| 90% |
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h; Cooling with ice
Stage #2: for 1 h; Cooling with ice |
With ice bath,To a solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (20.0 g, 130.4 mmol, 1.0 eq.In dry DMF, NaH (6.6 g, 57percent content, 156.8 mmol, 1.2 eq) was added. The reaction was stirred at room temperature for 1 hour,Further, SEMCl (26.1 g, 156.5 mmol, 1.2 eq.) Was added dropwise with cooling in an ice bath.After the addition was completed, the reaction mixture was stirred in an ice bath for 1 hour, quenched with water,Extraction with ethyl acetate and washing of the combined organic phases with brine,Dried over sodium sulfate, filtered and concentrated in vacuo.Column chromatography silica gel column isolated4-Chloro-7 - [2- (trimethylsilyl) ethoxy] methyl} -Pyrrolo [2,3-d] pyrimidine (33.4 g, 90percent yield). |
| 88.9% |
Stage #1: With sodium hydride In n-heptane; ISOPROPYLAMIDE at 0 - 20℃; Cooling with ice/brine bath
Stage #2: at 0 - 5℃; |
To a flask equipped with a nitrogen inlet, an addition funnel, a thermowell, and the mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and N,N-dimethylacetimide (DMAC, 9.6 L) at room temperature.
The mixture was cooled to 0-5° C. in an ice/brine bath before solid sodium hydride (NaH, 60 wt percent, 174 g, 4.35 mol, 1.1 equiv) was added in portions at 0-5° C.
The reaction mixture went to a dark solution during 15 minutes.
Trimethylsilylethoxymethyl chloride (2, SEM-Cl, 763 mL, 4.31 mol, 1.1 equiv) was then added slowly via an addition funnel at a rate that the internal reaction temperature did not exceed 5° C.
The reaction mixture was then stirred at 0-5° C. for 30 minutes.
When the reaction was deemed complete determined by TLC and HPLC, the reaction mixture was quenched by water (1 L).
The mixture was then diluted with water (12 L) and MTBE (8 L).
The two layers were separated and the aqueous layer was extracted with MTBE (8 L).
The combined organic layers were washed with water (2*4 L) and brine (4 L) and dried over sodium sulfate (Na2SO4).
The solvents were removed under reduced pressure.
The residue was then dissolved in heptane (2 L), filtered and loaded onto a silica gel (SiO2, 3.5 Kg) column eluding with heptane (6 L), 95percent heptane/ethyl acetate (12 L), 90percent heptane/ethyl acetate (10 L), and finally 80percent heptane/ethyl acetate (10 L).
The fractions containing the pure desired product were combined and concentrated under reduced pressure to give 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3, 987 g, 1109.8 g theoretical, 88.9percent yield) as a pale yellow oil which partially solidified to an oily solid on standing at room temperature.
|
| 88.9% |
Stage #1: With sodium hydride In N,N-dimethyl acetamide; mineral oil at -5℃; Inert atmosphere
Stage #2: at 5℃; Inert atmosphere |
4-Chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a).; To a flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and dimethylacetimide (9.6 L). The mixture was cooled to -5° C. in an ice/brine bath and sodium hydride (NaH, 60 wt percent, 174 g, 4.35 mol, 1.1 equiv) was added in portions as a solid. The mixture went to a dark solution during 15 minutes and trimethylsilylethoxymethyl chloride (2, 763 mL, 4.31 mol, 1.1 equiv) was added slowly via an addition funnel at a rate that the temperature did not exceed 5° C. The reaction was stirred for 30 minutes, determined to be complete by TLC and HPLC, and water (1 L) was slowly added to quench the reaction. The mixture was then diluted with water (12 L) and MTBE (8 L). The layers were separated and the aqueous was re-extracted with MTBE (8 L). The combined organic layers were washed with water (2.x.4 L) and brine (4 L), dried over sodium sulfate (NaSO4), and solvents removed under reduced pressure.The residue was dissolved in heptane (2 L), filtered and loaded onto a silica gel (3.5 kg) column eluting with heptane (6 L), 95percent heptane/ethyl acetate (12 L), 90percent heptane/ethyl acetate (10 L), and finally 80percent heptane/ethyl acetate (10 L). The pure fractions were combined and concentrated under reduced pressure to give 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 987 g, 1109.8 g theoretical, 88.9percent yield) as a pale yellow oil that partially solidified to an oily solid on standing at room temperature. For 3a: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, -1.48; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H). |
| 88.9% |
Stage #1: With sodium hydride In N,N-dimethyl acetamide; mineral oil at 0 - 5℃; for 0.25 h;
