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[ CAS No. 941678-49-5 ]

{[proInfo.proName]} (Synonyms:INCB 18424) ,{[proInfo.pro_purity]}
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Chemical Structure| 941678-49-5
Chemical Structure| 941678-49-5
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CAS No. :941678-49-5 MDL No. :MFCD12031592
Formula : C17H18N6 Boiling Point : -
Linear Structure Formula :- InChI Key :N/A
M.W :306.37 g/mol Pubchem ID :25126798
Synonyms :

1. Ruxolitinib

Safety of [ 941678-49-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 941678-49-5 ]

  • Downstream synthetic route of [ 941678-49-5 ]

[ 941678-49-5 ] Synthesis Path-Downstream   1~24

  • 1
  • [ 941678-49-5 ]
  • [ 110-16-7 ]
  • [ 1092939-15-5 ]
YieldReaction ConditionsOperation in experiment
In isopropyl alcohol; at 20℃; for 2.5h;Heating / reflux; Example 1; Preparation of <strong>[941678-49-5](R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile</strong> maleic acid salt; To a test tube was added <strong>[941678-49-5](R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile</strong> (153.7 mg, 0.5 mmol) and maleic acid (61.7 mg) followed by isopropyl alcohol (IPA) (4 mL). The resulting mixture was heated to clear, cooled to room temperature, and then stirred for another 2.5 hours. The precipitate was collected by filtration and the cake was washed with 0.8 mL of cold IPA. The cake was dried under vacuum to constant weight to provide the final salt product (173 mg).The maleic acid salt was shown to be a 1:1 salt by H1 NMR and crystallinity was confirmed by X-ray powder diffraction (XRPD). Differential scanning calorimetry (DSC) gave a sharp melting peak at about 175.96 C. (onset at 175.67 C.). The product showed only slight weight loss up to 150 C. by thermogravimetric analysis (TGA).
173 mg In isopropyl alcohol; at 20℃;Heating; To a test tube was added (3R)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-lH-pyrazol-l-yl]propanenitrile (153.7 mg, 0.5 mmol) and maleic acid (61.7 mg) followed by isopropyl alcohol (IPA) (4 mL). The resulting mixture was heated to clear, cooled to room temperature, and then stirred for another 2.5 hours. The precipitate was collected by filtration and the cake was washed with 0.8 mL of cold IPA. The cake was dried under vacuum to constant weight to provide the final salt product (173 mg).
  • 2
  • [ 941678-49-5 ]
  • [ 1092939-17-7 ]
YieldReaction ConditionsOperation in experiment
84% With phosphoric acid; In dichloromethane; isopropyl alcohol; at 20℃;Reflux;Product distribution / selectivity; Method B.; To a solution of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl)-3-cyclopentylpropanenitrile ((R)-12, 54.2 g, 177 mol) in dichloromethane (782 mL) and 2-propanol (104 mL) at reflux was added a solution of phosphoric acid (19.9 g, 0.173 mol, 1.15 equiv) in 2-propanol (34.0 mL) over a period of 47 minutes. Following the acid addition, the resulting mixture was heated to reflux for an additional 1 hour. The mixture was gradually cooled to ambient temperature and stirred for 3 hours. The solids were collected by filtration and washed with dichloromethane (390 mL), followed by n-heptane (390 mL). The solids were partially dried under vacuum at room temperature and then under vacuum at 62 C. to afford <strong>[941678-49-5](R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile</strong> phosphate (60.1 g, 84% yield) as white to off-white crystalline solids. Analysis by chiral HPLC (chiralcel OD, 90:10 hexane/ethanol) gave the enantiopurity as 99.2% ee. 1H NMR (DMSO-d6, 400 MHz) delta 12.11(bs, 1H), 8.79(d, 1H, J=0.59 Hz), 8.67(s, 1H), 8.36(s, 1H), 7.59(q, 1H, J=2.3 Hz), 6.98(q, 1H, J=1.6 Hz), 4.53(td, 1H, J=19.6, 4.4 Hz), 3.22(dq, 2H, J=9.6, 4.3 Hz), 2.40(m, 1H), 1.79(m, 1H), 1.65-1.13(m, 7H). C17H21N6O4P (MW, 404.36), LCMS (EI) m/e 307 (M++H) and m/e 329 (M++Na).
With phosphoric acid; In isopropyl alcohol; at 20℃; for 2h;Heating / reflux; Example 2; Preparation of <strong>[941678-49-5](R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile</strong> phosphoric acid salt; To a test tube was added <strong>[941678-49-5](R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile</strong> (153.5 mg) and phosphoric acid (56.6 mg) followed by isopropyl alcohol (IPA) (5.75 mL). 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 mL of cold IPA. The cake was dried under vacuum to constant weight to provide the final salt product (171.7 mg).The phosphoric acid salt was shown to be a 1:1 salt by 1H NMR and crystallinity was confirmed by X-ray powder diffraction (XRPD). Differential scanning calorimetry (DSC) gave a sharp melting peak at about 198.66 C. The product showed little weight loss up to 200 C. by TGA.
171.7 mg With phosphoric acid; In isopropyl alcohol; at 20℃;Heating; To a test tube was added (3R)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-lH-pyrazol-l-yl]propanenitrile (153.5 mg) and phosphoric acid (56.6 mg) followed by isopropyl alcohol (IPA) (5.75 mL). 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 mL of cold IPA. The cake was dried under vacuum to constant weight to provide the final salt product (171.7 mg).
