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CAS No. : | 1670-82-2 | MDL No. : | MFCD00210441 |
Formula : | C9H7NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GHTDODSYDCPOCW-UHFFFAOYSA-N |
M.W : | 161.16 | Pubchem ID : | 595230 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 45.26 |
TPSA : | 53.09 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.17 cm/s |
Log Po/w (iLOGP) : | 0.95 |
Log Po/w (XLOGP3) : | 1.57 |
Log Po/w (WLOGP) : | 1.87 |
Log Po/w (MLOGP) : | 1.08 |
Log Po/w (SILICOS-IT) : | 1.89 |
Consensus Log Po/w : | 1.47 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.32 |
Solubility : | 0.776 mg/ml ; 0.00482 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.3 |
Solubility : | 0.817 mg/ml ; 0.00507 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.65 |
Solubility : | 0.364 mg/ml ; 0.00226 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.09 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With lithium hydroxide monohydrate In tetrahydrofuran; methanol; water | (c) A solution of methyl indole-6-carboxylate (11.0 g) in a mixture of tetrahydrofuran (150 ml), methanol (150 ml), and water (63 ml) was treated with lithium hydroxide monohydrate (15.8 g). The mixture was stirred at 60° C. for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 50percent (v/v) hydrochloric acid. The precipitate which formed was collected by filtration and dried to give indole-6-carboxylic acid (9.6 g, 95percent) as a tan powder; mp 253°-254°: NMR (80 MHz; CDCl3) 6.51(m, 1H, H3 -indole), 8.04(m, 1H, H7 -indole), 11.43(broad s, 1H, NH), 12.42(broad s, 1H, OH). |
95% | With lithium hydroxide monohydrate In tetrahydrofuran; methanol; water | (c) A solution of methyl indole-6-carboxylate (11.0 g) in a mixture of tetrahydrofuran (150 ml), methanol (150 ml), and water (63 ml) was treated with lithium hydroxide monohydrate (15.8 g). The mixture was stirred at 60°C for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 50percent (v/v) hydrochloric acid. The precipitate which formed was collect by filtration and dried to give indole-6-carboxylic acid (9.6 g, 95percent) as a tan powder; mp 253-254°; NMR (80 MHz; CDCl3): 6.51(m, 1H, H3-indole), 8.04(m, 1H, H7-indole), 11.43(broad s, 1H, NH), 12.42(broad s, 1H, OH). |
88% | Stage #1: With lithium hydroxide; water In tetrahydrofuran at 80℃; for 16 h; Stage #2: With hydrogenchloride In water |
Step 1: Lithium hydroxide (0.72 g, 17.2 mmol, 3 equiv.) in water (10 mL) was added to methyl indole-6-carboxylate (1 g, 5.7 mmol, 1 equiv.) in tetrahydrofuran (10 mL) and the mixture stirred at 80° C. for 16 hours. The solution was concentrated under vacuum then diluted with dichloromethane (10 mL) and the organic layer extracted with water (3.x.10 mL). The aqueous phase was acidified to pH<1 with concentrated HCl forming a precipitate. The precipitate was filtered and washed with 1 M aqueous HCl (3.x.10 mL) to afford 1H-indole-6-carboxylic acid as a white solid, 0.807 g (88percent yield). LC (at)215 nm; Rt 1.02: 100percent, m/z (ES+): 162 (M+H+.); δH (400 MHz; MeOD) 8.15 (1H, d), 7.72 (1H, m), 7.67 (1H, m), 7.45 (1H, m), 6.53 (1H, m). |
85% | Stage #1: With water; lithium hydroxide In methanol for 1 h; Reflux Stage #2: With hydrogenchloride In water |
To a solution of methyl indole-6-carboxylate (3.0 g) in MeOH (34 mL), a 3M aqueous solution of LiOH (17 mL, 3.0 equiv.) was added. The reaction mixture was heated at reflux for 1 Hr, then cooled at 0°C, diluted with water (50 mL) and acidified with HCl 12M (5 mL). The mixture was extracted with AcOEt (3*30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4 and concentrated to give the product as a yellow solid (2.3 g, 85percent). M/Z (M+H)+ = 162. |
57% | Stage #1: With lithium hydroxide monohydrate; water In tetrahydrofuran; methanol at 60℃; Stage #2: With hydrogenchloride In water |
Step 4. 1H-Indole-6-carboxylic acid A solution of methyl 1H-indole-6-carboxylate (1.3 g, 7.43 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) was placed into a 250-mL round-bottom flask. Then CH3OH (20 mL), H2O (10 mL), LiOH.H2O (1.9 g, 45.24 mmol, 6.09 equiv) were added. The resulting solution was stirred overnight at 60° C. The resulting mixture was concentrated in vacuo, and diluted with water. The resulting solution was extracted with 2*100 mL of ether and the aqueous layers were combined. The pH value of the solution was adjusted to pH 3 with hydrochloric acid, and the solids were collected by filtration. This resulted in 0.68 g (57percent) of 1H-indole-6-carboxylic acid as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | 199.d EXAMPLE 199 (d) Indole-6-carboxylic acid was reacted with 1-cyclopentylmethylamine using a similar procedure to that described for indole GG in Example 193 to give 6-N-(cyclopentylmethyl)carbamoylindole (II) in 42% yield as a pale pink powder; NMR: 3.19 (d,2H,CH2 NH), 6.46 (d,1H, H3 -indole), 7.91 (d,1H,H7 -indole), 8.29 (t,1H,CH2 NH). | |
With 1,1'-carbonyldiimidazole 1.) CH2Cl2, reflux, 30 min, 2.) CH2Cl2, reflux, 30 min; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; | (c) A solution of methyl indole-6-carboxylate (11.0 g) in a mixture of tetrahydrofuran (150 ml), methanol (150 ml), and water (63 ml) was treated with lithium hydroxide monohydrate (15.8 g). The mixture was stirred at 60 C. for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 50% (v/v) hydrochloric acid. The precipitate which formed was collected by filtration and dried to give indole-6-carboxylic acid (9.6 g, 95%) as a tan powder; mp 253-254: NMR (80 MHz; CDCl3) 6.51(m, 1H, H3 -indole), 8.04(m, 1H, H7 -indole), 11.43(broad s, 1H, NH), 12.42(broad s, 1H, OH). |
95% | With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; | (c) A solution of methyl indole-6-carboxylate (11.0 g) in a mixture of tetrahydrofuran (150 ml), methanol (150 ml), and water (63 ml) was treated with lithium hydroxide monohydrate (15.8 g). The mixture was stirred at 60C for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 50% (v/v) hydrochloric acid. The precipitate which formed was collect by filtration and dried to give indole-6-carboxylic acid (9.6 g, 95%) as a tan powder; mp 253-254; NMR (80 MHz; CDCl3): 6.51(m, 1H, H3-indole), 8.04(m, 1H, H7-indole), 11.43(broad s, 1H, NH), 12.42(broad s, 1H, OH). |
88% | Step 1: Lithium hydroxide (0.72 g, 17.2 mmol, 3 equiv.) in water (10 mL) was added to methyl indole-6-carboxylate (1 g, 5.7 mmol, 1 equiv.) in tetrahydrofuran (10 mL) and the mixture stirred at 80 C. for 16 hours. The solution was concentrated under vacuum then diluted with dichloromethane (10 mL) and the organic layer extracted with water (3×10 mL). The aqueous phase was acidified to pH<1 with concentrated HCl forming a precipitate. The precipitate was filtered and washed with 1 M aqueous HCl (3×10 mL) to afford 1H-indole-6-carboxylic acid as a white solid, 0.807 g (88% yield). LC (at)215 nm; Rt 1.02: 100%, m/z (ES+): 162 (M+H+.); deltaH (400 MHz; MeOD) 8.15 (1H, d), 7.72 (1H, m), 7.67 (1H, m), 7.45 (1H, m), 6.53 (1H, m). |
85% | To a solution of methyl indole-6-carboxylate (3.0 g) in MeOH (34 mL), a 3M aqueous solution of LiOH (17 mL, 3.0 equiv.) was added. The reaction mixture was heated at reflux for 1 Hr, then cooled at 0C, diluted with water (50 mL) and acidified with HCl 12M (5 mL). The mixture was extracted with AcOEt (3*30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4 and concentrated to give the product as a yellow solid (2.3 g, 85%). M/Z (M+H)+ = 162. | |
57% | Step 4. 1H-Indole-6-carboxylic acid A solution of methyl 1H-indole-6-carboxylate (1.3 g, 7.43 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) was placed into a 250-mL round-bottom flask. Then CH3OH (20 mL), H2O (10 mL), LiOH.H2O (1.9 g, 45.24 mmol, 6.09 equiv) were added. The resulting solution was stirred overnight at 60 C. The resulting mixture was concentrated in vacuo, and diluted with water. The resulting solution was extracted with 2*100 mL of ether and the aqueous layers were combined. The pH value of the solution was adjusted to pH 3 with hydrochloric acid, and the solids were collected by filtration. This resulted in 0.68 g (57%) of 1H-indole-6-carboxylic acid as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In benzene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | A stirred solution of <strong>[1670-82-2]indole-6-carboxylic acid</strong> (5.4 g, 33 mmole) in DMF (100 ml) under argon was treated portionwise with sodium hydride (60% oil dispersion, 4.0 g, 100 mmole). After 30 minutes, benzyl bromide (16.5 ml, 140 mmole) was added and the solution stirred for 16 h at room temperature. After removal of the DMF in vacuo the residue was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organics washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with DCM/hexanes (40:60) to afford a white crystalline solid (13.2 g, 90%). MS: m/z (MH+) = 342. 1H-NMR (250 MHz, CDCl3): delta (ppm): 8.12 (s, 1H), 7.84 (dd, 1H), 7.66 (d, 1H), 7.40 (m, 10H), 7.12 (dd, 1H), 6.58 (d, 1H), 5.36 (s, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; at 5 - 10℃; for 4h;Reflux; | Example 33 6-Ethoxycarbonyl-1H-indole Combine 6-carboxy-1H-indole and ethanol (110 ml) and cool to 5C. Add dropwise concentrated H2SO4 (96%, 11.08 ml) while keeping the temperature below 10C. Heat to reflux. After 4 hours, cool and pour onto ice/water, adjust the pH to about pH 9 and extract with ethyl acetate. Combine the organic extracts, wash with brine, dry (Na2SO4) then concentrate to residue. Chromatograph the residue on silica gel eluting with chloroform to give, after evaporation, the title compound: mp 72-75 C. MS (ACPI): m/e 189.9 (M+1). | |
With thionyl chloride; for 3h;Reflux; | A solution of <strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong> (0.5 g, 0.3 mmol) in EtOH (15 mL), then SOCl2 (0.22 mL, 3 mmol)was added dropwise into the solution at 0 C and refluxed for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (50 mL) and then washed with saturated NaHCO3 solution, finally washed with water and dried over anhydrous Na2SO4. The solvent was removed under vacuum to get carboxylic acid ester. The ester obtained was taken as such in the next step of synthesis. LC-MS m/z: 162.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Step 3. 3-Cyclohex-l-eny1-<strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong> (163)[0309] In a 3 L round-bottomed flask a solution made of <strong>[1670-82-2]indole 6-carboxylic acid</strong>(50.5g), cyclohexanone (96.4niL, 3 eq.) sodium methoxide (25 wt%, 433 mL 6.0 eq) and MeOH (1 L) was refluxed under argon atmosphere for 17hrs. Some precipitation was noted after 3-4 hrs and became pronounced at the end of the reaction. The solution was worked up by adding 300 mL H2O, removing the majority of MeOH via vacuum distillation, adding cone. HCl (160 mL) to pH 1, filtering, washing the precipitate with water and drying to get compound 163 in quantitative yield (75.5g). It was pure enough to be used without further purification in Step 4. | |
