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CAS No. : | 55052-28-3 |
Formula : | C7H5ClN2 |
M.W : | 152.58 |
SMILES Code : | ClC1=C2C(=NC=C1)[NH]C=C2 |
MDL No. : | MFCD08272232 |
InChI Key : | HNTZVGMWXCFCTA-UHFFFAOYSA-N |
Pubchem ID : | 11389493 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319 |
Precautionary Statements: | P264-P280-P302+P352-P337+P313-P362+P364-P332+P313 |
* 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 |
---|---|---|
96.33% | To a stirred solution of 4-chloro-lH-pyrrolo[2,3-b]pyridine (1.0 g, 6.554 mmol, 1.0 eq) in DMF (20 mL) was added NaH (60%) (0.53 g, 13.188 mmol, 2.0 eq) at 0C. The resulting mixture was allowed to stirred at the same temperature for 5 min followed by ad dition of CH3I (0.45 mL, 7.209 mmol, 1.1 eq). The resulting mixture was stirred at rt for 15 min. The progress of reaction was monitored by LCMS. The reaction mixture was poured into ice cold water (50 mL), extracted with EtOAc (2 x 50 mL), the combined organic layers were washed with water (50 mL), with brine (50 mL), dried over Na2S04, concentrated to afford the desired compound (1.05 g, 96.33%) as brown liquid. LCMS: (M+l)+l67.0 | |
General Procedure for Preparation of XYInt01; To a solution of azaindole derivative X in hexamethylphosphoramide (HMPA) at 0 C., natrium hydrogen (NaH; 1.2 eq) was added and stirred further. After 1 hour, an alkyl halides Y such as methyl iodide, ethyl iodide, n-propyl bromide, iso-propyl bromide, n-butyl bromide, isobutyl bromide (1.5 eq, 1 h) or O-t-butyldimethylsilyl-2-chloroethanol (10 eq, 24 h) or O-t-butyldimethylsilyl-2-chloropropanol (1.5 eq) was added and stirred. After completion of the reaction (monitored by thin layer chromatography (TLC)), the reaction was quenched by ice cold water and extracted with ethyl acetate (EtOAc; 3×). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to leave a residue of crude product. The crude product was purified by column chromatography to afford XYInt01 (75-85% yield).; Example 264; 4-chloro-N-(cycloheptylmethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; Synthesised according to the procedure disclosed in Example 2 where X is 4-chloro-7-azaindole, Y is methyl iodide, and Z is cycloheptylmethyl amine. Formula: C17H22ClN3O; Molecular Weight: 319.8; Mass/charge ratio: 319.1 (100.0%), 321.1 (32.4%), 320.1 (19.5%), 322.1 (6.3%), 321.2 (1.6%); Elemental analysis: C, 63.84; H, 6.93; Cl, 11.08; N, 13.14; O, 5.00. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium hydroxide; sodium iodide; In tetrahydrofuran; acetonitrile; | Part 2 4-Iodo-1H-pyrrolo[2,3-b]pyridine: To a solution of 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 84.3 mmol) and NaI (40 g, 168 mmol) in acetonitrile (150 mL) was slowly added acetyl chloride (12.6 mL, 176 mmol). The mixture was allowed to stir at 80 C. for 4 days, and then the excess acetonitrile was removed in vacuo. 300 mL of 10% K2CO3 (aq) was added to the residue and the mixture extracted with CH2Cl2 (3*100 mL). The combined organic extracts were washed with 10% sodium bisulfite (aq) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product (22.2 g). To a solution of this crude product in THF (150 mL) was added 1M NaOH (100 mL). The mixture was stirred at room temperature for 2 hr prior to evaporation of the solvent in vacuo, dilution with water and extraction with CH2Cl2. The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting brown solid was purified by chromatography over silica gel and recrystallized from acetonitrile to give pure 4-Iodo-1H-pyrrolo[2,3-b]pyridine (9.75 g, 48%). MS (ES+): 245 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; | General procedure: 1H-4-chloro-pyrrolo[2,3-b]pyridine (0.763g, 5.0mmol, 1 eq.) was dissolved in DMF (7.5mL, 1.5mL/mmol SM) and NCS (0.701g, 5.25mmol, 1.05 eq.) was added. The resulting mixture was stirred at ambient temperature overnight, protected from light. Then, ice-cold water (25mL, 5mL/mmol SM) was added and the resulting precipitate filtered. The solids were washed four additional times with ice-cold water (4×10mL, 2mL/mmol SM). The solid was collected and dried under high vacuum to give 60 (0.861g, 4.6mmol) as an off-white solid in 92% yield. Melting point: 236C (decomposed). 