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Chemical Structure| 941678-49-5
Chemical Structure| 941678-49-5
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Product Details of [ 941678-49-5 ]

CAS No. :941678-49-5 MDL No. :MFCD12031592
Formula : C17H18N6 Boiling Point : -
Linear Structure Formula :- InChI Key :HFNKQEVNSGCOJV-OAHLLOKOSA-N
M.W : 306.37 Pubchem ID :25126798
Synonyms :
INCB18424;INCB 018424
Chemical Name :(R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile

Calculated chemistry of [ 941678-49-5 ]

Physicochemical Properties

Num. heavy atoms : 23
Num. arom. heavy atoms : 14
Fraction Csp3 : 0.41
Num. rotatable bonds : 4
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 87.66
TPSA : 83.18 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.83 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.02
Log Po/w (XLOGP3) : 1.89
Log Po/w (WLOGP) : 3.47
Log Po/w (MLOGP) : 1.36
Log Po/w (SILICOS-IT) : 2.74
Consensus Log Po/w : 2.3

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.12
Solubility : 0.234 mg/ml ; 0.000765 mol/l
Class : Soluble
Log S (Ali) : -3.26
Solubility : 0.169 mg/ml ; 0.000551 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.75
Solubility : 0.00544 mg/ml ; 0.0000177 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.16

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 ]

* 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 [ 941678-49-5 ]

[ 941678-49-5 ] Synthesis Path-Downstream   1~93

  • 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.
  • 25
  • [ 7647-01-0 ]
  • [ 941678-49-5 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% In ethanol; water; at 50℃; for 1h; 200 mg (0.653 mmol) of (3R)-3-cycopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile was dissolved in 8 mL of ethanol by heating to 50C applying a continuous agitation. 56.7 mu (0.653 mmol; 35% solution) of hydrochloric acid was diluted with 2 mL of ethanol at room temperature. The ethanol solution of hydrochloric acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile 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: 172 mg; yield: 77% 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 8.
  • 26
  • [ 941678-49-5 ]
  • [ 120-18-3 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile 2-naphthalenesulphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% 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. 182.9 mg (0.653 mmol) of 2-naphthalenesulphonic acid was dissolved in 2 mL of methanol at room temperature. The methanol solution of 2-naphthalenesulphonic acid was drop-wise added to the solution of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2/3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile 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: 278 mg; yield: 73% 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 9.
  • 27
  • [ 87-69-4 ]
  • [ 941678-49-5 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile tartrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% In ethanol; 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 ethanol by heating to 50C applying a continuous agitation. 98 mg (0.653 mmol) of L-tartaric acid was dissolved in 2 mL of ethanol at room temperature. The ethanol solution of L-tartaric acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazoi-l-yl]propanenitrile 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: 211 mg; yield: 70% HPLC purity: 90.0% 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 10.
  • 28
  • [ 941678-49-5 ]
  • [ 104-15-4 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile p-toluenesulphonate [ 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. 124.2 mg (0.653 mmol) of p-toluenesulphonic acid was dissolved in 2 mL of ethanol at room temperature. The ethanol solution of p-toluenesulphonic acid was drop-wise added to the solution of (3R)- 3-cyc[opentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile 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: 243 mg; yield: 75% HPLC purity: 98.7% 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 11.
  • 29
  • [ 941678-49-5 ]
  • [ 65-85-0 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% 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. 79.7 mg (0.653 mmol) of benzoic acid was dissolved in 2 mL of methanol at room temperature. The methanol solution of benzoic acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pYrrolo[2,3-d]pyrimidin-4-yl)pvrazol-l-yl]propanenitrile 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 suctio . Product: 168 mg; yield: 60% 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 1.
  • 30
  • [ 941678-49-5 ]
  • [ 98-66-8 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile4-chlorobenzenesulphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% 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- yllpropanenitrile was dissolved in 8 mL of methanol by heating to 50C applying a continuous agitation. 125.7 mg (0.653 mmol) of 4-chlorobenzenesulphonic acid was dissolved in 2 mL of methanol at room temperature. The methanol solution of 4-chlorobenzenesulphonic acid was drop-wise added to the solution of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2f3-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: 235 mg; yield: 72% 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 3.
