 g) was dissolved in dichloromethane (10 mL). At room temperature, 1 M boron tribromide (1.5 mL) was added dropwise. The reaction mixture was heated to reflux overnight, and then cooled, quenched with saturated sodium hydrogencarbonate solution, and extracted with dichloromethane. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (0-10% 2M ammonia in methanol/dichloromethane) to give the title compound (0.12 [G).'H] NMR (400 MHz, [CDCTS/CDSOD)] : [8] 7.22 (d, J = 8.41 Hz, 1H), 6.62 (d, J = 2.15 Hz, [1H),] 6. [5'-6.] 47 (m, 2H), 3.69 [(BR S,] 4H), 2.30 (t, J = 5.09 Hz, 4H), 2.13 {s, 3H). MS (electrospray) : exact mass calculated for [C14H17N302,] 259.13 ; m/z found, 260.1 [M+H] +.
General procedure: (5-Chloro-7-fluoro-1H-indole-2-yl)-carboxylic acid (5a) (50 mg, 0.23 mmol), N,N-diisopropylethylamine (82 mul, 0.47 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (89 mg, 0.23 mmol) were dissolved in 550 mul N,N-dimethylformamide. After stirring for 10 min 4-methyl-piperazin 6a (26 mul, 0.23 mmol) was added and the reaction mixture was stirred for 16 h at 20 C. The solvent was evaporated under reduced pressure and the crude product was purified using chromatography method P1, yielding 37 mg (53%) of the title compound.
6.6 g
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;
<strong>[16732-73-3]6-Methoxy-1H-indole-2-carboxylic acid</strong> ethyl ester (5.0 g) was treated with lithium hydroxide (2.33 g) in THF (90 mL) followed by water (30 mL) and stirred at ambient temperature for 16 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford <strong>[16732-73-3]6-Methoxy-1H-indole-2-carboxylic acid</strong> (4.60 g). This material (4.64 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.60 g) in dichloromethane (200 mL) were treated with N-methylpiperazine (3.23 mL) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (200 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% 2M ammonia in methanol/dichloromethane) to give (6-Methoxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (6.60 g). This material (0.16 g) was dissolved in dichloromethane (10 mL). At room temperature, 1 M boron tribromide (1.5 mL) was added dropwise. The reaction mixture was heated to reflux overnight, and then cooled, quenched with saturated sodium hydrogencarbonate solution, and extracted with dichloromethane. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (0-10% 2M ammonia in methanol/dichloromethane) to give the title compound
With lithium hydroxide; In tetrahydrofuran; water;
Example 63 (6-Hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone 6-Methoxy-1H-indole-2-carboxylic acid ethyl ester (5.0 g) was treated with lithium hydroxide (2.33 g) in THF (90 mL) followed by water (30 mL) and stirred at ambient temperature for 16 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 6-Methoxy-1H-indole-2-carboxylic acid (4.60 g).
With lithium hydroxide; water; In tetrahydrofuran; at 20℃; for 16h;
6-Methoxy-1 H-indole-2-carboxylic acid ethyl ester (5.0 g) was treated with lithium hydroxide (2.33 g) in THF (90 mL) followed by water (30 mL) and stirred at ambient temperature for 16 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 6-Methoxy-1 H-indole-2-carboxylic acid (4.60 g). This material (4.64 g) and [1- (3-DIMETHYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE] hydrochloride (5.60 g) in dichloromethane (200 mL) were treated with N- methylpiperazine (3.23 mL) and stirred at ambient temperature for 16 h. The reaction mixture was poured into [DICHLOROMETHANE] (200 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% 2M ammonia in methanol/dichloromethane) to give [(6-METHOXY-1] [H-INDOL-2-YL)- (4-METHYL-] piperazin-1-yl)-methanone (6.60 g). This material (0.16 g) was dissolved in dichloromethane (10 mL). At room temperature, 1 M boron tribromide (1.5 mL) was added dropwise. The reaction mixture was heated to reflux overnight, and then cooled, quenched with saturated sodium hydrogencarbonate solution, and extracted with dichloromethane. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (0-10% 2M ammonia in methanol/dichloromethane) to give the title compound (0.12 [G).'H] NMR (400 MHz, [CDCTS/CDSOD)] : [8] 7.22 (d, J = 8.41 Hz, 1H), 6.62 (d, J = 2.15 Hz, [1H),] 6. [5'-6.] 47 (m, 2H), 3.69 [(BR S,] 4H), 2.30 (t, J = 5.09 Hz, 4H), 2.13 {s, 3H). MS (electrospray) : exact mass calculated for [C14H17N302,] 259.13 ; m/z found, 260.1 [M+H] +.