1H NMR (300MHz, DMSO-d6) delta: 7.21 (d, J=4.2Hz, 1H, H-5), 7.77 (s, 1H, H-2), 8.20 (d, J=4.2Hz, 1H, H-6), 12.35 (br. s, 1H, NH). 13C NMR (75MHz, DMSO-d6) delta: 101.1 (C-3), 113.7 (C-3a), 117.1 (C-5), 125.1 (C-2), 133.8 (C-4), 144.4 (C-6), 147.6 (7a). HRMS (ESI): calculated for C7H5Cl2N2 ([M+H]+): 186.9824, found: 186.9824. |
96% | With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; | 1H-4-chloro-pyrrolo[2,3-b]pyridine (0.765 g, 5 mmol, 1 eq.) was dissolved in DMF (7.5 mL, 1 .5 mL / mmol SM). NBS (0.935 g, 5.25 mmol) was added and the resulting solution was stirred at ambient temperature overnight, protected from light. Then, the solution was poured into ice-cold water (25 mL, 5 mL / mmol SM) and cooled into an ice bath. After ~10min the remaining suspension was filtered and the solid washed four times with 10 mL ice-cold water. Then the solid was collected and dried under high vacuum to give FH5295 as a yellow solid (1 .12 g, 4.8 mmol) in 96 % yield. 1H NMR (300 MHz, DMSO-d6) delta: 7.23 (d, J = 5.1 Hz, 1 H, H-5), 7.81 (d, J = 2.7 Hz, 1 H, H-2), 8.21 (d, J = 5.1 Hz, 1 H, H-6), 12.44 (br s, 1 H, N-H). 13C NMR (75 MHz, DMSO-d6) delta: 85.03 (C-3), 1 14.58 (C-3a), 1 17.13 (C-5), 127.71 (C-2), 134.17 (C-4), 144.18 (C-6), 147.98 (C-7a). HRMS (ESI): calculated for C7H5BrCIN2 ([M+H]+): 230.9319, found: 230.9332. Melting point: 210 C (decomposed). |
90.9% | With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 6h; | A 50ml of flask was charged with 1.52 g of 4-chloro-lH-pyrrolo[2,3-b]pyridine (prepared according to Tetrahedron Letters (2007), 48(9), 1527-1529), 2.7 gNBS and 29ml DMF. The mixture was stirred at rt for 6h. The solvent was evaporated off and purified by chromatography to give the 2.11 g of product, yield: 90.9%. |
58% | With N-Bromosuccinimide; In acetone; at 25℃; for 1h; | Step 1 : A solution of C11 (9 g, 59.016 mM) in acetone (60 mL) was slowly added to a solution of N-N-bromosuccinimide (NBS) (10.44 g, 59.01 mM) in acetone (100 mL) at 25C, and the reaction mixture was stirred for 1 hr. at 250C. The solids were collected by filtration, washed with chilled acetone (5OmL), and dried under reduced pressure to provide 3-bromo-4- chloro-1 H-pyrrolo[2,3-b]pyridine (C38) as pale yellow solid. Yield: 7.5g, 58%. 1HNMR(CDCI3) delta: 11.6-11.7 (b, 1 H), 8.1-8.2 (d, 1 H), 7.2-7.4 (s, 1 H), 7.0-7.01 (d, 1 H). Mass:(M+1) 231 calculated for mol. form. C7H4BrCIN2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Part 2: [0195] 4-Iodo-1H-pyrrolo[2,3-b]pyridine: To a solution of 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 84.3 mmol) and NaI (40 g, 168 mmol) in acetonitrile (150 mL) was slowly added acetyl chloride (12.6 mL, 176 mmol). The mixture was allowed to stir at 80 C. for 4 days, and then the excess acetonitrile was removed in vacuo. 300 mL of 10% K2CO3 (aq) was added to the residue and the mixture extracted with CH2Cl2 (3x100 mL). The combined organic extracts were washed with 10% sodium bisulfite (aq) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product (22.2 g). To a solution of this crude product in THF (150 mL) was added 1M NaOH (100 mL). The mixture was stirred at room temperature for 2 hr prior to evaporation of the solvent in vacuo, dilution with water and extraction with CH2Cl2. The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting brown solid was purified by chromatography over silica gel and recrystallized from acetonitrile to give pure 4-Iodo-1H-pyrrolo[2,3-b]pyridine (9.75 g, 48%). MS (ES+): 245 [MH+]. | |