100% | A 12 L round-bottomed flask was equipped with a reflux condenser and a mechanical stirrer, and the system was purged with nitrogen gas. 6-indole carboxylic acid (300.00 g, 1.86 mole, 3 equivalents) was charged into the flask, followed by MEOH (5.5 L). After stirring for 10 min at room temperature, cyclohexanone (579 mL, 5.58 mole) was added. Methanolic sodium methoxide (25% w/w, 2.6 L, 11.37 mole, 6.1 equivalents) was added in portions over 10 min. The mixture was then refluxed FOR 48 h. After cooling to room temperature, water (4 L) was added and methanol removed under reduced pressure. The residual aqueous phase was acidified to pH 1 with concentrated HCI (-1. 2 L). The resulting yellowish precipitate was collected by filtration, washed with water and dried under vacuum at 50 C. The desired cyclohexene derivative was obtained as a beige solid (451. 0G, 100% yield). | |
97.5% | With sodium methylate; In methanol; at 22℃; for 18h;Heating / reflux; | 3-cyclohexenyl-<strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong>. Cyclohexanone (96 mL, 0.926 mol) was added to a stirred mixture of <strong>[1670-82-2]indole-6-carboxylic acid</strong> (50.0 g, 0.335 mol) in methanol (920 mL) at 22 C. Methanolic sodium methoxide (416 mL of 25% w/w, 1.82 mol) was added in portions over 10 minutes. The mixture was stirred at reflux for 18 hours, cooled to room temperature, concentrated, diluted with cold water, and acidified with 36% HCl. The resulting precipitate was collected by filtration, washed with cold water, and dried over phosphorous pentoxide (0.1 mm) to provide the desired product (80.9 g, 97.5% yield). |
97.5% | 3-Cyclohexenyl-<strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong>.; Cyclohexanone (96 mL, 0.926 mol) was added to a stirred solution of methyl <strong>[1670-82-2]indole-6-carboxylic acid</strong> (50.0 g, 0.335 mol) in methanol (920 mL) at 22 C. Methanolic sodium methoxide (416 mL of 25% w/w, 1.82 mol) was added in portions over 10 minutes. The mixture was stirred at reflux for 18 hours, cooled to room temperature, concentrated, diluted with cold water, and acidified with 36% HCl solution. The resulting precipitate was collected by filtration, washed with cold water, and dried over phosphorous pentoxide (0.1 mm) to provide the the title compound as a tan colored solid (80.9 g, 97.5% yield). | |
97.5% | Intermediate 16 3-Cyclohexenyl-<strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong>. Cyclohexanone (96 mL, 0.926 mol) was added to a stirred solution of methyl <strong>[1670-82-2]indole-6-carboxylic acid</strong> (50.0 g, 0.335 mol) in methanol (920 mL) at 22 C. Methanolic sodium methoxide (416 mL of 25% w/w, 1.82 mol) was added in portions over 10 minutes. The mixture was stirred at reflux for 18 hours, cooled to room temperature, concentrated, diluted with cold water, and acidified with 36% HCl solution. The resulting precipitate was collected by filtration, washed with cold water, and dried over phosphorous pentoxide (0.1 mm) to provide the title compound as a tan colored solid (80.9 g, 97.5% yield). | |
97.5% | Cyclohexanone (96 mL, 0.926 mol) was added to a stirred solution of methyl <strong>[1670-82-2]indole-6-carboxylic acid</strong> (50.0 g, 0.335 mol) in methanol (920 mL) at 22 C. Methanolic sodium methoxide (416 mL of 25% w/w, 1.82 mol) was added in portions over 10 minutes. The mixture was stirred at reflux for 18 hours, cooled to room temperature, concentrated, diluted with cold water, and acidified with 36% HCl solution. The resulting precipitate was collected by filtration, washed with cold water, and dried over phosphorous pentoxide (0.1 mm) to provide the the title compound as a tan colored solid (80.9 g, 97.5% yield). | |
80.1% | With sodium methylate; In methanol; for 120h;Heating / reflux; | Example 1 : Synthesis of 17-cyclohexyl- 18-(furan-3-yl)- 1 ,4, 11 -triaza-tricyclo- ri l.5.2.016'19licosa-7J3(20).14J6(19)J7-pentaene-3J2-dione (l).Step A.Cyclohexanone (18.2 g, 186 mmol) was added to a solution of <strong>[1670-82-2]indole-6-carboxylic acid</strong> 1-1 (10.0 g, 62.0 mmol) in methanol (100 mL). Then, a solution of sodium methoxide (20.4 g, 378.5 mmol) in methanol (50 mL) was added dropwise. The resulting solution was heated to reflux. After 5 days, the reaction mixture was evaporated and ice-cold water (250 mL) was added. The precipitate was filtered off, washed with water and dried under vacuum to give 12.0 g (80.1%) of the target compound 1-2: m/z = 242 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium hydroxide; In methanol; water; at 0 - 75℃; for 22h; | A 3 L three-necked flask equipped with a mechanical stirrer was charged with <strong>[1670-82-2]indole 6-carboxylic acid</strong> (220 g, 1.365 mole) and KOH pellets (764.45 g, 13.65 mole, 10 equivalents). Water (660 mL) and MEOH (660 mL) were added and the mixture heated to 75 C. Cyclopentanone (603.7 mL, 6.825 mole, 5 equivalents) was added dropwise over 18 h using a pump. The reaction mixture was heated for an additional 3 h (after which the reaction was judged complete by HPLC) and cooled to 0 C for 1 h. The precipitated potassium salt is collected by filtration, and washed with TBME (2 X 500 mL) to remove cyclopentanone self-condensation products. The brown solid was re-dissolved in water (2.5 L) and the solution washed with TBME (2 X 1 L). Following acidification to pH 3 with conc. HCI (425 mL), the beige precipitate was collected by filtration, washed with water (2 X 1 L) and dried under vacuum at 70 C. The crude product weighed 275.9 g (88.9 % mass recovery) and had an homogeneity of 85% (HPLC). |
With sodium hydroxide; In water; glycerol; at 100℃; | Example 12; Preparation of a Bromoindole; In one embodiment, the present invention is directed to the following general multi-step synthetic method for preparing the intermediate compounds of general formula I, as set forth in Scheme I below, as well as the individual steps and intermediates set forth therein: Condensation of the indole carboxylic acid with cyclopentanone in the presence of aqueous sodium hydroxide gave the 3-cyclopenteneyl indole carboxylic acid, which was subjected to hydrogenation in the presence of catalytic amount of palladium on carbon to afford the corresponding cyclopentyl carboxylic acid in 80% overall yield. Double methylation of the carboxylic acid and the nitrogen with methyl carbonate in NMP at 130 C. provided the N-methyl indole carboxylate methyl ester in 90% yield. Bromination of the indole carboxylate with bromine in acetonitrile furnished the 2-bromo-3-cyclopentyl indole carboxylate in 90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Example 20 N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-indole-6-carboxamide (31) To a solution of <strong>[1670-82-2]indole-6-carboxylic acid</strong> (85 mg, 0.528 mmol), 4-aminomethyl 1-(4-iodophenyl)imidazole 1-2 prepared in Example 1 (136 mg, 0.455 mmol) and TEA (0.150 mL, 1.08 mmol) in DMF (4 mL), BOP (280 mg, 0.633 mmol) was added. After the mixture was stirred at room temperature overnight, water and EtOAc were added. The organic layer was separated, washed with 5% aq. NaHCO3, dried over Na2SO4, concentrated in vacuo to give N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)-1H-indole-6-carboxamide as a crude sample, which was used in the next reaction without further purification. MS 443.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Step 1 (1H-Indol-6-yl)-(4-isopropyl-piperazin-1-yl)-methanone A mixture of 1 g (6 mmol) indole-6-carboxylic acid (commercially available), 0.96 g (0.7 mmol) 1-(2-propyl)-piperazine (commercially available), 2.39 g (7 mmol) TBTU and 4 g (31 mmol) DIPEA in 30 ml THF was stirred for 1 h at room temperature. After evaporation of all volatiles Na2CO3 (10percent aq.) and ethyl acetate was added. The mixture was extracted with ethyl acetate and the combined organic fractions were washed with NaCl (sat. aq.), dried with Na2SO4 and evaporated to dryness. The residue was purified by flash column chromatography on silica eluding with a mixture formed from DCM, MeOH and NH3 aq. to yield after evaporation of the combined product fractions 1.64 g (97percent) of the title compound as light yellow solid. MS (m/e): 272.5 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Step 1 3-[1-(4-Methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-<strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong> hydrochloride A mixture of 0.3 g (1.8 mmol) <strong>[1670-82-2]indole-6-carboxylic acid</strong>, 0.764 g (3.7 mmol) 1-(4-Methoxy-phenyl)-piperidin-4-one and 0.348 g (6.2 mmol) KOH pellets in 8 ml methanol was stirred at reflux for 24 h. The precipitate was filtered off, washed with methanol and diethyl ether and transferred into the respective hydrochloride salt ba treatment with 2N HCl in methanol. Filtration of the mixture, washing of the precipitate with diethyl ether and drying yielded 0.506 g (70%) of the title compound as red solid. MS (m/e): 349.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
