* 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.
Diethyl lH-indole-2,6-dicarboxylate (3): Ethyl 4-(3-ethoxy-2,3-dioxopropyl)-3- nitrobenzoate (2) (8.5 g, 27.5 mmol) was suspended in acetic acid (75 mL) and heated to 75 °C. After the solid material was dissolved, water (56 mL) followed by activated zinc dust (17.9 g, 27.5 mmol) was added in small portions and the temperature was kept at 80 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and filtered through a celite pad. Filtrate was washed with water (2x100 mL), saturated NaHC03 (2x100 mL) and brine solution (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3 (6.0 g, 83percent) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 1.33 (m, 6H), 4.34 (m, 4H), 7.21 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 8.12 (s, 1H), 12.25 (s, 1H). MS m/z (M-H): 259.9
58%
With acetic acid; zinc In water at 85℃; for 1 h;
The above ethyl ester (91 g, 0.29 mol) was suspended in 800 mL of HOAc and the suspension was heated with stirring to 75° C. Once the solids had dissolved, water was added. Zinc dust (189.63 g, 2.9 mmol) was added carefully in a portion-wise manner, keeping the reaction temperature below 85° C. Once the zinc was added, the mixture was stirred vigorously for an additional hour, then EtOAc (1.5 L) was added to dissolve most of the precipitate. The mixture was then filtered through diatomaceous earth, washing with EtOAc (1.5 L). The filtrate was washed twice with water (1.5 L), four times with saturated NaHCO3 (1 L), and once with brine (1 L). The solution was dried with Na2SO4, filtered, and concentrated to provide a yellow powder. Recrystallization from toluene provided 44.6 g of 1H-indole-2,6-dicarboxylic acid diethyl ester as a yellow powder, yield 58percent.
58%
With acetic acid; zinc In water at 85℃; for 1 h;
Step 3: Synthesis of diethyl 1H-indole-2,6-dicarboxylateEthyl 4-(3-ethoxy-2,3-dioxopropyl)-3-nitrobenzoate (91 g, 0.29 mol) is suspended in 800 mL of acetic acid and it is heated with stirring to 75 °C. Once the solid is dissolved, water (600 mL) is added. Zinc dust (189 g, 2.9 mol) is added carefully in small portions and the reaction temperature is kept below 85 °C. The mixture is then stirred vigorously for 1 hour after the addition. EtOAc (1500 mL) is added and the mixture was filtered through Celite. The solid is washed with more EtOAc (1500 mL) and the filtrates are combined, washed twice with water (1500 mL), four times with saturated NaHC03 (1000 mL), and once with brine (1000 mL). The filtrate is dried (Na2S04), filtered, and concentrated to afford the crude compound which was recrystallized from toluene to afford the title compound (44.6 g, 58percent) as a yellow powder.
Reference：
[1] Patent: WO2014/149164, 2014, A1, . Location in patent: Paragraph 00802; 00826
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 9, p. 2588 - 2599
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 938 - 941
[4] Patent: US2006/276453, 2006, A1, . Location in patent: Page/Page column 32-33
[5] Patent: WO2011/71716, 2011, A1, . Location in patent: Page/Page column 40-41
[6] Journal of the Chemical Society, 1924, vol. 125, p. 2288
2
[ 103027-97-0 ]
[ 107516-75-6 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 1745,1747
[2] Journal of the American Chemical Society, 1957, vol. 79, p. 1745,1747
3
[ 327-20-8 ]
[ 107516-75-6 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 1745,1747
4
[ 327-21-9 ]
[ 107516-75-6 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 1745,1747
5
[ 96315-16-1 ]
[ 107516-75-6 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 9, p. 2588 - 2599
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 20h;
To a stirred suspension of NaH (260 mg of 60 wt % in mineral oil, 6.50 mmol) in DMF (5 mL) under an atmosphere of dry nitrogen was added 1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong> (see Example 1) (1.50 g, 5.74 mmol) in DMF (40 mL) over 5 min. Ethyl 4-bromobutyrate (1.40 g, 7.2 mmol) was added dropwise, and the reaction was stirred at room temperature for 20 h. The reaction was quenched with water and extracted into methylene chloride (3×50 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude tri-ester intermediate was taken up in dry THF (30 mL) and to this solution was added potassium tert-butoxide (20 mL of a 1.0 M solution in THF, 20 mmol). After stirring at room temperature for 16 h, the reaction was quenched with water (60 mL) and concentrated HCl (75 mL) and refluxed for 5 h. The resulting suspension was cooled, filtered, then washed with water followed by hexanes. The resulting solid was dried in a vacuum oven to give 9-oxo-6,7,8,9-tetrahydro-pyrido[1,2-a]indole-3-carboxylic acid (1.25 g, 95%) as an analytically pure purple powder.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;Inert atmosphere;