39% | Intermediate 1.1: 4-iodo-1H-pyrrolo[2,3-b]pyridine Acetyl chloride (2.34 mL, 2.57 g, 32.8 mmol) was added dropwise to a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 13.1 mmol) and sodium iodide (13.8 g, 91.8 mmol) in acetonitrile (25 mL). The resulting suspension was heated at 80 C. for 7 days. After cooling to room temperature, the reaction mixture was concentrated under vacuo, and a saturated aqueous solution of potassium carbonate (50 mL) was added to the residue. The mixture was then extracted with dichloromethane (3*50 mL), the combined organic phase was washed with a saturated solution of sodium bisulfite (2*50 mL) and brine (50 mL), dried over sodium sulfate and concentrated under vacuo. The residue was dissolved in THF (25 mL) and added to an aqueous solution 1N of sodium hydroxide (15 mL). The resulting solution was stirred at 25 C. for 3 h. The reaction mixture was then concentrated under vacuo, and water (100 mL) was added to the residue. The mixture was extracted with dichloromethane (3*50 mL), the combined organic phase was washed with brine (50 mL), dried over sodium sulfate and concentrated under vacuo. The residue was purified by chromatography on a SP1 Biotage system, using hexanes and ethyl acetate as eluents to afford the title compound (1.26 g, 39%) as a yellow solid (HPLC: 66%, RT: 5.77 min) 1H NMR (CDCl3) delta=11.77 (br s, 1H), 7.94 (d, J=5.1 Hz, 1H), 7.51 (d, J=5.1 Hz, 1H), 7.44 (d, J=3.7 Hz, 1H), 6.41 (d, J=3.3 Hz, 1H); MS (m/z) 245 [M+H]+ (127I). | |
39% | With acetyl chloride; sodium iodide; In acetonitrile; at 80℃; for 168h; | Step 1 : To a solution of 4-chloro-1 H-pyrrolo[2,3-b]pyridine (2.00 g, 13.1 mmol) and sodium iodide (13.8 g, 91.8 mmol) in acetonitrile (25 mL) was added dropwise acetyl chloride (2.34 mL, 2.57 g, 32.8 mmol) and the resulting suspension was heated at 80 C for 7 days. After cooling the reaction mixture was concentrated under vacuo and a saturated aqueous solution of potassium carbonate (50 mL) was added to the residue. The mixture was extracted with dichloromethane (3 x 50 mL), the combined organic phase washed with a saturated solution of sodium bisulfite (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. To a solution of the residue in THF (25 mL) was added an aqueous solution 1 N of sodium hydroxide (15 mL) and the resulting solution was stirred at room temperature for 3 h. The reaction mixture was then concentrated under vacuo and water (100 mL) was added to the residue. The mixture was extracted with dichloromethane (3 x 50 mL), the combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. The residue was purified on silica gel column using column using hexane / ethyl acetate as eluent to give 4-iodo- H-pyrrolo[2,3- b]pyridine (1.26 g, 39%) as a yellow solid; LCMS (ESI) 245 (M+H); HPLC 66%, RT: 5.77 min; H NMR (400 MHz, CHLOROFORM-d) delta ppm: 1 1.77 (br s, 1 H), 7.94 (d, J=5.1 Hz, 1 H), 7.51 (d, J=5.1 Hz, H), 7.44 (d, J=3.7 Hz, 1 H), 6.41 (d, J=3.3 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[249] A mixture of 4-chloro-7-azaindole (1.516g, 10 mmole) in 1,4-dioxane (48mL) and water ?(12mL) in a 25OmL, two-necked round bottomed flask was charged with K2CO3 (0.82Og, 5.9mmole), [4- (N-BOC-aminornethyl)phenylboronic acid (2.88g, 11.5mmole), Pd(dppf)2Cl2-CH2Cl2 catalyst (371mg, 0.45mmole). Nitrogen was bubbled into the reaction mixture for 15min at rt and then heated at 1000C overnight under nitrogen atmosphere. The reaction mixture was cooled to rt and added triethylamine (3mL) and evaporated to dryness and purified by column chromatography. The crude was taken in methylene chloride and loaded onto the column. The column was eluted with 20-40% ethyl acetate in methylene chloride, the desired fractions from column were collected and the resulting solid was triturated with hot isopropyl ether, cooled to rt and filtered to give the title compound as a pale yellow solid. 