* 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 palladium 10% on activated carbon; hydrogen In tetrahydrofuran at 20℃;
10percent Pd/C (0.18 g/g of startingmaterial) was added to a solution of starting material dissolved inTHF (54 mL/g of starting material). Reaction flask was sealed andvacuum was used to remove air. A balloon filled with hydrogen gaswas then attached to the flask. The reaction was stirred at roomtemperature for 24e48 h or until disappearance of starting materialwas observed by TLC. The reaction was then filtered through celite.Filtrate was rotovapped to give a brown solid; 100percent; 1H NMR(DMSO): δ 7.15-7.05 (m, 2H), 6.71 (dd, J 3.0, 0.9 Hz, 1H), 6.57 (dd,J 8.5, 2.1 Hz, 1H), 6.12 (dd, J 3.0, 0.9 Hz, 1H), 3.67 (s, 3H); 13CNMR (DMSO): δ141.30, 131.12, 129.49, 129.44, 129.41, 112.31, 110.11,104.21, 99.13, 32.86.
95.8%
With iron; acetic acid In ethanol at 78℃; for 1 h;
1-Methyl-5-nitro -1H- indole (270mg, 1mmol), Fe powder (1.12g, 20mmol, 10equiv) was added ethanol (15ml) and glacial acetic acid (2ml) in, 78 heated at reflux for 1h, TLC monitoring. After completion of the reaction, it was filtered through Celite, washed with ethanol to precipitate a colorless, ethanol rotary evaporation. The solid was dissolved in ethyl acetate followed by the addition, ultrasonic minutes, extracted with saturated NaHCO3 wash, water, NaCl wash, saturated MgSO4 dry. The organic layer by rotary evaporation, dried, the crude product was purified by column chromatography to give 230mg of yellow product, 1-methyl-5-amino-1H- indole, yield 95.8percent.
95.5%
With palladium on activated charcoal; hydrogen In ethanol at 50℃; for 5 h;
A2 (1.0 g, 5.7 mmol) was dissolved in ethanol and catalyzed with Pd/C and H2 for 5 hours at 50°C. The catalyst was filtered off and the solvent was removed to give 0.85 g of A3. The yield in this step was 95.5percent without further purification.
81%
With hydrazine hydrate In ethanol at 80℃; for 1 h; Inert atmosphere
General procedure: Hydrazine hydrate was chosen as the hydrogen donor for the low emission of pollutants. In a typical procedure, hydrazine hydrate (4 equiv) was added into the reactor which containing fresh prepared catalyst as described above. Then the reactor was put into a preheated oil bath with a stirring speed of 500 rpm, and the substrate (1 mmol)dissolved in 1 mL ethanol was added drop-wisely under argon. The reactions were monitored by TLC. After the reaction, the reaction mixture was vacuum filtered through a pad of silica on a glass-fritted funnel and an additional 15 mL of ethyl acetate (5 mL portions) was used to rinse the product from the silica, the filtrate was concentrated in vacuum and analyzed by GC. Products were purified by column chromatography and identified by 1H NMR and 13C NMR.
77%
With hydrogen In tetrahydrofuran; ethanol for 4 h;
Step G: Synthesis of 1 -methyl- lH-indol-5 -amine as an intermediate <n="38"/>; [0100] A mixture of l-methyl-5-nitro-lH-indole (2.00 g, 11.3 mmol) and platinum (IV) oxide (0.20 g, 10percent by weight) in a mixture of ethanol (20 mL) and tetrahydrofuran (20 mL) was shaken under an atmosphere of hydrogen at 40 psi for 4 h. After this time, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure. Purification by flash chromatography (silica, 1 :3, ethyl acetate/hexanes) afforded 1-methyl- lH-indol-5-amine (1.28g, 77percent) as a red oil: 1H NMR (500 MHz, CDCl3) δ 7.12 (d, J= 8.5 Hz, IH), 6.95 (d, J= 3.0 Hz, IH), 6.92 (d, J= 2.0 Hz, IH), 6.69 (dd, J= 2.0, 8.5 Hz, IH), 6.28 (d, J= 3.0 Hz, IH), 3.72 (s, 3H), 3.47 (bs, 2H).
27%
With tin(ll) chloride In ethyl acetate at 20℃;
To l-methyl-5-nitro-lH-indole (0.5g, 2.84mmol) in ethyl acetate (10ml), tin (II) chloride hydrate (2.5g, 11.4mmol, 4eq) was added and the reaction mixture stirred overnight at room temperature. The reaction mixture was basified with aqueous sodium EPO <DP n="50"/>hydroxide solution (pH 8) and the compound extracted using ethyl acetate. The crude compound obtained was purified by column chromatography over silica gel using ethyl acetate/ hexane (1:1) as eluent to give 1 -methyl- lH-indol-5ylamine (120mg, 27percent).