acetic anhydride; In acetic acid; at 80℃; for 24h;Under N2; | Intermediate 17 Preparation of N-Acetyl-6-carboxytryptophan A mixture of <strong>[1670-82-2]indole-6-carboxylic acid</strong> (5.0 g, 31 mmol), DL-serine (3.25 g, 31 mmol), and acetic anhydride (8.8 ML, 93 mmol) in glacial acetic acid (50 ML) was heated under a nitrogen blanket at 80 C. for 24 hours.The resulting brown solution was cooled to room temperature, then the solvent was removed under reduced pressure to provide Intermediate 17 as a brown foam, which was used without further purification (11.0 g): 1H NMR (300 MHz, D2O): delta 8.08 (s, 1H), 7.72 (s, 2H), 7.40 (s, 1H), 4.61-4.53 (m, 1H), 3.45-3.35 (m, 1H), 3.23-3.13 (m, 1H), 1.92 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; | To a stirred solution of <strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong> (81 mg, 0.5 mmol) in anhydrous DMF (10 mL) are added DIEA (265 muL, 1.52 mmol) and exo-(4S)-[2.2.1]-Amine (228 mg, 0.5 mmol). The mixture is cooled to 0 C., and HATU (190 mg, 0.5 mmol) is added in one portion. The reaction mixture is allowed to warm to rt and stir overnight. The solvent is removed in vacuo, and the residue is partitioned between saturated aqueous potassium carbonate solution and CHCl3. The aqueous layer is extracted with CHCl3 (2×). The combined organic layers are washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel. Elution with CHCl3-MeOH-NH4OH (89:9:1) gives the free base as a yellow solid (84 mg, 66%). [0630] To a stirred solution of the free base (84 mg, 0.33 mmol) in MeOH (5 mL) is added a warm solution of fumaric acid (38 mg, 0.33 mmol) in MeOH (5 mL). The mixture is stirred for 10 min at 50 C. The solvent is removed in vacuo, and the remaining residue is diluted with acetone (5 mL). The mixture is stirred overnight at rt. The solid is collected by filtration, washed with acetone, and dried under high vacuum overnight gives 88 mg (72%) of Example 2 as a white solid. 1H NMR (400 MHz, CD3OD) delta11.38, 8.32-8.31, 7.94, 7.58-7.50, 6.54, 6.48, 3.86-3.82, 3.15-3.10, 2.97-2.89, 2.67-2.55, 1.78-1.69, 1.38-1.31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | sulfuric acid; for 16h;Heating / reflux; | Step 1; 1-2 Step 2 1-3 0 Step 3 NaH, Mel 5 t . fnn N CO, Me Stem 4 Step 4 F lla F 1-5 14 F F 0 Step 1 : <strong>[1670-82-2]Indole-6-carboxylic acid</strong> 1-1 (5. 0 g, 31.0 mmol) was dissolved in MeOH (100 mL), a catalytic amount of H2SO4 (1.0 mL) was added and the reaction mixture was stirred at reflux for 16 h. A small amount of solid K2CO3 was added, in order to neutralize the excess H2SO4, and stirring was continued at RT for 1 h. The reaction mixture was concentrated under vacuum to remove the MeOH, diluted with saturated aqueous NaHC03 (-50 mL) and extracted with EtOAc (-200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous MgS04 and concentrated to dryness. The resulting residue was purified by flash column chromatography, using 30% EtOAc in hexane as the eluent, to obtain the pure methyl ester 1-2 (4.78 g, 88% yield). |
88% | To a stirred solution of 1 H-<strong>[1670-82-2]indole-6-carboxylic acid</strong> (1.5 g, 9.31 mmol) in MeOH (200 mL) was added cone. H2SO4 (3 mL). The reaction was refluxed for 15 h and cooled to RT. The mixture was neutralized with sat. NaHCO3 and MeOH was removed under reduced pressure. The remaining mixture was extracted with EtOAc (50 mL x 3). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Chromatography (20% EtOAc/hexanes) provided 2A (1 Ag, 88%) as a white solid. EPO <DP n="39"/> | |
88% | Stepl 1; lndole-6-carboxylic acid 1-1 (5.0 g, 31.0 mmol) was dissolved in MeOH (100 ml), acatalytic amount of H2SO4 (1.0 ml) was added and the reaction mixture was stirred atreflux for 16 h. A small amount of solid K2CO3 was added, in order to neutralize theexcess HfeSO^ and stirring was continued at RT for 1h. The reaction mixture wasconcentrated under vacuum to remove the MeOH, diluted with saturated aqueousNaHCO3 (~50 ml_) and extracted with EtOAc (-200 ml). The organic layer waswashed with brine (100 mL), dried over anhydrous MgSO4 and concentrated to dryness. The resulting residue was purified by flash column chromatography, using30% EtOAc in hexane as the eluent, to obtain the pure methyl ester 1-2 (4.78 g, 88%yield). |
85% | With sulfuric acid; for 16h;Reflux; | 1 H-<strong>[1670-82-2]indole-6-carboxylic acid</strong> (500 mg)In methanol (10 mL) was added concentrated sulfuric acid (0.1 mL)The mixture was stirred under heating reflux for 16 hours.After the reaction solution was cooled to room temperature, potassium carbonate was added to neutralize it,And the mixture was stirred at room temperature for 1 hour. After distilling off the solvent of the reaction solution under reduced pressure,Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added,The mixture was extracted with ethyl acetate and washed with saturated brine.The organic layer was dried over sodium sulfate,The solvent was evaporated under reduced pressure to obtain a residue,Purification by silica gel column chromatography (hexane-ethyl acetate), Methyl1 H-indole-6-carboxylate462 mg (yield 85%) was obtained |
53% | With sulfuric acid;Heating / reflux; | To a solution of 1H-<strong>[1670-82-2]Indole-6-carboxylic acid</strong> (1.500 g, 9.31 mmol) in methanol (50 mL) was added concentrated H2SO4 (550 KL, 10.24 mmol). The mixture was stirred overnight at reflux temperature. The mixture was then neutralised to pH 7 by addition of saturated aqueous NAHC03 and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a yellow powder. The product was recrystallised from heptane/ethyl acetate to give the title compound as GREEN/YELLOW crystals (688 mg, yield = 53%) IH NMR (CDCl3) : 8 3.94 (s, 3H, CH30CO), 6.60 (m, 1H), 7. 37 (t, 1H, J = 4.7 Hz), 7.66 (d, IH, J = 8.2 Hz), 7.82 (dd, 1H, J1 = 8.2 Hz, J2 = 1.0 Hz), 8.18 (s, 1H), 8.73 (s, 1H, NH) |
sulfuric acid; for 10h;Steam bath heating; | A solution of <strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong> (10 g) in methanol (300 mL) was treated with concentrated sulfuric acid (0.5 mL) then heated on a steam bath for 10 hours. The solvent was removed under reduced pressure and the residue partitioned between saturated sodium bicarbonate solution (150 mL) and dichloromethane (150 mL). The aqueous layer was further extracted twice with dichloromethane (150 mL). The combined organics were dried over sodium sulfate then evaporated. The residue was subjected to flash chromatography on silica eluding with a mixture of ethyl acetate and pentane (7:3, v/v) to give the title compound (7.4 g) as a white solid, m.p. 79-81 C. MS: 176(MH+). | |
With sulfuric acid;Heating / reflux; | Indole 6-carboxylic acid (10.00 g, 62 MMOL) was esterified by refluxing overnight in a mixture of MEOH (200 mL) and conc. H2SO4 (1 mL). After cooling, the reaction mixture was poured into sat. aqueous NAHC03 and extracted with EtOAc. The extract was washed with aqueous NAHC03 twice and water. Drying (MGS04) and removal of volatiles gave the desired methyl ester as a brown oil (10.4 g). | |
With sulfuric acid; at 80℃; | General procedure: H2SO4 (98%) (0.5mL) was added to a stirred solution of raw material1 in CH3OH (10mL) at room temperature and the mixture was then stirred for 2-3 h at 80 C. TLC was used to monitor the reaction progress until it was complete. A large amount of ice water was then added to the mixture. A saturated solution of sodium carbonate was used to neutralise the mixture until white solid appeared. After filtering the mixed solution, compounds 2a-h (yield 91-99) were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; acetonitrile; at 20℃; for 5h; | To a mixture of LH-INDOLE-6-CARBOXYLIC acid (2.6 g, 16 mmol), WSC (3.9 g, 20 mmol) and HOBt (3.1 g, 20 mmol) were added 2.0 M dimethylamine-THF solution (20 mL) and acetonitrile (10 mL) and the mixture was stirred at room temperature for 5 hrs. To the reaction solution were added saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate and the mixture was subjected to extraction. The organic layer was filtered by passing through a silica gel layer, and concentrated under reduced pressure. A mixed solvent of ethyl acetate-diisopropyl ether-diethyl ether was added to the residue to solidify the product. The obtained solid powder was filtered, washed with diethyl ether and dried under reduced pressure to give the title compound (2.6 g, yield 86%). IH NMR (300 MHz, CDC13) ppm : 3.08 (s, 6 H), 6. 52-'6. 57 (m, 1 H), 7.15 (dd, J = 8.1, 1.3 Hz, 1 H), 7.24-7. 30 (m, 1 H), 7.51 (s, 1 H), 7.62 (d, J = 8.3 Hz, 1 H), 8.81 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With lithium aluminium tetrahydride; In tetrahydrofuran; | <strong>[1670-82-2]Indole-6-carboxylic acid</strong> (1.0 g, 6.2 mmol) was dissolved into anhydrous THF (20 mL) under argon. Lithium aluminum hydride (494 mg, 13 mmol) was added portionwise and the mixture was stirred overnight. The mixture was cooled to 0C and ethyl acetate (10 mL) was carefully added, followed by methanol (5 mL) and water (5 mL). The mixture was stirred for 30 min. and filtered through celite. The solution was concentrated and dissolved into ethyl acetate (200 mL) and washed with brine (2 x 20 mL), dried over MGS04 and concentrated to afford the title compound as a brown oil (880 mg, 96%). 1H NMR (300 MHz, CDC13) 8 8.30 (s, 1H), 7.58 (d, J= 8.1 Hz, 1H), 7.23 (d, J= 1.1 Hz, 1H), 7.13-7. 05 (m, 2H), 6.51-6. 49 (m, 1H), 4.70 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With dmap; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); acetonitrile; at 20℃; for 24h; | 1-t-Butyloxycarbonylindole-6-carboxylic Acid [CHEMMOL-00018] [0233] To a suspension of <strong>[1670-82-2]indole-6-carboxylic acid</strong> (2.5 g, 15.5 mmol) in CH3CN (5 mL) and DMF (20 mL) was added 4-dimethylaminopyridine (1.9 g, 15.5 mmol), diisopropyl-ethylamine (2.7 mL, 15.5 mmol), and di-tert-butyl dicarbonate (3.7 mL, 16.3 mmol). After the reaction mixture was stirred for 24 h at room temperature, the reaction solvent was removed in vacuo; and the residue was suspended in 1 N NaHCO3 (100 mL) and Et2O (100 mL). The aqueous layer was separated and extracted with Et2O (2×200 mL). The aqueous layer was acidified to pH 2.5 with 5 N HCl and extracted with EtOAc (500 mL). The organic layer was dried (MgSO4) and concentrated to dryness in vacuo to give the title compound (2.35 g, 58%). [0234] TLC Rf (B) 0.49; [0235] MS 262 (M+H)+; [0236] Analysis for C14H15NO4: [0237] Calcd: C, 64.36; H, 5.79; N, 5.36; [0238] Found: C, 66.69, H, 5.43, N, 6.23.; 1-t-Butyloxycarbonylindole-6-carboxylic Acid [0261] The title compound was prepared according to the procedure described in Example 2A.; 1-t-Butyloxycarbonyl<strong>[1670-82-2]indole-6-carboxylic acid</strong> [0303] The title compound was prepared according to the procedure described in Example 2A.; 1-t-Butyloxycarbonylindole-6-carboxylic Acid [0327] The title compound was prepared by the procedures described in Example 2A.; 1-t-Butyloxycarbonyl<strong>[1670-82-2]indole-6-carboxylic acid</strong> [0341] The title compound was prepared according to the procedure described in Example 2A. |
