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CAS No. : | 479633-63-1 | MDL No. : | MFCD09907939 |
Formula : | C13H10ClN3O2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BTOJSYRZQZOMOK-UHFFFAOYSA-N |
M.W : | 307.76 | Pubchem ID : | 44228967 |
Synonyms : |
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 15 |
Fraction Csp3 : | 0.08 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 76.57 |
TPSA : | 73.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.93 cm/s |
Log Po/w (iLOGP) : | 2.44 |
Log Po/w (XLOGP3) : | 3.17 |
Log Po/w (WLOGP) : | 3.71 |
Log Po/w (MLOGP) : | 2.93 |
Log Po/w (SILICOS-IT) : | 1.86 |
Consensus Log Po/w : | 2.82 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.17 |
Solubility : | 0.0209 mg/ml ; 0.0000679 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.38 |
Solubility : | 0.0129 mg/ml ; 0.0000418 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -5.14 |
Solubility : | 0.00221 mg/ml ; 0.00000718 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.58 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
85% | Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 0.583333 h; Stage #2: at 20℃; for 1 h; |
Example 1; Preparation of Thiazolyl-Pyrrolo[2,3-</]Pyrimidines of the Invention; [0221] 4-Chloro-7-(toluene-4-sulfonyl)-7H-pyrroIo[2,3-*/]pyrimidine; To a solution of (10 g, 65.1 mmol] of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine in 25OmL of dry THF was cautiously added portionwise over 5 minutes time [2.86 g, 71.6 mmol] <n="63"/>sodium hydride (60percent oil dispersion). Reaction was then allowed to stir for 30 minutes at ambient temperature under a blanket of nitrogen gas. [12.96 g, 68.0 mmol] of solid toluene sulphonyl chloride was then added, in one portion and the reaction mixture was allowed to stir for one hour additional at ambient temperature. Ten mL of water was then cautiously added to the reaction (a quench for the excess hydride) and the solvent was removed under reduced pressure to 1/4 the original volume. The residue was then suspended in 300 mL of water, stirred at ambient temperature for 30 minutes and isolated as a white solid via suction filtration. The material was washed with additional water and the damp cake was suspended in a minimum of acetonitrile and stirred overnight at ambient temperature. The precipitate was isolated via suction filtration and washed cautiously with cold acetonitrile and washed with hexanes; material air dried. Yield: 17.2g of an off white solid (85percent). [0222 ] NMR: 500MHz in CDCL3 δ8.75(s,lH), 8.09(d,2H J=8.5Hz),7.78(d,lH J= 4.1Hz), 7.36(d,2H J=8.5Hz), 6.70(d,lH J= 4.1Hz), 2.4(s,3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium hydroxide In water; acetone at 0 - 20℃; for 6 h; | EXAMPLE 13-((3Λ,4Λ)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-rf]pyrimidin-4- yl)amino)piperidin-l-yl)-3-oxopropanenitrile mono citrate salt (CP-690550 citrate salt)Step 1[00151] 4-Chloro-7-tosyl-7H-pyrrolor2,3-6πpynmidine: At about O 0C, sodium hydroxide (2 mol/L in water, 8 mL, 1.20 equiv.) was added to a solution of 4- methylbenzene-1-sulfonyl chloride (2.7 g, 13.9 mmol, 1.10 equiv.) and 4-chloro- 7H-pyrrolo[2,3-J]pyrimidine (2 g, 12.8 mmol, 1.00 equiv.) in acetone (20 mL). The resulting solution was stirred at about 20 0C for about 6 hours. The solids were collected by filtration and washed with acetone/water to give the title product as a white solid (4.0 g; yield = 97percent). 1H NMR (300 MHz, CDCl3) δ: 8.78 (s, IH), 8.11 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 4.2 Hz, IH), 7.34 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 4.2 Hz, IH), 2.42 (s, 3H). LC-MS: m/z = 308/310 (M+H)+. |
95% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h; | Example 1; 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine; A slurry of 1 (307 mg, 2.00 mmol), Tosyl-chloride (418 mg, 2.20 mmol) and freshly ground K2CO3 (1.1 g, 8.0 mmol) in DMF (5.0 mL) was stirred at R.T. for 2 h. The mixture was partitioned between water and EtOAc and the organic phase was washed with brine (2.x.), dried (Na2SO4), filtered, and concentrated to provide the title compound (583 mg, 1.89 mmol, 95percent yield) as a white solid. |
95% | With sodium hydroxide In acetone at 20℃; | Dissolve 4-chloro-pyrrolo[2,3-d]pyrimidine or intermediate 2 (10 mmol) in acetone (35 mL), add p-toluenesulfonyl chloride (1 mmol) in an ice bath, and then add 2.0 mol/L NaOH solution (12·5 mmol, 6.2 mL) was stirred overnight at room temperature. After the reaction was completed, a large amount of white solids precipitated, which was filtered. The filter cake was washed with 20 mL of acetone/water (1:1) and dried to obtain Intermediate 3. 4-Chloro-7-p-toluenesulfonyl 7H-pyrrolo[2,3-d]pyrimidine (3a) White solid, 95percent yield |
90.1% | With sodium hydroxide In water; acetone at -5 - 30℃; for 5 h; | Example 7; Preparation of 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine:; To a clean, dry, nitrogen-purged reactor were charged acetone (87.5 ml), p-toluenesulfonyl chloride (17.1 g, 0.09 mol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 0.16 mol). The reactor was cooled to between -5.0 to 5.00C and 2.5 M sodium hydroxide (78.1 ml) was added at a rate to maintain the temperature below 5.00C. The reactor was warmed to between 20-300C and stirred for a minimum of 5 hours. The resulting solids were isolated by filtration and washed with acetone/water (1 :1 , 25 ml each). After drying for a minimum of 12 hours under vacuum at 40-500C with slight nitrogen bleed, 44.9 g (90.1percent) of the title compound were isolated. Mp 140.2-147.70C. Anal. Calcd. for C13H10CIN3O2S: C, 50.73; H, 3.28; N, 13.65. Found: C,50.50; H, 3.06; N, 13.63. 1H NMR (400 MHz, CZ6-DMSO): δ 8.79 (s, 1 H), 8.09 (d, J=4.2 Hz, 1 H), 8.01 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 6.92 (d, J=4.2 Hz, 1 H), 2.32 (s, 3H). 13C NMR (400 MHz, dg- DMSO): δ 153.2, 152.7, 151.2, 147.2, 134.3, 131.0, 129.3, 128.5, 119.9, 103.9, 21.8. |
90% | With sodium hydroxide In water; acetone at 0 - 20℃; for 6 h; | P-toluenesulfonyl chloride (67.5 g, 348 mmol, 1.10 eq.) and 4-chloro-7-Hpyrrolo[2,3-d]pyrimidine (50 g,320 mmol, 1.0 eq.) was dissolved in acetone (500 ml), sodium hydroxide solution (2 Min water, 200 ml, 1.20 eq.) was slowly added thereto at 0°C, and the reaction was stirred at 20°C for 6 hours to precipitate the solid. Filtration and washing with acetone and water gave the white target compound (90 g, yield = 90percent). |
80% | With sodium hydroxide In acetone at 20℃; | A mixture of 4-c oro-7B~pyrfolo[2.s3-dJpyrimidme (10.0 g, 65 mraol), TsCl (13.7 g, 72 iirniol) and NaOH (40 ml,, 2N) in acetone (100 mL) was stirred at room temperature overnight. The resulting solid w s collected by filtration and washed with acetone and then with water to give the title compound as a white solid (16 g„ 80percent). H NM (400 MHz, CDCh) 5 8.7? (s, I B), 8.09 id J 8 0 Hz, 20), 7.77 (d, J 4.0 Hz, 1.H), 7.33 (4 J .0 1 . 2Π ). 6,70 (d, -4.0 1 / , 2H). 2.40 (s, 3H), |
79.2% | With triethylamine In dichloromethane at 20℃; for 5 h; | The mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.0g, 20mM), NEt3 (6.1g, 60mM) and p-toluene sulfonyl chloride (2.6g, 24mM) were stirred at room temperature in dichloromethane (100mL). After 5h, TLC analysis showed the complete consumption of 4-chloro-7H-pyrrolo [2, 3-d] pyrimidine. The reaction mixture was quenched by the addition of water (70mL). After quenching the reaction, the reaction mixture was poured into separator funnel and the aqueous layer was extracted with dichloromethane (100mL×3). The combined organic layers were evaporated in vacuo and purified by silica gel column chromatography to get the product 2a (4.9g, 79.2percent) as a white solid. ESI-MS m/z: 308.0 [M+H]+. 1H NMR (300MHz, DMSO‑d6): δ 2.37 (3H, s, CH3), 6.96 (1H, d, pyrrolyl-H, J=4.0Hz), 7.48 (2H, d, ArH, J=8.1Hz), 8.05 (2H, d, ArH, J=8.1Hz), 8.12 (1H, d, pyrrolyl-H, J=4.0Hz), 8.82 (1H, s, pyrimidiny-H). |
45% | With sodium hydroxide In water; acetone at 0 - 20℃; for 6 h; | [0152] To a stirred solution of TsCI (1.35 g, 7.0 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.4 mmol) in acetone (10 mL) was added 2.0 M aqueous NaOH (8 mL, 16 mmol) at 0°C. The mixture was stirred at ambient temperature for 6 hours yielding a suspension. The solid product was collected by filtration and washed with acetone/water to afford the title compound as a white solid (0.9 g, 45percent). MS (ESl) calcd for C13H10C1N3025: 307.0; found:308.1[M+H]. 1H NMR (400 MHz, CDCI3) 6 8.77 (s, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 4.0Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 4.0 Hz, 1H), 2.41 (s, 3H). |
Ca. 2 kg | With sodium hydroxide In acetone at -5 - 30℃; for 1 h; Autoclave; Large scale | Autoclave, 3.5L of acetone, p-toluenesulfonyl chloride and 1.36kg 1kg compound 7, followed by stirring under cooling to 0 ~ -5 , maintained at below 5 2.5M sodium hydroxide solution was added dropwise 3.5L, warmed to completion of the dropwise 20-30 deg.] C for 1 h, TLC monitoring completion of the reaction was filtered, washed with 50percent acetone, slurried, filtered, drained, and dried in vacuo 50 ° to give compound 6 about 2kg. |
124 g | With tetrabutyl-ammonium chloride; potassium carbonate In dichloromethane; water at 20℃; | A mixture of 66 g (0.43 mol) 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 607 g dichloromethane, 3.0 g tetrabutylammonium chloride, 90 g tosyl chloride, 85 g potassium carbonate and 381 g water is stirred efficiently at room temperature until reaction is complete. The phases are separated and the organic phase is washed with 340 g water. The organic phase is treated with 6.0 g of activated charcoal, completed with 318 g water and the organic solvent removed by distillation. The mixture is supplemented by 318 g heptane and the product is centrifuged, washed with heptane and water and vacuum dried at a temperature of not more than 8o°C, yielding 124 g (yield: 0.40 mol, 94percent conversion rate) of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine having a purity of 99.9 area-percent measured by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In water at 100℃; for 16 h; | Dissolve the compound (3R,4R)-1-benzyl-N,4-dimethyl-piperidin-3-amine (4.3 g, 19.7 mmol, 1.0 eq.)In 180 ml of water, the compound 4-chloro-7-(p-toluenesulfonyl)-pyrrolo[2,3-d]pyrimidine is then added thereto.(12.3 g, 39.2 mmol, 2.0 eq.) and potassium carbonate (16.6 g, 119 mmol, 6.0 eq.). The reaction is performed at 100oC for 16 hoursWhen it is, it is then cooled to room temperature. After adding three times with ethyl acetate (500ml), it is backwashed with water and brine.After drying over sodium sulfate and spin-drying, the resulting crude compound was isolated by column chromatography (ethyl acetate/petroleum ether = 1:1) to give pale yellowThe target compound (8.6 g, yield = 90percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine In water; dimethyl sulfoxide at 107℃; for 9 h; Large scale | Add SMA 11.0kg, SMB 12.8kg, DIPEA 19.5kg, DMSO to a 200L reactor50.0 kg, 15.0 kg of purified water, and the temperature was raised to 107°C. After the reaction is complete, add 24.0kg absolute ethanol to room temperature and addWater 30.0kg, stirring and decrystallization 2h, suction filtration, drying at 60±5°C, 17.2kg of white solid. Yield 93.0percent, SMB residue0.3percent, HPLC purity 98.9percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.1% | With potassium carbonate In water at 95 - 105℃; for 10 h; | Example 8; Preparation of [(3R, 4R)-1-benzyl-4-methyl-piperidin-3-yl]-methyl-[7-(4-methyl-benzenesulfonyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amine:; To a clean, dry, nitrogen-purged reactor were charged 4-chloro-7-(4-methyl-benzenesulfonyl)- 7H-pyrrolo[2,3-d]pyrimidine (25.12 g, 0.082 mol), bis-(3R, 4R)-(1-benzyl-4-methyl-piperidine-3-yl)- methylamine di-p-toluoyl-L-tartaric acid (40.31 g, 0.041 mol), potassium carbonate (34.2 g, 0.245 mol), and water (125.6 ml). The mixture was heated to 95-1050C for a minimum of 10 hours, then cooled to 45-550C. Acetonitrile (25 ml) was charged and the slurry was held at 45-55°C for a minimum of 1 hour. The mixture was further cooled to 20-300C and stirred for a minimum of 5 hours. The resulting solids were isolated by filtration and washed with water (50 ml). After drying, 32.8 g (82.1percent) of the title compound were isolated.Mp 181.7-184.4C. Anal. Calcd. for C27H31N5O2S: C, 66.231; H, 6.38; N, 14.3. Found: C, 66.04; H, 6.47; N, 14.44. 1H NMR (400 MHz, CDCI3): δ 8.34 (s, 1 H), 8.06 (d, J=8.7 Hz, 2H), 7.43 (d, J=4.2 Hz, 1 H), 7.30-7.29 (m, 6H), 7.25-7.21 (m, 1H), 6.67-6.66 (m, 1H), 5.14 (bs, 1 H), 3.56-3.44 (m, 5H), 2.82-2.78 (m, 1H), 2.73 (bs, 1H), 2.58-2.55 (m, 1H), 2.38 (s, 3H), 2.31 (bs, 1 H), 2.12 (bs, 1H), 1.74 (bs, 1H), 1.69- 1.61 (m, 1 H), 0.90 (d, J=7.0 Hz, 3H). 