Reference:
[1] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1202 - 1213
[2] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 10, p. 3531 - 3541
[3] New Journal of Chemistry, 2015, vol. 39, # 7, p. 5360 - 5365
[4] Patent: CN104163815, 2017, B, . Location in patent: Paragraph 0065; 0066; 0068
[5] Patent: CN107163029, 2017, A, . Location in patent: Paragraph 0049; 0053; 0054; 0055; 0056; 0057; 0058
[6] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 5, p. 1461 - 1464
[7] Catalysis Communications, 2016, vol. 84, p. 25 - 29
[8] Patent: WO2009/42907, 2009, A1, . Location in patent: Page/Page column 36-37
[9] Synthetic Communications, 1998, vol. 28, # 1, p. 147 - 157
[10] Canadian Journal of Chemistry, 2003, vol. 81, # 10, p. 1108 - 1118
[11] Patent: WO2006/123145, 2006, A1, . Location in patent: Page/Page column 48-49
[12] Journal of Medicinal Chemistry, 1993, vol. 36, # 8, p. 1104 - 1107
[13] Organic Letters, 2004, vol. 6, # 17, p. 2897 - 2900
[14] Archiv der Pharmazie, 2005, vol. 338, # 2-3, p. 67 - 73
[15] Journal of the American Chemical Society, 2005, vol. 127, # 22, p. 8050 - 8057
[16] Journal of Medicinal Chemistry, 2007, vol. 50, # 22, p. 5509 - 5513
[17] Patent: WO2006/40520, 2006, A1, . Location in patent: Page/Page column 125-126
[18] Patent: US2011/190299, 2011, A1, . Location in patent: Page/Page column 22-23
[19] Synthetic Communications, 2013, vol. 43, # 4, p. 498 - 504
[20] Patent: CN106349241, 2017, A, . Location in patent: Paragraph 0571; 0572; 0573; 0574
2
[ 6146-52-7 ]
[ 102308-97-4 ]
Reference:
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 10, p. 3531 - 3541
[2] Journal of the American Chemical Society, 2005, vol. 127, # 22, p. 8050 - 8057
[3] Archiv der Pharmazie, 2005, vol. 338, # 2-3, p. 67 - 73
[4] Organic Letters, 2004, vol. 6, # 17, p. 2897 - 2900
[5] Synthetic Communications, 1998, vol. 28, # 1, p. 147 - 157
[6] Journal of Medicinal Chemistry, 1993, vol. 36, # 8, p. 1104 - 1107
[7] Patent: US2011/190299, 2011, A1,
[8] Patent: WO2006/123145, 2006, A1,
[9] Patent: CN107163029, 2017, A,
[10] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1202 - 1213
3
[ 10075-52-2 ]
[ 102308-97-4 ]
Reference:
[1] Chemistry - A European Journal, 2009, vol. 15, # 18, p. 4528 - 4533
4
[ 6146-52-7 ]
[ 74-88-4 ]
[ 102308-97-4 ]
Reference:
[1] Patent: US2003/195201, 2003, A1,
5
[ 67-56-1 ]
[ 29906-67-0 ]
[ 102308-97-4 ]
Reference:
[1] Canadian Journal of Chemistry, 2003, vol. 81, # 10, p. 1108 - 1118
6
[ 67-56-1 ]
[ 29906-67-0 ]
[ 102308-97-4 ]
Reference:
[1] Canadian Journal of Chemistry, 2003, vol. 81, # 10, p. 1108 - 1118
7
[ 67-56-1 ]
[ 29906-67-0 ]
[ 108-98-5 ]
[ 102308-97-4 ]
Reference:
[1] Canadian Journal of Chemistry, 2003, vol. 81, # 10, p. 1108 - 1118
8
[ 131013-67-7 ]
[ 102308-97-4 ]
Reference:
[1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 317,322; engl. Ausg. S. 322, 326
9
[ 824-21-5 ]
[ 102308-97-4 ]
Reference:
[1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 317,322; engl. Ausg. S. 322, 326
10
[ 64180-07-0 ]
[ 102308-97-4 ]
Reference:
[1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 317,322; engl. Ausg. S. 322, 326
11
[ 108981-60-8 ]
[ 102308-97-4 ]
Reference:
[1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 317,322; engl. Ausg. S. 322, 326
12
[ 106883-07-2 ]
[ 102308-97-4 ]
Reference:
[1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 317,322; engl. Ausg. S. 322, 326
In tetrahydrofuran; water; N,N-dimethyl-formamide; mineral oil;
(a) 1-Methylindole-5-ylamine. To a round-bottomed flask was added 5-nitroindole (0.81 g, 5.0 mmol, Aldrich) and anhydrous DMF (40 mL). The solution was stirred magnetically and treated with sodium hydride (0.40 g, 10 mmol, 60% dispersion in mineral oil, Aldrich) followed by iodomethane (0.71 gm 10 mmol, Aldrich). Stirring was continued at 25 C. for 30 min, then the reaction mixture was quenched by the addition of water (75 mL) and extracted with EtOAc. The organic extract was concentrated in vacuo to provide a crude residue. Analogous to the procedure of Goswami, P.; Chowdhury, P.; Indian J Chem, Sect B, 1997, 36 (2), 185-186, the crude residue was dissolved in THF (40 mL) and added to Zn dust (0.22 g, 3.3 mmol, Aldrich) and AlCl3.6H2O (4.78 g, 19.8 mmol, Aldrich) in water (1 mL), magnetically stirred at 25 C. The reaction mixture was stirred at 25 C. for 16 h, then filtered. The filtrate was added to cold water (300 mL) and extracted with CH2Cl2 (3*100 mL). The combined organic extract was concentrated in vacuo to provide the title product. MS (ESI, pos. ion) m/z: 147 (M+1).
In 1-methyl-pyrrolidin-2-one; methanol; dichloromethane; water;
EXAMPLE 1 1-Methyl-5-(4-pyridinylamino)-1H-indole 4-Chloropyridine hydrochloride (8 g) was added to a solution of 5-amino-1-methylindole (7 g) in 75 ml 1-methyl-2-pyrrolidinone preheated to 100 C. The addition of 4-chloropyridine hydrochloride (4 g) after one hour caused no further reaction as determined by TLC. After two hours the reaction mixture was cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The dried (anhydrous magnesium sulfate) organic layer was filtered and evaporated to 12.7 g of an oil. The oil was eluted through silica with 10% methanol in dichloromethane via flash column chromatography to give the product which was triturated with ether to yield 5.7 g of a solid, m.p. 202-203 C. Recrystallization from acetonitrile yielded 5 g of product as crystals, mp 209-211 C. Analysis: Calculated for C14 H13 N3: 75.31% C; 5.87%H; 18.82% N; Found: 75.13% C; 6.08% H; 18.76% N.
N-(1,2-Dimethyl-3-ethyl-1H-indol-5-yl)-N'-(pyridin-3-yl)urea hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
Method A The title compound was prepared from <strong>[102308-97-4]5-amino-1-methyl-1H-indole</strong>(D3), phosgene and 3-aminopyridine using a procedure similar to that described for Example 1, in 27% yield m.p. 175-180 C. NMR (d6 -DMSO) delta: 3.76 (3H, s), 6.34 (1H, d, J=2), 7.16 (1H, dd, J=8, 2), 7.29 (1H, d, J=2), 7.37 (1H, d, J=8), 7.70 (1H, s), 7.87 (1H, dd, J=8, 8), 8.30 (1H, m), 8.45 (1H, J=8), 9.08 (1H, m), 9.24 (1H, s), 10.03 (1H, s).