With dmap; In tetrahydrofuran; for 16h; | Example 43[00362] f^;-(Indol-6-oyloxy)-l-azatricyclo[3.3.1.13>7]decane|00363] A solution of lH-<strong>[1670-82-2]indole-6-carboxylic acid</strong> (161 mg, 1.0 mmol; Aldrich) in anhydrous tetrahydrofuran (5 mL) was treated with di-tert-butyl dicarbonate (437 mg, 2.0 mmol; Aldrich) and 4-dimethylaminopyridine (DMAP; 20 mg, 0.16 mmol; Aldrich) with stirring under nitrogen for 16 hours. After removing the volatiles and drying the solid under vacuum for 1 hour, the residue was dissolved in anhydrous tetrahydrofuran (5 mL) and was treated with Example 36A (334 mg, 2.0 mmol) and N,N'-dicyclohexylcarbodiimide (412 mg, 2.0 mmol; Aldrich). This mixture was stirred at room temperature for 60 hours and then purified by flash chromatography (80 g silica gel column, 3: 1 hexanes-ethyl acetate). The resulting N-borane complex was deprotected according to Method D, followed by brief treatment with trifluoroacetic acid (2 mL, Aldrich) to complete removal of the N-tert- butoxycarbonyl group. The product was purified by preparative etaPLC (Waters XTerra 5 mum 40x100 mm column, flow rate 40 mL/minute, 10-90% gradient over 25 minutes of acetonitrile in 0.1% aqueous trifluoroacetic acid, with UV detection at 254 nm) to afford the trifluoroacetate salt of the titled compound. 1H NMR (300 MHz, methanol-d4) delta ppm 2.00 (s, 1 H), 2.05 (s, 1 H), 2.26 (s, 1 H), 2.40 - 2.56 (m, 4 H), 3.56 - 3.77 (m, 6 H), 5.43 (t, ./=3.2 Hz, <n="59"/>1 H), 6.55 (dd, J=3.2, 0.8 Hz, 1 H), 7.47 (d, J=3.1 Hz, 1 H), 7.64 (d, J=8.5 Hz, 1 H), 7.76 (dd, J=8.1, 1.4 Hz, 1 H), 8.20 (d, J=O.7 Hz, 1 H). MS (DCI/NH3) m/z 297 (M+H)+. Anal. Calcd. for Ci8H2ON2O2-I -OSC2HF3O2: C, 58.02; H, 5.10; N, 6.73; Found: C, 57.93; H, 5.17; N, 6.65. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In methanol; water; cyclohexanone; | Example 2 3-Cyclohexenyl-6-indole Carboxylic Acid: A 12 L round-bottomed flask was equipped with a reflux condenser and a mechanical stirrer, and the system was purged with nitrogen gas. 6-Indole carboxylic acid (300.00 g, 1.86 mole, 3 equivalents) was charged into the flask, followed by MeOH (5.5 L). After stirring for 10 min at room temperature, cyclohexanone (579 mL, 5.58 mole) was added. Methanolic sodium methoxide (25% w/w, 2.6 L, 11.37 mole, 6.1 equivalents) was added in portions over 10 min. The mixture was then refluxed for 48 h. After cooling to room temperature, water (4 L) was added and methanol removed under reduced pressure. The residual aqueous phase was acidified to pH 1 with concentrated HCl (~1.2 L). The resulting yellowish precipitate was collected by filtration, washed with water and dried under vacuum at 50 C. The desired cyclohexane derivative was obtained as a beige solid (451.0 g, 100% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; mineral oil; | Example 2 N-([3,5-bis(Trifluoromethyl)phenyl]amino}carbonyl)(1-methylindol-6-yl) carboxamide (98) Sodium hydride (0.77 g of a 60% suspension in mineral oil) was washed with anhydrous hexane (2*10 mL) under a nitrogen atmosphere and then suspended in anhydrous N,N-dimethylformamide (DMF, 30 mL). A solution of indole-6-carboxylic acid (1.01 g) in DMF (20 mL) was added over 5 min and the solution stirred at room temperature for an additional 30 min. Iodomethane (1.2 mL) was added and the mixture stirred for 1 h. The solution was poured onto ice and allowed to warm up to room temperature. The resulting solid was collected by filtration, washed with water and dried under high vacuum to afford methyl 1-methylindole-6-carboxylate. | |
Step 1: Methyl 1-METHYL-LH-INDOLE-6-CARBOXYLATE (166) [0333] LH-INDOLE-6-CARBOXYLIC acid 37 (0.20g, 1.24 MMOL) was dissolved in dimethylformamide (10 mL) and cooled to 0C for the portion-wise addition of sodium hydride (0.20g, 4.96 MMOL). After complete addition, the reaction mixture was allowed to warm to rt and stirred for 1 hr then methyl iodide (0.15 mL, 2.48 MMOL) was added to the reaction mixture. Quenching with water followed by rotary evaporation led to the crude residue, which was taken up with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated to provide crude 166 (it was used crude in the next step). MS: 189.08 (CALC), 190.1 (obs). | ||
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere; | Step 1. Synthesis of 1-Methyl-1H-indole-6-carboxylic acid methyl ester Iodomethane (2.3 mL, 36.9 mmol) was added to a suspension of indole-6-carboxylic acid (1.55 g, 9.62 mmol) and potassium carbonate (1.98 g, 14.3 mmol) in DMF (32 mL) under argon. The reaction was stirred at room temperature for 24 hr. The reaction was quenched with sat. NH4Cl and extracted with ethyl acetate (2*). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-60% EtOAc:Hexane). ESI-MS m/z 190 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55 mg (44%) | With N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; | F 4-(tert-butyldimethylsilyloxy)-N1-(6-indolylcarbonyl)-N2-[1-(4-pyridyl)piperidin-4-yl]methoxycarbonyl-1,2-benzenediamine A mixture of indole-6-carboxylic acid (71 mg, 0.44 mmol), bromotris(pyrrolidino)phosphonium hexafluorophosphate (204 mg, 0.44 mmol) and diisopropylethylamine (0.153 mL, 0.88 mmol) in dry methylene chloride (5 mL) was stirred 10 min. 4-(tert-Butyldimethylsilyloxy)-N2-[1-(4-pyridyl)piperidin-4-yl]methoxycarbonyl-1,2-benzenediamine (100 mg, 0.22 mmol) and N,N-dimethylformamide (2 mL) were added and the resulting mixture stirred 64 h at ambient temperature. Saturated aqueous sodium hydrogen carbonate solution (4 mL) was added, and the resultant mixture stirred for 30 min. The mixture was partitioned between ethyl acetate and water, the organic solution separated, dried (anhydrous magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride, 9:1 methylene chloride/methanol, 9:1:0.1 methylene chloride/methanol/ammonium hydroxide) to yield 55 mg (44%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg (71%) | With N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | D N4-Acetyl-N2-(4-t-butylbenzoyl)-N1-(6-indolylcarbonyl)-1,2,4-benzenetriamine To a stirring solution of 2-(4-t-butylbenzoyl)amino-4-(acetylamino)aniline (40 mg, 0.12 mmol), 6-indolecarboxylic acid (40 mg, 0.24 mmol) and bromotris(pyrrolidino)phosphonium hexafluorophosphate (112 mg, 0.12 mmol) in dichloromethane (10 mL) and DMF (1 mL) was added N,N-diisopropylethylamine (42 mg, 0.36 mmol). After 3 days, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed once with 1 N HCl, once with satd aq sodium bicarbonate, dried with MgSO4, filtered and concentrated in vacuo. The residue was then chromatographed over silica gel, eluding with 10% methanol/dichloromethane and the product containing fractions were combined and concentrated to give 40 mg (71%) of the title compound. 1H-NMR FD-MS, m/e 469.2 (M+) Analysis for C28H28N4O3: Calc: C, 71.78; H, 6.02; N, 11.96. Found: C, 69.22; H, 6.26; N, 11.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.35 g (100%) | With sodium nitrite In water | 53.a 3-(1H-Benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6 carboxamide The starting material was prepared as follows: To 1H-indole-6-carboxylic acid (2.0 g, 12.42mmol) in water (10 0 mL) was added NaNO2 (8.56 g, 124.2 mmol). To this suspension was then slowly added dropwise via addition funnel 6N HCL (16mL). The resulting slurry was allowed to stir at room temperature overnight. The solid precipitate was filtered and washed with water (50 mL) to provide 2.35 g (100%) of 3-formyl-1H-indazole-6-carboxylic acid. 1H NMR (DMSO-d6) δ 14.46 (1H, s), 10.21 (1H, s), 8.26 (1H, s), 8.20 (1H, d, J=8.5 Hz), 7.90 (1H, d, J=8.3 Hz). MS (APCI positive) 205 (methyl ester). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Compound 22H (42 mg, 0.12 mmol) and compound 22J (26mg, 0.16 mmol) were dissolved in DMF (20 ml). EDCI (30 mg, 0.16 mmol),HOBT (21 mg, 0.16 mmol) and DIPEA (0.05 ml, 0.28 mmol) were added andthe reaction mixture was stirred at room temperature for 2 hr. Solvent wasremoved and the crude material was and purified via sgc (10%NH3-MeOH/CH2CI2) to give 7 mg (13%) of compound 221. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In dichloromethane; | (d) A solution of <strong>[1670-82-2]indole-6-carboxylic acid</strong> (9.41 g) and 1,1'carbonyldiimidazole (10.6 g) in methylene chloride (290 ml) was heated at reflux, under nitrogen, for 30 minutes. The solution was cooled and treated with cyclopentylmethylamine (7.0 g). This mixture was heated to reflux for 30 minutes. The resultant solution was then diluted with methylene chloride, washed successively with 10% (v/v) hydrochloric acid, 20% (w/v) aqueous sodium hydroxide, and brine, dried (MgSO4), and evaporated to give 6-(N-cyclopentylmethylcarbamoyl)indole (14.4 g, 91%) as an ivory powder, mp 148-150; NMR (80 MHz, DMSO-d6): 3.19(dd, 2H, CH2 NH), 6.46(br d, 1H, H3 -indole), 7.91(d, 1H, H7 -indole), 8.29(t, 1H, CH2 NH). |
91% | In dichloromethane; | (d) A solution of <strong>[1670-82-2]indole-6-carboxylic acid</strong> (9.41 g) and 1,1'-carbonyldiimidazole (10.6 g) in methylene chloride (290 ml) was heated at reflux, under nitrogen, for 30 minutes. The solution was cooled and treated with cyclopentylmethylamine (7.0 g). This mixture was heated to reflux for 30 minutes. The resultant solution was then diluted with methylene chloride, washed successively with 10% (v/v) hydrochloric acid, 20% (w/v) aqueous sodium hydroxide, and brine, dried (MgSO4), and evaporated to give 6-(N-cyclopentylmethylcarbamoyl)indole (14.4 g, 91%) as an ivory powder, mp 148-150; NMR (80 MHz, DMSO-d6): 3.19(dd, 2H, C H 2NH), 6.46(br d, 1H, H3-indole), 7.91(d, 1H, H7-indole), 8.29(t, 1H, CH2N H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triphenylphosphine; In tetrahydrofuran; methanol; dichloromethane; | a. Methyl indole-5-carboxylate Methanol (10 ml) was added to a solution of <strong>[1670-82-2]indole-6-carboxylic acid</strong> (20.0 g) and triphenylphosphine (65.2 g) in tetrahydrofuran (420 ml) at 0 under a nitrogen atmosphere, followed by slow addition of diethyl azodicarboxylate (43.3 g). The reaction was allowed to warm to 25 and stir for 1 hr. The solvent was evaporated and the residue was dissolved in methylene chloride and preadsorbed onto silica gel (200 g, 70-230 mesh) by evaporation of methylene chloride. The crude product preadsorbed on silica gel was purified by flash chromatography on silica gel, eluding with 1:9 ethyl acetate:hexane to give methyl indole-5-carboxylate (21.7 g, 100%) as a white powder: NMR (80 MH2, CDCl3): 3.93(s, 3H, OCH3), 6.63 (m,1H, H3 -indole), 7.91(dd, 1H, H6 -indole) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; at -15℃; for 1h; | Methyl 1H-indole-6-carboxylate; An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using MDC as eluant. | |