Diethyl l-(cyanomethyl)-lH-indole-2,6-dicarboxylate (4): A stirring solution of diethyl lH-indole-2,6-dicarboxylate (3) (6.0 g, 22.9 mmol) in dry DMF (60 mL) was added K2C03 (9.52 g, 68.9 mmol) at room temperature and stirred under nitrogen atmosphere for 30 min. Then bromoacetonitrile (5.5 g, 45.9 mmol) was added to the reaction mixture and heated to 80 C for 4 h. The reaction mixture was cooled to room temperature and treated with EtOAc (50 mL), brine solution (50 mL) and cold water (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4 (6.0 g, 87%) as off white solid. 1H NMR (400 MHz, CDC13) delta 1.45 (m, 6H), 4.44 (m, 4H), 5.65 (s, 2H), 7.41 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.92-7.94 (dd, J = 1.2, 8.4 Hz, 1H), 8.18 (s, 1H). MS m z (M+H): 301.4
84%
Step 1: Synthesis of diethyl l-(cyanomethyl)-1H-indole-2,6-dicarboxylateTo a solution of <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (Intermediate A, 4.0 g, 15.3 mmol) in dry DMF (50 mL) is added K2CO3 (6.3 g, 45.9 mmol). The reaction mixture is stirred under N2 for 30 min. Bromoacetonitrile (2.1 mL, 30.6 mmol) is added and the reaction mixture is heated to 80 C for 4 h. After cooling, the reaction mixture is taken up in EtOAc (300 mL) and washed with water, then brine, dried (Na2S04) and concentrated. The residue is recrystallized from ethanol to afford the title compound (3.9 g, 84%) as fine off-white needles.
a: 1-Cyanomethyl-1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong> A mixture of 60% NaH in mineral oil (115 mg, 2.9 mmol) and 1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong> (500 mg, 1.9 mmol) in DMF (3 mL) was stirred at room temperature for 0.5 h. Then bromo-acetonitrile in DMF (1 mL) was added and the reaction was warmed to 77 C. and kept at this temperature overnight. The reaction was cooled and quenched with ice water. A large amount of precipitate formed which was filtered and rinsed with water, followed by cold ether. The wet cake was dried in the vacuum oven (50 C.) to give 585 mg of 1-cyanomethyl-1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong>.
b: 1-(Cyano-methyl-methyl)-1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong> A mixture of K2CO3 (7.93 g, 57.0 mmol) and 1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong> (5.0 g, 19.14 mmol) in DMF (30 mL) was stirred at room temperature for 0.5 h. Then 2-bromo-propionitrile (3.4 mL, 38.3 mmol) in DMF (10 mL) was added. The reaction was warmed to 80 C. and kept at this temperature for 6 h. Then the reaction was cooled down to the room temperature. Most of the DMF solvent was removed in vacuo and the crude residue was extracted several times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated. The crude product was triturated with MeCN to give 3.9 g of 1-(cyano-methyl-methyl)-1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong> as a white fluffy solid. The filtrate was concentrated and purification by silica gel chromatography provided 1.6 g of 1-(cyano-methyl-methyl)-1H-<strong>[107516-75-6]indole-2,6-dicarboxylic acid diethyl ester</strong>, yield 91%.
91%
Step 1: Synthesis of diethyl l-(l-cyanoethyl)-1H-indole-2,6-dicarboxylateA mixture of K2C03 (7.9 g, 57.4 mmol) and diethyl lH-indole-2,6-dicarboxylate (Intermediate A, 5.0 g, 19.1 mmol) in DMF (30mL) is stirred at room temperature for 30 min. A solution of 2-bromo-propionitrile (3.4 mL, 38.3 mmol) in DMF (10 mL) is added. The reaction mixture is warmed to 80 C for 6 h and then cooled to room temperature and stirred for another 16 h. Solvent is removed and the residue is partitioned between EtOAc and water. The organic layer is separated, dried and concentrated to afford crude compound which is purified by flash column chromatography using EtOAc in hexanes followed by trituration with acetonitrile to afford the title compound (5.5 g, 91 ).