  • 31
  • [ 941678-49-5 ]
  • [ 77-92-9 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile citrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% 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. 125.4 mg (0.653 mmol) of citric acid was dissolved in 2 mL of methanol at room temperature. The methanol solution of citric acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile 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: 277 mg; yield: 85% HPLC purity: 98.4% 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 4.
  • 32
  • [ 941685-27-4 ]
  • [ 941678-49-5 ]
  • (3S)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile [ No CAS ]
  • 33
  • [ 591769-05-0 ]
  • [ 941678-49-5 ]
  • (3S)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile [ No CAS ]
  • 34
  • [ 941685-39-8 ]
  • [ 941678-49-5 ]
  • (3S)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With trifluoroacetic acid; In dichloromethane; for 6h; To a solution of 1.0 M potassium tert-butoxide in THF (235mE) at 0 C. was added dropwise a solution of diethyl cyanomethylphosphonate (39.9 mE, 0.246 mol) in THF (300mE). The cold bath was removed and the reaction waswarmed to room temperature followed by recooling to 0 C.,at which time a solution of cyclopentanecarbaldehyde (22.0g, 0.224 mol) in THF (60 mE) was added dropwise. The bathwas removed and the reaction warmed to ambient temperature and stirred for 64 hours. The mixture was partitionedbetween diethyl ether and water, the aqueous phase wasextracted with three portions of ether, followed by two portions of ethyl acetate. The combined extracts were washedwith brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture containing 24.4 g ofolefin isomers which was used without thrther purification(89%).?H NMR (400 MHz, CDC13): oe 6.69 (dd, 1H, trans olefin),6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefln), 5.20 (d, 1H,cis olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H,trans product), 1.98-1.26 (m, 16H). - Synthesis of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile maleic 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 (153.7 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). - To a test tube was added (3R)-3-Cyclopentyl-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1 -yl]propanenitrile (153.7 mg, 0.5 mmol) and maleic acid (61.7 mg) followed by isopropyl alcohol (IPA) (4 mE). 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 mE of cold IPA. The cake was dried under vacuum to constant weight to provide the final salt product (173 mg).
  • 35
  • [ 941678-49-5 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile hydrobromic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With hydrogen bromide; In ethanol; water; at 50℃; for 17h;Cooling; Preparation of Crystal modification 1 of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile hydrobromic acid salt 2 g (6.528 mmol) of <strong>[941678-49-5]ruxolitinib</strong> free base was dissolved in 10 mL of ethanol by heating to 50C applying a continuous stirring. 0.7 mL of hydrobromic acid (6.528 mmol; 48% aqueous solution) was drop-wise added to the ethanol solution of <strong>[941678-49-5]ruxolitinib</strong> at 50C, while continuously stirred. Precipitation occurred. The suspension was stirred at this temperature for 1 hour then placed onto ice to cool. The solid obtained was placed into fridge for 16 hours, then filtered off and dried at laboratory condition. Product: 1.79 g (4.615 mmol) off-white crystalline solid Yield: 71% HPLC: 99.7% XRPD pattern was measured (Figure 1) and showed that the compound is in a crystalline state that was designated as Crystal modification 1 of <strong>[941678-49-5]ruxolitinib</strong> hydrobromic acid salt.
