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Chemical Structure| 941685-40-1
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Product Details of [ 941685-40-1 ]

CAS No. :941685-40-1 MDL No. :
Formula : C23H32N6OSi Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 436.63 Pubchem ID :-
Synonyms :

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* 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.

  • Downstream synthetic route of [ 941685-40-1 ]

[ 941685-40-1 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 941685-40-1 ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
92.1% Step 6: (R)-3-cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile 35 g of (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile was added to 700 mL of acetonitrile, and then 31.5 mL of boron trifluoride ethyl ether was added dropwise thereto. After the addition was completed, the resulting mixture was heated to 60?70 C. and reacted for 5 hours, and then 270 mL of aqueous ammonia and 540 mL of purified water were added thereto and stirred at room temperature for 12 hours. After the reaction was completed, to the reaction solution were added 200 mL of ethyl acetate and 200 mL of saturated ammonium chloride, the aqueous phase was extracted three times with ethyl acetate (300 mL*3), and the organic phase was concentrated under reduced pressure to obtain (R)-3-cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) propionitrile (22.61 g, 92.1%). 1H-NMR (500 MHz, DMSO-d6): delta=12.10 (bs, 1H), 8.80 (d, J=0.4 Hz, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 7.60 (dd, J=2.3, 3.5 Hz, 1H), 6.99 (dd, J=1.4, 3.4 Hz, 1H), 4.53(td, J=9.5, 4.3 Hz, 1H), 3.26 (dd, J=17.3, 9.9 Hz, 1H),3.19 (dd, J=17.4, 4.3 Hz, 1H), 2.39 (m, 1H), 1.82 (m, 1H), 1.60?1.08 (m, 7H); MS (ES): 307.17 (M+H+).
58% With trifluoroacetic acid; In dichloromethane; for 6h; Step 3. To a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (6.5 g, 0.015 mol, R or S enantiomer as isolated above) in DCM (40 mL) was added TFA (16 mL) and this was stirred for 6 hours. The solvent and TFA were removed in vacuo. The residue was dissolved in DCM and concentrated using a rotary evaporator two further times to remove as much as possible of the TFA. Following this, the residue was stirred with ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL) overnight. The solvent was removed in vacuo, water was added and the product was extracted into three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to afford the crude product which was purified by flash column chromatography (eluting with a gradient of methanol/DCM). The resulting mixture was further purified by preparative-HPLC/MS (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford product (2.68 g, 58%). 1H NMR (400 MHz, D6-dmso): delta 12.11 (br s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.98 (d, 1H), 4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), 2.48-2.36 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.13 (m, 7H); MS(ES): 307 (M+1).
58% With trifluoroacetic acid; In dichloromethane; for 6h; Step 3. To a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (6.5 g, 0.015 mol, R or S enantiomer as isolated above) in DCM (40 mL) was added TFA (16 mL) and this was stirred for 6 hours. The solvent and TFA were removed in vacuo. The residue was dissolved in DCM and concentrated using a rotary evaporator two further times to remove as much as possible of the TFA. Following this, the residue was stirred with ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL) overnight. The solvent was removed in vacuo, water was added and the product was extracted into three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to afford the crude product which was purified by flash column chromatography (eluting with a gradient of methanol/DCM). The resulting mixture was further purified by preparative-HPLC/MS (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford product (2.68 g, 58%). 1H NMR (400 MHz, D6-dmso): delta 12.11 (br s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.98 (d, 1H), 4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), 2.48-2.36 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.13 (m, 7H); MS(ES): 307 (M+1).
To a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (6.5 g, 0.015 mol, R or S enantiomer as isolated above) in DCM (40 mL) was added TFA (16 mL) and this was stirred for 6 hours. The solvent and TFA were removed in vacuo. The residue was dissolved in DCM and concentrated using a rotary evaporator two further times to remove as much TFA as possible. Following this, the residue was stirred with ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL) overnight. The solvent was removed in vacuo, water was added and the product was extracted into three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to afford the crude product which was purified by flash column chromatography (eluting with a gradient of methanol/DCM). The resulting mixture was further purified by preparative-HPLC/MS (CI 8 eluting with a gradient of ACN/H20 containing 0.15% NH4OH) to afford product (2.68 g, 58%).1H NMR (400 MHz, DMSO-d6): delta 12.11 (br s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.98 (d, 1H), 4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), 2.48- 2.36 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.13 (m, 7H); MS(ES): 307 (M+l).
With lithium tetrafluoroborate; In water; acetonitrile; at 0.8 - 27℃; for 11h; The starting material (244 g; 0.559 mol) was dissolved in 2370 ml MeCN, followed by the addition of 210 ml water and lithium tetrafluoroborate (LiBF4, 520.48 g; 5.55 mol) at room temperature (rt). The reaction temperature decreased by addition of water to 14C (Ti=22C) and increased by addition of LiBF4 to 27C. The reaction mixture was heated to reflux (-80C) for 11 h. The reaction was monitored by HPLC. After complete consumption of the starting material the reaction mixture was cooled to 5C, followed by dropwise addition of20% aqueous ammonium hydroxide (274 ml) to adjust to pH 9. The ice bath was removedand the reaction mixture was gradually warmed to rt. After complete deprotection, which was monitored by HPLC/TLC, the reaction mixture was filtered and the solids were washed with MeCN (530 ml). The combined filtrates were evaporated under reduced pressure at 46C and to the residue 3160 ml EtOAc and 1580 ml half saturated brine were added. The two layers were separated and the aqueous layer was extracted with EtOAc (1050 ml). The combined organic layers were washed with half saturated NaHCO3 (1600 ml) and brine (1600 ml), dried over Na2SO4 and concentrated under reduced pressure to yield the crude product as orange oil. The crude product was purified by flash chromatography on silica (eluent: EtOAc). Purification procedure: the crude product was dissolved in 250 ml ethylacetate and was divided in two nearly equal portions; each portion was purified separately by a silica column (prepacked puriflash columnlpuriflashll600 g/50 tim) on a Armen spot flash system flow: 80 mlJmin. The obtained colorless oil was evaporated, resulting in a foam, which was triturated with 200 ml n-pentane (each portion) resulting in a colorless solid which was filtrated off and dried under vacuum at rt. The obtained product was stored under argon atmosphere in the fridge.
With trifluoroacetic acid; In dichloromethane; for 6h; (3R)- and (3S)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile[0113] To a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (6.5 g, 0.015 mol, Ror S enantiomer as isolated above) in DCM (40 mL) wasadded TFA (16 mL) and this was stirred for 6 hours. The solvent and TFA were removed in vacuo. The residuewas dissolved in DCM and concentrated using a rotaryevaporator two further times to remove as much as possible of the TFA. Following this, the residue was stirredwith ethylenediamine (4 mL, 0.06 mol) in methanol (30mL) overnight. The solvent was removed in vacuo, waterwas added and the product was extracted into three portions of ethyl acetate. The combined extracts werewashed with brine, dried over sodium sulfate, decantedand concentrated to afford the crude product which waspurified by flash column chromatography (eluting with agradient of methanol/DCM). The resulting mixture wasfurther purified by preparative-HPLC/MS (C18 elutingwith a gradient of ACN/H2O containing 0.15% NH4OH)to afford product (2.68 g, 58%).1H NMR (400 MHz, D6-dmso): delta12.11 (br s, 1H), 8.80(s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.98 (d,1H), 4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), 2.48-2.36(m, 1H), 1.86-1.76 (m, 1H), 1.68-1.13 (m, 7H);MS(ES):307(M+1).