With Triton B; In 1,4-dioxane; methanol; at 20 - 55℃; for 18.5h;
Intermediate J: l-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8- carboxylic acidStep 1: Synthesis of diethyl l-(2-cyanoethyl)-1H-indole-2,6-dicarboxylateA 40% solution of Triton B in methanol (0.50 mL, 1.1 mmol) is added to a suspension of <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (Intermediate A, 2.6 g, 10.0 mmol) and acrylonitrile (2.2 mL, 33.4 mmol) in 1,4-dioxane (25 mL). The reaction mixture is warmed to 55 C for 30 min and then it is stirred at room temperature for 18 h. Water (30 mL) is added and the mixture is extracted with EtOAc. The organic layer is washed with water, brine, dried (Na2S04) and concentrated to afford the title crude compound (3.0 g, 96%) as a yellow solid which is used in the next step without purification.
Example 5 Synthesis of (R)-3-aminomethyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid pyridin-3-ylamide A mixture of K2CO3 (1.06 g, 7.65 mmol) and 1H-indole-2,6-dicarboxylic acid diethyl ester (1.0 g, 3.8 mmol) in DMF (15 mL) was stirred at room temperature for 0.5 h. Then toluene-4-sulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-yl methyl ester (1.20 g, 4.2 mmol) in DMF (5 mL) was added. The reaction mixture was warmed to 100 C. and kept at this temperature overnight. The reaction was concentrated and the residues were extracted with EtOAc several times. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated. Purification by silica gel chromatography gave 1.34 g of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-indole-2,6-dicarboxylic acid diethyl ester as white solid, yield 93%. ESI-MS m/z 376.42 [M+H]+.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 16h;
Step 2: Synthesis of diethyl l-{3-[(tert-butoxycarbonyl)amino]-3-methylbutyl}-1H- indole-2,6-dicarboxylateTo a solution of <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (Intermediate A, 100 mg, 0.38 mmol), crude tert-butyl (4-hydroxy-2-methylbutan-2-yl)carbamate (155 mg, 0.76 mmol) and triphenylpho spine (251 mg, 0.96 mmol) in THF (1.5 mL) is added diisopropyl azodicarboxylate (0.20 mL, 0.96 mmol). The mixture is stirred for 16 h at room temperature. The solvent is evaporated and the residue is purified by flash column chromatography to afford a mixture of diethyl l-{3-[(tert-butoxycarbonyl)amino]-3- methylbutyl}-1H-indole-2,6-dicarboxylate and <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (131 mg) which is used in the next step without purification.
Step 4: Synthesis of diethyl l-{(2R)-1-[(tert-butoxycarbonyl)amino]propan-2-yl}- 1H-indole-2,6-dicarboxylate A stirred suspension of 60% NaH (371 mg, 9.3 mmol) in DMF (10 mL) is cooled in an ice bath, and a solution of <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (Intermediate A, 2.6 g, 10.1 mmol) in DMF (10 mL) is added. The mixture is stirred for 20 min, then a solution of tert-butyl (5S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.0 g, 8.4 mmol) in DMF (10 mL) is added. The reaction mixture is stirred for 30 min at 0 C and then warmed to room temperature and stirred for 48 h. The reaction is poured into ice water and the resultant solid is removed by filtration. The filtrate is acidified to pH 3 with IN aqueous HCl and extracted with EtOAc. The combined extracts are washed with water, brine, dried (Na2S04) and concentrated to afford the title compound (2.7 g, crude) as an oil.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 60h;
Step 2: Synthesis of diethyl l-{3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropyl}- 1H-indole-2,6-dicarboxylate To a solution of <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (25.3 g, 97 mmol), tert-butyl (3- hydroxy-2,2-dimethylpropyl)carbamate (19.7, 97 mmol) and triphenylphosphine (50.9 g, 194 mmol) in THF (200 mL) is added and diisopropyl azodicarboxylate (40.2 mL, 194 mmol). The mixture is stirred for 60 h at room temperature and then the solvent is removed. The residue is separated into two portions and each of them is filtered through a short plug of silica gel (400 g) using 20% EtOAc in heptane. A mixture of diethyl l-{3- [(tert-butoxycarbonyl)amino]-2,2-dimethylpropyl}-1H-indole-2,6-dicarboxylate and <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (55 g) is obtained and the mixture is used in the next step without further purification.