  • 36
  • [ 941678-49-5 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile hydrochloric acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With hydrogenchloride; In water; ethyl acetate; at 20 - 50℃; for 1h; Preparation of Crystal modification 4 of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile hydrochloric acid salt 1 g (3.264 mmol) of <strong>[941678-49-5]ruxolitinib</strong> was suspended in 5 mL of ethyl acetate at 50C applying a continuous stirring. 0.31 mL of hydrochloric acid (3.590 mmol; 35% aqueous solution) was drop-wise added to the ethyl acetate solution of <strong>[941678-49-5]ruxolitinib</strong> at 50C, while continuously stirred. The solution is further stirred at 50C for additional 1 hour, while no precipitation occurred. The solution was then cooled back to room temperature while precipitation occurred and then stirred overnight at that temperature. The solid obtained was collected by filtration and dried by vacuum suction at laboratory condition. Product: 0.99 g (2.877 mmol) white crystalline solid Yield: 88% HPLC: 98.7% XRPD pattern was measured (Figure 46) and showed that the compound is in a crystalline state that was designated as Crystal modification 4 of <strong>[941678-49-5]ruxolitinib</strong> hydrochloric acid salt.
  • 37
  • [ 941678-49-5 ]
  • C22H40O4 [ No CAS ]
  • C39H56N6O3 [ No CAS ]
  • 38
  • [ 941678-49-5 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile phosphoric acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With phosphoric acid; In water; ethyl acetate; at 50℃; for 1h; 2 g (6.528 mmol) of <strong>[941678-49-5]ruxolitinib</strong> free base was suspended in 10 mL of ethyl-acetate by heating to 50C applying a continuous stirring.0.4 mL of phosphoric acid (6.528 mmol; 85% aqueous solution) was drop-wise added to the suspension of <strong>[941678-49-5]ruxolitinib</strong> at 50C, while continuously stirred. The suspension was stirred at this temperature for 1 hour then placed onto ice to cool. The solid obtained was filtered off and dried at laboratory condition.Product: 2.506 g (6.19 mmol) off-white crystalline solid Yield: 95% HPLC: 99.8% XRPD pattern was measured (Figure 6) and showed that the compound is in a crystalline state that was designated as Crystal modification 1 of <strong>[941678-49-5]ruxolitinib</strong> phosphoric acid salt. 1H-NMR spectrum was measured (Figure 11) and showed that the compound confirms the structure with an API : phosphoric acid stoichiometry of 1:1.
  • 39
  • [ 941678-49-5 ]
  • [ 110-17-8 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile fumaric acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% In ethanol; at 50℃; 25 2 g (6.528 mmol) of <strong>[941678-49-5]ruxolitinib</strong> free base was dissolved in 5 mL of ethanol at 50C applying a continuous stirring.The solution of 0.8 g of fumaric acid dissolved in 2 mL ethanol was drop-wise added to the solution of <strong>[941678-49-5]ruxolitinib</strong> at 50C, while continuously stirred. Precipitation occurred. The suspension was further stirred at 50C for additional 1 hour and then cooled back to room temperature. The suspension was further stirred at laboratory conditions overnight.The solid precipitated is collected by filtration and dried at laboratory condition. Product: 1.96 g (5.378 mmol) off-white crystalline solid Yield: 89%. HPLC: 97.7% XRPD pattern was measured (Figure 12) and showed that the compound is in a crystalline state that was designated as Crystal modification 1 of <strong>[941678-49-5]ruxolitinib</strong> fumaric acid salt. 1H-NMR spectrum was measured (Figure 17) and showed that the compound confirms the structure with an API : fumaric acid stoichiometry of 2:1
  • 40
  • [ 87-69-4 ]
  • [ 941678-49-5 ]
  • (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile L-tartaric acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% In ethanol; at 50℃; 1g (3.264 mmol) of <strong>[941678-49-5]ruxolitinib</strong> is suspended in 8 mL of acetonitrile at 50C applying a continuous stirring. The solution of 0.54 g of L-tartaric acid (3.6 mmol)in 2 mL ethyl-acetate is drop-wise added to the suspension of <strong>[941678-49-5]ruxolitinib</strong> at 50C, while continuously stirred, forming a clear solution. The solution is further stirred at 50C for additional 1 hour, while precipitation occurred.The suspension formed was cooled back to room temperature and stirred overnight at that temperature. The solid precipitated is collected by filtration and dried at laboratory condition Product: 1.18 g (2.587 mmol) off-white crystalline solid Yield: 79% HPLC: 99.4% XRPD pattern was measured (Figure 24) and showed that the compound is in a crystalline state that was designated as Crystal modification 5 of <strong>[941678-49-5]ruxolitinib</strong> L-tartaric acid salt.1H-NMR spectrum was measured (Figure 29) and showed that the compound confirms the structure with an API: L-tartaric acid stoichiometry of 1:1.5