EXAMPLE 13 N-(1-Methyl-1H-indol-5-yl)-N'-(2-chloropyrid-3-yl)urea hydrochloride (E13) A stirred suspension of carbonyl diimidazole (0.34 g, 2.1 mM) in dry dichloromethane (5 ml) was treated with a solution of <strong>[102308-97-4]5-amino-1-methyl-1H-indole</strong> (D3) (0.29 g, 2 mM) in dry dichloromethane (5 ml). After 0.25 h the reaction mixture was evaporated to dryness, and the residue dissolved in dimethylformamide (10 ml). 3-Amino-2-chloro-pyridine (0.23 g, 22 mM) was added to the reaction mixture which was heated to 90 C. for 1 h, then cooled and added to water (200 ml) with vigorous stirring. The precipitate was filtered, dried and recrystallized from ethanol affording the title compound as an off white solid (0.25 g; 42%) which was converted to the hydrochloride salt using hydrogen chloride in ether, m.p. 155 C.
EXAMPLE 14 N-(1-Methyl-1H-indol-5-yl)-N'-(2-chloropyrid-5-yl)urea hydrochloride (E14) The title compound was prepared in 60% yield from <strong>[102308-97-4]5-amino-1-methyl-1H-indole</strong> (D3), carbonyl diimidazole and 5-amino-2-chloropyridine, using a procedure similar to that described in Example 13. m.p. 212 C. NMR (D6 -DMSO) delta: 3.78 (3H, s), 6.32 (1H, d, J=5), 7.15 (1H, dd, J=12,3), 7.28 (1H, d, J=5), 7.40 (2H, m), 7.70 (1H, d, J=3), 8.00 (1H, dd, J=12,5), 8.50 (1H, d, J=5).
N-(1-Methyl-1H-indol-5-yl)-N'-(3-pyridyl)urea hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; dichloromethane; toluene;
Method B A solution of the aminoindole (D3)(1.95 g; 13 mM) in dichloromethane (20 ml) was added dropwise to a solution of 3-pyridyl isocyanate (D4) (prepared from 3-pyridinecarbonyl azide (2.14 g; 15 mM) in toluene) at room temperature. The reaction mixture was stirred for 17 h, then cooled, and the precipitate filtered off to give the crude product (3.36 g; 95%). This was dissolved in hot ethanol and ethereal hydrogen chloride added to afford the title compound as its hydrochloride salt (3.1 g; 80%) identical with the material prepared by method A.
N-(1-Methyl-1H-indol-5-yl)-N'-(pyridin-2-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 11 N-(1-Methyl-1H-indol-5-yl)-N'-(2-pyridyl)urea (E11) STR6 The title compound was prepared from 5-amino-1-methylindole (D3) and 2-aminopyridine using a procedure similar to that described for Example 8. The crude product was obtained in 83% yield. Recrystallisation from ethanol afforded the title compound in 70% yield, m.p. 182-185 C. NMR (CDCl3) delta: 3.8 (3H, s), 6.42 (1H, d, J=3), 6.9 (1H, m), 7.05 (1H, d, J=1), 7.2 (1H, d, J=8), 7.25 (1H, d, J=1), 7.32 (1H, dd, J=8, 1), 7.61 (1H, m), 7.88 (1H, s), 8.25 (1H, d, J=3), 9.11 (1H, s), 11.18 (1H, s).
N-(1-Methyl-5-indolyl)-N'-(6-quinolyl)-urea hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
Example 11 N-(1-Methyl-5-indolyl)-N'-(8-quinolyl) urea (E11) The title compound was prepared from 8-aminoquinoline, 1, 1'-carbonyl diimidazole and 5-amino-1-methyl-indole (D2) using a procedure similar to that described for Example 10, in 31% yield, m.p. 205-209 C. NMR (D6 -DMSO) delta: 3.76 (3H, s), 6.35 (1H, d, J 3), 7.22 (1H, dd, J 6, 2), 7.27 (1H, d, J 3), 7.36 (1H, d, J 6), 7.5-7.54 (2H, m), 7.60-7.65 (1H, m), 7.8 (1H, s), 8.39 (1H, d, J 6), 8.57 (1H, m), 8.92 (1H, d, J 2), 9.62 (2H, s). Found: M+ 316 C19 H16 N4 O requires 316
N-(1-Methyl-5-indolyl)-N'-(6-quinolyl)-urea hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
In dichloromethane; water; N,N-dimethyl-formamide;
Example 10 N-(1-Methyl-5-indolyl)-N'-(6-quinolyl)-urea hydrochloride (E10) A stirred suspension of carbonyl diimidazole (0.34 g, 2.1 mM) in dry dichloromethane (5 ml) was treated with a solution of 5-amino 1-methyl indole (D2, 0.29 g, 2 mM) in dry dichloromethane (5 ml). After 0.25 h, the reaction mixture was evaporated to dryness and the residue dissolved in DMF (10 ml). 6-Aminoquinoline (0.32 g, 2.2 mM) was added and the reaction mixture heated to 90 C. for 1 h then cooled and added to water (200 ml) with vigorous stirring. The precipitate was filtered, dried and recrystallized from ethanol, affording the product as a white solid (0.32 g, 51%).