6.4 g With phosphoric acid; In isopropyl alcohol; at 25 - 75℃; A mixture of (i?)-3-(4-(7H-pyrrolo[2,3-ii|pyrimidin-4-yl)-lH-pyrazol-l-yl)-3- cyclopentylpropanenitrile (Formula V, as prepared in Example 4) and isopropyl alcohol (84 mL) was heated to 60C to 65C for 10 minutes to 15 minutes. A solution of phosphoric acid (2.1 g dissolved in 16.8 mL isopropyl alcohol) was added drop-wise to the reaction mixture at 60C to 65C. The reaction mixture was heated to 75C and stirred for 1 hour at the same temperature. The reaction mixture was cooled to 25C over 1.5 hours to 2 hours. The slurry obtained was stirred at 20C to 25 C for 15 hours. The solid obtained was filtered, washed with isopropyl alcohol (12 mL), and then dried under reduced pressure at 40C to 45C to obtain the title compound. (0241) Yield: 6.4 g (0242) Chiral purity: 99.96% (0243) Chromatographic purity: 99.93 %
171.7 mg With phosphoric acid; In isopropyl alcohol; at 20℃; for 2h; <strong>[941678-49-5]Ruxolitinib</strong> prepared according to the steps above, or any other procedure, may be used as its free base for the compositions and methods described heren. <strong>[941678-49-5]Ruxolitinib</strong> may also be used in a salt form. For example, a crystalline phosphoric acid salt of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile may be prepared from the free base as follows according to the procedure given in Example 2 of U.S. Patent No.8,722,693, the disclosure of which is specifically incorporated herein by reference. To a test tube was added <strong>[941678-49-5](R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile</strong> (153.5 mg) and phosphoric acid (56.6 mg) followed by isopropyl alcohol (IPA) (5.75 mL). 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 mL of cold IPA. The cake was dried under vacuum to constant weight to provide the final salt product (171.7 mg). The phosphroic acid salt is a 1:1 salt by 1H NMR and crystallinity is confirmed by X-ray powder diffraction (XRPD). Differential scanning calorimetry (DSC) of the produce yields a sharp melting peak at about 198.7 C.
171.7 mg With phosphoric acid; In isopropyl alcohol; at 20℃; for 2h;Heating; <strong>[941678-49-5]Ruxolitinib</strong> prepared according to the steps above, or any other procedure, may be used as its free base for the compositions and methods described heren. <strong>[941678-49-5]Ruxolitinib</strong> may also be used in a salt form. For example, a crystalline phosphoric acid salt of (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile may be prepared from the free base as follows according to the procedure given in Example 2 of U.S. Patent No.8,722,693, the disclosure of which is specifically incorporated herein by reference. To a test tube was added <strong>[941678-49-5](R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile</strong> (153.5 mg) and phosphoric acid (56.6 mg) followed by isopropyl alcohol (IPA) (5.75 mL). 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 mL of cold IPA. The cake was dried under vacuum to constant weight to provide the final salt product (171.7 mg). The phosphroic acid salt is a 1:1 salt by 1H NMR and crystallinity is confirmed by X-ray powder diffraction (XRPD). Differential scanning calorimetry (DSC) of the produce yields a sharp melting peak at about 198.7 C.
171.7 mg With phosphoric acid; In isopropyl alcohol; at 20℃; for 2h;Heating; To a test tube was added <strong>[941678-49-5](R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile</strong>(153.5 mg) and phosphoric acid (56.6 mg) followed by isopropyl alcohol (IPA) (5.75 mL). The resulting mixture washeated to clear, cooled to room temperature, and then stirred for another 2 hours. The precipitate was collected byfiltration and the cake was washed with 0.6 mL of cold IPA. The cake was dried under vacuum to constant weight toprovide the final salt product (171.7 mg).The phosphoric acid salt was shown to be a 1:1 salt by 1H NMR and crystallinity was confirmed by X-ray powderdiffraction (XRPD). Differential scanning calorimetry (DSC) gave a sharp melting peak at about 198.66 C. The productshowed little weight loss up to 200 C by TGA
With phosphoric acid; In isopropyl alcohol; at 20℃; for 3h; The (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile prepared according to Example 10 was weighed. Crude product,Soluble in isopropanol (20 volumes), to which was added dropwise a solution of isopropanol phosphoric acid (1.1 eq), the mixture was stirred at room temperature for 3 h,During the period, a large amount of white solids gradually precipitated, and the feed liquid was cooled in an ice bath to 5 to 10 C., stirred for 0.5 h, filtered, and dried.Obtain white solid (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate (yield: 90% ), the purity is higher than 99%.