4.6 g
With water; lithium hydroxide; In tetrahydrofuran; at 20℃; for 16h;
6-Methoxy-1H-indole-2-carboxylic acid ethyl ester (5.0 g) was treated with lithium hydroxide (2.33 g) in THF (90 mL) followed by water (30 mL) and stirred at ambient temperature for 16 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 6-Methoxy-1H-indole-2-carboxylic acid (4.60 g). This material (4.64 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.60 g) in dichloromethane (200 mL) were treated with N-methylpiperazine (3.23 mL) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (200 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% 2M ammonia in methanol/dichloromethane) to give (6-Methoxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (6.60 g). This material (0.16 g) was dissolved in dichloromethane (10 mL). At room temperature, 1 M boron tribromide (1.5 mL) was added dropwise. The reaction mixture was heated to reflux overnight, and then cooled, quenched with saturated sodium hydrogencarbonate solution, and extracted with dichloromethane. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (0-10% 2M ammonia in methanol/dichloromethane) to give the title compound
1.2 g
With sodium hydroxide; In ethanol; water; at 70℃; for 1h;
A suspension of ethyl 6-methoxy-1H-indole-2-carboxylate (1.5 g6.84 mmol) in ethanol (80 mL) was treated with a 1 mol/L aqueous NaOH solution (14 mL) and heated at 70C for 1 h. After the reaction, the solvent was evaporated in vacuo and 100 mL water was added. The solution then was washed by CH2Cl2 (100 mL×3) and the water phase was acidified with 2 mol/L HCl and the precipitate formed was isolated by filtration, and washed with water to give 1.2 g white solid. LC-MS: m/z= 189.1 [M-H]-. m.p. 203-205C.
1.2 g
With water; sodium hydroxide; at 70℃; for 1h;
To a 100 mL eggplant flask was added ethyl 6-methoxy-1H-indole-2-carboxylate (1.5 g, 6.84 mmol)1mol / L aqueous sodium hydroxide solution 14mL,70 reflux 1h,Stop the reaction.Methanol was distilled off,Add 100mL water,The aqueous layer was washed with dichloromethane (100 mL × 3)PH adjusted to 2 with 2N hydrochloric acid,Precipitation,Stirring,Suction filtration,Washed,The filter cake was dried to give 6-methoxy-1H-indole-2-carboxylic acid (1.2 g) as a white solid.The product was separated and purified directly to the next reaction.
1-[6-Methoxyindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
EXAMPLE 87 1-[6-Methoxyindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine (III) Following the general procedure of EXAMPLE 16 and making non-critical variations but starting with <strong>[16732-73-3]6-methoxyindole-2-carboxylic acid</strong> (PREPARATION 63, 0.35 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.40 g), 1,1'-carbonyldiimidazole (0.31 g) and THF (6.6 ml), the title compound is obtained, mp 191-193.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
To a 0.1 M stirred solution of an indole-2-carboxylic acid derivative of type (II) in CH2Cl2 are added EDC (1.3 eq), HOBt (1.3 eq), Et3N (1.3 eq) and the amine derivative (A-H, as defined above, 1 eq). The mixture is stirred overnight at room temperature and then poured onto water and extracted with CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. Flash chromatography or preparative HPLC affords a compound of formula (I).