N-(1-Methyl-5-indolyl)-N'-(3-quinolyl)-urea hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
In dichloromethane; water; N,N-dimethyl-formamide;
Example 9 N-(1-Methyl-5-indolyl)-N'-(3-quinolyl)-urea hydrochloride (E9) A stirred suspension of carbonyl diimidazole (0.34 g, 2.1 mmol) in dry dichloromethane (5 ml) was treated with a solution of 5-amino-1-methylindole (D2, 0.29 g, 2 mmol) in dry dichloromethane (5 ml). After 0.25 h, the reaction mixture was evaporated to dryness and the residue dissolved in DMF (10 ml). 3-Aminoquinoline (0.32 g 2.2 mmol) was added and the reaction minute heated to 90 C. for 1 h then cooled and added to water (200 ml) with vigorous stirring. The precipitate was filtered, dried and recrystallized from ethanol affording the product as an off-white solid (0.4 g, 66% yield). This was converted into the title compound using HCl in ether. mp 230 C. (from ethanol)
N-(1-Methyl-5-indolyl)-N'-(2-methyl-4-quinolyl)-urea hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
Example 13 N-(1-Methyl-5-indolyl)-N'-(2-methyl-4-quinolyl) urea hydrochloride (E13) The title compound was prepared from 4-aminoquinaldine, 1,1'-carbonyl diimidazole and 5-amino-1-methyl-indole (D2) using a procedure similar to that described for Example 10 and then converted to the hydrochloride salt, in 24% overall yield, m.p. 215-220 C. NMR (D6 -DMSO) delta: 2.80 (3H, s), 3.77 (3H, s), 6.39 (1H, d, J 2), 7.23-7.33 (2H, m), 7.42 (1H, d, J 6), 7.79-7.84 (2H, m), 8.0-8.11 (2H, dd J 6,6), 8.60 (1H, s), 9.08 (1H, d, J 8), 10.8 (1H, s), 10.92 (1H, s), 15.0 (1H, broad s). Found: M+ 330 C20 H18 N4 O requires 330
N-1-isoquinolinyl-N'-(1-methyl-1H-indol-5-yl)urea[ No CAS ]
N-(1-Methyl-5-indolyl)-N'-(5-isoquinolyl)-urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
Example 16 N-(1-Methyl-5-indolyl)-N'-(1-isoquinolyl) urea (E16) The title compound was prepared from 1-aminoisoquinoline, 1, 1'-carbonyl diimidazole and 5-amino-1-methyl-indole (D2) using a procedure similar to that described for Example 15, in 11% yield, m.p. 230-233 C. NMR (CDCl3) delta: 3.81 (3H, s), 6.47 (1H, d, J 2), 7.07 (1H, d, J 3), 7.30 (2H, m), 7.46 (1H, dd J 6,2), 7.61-7.82 (3H, m), 7.97 (1H, s), 8.09-8.16 (3H, m), 12.4 (1H, broad s). Found: M+ 316 C19 H16 N4 O requires 316
1-methyl-N-(4-nitro-3-pyridinyl)-1H-indol-5-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
EXAMPLE 2 1-Methyl-N-(4-nitro-3-pyridinyl)-1H-indol-5-amine, N5 -oxide A solution of 3-fluoro-4-nitropyridine-1-oxide (6 g) and <strong>[102308-97-4]1-methyl-1H-indol-5-amine</strong> (5.5 g) in 125 ml ethanol was warmed on a steam bath for thirty minutes and thereafter cooled, diluted with ether and filtered to give 10 g solid, d 232-234. Three grams were recrystallized from ethanol to give 2.2 g needles, d 237-238.
In ethanol;
EXAMPLE 2 1-Methyl-N-(4-nitro-3-pyridinyl)-1H-indol-5-amine, N5 -oxide A solution of 3-fluoro-4-nitropyridine-1-oxide (6 g) and <strong>[102308-97-4]1-methyl-1H-indol-5-amine</strong> (5.5 g) in 125 ml ethanol was warmed on a steam bath for thirty minutes and thereafter cooled, diluted with ether and filtered to give 10 g solid, d 232-234. Three grams were recrystallized from ethanol to give 2.2 g needles, d 237-238. ANALYSIS: Calculated for C14 H12 N4 O3: 59.15% C., 4.25% H, 19.71% N. Found: 59.31% C., 4.20% H, 19.71% N.
With triethylamine; In tetrahydrofuran; at 20℃; for 18h;
4.3 N-(1-Methyl-1H-indol-5-yl)-1-(4-isopropylphenyl)-1H-indole-2-carboxamide (Compound No. 30) A solution of 119 mg (0.4 mmol) of 1-(4-isopropylphenyl)-1H-indole-2-carbonyl chloride, obtained in Stage 4.2, 70 mg (0.48 mmol) of 1-methyl-1H-5-aminoindole and 110 ml (0.8 mmol) of triethylamine in 2 ml of tetrahydrofuran is stirred at ambient temperature for 18 hours. The reaction mixture is concentrated under reduced pressure and is taken up in 20 ml of water and 50 ml of dichloromethane. The organic phase is separated, washed with 50 ml of 1N hydrochloric acid, dried over magnesium sulfate and then concentrated under reduced pressure. The residue is purified by chromatography on a silica column, elution being carried out with a mixture of cyclohexane and of ethyl acetate. 0.133 g of product is obtained. Melting point: 178-179 C. 1H NMR (CDC13): delta (ppm): 1.39 (d, 6H), 3.05 (sept., 1H), 3.8 (s, 3H), 6.4 (d, 1H), 7.29 (m, 11H), 7.78 (m, 3H).
N-(1-Methyl-1H-indol-5-yl)-1-(3-trifluoromethylphenyl)-1H-indole-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With diethyl cyanophosphonate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;
A solution of 2 g (6.55 mmol) of 1-(3-trifluoromethylphenyl)-1H-indole-2-carboxylic acid (prepared by analogy with the method described in Stage 4.1 of Example 4), 1.14 g (7.86 mmol) of 1-methyl-1H-5-aminoindole (I. T. Forbes, J. Med. Chem., 1993, 36 (8), 1104), 1.2 ml (7.86 mmol) of diethyl cyanophosphonate and 2.03 ml (14.41 mmol) of triethylamine in 20 ml of dimethylformamide is stirred at ambient temperature for 18 hours. The reaction mixtures is concentrated under reduced pressure and then it is taken up in 50 ml of water. This solution is extracted with two times 50 ml of dichloromethane. The organic phases are combined, dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column, elution being carried out with a mixture of cyclohexane and of ethyl acetate. 1.97 g of product are isolated. Melting point: 225-226 C. 1H NMR (d6-DMSO): delta (ppm): 3.79 (s, 3H), 6.41 (d, 1H), 7.05 (d, 1H), 7.28 (m, 3H), 7.77 (m, 7H).
Dissolve phenyl chloroformate (1.56g, 10mmol) in 4ml of dichloromethane. A solution of A3 (1.46 g, 10 mmol) in dichloromethane (4 ml) was slowly added dropwise to the solution at 0C. While stirring, the reaction was continued at 0C for 10 minutes after the addition was complete, and a solution of triethylamine (1.64 ml, 12.5 mmol) in dichloromethane (2 ml) was slowly added dropwise. After 15 minutes of reaction, after completion of the reaction, 50 ml of water and 50 ml of methylene chloride are added and extracted two or three times. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed to give 2.55 g of A4. The yield of this step was 95.9%, but it was purified by column chromatography to give a white solid;
94%
To a solution of 5.62g (35.91mmols) of phenylchloroformate b in 25mL of dichloromethane at 0 0C was added, a solution of 5.Og (34.20 mmols) of indoleamine a in 25mL of dichloromethane drop wise (20 min) at 0 0C. The resultant mixture was then stirred for lOmin at 0 0C and a solution of 6mL (42.75 mmols) of triethylamine in 1 OmL of dichloromethane was added drop wise (15min) at 0 0C and stirred for 5min. To the mixture was then added 5OmL of water and organic layer separated. The aqueous layer was then extracted with 2OmL of dichloromethane and organic layers combined and dried over Na2Stheta4. The solution was then passed through a pad of silica gel, eluted with additional 5OmL of 3: 1 hexane:ethylacetate and concentrated. The crude product was then crystallized with 4: 1 hexanexthyl acetate to obtain 7.8g (85.7%, 99.5% pure, I crop) and 0.78g (8.5%, 98% pure, II crop) with a combined yield of 94% product.