  • 3
  • [ 941678-49-5 ]
  • [ 1092939-16-6 ]
YieldReaction ConditionsOperation in experiment
With sulfuric acid; In acetonitrile; at 20℃; for 2h;Heating / reflux; Example 3; Preparation of <strong>[941678-49-5](R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile</strong> sulfuric acid saltTo a test tube was added <strong>[941678-49-5](R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile</strong> (153.0 mg) and sulfuric acid (56.1 mg) followed by acetonitrile (7.0 mL). 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 0.8 mL of cold acetonitrile. The cake was dried under vacuum to constant weight to provide the final salt product (180 mg).The sulfuric acid salt was shown to be a 1:1 salt by 1H NMR and crystallinity was confirmed by X-ray powder diffraction (XRPD). Differential scanning calorimetry (DSC) gave a sharp melting peak at about 186.78 C. The product showed little weight loss up to 175 C. by TGA.
180 mg With sulfuric acid; In acetonitrile; at 20℃;Heating; To a test tube was added (3R)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-lH-pyrazol-l-yl]propanenitrile (153.0 mg) and sulfuric acid (56.1 mg) followed by acetonitrile (7.0 mL). 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 0.8 mL of cold acetonitrile. The cake was dried under vacuum to constant weight to provide the final salt product (180 mg).
  • 4
  • [ 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).