1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-amine[ No CAS ]
[ 1300087-91-5 ]
Yield
Reaction Conditions
Operation in experiment
Example 53j 6-(methyloxy)-/V-(1 -methyl-6-phenyl-4H-ri.2.4ltriazolor4.3- alH ,4lbenzodiazepin-4-yl)-1 /-/-indole-2-carboxamide A solution of HOBt (135mg, 1 mmol), EDC (191 mg, 1 mmol), N,N-diisopropylethylamine (140muIota) and 6-(methoxy)-1 H-indole-2-carboxylic acid (Aldrich) (96mg, 0.6mmole) in dry THF (10 mL) was stirred at RT for 10 min. Intermediate 28 (145mg, 0.5mmol) in DCM (10 mL) was added and stirred for 24 hours. DCM (100 mL) and 8% sodium bicarbonate solution (1 mL) were then added and the organic phase was dried (Na2SC>4). The mixture was filtered and concentrated in vacuo to give a residue that was triturated with water to give a precipitate which was filtered and washed with iP^O (20 mL). Recrystallisation from acetonitrile gave the title compound; m.p.160-170C, LC/MS: APCI m/z 463.32 [M+H]+, Rt = 2.79 min.
Example 53 6-(methyloxy)-N-(1-methyl-6-phenyl-4H-[1,2,4]-triazolo[4,3-a][1,4]benzodiazepin-4-yl)-1H-indole-2-carboxamide A solution of HOBt (135 mg, 1 mmol), EDC (191 mg, 1 mmol), N,N-diisopropylethylamine (140 mul) and 6-(methoxy)-1H-indole-2-carboxylic acid (Aldrich) (96 mg, 0.6 mmole) in dry THF (10 mL) was stirred at RT for 10 min. Intermediate 28 (145 mg, 0.5 mmol) in DCM (10 mL) was added and stirred for 24 hours. DCM (100 mL) and 8% sodium bicarbonate solution (1 mL) were then added and the organic phase was dried (Na2SO4). The mixture was filtered and concentrated in vacuo to give a residue that was triturated with water to give a precipitate which was filtered and washed with iPr2O (20 mL). Recrystallisation from acetonitrile gave the title compound; m.p. 160-170 C., LC/MS: APCI m/z 463.32 [M+H]+, Rt=2.79 min.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;
General procedure: To a solution of the commercially available L-leucine tert-butyl ester (12, 0.89mmol) in DMF (15mL) were added an appropriate carboxylic acid (8, 1.1mmol), HOBt·H2O (1.1mmol), and EDC·HCl (1.1mmol). The resulting solution was cooled to 0C under ice bath conditions, and TEA was added dropwise. After 5min, the ice bath was removed, and the mixture was allowed to stir for 2h at ambient temperature. DMF was removed under high vacuum, and the resulting residue was dissolved in EtOAc (30mL). The organic layer was washed with 5% citric acid (20mL×2), 5% NaHCO3 (20mL×2), and brine (20mL). The solution was dried over Na2SO4, filtered, and evaporated under reduced pressure to give compound 13. The resulting crude compound was purified by silica gel column chromatography using hexane-EtOAc as eluents.
6-Methoxy-lH-indole-2-carboxylic acid acid (1 g, 5.23 mmol, commercially available from, for example, Amfinecom Inc.) was dissolved in methanol (16 mL), to this solution HC1 (12.39 M, 1.689 mL, 20.92 mmol) was added. The reaction was stirred at 65 C under nitrogen for 3 h. The reaction was left stirring at 65 C under nitrogen overnight, LCMS showed 43%) conversion to desired product. The reaction was left stirring at 65 C under nitrogen for a further 4.5 h. The solution was then allowed to cool and taken to pH14 using NaOH (2 M). The desired product was filtered off to give the desired product (328 mg) a brown solid.LCMS (Method B): Rt = 0.92 min, MH+ = 442.1.
(R)-6-methoxy-N-[1-(1-naphthyl)ethyl]-1H-indole-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;
General procedure: To a suspension of 4-methoxyindole-2-carboxylic acid (6, 93.7 mg, 0.49 mmol) in anhydrous dichloromethane (2 mL) was added at room temperature (R)-1-(1-naphthyl)ethylamine (19, 88 mg, 0.52 mmol). The mixture was cooled to 0 C and N-hydroxybenzotriazole (HOBt, 70.3 mg, 0.52 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDCI, 80.7 mg, 0.52 mmol) and triethylamine (52.6 mg, 0.52 mmol) were added. The reaction mixture was stirred for 1 h at 0 C and then at room temperature for 5 h. Water was added, the mixture was extracted with dichloromethane, the organic extract was dried over sodium sulfate and the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel (ethyl acetate/heptane 1:4 then 2:3), providing compound 20 as a white powder (153 mg, 91%);
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