  • 2
  • [ 941685-40-1 ]
  • [ 941678-49-5 ]
  • [ 1236033-03-6 ]
YieldReaction ConditionsOperation in experiment
With lithium tetrafluoroborate; water; In acetonitrile; at 12 - 80℃; (3R)-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-13, free base).; Method B.; To a solution of (3R)-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile ((R)-20, 463 g, 1.06 mol, 98.6% ee) in acetonitrile (4.5 L) was added water (400 mL) followed immediately by lithium tetrafluoroborate (LiBF4, 987.9 g, 10.5 mol, 10.0 equiv) at room temperature. The reaction temperature was observed to decrease from ambient to 12 C. upon addition of the water and then increase to 33 C. during the addition of lithium tetrafluoroborate (LiBF4). The resulting reaction mixture was heated to reflux (about 80 C.) for overnight. An aliquot was quenched into ethyl acetate/water and checked by LCMS and TLC (95:5 ethyl acetate/methanol, v/v). When LCMS and TLC analyses showed both the hydroxyl methyl intermediate ((R)-25) and fully de-protected material ((R)-13, free base) produced but no starting material ((R)-20) left, the reaction mixture was cooled gradually to <5 C. before a 20% aqueous solution of ammonium hydroxide (NH4OH, 450 mL) was added gradually to adjust the pH of the reaction mixture to 9 (checked with pH strips). The cold bath was removed and the reaction mixture was gradually warmed to room temperature and stirred at room temperature for overnight. An aliquot was quenched into ethyl acetate/water and checked by LCMS and TLC (95:5 ethyl acetate/methanol, v/v) to confirm complete de-protection. When LCMS and TLC showed the reaction was deemed complete, the reaction mixture was filtered and the solids were washed with acetonitrile (1 L). The combined filtrates were then concentrated under reduce pressure, and the residue was partitioned between ethyl acetate (EtOAc, 6 L) and half-saturated brine (3 L). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 L). The combined organic layers were washed with half-saturated sodium bicarbonate (NaHCO3, 3 L) and brine (3 L), dried over sodium sulfate (Na2SO4), and concentrated under reduced pressure to give the crude product as an orange oil. The crude material was then purified by flash column chromatography (SiO2, 40 to 100% ethyl acetate/heptane gradient elution) to afford (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-13, free base, 273 g, 324.9 g theoretical, 84% yield) as a white foam. This material was checked by 19F NMR to ensure no lithium tetrafluoroborate (LiBF4) remained and by chiral HPLC (Chiralcel OD, 90:10 hexane/ethanol) to confirm enantiomeric purity and was used without further purification to prepare the corresponding phosphate salt. For (R)-13 (free base): 1H NMR (DMSO-d6, 400 MHz) delta ppm 12.1 (bs, 1H), 8.80 (d, 1H, J=0.42 Hz), 8.67 (s, 1H), 8.37 (s, 1H), 7.59 (dd, 1H, J=2.34, 3.51 Hz), 6.98 (dd, 1H, J=1.40, 3.44 Hz), 4.53 (td, 1H, J=19.5, 4.63 Hz), 3.26 (dd, 1H, J=9.77, 17.2 Hz), 3.18 (dd, 1H, J=4.32, 17.3 Hz), 2.40 (m, 1H), 1.79 (m, 1H), 1.65 to 1.13 (m, 7H); C17H18N6(MW, 306.37) LCMS (EI) m/e 307 (M++H).
  • 5
  • [ 941685-40-1 ]
  • [ 1092939-17-7 ]
YieldReaction ConditionsOperation in experiment
95% With phosphoric acid In propan-2-one at 55 - 60℃; 11-12 Example 11 (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile phosphate (Compound 9 ) preparationSeveral (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Pyrimidine-4-yl)-1H-pyrazol-1-yl)propionitrile was added to 18 times the volume of acetone,Stir to dissolve.20~30,Phosphoric acid (1.4eq) was added dropwise to it2 volumes of acetone solution.After adding, the temperature was raised to 55~60°C and stirred for 1~2h,Cool to 20~30 and stir for 2h,filter,The filter cake was washed with an appropriate amount of acetone.Blow dry at 40~45 to obtain (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentan Acrylonitrile Phosphate,Yield 95%,Optical purity ≥99.8%, chemical purity ≥99.7%.
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 6 h 2: phosphoric acid / isopropanol / 20 °C / Heating
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 6 h 2: phosphoric acid / isopropanol / 2 h / 20 °C
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 6 h 2: phosphoric acid / isopropanol / 2 h / 20 °C / Heating
17.7 mg With phosphoric acid In isopropanol at 20℃; for 2h; Synthesis of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1 H-pyrazol- 1 -yl]propanenitrilephosphoric acid salt To a test tube was added (3R)-3-Cyclopentyl-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1 -yl]propanenitrile (153.5 mg) and phosphoric acid (56.6 mg) followed by isopropyl alcohol (IPA) (5.75 mE). The resulting mixture was heated to clear, cooled to room temperature, and then stirred for another 2 hours. The precipitate was collected by filtration and the cake was washed with 0.6 mE of cold IPA. The cake was dried under vacuum to constant weight to provide the final salt product (171.7 mg).