13C NMR (400 MHz, CDCI3): δ 158.2, 152.9, 152.1 , 145.5, 138.7, EPO <DP n="23"/>135.4, 129.9, 129.1, 128.5, 128.4 127.3, 120.8, 106.6, 104.9, 63.7, 55.5 (b), 53.0 (b), 51.8 (b), 35.9 (b), 32.8, 31.4, 21.7 15.9 (b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75 mg | With potassium carbonate In water at 120℃; for 16 h; Inert atmosphere | A mixture of chromium trioxide (49 mg, 0.49 mmol) in sulfuric acid (0.16 mL), acetic acid (0.16 mL) and water (0.11 mL) was added to a stirred solution of 14 (50 mg, 0.24 mmol) in acetone (0.5 mL) at 0 °C. After 2 h at <20 °C the reaction was basified to pH 12 with 33percent aq NH3 at 0 °C and extracted with ether (4*5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in MeOH (0.17 mL) followed by addition of NH2Me (40percent in MeOH, 0.05 mL, 0.49 mmol) and Ti(OiPr)4 (0.08 mL, 0.27 mmol) at 0 °C. After stirring 30 min at room temperature, the reaction mixture was added sodium borohydride (46.5 g, 1.23 mol) in a small portion in 30 min at °0 C and stirred for an additional hour at the same temperature. The reaction mixture was filtered off to obtain crude amine. The crude amine in water (0.65 mL) was added K2CO3 (65 mg, 0.47 mmol) and 15 (120 mg, 0.39 mmol), and the mixture was refluxed (120 °C) for 16 h under argon. After cooling to rt, the resulting mixture was added CH2Cl2 (5 ml) and sonicated crush the solid. The mixture was extracted with CH2Cl2 (4*5 mL) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes, 1:1) to give trans-16 (8 mg, 7percent) as a white solid and cis-16 (75 mg, 63percent) as a white solid. Rf = 0.4 (trans-16), 0.48 (cis-16) (EtOAc/hexanes, 1:1). trans-16: 1H NMR (400 MHz, CDCl3) δ: 8.35 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.37 (d,J = 4 Hz, 1H), 7.32–7.18 (m, 7H), 6.53 (br s, 1H), 3.56, 3.45 (ABq, JAB = 12.8 Hz, 2H), 3.08 (s, 3H), 2.90–2.84 (m, 2H), 2.36 (s, 3H), 2.10–1.95 (m, 2H), 1.80–1.65 (m, 3H), 1.50–1.39 (m, 1H), 0.81 (d, J = 6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 158.0, 152.8, 151.7, 145.2, 138.1, 135.1, 129.6, 129.0, 128.2, 127.1, 120.9, 105.6, 104.7, 62.8, 55.4, 53.4, 33.6, 33.4, 21.6, 18.3. cis-16: [a]D28 = +19.3(c 1.0 CHCl3). 1H NMR (400 MHz, CDCl3) δ: 8.31 (s, 1H), 8.03 (d,J = 8 Hz, 2H), 7.40 (d, J = 3 Hz, 1H), 7.27–7.17 (m, 7H), 6.63 (d,J = 3.2 Hz, 1H), 5.16 (br s, 1H), 3.56 (s, 3H), 3.47, 3.42 (ABq, JAB = 13.2 Hz, 2H), 2.79–2.76 (m, 1H), 2.75 (br s, 1H), 2.52 (d, J = 10.8, 1H), 2.36 (s, 2H), 2.35–2.22 (m, 1H), 2.10–2.03 (m, 1H), 1.70–1.610 (m, 2H), 0.87 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 189.3, 157.9, 152.5, 151.8, 145.2, 135.1, 129.6, 128.9, 128.2, 128.1, 127.1, 120.6, 106.2, 104.6, 63.5, 55.2 (br), 53.1 (br), 51.6 (br), 35.8 (br), 32.5, 31.2, 21.6, 15.7 (br). HRMS (ESI) calcd for C27H31N5O2S [M+H]+: 490.2277, found: 490.2273. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Example 1; Preparation of Thiazolyl-Pyrrolo[2,3-</]Pyrimidines of the Invention; [0221] 4-Chloro-7-(toluene-4-sulfonyl)-7H-pyrroIo[2,3-*/]pyrimidine; To a solution of (10 g, 65.1 mmol] of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine in 25OmL of dry THF was cautiously added portionwise over 5 minutes time [2.86 g, 71.6 mmol] <n="63"/>sodium hydride (60% oil dispersion). Reaction was then allowed to stir for 30 minutes at ambient temperature under a blanket of nitrogen gas. [12.96 g, 68.0 mmol] of solid toluene sulphonyl chloride was then added, in one portion and the reaction mixture was allowed to stir for one hour additional at ambient temperature. Ten mL of water was then cautiously added to the reaction (a quench for the excess hydride) and the solvent was removed under reduced pressure to 1/4 the original volume. The residue was then suspended in 300 mL of water, stirred at ambient temperature for 30 minutes and isolated as a white solid via suction filtration. The material was washed with additional water and the damp cake was suspended in a minimum of acetonitrile and stirred overnight at ambient temperature. The precipitate was isolated via suction filtration and washed cautiously with cold acetonitrile and washed with hexanes; material air dried. Yield: 17.2g of an off white solid (85%). [0222 ] NMR: 500MHz in CDCL3 delta8.75(s,lH), 8.09(d,2H J=8.5Hz),7.78(d,lH J= 4.1Hz), 7.36(d,2H J=8.5Hz), 6.70(d,lH J= 4.1Hz), 2.4(s,3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium hydroxide; In water; acetone; at 0 - 20℃; for 6h; | EXAMPLE 13-((3Lambda,4Lambda)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-rf]pyrimidin-4- yl)amino)piperidin-l-yl)-3-oxopropanenitrile mono citrate salt (CP-690550 citrate salt)Step 1[00151] 4-Chloro-7-tosyl-7H-pyrrolor2,3-6?pynmidine: At about O 0C, sodium hydroxide (2 mol/L in water, 8 mL, 1.20 equiv.) was added to a solution of 4- methylbenzene-1-sulfonyl chloride (2.7 g, 13.9 mmol, 1.10 equiv.) and 4-chloro- 7H-pyrrolo[2,3-J]pyrimidine (2 g, 12.8 mmol, 1.00 equiv.) in acetone (20 mL). The resulting solution was stirred at about 20 0C for about 6 hours. The solids were collected by filtration and washed with acetone/water to give the title product as a white solid (4.0 g; yield = 97%). 1H NMR (300 MHz, CDCl3) delta: 8.78 (s, IH), 8.11 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 4.2 Hz, IH), 7.34 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 4.2 Hz, IH), 2.42 (s, 3H). LC-MS: m/z = 308/310 (M+H)+. |
97.7% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h;Large scale; | 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2kg, 12.96mol) and dichloromethane (40L) were added to the reaction flask at room temperature, stirred and dissolved.Triethylamine (3.88 kg, 38.4 mol) and 4-dimethylaminopyridine (157.6 g, 1.28 mol) were added in that order, and after stirring and dissolved, p-toluenesulfonyl chloride (2.6 kg, 13.6 mol) was added dropwise at 0 C. The chloromethane (30 L) solution was added dropwise, and the mixture was stirred at room temperature for 30 min. After the TLC was applied, the mixture was washed with water (16L×3). The title product (3.9 kg, yield 97.7%) was obtained after drying under reduced pressure. |
97.7% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃;Industrial scale; | 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2 kg, 12.96 mol) and dichloromethane (40 L) were added to a reaction flask at room temperature, and stirred to dissolve. Triethylamine (3.88 kg, 38.4 mol) and 4-dimethylaminopyridine (157.6 g, 1.28 mol) were added successively, and stirred to dissolve. A solution of p-toluenesulfonyl chloride (2.6 kg, 13.6 mol) in dichloromethane (30 L) was added dropwise at 0 C., followed by stirring at room temperature for 30 minutes. After TLC showed that the reaction was completed, the reaction solution was washed with water (16 L×3). The organic phases were combined, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and dried under reduced pressure to obtain the title product (3.9 kg, yield 97.7%). (0109) MS m/z (ESI): 309.0 [M+1] (0110) 1H-NMR (400 MHz, CDCl3) delta 8.77 (s, 1H), 8.10-8.08 (d, 2H), 7.79-7.78 (d, 1H), 7.34-7.32 (d, 2H), 6.72-6.71 (d, 1H), 2.41 (s, 3H). |
95% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | Example 1; 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine; A slurry of 1 (307 mg, 2.00 mmol), Tosyl-chloride (418 mg, 2.20 mmol) and freshly ground K2CO3 (1.1 g, 8.0 mmol) in DMF (5.0 mL) was stirred at R.T. for 2 h. The mixture was partitioned between water and EtOAc and the organic phase was washed with brine (2×), dried (Na2SO4), filtered, and concentrated to provide the title compound (583 mg, 1.89 mmol, 95% yield) as a white solid. |
95% | With sodium hydroxide; In acetone; at 20℃; | Dissolve 4-chloro-pyrrolo[2,3-d]pyrimidine or intermediate 2 (10 mmol) in acetone (35 mL), add p-toluenesulfonyl chloride (1 mmol) in an ice bath, and then add 2.0 mol/L NaOH solution (12·5 mmol, 6.2 mL) was stirred overnight at room temperature. After the reaction was completed, a large amount of white solids precipitated, which was filtered. The filter cake was washed with 20 mL of acetone/water (1:1) and dried to obtain Intermediate 3. 4-Chloro-7-p-toluenesulfonyl 7H-pyrrolo[2,3-d]pyrimidine (3a) White solid, 95% yield |
90.1% | With sodium hydroxide; In water; acetone; at -5 - 30℃; for 5h; | Example 7; Preparation of 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine:; To a clean, dry, nitrogen-purged reactor were charged acetone (87.5 ml), p-toluenesulfonyl chloride (17.1 g, 0.09 mol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 0.16 mol). The reactor was cooled to between -5.0 to 5.00C and 2.5 M sodium hydroxide (78.1 ml) was added at a rate to maintain the temperature below 5.00C. The reactor was warmed to between 20-300C and stirred for a minimum of 5 hours. The resulting solids were isolated by filtration and washed with acetone/water (1 :1 , 25 ml each). After drying for a minimum of 12 hours under vacuum at 40-500C with slight nitrogen bleed, 44.9 g (90.1%) of the title compound were isolated. Mp 140.2-147.70C. Anal. Calcd. for C13H10CIN3O2S: C, 50.73; H, 3.28; N, 13.65. Found: C,50.50; H, 3.06; N, 13.63. 1H NMR (400 MHz, CZ6-DMSO): delta 8.79 (s, 1 H), 8.09 (d, J=4.2 Hz, 1 H), 8.01 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 6.92 (d, J=4.2 Hz, 1 H), 2.32 (s, 3H). 13C NMR (400 MHz, dg- DMSO): delta 153.2, 152.7, 151.2, 147.2, 134.3, 131.0, 129.3, 128.5, 119.9, 103.9, 21.8. |
90% | With sodium hydroxide; In water; acetone; at 0 - 20℃; for 6h; | P-toluenesulfonyl chloride (67.5 g, 348 mmol, 1.10 eq.) and 4-chloro-7-Hpyrrolo[2,3-d]pyrimidine (50 g,320 mmol, 1.0 eq.) was dissolved in acetone (500 ml), sodium hydroxide solution (2 Min water, 200 ml, 1.20 eq.) was slowly added thereto at 0C, and the reaction was stirred at 20C for 6 hours to precipitate the solid. Filtration and washing with acetone and water gave the white target compound (90 g, yield = 90%). |
80% | With sodium hydroxide; In acetone; at 20℃; | A mixture of 4-c oro-7B~pyrfolo[2.s3-dJpyrimidme (10.0 g, 65 mraol), TsCl (13.7 g, 72 iirniol) and NaOH (40 ml,, 2N) in acetone (100 mL) was stirred at room temperature overnight. The resulting solid w s collected by filtration and washed with acetone and then with water to give the title compound as a white solid (16 g? 80%). H NM (400 MHz, CDCh) 5 8.7? (s, I B), 8.09 id J 8 0 Hz, 20), 7.77 (d, J 4.0 Hz, 1.H), 7.33 (4 J .0 1 . 2Pi ). 6,70 (d, -4.0 1 / , 2H). 2.40 (s, 3H), |
79.2% | With triethylamine; In dichloromethane; at 20℃; for 5h; | The mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.0g, 20mM), NEt3 (6.1g, 60mM) and p-toluene sulfonyl chloride (2.6g, 24mM) were stirred at room temperature in dichloromethane (100mL). After 5h, TLC analysis showed the complete consumption of 4-chloro-7H-pyrrolo [2, 3-d] pyrimidine. The reaction mixture was quenched by the addition of water (70mL). After quenching the reaction, the reaction mixture was poured into separator funnel and the aqueous layer was extracted with dichloromethane (100mL×3). The combined organic layers were evaporated in vacuo and purified by silica gel column chromatography to get the product 2a (4.9g, 79.2%) as a white solid. ESI-MS m/z: 308.0 [M+H]+. 1H NMR (300MHz, DMSO-d6): delta 2.37 (3H, s, CH3), 6.96 (1H, d, pyrrolyl-H, J=4.0Hz), 7.48 (2H, d, ArH, J=8.1Hz), 8.05 (2H, d, ArH, J=8.1Hz), 8.12 (1H, d, pyrrolyl-H, J=4.0Hz), 8.82 (1H, s, pyrimidiny-H). |
45% | With sodium hydroxide; In water; acetone; at 0 - 20℃; for 6h; | [0152] To a stirred solution of TsCI (1.35 g, 7.0 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.4 mmol) in acetone (10 mL) was added 2.0 M aqueous NaOH (8 mL, 16 mmol) at 0C. The mixture was stirred at ambient temperature for 6 hours yielding a suspension. The solid product was collected by filtration and washed with acetone/water to afford the title compound as a white solid (0.9 g, 45%). MS (ESl) calcd for C13H10C1N3025: 307.0; found:308.1[M+H]. 1H NMR (400 MHz, CDCI3) 6 8.77 (s, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 4.0Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 4.0 Hz, 1H), 2.41 (s, 3H). |
Ca. 2 kg | With sodium hydroxide; In acetone; at -5 - 30℃; for 1h;Autoclave; Large scale; | Autoclave, 3.5L of acetone, p-toluenesulfonyl chloride and 1.36kg 1kg compound 7, followed by stirring under cooling to 0 ~ -5 , maintained at below 5 2.5M sodium hydroxide solution was added dropwise 3.5L, warmed to completion of the dropwise 20-30 deg.] C for 1 h, TLC monitoring completion of the reaction was filtered, washed with 50% acetone, slurried, filtered, drained, and dried in vacuo 50 to give compound 6 about 2kg. |
124 g | With tetrabutyl-ammonium chloride; potassium carbonate; In dichloromethane; water; at 20℃; | A mixture of 66 g (0.43 mol) 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 607 g dichloromethane, 3.0 g tetrabutylammonium chloride, 90 g tosyl chloride, 85 g potassium carbonate and 381 g water is stirred efficiently at room temperature until reaction is complete. The phases are separated and the organic phase is washed with 340 g water. The organic phase is treated with 6.0 g of activated charcoal, completed with 318 g water and the organic solvent removed by distillation. The mixture is supplemented by 318 g heptane and the product is centrifuged, washed with heptane and water and vacuum dried at a temperature of not more than 8oC, yielding 124 g (yield: 0.40 mol, 94% conversion rate) of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine having a purity of 99.9 area-% measured by HPLC. |
With triethylamine;dmap; In dichloromethane; for 0.5h; | Into a solution of 6-chloro deazapurine (2.0 g, 13 mmol, 1.0 eq.) in dichloromethane (65 ml) are added triethylamine (1.98 ml, 14.3 mmol, 1.1 eq.) and 4- dimethylamino pyridine (catalytic). Tosyl chloride (2.55 g, 13.4 mmol, 1.03 eq.) is added in portions into the reaction mixture which is further equilibrated for 30 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to afford the 4- chloro-7-(toluene-40sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine which is used in the next step without further purification. | |