tert-butyl N-(3-hydroxy-1-methylpropyl)carbamate[ No CAS ]
[ 1311369-38-6 ]
Yield
Reaction Conditions
Operation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 16h;
Step 2: Synthesis of diethyl l-{3-[(tert-butoxycarbonyl)amino]butyl}-1H-indole-2,6- dicarboxylateTo solution of <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (Intermediate A, 729 mg, 2.8 mmol), triphenylphosphine (879 mg, 3.3 mmol) and tert-butyl (4-hydroxybutan-2-yl)carbamate (634 mg, 3.3 mmol) in CH2C12 (10 mL) cooled to 0 C is added diisopropyl azodicarboxylate (0.69 mL, 3.3 mmol). The reaction mixture is warmed to room temperature and stirred for 16 h. The solvent is removed and the residue is purified by flash column chromatography using methanol in CH2CI2 to afford the mixture of diethyl l-{ 3-[(tert-butoxycarbonyl)amino]butyl}- 1H-indole-2,6-dicarboxylate and un-reacted <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (604 mg). The mixture is used in the next step without further purification
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 60h;
Step 3: Synthesis of diethyl l-[(l-[(tert- butoxycarbonyl)amino]methyl}cyclopropyl)methyl]-1H-indole-2,6-dicarboxylateTo a solution of tert-butyl { [l-(hydroxymethyl)cyclopropyl]methyl}carbamate (20 g, 99.5 mmol), <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (26 g, 99.5 mmol) and triphenylphosphine (52 g, 199 mmol) in THF (300 mL) is added diisopropyl azodicarboxylate (31 mL, 199 mmol) at room temperature. The reaction mixture is stirred for 60 h and the solvent is evaporated. The residue is purified by flash column chromatography using 12% EtOAc in petroleum ether to afford a mixture of diethyl 1- [(l-{ [(tert-butoxycarbonyl)amino]methyl}cyclopropyl)methyl]-1H-indole-2,6- dicarboxylate and <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (36 g) as a white solid. The mixture is used in the next step without further purification.
Step 4: Synthesis of diethyl l-{4-[(tert-butoxycarbonyl)amino]butan-2-yl}-1H- indole-2,6-dicarboxylateTo a stirred suspension of 60% NaH dispersion in mineral oil(78.8 mg, 2.0 mmol) in DMF (2.5 mL) cooled to 0 C is added a solution of <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (Intermediate A, 561 mg, 2.1 mmol) in DMF (3 mL). The mixture is stirred for 20 min and a solution of tert-butyl 6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (450 mg, 1.8 mmol) in DMF (2.5 mL) is added. The reaction mixture is stirred for 30 min at 0 C and it is warmed to room temperature and stirred for 48 h. Saturated NH4C1 solution is added and the reaction mixture is extracted with EtOAc. The organic layer is separated, washed with water, then brine, dried (MgS04) and concentrated to afford the title compound (1.04 g, 50% pure) as an oil.
Step 5: Synthesis of diethyl l-{(2R)-4-[(tert-butoxycarbonyl)amino]butan-2-yl}-1H- indole-2,6-dicarboxylate A stirred suspension of 60% NaH (840 mg, 21 mmol) in NMP (40 mL) is cooled in an ice bath, and a solution of <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (Intermediate A, 5.8 g, 22 mmol) in NMP (20 mL) is added. The mixture is stirred for 20 min, then a solution of tert-butyl (6S)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (5.0 g, 20 mmol) in NMP (20 mL) is added. The reaction mixture is stirred for 30 min at 0 C and is warmed to room temperature and stirred for 48 h. The reaction is poured into ice water and the resultant solid is isolated by filtration. The filtrate is acidified to pH 3 with IN aqueous HCl and extracted with EtOAc. The combined extracts are washed with water 4 times, then brine, dried (Na2S04) and concentrated to afford the title compound (6.0 g, crude) as an oil which was used in the next step without purification.