94%
With triethylamine; In dichloromethane; at 0℃; for 0.833333h;
Example 4Synthesis of the Compound of Formula (XXIVA)Step 1: Synthesis of phenyl 1-methyl-1H-indol-5-ylcarbamate 5A; Step 1: Synthesis of phenyl 1-methyl-1H-indol-5-ylcarbamate 5A To a solution of 5.62 g (35.91 mmols) of phenylchloroformate 4A in 25 mL of dichloromethane at 0 C. was added, a solution of 5.0 g (34.20 mmols) of indoleamine 3A in 25 mL of dichloromethane drop wise (20 min) at 0 C. The resultant mixture was then stirred for 10 min at 0 C. and a solution of 6 mL (42.75 mmols) of triethylamine in mL of dichloromethane was added drop wise (15 min) at 0 C. and stirred for 5 min. To the mixture was then added 50 mL of water and organic layer separated. The aqueous layer was then extracted with 20 mL of dichloromethane and organic layers combined and dried over Na2SO4. The solution was then passed through a pad of silica gel, eluted with additional 50 mL of 3:1 hexane:ethylacetate and concentrated. The crude product was then crystallized with 4:1 hexane:ethylacetate to obtain 7.8 g (85.7%, 99.5% pure, I crop) and 0.78 g (8.5%, 98% pure, II crop) with a combined yield of 94% product.
94%
With triethylamine; In dichloromethane; at 0℃; for 0.25h;
To a solution of 5.62g (35.91 mmols) of phenylchloroformate b in 25mL of dichloromethane at 0 0C was added, a solution of 5.Og (34.20 mmols) of indoleamine a in 25mL of dichloromethane drop wise (20 min) at 0 0C. The resultant mixture was then stirred for lOmin at 0 0C and a solution of 6mL (42.75 mmols) of triethylamine in 1 OmL of dichloromethane was added drop wise (15min) at 0 0C and stirred for 5min. To the mixture was then added 5OmL of water and organic layer separated. The aqueous layer was then extracted with 2OmL of dichloromethane and organic layers combined and dried over Na2SC^. The solution was then passed through a pad of silica gel, eluted with additional 5OmL of 3: 1 hexane:ethylacetate and concentrated. The crude product was then crystallized with 4:1 hexane:ethyl acetate to obtain 7.8g-(85.7%, 99.5% pure, I crop) and 0.78g (8.5%, 98% pure, II crop) with a combined yield of 94% product.
94%
With triethylamine; In dichloromethane; at 0℃; for 0.833333h;
Synthesis of N-(I -methyl- lH-indol-5-yOhydrazinecarboxamide (aminourea 3)Step 1: Synthesis of phenyl l-methyl-lH-indol-5-ylcarbamate 7:To a solution of 5.62g (35.91mmols) of phenylchloroformate 6 in 25mL of dichloromethane at 0 C was added, a solution of 5.Og (34.20 mmols) of indoleamine 5 in 25mL of dichloromethane drop wise (20 min) at 0 C. The resultant mixture was then stirred for lOmin at 0 C and a solution of 6mL (42.75 mmols) of triethylamine in 1OmL of dichloromethane was added drop wise (15min) at 0 C and stirred for 5min. To the mixture was then added 5OmL of water and organic layer separated. The aqueous layer was then extracted with 2OmL of dichloromethane and organic layers combined and dried over Na2SO4. The solution was then passed through a pad of silica gel, eluted with additional 5OmL of 3:1 hexaneiethylacetate and concentrated. The crude product was then crystallized with 4:1 hexane:ethylacetate to obtain 7.8g (85.7%, 99.5% pure, I crop) and 0.78g (8.5%, 98% pure, II crop) with a combined yield of 94% product.
94%
To a solution of 5.62g (35.91 mmols) of phenylchloroformate b in 25mL of dichloromethane at 0 0C was added, a solution of 5.Og (34.20 mmols) of indoleamine a in 25mL of dichloromethane drop wise (20 min) at 0 C. The resultant mixture was then stirred for lOmin at 0 0C and a solution of 6mL (42.75 mmols) of triethylamine in 1OmL of dichloromethane was added drop wise (15min) at0 0C and stirred for 5min. To the mixture was then added 5OmL of water and organic layer separated. The aqueous layer was then extracted with 2OmL of dichloromethane and organic layers combined and dried over Na2SO4. The solution was then passed through a pad of silica gel, eluted with additional 5OmL of 3:1 hexane:ethylacetate and concentrated. The crude product was then crystallized with 4: 1 hexane:ethyl acetate to obtain 7.8g (85.7%, 99.5% pure, I crop) and 0.78g(8.5%, 98% pure, II crop) with a combined yield of 94% product.
1.4 N-(1-methyl-1H-indol-5-yl)-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (compound 1); A solution of 0.29 g (2.01 mmol) of 5-amino-1-methylindole in 10 ml of dry toluene is added, without heating, under argon and with magnetic stirring, to a solution of 1.68 ml (3.35 mmol) of trimethylaluminum in 5 ml of dry toluene. The reaction medium is maintained at 50 C. for 15 minutes. 0.5 g (1.68 mmol) of ester obtained in step 1.3 dissolved in 15 ml of toluene is then added slowly and the mixture is refluxed for 20 hours. Ice, dilute hydrochloric acid and then ethyl acetate are added to the cooled solution. The insoluble material is collected and taken up in dichloromethane and sodium hydroxide solution. The organic phase is washed with water, dried and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica eluting with a mixture of dichloromethane and ethyl acetate. The solid obtained is triturated with petroleum ether, collected by filtration and dried under reduced pressure. 0.385 g of expected product is isolated.Melting point: 213-214.5 C.1H NMR (DMSO D6), delta (ppm): 10.45 (s, 1H); 8.95 (s, 1H); 8.2 (d, 1H); 7.95 (s, 1H); 7.7 (d, 1H); 7.3 (m, 5H); 7.0 (m, 3H); 6.4 (d, 1H); 5.95 (s, 2H); 3.75 (s, 3H).