With triethylamine;dmap; In dichloromethane; for 0.5h;Product distribution / selectivity; | To a solution of 6-chloro deazapurine (2.0 g, 13 mmol, 1.0 eq.) in dichloromethane (65 ml) is added triethylamine (1.98 ml, 14.3 mmol, 1.1 eq.) and A- dimethylamino pyridine (catalytic). Tosyl chloride (2.55 g, 13.4 mmol, 1.03 eq.) is added in portions into the reaction mixture which is further equilibrated for 30 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to afford the title product 2. The titled compound is used in the next step without further purification.; 5. 4-Chloro-7-(toluene-4-sulfonyl)-7H-py rrolo [2,3-d] py rimidine[00115] Into a solution of 6-chloro deazapurine (4, 10.0 g, 65 mmol, 1.0 eq.) in dichloromethane (325 ml) are added triethylamine (9.9 ml, 71.5 mmol, 1.1 eq.) and 4- dimethylamino pyridine (catalytic). Tosyl chloride (12.76 g, 66.9 mmol, 1.03 eq.) is added in portions into the reaction mixture which is further equilibrated for 30 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated EPO <DP n="35"/>and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to afford the title product which is used in the next step without further purification. | |
In acetone; at 20℃; for 8h; | Weigh 10 grams of 4-chloropyrrole[2,3-d]pyrimidine and 18.6 grams of p-methylsulfonyl chloride into a three-necked flask, measure 20 ml of acetone solution as a solvent, and stir at room temperature for 8 h to obtain Ts protection 4-chloropyrrole[2,3-d]pyrimidine, when the reaction system is too hot, the temperature can be lowered by taking an ice bath. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium acetate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 150℃; for 0.166667h;Microwave; | 4-cyclopentenyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine; A mixture of 4-chloro-7-tosyl-7H-pyrrolo[2,3-dlpyrimidine (62 mg, 0.20 mmol), cyclopenteneboronic acid (27 mg, 0.24 mmol), KOAc (78 mg, 0.80 mmol), and Pd(PPh3)4 (11 mg, 0.010 mmol), in dioxane (0.6 mL) was heated to 150 C. (MW, 600s) in a sealed tube. The reaction mixture was subjected to flash chromatography (SiO2, 0-50% EtOAc-hexanes, gradient elution) to provide the title compound (55 mg, 0.16 mmol, 81 % yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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88% | With hydrogen iodide; In water; at 0 - 20℃; for 6h; | Example 9; 4-Iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine: [5 g. 16.2 mmol] of 4-Chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (as described in Example 1) was added in small portions, to 100 mL of cold stirring 47% stabilized hydriodic acid at 0 C. and stirred for one hour cold; the temperature was then allowed to warm to ambient temperature and stirred an additional 5 hrs. The reaction mixture was diluted with water and the solid was isolated via suction filtration, the solid being washed with additional water. The crude solid was dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate solution twice, brined, dried (Na2SO4) and the solvent was removed under reduced pressure and triturated with a 2:1 mixture of hexanes/ MTBE to yield 5.7 g of a white material (88%). 1H NMR: 500 Mhz in CDCL3 delta8.61(s,1H), 8.06(d,2H J=8.5 Hz), 7.75(d,1H J=4.1 Hz), 7.32(d,2H J=8.5 Hz), 6.45(d,1H J=4.1 Hz), 2.4(s,3H). |
88% | 4-Iodo-7-(toluene-4-sulfonyI)-7H-pyirolo[2,3-d]pyriinidine; [5g. 16.2mmol] of 4-Chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1,3-dimethyl-2-imidazolidinone; at 120℃; for 8h; | A mixture of N-[3-(1H-imidazol-2-ylamino)-4-methyl-phenyl]-benzamide (627 mg, 2.14 mmol), 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (600 mg, 1.95 mmol), DIEA (1.02 mL, 5.86 mmol) in 1,3-dimethyl-2-imidazolidinone (2.0 ml) is heated at 120 C. for 8 hours. The reaction mixture is cooled to room temperature. Water is added. The solid is collected by filtration, washed with water, dried and used for the next reaction without any further purification. The solid is dissolved in THF (30 mL) and TBAF (1M in THF, 3.0 mL, 3.0 mmol) is added. The reaction mixture is heated at 60 C. After about 16 hours, the reaction mixture is cooled to room temperature, THF is removed and water is added. The solid is collected by filtration, washed with methanol and dried to afford N-{4-methyl-3-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-imidazol-2-ylamino]-phenyl}-benzamide, which is used for the next reaction without any further purification: 1H NMR 400 MHz (DMSO-d6) delta 12.63 (s, 1H), 11.23 (s, 1H), 10.25 (s, 1H), 8.82 (d, 1H, J=2.0 Hz), 8.80 (s, 1H), 7.99 (d, 2H, J=7.2 Hz), 7.86 (d, 1H, J=2.8 Hz), 7.74 (t, 1H, J=3.2 Hz), 7.60-7.56 (m, 1H), 7.52 (t, 2H, J=7.6 Hz), 7.36 (dd, 1H, J=8.0, 1.9 Hz), 7.18 (d, 1H, J=1.8 Hz), 7.06 (m, 1H), 6.99 (d, 1H, J=2.4 Hz), 2.40 (s, 3H); MS m/z 410.1 (M+1). | |
With N-ethyl-N,N-diisopropylamine; In 1,3-dimethyl-2-imidazolidinone; at 120℃; for 8h; | A mixture of N-[3-(lH-imidazol-2-ylamino)-4-methyl-phenyl]-benzamide(627 mg, 2.14 mmol), 4-chloro-7-(toluene-4-sulfonyl)-7Eta-pyrrolo[2,3-d]pyrimidine (600 mg, 1.95 mmol), DIEA (1.02 mL, 5.86 mmol) in l,3-dimethyl-2-imidazolidinone (2.0 ml) is heated at 12O0C for 8 hours. The reaction mixture is cooled to room temperature. Water is added. The solid is collected by filtration, washed with water, dried and used for the next reaction without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
NaH (60% dispersion in mineral oil, 94 mg, 2.35 mmol) is added to a solution of 2-chloro-lH- imidazole (252mg, 2.47 mmol) in DMSO (10 mL) at room temperature. After 30 minutes, 4-chloro-7-(toluene-4-sulfonyl)-7Eta-pyrrolo[2,3- d]pyrimidine (691 mg, 2.25 mmol) is added. The flask is sealed and heated at 8O0C for 1 hour. The reaction is cooled to room temperature, neutralized with saturated ammonium chloride and extracted with ethyl acetate twice. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography (silica gel, eluting with ethyl acetate: hexanes from 5% to 50%) affords 4- (2-chloro-imidazol-l-yl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-J]pyrimidine: 1H NMR 400 MHz (CDCl3) delta 8.99 (s, IH), 8.15(d, 2H, J= 8.0Hz), 7.88 (d, IH, J= 8.4 Hz), 7.36 - 7.38 (m, 3H), 7.16 (d, IH, J= 2.0 Hz), 6.70 (d, IH, J= 8.0 Hz), 2.43 (s, 3H); MS m/z 374.00 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | To the suspension of NaH (25 mg, 0.62 mmol, 3.1 eq.) in DMSO (2.0 ml) is added dimethyl malonate (0.071 ml, 0.62 mmol, 3.1 eq.) at 230C. After the evolution of hydrogen had ceased, 2 (64 mg, 20 mmol, 1.0 eq.) is added. The reaction is further equilibrated at 80C for 3 hours. The reaction is then cooled to room temperature, and quenched with saturated NH4Cl. The organics are extracted out using ethyl acetate as solvent, dried over Na2SO4, filtered and concentrated to afford the desired product (79 mg, 94%). |
Yield | Reaction Conditions | Operation in experiment |
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82.1% | With potassium carbonate; In water; at 95 - 105℃; for 10.0h; | Example 8; Preparation of [(3R, 4R)-1-benzyl-4-methyl-piperidin-3-yl]-methyl-[7-(4-methyl-benzenesulfonyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amine:; To a clean, dry, nitrogen-purged reactor were charged 4-chloro-7-(4-methyl-benzenesulfonyl)- 7H-pyrrolo[2,3-d]pyrimidine (25.12 g, 0.082 mol), bis-(3R, 4R)-(1-benzyl-4-methyl-piperidine-3-yl)- methylamine di-p-toluoyl-L-tartaric acid (40.31 g, 0.041 mol), potassium carbonate (34.2 g, 0.245 mol), and water (125.6 ml). The mixture was heated to 95-1050C for a minimum of 10 hours, then cooled to 45-550C. Acetonitrile (25 ml) was charged and the slurry was held at 45-55C for a minimum of 1 hour. The mixture was further cooled to 20-300C and stirred for a minimum of 5 hours. The resulting solids were isolated by filtration and washed with water (50 ml). After drying, 32.8 g (82.1%) of the title compound were isolated.Mp 181.7-184.4C. Anal. Calcd. for C27H31N5O2S: C, 66.231; H, 6.38; N, 14.3. Found: C, 66.04; H, 6.47; N, 14.44. 1H NMR (400 MHz, CDCI3): delta 8.34 (s, 1 H), 8.06 (d, J=8.7 Hz, 2H), 7.43 (d, J=4.2 Hz, 1 H), 7.30-7.29 (m, 6H), 7.25-7.21 (m, 1H), 6.67-6.66 (m, 1H), 5.14 (bs, 1 H), 3.56-3.44 (m, 5H), 2.82-2.78 (m, 1H), 2.73 (bs, 1H), 2.58-2.55 (m, 1H), 2.38 (s, 3H), 2.31 (bs, 1 H), 2.12 (bs, 1H), 1.74 (bs, 1H), 1.69- 1.61 (m, 1 H), 0.90 (d, J=7.0 Hz, 3H). 13C NMR (400 MHz, CDCI3): delta 158.2, 152.9, 152.1 , 145.5, 138.7, EPO <DP n="23"/>135.4, 129.9, 129.1, 128.5, 128.4 127.3, 120.8, 106.6, 104.9, 63.7, 55.5 (b), 53.0 (b), 51.8 (b), 35.9 (b), 32.8, 31.4, 21.7 15.9 (b). |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine;dmap; In dichloromethane; for 0.5h; | Into a solution of 6-chloro deazapurine (2.0 g, 13 mmol, 1.0 eq.) in dichloromethane (65 ml) are added triethylamine (1.98 ml, 14.3 mmol, 1.1 eq.) and 4-dimethylamino pyridine (catalytic). Tosyl chloride (2.55 g, 13.4 mmol, 1.03 eq.) is added in portions into the reaction mixture which is further equilibrated for 30 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to afford the 4-chloro-7-(toluene-40sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine which is used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
NaH (60% dispersion in mineral oil, 94 mg, 2.35 mmol) is added to a solution of <strong>[16265-04-6]2-chloro-1H-imidazole</strong> (252 mg, 2.47 mmol) in DMSO (10 mL) at room temperature. After 30 minutes, 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (691 mg, 2.25 mmol) is added. The flask is sealed and heated at 80 C. for 1 hour. The reaction is cooled to room temperature, neutralized with saturated ammonium chloride and extracted with ethyl acetate twice. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography (silica gel, eluding with ethyl acetate:hexanes from 5% to 50%) affords 4-(2-chloro-imidazol-1-yl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine: 1H NMR 400 MHz (CDCl3) delta 8.99 (s, 1H), 8.15 (d, 2H, J=8.0 Hz), 7.88 (d, 1H, J=8.4 Hz), 7.36-7.38 (m, 3H), 7.16 (d, 1H, J=2.0 Hz), 6.70 (d, 1H, J=8.0 Hz), 2.43 (s, 3H); MS m/z 374.00 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; at 100℃; under 15001.5 Torr; for 22h; | Description 83; Ethyl 7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-c/lpyrimidine-4-carboxylate (E83)4-Chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (2 g, 6.50 mmol), 1 ,1 '-bis(diphenylphosphino)ferrocene (0.36 g, 0.649 mmol), palladium(ll) acetate (0.146 g, 0.650 mmol) and sodium acetate (1.066 g, 13.00 mmol) were stirred in ethanol (40 ml.) in a 100 ml. Parr apparatus. The vessel was pressurised to 20 bar with carbon monoxide then heated at 100 0C for 22 hours. After cooling and release of carbon monoxide, the solvent was evaporated and the residue purified by flash <n="77"/>chromatography (0-50% ethyl acetate/isohexane) to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 346 (Ci6H15N3O4S requires [M+H]+ at m/z 346). |
Yield | Reaction Conditions | Operation in experiment |
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With zinc;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl acetamide; at 120℃; for 3h; | Description 77; 7-[(4-Methylphenyl)sulfonyl]-7H-pyrrolo[2,3-cf]pyrimidine-4-carbonitrile (D77)4-Chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 3.25 mmol), zinc (25.5 mg, 0.390 mmol), 1 ,1 '-bis(diphenylphosphino)ferrocene (72.1 mg, 0.130 mmol), tris(dibenzylideneacetone)dipalladium(0) (59.5 mg, 0.065 mmol) and zinc cyanide (229 mg, 1.950 mmol) were added together in N,N-dimethylacetamide (6.5 mL) and the resulting mixture was heated at 120 0C under argon for 3 hours. The reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (x 3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-40 % ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a white solid. LC/MS (ES+ve): [M+H]+ at m/z 299 (Ci4H10N4O2S requires [M+H]+ at m/z 299). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In water; at 100℃; for 16.0h; | Dissolve the compound <strong>[477600-70-7](3R,4R)-1-benzyl-N,4-dimethyl-piperidin-3-amine</strong> (4.3 g, 19.7 mmol, 1.0 eq.)In 180 ml of water, the compound 4-chloro-7-(p-toluenesulfonyl)-pyrrolo[2,3-d]pyrimidine is then added thereto.(12.3 g, 39.2 mmol, 2.0 eq.) and potassium carbonate (16.6 g, 119 mmol, 6.0 eq.). The reaction is performed at 100oC for 16 hoursWhen it is, it is then cooled to room temperature. After adding three times with ethyl acetate (500ml), it is backwashed with water and brine.After drying over sodium sulfate and spin-drying, the resulting crude compound was isolated by column chromatography (ethyl acetate/petroleum ether = 1:1) to give pale yellowThe target compound (8.6 g, yield = 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In water; at 100℃; for 16h; | Step 7[00157] N-(l-Benzyl-4-methylpiperidin-3-yl)-N-methyl-7-tosyl-7H-pyrrolo[2,3- 6ripyrimidin-4-amine: 4-Chloro-7-tosyl-7H-pyrrolo[2,3-J]pyrimidine (2 g, 6.37 mmol, 2.00 equiv.) and potassium carbonate (2.7 g, 19.4 mmol, 6.00 equiv.) were added to a solution of (l-benzyl-4-methyl-pipendin-3-yl)-methyl-amine (700 mg, 2.89 mmol, 1.00 equiv.) in water (30 mL). The solution was stirred at about 100 C for about 16 hours, and then was cooled to ambient temperature. Following standard extractive workup with ethyl acetate (3 x 100 mL), the crude residue was purified by silica gel column chromatography (ethyl acetate / petroleum (1: 1)) to give the title product as a light yellow solid (1.5 g; yield = 96%). 1H NMR (300 MHz, CDCl3) delta: 8.36 (s, IH), 8.08 (d, / = 8.4 Hz, 2H), 7.45 (d, / = 4.2 Hz, IH), 7.20-7.42 (m, 7H), 6.75 (d, / = 4.2 Hz, IH), 5.05-5.20 (m, IH), 3.40-3.65 (m, 5H), 2.70-2.92 (m, 2H), 2.50-2.70 (m, IH), 2.42 (s, 3H), 2.23-2.42 (m, IH), 2.10-2.23 (m, IH), 1.55-1.75 (m, 2H), 0.92 (d, / = 6.9 Hz, 3H). LC-MS: m/z = 490 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 16h; | A mixture of 4- chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.32 mmol) (synthesized as describe by Cox, P. J.; Majid, T.; Amendola, S.; Deprets, S. D.; Edlin, C; Pedgrift, B.; Halley, F.; Edwards, M.; Baudoin, B., Mclay, L; Aldous, D. J. PCT Int. Appl. (2003), 66 pp. WO 2003000695), piperidin-3-one (32 mg, 0.32 mmol) and Et3N (90 mu, 0.64 mmol) in DMF (4 mL) was heated at 80 C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with aq. citric acid and aq. NaHC03, dried ( a2S04), filtered and concentrated in vacuo to afford a residue which was purified by chromatography (silica gel, gradient EtOAc in hexanes) to afford 86.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 4h; | tert-Butyl l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylcarbamate. To a mixture of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1 1.7 g, 25 mmol) and tert-bu yl piperidin-3- ylcarbamate (5.0, 25 mmol) in DMF (50 mL) was added DIEA (3.2 g, 4.3 mL, 25 mmol) and the solution stirred was at 80 C for 4 h. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography to give compound 16.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 12h; | To a solution of compound 23.7 in MeOH (2 mL) and water (1 mL) was added K2C03 (6 eq.). The resulting mixture was stirred at 70 C for 1 h. The reaction mixture was cooled to RT, filtered and concentrated in vacuo to afford a residue, which was then purified by reverse phase chromatography C18 column and 10% acetonitrile/water containing 0.1% TFA to afford compound 124. EIMS (m/z): 527 (M+l); .H NMR (CD3OD, 400 MHz): delta 2.14 (m, 2 H), 2.44 (t, J = 1 1.49 Hz, 1 H), 2.74 (m, 1 H), 3.19 (m, 2 H), 3.39 (m, 4 H), 3.59 (m, 3 H), 4.62 (m, 1 H), 4.75 (d, J= 12.72 Hz, 1 H), 6.54 (d, J = 2.45 Hz, 1 H), 7.1 1 (d, J = 2.45 Hz, 1 H), 7.16 (d, J = 7.34 Hz, 1 H), 7.29 (m, 3 H), 7.44 (m, 3 H), 7.57 (s, 1 H), 8.12 (s, 1 H) ppm. |
52% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 4h;Heating; | A mixture of 2-(3-nitrophenyl)piperazine 44 (0.9 g, 4.35 mmol,1.0 eq), 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.4 g,4.56 mmol, 1.1 eq) and DIEA (0.84 g, 6.53 mmol, 1.5 eq) in DMF (15 mL) was stirred at 60 C for 4 hr. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried (Na2SO4), filtrated and concentrated in vacuo to afford a residue which purified by silica gel column (Petroleum ether/EtOAc=1/1) to afford 4-(3-(3-nitrophenyl)piperazin-1-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 45 as light yellow solid (1.2 g, 52%).1H NMR (400 MHz, CDCl3) delta: 8.43 (s, 1H), 8.38 (s, 1H), 8.18 (dd,J=8.4, 1.2 Hz, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 7.57-7.50(m, 2H), 7.29 (d, J=8.0 Hz, 2H), 6.56 (d, J=4.4 Hz, 1H), 4.71 (d,J=12.4 Hz, 1H), 4.57 (d, J=12.4 Hz, 1H), 3.98 (dd, J=10.4, 2.8 Hz,1H), 3.37-3.23 (m, 2H), 3.08-2.99 (m, 2H), 2.39 (s, 3H). 13C NMR(400 MHz, CDCl3) delta: 156.9, 152.9, 152.2, 148.5, 145.5, 143.5, 135.0,133.3, 129.7, 129.6, 128.3, 123.1, 122.1, 122.0, 105.0, 104.6, 59.5,52.6, 46.2, 45.8, 21.7; HR-ESI-MS (m/z): 479.1497, calcd for [M+H]+C23H22N6O4S: 479.1496. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine; In N,N-dimethyl-formamide; at 110℃; for 12h; | To a solution of (4-methyl-3-piperidin-3-yl-phenyl)- carbamic acid tert-butyl ester (0.050 g, 0.17 mmol) in DMF (0.7551 g, 10.33 mmol) was added 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-JJpyrimidine (0.058 g, 0.19 mmol) and Et3N (0.035 g, 0.34 mmol). The solution was heated to 1 10 C for 12 h, cooled to RT, and diluted with water and EtOAc. The organic phase was separated, washed with brine, water, dried (Na2SC>4), filtered and concentrated in vacuo to afford an oil. The oil was purified by silica gel chromatography (gradient Hexane-EtOAc) to afford the named compound (72% yield). .H NMR (CDCI3, 400 MHz): delta 8.42 (s, 1H), 8.06-8.12 (m, 2H), 8.04 (s, 1H), 7.48 (d, J = 4.04 Hz, 1H), 7.36-7.43 (m, 1H), 7.31 (d, J = 7.58 Hz, 2H), 7.07-7.13 (m, 1H), 7.05 (d, J = 2.02 Hz, 1H), 6.56 (d, J = 4.55 Hz, 1H), 6.40-6.49 (m, 1H), 4.66-4.81 (m, 2H), 3.03-3.20 (m, 2H), 2.41 (s, 3H), 2.28 (s, 3H), 1.99-2.09 (m, 1H), 1.70-1.98 (m, 3H), 1.54 (s, 8H). EIMS (m/z): calcd. for C30H35O4N5S (M+1H) 562, found 562. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 12h; | A solution of (5-piperidin-3-yl-2-trifluoromethoxy-phenyl)-carbamic acid tert- butyl ester (316.0 mg, 0.877 mmol), 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3- d]pyrimidine (270 mg, 0.88 mmol), and DIEA (305 uL, 1.75 mmol) in DMF (3.0 mL, 0.039 mol) was heated at 90 C for 12 h. The reaction mixture was diluted with EtOAc and washed with water, dil. citric acid, and aq. NaHC03. The organic phase was dried ( a2S04), filtered and concentrated in vacuo to afford a residue, which was purified by flash chromatography to afford the indicated compound, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | A mixture of compound 1.2 (30 mmol) in 4.0 N HCI in 1 ,4-dioxane(100 mL) was stirred at RT. After stirring at RT for several hours, the reaction mixture was concentrated in vacuo, and the residue was treated with compound 6.1 (30 mmol), DIEA (120 mmol) in DMF (60 mL). After stirring at 90 C for 4 h, the solvent was removed in vacuo, and the residue was purified by reverse phase chromatography C18 column and 10% acetonitrile/water containing 0.1% TFA to afford compound 6.2 in 90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | General procedure: The N-protected diarylimidazole was dissolved in THF and cooled to -78 C. Then n-BuLi was added. The reaction mixture was stirred for 60 min at -78 C, then ClSnBu3 was added and the reaction mixture was stirred for 30 min at rt. The solvent was removed under reduced pressure and the obtained oily product was used for following coupling reactions without further purification. The halogenated N-protected heterocycle, PdCl2(PPh3)2 (0.3 mol %) and the stannylimidazole (2 equiv) was dissolved in 3-6 ml THF (procedure A) or dioxane (procedure B). The reaction mixture was stirred at reflux temperature under argon atmosphere for up to 4 h. After quenching with KF (40% in water) and extracting with EtOAc, the crude product was purified by flash-chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 4h; | Example 1[0155] Synthesis of 2-(3-chloro-5-fluorophenylamino)-l-((lS')-3-(7H-pyrrolo[2,3-J]pyrimidin-4-ylamino)piperidin- 1 -yl)ethanone: Reagents and conditions: a) 4-Chloro-7-tosyl-7H-pyrrolo[2,3-J]pyrimidine, DIEA, DMF, 90 °C, 15 h; b) EtOH:HCl, rt, 30 min.; c) 2-(3-Chloro-5-fluorophenylamino)acetic acid, EDCI, HOBt, DIEA, DMF, rt, 5 h; e) K2C03, MeOH:H20, 50 °C, 2 h.[0156] Synthesis of (S)-ieri-butyl 3-(7-tosyl-7H-pyrrolo[2,3-J]pyrimidin-4- ylamino)piperidine-l-carboxylate: To a solution of (S)-l -benzyl -N-methylpiperidin-3-amine (2.2 g, 11.0 mmol) and 4-chloro-7-tosyl-7H-pyrrolo[2,3-J]pyrimidine (3.4 g, 11.0 mmol) in anhydrous DMF (30 mL), Et3N (3.8 mL, 27.6 mmol) was added and the reaction mixture was stirred at 90 °C for 4h. After completion of the reaction (TLC), the reaction mixture was diluted with EtOAc (100 mL) and was washed with water (3 X 40 mL). The EtOAc layer was then dried over Na2S04 and evaporated under vacuo to give a residue that was subjected to purification by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (3.4 g, 65percent). XH NMR (400 MHz, DMSO-d6): delta 8.22 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 2.5 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 6.92 (s, 1H), 3.98-3.90 (m, 2H), 3.70-3.60 (m, 2H), 3.21- 2.90 (m, 1H), 2.17 (s, 3H), 1.97-1.78 (m, 2H), 1.71-1.60 (m, 2H), 1.12 (s, 9H). LC-MS: m/z [M+l] = 472. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 3h; | Example 79[0430] Synthesis of 2-(3, 5-dichlorophenylamino)-l-(3-(7 H-pyrrolo [2, 3-d] pyrimidi4-ylamino) azepan-l-yl) ethanone:Reagents and condition: a) 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, DIEA, DMF, 100 C, 4 h; b) 4 N HC1 in 1,4-dioxane, rt, 2h; c) 2-(3,5-dichlorophenylamino)acetic acid, EDCI, HOBt, DIEA, DMF, rt, 15 h; d) K2C03, MeOH:H20, 60 C, 1 h.[0431] Synthesis of ieri-butyl 3-(7-tosyl-7H-pyrrolo[2,3-J]pyrimidin-4-ylamino)azepane-1 -carboxylate: To a solution of ieri-butyl 3-aminoazepane-l-carboxylate (1 g, 4.7 mmol), 4- chloro-7-tosyl-7H-pyrrolo[2,3-J]pyrimidine (3.1 g, 5.1 mmol) in DMF (10 mL) was added DIEA (1.2 mL, 7.0 mmol) and the reaction mixture was heated to 90 C for 3h. The reaction was cooled to rt and diluted with ice cooled water (50 mL). The mixture was extracted with EtOAc (3 x 100 mL), the EtOAc layers were combined, dried over Na2S04 and evaporated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient 0-20% EtOAc hexane) to afford the titled intermediate (1.4 g, 89%) . LC-MS: m/z [M+l] = 486. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 15h;Product distribution / selectivity; | Example 44Reagents and conditions: (a) DIEA, DMF, 80 C, 4 h. (b) HCl, MeOH, reflux, (c) Cbz, Et3N, DCM. (d) Sodium hydride, C3H5Br, DMF. (e) i. Os04, THF/water. ii. NaI04, DCM. (f) NaBH4, MeOH. (g) Pd/C, EtOH. (h) C8H702NCl2, EDCI, HOBt, DIEA, DMF.[0280] Synthesis of (R)-tert-buty 3-(7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-4-ylamino) piperidine-l-carboxylate: To a solution of 4-chloro-7-tosyl-7H-pyrrolo[2,3-J]pyrimidine (15.4 g, 50 mmol) and (R)-tert-buty 3-aminopiperidine-l-carboxylate (10 g, 50 mmol) in DMF (200 mL) was added DIEA (13.3 mL, 75 mmol). The reaction mixture was stirred at rt for 15 h before it was poured on ice and extracted with EtOAc. The EtOAc layer was washed with water, brine and dried over Na2S04, concentrated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient 10-20% EtOAc in hexanes) to give titled compound (20 g, 86%). lH NMR (400 MHz, CDC13): delta 8.42 (s, 1H), 8.05 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 4.0 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 6.42 (d, J = 4.0 Hz, 1H), 4.23-4.19 (m, 1H), 3.67 (d, J = 12.4 Hz, 1H), 3.48-3.30 (m, 3H), 2.38 (s, 3H), 1.99-1.91 (m, 3H), 1.76-1.69 (m, II1.62- 1.55 (m, 1H), 1.25 (s, 9H). LCMS [M+l]: 472. |
42% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 70℃; | Step 1. (R)-tert-Butyl 3-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. To a stirred solution of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (8.73 g, 28.4 mmol) in n-Butanol (100 mL) was added DIPEA (6.0 mL, 1.2 eq) and (R)-3-amino piperidine-1-carboxylic acid tert-butyl ester (6.82 g, 1.2 eq). The reaction mixture was heated at 70 C. for overnight. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography (100-200 mesh silica, 0-3% MeOH in DCM) to obtain (R)-tert-butyl 3-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (5.6 g, 42%). LC/MS (M+H)=472.2. 1H NMR (400 MHz, CDCl3) delta ppm 1.09-1.30 (m, 4H) 1.33 (br s, 9H) 1.49-1.94 (m, 2H) 2.34 (s, 3H) 3.37 (br s, 2H) 3.67 (d, J=12.88 Hz, 1H) 4.09-4.21 (m, 1H) 6.39 (d, J=4.10 Hz, 1H) 7.10-7.29 (m, 2H) 7.42 (d, J=4.10 Hz, 1H) 7.92-8.07 (m, 2H) 8.39 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 4h; | Synthesis of (^-benzyl 3-(ethyl(7-tosyl-7H-pyrrolo[2,3-J]pyrimidin-4- yl)amino)piperidine-l-carboxylate: To a solution of (^-benzyl 3-(ethylamino)piperidine-l- carboxylate (200 mg, 0.76 mmol), 4-chloro-7-tosyl-7H-pyrrolo[2,3-J]pyrimidine (234 mg, 0.76 mmol) and DIEA (0.27 mL, 1.52 mmol) in DMF (3 mL) was heated to 100 C for 4 h. The reaction was cooled to rt, diluted with ice cooled water (10 mL) and extracted with EtOAc (3 x 25 mL). The combined EtOAc layer was dried over Na2S04 and concentrated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient 0-10% EtOAc hexane) to afford the titled intermediate (300 mg, 73%). lH NMR (400 MHz, DMSO- d6): delta 8.22 (d, J = 5.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.95 (s, 1H), 7.58-7.57 (m, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.39-7.29 (m, 5H), 5.12 and 5.09 (2s, 2H), 4.69-4.63 (m, 1H), 4.05-3.98 (m, 3H), 3.65-3.63 (m, 2H), 3.01-2.77 (m, 1H), 2.36 (s, 3H), 1.89-1.75 (m, 3H), 1.51-1.39 (m, 1H), 1.17 (t, J = 6.8 Hz, 3H). LC-MS: m/z [M+l] =534. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; | Synthesis of 2-(3,5-dichlorophenylamino)-l-(4-methyl-3-(7-tosyl-7H-pyrrolo[2,3-J]pyrimidin-4-ylamino)piperidin-l-yl)ethanone: To a solution of l-(3-amino-4-methylpiperidin- l-yl)-2-(3,5-dichlorophenylamino)ethanone (180 mg, 0.56 mmol) and 4-chloro-7-tosyl-7H- pyrrolo[2,3-J]pyrimidine (192 mg, 0.62 mmol) in DMF (5 mL), was added DIEA (0.15 mL, 0.85 mmol) and the reaction mixture was stirred at 60 C overnight. The reaction mixture was cooled to rt and diluted with EtO Ac/water (1 :2, 120 mL). The EtOAc layer was separated, dri over Na2S04 and evaporated in vacuo to give a residue that was purified by colur chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (120 n 35%). LC-MS: m/z [M+l] = 587. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; | Synthesis of 2-(3,5-dichlorophenylamino)-l-(4-(7-tosyl-7H-pyrrolo[2,3-J]pyrimidin-4-ylamino)-3,4-dihydroisoquinolin-2(lH)-yl)ethanone: To a solution of 2-(3,5- dichlorophenylamino)-l-(4-amino-3,4-dihydroisoquinolin-2(lH)-yl)ethanone (0.2 g, 0.6 mmol) in DMF was added 4-chloro-7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (0.17 g, 0.57 mmol) and DIEA (0.11 g, 0.85 mmol). The reaction mixture was stirred at 90 C overnight, the mixture was diluted with EtOAc (100 mL) and washed with water (20 mL x 3). The EtOAc layer was concentrated in vacuo to give a mixture which was purified by column chromatography (silica gel, gradient EtOAc in Hexanes) to give (0.160g, 57%) of the titled intermediate. XHNMR (CDCI3, 400 MHz): delta 8.41 (s, 1 H), 8.08 (s, 1 H), 8.06 (s, 1 H), 8.01 (s, 1 H), 7.54 (d, 1 H, J = 3.6 Hz), 7.33-7.19 (m, 6 H), 6.83-6.67 (m, 3 H), 6.35 (s, 2 H), 5.35-5.25 (m, 1 H), 5.18 (d, J = 16.4 Hz, 1 H), 4.76 (d, J = 16.4 Hz, 1 H), 4.51 (dd, J = 1.8, 16 Hz, 1 H), 4.33 (t, J = 1.8 Hz, 1 H), 3.82 (dd, J = 1.8, 10 Hz, 1 H), 3.72 (d, J = 5.2 Hz, 1 H), 2.38 (s, 3 H). LCMS: M/z: (M+l):621 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 18h; | Cmpd 107.4 (tert-butyl 6-(methyl-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-l,4-oxazepane-4-carboxylate). A solution of 4-chloro-7-(toluene-4-sulfonyl)-7H- pyrrolo[2,3-d]pyrimidine (110 mg (0.36 mmol) 107.a, of ieri-butyl 6-(methylamino)-l,4- oxazepane-4-carboxylate (84 mg (0.36 mmol) X.3, and DIEA (0.127 mL (0.730 mmol) in DMF (2.8 mL) was heated at 90 C in a sealed tube for 18 hr. The mixture was diluted with H20 and extracted with EtOAc (2x). The combined organics were washed with H20 and brine, dried over MgS04, filtered, and concentrated in vacuo , absorbing onto 4 g Si02. Purification by flash column chromatography (ISCO 24 g Si02, 10% EtOAc/hexanes then gradient to 80% EtOAc/hexanes) afforded ieri-butyl 6-(methyl-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 1 ,4-oxazepane-4-carboxylate (0.142 g ) 107.4 as a yellow glassy solid. LCMS (ESI) m/z: 502. [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 24h; | Cmpd 127.3 (tert-butyl (2S,6S,8afl)-3-oxo-6-(7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)octahydroindolizin-2-ylcarbamate) and Cmpd 127.4 (tert-butyl (2,S',67?,8alS')-3-oxo-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)octahydroindolizin-2- ylcarbamate). To a solution of tert-butyl (2S)-6-amino-3-oxooctahydroindolizin-2-ylcarbamate 127.2 (0.913 g, 3.39 mmol) in DMF (25 ml) and was added 4-chloro-7-tosyl-7H-pyrrolo[2, d]pyrimidine (100 mg (3.4 mmole) 127.a and DIEA (1.18 mL (6.78 mmole) at solution w heated 90 C for 24 hr. After cooling to room temperature, the rmixture was diluted with H and washed with EtOAc (2x). The combined organics were washed with H20 and brine, dri over MgS04, filtered, and concentrated in vacuo, absorbing onto 6 g silica gel. Purification flash column chromatography (ISCO 40 g Si02, 50% EtOAc/hexanes then gradient to IOC EtOAc/hexanes) yielded 0.52 g of ieri-butyl (2lS,,6.S',8alS')-3-oxo-6-(7-tosyl-7H-pyrrolo[2, d]pyrimidin-4-ylamino)octahydroindolizin-2-ylcarbamate 127.3 and 0.55 g of tert-bu (2,S',67?,8a ?)-3-oxo-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)octahydroindolizin-2- ylcarbamate 127.4.[0537] Compound 127.3 (teri-butyl (2S,6S,8afl)-3-oxo-6-(7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)octahydroindolizin-2-ylcarbamate): 1H NMR (400MHz, DMSO-d6) delta 8.26 (s, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 4.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 5.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 3.8 Hz, 1H), 4.29 (br. s., 1H), 4.15 - 4.06 (m, 2H), 3.55 - 3.41 (m, 1H), 2.96 - 2.81 (m, 2H), 2.73 (m, 1H), 2.35 (s, 3H), 1.95 (dd, J = 4.0, 9.3 Hz, 1H), 1.82 (m, 3H), 1.67 - 1.56 (m, 1H), 1.36 (s, 9H); LCMS (ESI) m/z: 541.3 [M+H]+.[0538] Compound 127.4 (teri-butyl (2S,6tf,8aS)-3-oxo-6-(7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)octahydroindolizin-2-ylcarbamate): lU NMR (400MHz ,DMSO-d6) delta 8.28 (s, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 3.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.09 - 6.95 (m, 3H), 4.30 (br. s., 1H), 4.13 (d, J = 12.8 Hz, 1H), 3.44 - 3.33 (m, 1H), 2.89 (m, 1H), 2.35 (s, 3H), 1.92 (d, J = 13.3 Hz, 2H), 1.82 (dt, J = 3.5, 13.3 Hz, 1H), 1.75 (d, J = 15.8 Hz, 2H), 1.70 - 1.60 (m, 1H), 1.37 (s, 9H); LCMS (ESI) m/z: 541.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; | Synthesis of ( ?)-N-(l-benzylpiperidin-3-yl)-N-methyl-7-tosyl-7H-pyrrolo[2,3-J]pyrimidin-4-amine: To a solution of (R)- 1 -benzyl -N-methylpiperidin-3 -amine (800 mg, 3.9 mmol) and 4-chloro-7-tosyl-7H-pyrrolo[2,3-J]pyrimidine (1.2 g, 3.9 mmol) in DMF (10 mL), DIEA (2.02 mL, 15.6 mmol) was added and the reaction mixture was stirred at 60 C overnight. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (100 mL) and was washed with water (3 x 40 mL). The EtOAc layer was then dried over Na2S04 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (750 mg, 40%). 1H-N (400 MHz, CDCls): delta 8.37 (s, 1H), 8.02 (d, J =8.4 Hz, 2H), 7.38 (d, J =4.0 Hz, 1H), 7.28 ( 7H), 6.53 (d, J=3.6 Hz, 1H), 3.59 (d, J =13.2 Hz, 1H), 3.46 (d, J =13.2 Hz, 1H), 3.13 (s, 31 2.89 (m, 2H), 2.37 (s, 3H), 2.09 (t, 7 =10.8 Hz, 1H), 1.96 (dt, 7 =1.2, 10.8 Hz, 1H), 1.83 (m, 21 1.65 (m, 3H). LC-MS: m/z [M+l] = 476. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 75℃; for 6h;Inert atmosphere; | Step 1: Benzyl [cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]carbamate 4-Chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (15 g, 48.7 mmol) and benzyl [cis-3-(methylamino)cyclobutyl]carbamate (17.2 g, 63.5 mmol) were mixed with isopropyl alcohol (180 mL) and diisopropylethylamine (28 mL, 161 mmol). The resulting slurry was heated at 75 C. for 6 hours. The reaction was cooled to room temperature, filtered, washed with isopropyl alcohol (150 mL) and dried in an oven at 50 C. to give the title compound (23.5 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 8.38 (s, 1H), 8.03 (d, 2H), 7.45 (d, 1H), 7.38-7.28 (m, 4H), 7.26 (s, 1H), 7.25 (d, 1H), 6.61 (d, 1H), 5.08 (s, 2H), 4.96 (d, 1H), 4.77 (m, 1H), 3.88 (m, 1H), 3.23 (s, 3H), 2.71 (m, 2H), 2.36 (s, 3H), 2.18 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6 g | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 80℃; | Step 1. Rac-N-(8-Methyl-8-azabicyclo[3.2.1]octan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine. A solution of the 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 8-methyl-8-azabicyclo[3.2.1]octan-2-amine (Pharmablock), and DIEA in 1-butanol (30 mL) was heated to 80 C. overnight. LCMS showed the pyrrolopyrimidine was consumed, and ionization consistent with the desired product. The reaction was concentrated in vacuo, and the crude material was partitioned between ethyl acetate (10 mL) and water (20 mL). The mixture was filtered and the solid was washed with ether to give 6 g of rac-N-(8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine. LC/MS (M+H)=412.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; for 24h;Reflux; | Step 1. N-((3R,5R)-1-Benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine. To a stirred solution of (3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-amine (4 g, 12.479 mmol) in n-butanol (25 ml) was added 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4.608 g, 14.974 mmol) and DIPEA (4.443 ml, 24.957 mmol). The resulting mixture was heated to reflux for 24 h. The reaction mixture was cooled to ambient temp. After TLC (70% EtOAc in hexane) indicated starting material to be consumed, the solvent was removed in vacuo to provide the crude compound, which was purified by chromatography (silica, EtOAc/hexane 0-20%) to afford 5 g (68%) of N-((3R,5R)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a light yellow solid. LC/MS (M+H) 592.0. 1H NMR (400 MHz, CDCl3) 6-0.07 (s, 6H) 0.87 (s, 9H) 1.44 (d, J=18.10 Hz, 1H) 1.93-2.31 (m, 3H) 2.37 (s, 3H) 2.65 (d, J=10.76 Hz, 1H) 2.94 (br s, 1H) 3.36-3.71 (m, 2H) 3.81-3.98 (m, 1H) 4.43 (br s, 1H) 5.63 (br s, 1H) 6.43 (d, J=3.91 Hz, 1H) 7.13-7.35 (m, 7H) 7.47 (d, J=3.91 Hz, 1H) 8.06 (d, J=8.31 Hz, 2H) 8.39 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; for 36h;Reflux; | Step 6. (3S,5R)-tert-Butyl 3-((tert-butyldimethylsilyl)oxy)-5-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. To a stirred solution of (3R,5S)-tert-butyl 3-amino-5-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (1.52 g, 4.598 mmol) in n-butanol (10 ml) was added 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.698 g, 5.518 mmol) and DIPEA (1.642 ml, 9.197 mmol). The resulting mixture was refluxed for 36 h, and then the volatiles were removed under reduced pressure. The crude material was purified by CombiFlash (EtOAc/hexane as eluent, 100% hexane to 60% EtOAc in hexane) to afford 2 g (72%) (3S,5R)-tert-butyl 3-((tert-butyldimethylsilyl)oxy)-5-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 0.09 (s, 6H) 0.87 (s, 9H) 1.12-1.58 (m, 10H) 2.13 (d, J=10.76 Hz, 1H) 2.33 (br s, 3H) 2.80-3.00 (m, 1H) 3.53-3.92 (m, 3H) 3.98-4.13 (m, 2H) 6.61-6.88 (m, 1H) 7.43 (d, J=8.31 Hz, 2H) 7.59 (br s, 2H) 7.96 (d, J=8.31 Hz, 2H) 8.25 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 80℃; for 4h; | To a flask containing 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (276 mg, 0.89 mmol) was added n-BuOH (5 mL), 1-benzhydryl-6-tosyloctahydro-1H-pyrrolo[2,3-c]pyridine (251 mg, 0.89 mmol) and DIPEA (1.14 mL, 6.53 mmol). The reaction was heated to 80 C. for 4 hrs and then diluted with water/ethyl acetate. The layers were separated and the organic extract collected and dried (Na2SO4). The solvent was removed to give the crude, which was purified by chromatography (silica, EtOAc/Hep, 0 to 40%) to give two peaks with same molecular weight. Pk1 (cis-isomer, 25 mg), compared to Example 8, Step 8 material treated with TsCl. LC/MS (M+H) 552.0. Pk2 (trans-isomer, 85 mg): LC/MS (M+H) 552.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 85℃; for 16h; | Step 3. rac-4-((3aS,7aR)-6-Benzyl-3a-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine. To a flask containing (3aS,7aS)-6-benzyl-3a-methyloctahydro-1 H-pyrrolo[2,3-c]pyridine (607 mg, 2.64 mmol) was added n-butanol (8.5 mL) 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (815 mg, 2.65 mmol) and DIPEA (3.8 mL, 22 mmol). The reaction mixture was stirred at 85 C. for 16 h. The reaction was cooled to rt and the solvent removed in vacuo. The crude material was purified by chromatography (silica, EtOAc/Heptane) to give 4-((3aS,7aR)-6-benzyl-3a-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (913 mg, 69%) as an off-white solid. LC/MS (M+H) 502.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.6% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 110℃; | Step 1. N-(1-Benzyl-6,6-dimethylpiperidin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine. A flask containing 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (212 mg 0.688 mmol), 1-benzyl-6,6-dimethyl-piperidin-3-amine (200 mg, 0.688 mmol), DIEA (1.22 mL, 6.88 mmol) and n-BuOH (2.5 mL) were heated to 110 C. overnight. The mixture was concentrated under reduced pressure, and the residue was purified via flash chromatography (CombiFlash, 12 g gold column, 10 to 50% EA in heptane) to give 140 mg (41.6%) of N-(1-benzyl-6,6-dimethylpiperidin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine. [0456] LC/MS (M+H) 490.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | at 140℃; | Step 5. tert-Butyl 3-methyl-3-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate. tert-Butyl 3-amino-3-methylpiperidine-1-carboxylate (3.3 g, 15.398 mmol) and <strong>[1158759-06-8]tert-butyl 3-amino-3-methylpiperidine-1-carboxylate</strong> (3.9 g, 12.7 mmol) was stirred at 140 C. overnight. After TLC showed <strong>[1158759-06-8]tert-butyl 3-amino-3-methylpiperidine-1-carboxylate</strong> to be consumed, the mixture was diluted with DCM (80 ml). The DCM layer was washed with sat NaHCO3 (aq) and brine and concentrated to dryness to give crude product which was purified by chromatography (silica, EtOAc/Petroleum ether, 0-40%) to give tert-butyl 3-methyl-3-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (2.4 g, 40%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate;Sealed tube; Inert atmosphere; Heating; | To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzylcarbamate (320 mg, 0.96 mmol, 1.0 eq) in DMF (3 mL) were added K2CO3(187 mg, 1.4 mmol, 1.5 eq), Pd(dppf)Cl2(81 mg, 0.1 mmol, 0.01 eq) and 4-chloro-7-tosyl-7H-pyrrolo[2,3- d]pyrimidine (340 mg, 1.1 mmol, 1.2 eq). The mixture was stirred at 100 C in a sealed tube N2for 16 h. After cooling down to rt, the residue was purified by column chromatography (silica, petroleum ether/EtOAc = 5:1) to afford tert-butyl 4-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)benzylcarbamate (370 mg, yield: 80%) as a yellow soild. ESI-MS (M+H)+: 479.17.1H NMR (400 MHz, CDCl3) : 9.06 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 3.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 4.0 Hz, 1H), 4.41 (d, J = 5.6 Hz, 2H), 2.40 (s, 3H), 1.47 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With tetrakis(triphenylphosphine) palladium(0); bis(tri-n-butyltin); In toluene; for 16h;Reflux; | To a solution of di-tert-butyl 4-bromo-2-cyanobenzylcarbamate (2.0 g, 4.9 mmol, 1.0 eq), 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 4.9 mmol, 1.0 eq) in toluene (15 mL), Bu3Sn-SnBu3(5.7 g, 9.8 mmol, 2.0 eq) and Pd(PPh3)4(400 mg, 0.2 eq) were added. The mixture was refluxed for 16 h. The mixture was diluted with EtOAc (200 mL) and washed with brine (100 mLx2). The organic phase was dried, filtered and concentrated. The residue was purified by chromatography (petroleum ether: EtOAc 4:1) to afford the desired compound (1.8 g, yield 14%) as a yellow solid. ESI-MS (M+H)+: 604.2.1H NMR (400 MHz, CDCl3) : 9.09 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.23 (dd, J = 8.0, 2.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 4.0 Hz, 1H), 5.12 (s, 2H), 2.42 (s, 3H), 1.48 (s, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water;Inert atmosphere; Microwave irradiation; | To a solution of the boronate ester (1.7 g, 4.9 mmol) in dioxane/H2O (4:1) (15 mL) was added 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 4.9 mmol) followed by Pd(dppf)Cl2DCM (457 mg, 0.5 mmol) and K2CO3(2.0 g, 14.7 mmol) under nitrogen. The mixture was stirred at 90 C for 6 h. After cooling to rt, the mixture was diluted with water and extracted with EtOAc (100 mL x 2). The organic layer was washed with brine (80 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by columnchromatography (petroleum ether /EtOAc, 3:1) to give the title compound (650 mg, yield 28%) as a white solid. ESI-MS (M+H)+: 537.0.1H NMR (400 MHz, CDCl3) : 9.03 (s, 1H), 8.11 (d, J = 8.8 Hz, 2H), 7.89-7.85 (m, 3H), 7.76-7.71 (m, 3H), 7.40 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 2.96 (q, J = 7.6 Hz, 2H), 2.42 (s, 3H), 1.29 (t, J = 7.6 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water;Inert atmosphere; Heating; | To a solution of boronate (1.7 g, 4.9 mmol) in dioxane/H2O (4:1) (15 mL) was added 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 4.9 mmol) followed by Pd(dppf)Cl2DCM (457 mg, 0.5 mmol) and K2CO3 (2.0 g, 14.7 mmol) under nitrogen. The mixture was stirred at 90 C for 6 h. After cooling to rt, the mixture was diluted with water and extracted with EtOAc (100 mL x 2). The organic layer was washed with brine (80 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (petroleum ether /EtOAc, 3:1) to give the title compound (1.8 g, yield: 75%) as an orange oil. ESI-MS (M+H)+: 493.