1H NMR (CDCl3): delta 1.49 (s, 9H), 4.41 (d, 2H, J = 6.3 Hz), 4.98 (brs, IH), 6.79 (m, IH), 7.17 (d, IH, J = 4.8 Hz), 7.39 (t, IH, J = 3.0 Hz), 7.44 (d, 2H, J = 8.4 Hz), 7.73 (d, 2H, J = 8.4 Hz), 8.37 (d, IH5 J = 5.1 Hz), 10.01 (brs, IH); MS (ES+): m/z 324.09 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | A solution of meta-chlorobenzoic acid (14 g, 54 mmol) in ethyl acetate (30 mL) was dropwise added to a solution of 1H-pyrrolo[2,3-b]pyridine (5.3 g, 45 mmol) in ethyl acetate (45 mL) over 1 hr with stirring at 0C. After completion of the dropping, the mixture was stirred at room temperature for 3 hr, followed by leaving to stand at 0C. The resulting crystals were collected by filtration, washed with ethyl acetate, and then dried under reduced pressure. The crystals were dissolved in water (30 mL), and then 30% K2CO3 was added until the pH of the solution reached 10. The solution was left to stand at room temperature for 1 hr and then at 0C for 1 hr. The resulting precipitate was collected by filtration and was washed with ether to yield 3.5 g (58%) of N-oxide. The N-oxide (3.0 g, 22 mmol) was dissolved in DMF (16 mL). The resulting solution was heated at 50C, and a solution of methanesulfonyl chloride (4.7 mL, 60 mmol) in DMF (6.4 mL) was dropwise added to the solution at 70C. This reaction solution was stirred at 75C for 2 hr. The reaction solution was added to ice and was neutralized with 10 N NaOH at 0C, followed by stirring at room temperature for 1 hr. The resulting precipitate was collected by filtration, washed with water, and dried at 60C under reduced pressure to yield 2.7 g (80%) of the target 4-chloro-1H-pyrrolo[2,3-b]pyridine. 4-Chloro-1H-pyrrolo[2,3-b]pyridine (2.7 g, 18 mmol) and NaI (13 g, 88 mmol) were dissolved in acetonitrile (28 mL), and CH3COCl (3.5 mL, 50 mmol) was added thereto with stirring at room temperature. The reaction solution was heated at 85C for 12 hr and then cooled to room temperature, and 10% Na2CO3 (28 mL) and 10% NaHSO3 (28 mL) were added thereto, followed by stirring at room temperature for 15 min. Ethyl acetate was added thereto for separation, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with a silica gel column to yield 4-iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g) and 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g). 4-Iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g, 7.0 mmol) was dissolved in ethanol (70 mL) and refluxed in methanol containing 28% sodium methoxide (1.4 mL, 7.0 mmol) for 1 hr. The reaction solution was concentrated and separated between ethyl acetate and an aqueous saturated ammonium chloride solution. The organic layer was washed with an aqueous saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated, and then combined with 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g) obtained above. The mixture was recrystallized from ethanol to yield 4-iodo-1H-pyrrolo[2,3-b]pyridine (4.0 g, 92%). 4-Iodo-1H-pyrrolo[2,3-b]pyridine: 1H NMR (500 MHz, DMSO-d6) delta 12.01 (s, 1H), 7.89 (d, 1H, J = 5.0 Hz), 7.59 (t, 1H, J = 3.1 Hz), 7.51 (d, 1H, J = 5.0 Hz), 6.27 (d, 1H, J = 3.4 Hz). |
Tags: 4-Chloro-7-azaindole | Other Aromatic Heterocycles | Pyrroles | Pyridines | Chlorides | Indoles | Organic Building Blocks | Heterocyclic Building Blocks | 55052-28-3
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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 |
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