Stage #2: at 0 - 5℃; for 0.5 h; |
Step 1. 4-Chlow-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3) To a flask equipped with a nitrogen inlet, an addition funnel, a thermowell, and the mechanical stirrer was added 4-chloro-7H-pyirolo[2,3-c/]pyrirnidine (1, 600 g, 3.91 mol) and N,N-dimethylacetimide (DMAC, 9.6 L) at room temperature. The mixture was cooled to 0 - 5 °C in an ice/brine bath before solid sodium hydride (NaH, 60 wtpercent, 174 g, 4.35 mol, 1.1 equiv) was added in portions at 0 - 5 °C. The reaction mixture turned into a dark solution after 15 minutes. Trimethylsilylethoxymethyl chloride (2, SEM-C1, 763 mL, 4.31 mol, 1.1 equiv) was then added slowly via an addition funnel at a rate that the internal reaction temperature did not exceed 5 °C. The reaction mixture was then stirred at 0 - 5 °C for 30 minutes. When the reaction was deemed complete determined by TLC and HPLC, the reaction mixture was quenched by water (1 L). The mixture was then diluted with water (12 L) and methyl tert-b ty] ether (MTBE) (8 L). The two layers were separated and the aqueous layer was extracted with MTBE (8 L). The combined organic layers were washed with water (2 x 4 L) and brine (4 L) and solvent switched to 1-butanol. The solution of crude product (3) in 1 -butanol was used in the subsequent Suzuki coupling reaction without further purification. Alternatively, the organic solution of the crude product (3) in MTBE was dried over sodium sulfate (Na2SC>4). The solvents were removed under reduced pressure. The residue was then dissolved in heptane (2 L), filtered and loaded onto a silica gel (S1O2, 3.5 Kg) column eluting with heptane (6 L), 95percent heptane/ethyl acetate (12 L), 90percent heptane/ethyl acetate (10 L), and finally 80percent heptane/ethyl acetate (10 L). The fractions containing the pure desired product were combined and concentrated under reduced pressure to give 4-chloro-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-i/]pyrimidine (3, 987 g, 1 109.8 g theoretical, 88.9percent yield) as a pale yellow oil which partially solidified to an oily solid on standing at room temperature. For 3: NMR (DMSO-af6, 300 MHz) δ 8.67 (s, 1 H), 7.87 (d, 1 H, J = 3.8 Hz), 6.71 (d, 1 H, J= 3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J= 7.9 Hz), 0.80 (t, 2H, J= 8.1 Hz), 1.24 (s, 9H) ppm; 13C NMR (DMSO-cfe, 100 MHz) δ 151.3, 150.8, 150.7, 131.5, 1 16.9, 99.3, 72.9, 65.8, 17.1 , -1 .48 ppm; C,2H,8ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M+ + H). |
| 87% |
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1.5 h; |
General procedure: To a mixture of sodium hydride (60percent dispersion in mineral oil; 276 mg; 6.89 mmol) in DMF (10 mL) at 0 °C was added drop-wise a solution of 4-chloro-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine [prepared as detailed in Ref. 45] (1.145 g; 5.74 mmol) in anhydrous DMF (20 mL). When the addition was complete, 2-(trimethylsilyl)ethoxymethyl chloride (1.32 ml; 7.46 mmol) was added drop-wise and the reaction mixture was stirred at 0 °C for 1.5 h then allowed to warm to ambient temperature. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic phase was separated, dried over Na2SO4 and then filtered and the filtrate solvents evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (70 g) eluting with a solvent gradient of 05percent ethyl acetate in hexane to afford the title compound 42 (1.73 g, 91percent) as a colourless oil. |
| 81% |
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 2 h;
Stage #2: at 20℃; |
To a solution of NaH (3 g, 0.13 mol) in DMF (60 mL)Suspension is slowSlow to join 1(10 g, 0.066 mol) in DMF (40 mL).The reaction mixture was stirred at 0 & lt; 0 & gt; CStirring for 2 hours,A light brown cloudy mixture was obtained.And then slowly added to the mixture2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) (12.7 g, 0.08 mol)Stirred overnight at room temperature,The reaction was quenched with water and extracted with ethyl acetate,The filtrate was concentrated under reduced pressure. Purification by flash chromatography gave intermediate 2(15 g, 81percent),As a pale yellow oil; |
| 79% |
Stage #1: With sodium hydride In N,N-dimethyl acetamide; mineral oil at 0 - 5℃; for 0.416667 h; Inert atmosphere
Stage #2: at 4 - 7℃; for 1.75 h; Inert atmosphere |