  • 5
  • [ 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).
  • 6
  • [ 1146629-80-2 ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
100% With water; sodium hydroxide; In methanol; at 20℃;Product distribution / selectivity; (3R)-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-12, free base).; Method B.; To a stirred solution of (4-{1-[(1R)-2-cyano-1-cyclopentylethyl]-1H-pyrazol-4-yl}-7H-pyrrolo [2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-21, 376 mg, 0.894 mmol) in methanol (4.0 mL, 99 mmol) at room temperature was added 1.0 M solution of sodium hydroxide in water (NaOH, 179 muL, 0.179 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for overnight (15 h). When LCMS showed the reaction was done cleanly, the reaction mixture was quenched with water (10 mL) and saturated aqueous NaCl solution (20 mL), and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-12, free base, 274 mg, 274 mg theoretical, 100% yield) as a pale yellow foam, which was found to be identical as the material made from Method A.
  • 7
  • [ 1146629-84-6 ]
  • [ 3680-69-1 ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
64.3% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 20 - 95℃;Inert atmosphere;Product distribution / selectivity; (3R)-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-12, free base).; Method C.; To a 25 mL round bottom flask equipped with a stir bar, condenser, and three-way valve connected to nitrogen and vacuum was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 154 mg, 1.00 mmol), (3R)-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile ((R)-24, 445 mg, 1.41 mmol, 1.41 equiv), 1,4-dioxane(2.78 mL, 35.6 mmol), water (1.39 mL, 77.2 mmol), and potassium carbonate (K2CO3, 693 mg, 5.02 mmol, 5.0 equiv) at room temperature. The resulting mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.180 mmol, 0.18 equiv). The resulting reaction mixture was degassed four times back filling with nitrogen each time and then warmed to 95 C. The reaction mixture was stirred at 95 C. for 17 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (20 mL) and 20% aqueous brine (11 mL). The mixture was stirred vigorously at room temperature until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were washed with saturated brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2, 0-100% ethyl acetate/hexanes gradient elution) to afford (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile ((R)-12, 197 mg, 306.4 mg theoretical, 64.3% yield) as colorless oil, which was solidified upon standing at room temperature. For (R)-12: 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].
  • 9
  • [ 1236033-03-6 ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
With ammonia; water; In acetonitrile; at 0 - 20℃;Product distribution / selectivity; (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (R)-10.; A solution of (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile ((R)-10, 75.0 g, 0.172 mol, 98.8% ee) in acetonitrile (600 mL) was cooled to 0-5 C. To the cooled solution was added boron trifluoride diethyl etherate (54.4 mL, 0.429 mol) over 10 minutes while maintaining the internal reaction temperature below 5 C. Following the addition, the cold bath was removed and the reaction mixture was allowed to warm to room temperature. When HPLC analysis indicated that the level of (R)-10 was below 1%, the initial phase of the deprotection reaction was considered complete. The reaction was then cooled to 0-5 C., followed by the slow addition of water (155 mL). Following the water addition, the cold bath was removed and the resulting reaction mixture was allowed to warm to 13-17 C., and stirred for an additional 2-3 hours. The resulting reaction mixture was cooled again to 0-5 C. To the cooled reaction mixture was added slowly a solution of ammonia in water [prepared by mixing aqueous 28% ammonia solution (104.5 mL) and water (210.5 mL)] while maintaining the internal reaction temperature at below 5 C. After the aqueous ammonia solution was added, the cold bath was removed and the reaction was allowed to warm to room temperature. The hydrolysis was deemed complete when the level of the hydroxylmethyl intermediate was below 1% by HPLC analysis.The resulting reaction mixture was diluted with ethyl acetate (315 mL) and washed with 20% brine (315 mL). The aqueous fraction was back extracted with ethyl acetate (315 mL). The organic fractions were combined and concentrated under vacuum with a bath temperature of 40 C. to a volume of 380 mL. The concentrated residue was diluted with ethyl acetate (600 mL) and washed with 1M NaHCO3 (2×345 mL) and 20% brine (345 mL). The aqueous washes were combined and back extracted with ethyl acetate (345 mL). The organic fractions were combined and polish filtered into a clean 2L round bottom flask. The organic fraction was washed with warm water (50 C., 2×450 mL) and then treated with activated charcoal at 65 C. with stirring for 1.5 hours. The slurry was filtered through a celite bed. The filtrate was concentrated under vacuum with a bath temperature of 40 C. The resulting syrup was placed under high vacuum to provide (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile [(R)-12, 54.2g, 103% yield] as a light yellow foam. This material was checked by 19F NMR to ensure that the product was not contaminated by any fluorinated impurities. The chemical purity of the isolated free base was 96.3%. The chiral purity of the free base was 98.8% by chiral HPLC (chiralcel OD, 90:10 hexane/ethanol). The free base was used without further purification to prepare the phosphate salt. 1H NMR (DMSO-d6, 400 MHz) delta 12.11(bs, 1H), 8.79(d, 1H, J=0.43 Hz), 8.67(s, 1H), 8.37(s, 1H), 7.59(q, 1H, J=2.3 Hz), 6.98(q, 1H, J=1.6 Hz), 4.53(td, 1H, J=19.2, 4.1 Hz), 3.22(dq, 2H, J=9.8, 4.3 Hz), 2.40(m, 1H), 1.79(m, 1H), 1.65-1.13(m, 7H). C17H16N6 (MW, 306.37), LCMS (EI) m/e 307 (M++H).