  • 41
  • C17H24ClN3O5 [ No CAS ]
  • [ 941678-49-5 ]
  • 42
  • C28H38N6O5 [ No CAS ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In tetrahydrofuran; water; at 20℃;Reflux; Weigh the above step crude (3R)-cyclopentyl-3-[4-(5-(2-methoxyvinyl)pyrimidin-4-ylamine)pyrazol-1-yl]propionitrile,Soluble in THF solution (4 volumes) to which concentrated hydrochloric acid (2.2 eq) was added.The feed solution was stirred at room temperature for 2~3h, and then heated to reflux. The reaction was stirred for 5h. TLC test.The basic reaction of raw materials is complete, the feed liquid is cooled to room temperature, saturated NaHCO3 solution is added, and the pH is adjusted to 8-9.Ethyl acetate extraction (10x) was added and the organic phase was washed with water (3 volumes) and dried over anhydrous sodium sulfate.Filtration, vacuum concentrationGave crude (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile (yield: 90%).
  • 43
  • [ 5305-40-8 ]
  • [ 941678-49-5 ]
  • 44
  • [ 137-43-9 ]
  • [ 941678-49-5 ]
  • 45
  • [ 14160-93-1 ]
  • [ 941678-49-5 ]
  • 46
  • 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine [ No CAS ]
  • [ 941678-49-5 ]
  • 47
  • [ 136823-41-1 ]
  • [ 941678-49-5 ]
  • 48
  • methyl 3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionate [ No CAS ]
  • [ 941678-49-5 ]
  • 49
  • 3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionic acid [ No CAS ]
  • [ 941678-49-5 ]
  • 50
  • (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionic acid [ No CAS ]
  • [ 941678-49-5 ]
  • 51
  • (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentanamide [ No CAS ]
  • [ 941678-49-5 ]
  • 52
  • (R)-3-(4-boronic acid 1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile [ No CAS ]
  • [ 941678-49-5 ]
  • 53
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-(2-((chlorocarbonyl)(methyl)amino)-4-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • (2S,3R,4S,5S,6S)-2-(2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)-4-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; Step 11-7-Preparation of (2S,3R,4S,5S,6S)-2-(2-(4-(1-((R)-2-Cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)-4-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate To a solution of <strong>[941678-49-5]ruxolitinib</strong> (0.69 mmol) in DCM (5.7 mL) at 0 C. is added triethylamine (0.12 mL, 0.86 mmol), DMAP (6.99 mg, 0.06 mmol) and (2S,3R,4S,5S,6S)-2-(2-((chlorocarbonyl)(methyl)amino)-4-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.31 g, 0.57 mmol) as a solution in DCM (5.7 mL). The reaction mixture is stirred at 0 C. for 2 h and warmed to room temperature overnight. Water (1 mL) is added to the solution, the layers are separated and the aqueous layer is extracted with DCM (3*2 mL). The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by column chromatography to afford the title compound.
  • 54
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-(2-((chlorocarbonyl)(methyl)amino)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • (2S,3R,4S,5S,6S)-2-(2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; triethylamine; In dichloromethane; at 0℃; for 2h; Step 14-6-Preparation of (2S,3R,4S,5S,6S)-2-(2-(4-(1-((R)-2-Cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate To a solution of <strong>[941678-49-5]ruxolitinib</strong> (1.80 mmol) in DCM (16.4 mL) at 0 C. is added triethylamine (0.38 mL, 2.70 mmol), DMAP (22 mg, 0.18 mmol) and (2S,3R,4S,5S,6S)-2-(2-((chlorocarbonyl)(methyl)amino)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.91 g, 1.80 mmol) as a solution in DCM (16.4 mL) and the reaction mixture is stirred at 0 C. for 2 h. Water is added to the solution (1 mL), the layers are separated and the aqueous layer is extracted with DCM (3*2 mL). The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by column chromatography to afford the title compound.