In diethyl ether; at -15℃; for 1h; | Methyl 1H-indole-6-carboxylate.; An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using DCM as eluant. | |
In diethyl ether; at -15℃; for 1h; | Methyl 1H-indole-6-carboxylate.; An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using MDC as eluant. |
In diethyl ether; at -15℃; for 1h; | Intermediate 19 Methyl 1H-indole-6-carboxylate. An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using MDC as eluant. | |
In diethyl ether; at -15℃; for 1h; | An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using DCM as eluant. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Step 1: A solution of <strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong> (1.00 g, 6.20 mmol), tert-butyl 4-aminobenzoate (1.20 g, 6.20 mmol), 4-methylmorpholine (3.14 g, 31.0 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (3.53 g, 9.31 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (758 mg, 6.20 mmol) was added, and the solution was stirred at 60 C. for 3 days. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) followed by trituration in dichloromethane yielded 4-[(1H-indole-6-carbonyl)-amino]-benzoic acid tert-butyl ester (629 mg, 30%). White solid, MS (ISP): m/e 337.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In methanol; for 48h;Heating / reflux; | Step 1; Indole 6-carboxylic acid 1-1 (10.0 g, 62 mmol) was dissolved in dry MeOH (200 ml_)and 1,4-cyclohexanedione-mono-2,2-dimethyltrimethylene ketal (16.4 g, 81 mmol, 1.3equivalent) was added. NaOMe (0.25 M in MeOH, 110 ml_) was added and themixture was refluxed for 48 h. The reaction mixture was then diluted with water (200ml) and the MeOH removed under reduced pressure. Additional water (200 ml_) wasadded to the residue and the mixture was stirred at 45C for 30 min to dissolve mostsolids. The solution was filtered to remove some insoluble material and the filtrate was acidified with formic acid to neutral pH (-10 ml). The precipitated solid was collected by filtration, washed with water (500 ml) and hexane (200 ml_) and dried in vacuum togive the desired alkylated indole 2-1 as an off-white solid (23 g). | |
Step 1 :Indole 6-carboxylic acid 11a (10.0 g, 62 mmol) was dissolved in dry MeOH (200 mL) and 1 ,4-cyclohexanedione-mono-2,2-dimethyltrimethylene ketal (16.4 g, 81 mmol, 1.3 equivalent) was added. NaOMe (0.25 M in MeOH, 110 mL) was added and the mixture was refluxed for 48 h. The reaction mixture was then diluted with water (200 mL) and the MeOH removed under reduced pressure. Additional water (200 mL) was added to the residue and the mixture was stirred at 450C for 30 min to dissolve most solids. The solution was filtered to remove some insoluble material and the filtrate was acidified with formic acid to neutral pH (-10 mL). The precipitated solid was collected by filtration, washed with water (500 mL) and hexane (200 mL) and dried in vacuum to give the desired alkylated indole 11b as an off-white solid (23 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-chloro-succinimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h; | To a solution of <strong>[1670-82-2]indole-6-carboxylic acid</strong> in dichloromethane (40 mL) and DMF (4 mL) was added N-chlorosuccinimide and allowed to stir at room temperature 3 hours. The reaction mixture was then concentrated under reduced pressure and the crude material was stirred in dichloromethane (100 mL) for 2 hours, filtered dried overnight to obtain the title compound (1.15 g, 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 60℃; for 18h; | A solution of indole-6-carboxylic acid (2.00 g, 12.40 mmol) in dimethylformamide (20.00 mL) under argon was treated with N-methyl morpholine (6.82 mL, 62.04 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU) (7.08 g, 18.62 mmol) and <strong>[174579-31-8](4-amino-phenyl)-acetic acid tert-butyl ester</strong> (2.57 g, 12.40 mmol). The mixture was warmed at 60 C. and stirred for 18 hours. After cooling to room temperature, water (15.00 mL) was added. The resulting slurry was extracted with ethyl acetate and the combined organic phases washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), to yield pure {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester (0.51 g) and a mixture of {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester and 1H-indole-6-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (3.41 g). This was dissolved in tetrahydrofuran (34.00 mL) and treated with 1N NaOH. The mixture was stirred at room temperature for 4 hours, then extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulphate and evaporated, and the residue triturated in ether to afford {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester (1.36 g), which was combined with the aliquot obtained by flash chromatography. Total yield of {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester, 1.87 g (43%), MS (mass spectrometry) (ISP): m/e=351.3 (M+H). As used herein (M+H)=the molecular weight of the compound plus a proton. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Example 1 N-(2-(4-(Dimethylamino)-4-phenyl piperidin-1-yl)ethyl)-N-methyl-1H-indol-6-amide A solution of <strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong> (1 eq/0.637 mmol/102 mg), 1-hydroxybenzotriazole hydrate (1 eq/0.637 mmol/84 mg) and N-ethyl diisopropylamine (5 eq/3.185 mmol/0.54 ml) in 5 ml tetrahydrofuran was cooled to 0 C., mixed with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq/0.956 mmol/181 mg) and stirred for 15 min at 0 C. N,N-Dimethyl-1-(2-(methylamino)ethyl)-4-phenylpiperidin-4-amine (1.5 eq/0.956 mmol/250 mg) was added to this reaction mixture and it was heated to room temperature and stirred for 12 h. The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete, the reaction mixture was washed 3 times with saturated sodium hydrogen carbonate solution and the organic phase was dried over magnesium sulfate. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (alumina neutral; 1% MeOH/CH2Cl2). 198 mg (76%) of product were obtained in the form of a yellow oil. HPLC/MS analysis1: Rt=1.8 min; purity (UV 200-400 nm) 99%; m/z=405.3 [MH]+, 360.3 [M-N(CH3)2]+[1] Equipment and methods for HPLC-MS analysis: HPLC: Waters Alliance 2795 with PDA Waters 996; MS: ZQ 2000 MassLynx Single Quadrupol MS Detector; Column: Waters Atlantis dC18, 3 mum, 2.1*30 mm; Column temperature: 40 C., Eluent A: purified water+0.1% formic acid; Eluent B: acetonitrile (gradient grade)+0.1% formic acid; Gradient: 0% B to 100% B in 8.8 min, 100% B for 0.4 min, 100% B to 0% B in 0.01 min, 0% B for 0.8 min; Flow: 1.0 ml/min; Ionisation: ES+, 25 V; Make-up: 100 mul/min 70% methanol+0.2% formic acid; UV: 200-400 nm. | |
76% | Example 1 : N-(2-(4-(Dimethylamino)-4-phenvlpiperidin-1 -vl)ethvl)-N-methvl-1H-indol-6- amide; A solution of I H-<strong>[1670-82-2]indole-6-carboxylic acid</strong> (1 eq/0.637 mmol/102 mg), 1-hydroxybenzotriazole hydrate (1 eq/0.637 mmol/84 mg) and N-ethyl diisopropylamine (5 eq/3.185 mmol/0.54 ml) in 5 ml tetrahydrofuran was cooled to 0C, mixed with 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.5 eq/0.956 mmol/181 mg) and stirred for 15 min at 00C. lambda/,lambda/-Dimethyl-1-(2-(methylamino)ethyl)-4-phenylpiperidin-4-amine (1.5 eq/0.956 mmol/250 mg) was added to this reaction mixture and it was heated to room temperature and stirred for 12 h.The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane).Once the conversion was complete, the reaction mixture was washed 3 times with saturated sodium hydrogen carbonate solution and the organic phase was dried over magnesium sulfate. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (alumina neutral; 1% MeOH/CH2CI2). 198 mg (76%) of product were obtained in the form of a yellow oil.HPLC/MS analysis1: R, = 1.8 min; purity (UV 200-400 nm) 99%; m/z = 405.3 [MH]+, 360.3 [M-N(CHs)2]* |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | EXAMPLE 2; 643-(4-Memochiy-phenylH1.2,41oxadiazol-5-yl1-lH-indole <n="54"/>; To a stirred mixture of lT-<strong>[1670-82-2]Indole-6-carboxylic acid</strong> (58 mg, 0.36 mmol) in 1:1 CH2Cl2 / pyridine (1 mL) was added l-chloro-lambdar,N-24rimethyl-l-propenylamine (68 mg, 0.51 mmol). After stirring the mixture for 30 min, a solution of iV-Hydroxy-4-methoxy-benzamidine (60 mg, 0.361) in CH2Cl2 (1 mL) was added, and the resulting mixture was heated by microwave to 150 0C for 10 min. After cooling, the reaction mixture was concentrated and the crude residue was purified by reversed phase HPLC to afford 6-[3-(4-Methoxy-phenyl)-[l,2J4]oxadiazol-5-yl]-l/f-indole (16.4 mg, 0.056 mmol, 16% yield). ES MS (M+H+) = 292; 1H NMR (499 MHz, DMSO): delta 11.63 (1 H, s), 8.26 (1 H, s), 8.08-8.02 (2 H9 m)s 7.83-7.77 (2 H, m), 7.67 (1 H, t, J = 2.71 Hz), 7.18-7.12 (2 H, m), 6.61 (1 H, m), 3.86 (3 H, s); HRMS m/z 292.1081 (Ci7Hi3N3O2 + H+ requires 292.1008). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | To a mixture of LH-INDOLE-6-CARBOXYLIC acid (1.0 g, 6.3 mmol), 1-HYDROXY-LH-BENZOTRIAZOLEAMMONIUM salt (1.3 g, 8.5 mmol) and WSC (1.6 g, 8.2 mmol) was added acetonitrile (12 mL) and the suspension was stirred at room temperature for 30 min. DMF (6.0 mL) was added to the reaction suspension and the mixture was stirred at room temperature for 2 days. To the reaction solution were added saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate and the mixture was subjected to extraction. The organic layer was washed with 1N aqueous hydrochloric acid solution and water and dried (MGS04). The mother liquor was filtered by passing through a silica gel layer and concentrated under reduced pressure. To the residue was added dropwise 1.0 M borane-THF solution (25 mL) at room temperature and the mixture was refluxed overnight. The reaction solution was returned to room temperature and excess methanol (ca. 25 mL) was added at room temperature until a gas ceased to occur and the mixture was further refluxed overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (5.0 mL). To this solution was added ethyl trifluoroacetate (0.55 mL, 4.6 mmol) at room temperature and the mixture was stirred at room temperature for 3 days. The solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound (0.13 g, yield 12%). 1H NMR (300 MHz, CDC13) 8 ppm: 3.02 (t, J = 8.4 Hz, 2 H), 3.58 (t, J = 8.4 Hz, 2 H), 4.41 (d, J = 5.7 Hz, 2 H), 6.47 (s, 1 H), 6.55 (s, 1 H), 6.60 (dd, J = 7.4, 1.4 Hz, 1 H), 7.08 (d, J = 7.3 Hz, 1 H). LC/MS (ESI) m/z 245 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | I 8a) (1 H- 1ndol-6-yl(morpholino)methanoneA solution of IH-<strong>[1670-82-2]indole-6-carboxylic acid</strong> (10.0 g, 62.1 mmol) and CDI (11.07 g, 68.32 mmol) in dichloromethane (300 mL) was refluxed for 30 mm. Morpholine (3.25 mL) was added to the reactionmixture and heating was continued for 16 h. The reaction mixture was then cooled and quenched with I Nhydrogen chloride solution (100 rnL). The organic layer was separated, washed with I N sodiumhydroxide solution (100 mL) and brine (100 mL), and dried over sodium sulfate. Evaporation of thesolvent under reduced pressure provided the product as white solid which was used in the next step without further purification. Yield: 13.0 g (91% of theory). HPLC-MS (method 3): R = 2.45 miii.; m/z[M+H] = 23 1.2 (MW calc. 230.26) | |
76% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Example 3; 4-(2-Fluorophenyl)-7-(morpholine-4-carbon l)-9H-pyrido [3 ,4-b] indole- 1 -carboxamide; 1. (1 H-Indol-6-yl)(morpholino)methanone; A solution of morpholine (1.320 mL, 15.14 mmol), <strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong> (2.0332 g, 12.62 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (3.63 g, 18.92 mmol), 1-hydroxybenzotriazole (HOBt) (2.90 g, 18.92 mmol) and diisopropylethylamine (DIPEA) (6.61 mL, 37.8 mmol) in DMF (31.5 mL) was stirred overnight. The reaction was poured into a 1 : 1 watenbrine solution and extracted with EtOAc (2x). The organic layers were combined and washed with 0.25 M aqueous KHSO4, water, brine and 10% aqueous LiCl; dried over a2S04, filtered and concentrated in vacuo. Trituration with Et20 provided the desired product (2.20 g, 9.58 mmol, 76% yield) as a light tan solid. |
56% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h; | [0245] 1-Hydroxy-7-azabenzotriazole (0.844 g, 6.21mmol, 0.05 eq), EDCxHCl (26.09 g, 136.64 mmol, 1.1 eq)andmorpholine (12.9 g, 149.06 mmol, 1.2 eq) were added toa stirred solution of <strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong> (20.0 g,124.22 mmol, 1.0 eq) in DMF (150 mL). Stirring was continuedfor 16 hat room temperature and water (200 mL) wasthen poured into the reaction mixture. The mixture wasextracted with dichloromethane (2x150 mL) and the combinedorganic layers were washed with brine (1 00 mL ), driedover anhydrous sodium sulphate and evaporated. White solid.Yield: 16.0 g (56% of theory).[0246] 1H NMR (400 MHz, DMSO-d6, o ppm): 11.28 (s,lH), 7.58 (d, J=8.1 Hz, lH), 7.49-7.43 (m, 2H), 7.04 (dd,J=8.0, 1.5 Hz, lH), 6.49 (s, lH), 3.65-3.48 (m, 8H). |
Example 13 1-Benzyl-6-(morpholine-4-carbonyl)-1H-indole-3-carboxylic acid thiazol-2-ylamide <strong>[1670-82-2]Indole-6-carboxylic acid</strong> (0.60 g, 3.7 mmol) was dissolved in DCM (15 mL) and carbonyl diimidazole (0.63 g, 3.9 mmol) was added and the reaction mixture was refluxed under N2 for 30 min. The mixture was allowed to cool to room temperature before morpholine (0.39 g, 4.5 mmol) was added and the reaction mixture was refluxed for 16 hours. The mixture was allowed to cool to room temperature before it was washed in seqence with HCI (50 mL, 1 N in water), NaOH (50 mL, 1 N in water) and brine (50 mL). The organic phase was dried with MgSO4, and the solvent was removed in vacuo to give 0.74 g of (1 H-indol-6-yl)-morpholin-4-yl-methanone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | Step 2: Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (8.3 g, 17.8 mmol, 1.1 equiv.) and diisopropyl ethyl amine (4.4 ml, 33.9 mmol, 2.1 equiv.) were added to 1H-indole-6-carboxylic acid (2.6 g, 16.2 mmol, 1 equiv.) in tetrahydrofuran (30 mL) and the mixture was shaken for 5 minutes at room temperature. 4-Amino-2-chlorobenzoic acid methyl ester (3.3 g, 17.9 mmol, 1.1 equiv.) was added and the resultant mixture was shaken at room temperature for 16 hours. The solvent was removed under vacuum and the residue triturated with dichloromethane (10 mL). The solid was filtered to afford 2-chloro-4-[(1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester, 1.4 g (26% yield). LC (at)215 nm; Rt 1.36: 90%, m/z (ES+): 329 (M+H+.); deltaH (400 MHz; d6-DMSO) 11.65 (1H, s), 10.59 (1H, s), 8.16 (1H, s), 8.10 (1H, s), 7.93 (2H, m), 7.65 (2H, s), 7.59 (1H, m), 6.62 (1H, s), 3.85 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Step 1: A 2 N trimethylaluminium solution in heptane (30.8 mmol, 15.41 mL, 3 equiv.) was added dropwise over 10 minutes to a solution of <strong>[654-70-6]4-amino-2-trifluoromethylbenzonitrile</strong> (30.8 mmol, 5.7 g, 3 equiv.) in dry dioxane (20 mL). The reaction mixture was stirred for a further 30 minutes then a solution of 1H-indole-6-carboxylic acid methyl ester (10.3 mmol, 1.8 g, 1 equiv.) in dioxane was added portionwise over 5 minutes and the reaction mixture was stirred at 106 C. for 16 hours. The solution was poured onto a 1M aqueous sodium tartrate solution (100 mL) and diluted with dichloromethane (50 mL). The organic layer was separated, dried over Na2SO4 and the solvent was removed under vacuum. The residue was dissolved in dichloromethane (10 mL) and sonicated for 5 minutes. The resultant solid was filtered to afford 1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide, 2.4 g (71% yield). LC (at)215 nm; Rt 1.50: 97%, m/z (ES+): 330 (M+H+.); deltaH (250 MHz; d6-DMSO) 10.89 (1H, s), 8.54 (1H, s), 8.32 (2H, m), 8.17 (1H, s), 8.13 (1H, s), 7.70 (2H, m), 7.62 (1H, t), 6.57 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With N-ethyl-N,N-diisopropylamine; HATU; In ISOPROPYLAMIDE; at 20℃; for 18h; | O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added in one portion to 8-(8-aminodibenzo[b,d]thiophen-4-yl)-2-morpholino- 4H-chromen-4-one (A8 100 mg, 0.23 mmol), 1 H-<strong>[1670-82-2]indole-6-carboxylic acid</strong> (39.5 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.102 ml_, 0.58 mmol) in DMA (1.5 mL) at ambient temperature. The resulting solution was stirred at ambient temperature for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. This was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl)-1H-indole-6- carboxamide (55 mg, 41%) as a cream solid; 1H NMR (400 MHz, DMSOd6) delta 3.13 (4H, t), 3.45 (4H, t), 5.59 (1 H, s), 6.56 - 6.57 (1 H, m), 7.56 - 7.60 (2H, m), 7.69 (3H1 1), 7.73 - 7.75 (1 H, m), 7.90 - 7.94 (2H, m), 7.98 (1H1 d), 8.08 - 8.10 (1 H, m), 8.16 (1 H1 s), 8.33 - 8.35 (1H, m), 8.89 - 8.91 (1 H, m), 10.43 (1H, s), 11.49 (1H1 s); m/z: 572.08 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.9% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere; | In a 250 mL three-necked flask, N, N-diisopropylethylamine (40 · 1 g, 310 · 3 mmo 1) and N, N-dimethylformamide (100 mL), slowly added dimethylhydroxylamine hydrochloride (18.2 g, 186.2 mmol) and HATU (47.2 g, 124 l), nitrogen Under the protection of 6-indole carboxylic acid (10.0g, 62. lmmo 1), room temperature reaction 2h, the reaction is completed, The reaction solution was poured into water to precipitate a solid, suction filtered and dried in vacuo to give 10.9 g of 6- (N-methoxy-N-methyl) formylamino-1H-indole in a yield of 85.9% |
With pyridine; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In tetrahydrofuran; at 20℃; for 40h; | EXAMPLE 6; 2-{2-[2-(1H-Indol-6-yl)imidazo[1,2-a]pyridin-6-yl]pyridin-4-yl}propan-2-ol (Compound 152 of the Table)6.1 N-Methoxy-N-methylindole-6-carboxamideIn a round-bottomed flask, 5.0 g of <strong>[1670-82-2]indole-6-carboxylic acid</strong>, 3.3 g of N,O-dimethylhydroxylamine hydrochloride, 11.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 10 ml of pyridine are placed in 150 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 40 h. The mixture is concentrated, and the residue is taken up in 150 ml of ethyl acetate and 50 ml of water. The organic phase is washed with 50 ml of a 1N solution of sodium hydroxide and 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 6.8 g of compound are obtained.1H NMR (CDCl3, delta in ppm): 3.3 (s, 3H); 3.5 (s, 3H); 6.45 (m, 1H); 7.25 (t, 1H); 7.4 (dd, 1H); 7.55 (d, 1H); 7.75 (s, 1H); 8.8 (s, 1H). M+H=205. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Under a nitrogen atmosphere, to a solution of <strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong> (121 g, 752 mmol) in N,N-dimethylformamide (360 ml) was added potassium carbonate (124 g, 900 mmol), and the mixture was stirred at room temperature for 1 hr. Then, iodomethane (56 ml, 900 mmol) was added dropwise at room temperature over 15 min, and the mixture was stirred for 2 hr. Then, to the reaction solution were added water (1.2 L) and hexane (100 ml), and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, washed successively with water and hexane, and dried under reduced pressure to give the title compound (115 g, yield 87%).1H-NMR (400 MHz, DMSO-d6) delta: 3.85 (3H, s), 6.53 (1H, d, J=1.61 Hz), 7.60-7.63 (3H, m), 8.07 (1H, s), 11.48 (1H, s). | |
83% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | A magnetically stirred solution of 1 H-<strong>[1670-82-2]indole-6-carboxylic acid</strong> (5.00 g, 31 .02 mmol) in DMF (40 mL) was treated with potassium carbonate (4.29 g, 31 .02 mmol) and dropwise with methyl iodide (1 .93 mL, 31 .02 mmol). After stirring at room temperature for 3 h, the resulting mixture was diluted with diethyl ether (150 mL) then washed with water (2 x 100 mL) before being dried over magnesium sulphate, filtered and concentrated under reduced pressure. The ensuing residue was subjected to flash chromatography [silica, 20:80 v/v diethyl ether/hexane] and concentration of the appropriate fractions (Rf = 0.42) afforded methyl 1 H-indole-6-carboxylate (4.29 g, 83%) as a light yellow crystalline solid. H NMR (400 MHz, chloroform-d) delta 8.71 (brs, 1 H), 8.19 (s, 1 H), 7.84 (dd, J = 8.4 and 1 .3 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.37 (t, J = 2.8 Hz, 1 H), 6.60 (s, 1 H), 3.95 (s, 3H); 13C NMR (100 MHz, chloroform-d) delta 168.5, 135.3, 131 .7, 127.8, 123.6, 120.9, 120.4, 1 13.7, 103.0, 52.1 ; (+)-LRESIMS m/z (rel. int.) 198 (100) [M + Naf; vmax 3337, 1680, 1617, 1569, 1508, 1438, 1335, 1290, 1262, 1220, 1205, 1 128, 1 1 15, 1084, 982, 91 1 , 828, 775, 736, 659 cm"1. |