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.6 g; 0.4 g | With triethylamine; potassium iodide; In acetone;Reflux; Inert atmosphere; | Potassium iodide (173 mg) and triethylamine (1 3 mL, 93.8 mmol) were added to a solu- tion of cis/trans-[3-(methylamino)cyclobutyl]methanol (6.0 g, 52.1 mmol) in acetone (250 mL). 4- Chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (14.4 g, 46.9 mmol) was then added and the resulting mixture was heated to reflux overnight. After evaporation of the solvent under reduced pressure, the residue was diluted with dichloromethane (500 mL). The solution was washed sequentially with water (300 mL), 2% aqueous citric acid (300 mL) and brine (300 mL), and then dried over sodium sulfate. After filtration, the solution was filtered and concen- trated to afford the title mixture as a light solid (15.3 g, 85%). A portion (5.0 g) of the cis/trans- [3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)- cyclobutyl]methanol mixture was separated by supercritical fluid chromatography using a Chi- ralpak-AD column: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 75℃; for 6h;Inert atmosphere; | 4-Chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (15 g, 48.7 mmol) and benzyl [cis-3-(methylamino)cyclobutyl]carbamate (17.2 g, 63.5 mmol) were mixed with isopropyl alcohol (1 80 mL) and diisopropylethylamine (28 mL, 1 61 mmol). The resulting slurry was heat- ed at 75C for 6 hours. The reaction was cooled to room temperature, filtered, washed with iso- propyl alcohol (150 mL) and dried in an oven at 50C to give the title compound (23.5 g, 95%) as a white solid.1H NMR (400 MHz, DMSO-d6): 8.38 (s, 1 H), 8.03 (d, 2 H), 7.45 (d, 1 H), 7.38-7.28 (m, 4 H), 7.26 (s, 1 H), 7.25 (d, 1 H), 6.61 (d, 1 H), 5.08 (s, 2 H), 4.96 (d, 1 H), 4.77 (m, 1 H), 3.88 (m, 1 H), 3.23 (s, 3 H), 2.71 (m, 2 H), 2.36 (s, 3 H), 2.18 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; | Intermediate 3 (10 mmol) was completely dissolved in NMP (15 mL) and DIEA (15 mmol, 2.6 mL), 1-tert-butoxycarbonyl-4-aminopiperidine or 4-tert-butoxycarbonylaminopiperidine (10.5 mmol) was added sequentially. ), microwave reaction 150 C for 30 minutes, the reaction is completed, the reaction solution was quenched with ice water (150mL), ethyl acetate (3 × 30mL) extraction, the organic phase with saturated ammonium chloride (3 × 20mL), saturated brine Wash (3×20 mL), dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure. Purify by column chromatography (petroleum ether:ethyl acetate=9:1) to obtain Intermediate 4 or 7. Tert-butyl 4-((7-p-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrim-4-yl)amino)piperidine-1-carboxylate (4a). White solid, yield 95% |
67% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one;Reflux; | A mixture of loro-7-tosyi-7H-pyrroIo[2,3- i)pyrittditte (10.0 g, 32 -mmol), tert-butyl 4-aminQpiper-dine-.l -carboxylate (6.4 g, 32 mmol) and DIP.EA {1.0 niL) iti. NMP (100 ml.) was heated under reflux overnight. The mixture was .filtered. The solid was then washed with ethyl acetate and dried tinder vacumn to afford, the title product as a white solid (10 g, 67%). H NM (400 MHz, DMSO~d6) a 8,23 (s, 1H), 7.95 (d, J-8.0 Hz, 211), 7.65 (d J===8.0 Hz, IH), 7.54 (d, J=4.0 Hz, 1H), 7.42 (d, J-8.0 Hz, 2H), 6.88 (d, J=4.0 Hz, IBl 4.16-4,23 (m, 10), 3.92-3.95 to, 2H), 2,70-2 82 (m, 2H), 2.35 (s, 3H), 1.84-1.88 (m, 2H), 1.40 (s, 9B), 1.32-1.36 (m? 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 150℃; for 2h;Microwave irradiation; | 0.4g of <strong>[479633-63-1]4-chloro-7-p-methylphenylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine</strong> and 0.15g of compound 15a were dissolved in 20mL n-butanol. o the above solution was added dropwise 0.32g of DIPEA and was allowed to react under microwave conditions 150C for 2h. After completion of the reaction, the solvent was evaporated to dryness using a rotary evaporator under reduced pressure to obtain a crude product. The resulting crude product was purified by column chromatography (dichloromethane/methanol 40:1) to give 0.3g of compound 18a as an off-white solid, yield: 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; | Compound 18 (60mg, 0.16mmol), compound 12 (48mg, 0.16mmol), tetrakistriphenylphosphine palladium (9mg, 0.008mmol) and potassium carbonate (207mg, 1.5mmol), the reaction flask placed in 50mL single port, nitrogen under protection, at room temperature was added 1,4-dioxane (4mL) and H2O (1mL), and stir until evenly dispersed in the system, and then heated to 80 , under nitrogen protection reaction 2h. After completion of the reaction, and ethyl acetate was added 30mL H2O (10mL), extract liquid separation. The organic phase was dried over sodium sulfate, spin dry, column chromatography (petroleum ether: ethyl acetate = 3: 1-1: 1) to give a white solid 24mg, 30% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; | Compound 11 (160mg, 0.5mmol), compound 12 (153mg, 0.5mmol), tetrakistriphenylphosphine palladium (29mg, 0.025mmol) and potassium carbonate (207mg, 1.5mmol), the reaction flask placed in 50mL single port, nitrogen under protection, at room temperature was added 1,4-dioxane (4mL) and H2O (1mL), and stir until evenly dispersed in the system, and then heated to 80 , under nitrogen protection reaction 2h. After completion of the reaction, and ethyl acetate was added 30mL H2O (10mL), extract liquid separation. The organic phase was dried over sodium sulfate, spin dry, column chromatography (petroleum ether: ethyl acetate = 3: 1-1: 1) to give a white solid 132mg, 55% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃;Inert atmosphere; | [0183] A mixture of 3,3-difluoro-1-(4-(trifluoromethyl)phenethyl)piperidin-4-amine (111 mg, 0.36 mmol), 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (111 mg, 0.36 mmol) and DIPEA (0.16 mL, 0.9 mmol) in NMP (1.4 mL) was heated to 120C under N2. After stirring overnight at 120C, the mixture was diluted with EtOAc, and washed with water. The organic phase was dried over Na2SO4, and concentrated. The residue was purified by column chromatography over silica gel (hexane/ethyl acetate = 3/1) to afford the title compound as a pale yellow solid (150 mg, 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 130℃;Inert atmosphere; | A mixture of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (615 mg, 1.99 mmol), R-tert-butyl 4-(aminomethyl)-3,3-difluoropiperidine-1-carboxylate (600 mg, 2.39 mmol) and DIPEA (0.66 mL, 3.99 mmol) in n-BuOH (8 mL) was heated to 130 C under nitrogen atmosphere overnight. The mixture was allowed to cool to rt and concentrated under vacuum. The concentrate was partitioned into ethyl acetate and water. The organic layer was washed with water, brine, dried over Na2504 and concentrated in vacuo. The residue was purified by column chromatography over silica gel (hexane/EtOAc = 3/2) to afford the title compound as an off-white powder (850 mg, 82%). MS (ESI) calcd for C24H29F2N5045: 521.2; found: 522.5 [M+H]. 1H NMR (400 MHz, CDCI3) 6 8.44 (s, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 4.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.41 (d, J = 4.0 Hz, 1H), 5.23-5.16 (m, 1H), 4.45-4.25 (m, 2H), 3.88-3.70 (m, 2H), 3.02-2.67 (m, 2H), 2.39 (s, 3H), 2.35-2.19 (m, 1H), 1.85-1.77 (m, 1H), 1.62-1.50 (m, 1H), 1.46 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75 mg; 8 mg | With potassium carbonate; In water; at 120℃; for 16.0h;Inert atmosphere; | A mixture of chromium trioxide (49 mg, 0.49 mmol) in sulfuric acid (0.16 mL), acetic acid (0.16 mL) and water (0.11 mL) was added to a stirred solution of 14 (50 mg, 0.24 mmol) in acetone (0.5 mL) at 0 C. After 2 h at <20 C the reaction was basified to pH 12 with 33% aq NH3 at 0 C and extracted with ether (4*5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in MeOH (0.17 mL) followed by addition of NH2Me (40% in MeOH, 0.05 mL, 0.49 mmol) and Ti(OiPr)4 (0.08 mL, 0.27 mmol) at 0 C. After stirring 30 min at room temperature, the reaction mixture was added sodium borohydride (46.5 g, 1.23 mol) in a small portion in 30 min at 0 C and stirred for an additional hour at the same temperature. The reaction mixture was filtered off to obtain crude amine. The crude amine in water (0.65 mL) was added K2CO3 (65 mg, 0.47 mmol) and 15 (120 mg, 0.39 mmol), and the mixture was refluxed (120 C) for 16 h under argon. After cooling to rt, the resulting mixture was added CH2Cl2 (5 ml) and sonicated crush the solid. The mixture was extracted with CH2Cl2 (4*5 mL) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes, 1:1) to give trans-16 (8 mg, 7%) as a white solid and cis-16 (75 mg, 63%) as a white solid. Rf = 0.4 (trans-16), 0.48 (cis-16) (EtOAc/hexanes, 1:1). trans-16: 1H NMR (400 MHz, CDCl3) delta: 8.35 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.37 (d,J = 4 Hz, 1H), 7.32-7.18 (m, 7H), 6.53 (br s, 1H), 3.56, 3.45 (ABq, JAB = 12.8 Hz, 2H), 3.08 (s, 3H), 2.90-2.84 (m, 2H), 2.36 (s, 3H), 2.10-1.95 (m, 2H), 1.80-1.65 (m, 3H), 1.50-1.39 (m, 1H), 0.81 (d, J = 6 Hz, 3H). 13C NMR (100 MHz, CDCl3) delta: 158.0, 152.8, 151.7, 145.2, 138.1, 135.1, 129.6, 129.0, 128.2, 127.1, 120.9, 105.6, 104.7, 62.8, 55.4, 53.4, 33.6, 33.4, 21.6, 18.3. cis-16: [a]D28 = +19.3(c 1.0 CHCl3). 1H NMR (400 MHz, CDCl3) delta: 8.31 (s, 1H), 8.03 (d,J = 8 Hz, 2H), 7.40 (d, J = 3 Hz, 1H), 7.27-7.17 (m, 7H), 6.63 (d,J = 3.2 Hz, 1H), 5.16 (br s, 1H), 3.56 (s, 3H), 3.47, 3.42 (ABq, JAB = 13.2 Hz, 2H), 2.79-2.76 (m, 1H), 2.75 (br s, 1H), 2.52 (d, J = 10.8, 1H), 2.36 (s, 2H), 2.35-2.22 (m, 1H), 2.10-2.03 (m, 1H), 1.70-1.610 (m, 2H), 0.87 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) delta: 189.3, 157.9, 152.5, 151.8, 145.2, 135.1, 129.6, 128.9, 128.2, 128.1, 127.1, 120.6, 106.2, 104.6, 63.5, 55.2 (br), 53.1 (br), 51.6 (br), 35.8 (br), 32.5, 31.2, 21.6, 15.7 (br). HRMS (ESI) calcd for C27H31N5O2S [M+H]+: 490.2277, found: 490.2273. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In Isopropyl acetate; water; at 95 - 100℃; | A solution of 2-(3-(4-(5,5-dimethyl-1,3,2-dioxaborate-2-yl)-1H-pyrazol-1-yl)-1-yl)acetonitrile (36.62 g, 1OO mmol), <strong>[479633-63-1]4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (32.31 g, (113 g, 0.5 mmol) was added under nitrogen, and the ligand XtanPhos (& lt; RTI ID = 0.0 & gt; (180 mL), the mixture was added to ethyl acetate (180 mL) and extracted twice, and the mixture was heated to 95 to 100 C for 5 to 6 hours. (180 mL), dried over sodium sulfate, filtered through celite, concentrated and recrystallized from isopropyl ether to give 2-(1- (ethylsulfonyl)-3-(4-(7-p-toluenesulfonamide acetyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-azetidin-3-yl)acetonitrile (43.10 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In water; acetonitrile; at 75℃; for 4h; | To a flask containing trans-4-((methylamino)cyclohexyl)methanesulfonic acid (Intermediate C, 44.0 g, 212 mmol) and 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (60.0 g, 195 mmol, Intermediate G) was added water (120 mL), acetonitrile (90 mL) and potassium carbonate (70.8 g, 507 mmol). The solution was heated at about 75 C. for about 4 hours and was then warmed to about 80 C. and about 65 mL of solvent was removed by distillation. To the reaction was charged n-butanol (300 mL) and water (40 mL). The reaction was warmed to about 70 C. and the lower aqueous layer was removed and discarded. The remaining organics were heated to about 70 C. and an additional amount of n-butanol (600 mL) was added. The solution was cooled to about 15 C. over about 3 hours. The product crystallized during this time and was isolated by filtration and was washed with n-butanol (100 mL). The product was dried at about 60 C. under vacuum to afford 94.7 g of a white powder (Intermediate H). 1H NMR (DMSO-d6, 600 MHz): 8.22 (s, 1H), 7.97 (d, 2H), 7.59 (d, 1H), 7.44 (d, 2H), 6.80 (br s, 1H), 4.7 (br s, 1H), 3.12 (s, 3H), 2.37 (s, 3H), 2.35 (d, 2H), 2.07 (m, 2H), 1.74 (m, 1H), (1.60 (m, 4H), 1.08 (m, 2H). MS M+H-Na=479 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.80 g | With triethylamine; In 1,4-dioxane; at 110℃; for 24h;Inert atmosphere; | Step 5: 4-aminomorpholine-2-carboxylic acid methyl ester (4.30 g, 26.85 mmol) and 4-chloro-7-(tosyl)pyrrolo[2,3-d]pyrimidine (8.26 g, 26.85 mmol) were dissolved in dioxane (100.00 mL), and triethylamine (8.15 g, 80.55 mmol) was added under nitrogen protection. The foregoing mixture was stirred for 24 h at 110C. TLC show there was no much more progress in the reaction. The mixture was cooled to 25 C, and then concentrated under reduced pressure at 50C. Residues were diluted by water (50 mL), the aqueous phase was extracted by ethyl acetate (100 mL*3), merged organic phases were washed by saturated saline water (20 mL * 2), dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residues were purified by a silica gel column chromatography (100-200 mesh silica gel, petroleum ether: ethyl acetate: dichloromethane = 5:1:0.5 to 1:1:1) to obtain 4-[[7-(tosyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]morpholine-2-carboxylic acid methyl ester (3.80 g, 7.93 mmol, yield was 29.52%) which was yellow solid. The value of C19H21N5O5S[M+H]+432, was calculated using MS ESI, and was 432. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.60 g | With triethylamine; In dichloromethane; at 25℃; for 10h; | Step 4: Ethyl 1-aminopiperidyl-3-carboxylate (6.50 g, 37.74 mmol) and 4-cloro-7--tosyl-7H-pyrrolo[2,3-d]pyrimidine (12.78 g, 41.51 mmol) were dissolved in DCM (60 mL). Triethylamine (11.46 g, 113.22 mmol) was added into the foregoing solution at 25C. The mixed solution was stirred to react for 10 h at 25C. TLC showed that the reaction was completed. The mixture was concentrated to be dry under reduced pressure. Residues were poured into water (100 mL), and the aqueous phase was extracted using ethyl acetate (100 mL*2). Consolidated organic phases were washed by saturated saline solution (50 mL*2), dried by anhydrous sodium sulfate, filtered and concentrated to be dry under reduced pressure. Residues were purified by silica column chromatography (dichloromethane: ethyl acetate = 1:0 to 2:1) to obtain 1-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidyl-3-carboxylic acid ethyl ester which was white spumescent solid (5.60 g, wherein the yield was 33.47%). Residues were purified by silica column chromatography (dichloromethanedichloromethane: ethyl acetate = 1:0 to 2:1) to obtain 1-((7-p-tosyl-7H-pyrrolo [2,3-d] pyrimidine-4-yl) amino) piperidyl-3-carboxylic acid ethyl ester which was white spumescent solids (5.60 g, the yield was 33.47%). The value of C21H25N5O4S[M+H]+444 was calculated using MS ESI, and was 444. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.5 g | With triethylamine; In 1,4-dioxane; at 110℃; for 12h;Inert atmosphere; | Step 3: a mixture of 1-aminopiperidyl-4-carboxylic acid ethyl ester (9.80 g, 48.37 mmol, 1.00 Eq) and 4-chlro-7-(tosyl)pyrrolo[2,3-d]pyrimidine (16.37 g, 53.21 mmol, 1.10 Eq) was dissolved in dioxane (100 mL), and triethylamine (14.68 g, 145.11 mmol, 3.00 Eq) was added under nitrogen protection, then the mixture was stirred for 12 h at 110C. TLC showed that the reaction was completed. The mixture was cooled to 25C, and concentrated under reduced pressure at 60C, then residues were poured into water (50 mL). The aqueous phase was extracted using ethyl acetate (100 mL*3). Merged organic phases were washed by saturated saline water (20 mL*3), dried by anhydrous sodium sulfate, and filtered, and dried under vacuum. The residues were purified by a silica gel chromatography (100-200 mesh silica gel, petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain 1-[[7-(tosyl)pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidyl-4-carboxylic acid ethyl ester (9.50 g, yield was 44.28%) which was pale yellow solid. The value of C21H25N5O4S[M+H]+444 was calculated using MS ESI, and was 444. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.1% | With caesium carbonate; In 1,4-dioxane; at 20 - 110℃; for 20h;Inert atmosphere; | Step 4: methyl 1-amino-6-methyl-piperidyl-3-carboxylate(15.00 g, 46.16 mmol) and 4-chloro-7-(tosyl)pyrrolo[2,3-d]pyrimidine (20.00 g, 64.99 mmol) were dissolved in a dioxane solution (200 mL), and added with solid caesium carbonate (15.04 g, 46.16 mmol) under nitrogen protection at 20C; the reaction solution was heated to 110C and stirred for 20 h. The mixture was cooled to 20C, and the solvent was concentrated to be dry under reduced pressure. The residues were purified by a silica gel chromatography (petroleum ether: ethyl acetate = 1:1) to obtain methyl 6-methyl-1-[[7-(tosyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]piperidyl-3-carboxylate(3.5 0 g, yield was 17.10%) which was white solid. The value of C21H25N5O4S[M+H]+444 was calculated using MS ESI, and was 444. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.83 g | With triethylamine; In dichloromethane; at 60℃; for 10h; | Step 2: tert-butyl N-(1-amino-3-piperidinyl) carbamate (1.80 g, 8.36 mmol) and 4-chlro-7-(tosyl)pyrrolo[2,3-d]pyrimidine (2.83 g, 9.20 mmol) were dissolved in a dichloromethane solution (20 mL), and added with triethylamine (2.54 g, 25.08 mmol), then the reaction solution was heated to 60C and stirred for 10 h. LCMS showed that the reaction was completed. The mixture was cooled to 25C, and the solvent was concentrated to be dry under reduced pressure. Residues were poured into water (20 mL), the aqueous phase was extracted using ethyl acetate (30 mL * 3), merged organic phases were washed by saturated saline solution (15 mL*2), dried by anhydrous sodium sulfate, and filtered and concentrated in vacuum. Residues were purified by silica column chromatography (dichloromethane/ethyl acetate = 5:1/3:1) to obtain tert-butyl N-[1-[[7-(tosyl)pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-piperidyl] carbamate which was yellow spumescent solid (1.83 g, yield was 43.18%). The value of C23H30N6O4S[M+H]+487 was calculated using MS ESI, and was 487. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 g | With triethylamine; In dichloromethane; at 60℃; for 10h; | Step 5: 1-aminopyrrolidyl-3-carboxylic acid ethyl ester (1.60 g, 10.11 mmol) and 4-chloro-7-(tosyl)pyrrolo[2,3-d]pyrimidine (3.42g, 11.12 mmol) were dissolved in a dichloromethane solution (20 mL), and added with triethylamine (3.07g, 30.33 mmol), then the reaction solution was heated to 60C and stirred for 10 h. LCMS showed that the reaction was completed. The solvent was spin-dried, residues were poured into water (20 mL), and an aqueous phase was extracted using ethyl acetate (20 mL * 3). Merged organic phases were washed by saturated saline solution (15 mL * 2), dried by anhydrous sodium sulfate, filtered and concentrated to be dry under reduced pressure. Residues were purified by silica column chromatography (dichloromethane: ethyl acetate = 5:1 to 3:1) to obtain 1-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidyl-3-carboxylic acid ethyl ester which was yellow solid (1.00 g, yield was 22.11%). The value of C20H23N5O4S[M+H]+430 was calculated using MS ESI, was 430. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.7 g | With triethylamine; In 1,4-dioxane; at 25 - 110℃; for 5h; | Step 3: triethylamine (3.76 g, 37.16 mmol) was added into a dioxane solution (100 mL) of 4-amino-1,4-diazepan-1-carboxylic acid tert-butyl ester (4.00 g, 18.58 mmol) and 4-chloro-7-(tosyl)pyrrolo[2,3-d]pyrimidine at 25C. The mixture was stirred for 5 h at 110C. LC-MS showed the reaction was completed. The mixture was cooled to 25C, and was concentrated to be dry under reduced pressure. The residues were purified by a silica gel chromatography (petroleum ether: ethyl acetate = 3:1 to 1:1) to obtain 4-[[7-(tosyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-1,4-diazepan-1-carboxylic acid tert-butyl ester (1.70 g, yield was 18.80%) which was yellow solid. The value of C23H30N6O4S[M+H]+487 was calculated using MS ESI, and was 487. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.96% | With triethylamine; In 1,4-dioxane; at 110℃; for 5h; | Step 5: ethyl 1-amino-3-methylpiperidyl-3-carboxylate (2.80 g, 15.03 mmol, 1.00 Eq) and 4-chloro-7-(tosyl)pyrrolo[2,3-d]pyrimidine (4.86 g, 15.79 mmol, 1.05 Eq) were dissolved in dioxane (30 mL) and added with triethylamine (2.28 g, 22.55 mmol, 1.50 Eq). The mixture was stirred for 5 h at 110C. TLC showed that the reaction was completed. The mixture was cooled to 25C. The mixture was diluted by water (20 mL), the aqueous phase was extracted using ethyl acetate (100 mL*2), organic phases were merged and were successively washed by water (30 mL * 2) and saturated saline water (20 mL), dried by anhydrous sodium sulfate, filtered and concentrated in vacuum. The residues were purified by a silica gel chromatography (petroleum ether: ethyl acetate = =5:1 to 1:1) to obtain ethyl 3-methyl-1-[[7-(tosyl)pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidyl-3-carboxylate (1.10 g, 2.40 mmol, yield was 15.96%) which was yellow solid. The value of C22H27N5O4S[M+H]+458 was calculated using MS ESI, and was 458. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
161.8 mg | With triethylamine; In dichloromethane; at 25℃; for 16h;Inert atmosphere; | Step 3: 4-chloro-7-(tosyl)pyrrole[2,3-d]pyrimidine (169.00 mg, 549.13 umol) and 5-amino-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-tert-butyl formate (149.78 mg, 658.96 umol) were dissolved in DCM (6.40 mL), added with triethylamine(278.13 mg, 2.75 mmol), and stirred to react for 16 h at 25C. LC-MS showed the reaction was completed. Stirring wasstopped and water (10ml) was added, then the mixture was extracted by DCM (5 mL33), and organic layers weremerged, washed by saturated saline solution (25 mL 3 1), dried by anhydrous sodium sulfate, filtered and concentratedunder reduced pressure, and separated by a preparation type TLC (SiO2, PE: EA = 1:1) to obtain faint yellow solid5-[[7-(tosyl)pyrrole[2,3-d]pyrimidine-4-]amino]-hexahydropyrrolo[3,4-c]pyrrole-2(1H )-tert-butyl formate (161.80 mg,59.10%). The value of C24H30N6O4S[M+H]+499.20 was calculated using MS ESI, and was 499. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
270 mg | With triethylamine; In dichloromethane; at 50℃; for 10h; | Step 3: a dichloromethane solution (15.00 mL) of tert-butyl-5-aminohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylic ester (620.00 mg, 2.06 umol), 4-chloro-7-(tosyl)pyrrolo[2,3-d]pyrimidine (633.12 mg, 2.06 umol) and triethylamine (1.25 g, 12.36 mmol) was heated to 50 C and stirred for 10 h at 50C. LC-MS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to obtain residues. The residues were purified through column chromatography (petroleum ether: ethyl acetate = 5/1 to 2/1) to obtain tert-butyl 5-(7-(tosyl)pyrrolo[2,3-d]pyrimidin-4-yl]aminohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylic ester (270.00 mg, yield was 20.97%) which was white solid. The value of C25H32N6O4S[M+H]+513 was calculated using MS ESI, and was 513. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35 mg | With triethylamine; In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere; | Step 4: 3-amino-3-azaspiro[5.5]undecane-9-ethyl formate (200.00 mg, 832.15 umol) was dissolved in dioxane (10.00 mL), and added with triethylamine (421.03 mg, 4.16 mmol) and 4-chloro-7-(tosyl)pyrrolo[2,3-d]pyrimidine (256.10 mg, 832.15 umol); then the foregoing mixture was stirred for 16 h under nitrogen protectionat 110C. LC-MS showed that 60% 4-chloro-7-(tosyl)pyrrolo[2,3-d]pyrimidine was remained and didn't convert anymore. The mixture was added with water (10.00 mL) to quench at 25C, and extracted using ethyl acetate (50 mL*2). Merged organic phases were washed by saturated saline water (20 mL), dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Residues were purified by a preparation TLC (silica gel, petroleum ether: ethyl acetate = 1:1) to obtain 3-[[7-(tosyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-azaspiro[5.5]undecane-9-ethyl formate (35.00 mg, yield was 6.58%) which was faint yellow solid. The value of C26H33N5O4S[M+H]+512 was calculated using MS ESI, and was 512. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 6 h / 75 °C / Inert atmosphere 2.1: hydrogen bromide; acetic acid / ethyl acetate / 2 h / 20 - 25 °C / Inert atmosphere 3.1: triethylamine / 2-methyltetrahydrofuran / 1 h / 20 °C / Inert atmosphere 3.2: 1.17 h / 20 °C / Inert atmosphere 4.1: sodium hydroxide / 2-methyltetrahydrofuran; water / 1 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 7 h / 75 °C 2: hydrogen bromide; acetic acid / 0.5 h / 90 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 0 - 20 °C 4: lithium hydroxide monohydrate; water / isopropyl alcohol / 13 h / 60 °C | ||
Multi-step reaction with 4 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / isopropyl alcohol / 85 °C / Schlenk technique 2: [bis(acetoxy)iodo]benzene / water; N,N-dimethyl-formamide; acetonitrile 3: triethylamine / 2-methyltetrahydrofuran / -10 - 0 °C 4: sodium hydroxide / water / 4 h / 70 °C |
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol 2: hydrogen bromide / ethyl acetate 3: triethylamine / 2-methyltetrahydrofuran / -10 - 0 °C 4: sodium hydroxide / water / 4 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.4% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; for 16h;Reflux; | 100 mg of intermediate 3 and <strong>[479633-63-1]4-chloro-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine</strong> 137 mg were dissolved in 5 ml n-butanol, and 158 mg DIEA (N,N-diisopropylethylamine) was continuously added. ), magnetic stirring, heating to reflux reaction for 16h, TLC detection reaction is complete, the reaction solution is concentrated under pressure, the residue is diluted with 10 ml of water, the aqueous phase is extracted with ethyl acetate 3 times, 20 ml each time, the organic layer is combined and the organic layer solution is used The mixture was dried over anhydrous sodium sulfate overnight, suction-filtered, and concentrated under reduced pressure. The residue was separated using silica gel column chromatography (RhoEpsilon: EpsilonAlpha=1:2) to give 68 mg of a pale yellow solid, namely Intermediate 4, with a yield of 32.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: sodium ethanolate / ethanol / Reflux 2: hydrogenchloride / water / 45 °C 3: trichlorophosphate; N-ethyl-N,N-diisopropylamine / toluene / 50 °C 4: tetrabutyl-ammonium chloride; potassium carbonate / water; dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.1% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; for 16h;Reflux; | [0066] Step 6: Ethyl 7-amino-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate hydrochloride (100 mg, 0.4 mmol) and 4-chloro-7-tosyl-pyrrolo[2,3-d]pyrimidine(137 mg, 0.4 mmol) was dissolved in n-BuOH (5 mL), and DIEA (158 mg, 1.2 mmol) was added. The resulting mixture was stirred and refluxed for reacting for 16 hours. LC-MS showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with H2O (10 mL), the water phase was extracted with EA (20 mL33). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified through preparative TLC (PE:EA=0:1) to give ethyl 7-[[7-tosyl-pyrrolo [2,3-d]pyrimidine-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate (55 mg, 0.11 mmol, 28.1% yield) as a pale yellow solid compound. MS (ESI) Calcd. for C23H24N6O4S 480, Found 481 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In water; dimethyl sulfoxide; at 107℃; for 9.0h;Large scale; | Add SMA 11.0kg, SMB 12.8kg, DIPEA 19.5kg, DMSO to a 200L reactor50.0 kg, 15.0 kg of purified water, and the temperature was raised to 107C. After the reaction is complete, add 24.0kg absolute ethanol to room temperature and addWater 30.0kg, stirring and decrystallization 2h, suction filtration, drying at 60±5C, 17.2kg of white solid. Yield 93.0%, SMB residue0.3%, HPLC purity 98.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide; water / 9 h / 107 °C / Large scale 2: sodium hydroxide; water / dimethyl sulfoxide / 1 h / 80 °C / Large scale 3: Pd(OH)2/C; hydrogen / ethanol / 3 h / 61 °C / 760.05 Torr / Large scale 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / ethanol / 1 h / 49 °C / Large scale 5: water / 96 °C / Large scale | ||