  • 6
  • [ 941685-27-4 ]
  • [ 591769-05-0 ]
  • [ 941685-40-1 ]
  • [ 941685-41-2 ]
YieldReaction ConditionsOperation in experiment
To a solution of -4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (15.0 g,0.0476 mol) in ACN (300 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (15 g, 0.12 mol) (as a mixture of cis and trans isomers),followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN wasevaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0 N HCl. The aqueous layerwas back-extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradientof ethyl acetate/hexanes) to yield a viscous clear syrup, which was dissolved in ethanol and evaporated several timesto remove ethyl acetate, to afford 19.4 g of racemic adduct (93percent). The enantiomers were separated by preparative-HPLC, (OD-H, 15percent ethanol/hexanes) and used separately in the next step to generate their corresponding final product.The final products (see Step 3) stemming from each of the separated enantiomers were found to be active JAK inhibitors;however, the final product stemming from the second peak to elute from the preparative-HPLC was more active thanits enantiomer.1H NMR (300 MHz, CDCl3): delta 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H),3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03-1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H), -0.06(s, 9H); MS(ES):437 (M+1).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; (3R)- and (3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile[0112] To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(15.0 g, 0.0476 mol) in ACN (300 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (15 g, 0.12 mol) (as a mixture of cisand trans isomers), followed by DBU (15 mL, 0.10 mol).The resulting mixture was stirred at room temperatureovernight. The ACN was evaporated. The mixture wasdiluted with ethyl acetate, and the solution was washedwith 1.0 N HCl. The aqueous layer was back-extractedwith three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The crude product waspurified by silica gel chromatography (gradient of ethylacetate/hexanes) to yield a viscous clear syrup, whichwas dissolved in ethanol and evaporated several timesto remove ethyl acetate, to afford 19.4 g of racemic adduct (93percent). The enantiomers were separated by preparative-HPLC, (OD-H, 15percent ethanol/hexanes) and usedseparately in the next step to generate their corresponding final product. The final products (see Step 3) stemming from each of the separated enantiomers were foundto be active JAK inhibitors; however, the final productstemming from the second peak to elute from the preparative-HPLC was more active than its enantiomer.1H NMR (300 MHz, CDCl3): delta8.85 (s, 1H), 8.32 (s, 2H),7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54(t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H),2.03-1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H), -0.06(s, 9H); MS(ES):437 (M+1).
  • 7
  • [ 591769-05-0 ]
  • [ 941685-40-1 ]
  • [ 941685-41-2 ]
  • 8
  • [ 941685-27-4 ]
  • [ 941685-40-1 ]
  • [ 941685-41-2 ]
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