  • 55
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-(2-((chlorocarbonyl)(methyl)amino)-4-methylphenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • (2S,3R,4S,5S,6S)-2-(2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)-4-methylphenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; Step 17-6-Preparation of (2S,3R,4S,5S,6S)-2-(2-(4-(1-((R)-2-Cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)-4-methylphenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate To a solution of <strong>[941678-49-5]ruxolitinib</strong> (2.16 mmol) in DCM (21.6 mL) at 0 C. is added triethylamine (0.45 mL, 3.24 mmol), DMAP (26 mg, 0.22 mmol) and (2S,3R,4S,5S,6S)-2-(2-((chlorocarbonyl)(methyl)amino)-4-methylphenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.12 g, 2.16 mmol) as a solution in DCM (21.6 mL). The reaction mixture is stirred at 0 C. for 2 h and then warmed to room overnight. Water is added to the solution (10 mL) and the layers are separated. The aqueous layer is extracted with DCM (3*20 mL). The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by column chromatography to afford the title compound.
  • 56
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-(2-((chlorocarbonyl)(methyl)amino)-4-(trifluoromethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • (2S,3R,4S,5S,6S)-2-(2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)-4-(trifluoromethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; Step 20-6-Preparation of (2S,3R,4S,5S,6S)-2-(2-(4-(1-((R)-2-Cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)-4-(trifluoromethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate To a solution of <strong>[941678-49-5]ruxolitinib</strong> (1.89 mmol) in DCM (18.9 mL) at 0 C. is added triethylamine (0.40 mL, 2.84 mmol), DMAP (23 mg, 0.19 mmol) and (2S,3R,4S,5S,6S)-2-(2-((chlorocarbonyl)(methyl)amino)-4-(trifluoromethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.08 g, 1.89 mmol) as a solution in DCM (18.9 mL). The reaction mixture is stirred at 0 C. for 2 h and then warmed to room temperature and stirred at this temperature overnight. Water is added to the solution (10 mL), the layers are separated and the aqueous layer is extracted with DCM (3*20 mL). The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by column chromatography to afford the title compound.
  • 57
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-(4-chloro-2-((chlorocarbonyl)(methyl)amino)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • (2S,3R,4S,5S,6S)-2-(4-chloro-2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; Step 23-6-Preparation of (2S,3R,4S,5S,6S)-2-(4-Chloro-2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate To a solution of <strong>[941678-49-5]ruxolitinib</strong> (2.05 mmol) in DCM (20.5 mL) at 0 C. is added triethylamine (0.43 mL, 3.07 mmol), DMAP (25 mg, 0.21 mmol) and (2S,3R,4S,5S,6S)-2-(4-chloro-2-((chlorocarbonyl)(methyl)amino)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.10 g, 2.05 mmol) as a solution in DCM (20.5 mL). The reaction mixture is stirred at 0 C. for 2 h and then warmed to room temperature overnight. Water is added to the solution (10 mL) and the layers are separated. The aqueous layer is extracted with DCM (3*20 mL). The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to afford the title compound.