Multi-step reaction with 4 steps 1.1: potassium carbonate / water / 100 °C 2.1: potassium hydroxide; methanol / 3.5 h / 20 - 45 °C 3.1: acetic acid; 10% Pd/C; hydrogen / water / 8 h / 50 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / butan-1-ol / 12 h / 45 °C 4.2: 2 h / 20 - 40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.4% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; for 16h;Reflux; | 100 mg of intermediate 3 and <strong>[479633-63-1]4-chloro-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine</strong> 137 mg dissolved in 5 mlButanol, continue to add 158mg DIEA (N, N-diisopropylethylamine), magnetic stirring, heating to reflux reaction for 16h, TLC detection reaction is complete, the reaction solution was concentrated under pressure,The residue was diluted with 10 ml of water. The aqueous phase was extracted with ethyl acetate 3 times, 20 ml each time. The organic layers were combined and the organic layer was dried overnight over anhydrous sodium sulfate. The mixture was filtered under suction, concentrated under reduced pressure, and the residue was separated using silica gel column chromatography. (PE:EA=1:2), 68 mg as a pale yellow solid, Intermediate 4, yield 32.4%.Among them, PE is petroleum ether and EA is ethyl acetate. In step c, the eluate used in the separation of the residue by silica gel column chromatography is selected from the mixed solution of petroleum ether and ethyl acetate, and the molar ratio of petroleum ether to ethyl acetate in the eluate is 1:2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate; In water; at 100℃; for 16h; | Dissolve compound 1-benzyl-N-methyl-piperidin-3-amine (1.4 g, 7.0 mmol, 1.0 eq.) in 50 ml of water.To this was added the compound <strong>[479633-63-1]4-chloro-7-(p-toluenesulfonyl)-pyrrolo[2,3-d]pyrimidine</strong> and potassium carbonate (5.6 g,42mmol, 6.0eq.) The reaction was carried out at 100oC for 16 hours and then cooled to room temperature and extracted with ethyl acetate (50ml)Three times, then backwash with water and saline once, dry with sodium sulfate, spin-dry, and obtain crude compounds separated by column(ethyl acetate / petroleum ether = 1:1) to give the target compound (1.26 g, yield = 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.4% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; for 16h;Reflux; | Will 100mg intermediate 3And 137 mg of <strong>[479633-63-1]4-chloro-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine</strong> dissolved in 5 mlN-butanol,Continue to add 158mg DIEA (ie N,N-diisopropylethylamine),Magnetic stirring,Heated to reflux for 16 h,TLC detects the reaction completely,The reaction solution is concentrated under pressure,The residue was diluted with 10 ml of water.The aqueous phase was extracted with ethyl acetate 3 times.The organic layer was combined and dried over anhydrous sodium sulfate overnight.Filter by suction, concentrate under reduced pressure,Residue column chromatography (PE: EA = 1:2) gave 68 mg of pale yellow solid, intermediate 4. The yield was 32.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.2% | Sodium hydride (0.5g, 13.2mM, 60%) was successively added to a solution of diethyl malonate (1.1g, 6.6mM) in THF (tetrahydrofuran, 50mL), while keeping internal temperature between 0 and 5C. The mixture was stirred at 0C for 0.5h, followed by addition of the required 2a (1.0g, 3.3mM) and heating to reflux for another 2.5h. After cooling the reaction, the mixture was diluted in 50mL saturated ammonium chloride solution, the aqueous layer was extracted with ethyl acetate (50mL×3). The combined organic layers were washed with brine (30mL×3), and then dried over anhydrous MgSO4. The mixture was evaporated in vacuo and purified by silica gel column chromatography to obtain 3a (1.4g, 98.6%) as colorless oil. ESI-MS m/z: 432.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere; | Under nitrogen protection,4-Chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (300 g, 0.98 mol), N-BOC-bicyclooctane ketone (234 g, 0.98 mol) and N, N - dimethylformamide (2.3 kg) was added to the reaction flask, stirred and dissolved, potassium carbonate (336 g, 2.44 mol) was added, and the reaction solution was heated to 100 C for 2 h with stirring. After the TLC was followed, the reaction solution was taken. After cooling to room temperature, ice water (15 kg) was added, and a large amount of EtOAc (EtOAc) was evaporated, evaporated, evaporated, evaporated, evaporated. The crude product was obtained, and the crude product was dissolved in ethyl acetate (1.2 kg), and petroleum ether (3.6 kg) was slowly added at room temperature. The solid was gradually precipitated, stirred for 1 hour, filtered, and the filter cake was dried under reduced pressure to give the title. Product (349 g, yield 70.0%). |
70% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere; | 4-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (300 g, 0.98 mol), N-BOC-bicyclooctanone (234 g, 0.98 mol) and N,N-dimethylformamide (2.3 kg) were added to a reaction flask under a nitrogen atmosphere, and stirred to dissolve. The reaction solution was added with potassium carbonate (336 g, 2.44 mol), and warmed up to 100 C. under stirring for 2 hours. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was added with ice water (15 kg), and a large amount of khaki solids were precipitated. The reaction mixture was stirred at room temperature for 1 hour and filtrated, and the filter cake was dissolved in dichloromethane (6 kg) and extracted. The organic phase was dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethyl acetate (1.2 kg) under heating, and slowly added with petroleum ether (3.6 kg) at room temperature to precipitate a solid gradually. The reaction mixture was stirred for 1 hour and filtrated, and the filter cake was dried under reduced pressure to obtain the title product (349 g, yield 70.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In isopropyl alcohol; at 85℃;Schlenk technique; | In a 20 mL Schlenk tube,Amino-amide hydrochloride (500 mg, 3.04 mmol 1.0 eq) and isopropanol (4 mL),This was followed by chloro-pyrrolopyrimidine (1.03 g, 3.34 mmol, 1.1 equiv) and DBU (0.97 g, 6.38 mmol).1, 2.1 equivalents).Heating the resulting mixture to 85 C.,Stir until the reaction is complete by UPLC.After completion, the mixture was cooled to 40 C.At that point, water (20 mL) was added to give a clear solution.Continuing to cool to 20 C. gives a solid that precipitates from the reaction.Filter the solids and rinse the filter cake with H2O (30 mL).The crude solid (1.18 g) was subjected to reverse phase chromatography.(Gradient 4: 6 MeOH: H2O to 100% MeOH, 20 CV).Combine the desired fractions, remove the methanol in vacuo,A precipitated solid was obtained.Filter the solid and rinse with H2O (10 mL)Dried at 50 C. in a vacuum dryer,Desired SNAr product resulted as white solid(686 mg, 57% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.7% | With N-Bromosuccinimide In acetonitrile at 20℃; for 4h; | 4.1; 5.1; 6.1; 7.1; 8.1; 9.1; 10.1; 11.1; 12.1; 13.1 step 1 Add 1 (5.0g, 16.29mmol) and acetonitrile (50mL) to a 250ml single-necked flask, add NBS (3.48g, 19.54mmol) in batches, stir at room temperature for 4 hours, add water (20ml), and extract with ethyl acetate (50ml×3), washed with saturated brine (50ml×3), dried with anhydrous sodium sulfate, spin-dried, column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product as a yellow solid (6.0g , Yield: 95.7%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; | 1 Synthesis of Cmp. B. To a stirred solution of Cmp. A (2.25 g, 9.89 mmol) in DMF (15mL) was added N,N-diisopropylethylamine (2.55 g, 19.78 mmol) and 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.19 g, 10.38 mmol). The mixture was stirred at 80 °C overnight. TLC showed the reaction was complete. The reaction mixture was added water and extracted ethyl acetate (50ml). The organic was washed with brine (3 x 40 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude residue which was purified through silica gel flash column chromatography (eluted with 5% ethyl acetate in hexane (50%) and dichloromethane (50%)) to afford Cmp. B (2.7 g, yield 56%) as white solid. (400 MHz, CDCh): d 1.27-1.38 (m, 4H), 1.45 (s, 9H), 1.76-1.79 (m, 2H), 2.06-2.12 (m, 2H), 2.38 (s, 3H),3.13(s, 3H), 3.40-3.45(m, 1H), 4.40-4.42 (m, 1H), 4.66-4.72 (m, 1H), 6.60(d, 7=4.4 Hz, 1H), 7.26(s, 1H), 7.29(s, 1H),7.44 (d, 7=4.0 Hz, 1H), 8.05 (d, 7=8.4 Hz, 2H), 8.37 (s, 1H); LC-MS: (ES+): m/z [M+H] + calcd for C25H33N5O4S: 499.23. Found 500.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium carbonate; tetrakis-(triphenylphosphine)-palladium / 1,4-dioxane; water monomer / 4 h / 80 °C / Inert atmosphere 2.1: acetonitrile / 60 °C 3.1: sodium hydroxide / water monomer; methanol / 2 h / 20 °C 3.2: 1 h | ||
Multi-step reaction with 6 steps 1: Cs2CO3 2: potassium etoxide 3: sodium hydroxide 4: anhydrous sodium perchlorate; trichlorophosphate | ||
Multi-step reaction with 6 steps 1: Cs2CO3 2: potassium etoxide 3: sodium hydroxide 4: anhydrous sodium perchlorate; trichlorophosphate |
Multi-step reaction with 6 steps 1.1: Cs2CO3 / N,N-dimethyl-formamide / 50 - 60 °C 2.1: potassium etoxide / ethanol / 12 h / 65 - 75 °C 3.1: sodium hydroxide; water monomer / water monomer; tetrahydrofuran; propan-2-one / 5 h / 20 °C 4.1: trichlorophosphate / 0.5 h / 80 - 90 °C 4.2: pH 7 - 8 4.3: 2 h / 0 - 20 °C 5.1: ethanol / 5 h / 20 °C 6.1: phosphoric acid / isopropanol; water monomer; dichloromethane / 2 h / 20 - 36 °C | ||
Multi-step reaction with 6 steps 1.1: Cs2CO3 / N,N-dimethyl-formamide / 50 - 60 °C 2.1: potassium etoxide / ethanol / 12 h / 65 - 75 °C 3.1: sodium hydroxide; water monomer / water monomer; tetrahydrofuran; propan-2-one / 5 h / 20 °C 4.1: trichlorophosphate / 0.5 h / 80 - 90 °C 4.2: pH 7 - 8 4.3: 2 h / 0 - 20 °C 5.1: ethanol / 5 h / 20 °C 6.1: phosphoric acid / isopropanol; water monomer; dichloromethane / 2 h / 20 - 36 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 80℃; for 4h; Inert atmosphere; | 1.1 1.3-cyclopentyl-3-(4-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1- yl)propanenitrile(Compound 4)Preparation Mix compound 2 (10g, 32.5mmol, 1eq) and compound 3 (12.3g, 39.0mmol, 1.2eq), add 100ml of dioxane, 50ml of water, potassium carbonate (17.9g, 0.13mol, 4eq), and replace with nitrogen. ; Add tetrakis (triphenylphosphine) palladium (0.2g, 2%wt), replace with nitrogen, and heat to 80°C for 4h. TLC detected that compound 2 was almost completely consumed, and the temperature was cooled down. The reaction solution was poured into 100 ml ethyl acetate and 100 ml water for quenching, stirred for 1 h, allowed to stand for separation, and the organic layer was washed with saturated sodium chloride (100 ml), dried over anhydrous sodium sulfate, and concentrated. The remaining ethyl acetate and n-hexane were refined to obtain about 12 g of off-white solid 4 (yield 81.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 0.5 h / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 0.5 h / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 0.5 h / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 0.5 h / 20 °C 7.2: 2.08 h / 26 °C |
Multi-step reaction with 7 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 0.5 h / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 0.5 h / 20 °C 7.2: 2.08 h / 26 °C | ||
Multi-step reaction with 5 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 20 °C 3.1: hydrogenchloride / water; ethanol 4.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 20 °C 3.1: hydrogenchloride / water; ethanol 4.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 30 min / 20 °C 7.2: 125 min / 26 °C | ||
Multi-step reaction with 7 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 30 min / 20 °C 7.2: 125 min / 26 °C | ||
Multi-step reaction with 8 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 20 °C 3.1: hydrogenchloride / water; ethanol 4.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 30 min / 20 °C 8.2: 125 min / 26 °C | ||
Multi-step reaction with 8 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 20 °C 3.1: hydrogenchloride / water; ethanol 4.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 30 min / 20 °C 8.2: 125 min / 26 °C |
Tags: 479633-63-1 synthesis path| 479633-63-1 SDS| 479633-63-1 COA| 479633-63-1 purity| 479633-63-1 application| 479633-63-1 NMR| 479633-63-1 COA| 479633-63-1 structure
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P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
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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