5.4 N-(1-methyl-1H-indol-5-yl)-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; A solution of 0.31 g (1.75 mmol) of 5-amino-1-methylindole in 10 ml of dry toluene is added, without heating, under argon and with magnetic stirring, to a solution of 1.75 ml (3.50 mmol) of trimethylaluminum in 5 ml of dry toluene. The reaction medium is maintained at 50 C. for 2 hours. 0.52 g (1.75 mmol) of ester obtained in step 5.3 dissolved in toluene is then added and the solution is refluxed for 5 hours. Ethyl acetate, ice-water and then 1 N hydrochloric acid are added to the cooled solution. After separation of the phases by settling, the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and with saturated sodium chloride solution, dried and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and ethyl acetate. The solid is taken up in a solution of sodium hydroxide and ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated under reduced pressure. The solid obtained is triturated from petroleum ether, collected by filtration and dried under reduced pressure. 0.56 g of the expected product is isolated.Melting point: 191-191.5 C.1H NMR (DMSO D6), delta (ppm): 10.3 (s, 1H); 8.45 (dd, 1H); 8.2 (dd, 1H); 7.95 (s, 1H); 7.35 (m, 3H); 7.25 (m, 3H); 6.95 (m, 3H); 6.4 (d, 1H); 5.95 (s, 2H); 3.75 (s, 3H).
2,4-Dibenzyloxy-5-isopropylbenzoic acid (5.64 g, 15.0 mmol, 1.00 equiv.) in 80 mL dichloromethane at room temperature was treated with oxalyl chloride (2.00 g, 15.75 mmol, 1.05 equiv.) and catalytic amount of DMF (0.1 mL) for 1 hour. Solvent and excess (COCl)2 were removed on rotary evaporator. The residue was dissolved in 100 mL dichloromethane, and treated with l,3-dimethyl-5-aminoindole (2.40 g, 15.0 mmol, 1.00 equiv.) and triethylamine (2.28 g, 22.5 mmol, 1.50 equiv.) at 0 0C for one hour. Normal aqueous workup and removal of solvent gave a light brown solid that was washed with ether to yield 2,4-dibenzyloxy-5-isopropyl-N-(l-methyl-lH-indol-5-yl)-benzamide (A) as off- white solid (7.20 g, 14.3 mmol, 95%)
93%
Example 1 Preparation of 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole 2,4-dibenzyloxy-5-isopropylbenzoic acid (43.0 mmol, 1.00 equiv.) in 300 mL dichloromethane at room temperature was treated with oxalyl chloride (47.3 mmol, 1.10 equiv.) and catalytic amount of DMF (0.5 mL) for 1 hour. Solvent and excess oxalyl chloride were removed on rotary evaporator. The residue was dissolved in 300 mL dichloromethane, and treated with 1,3-dimethyl-5-aminoindole (43.0 mmol, 1.00 equiv.) and triethylamine (64.5 mmol, 1.50 equiv.) at 0 C. for 1 hour. Normal aqueous workup and removal of solvent gave a light brown solid which was washed with ether to yield off-white solid (39.95 mmol, 93%). Example 5; Preparation of 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole; 2,4-dibenzyloxy-5-isopropylbenzoic acid (43.0 mmol, 1.00 equiv.) in 300 mL dichloromethane at room temperature was treated with oxalyl chloride (47.3 mmol, 1.10 equiv.) and catalytic amount of DMF (0.5 mL) for 1 hour. Solvent and excess oxalyl chloride were removed on rotary evaporator. The residue was dissolved in 300 mL dichloromethane, and treated with 1,3-dimethyl-5-aminoindole (43.0 mmol, 1.00 equiv.) and triethylamine (64.5 mmol, 1.50 equiv.) at 0 C. for 1 hour. Normal aqueous workup and removal of solvent gave a light brown solid which was washed with ether to yield off-white solid (39.95 mmol, 93%).
With trimethylaluminum; In toluene; at 20℃;Heating / reflux;
1.2 N-(1-Methyl-1H-indol-5-yl)-5-fluoro-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxamide hydrochloride (1:1) (Compound 3) 1.26 ml of trimethylaluminum (2M in toluene) are added under argon to a solution of 0.18 g (1.21 mmol) of <strong>[102308-97-4]5-amino-1-methyl-1H-indole</strong> (I. T. Forbes, J. Med. Chem. 1993, 36 (8), 1104) in 10 ml of dry toluene. After 15 minutes, 0.3 g (1.01 mmol) of ethyl 5-fluoro-1-[(pyrid-4-yl)methyl]-1H-indole-2-carboxylate, obtained in step 1.1, is added. The reaction medium is refluxed for 4 hours and then stirred at room temperature overnight. It is poured onto ice and extracted with twice 30 ml of dichloromethane. The organic phases are combined, washed with 50 ml of water and then dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane/acetone). 0.35 g of a solid is obtained, which is dried under reduced pressure. Melting point (base): 204-205 C. The resulting solid is taken up in 30 ml of dichloromethane and 0.26 ml of a 4N solution of hydrogen chloride in dioxane is added. The solution is concentrated under reduced pressure and the resulting solid is recrystallized from a mixture of isopropanol and methanol. 0.33 g of the expected product is thus obtained in the form of a hydrochloride. Melting point (1HCl): 258-260 C. 1H NMR (DMSO D6), delta (ppm): 3.76 (s, 3H); 6.1 (s, 2H); 6.33 (d, 1H); 7.11 (dxd, 1H); 7.25 (d, 2H); 7.37 (m, 2H); 7.52 (m, 5H); 7.9 (s, 1H); 8.7 (d, 2H).