  • 58
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-(2-((4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • 59
  • [ 941678-49-5 ]
  • (2S,3S,4S,5R,6S)-6-(2-((4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid [ No CAS ]
  • 60
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-(2-((4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)methyl)-4-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • 61
  • [ 941678-49-5 ]
  • (2S,3S,4S,5R,6S)-6-(2-((4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)methyl)-4-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid [ No CAS ]
  • 62
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-(((2-((4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)methyl)phenyl)carbamoyl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • 63
  • [ 941678-49-5 ]
  • (2S,3S,4S,5R,6S)-6-(((2-((4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)methyl)phenyl)carbamoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid [ No CAS ]
  • 64
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-(2-((((2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)ethyl)(methyl)carbamoyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • 65
  • [ 941678-49-5 ]
  • (2S,3S,4S,5R,6S)-6-(2-((((2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)ethyl)(methyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid [ No CAS ]
  • 66
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-((2-((((2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)ethyl)(methyl)carbamoyl)oxy)methyl)pyridin-3-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • 67
  • [ 941678-49-5 ]
  • (2S,3S,4S,5R,6S)-6-((2-((((2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)ethyl)(methyl)carbamoyl)oxy)methyl)pyridin-3-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid [ No CAS ]
  • 68
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-(((2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)ethyl)(methyl)carbamoyl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • 69
  • [ 941678-49-5 ]
  • (2S,3S,4S,5R,6S)-6-(((2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)ethyl)(methyl)carbamoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid [ No CAS ]
  • 70
  • [ 941678-49-5 ]
  • [ 7693-46-1 ]
  • 4-nitrophenyl (R)-4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; water; at 20℃; for 1h; Example 5 Preparation of 4-Nitrophenyl (R)-4-(1-(2-Cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate To a solution of <strong>[941678-49-5]ruxolitinib</strong> (2.40 mmol) in DCM (12 mL) is added a solution of sodium hydroxide (0.29 g, 7.20 mmol) in water (4.00 mL) and tetrabutylamonium bromide (0.08 g, 0.24 mmol). A solution of 4-nitrophenyl chloroformate (0.97 g, 4.80 mmol) in DCM (4 mL) is slowly added. The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is extracted with DCM and the organic layer is washed with saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by column chromatography to afford the title compound.
  • 71
  • [ 941678-49-5 ]
  • (2S,3R,4S,5S,6S)-2-(4-((((2-((chlorocarbonyl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)methyl)-2-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • (2S,3R,4S,5S,6S)-2-(4-((((2-(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)ethyl)(methyl)carbamoyl)oxy)methyl)-2-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
30% With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 16h; Step 2-5-Preparation of (2S,3R,4S,5S,6S)-2-(4-((((2-(4-(1-((R)-2-Cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)ethyl)(methyl)-carbamoyl)oxy)methyl)-2-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate To solution of (2S,3R,4S,5S,6S)-2-(4-((((2-((chlorocarbonyl)(methyl)amino)-ethyl)-(methyl)carbamoyl)oxy)methyl)-2-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (3.0 g, 4.53 mmol) in DCM (50 mL) was added triethylamine (1.90 mL, 13.59 mmol) and DMAP (3.3 g, 27.19) at 0 C.; followed by <strong>[941678-49-5]ruxolitinib</strong> (971 mg, 3.17 mmol). The resulting mixture was stirred at room temperature for 16 h (reaction complete by TLC monitoring). The reaction mixture was then evaporated under reduced pressure and the crude residue was purified by column chromatography on silica gel (60-120 mesh) using 2% MeOH in DCM as eluent to provide the title compound (1.50 g, 30%) as an off-white solid.
  • 74
  • 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylaldehyde [ No CAS ]
  • [ 941678-49-5 ]
  • 75
  • (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionic acid [ No CAS ]
  • [ 941678-49-5 ]
  • 76
  • (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide [ No CAS ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
77.3% With trichlorophosphate; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 20 - 30℃; for 3h; Step 5: (R)-3-cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile 14.6 g of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide was added to a mixed solvent of 480 mL of dichloromethane and 40 mL of NMP, and then 28 mL of phosphorus oxychloride was added dropwise thereto. The reaction was performed at room temperature, the temperature during this process was kept not higher than 30 C., and the reaction was carried out for 3 hours. After the reaction was completed, to the reaction solution was added 600 mL of purified water, and then a saturated sodium bicarbonate solution was added dropwise until the pH of the mixture solution was 7. The mixture solution was layered, 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 (10.6 g, 77.3%). 1H-NMR (500 MHz, DMSO-d6): delta=12.13 (bs, 1H), 8.84 (d, J=0.4 Hz, 1H), 8.69 (s, 1H), 8.37 (s, 1H), 7.63 (dd, J=2.3, 3.5 Hz, 1H), 7.01 (dd, J=1.4, 3.4 Hz, 1H), 4.56 (td, J=19.5, 4.6 Hz, 1H), 3.26 (dd, J=17.3, 9.9 Hz, 1H), 3.17 (dd, J=17.4, 4.3 Hz, 1H), 2.43 (m, 1H), 1.83 (m, 1H), 1.64?1.09 (m, 7H); MS (ES): 307.17 (M+H+).