  • 13
  • (R)-4-bromo-1-(1-cyclopentylallyl)-1H-pyrazole [ No CAS ]
  • [ 941678-49-5 ]
  • 14
  • (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropan-1-ol [ No CAS ]
  • [ 941678-49-5 ]
  • 17
  • [ 872-53-7 ]
  • [ 941678-49-5 ]
  • 18
  • [ 941688-05-7 ]
  • [ 941678-49-5 ]
  • 19
  • (2S,3S)-2,3-bis(benzoyloxy)butanedioic acid-(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile [ No CAS ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; In water; ethyl acetate; at 20 - 25℃;pH 9.5 - 10; A solution of sodium hydroxide (10%, 18 mL) was added to a mixture of (2S,3S)- 2,3-bis(benzoyloxy)butanedioic acid - (3i?)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-
  • 20
  • C23H32N6OSi*C18H14O8 [ No CAS ]
  • [ 941678-49-5 ]
  • 21
  • [ 941678-49-5 ]
  • [ 98-11-3 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile benzenesulphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% In isopropyl alcohol; at 60℃; To a solution of <strong>[941678-49-5]Ruxolitinib</strong> free base (2.5 g; 8.2mmol) in isopropanol (35 ml) at 60C was added benzenesulfonic acid (1.42 g; 9.0 mmol) in isopropanol (7 ml). The reaction mixture was stirred overnight. The precipitated product was filtrated off, washed with isopropanol (15 ml) and dried for 3 days at 45C and 20 mbar in a vacuum oven to yield 3.07 g (81% of theory) of the product as colourless crystalline solid.?H NMR (400 MHz, DMSO-d6) d ppm 1.10 - 1.23 (m, 1 H) 1.23 - 1.38 (m, 2 H) 1.39 -1.68 (m, 5 H) 1.77 - 1.85 (m, 1 H) 2.42 (m, 1=8.60 Hz, 1 H) 3.14 - 3.34 (m, 2 H) 3.70 - 3.81(m, 1 H) 4.60 - 4.67 (m, 1 H) 7.28 - 7.33 (m, 3 H) 7.36 - 7.39 (m, 1 H) 7.59 - 7.63 (m, 2 H)7.99 - 8.02 (m, 1 H) 8.64 (s, 1 H) 9.01 (s, 1 H) 9.14 (s, 1 H) 13.32 (br. s., 1 H) JR (ATR) [cm?1: 3174, 3109, 2949, 2866, 2814, 2247, 1618, 1597, 1554, 1444, 1427, 1387, 1346, 1313,1265, 1227, 1167, 1122, 1068, 1036, 1016, 997, 976, 926, 893, 872, 816, 756, 725, 694, 652,609 HPLC/UV at X= and 230 nm: > 99.9 %
49% In acetonitrile; at 50℃; for 1h; 200 mg (0.653 mmol) of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of acetonitrile by heating to 50C applying a continuous agitation. 103.3 mg (0.653 mmol) of benzenesulphonic acid was dissolved in 2 mL of acetonitrile at room temperature. The acetonitrile solution of benzenesulphonic acid was drop-wise added to the solution of (SRj-S-cyclopentyl-S-t -iTH-pyrrolo^S-dlpynmidin- -ylJpyrazol-l-yllpropanenitrile at 50C, agitated for additional 60 minutes at 50C and then cooled back to room temperature. The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction. Product: 148 mg; yield: 49% HPLC purity: 99.1% The sligthly yellowish powder obtained was analyzed by FT1R spectroscopy. Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 2.
  • 22
  • [ 594-45-6 ]
  • [ 941678-49-5 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile ethanesulphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% In methanol; at 50℃; for 1h; 200 mg (0.653 mmol) of {3R)-3-cyclopentyl-3-[4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of methanol by heating to 50C applying a continuous agitation. 76.1 mu (0.653 mmol) of ethanesulphonic acid was diluted with 2 mL of methanol at room temperature. The methanol solution of ethanesulphonic acid was drop-wise added to the solution of (3R)- 3-cyclopentyl-3-[4-(7H-pyrrolo[2i3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50eC, agitated for additional 60 minutes at 50C and then cooled back to room temperature. The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction. Product: 204 mg; yield: 75% HPLC purity: 98.9% The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy. Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 5.
  • 23
  • [ 941678-49-5 ]
  • [ 110-17-8 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile fumarate [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% In ethanol; at 50℃; for 1h; 200 mg (0.653 mmol) of (3 )-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of ethanol by heating to 50C applying a continuous agitation. 75.8 mg (0.653 mmol) of fumaric acid was dissolved in 2 mL of ethanol at room temperature. The ethanol solution of fumaric acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2 -d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50C, agitated for additional 60 minutes at 50eC and then cooled back to room temperature. The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction. Product: 215 mg; yield: 78% HPLC purity: 99.0% The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy. Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 6.
  • 24
  • [ 941678-49-5 ]
  • [ 10035-10-6 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile hydrobromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% In methanol; at 50℃; for 1h; 200 mg (0.653 mmol) of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pynmidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of methanol by heating to 50C applying a continuous agitation. 73.9 pL (0.653 mmol; 48% solution) of hydrobromic acid was diluted with 2 mL of methanol at room temperature. The methanol solution of hydrobromic acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2i3-d]pYrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50eC, agitated for additional 60 minutes at 50C and then cooled back to room temperature. The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction. Product: 177 mg; yield: 70% HPLC purity: 98.7% The sligthly yellowish powder obtained was analyzed by FT1R spectroscopy. Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 7.
Historical Records

Similar Product of
[ 941678-49-5 ]

Chemical Structure| 1092939-16-6

A567765[ 1092939-16-6 ]

Ruxolitinib sulfate

Reason: Free-salt