With trimethylaluminum; In toluene; at 0 - 20℃;Heating / reflux;
5.2 N-(1-Methyl-1H-indol-5-yl)-5-fluoro-1-[(pyrid-3-yl)ethyl]-1H-indole-2-carboxamide (Compound II) 0.54 ml of trimethylaluminum (2M in toluene) is added, at 0 C. under argon, to a solution of 0.7 g (0.478 mmol) of <strong>[102308-97-4]5-amino-1-methyl-1H-indole</strong> (I. T. Forbes, J. Med. Chem. 1993, 36 (8), 1104) in 5 ml of dry toluene. After 15 minutes, 0.125 g (0.4 mmol) of ethyl 5-fluoro-1-[(pyrid-3-yl)ethyl]-1H-indole-2-carboxylate, obtained in step 5.1, is added. The reaction medium is refluxed for 5 hours and then stirred at room temperature overnight. It is poured onto 50 g of ice, 10 ml of 1N hydrochloric acid and 30 ml of ethyl acetate. The organic phase is separated out and 15 ml of 1N sodium hydroxide are added to the aqueous phase, which is re-extracted with a further 30 ml of ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained is taken up in 15 ml of isopropyl ether and the insoluble material is filtered off and then dried under reduced pressure. 50 mg of the expected product are thus isolated in the form of a solid. Melting point (base): 188-189 C. 1H NMR (CDCl3), delta (ppm): 3.19 (t, 2H); 3.85 (s, 3H); 4.85 (t, 2H); 6.49 (d, 1H); 6.92 (s, 1H); 7.1 (m, 3H); 7.29 (m, 4H); 7.49 (dxt, 1H); 7.75 (m, 1H); 7.9 (s, 1H); 8.21 (d, 1H); 8.4 (d, 1H).
A flask was charged with <strong>[102308-97-4]5-amino-1-methyl-1H-indole</strong> (8.8 g; 60 mmol), thiocarbonyl diimidazole (10.7 g; 60 mmol) and ethyl acetate (200 mL). The reaction was heated at 50 C. for five minutes, and after cooling, the solvent was evaporated. The crude material was dissolved in dichloromethane (100 mL) and filtered through a short plug of silica gel, which was washed with another bolus of dichloromethane (100 mL). The organic eluent was evaporated to give 5-isothiocyanato-1-methyl-1H-indole (8.9 g; 47 mmol).
With N-ethyl-N,N-diisopropylamine; In ethanol; at 20 - 100℃;
Step C: Synthesis of 2-(l -methyl- lH-indol-5-yl)-4-nitroisoindolin-l -one; [0128] A mixture of 1 -methyl- lH-indol-5 -amine (0.38 g, 2.60 mmol), N,N- diisopropylethyl amine (0.45 mL, 2.60 mmol) in ethanol (50 mL) was stirred for 10 min in a sealed tube at room temperature. Ethyl 2-(bromomethyl)-3-nitrobenzoate (0.500 g, 1.73 mmol) was added portionwise over 3 h and the mixture was then heated to 100 0C overnight. The mixture was then cooled to room temperature, LiOH»H2O was added as a solution in water (2 mL), and the mixture stirred a further night at room temperature. The solids were collected by filtration to afford 2-(l -methyl- lH-indol-5-yl)-4-nitroisoindolin-l -one (0.481 g, 90%) as a yellow solid: mp 267-271 0C; 1H NMR (500 MHz, CDCl3) delta 8.45 (d, J= 8.5 Hz, IH), 8.29 (d, J= 7.5 Hz, IH), 7.97 (d, J= 2.0 Hz, IH), 7.75 (t, J= 7.5, 8.0 Hz, IH), 7.72 (dd, J= 2.5, 9.0 Hz, IH), 7.40 (d, J= 8.5 Hz, IH), 7.11 (d, J= 3.0 Hz, IH), 6.54 (d, J= 3.0 Hz, IH), 5.39 (s, 2H), 3.83 (s, 3H); APCI MS m/z 308 [M + H]+.
With N-ethyl-N,N-diisopropylamine; In ethanol; at 20 - 100℃;
Step H: Synthesis of 6-methoxy-2-(l -methyl- lH-indol-5-yl)isoindolin-l -one; [0101] A mixture of 1 -methyl- lH-indol-5 -amine (0.161 g, 1.10 mmol), NJV- diisopropylethyl amine (0.191 mL, 1.10 mmol) in ethanol (30 mL) was stirred for 10 min in a sealed tube at room temperature. After this time, ethyl 2-(bromomethyl)-5-methoxybenzoate (0.200 g, 0.73 mmol) was added portionwise over 3 h and the mixture was then heated to 100 0C overnight. The mixture was then cooled to room temperature, LiOH^H2O was added as a solution in water (2 mL), and the mixture stirred an additional night at room temperature. The mixture was then concentrated under reduced pressure and purification by flash chromatography (silica, 1 :5 ethyl acetate/hexanes) afforded 6-methoxy-2-( 1 -methyl- 1 H- indol-5-yl)isoindolin-l-one (0.068 g, 32%) as a brown/red solid: mp 193-197 0C; 1U NMR (500 MHz, CDCl3) delta 7.89 (d, J= 2.0 Hz, IH), 7.71 (dd, J= 2.0, 2.5, 8.5, 9.0 Hz, IH), 7.43 (d, J= 2.5 Hz, IH), 7.40 (d, J= 8.0 Hz, IH), 7.36 (d, J= 8.5 Hz, IH), 7.14 (dd, J= 2.5, 8.0 Hz, IH), 7.08 (d, J= 3.0 Hz, IH), 6.50 (d, J= 3.0 Hz, IH), 4.85 (s, 2H), 3.90 (s, 3H), 3.81 (s, 3H); APCI MS m/z 293 [M + H]+.
With N-ethyl-N,N-diisopropylamine; In ethanol; at 110℃;
Step C: Preparation of 6-(2-chloro-l,l,2-trifluoroethoxy)-2-(l-methyl-lH-indol-5- yl)isoindolin- 1 -one; [0113] A mixture of ethyl 2-(bromomethyl)-5-(2-chloro- 1 , 1 ,2-trifluoroethoxy)benzoate (0.250 g, 0.600 mmol), l-methyl-lH-indol-5-amine (0.098 g, 0.66 mmol) and N,N- diisopropylethylamine (0.117 mL, 0.66 mmol) in ethanol (10 mL) was heated in a sealed tube at 110 0C overnight. After this time, the mixture was cooled to room temperature and lithium hydroxide (0.076 g, 1.80 mmol) in water (2 mL) was added. The resulting mixture was stirred for 3 h and then concentrated under reduced pressure. Purification by flash chromatography (silica, gradient l-5%,methanol/methylene chloride) afforded 6-(2-chloro- l,l,2-trifluoroethoxy)-2-(l-methyl-l/-f-indol-5-yl)isoindolin-l-one (0.110 g, 42%) as an off- <n="44"/>white solid: mp 200-205 0C; 1H NMR (500 MHz, DMSO-J6) delta 7.95 (d, J= 1.8 Hz, IH), 7.79-7.77 (m, IH), 7.66 (dd, J= 2.0, 8.8 Hz, IH), 7.57-7.56 (m, 2H), 7.50 (d, J= 8.9 Hz, IH), 7.43-7.32 (m, 2H), 6.47-6.46 (m, IH), 5.08 (s, 2H), 3.81 (s, 3H); ESI MS m/z 395 [M H]+.