Step 5: Synthesis of diethyl l-{(2S)-4-[(tert-butoxycarbonyl)amino]butan-2-yl}-1H- indole-2,6-dicarboxylateTo a suspension of hexane washed 60% sodium hydride in mineral oil (91 mg, 2.3 mmol) in DMF (2.5 mL) under nitrogen atmosphere to 0 C is added a solution of diethyl 1H- indole-2,6-dicarboxylate (619 mg, 2.4 mmol) in DMF (4 mL). The mixture is stirred for 20 min at 0 C and a solution of tert-butyl (6R)-6-methyl-1,2,3-oxathiazinane-3- carboxylate 2,2-dioxide (518 mg, 2.1 mmol) in DMF (2.5 mL) is added. The reaction mixture is stirred for 30 min at 0 C and is warmed to room temperature and stirred for 72 h. Water and NH4C1 solution are added and the mixture is stirred for 15 min. The aqueous mixture is extracted with EtOAc (50 mL) and the organic layer is washed with water, brine, dried (MgS04) and concentrated to afford the title crude compound (1.1 g) which is used in the next step without purification.
N-(tert-butoxycarbonyl)-2-methyl-3-hydroxy-prop-1-ylamine[ No CAS ]
[ 1311369-07-9 ]
Yield
Reaction Conditions
Operation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 16h;
Step 2: Synthesis of diethyl l-{3-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1H- indole-2,6-dicarboxylateTo a solution of <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (Intermediate A, 1.9 g, 7.4 mmol), tert-butyl (3-hydroxy-2-methylpropyl)carbamate (2.8 g, 14.8 mmol) and triphenylphosphine (4.9 g, 18.5 mmol) in THF (35 mL) at 0 C is added diisopropyl azodicarboxylate (3.8 mL, 18.5 mmol). The mixture is stirred for 16 h at room temperature and then the solvent is removed. The residue is filtered through a pad of silica (300 g, 240-400 mesh) using 30% EtOAc in heptane to afford of mixture of the title compound and <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (3.2 g) which is used in the next step without further purification.
tert-butyl cis-5,6-dimethyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide[ No CAS ]
[ 107516-75-6 ]
diethyl 1-{4-[(tert-butoxycarbonyl)amino]-3-methylbutan-2-yl}-1H-indole-2,6-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step 6: Synthesis of diethyl l-{(2,3-syn)-4-[(tert-butoxycarbonyl)amino]-3- methylbutan-2-yl}-1H-indole-2,6-dicarboxylateA suspension of 60% sodium hydride (119 mg, 3.0 mmol) in DMF (3 mL) is cooled to 0 C and a solution of <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (Intermediate A, 934 mg, 3.6 mmol) is added. After the mixture is stirred for 20 min at 0 C, a solution of tert-butyl cis-5,6-dimethyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (790 mg, 3.0 mmol) in DMF (2.0 mL) is added. The reaction mixture is warmed to room temperature and stirred for 16 h. Water is added and the mixture is extracted with EtOAc. The organic layer is washed with brine, dried (Na2S04) and concentrated to afford the title crude compound (1.6 g) which is used in the next step without purification
With potassium carbonate; In N,N-dimethyl-formamide; at 135℃; for 1h;Microwave irradiation;
Step 3: Synthesis of diethyl l-(2,2-difluoro-3-[(4- methylphenyl)sulfonyl]oxy }propyl)- 1H-indole-2,6-dicarboxylateDiethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 3.5 g, 13.6 mmol), 2,2- difluoropropane-1,3-diyl bis(4-methylbenzenesulfonate) (6.0 g, 14.3 mmol) and K2CO3 (3.9 g, 28.5 mmol) are mixed in DMF (36 mL) and the reaction mixture is separated into 3 fractions. Each fraction is heated in a microwave reactor at 135 C for 1 h. The 3 fractions are combined, and water (300 mL) and EtOAc (300 mL) are added. The aqueous layer is separated and extracted with EtOAc (3 x 100 mL). The organic layers are combined, washed with water (3 x 200 mL), dried (Na2S04) and concentrated. The crude compound is purified by flash column chromatography using EtOAc in heptane to afford the title compound (4.7 g, 59% pure, 38% yield).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 60h;