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1.5g, 9.77 mmol) was stirred in anhydrous N,N- dimethylacetamide (30ml), under nitrogen, with cooling to between 0°C and 5 °C as sodium hydride (60percent dispersion, 430mg, 10.75 mmol) was added in portions. After all effervescence had ceased (25 min.), (2-chloromethoxy-ethyl)-trimethylsilane (1.79g, 10.75 mmol) was added dropwise, maintaining the temperature between 4 °C and 7 °C. After stirring for a further lh 45 min. saturated aqueous NH4C1 and a little water were added and the product was extracted with 2 portions of t-butyl methyl ether. The extracts were washed with water, brine, dried over Na2S04 and the solvent evaporated. Purification on a Si-SPE ® cartridge (70g) eluting with EtOAc- cyclohexane (1 : 10 followed by 1 :6) afforded the title compound as a colourless oil (2.19g, 79percent) LCMS (Method 1, ESI): Rt 4.11 min., m/z 325 [M+42]+, 284 [M+H]+, 1H NMR (400 MHz, CDCI3): δ 8.67 (1H, s), 7.39 (1H, d, J = 3.5Hz), 6.67 (1H, d, J = 3.5Hz), 5.65 (2H, s), 3.50-3.56 (2H, m), 0.88-0.93 (2H, m), -0.06 (9H, s). |
| 75% |
Stage #1: With sodium hydride In N,N-dimethyl acetamide at -10℃; for 0.5 h;
Stage #2: at 20℃; for 2 h; |
2L three-neck flask, 4-chloropyrrolopyrimidine (280 g, 1.83 mol) and N, N-dimethylacetamide (500 mL) were added, Cooling to -10 deg C, NaH (84 g) was added in triplicate, Plus, Stir for 0.5 hours. 2-(trimethylsilyl)ethoxymethyl chloride (385 mL, 1.98 mol) was added, Plus, After 2 hours of reaction at room temperature, The reaction solution was poured into 1 L of water, 500 mL of ethyl acetate was added, Stirring and extracting the ester layer, Washed with 300 mL of saturated sodium chloride once, Dried over anhydrous sodium sulfate, filter, Concentrated under reduced pressure to give 390 g of red product, Yield 75percent. |
| 70% |
With sodium hydride In N,N-dimethyl acetamide at 5℃; for 4.25 h; |
Under ice-cooling conditions, 2.0g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 50mL N,N-dimethylacetamide. 0.58g of NaH was added dropwise to the solution and stirred for 15 minutes. 2.2g of 2-chloromethoxyethyl trimethylsilane was added and the reaction was continued maintaining the temperature at 5°C for 4h. The solution was then quenched with saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water. Each 100mL saline solution was washed three times. The organic phase was dried over anhydrous magnesium sulfate overnight. The mixture was filtered and the solvent was distilled off under reduced pressure to give a crude product. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to give 2.6g of intermediate 2 as a colorless liquid, yield: 70percent. |
| 66% |
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25 h;
Stage #2: at 0 - 20℃; for 1 h; |
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 32.56 mmol, 1 equiv) in DMF (50 mL) was added 60percent sodium hydride (1.5 g, 39.07 mmol, 1.2 equiv) at 000 and stirred for 15 mm followed by addition of (2-(chloromethoxy)ethyl)trimethylsilane(5.7 mL, 32.56 mmol, 1.0 equiv) at same temperature. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice water. The crude product was extracted in to ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 4-chloro-7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo [2,3-d]pyrimidine as brown liquid (8.0 g, 66.0 percent). LCMS (ES) m/z =284.10 [M+H]. 1H NMR (400 MHz, DMSO-d6) O ppm -0.11 (s, 9H), 0.79-0.81 (m, 2H),3.50 (t, J= 8.0 Hz, 2H), 5.62 (s, 1H), 6.68-6.69 (m, 1H), 7.85 (d, J=4.0 Hz, 1H), 8.62 (s, 1H). |
| 0.96% |
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.25 h; Reflux
Stage #2: for 0.5 h; |
2.00 g of 4-hydroxypiperidine was added to a 100-mL round-bottomed flask, and then 20.0 mL of dichloromethane (CH2Cl2) and 20.0 mL of a saturated sodium hydrogen carbonate (NaHCO3) solution were added thereto. After 4.32 g of di-tert-butyl dicarbamate (Boc2O) was added thereto, the reaction mixture was vigorously stirred for about 15 hours and then concentrated under reduced pressure. The aqueous phase was extracted with 20.0 mL of ethyl acetate (EtOAc) to collect an organic phase. The collected organic phase was washed with 10.0 mL of deionized water and 15.0 mL of saturated brine. The organic phase was then filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure. As a result, 3.871 g of tert-butyl 4-hydroxypiperidine-1-carboxylate was obtained with a yield of about 97.2percent. (0319) 300 mg of 6-chloro-7-deazapurine was added to a 50-mL round-bottomed flask, and then 3.75 mL of N,N-dimethylformamide was added. After 86.0 mg of sodium hydride (60wtpercent) was added thereto at about 0°C, the reaction mixture was refluxed at room temperature for about 15 minutes. After 0.403 mL of 2-(trimethylsillyl)ethoxymethyl chloride) was added thereto, the