Step C: Preparation of 6-hydroxy-2-(l-methyl-lH-indol-5-yl)isoindolin-l-one; [0117] A mixture of ethyl 2-(bromomethyl)-5-(fert-butyldimethylsilyloxy)benzoate (1.75 g, 4.68 mmol), 1 -methyl- lH-indol-5 -amine (0.822 g, 5.60 mmol) and N,N- diisopropylethylamine (0.975 mL, 5.60 mmol) in ethanol (80 mL) was heated in a sealed tube at 80 0C overnight. The mixture was cooled to room temperature and lithium hydroxide (0.589 g, 14.0 mmol) in water (2 mL) was added. The resulting mixture was stirred for 3 h and then concentrated under reduced pressure. Purification by flash chromatography (silica, gradient l-5%,methanol/methylene chloride) afforded 6-hydroxy-2-(l -methyl- lH-indol-5- yl)isoindolin-l-one (0.360 g, 28% over 2 steps) as a brown solid: mp 230-235 0C; 1H NMR (300 MHz, DMSO-J6) delta 7.92 (d, J= 2.0 Hz, IH), 7.68-7.64 (m, IH), 7.49-7.35 (m, 3H), 7.09-7.03 (m, 2H), 6.44 (d, J= 3.0 Hz, IH), 4.90 (s, 2H), 3.80 (s, 3H); ESI MS m/z 279 [M + H]+.
The compound was prepared according to the procedure E from 2-(4-ethyl-6,6-dimethyl- 2-oxomorpholin-3-yl)acetic acid (0.276 mmol), diisopropylethylamine (0.240 mL; 1.378 mmol), HATU (0.127 g; 0.334 mmol) and 1-methyl-1 H-indol-5-amine (0.053 g; 0.363 mmol) in DMF (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20 - 80%) in heptane furnished 0.085 g (90%) of the title compound as a yellow foam.1H NMR (CDCI3) delta 1.10 (3H, t); 1.41 (3H, s); 1.46 (3H, s); 2.43 (1 H, d); 2.52 (1 H, m); 2.9- 3.1 (4H, m); 3.45 (1 H, m); 3.76 (3H, s); 6.42 (1 H, d); 7.03 (1 H, d); 7.23 (2H, s); 7.81 (1 H, s); 8.45 (1 H, brs).ESI/APCI(+): 344 (M+H); 366 (M+Na); 709 (2M+Na).ESI/APC -): 342 (M-H). To a solution of an acid (1.0 eq) in DMF (7.4 mUmmol) were added diisopropylethylamine (4.0-5.0 eq) and 0-(7-azabenzotriazol-1-yl)-/V,/V,/ ',A/- tetramethyluronium hexafluorophosphate (HATU, 1.0-1.2 eq). After 30 min at room temperature, the appropriate amine (1.0-1.3 eq) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The organic phase was washed with water and brine, dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column chromatography on silica gel followed by a recrystallization or purification by preparative HPLC or preparative TLC if needed.
To a solution of an acid (1.0 eq) in DMF (7.4 mL/mmol) were added diisopropylethylamine (4.0-5.0 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.0-1.2 eq). After 30 min at room temperature, the appropriate amine (1.0-1.3 eq) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The organic phase was washed with water and brine, dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column chromatography on silica gel followed by a recrystallization or purification by preparative HPLC or preparative TLC if needed.; The compound was prepared according to the procedure E from 2-(4-ethyl-6,6-dimethyl-2-oxomorpholin-3-yl)acetic acid (0.276 mmol), diisopropylethylamine (0.240 mL; 1.378 mmol), HATU (0.127 g; 0.334 mmol) and <strong>[102308-97-4]1-methyl-1H-indol-5-amine</strong> (0.053 g; 0.363 mmol) in DMF (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-80%) in heptane furnished 0.085 g (90%) of the title compound as a yellow foam.1H NMR (CDCl3) delta 1.10 (3H, t); 1.41 (3H, s); 1.46 (3H, s); 2.43 (1H, d); 2.52 (1H, m); 2.9-3.1 (4H, m); 3.45 (1H, m); 3.76 (3H, s); 6.42 (1H, d); 7.03 (1H, d); 7.23 (2H, s); 7.81 (1H, s); 8.45 (1H, brs).ESI/APCx+): 344 (M+H); 366 (M+Na); 709 (2M+Na).ESI/APCx-): 342 (M-H).
cyclopentyl-N-(1-methyl-1H-indol-5-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃;
General procedure: NaHCO3 (3.1 eq.) and chloroformate (1.1 eq.)were added to a solution of amine (1 eq.) in THF (3.1mL/mmol ofamine) and H2O (3.1mL/mmol of amine). The reaction was stirred at room temperature until disappearance of amine was observed by TLC.The reaction was washed 3 EtOAc. Combined organic layer wasdried with Mg2SO4 and rotovapped. White oil; 60-90%.
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere;
A round bottomed flask was charged with methyl (l-(2-chloropyrimidin-4- yl)-3-methyl-iH-pyrazol-4-yl)methanol (400 mg, 1.78 mmol), l-methyl-iH-indol-5- amine (338 mg, 1.3 equiv.), potassium carbonate (0.74 g, 3.0 equiv), palladium acetate (40 mg, 0.1 equiv), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphine) (Xantphos, 206 mg, 0.2 equiv.) and 40 mL of anhydrous dioxane. After being degassed by nitrogen bubbling, the reaction mixture was heated at 100 C for 12 hours. Volatiles were removed in vacuo and then the resulting residue was extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by recrystallization in acetonitrile to give 241mg (36 %) of the desired product as a brown solid. MS (ESI) m/z 335 [M+H]+