Step 2: Synthesis of diethyl l-[(l-[(tert- butoxycarbonyl)amino]methyl}cyclobutyl)methyl]-1H-indole-2,6-dicarboxylate To a solution of tert-butyl { [l-(hydroxymethyl)cyclobutyl]methyl}carbamate (12 g, 55.76 mmol), <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (14.56 g, 55.76 mmol) and triphenylphosphine (29.2 g, 111.5 mmol.) in THF (110 mL) is added diisopropyl azodicarboxylate (22.41 mL, 111.5 mmol) at room temperature and the reaction mixture is stirred for 60 h. The solvent is evaporated and the residue is purified by flash column chromatography using 12% EtOAc in petroleum ether to afford diethyl l-[(l-{ [(tert- butoxycarbonyl)amino]methyl}cyclobutyl)methyl]-1H-indole-2,6-dicarboxylate contaminated with un-reacted <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong>. The mixture is used in the next step without further purification.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 60h;
Step 4: Synthesis of diethyl l-[(4-[(tert-butoxycarbonyl)amino]methyl}tetrahydro- 2H-pyran-4-yl)methyl]-1H-indole-2,6-dicarboxylate To a solution of tert-butyl { [4-(hydroxymethyl)tetrahydro-2H-pyran-4- yl] methyl} carbamate (10 g, 40.81 mmol), <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (Intermediate A, 10.65 g, 40.81 mmol) and triphenylphosphine (21.3 g, 81.63 mmol) in THF (110 mL) at room temperature is added diisopropyl azodicarboxylate (16 mL, 81.63 mmol). The reaction mixture is stirred for 60 h and the solvent is removed under vacuum. The residue is purified by flash column chromatography using 12% EtOAc in petroleum ether to afford a mixture of diethyl l-[(4-{ [(tert- butoxycarbonyl)amino]methyl}tetrahydro-2H-pyran-4-yl)methyl]-1H-indole-2,6- dicarboxylate and un-reacted <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> as a white solid. The mixture is used in the next step without further purification.
Step 6: Synthesis of diethyl l-[l-(tert-butoxycarbonyl)-4-[(tert- butoxycarbonyl)amino]methyl}piperidin-4-yl]methyl}-1H-indole-2,6-dicarboxylateA solution of triphenylphosphine (19.4 g, 74.1 mmol) and DIAD (14.05 mL, 74.1 mmol) in THF (700 mL) is cooled to 0 C and stirred for 10 min. Diethyl 1H-indole-2,6- dicarboxylate (15.47 g, 59.3 mmol) is added and reaction mixture is stirred for another 10 min. tert-Butyl 4-{ [(tert-butoxycarbonyl)amino]methyl}-4-(hydroxymethyl)piperidine-1- carboxylate (17 g, 49.4 mmol) is added and the reaction mixture is stirred for 48 h at room temperature. The mixture is partitioned between water and ethyl acetate, and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (2 x 200 mL). The combined organic layers are dried (Na2S04), and concentrated. The residue is purified by flash column chromatography using 15% EtOAc in petroleum ether to afford the title compound (17 g, 32%) as a dark brown oil.
Step 5: Synthesis of diethyl l-{3-[(tert-butoxycarbonyl)amino]butan-2-yl}-1H- indole-2,6-dicarboxylateTo a stirred suspension of 60% NaH dispersion in mineral oil (596 mg, 14.9 mmol) in DMF (14 mL) at 0 C is added a solution of <strong>[107516-75-6]diethyl 1H-indole-2,6-dicarboxylate</strong> (Intermediate A, 3.9 g, 14.9 mmol) in DMF (14 mL). The mixture is stirred for 40 min, then a solution of tert-butyl 4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3.8 g, 14.9 mmol) in DMF (7 mL) is added. The reaction mixture is stirred for 30 min at 0 C and then is warmed to room temperature and stirred for 65 h. Water is added and the mixture is stirred for 15 min before EtOAc (50 mL) is added. Then the organic layer is separated, washed with aqueous NFLCl solution, water, and brine, dried (MgS04) and concentrated to afford the crude title compound, which was used directly in the next reaction.
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