reaction mixture was stirred for about 30 minutes and concentrated under reduced pressure. The reaction mixture was extracted with 4.50 mL of ethyl acetate (EtOAc) and 4.50 mL of deionized water to collect an organic phase. The collected organic phase was filtered with magnesium sulfate (MgSO4). The resulting filtrate was distilled under reduced pressure. As a result, 534 mg of 4-chloro-7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine was obtained with a yield of about 96.6percent. (0320) 408 mg of tert-butyl 4-hydroxypiperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 5.60 mL of dimethyl sulfoxide (DMSO) was added thereinto. After 61.4 mg of sodium hydride (60wtpercent) was added thereinto at about 0°C, the reaction mixture was refluxed at room temperature for about 1.5 hours. Then, a solution of 574 mg of 4-chloro-7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 4.60 mL of dimethyl sulfoxide (DMSO) was slowly dropwise added into the reaction mixture, and the reaction mixture was stirred at about 50°C for about 2 hours and then cooled down to room temperature. The reaction mixture was then extracted with 10.0 mL of ethyl acetate (EtOAc) and 10.0 mL of deionized water to collect an organic phase. The collected organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure, and then the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:5). As a result, 457 mg of tert-butyl 4-((7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was obtained with a yield of about 66.6percent. (0321) 452 mg of tert-butyl 4-((7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 5.00 mL of tetrahydrofuran was added thereinto. After 20.4 mL of a solution of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran was added thereinto, the reaction mixture was refluxed at room temperature for about 5 hours and then cooled down to room temperature. The reaction mixture was concentrated under reduced pressure and then extracted with 100 mL of ethyl acetate (EtOAc) and 100 mL of deionized water to collect an organic phase. The collected organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrated was distilled under reduced pressure, and then the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:6). As a result, 310 mg of tert-butyl 4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was obtained with a yield of about 95.7percent. (0322) 310 mg of tert-butyl 4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 6.00 mL of 1,4-dioxane was added thereinto. After 10.0 mL of 4N HCI solution was added thereinto, the reaction mixture was stirred at room temperature for about 2 hours. Then, 20.0 mL of ethyl acetate (EtOAc) was added into the reaction mixture and a 10percent ammonium hydroxide solution was added to basify the reaction mixture. An organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure. As a result, 230 mg of 4-(piperidine-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidine was obtained with a quantitative yield. (0323) 177 mg of 4-(piperidine-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidine was added to a 25-mL round-bottomed flask and then dissolved with 3.00 mL of dichloromethane (CH2Cl2). After 0.0480 mL of chloroacetyl chloride was added into the solution, the reaction mixture was treated with 0.211 mL of N,N-diisopropylethylamine and then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:6). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 56.0 mg of 1-(4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)-2-chloroethane-1-one was obtained with a yield of about 23.5percent. (0324) 55.6 mg of 1-(4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)-2-chloroethane-1-one was added to a 25-mL round-bottomed flask and then dissolved with 1.00 mL of N,N-dimethylformamide. After 24.3 mg of potassium cyanide was added into the solution, the reaction mixture was stirred overnight at about 30°C to 40°C. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:1). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 35.4 mg of 3-(4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)-3-oxopropanenitrile was obtained with a yield of about 49.4percent. (0325) 1H NMR (400 MHz, CDCl3) δ12.03 (s, 1H), 8.34 (s, 1H), 7.35 (t, J = 3.2 Hz, 1H), 6.47 (q, J = 2.0, 3.6 Hz, 1H), 5.58-5.43 (m , 1H), 4.08 (s, 2H), 3.90-3.86 (m, 1H), 3.63-3.59 (m, 1H), 3.47-3.32 (m, 2H), 2.09-2.00 (m, 2H), 1.82-1.77 (m, 1H), 1.69-1.61 (m, 1H). (0326) LRMS (ESI) calcd for (C14H15N5O2 + H+) 286.1, found 286.1. |
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