78.3% | 2g of <strong>[1670-82-2]indole-6-carboxylic acid</strong> was dissolved 20mLN, N- dimethylformamide was added 2.1g of potassium carbonate, N2The reaction atmosphere 1h, then, added to the system 1mL methyl iodide, the reaction was continued 2h, the reaction was completed, aqueous sodium thiosulfate was added was quenched reaction was added 100mL of water, a lot of white solid was precipitated, suction filtered, washed with water and dried to give an off-white The solid was purified by column chromatography to obtain a white solid 1.73g, yield 78.3%. |
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 19h;Inert atmosphere; | Step 1. Synthesis of 1H-<strong>[1670-82-2]Indole-6-carboxylic acid</strong> methyl ester Iodomethane (0.75 mL, 12.0 mmol) was added to a suspension of <strong>[1670-82-2]indole-6-carboxylic acid</strong> (1.68 g, 10.5 mmol) and potassium carbonate (2.16 g, 15.7 mmol) in DMF (30 mL) under argon. The reaction was stirred at room temperature for 19 hr. The reaction was quenched with sat. NH4Cl and extracted with ethyl acetate (2*). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-60% EtOAc:Hexane). ESI-MS m/z 176 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C 1.2: 2 h / 20 °C 2.1: dmap / tetrahydrofuran / 2 h / 20 °C 3.1: lithium diisopropyl amide; Triisopropyl borate / hexane; tetrahydrofuran / 2.5 h / -5 °C 3.2: Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Step 5. 5-(1H-Indole-6-carbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 2,2-Dimethyl-1,3-dioxane-4,6-dione (3.7 g, 25.69 mmol, 1.29 equiv), 4-dimethylaminopyridine (4.5 g, 36.89 mmol, 1.86 equiv), dichloromethane (30 mL), <strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong> (3.2 g, 19.88 mmol, 1.00 equiv), EDC.HCl (4.9 g, 25.52 mmol, 1.28 equiv) were placed into a 100-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to pH 3 with hydrochloric acid. The resulting solution was extracted with dichloromethane and the organic layers combined. The resulting mixture was concentrated in vacuo. This resulted in 5.3 g (93%) of 5-(1H-indole-6-carbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a reactor with a nitrogen inlet and temperature probe was charged lH-indole-6- carboxylic acid (1.00 kg, 6.21 mol, 1.00 equiv), N,N-dimethylaminopyridine (0.038 kg, 0.31 mol, 0.050 equiv), and tetrahydrofuran (7.00 L/kg, 6.22 kg/kg) followed by Iota, Gamma-carbonyldiimidazole (1.03 kg, 6.21 mol, in 4 x 0.257 kg aliquots, 1.00 equiv corrected for potency). The mixture was held at 5-20 °C until reaction completion was achieved and then cooled to 5-10 °C. Di-tert-butyldicarbonate (2.97 kg, 13.7 mol, 2.20 equiv) in THF (3 L/kg) was charged dropwise keeping the temperature between 2-8 °C. The mixture was held at 5-20 °C until reaction completion was achieved. N,N-Dimethylsulfamide (0.865 kg, 6.83 mol, 1.10 equiv) was charged at 25 ±5 °C. The mixture was aged for 0.5 h followed by addition of 1,8-diazabicyclo- undec-7-ene (1.24 kg, 8.07 mol, 1.30 equiv) keeping the temperature 98.0 and HPLC wtpercent >95.0. IR 3422, 3375, 3299, 2946, 1686, 1617, 1569, 1504, 1455, 1418, 1406, 1343, 1324, 1289, 1261, 1223, 1 187, 1150, 1135, 1 103, 1060, 978, 941, 898, 874, 818, 775, 733, 719, 660, 614 cm"1; NMR (400 MHz, DMSO-d6) delta 1 1.67 (s, 1H), 11.56 (s, 1H), 8.06 (s, 1H), 7.56-7.63 (m, 3H), 6.53 (s, 1H), 2.89 (s, 6H); 13C NMR (100 MHz, DMSO-d6) delta 167.2, 135.5, 131.7, 129.9, 124.7, 120.3, 119.5, 1 13.4, 102.1, 38.6; HRMS calculated for CnH1403N3S: 268.07504, found 268.07489 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h; | Example 11 Synthesis of {acute(alpha)}-Hydroxy Carboxylic Acids Method H Alfa hydroxy carboxylic acids were synthesized by reacting desired epoxide with tert-butyl 3-(1-(3-hydroxybenzoyl)piperidin-4-yl)benzyl carbamate in presence of base to yield Alfa hydroxy carboxylic esters that were hydrolyzed and de-protected to get the title compounds (Scheme-1). Similarly indole 5/6 carboxylic acids were coupled with tert-butyl 3-(piperidin-4-yl)benzyl carbamate and resulting coupled products were treated with desired epoxides. Alfa hydroxy ester formed in the reaction gets hydrolyzed during the work-up to yield alpha hydroxy acids which were subjected to Boc De-protection to get the title compounds (SCHEME 12, part Scheme-2). Step-1 & 5 [0456] Coupling of desired carboxylic acid was carried out with tert-butyl 3-(piperidin-4-yl)benzylcarbamate as per general procedure described in Method-A step-4 was followed. The details of compounds synthesized are as below in Table 36. <strong>[1670-82-2]Indole-6-carboxylic acid</strong> (1 eq), tert-butyl 3-(piperidin-4-yl) benzyl carbamate (1.3 eq.), EDCI (1.2 eq.), DMAP (2.0 eq.), DMF, DCM, RT, 3 h, Yield:- 73% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; In benzene; at 160℃; for 0.416667h;Inert atmosphere; Microwave irradiation; | General procedure: In a glove box, a microwave vial was charged with alpha-lactam (0.250mmol), indole (0.280mmol), and [RhCODCl]2 (0.0100mmol). The vial was closed with a cap fitted with a septum and benzene (1.5mL) was added via syringe. The reaction was removed from the glove box and heated in the microwave reactor for 25min at 160C. The reaction mixture cooled to room temperature and was removed from reactor. The mixture was exposed to air, filtered through a bed of silica, and washed with CH2Cl2. Compounds were purified using flash column chromatography (hexanes/CH2Cl2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; In benzene; at 160℃; for 0.416667h;Inert atmosphere; Microwave irradiation; | General procedure: In a glove box, a microwave vial was charged with alpha-lactam (0.250mmol), indole (0.280mmol), and [RhCODCl]2 (0.0100mmol). The vial was closed with a cap fitted with a septum and benzene (1.5mL) was added via syringe. The reaction was removed from the glove box and heated in the microwave reactor for 25min at 160C. The reaction mixture cooled to room temperature and was removed from reactor. The mixture was exposed to air, filtered through a bed of silica, and washed with CH2Cl2. Compounds were purified using flash column chromatography (hexanes/CH2Cl2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | [1260] EDCxHCl (17 .7 g, 93.00 mmol, 1.5 eq), 1-hydroxy-7 -azabenzotriazole ( 4.2 g, 31.01 mmol, 0.5 eq) followed bytriethylamine (28.7 mL, 204 mmol, 3.3 eq) were added atroom temperature to a stirred solution of lH-indole-6-carboxylicacid (10 g, 62.03 mmol, 1.0 eq) in dry DMF (50 mL).(R)-tert-butyl pyrrolidin-3-ylcarbamate (13.86 g, 74.44mmol, 1.2 eq) was added after 10 min and stirring was continuedfor 16 hat room temperature. The reaction mixture wasdiluted with icy water (100 mL), and the precipitating solidwas filtered off, washed with water (50 mL) and pet ether (50mL), and dried under vacuum. White solid. Yield: 11.0 g(55% of theory)[1261] Mass spectroscopy: m/z: [M+Ht=330.2[1262] 1H NMR (400 MHz, CDC13, o ppm): 8.44 (s, lH),7.64 (d, 1=7.6 Hz, 2H), 7.31 (t, 1=2.8 Hz, lH), 6.57 (t, 1=2.2Hz, lH), 4.66-4.59 (m, lH), 4.30-4.11 (m, lH), 3.92-3.38 (m,3H), 2.23-2.04 (m, lH), 1.92-1.85 (m, lH), 1.61-1.46 (m,2H), 1.39-1.27 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | Following general procedure B, Compound (i?)-26 was prepared from lH-indole-6- carboxylic acid and compound (i?)-A-104 (50 mg, 0.32 mmol), with a reaction time of 12 hours. The product was purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini C 18 150x25 mm, particle size: 10 mupiiota; Mobile phase: 28-58% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] . The resulting solid was dissolved in 0.2 M hydrochloric acid solution and again lyophilized to give: (i?)-N-(2,2-dimethylquinuclidin-3-yl)-lH-indole-6-carboxamide hydrochloride (compound (i?)-26) (20 mg, 21% yield) as a white solid: cSFC analytical (A) tR: 3.17 min., purity: 96%; LCMS (P): tR=1.672 min., 298.1 m/z (M+l); -NMR (CD3OD, 400 MHz): delta 7.93 (s, IH), 7.64 (d, J=8.4 Hz, IH), 7.51-7.49 (m, IH), 7.42 (d, J=2.8 Hz, IH), 6.54 (d, J=3.2Hz, IH), 4.07 (s, IH), 3.39-3.35 (m, 2H), 2.84-2.82 (m, 2H), 2.07-2.05 (m, IH), 1.96 (s, IH), 1.88-1.83 (m, 2H), 1.58-1.56 (m, IH), 1.50 (s, 3H), 1.33 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 5h; | Following general procedure B, Compound (i?)-79 was prepared from lH-indole-6- carboxylic acid (53 mg, 0.33 mmol) and compound (i?)-A-lll (50 mg, 0.33 mmol), with a reaction time of 5 hours. The product was purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini C18 150x30 mm, particle size: 10 mupiiota; Mobile phase: 25-55% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give: (R)-N-( 1 '-azaspiro [cyclopropane- 1 ,2'-bicyclo [2.2.2]octan] -3 '-yl)- lH-indole-6-carboxamide (compound (i?)-79) (24 mg, 25% yield) as a white solid: cSFC analytical (A) tR=2.77 min., purity: 97.84%; LCMS (G): tR=2.234 min., (ES+) m/z (M+H)+ = 296.1 ; -NMR (CD3OD, 400 MHz): delta 7.92 (s, IH), 7.63 (d, J=8.4 Hz, IH), 7.50 (dd, J=8.0, 1.2 Hz, IH), 7.41 (d, J=2.8 Hz, IH), 6.53 (d, J=2.8 Hz, IH), 4.24 (d, J=1.6 Hz, IH), 3.33-3.23 (m, IH), 3.10-3.08 (m, IH), 2.93-2.86 (m, 2H), 2.12 (d, J=3.2 Hz, IH), 2.02-1.90 (m, IH), 1.89-1.82 (m, 2H), 1.57 (m, IH), 0.93-0.87 (m, 2H), 0.79-0.70 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | Preparation of (2R,4R)-N-(5-(-(+)-l-amino-3-cyclopropyl-l-(pyridin-4-yl)propyl)-2- fluorophenyl)-l-(lH-indole-6-carbonyl)-4-methoxypyrrolidine-2-carboxamide (82a) To a solution of (2R,4R)-N-(3-(l -amino-3 -cyclopropyl- l-(pyridin-4- yl)propyl)phenyl)-4-methoxypyrrolidine-2-carboxamide (75d) (0.2 g, 0.41mmol) in DMF (3.0 mL) was added DIPEA (0.3 mL); HATU(0.15 g, 0.41mmol) and lH-<strong>[1670-82-2]indole-6-carboxylic acid</strong> (0.72g, 0.37 mmol). The reaction mixture was stirred at room temperature overnight, quenched with water (40 mL) and extracted with ethyl acetate (2 x 40 mL). The organic layers were combined washed with brine, dried, filtered and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel, 12 g, eluting with 0-10% methanol in ethyl acetate) to afford (2R,4R)-N-(5-(-(+)-l-amino-3- cyclopropyl- 1 -(pyridin-4-yl)propyl)-2-fluorophenyl)- 1 -( lH-indole-6-carbonyl)-4- methoxypyrrolidine-2-carboxamide (82a) (0.02 g, 10% yield) as white solid; 1H MR (300 MHz, DMSO-i) delta 11.32 (s, 1H), 9.64 (s, 1H), 8.50 - 8.36 (m, 2H), 7.96 (s, 1H), 7.71 - 7.41 (m, 3H), 7.41 - 7.29 (m, 2H), 7.19 (m, 3H), 6.48 (s, 1H), 4.84 - 4.66 (m, 1H), 4.09 - 3.88 (m, 1H), 3.88 - 3.68 (m, 1H), 3.68 - 3.50 (m, 1H), 3.20 (s, 3H), 2.37 - 2.06 (m, 4H), 2.06 - 1.85 (m, 1H), 1.02 (m, 2H), 0.64 (m, 1H), 0.34 (m, 2H), -0.03 - -0.14 (m, 2H); MS (ES+) 556.7 (M+l), 578.6 (M+Na), MS (ES-) 554.6 (M-l); Optical rotation [a]D = (+) 54.19 [0.155, MeOH]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | General procedure: To the stirred solution of an appropriate heteroaryl carboxylic acid (0.15 mmol) in dry dichloromethane (5 mL) under an argon atmosphere at 0 C was added EDCI (0.181 mmol), and the mixture allowed to stir for 15 min. Then a catalytic amount of DMAP (0.045 mmol) was added, followed by addition of MMB (0.151 mmol) in dry dichloromethane (3 mL) at 0 C and the resulting mixture stirred for 8h at room temperature. After completion of the reaction (monitoring by TLC), the reaction mixture was washed with water (10 mL) and the dichloromethane layer separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using 2-5% methanolic dichloromethane as eluent to afford the corresponding heteroaryl esters of MMB (7a-7o) as solids in 56-74% yield. Analytical data for the above MMB esters are provided below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | In a 100 mL eggplant flask, 1.89 g (10 mmol) of the starting material <strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong>40mL ethanol dissolved,Under an ice bath, 2.17 mL (30 mmol) of thionyl chloride,The reaction was completed after 4 hours,The solvent was evaporated to dryness,Add water 100mL,100 mL of ethyl acetate,The organic layer was washed with saturated aqueous sodium bicarbonate until neutral,Washed,Saturated sodium chloride washed,The organic layer was dried over anhydrous sodium sulfate overnight,Suction filtration,Dry the filtrate,Crude 35A,The crude product 35A was obtained by column chromatography using petroleum ether: acetone = 3: 1 (V: V) as eluent.Yield 55%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 40℃; for 20h; | General procedure: A mixture of intermediates 4a-e (0.60 mmol), EDCI (138 mg,0.72 mmol), corresponding carboxylic acid derivatives (0.60 mmol)and HOBt (97 mg, 0.72 mmol) in N,N-dimethylformamide (6.0 mL)was stirred for 20 h. The reaction mixture was diluted with ethylacetate and washed with brine, the organic layer was dried over magnesium sulfate and concentration in vacuo. The residue waspurified by silica gel column chromatography (5% methanol/chloroform)to afford the title compounds 6a-t as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 2.5h; | In a 100 mL round bottom flask, take <strong>[1670-82-2]1H-<strong>[1670-82-2]indole-6-carboxylic acid</strong></strong>, 20mL DMF was added to disoolve, then moved on a magnetic stirrer at room temperature and stirring was started,take a relatively equivalent amount of potassium hydroxide into the reaction system, and then take elemental iodine, 20mL DMF was added to the beaker to dissolve, transferred to a pressure-equalizing dropping funnel , slowly added dropwise to the reaction system, about 30min addition was complete, the reaction was continued 2hrs. TLC detected the progress of the reaction and the reaction as stoped after the reaction was completed.Take the relative equivalent of sodium thiosulfate in a 1L beaker and 500mL of ice water was added, then, the reaction solution was slowly poured into ice water, and then, concentrated hydrochloric acid was added to adjust the pH to about 3, a large amount of solid was precipitated, and the solid was dried in the intermediate I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | General procedure: To a solution of podophyllotoxin (0.29 mmol, 1 eq),appropriate indole carboxylic acid (1.5 eq), 4-dimethylamino-pyridine (1.2 eq) in N,N-dimethylformamide(4 mL) at 0 C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2 eq) was added. After stirringfor 2-8 h at room temperature under argon atmosphere, themixture was quenched with H2O and the crude was collectedby vacuum filtration, washed by water and dried invacuum oven. The crude product was further purified bycolumn chromatography (EtOAc/PE, 4:1) to provide thepure product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With barium(II) hydroxide; In ethylbenzene; at 130℃;Inert atmosphere; | 0.05 mol of <strong>[1670-82-2]1-benzopyrrole-6-carboxylic acid</strong> (purchased from Wuxi Zhongkun Biochemical Technology Co., Ltd., having the structure shown by formula (II), R1 and R2 are H, the same below),0.03mol of Barium hydroxide and 150mL of ethylbenzene were added to a 250mL two-necked flask equipped with a water separator. Under the protection of high-purity nitrogen, it was placed in an oil bath at 130 C to maintain a boiling reflux reaction until the water separator was basically The reaction was stopped until the liquid was separated, and a solution containing a bismuthene dibenzopyrrolecarboxylate compound (denoted as B1) at a concentration of 0.2 mol/L was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 12h; | Add in round bottom bottles<strong>[1670-82-2]Indole-6-carboxylic acid</strong> (0.271g, 1.68mmol),EDCI (0.387g, 2.02mmol),DMAP (0.062 g, 0.50 mmol) and 10 ml of anhydrous N,N-dimethylformamide;Amino acid (0.5 g, 1.68 mmol) was further added, and the reaction was stirred at room temperature for 12 h.TLC (dichloromethane: methanol = 10:1) was found to be completely complete.The N,N-dimethylformamide was recovered under reduced pressure, and the residue was dissolved in 20 ml of dichloromethane.Wash with water (2 x 30 ml) and saturated brine (30 ml),Dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure.Separation on a silica gel column (eluent: chloroform:methanol = 20:1-10:1),Obtained a tacrine- conjugate (light yellow oil) of 0.259 g,Yield 35%(The synthetic route is shown in Figure 33, and the characterization map is shown in Figure 34). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 50℃; for 1h; | A mixture of lH-<strong>[1670-82-2]indole-6-carboxylic acid</strong> (307mg, 1.90 mmol), 5-bromopyridin-3- amine (300 mg, 1.73 mmol) and EDCI.HCl (365 mg, 1.90 mmol) in pyridine (5 mL) was heated at 50 C for 1 hour. An orange solution was formed. LCMS (Rt = 0.733 min; MS Calcd: 315.0; MS Found: 315.9 [M+H]+). The mixture was concentrated and the residue was poured into water (20 mL) and stirred for 2 minutes. The aqueous layer was extracted with ethyl acetate (20 mL x3). The combined organic layer was washed with water (20 mL x2) and brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was triturated with pentane/EtOAC (3 mL, 3/1) to give N-(5-bromopyridin-3-yl)-lH-indole-6-carboxamide (440 mg, yield: 80%) as a light yellow solid. NMR (400 MHz DMSO-rie) d 6.55 (1H, t, J= 2.0 Hz), 7.60 (1H, t, J= 2.8 Hz), 7.68 (1H, s), 8.12 (1H, s), 8.43 (1H, d, J= 2.0 Hz), 8.49 (1H, s), 8.58 (1H, t, J= 2.1 Hz), 8.97 (1H, d, J = 2.3 Hz), 10.55 (1H, brs), 11.55 (1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h; | In a round bottom flask, 0.400 g of <strong>[1670-82-2]6-indolecarboxylic acid</strong>, 0.194 g of decanediamine, 0.476 g of EDCI, 0.027 g of DMAP, and 10 mL of anhydrous dichloromethane were successively added, and the mixture was stirred at room temperature for 12 hours. A white solid was isolated, suction filtered, washed sequentially with dichloromethane (2× 2.5 mL) and water (3×5 mL).Dry to give 0.243 g of a white solid.The yield was 47% (see Figure 31 for the synthetic route and Figure 32 for the characterization map) |
47% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h; | General procedure: Compounds 9e-35e were obtained by using one-pot reaction. A mixture of aromatic acid (6.30 mmol), EDCI (7.50 mmol), DMAP (0.60 mmol), and anhydrous dichloromethane (20 mL) was stirred to dissolve, then decane-diamine (3 mmol) was added and stirred at room temperature for 12 h. The mixture solution was filtered under reduced pressure. After that, the residue was washed with little amount of CH2Cl2and water successively, and dried to give the solid. Then, the residue was purified on preparative TLC eluted with chloroform/methanol = 40:1-7:1 to yield compounds 26e, 28e, 30e, and 31e. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With air; at 100℃; for 1h;Microwave irradiation; | To the microwave reaction tank, sequentially add bis[tris(2-methyl-2-phenylpropyl)]tin 3.1594 g (3.0 mmol), <strong>[1670-82-2]indole-6-carboxylic acid</strong> 0.9668 g (6.0 mmol), and no solvent 30 mL of water methanol was used to perform microwave reaction under air atmosphere with radiant power of 800 W and temperature of 100 for 120 min. After the reaction is completed, it is naturally cooled and filtered, and the solvent naturally volatilizes and crystals at room temperature to obtain white crystals, which are tris(2-methyl-2-phenylpropyl)tinindole-6-formate complexes. Yield: 66% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With air; In methanol; at 100℃; for 2h;Microwave irradiation; | Add to the microwave reactor in orderTricyclohexyl tin hydroxide 1.1557 g (3.0 mmol),<strong>[1670-82-2]Indole-6-carboxylic acid</strong> 0.4835 g (3 mmol),Solvent anhydrous methanol 30 mL,Under the air atmosphere,With a radiated power of 800 W,Perform microwave reaction at a temperature of 100C,The duration is 120 min.After the reaction,Natural cooling, filtering,At room temperature, the solvent will naturally volatilize and crystallize,To get white crystals,Tricyclohexyltin indole-6-formate complex. Yield: 72%, |
Tags: 1670-82-2 synthesis path| 1670-82-2 SDS| 1670-82-2 COA| 1670-82-2 purity| 1670-82-2 application| 1670-82-2 NMR| 1670-82-2 COA| 1670-82-2 structure
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P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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