  • 77
  • [ 1236033-02-5 ]
  • [ 941678-49-5 ]
  • 78
  • [ 1236033-01-4 ]
  • [ 941678-49-5 ]
  • 79
  • [ 5732-89-8 ]
  • [ 941678-49-5 ]
  • 80
  • [ 1246765-22-9 ]
  • [ 941678-49-5 ]
  • 81
  • (R)-5-cyclopentylpyrazolidin-3-one D-tartrate [ No CAS ]
  • [ 941678-49-5 ]
  • 82
  • C17H18ClN5O [ No CAS ]
  • [ 941678-49-5 ]
  • 83
  • C23H32ClN5O2Si [ No CAS ]
  • [ 941678-49-5 ]
  • 84
  • [ 2469103-61-3 ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
With phosphoric acid In dichloromethane; isopropanol at 20℃; 7; 7A Step 7: Preparation of (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)- 3-cyclopentylpropanenitrile (Ruxolitinib): To a stirred round bottom flask containing 15 (20 mg, 0.033 mmol), dichloromethane (0.40 mL, 20 volumes), and isopropanol (0.10 mL, 5 volumes) was added 85% phosphoric acid (20 µL). The reaction was stirred at room temperature for 1 hour before additional 85% phosphoric acid (30 µL) was added. After 1 hour stirring at room temperature, additional 85% phosphoric acid (50 µL) was added. The reaction was allowed to stir overnight at room temperature. After stirring overnight, reaction progress was monitored by LCMS. The reaction was determined to have proceeded to 77% conversion by UV. The crude cyclization mixture was quenched with water with saturated aqueous potassium carbonate. The quenched reaction was then extracted with DCM, dried over sodium sulfate, and the solvent was evaporated. The crude product was evaluated with chiral HPLC. Chiral HPLC (AD-H column, 1 mL/min flow, 50:50 MeOH:EtOH with 0.1% diethylamine) showed an enantiometic ratio of 97:3, ruxolitinib to ruxolitinib-X (undesired enantiomer).
With phosphoric acid In dichloromethane; isopropanol at 20℃; 7; 7A Step 7: Preparation of (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)- 3-cyclopentylpropanenitrile (Ruxolitinib): To a stirred round bottom flask containing 15 (20 mg, 0.033 mmol), dichloromethane (0.40 mL, 20 volumes), and isopropanol (0.10 mL, 5 volumes) was added 85% phosphoric acid (20 µL). The reaction was stirred at room temperature for 1 hour before additional 85% phosphoric acid (30 µL) was added. After 1 hour stirring at room temperature, additional 85% phosphoric acid (50 µL) was added. The reaction was allowed to stir overnight at room temperature. After stirring overnight, reaction progress was monitored by LCMS. The reaction was determined to have proceeded to 77% conversion by UV. The crude cyclization mixture was quenched with water with saturated aqueous potassium carbonate. The quenched reaction was then extracted with DCM, dried over sodium sulfate, and the solvent was evaporated. The crude product was evaluated with chiral HPLC. Chiral HPLC (AD-H column, 1 mL/min flow, 50:50 MeOH:EtOH with 0.1% diethylamine) showed an enantiometic ratio of 97:3, ruxolitinib to ruxolitinib-X (undesired enantiomer).
94 % ee With phosphoric acid In dichloromethane; isopropanol at 20℃; 1.7 Step 7: Preparation of (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (Ruxolitinib) To a stirred round bottom flask containing 15 (20 mg, 0.033 mmol), dichloromethane (0.40 mL, 20 volumes), and isopropanol (0.10 mL, 5 volumes) was added 85% phosphoric acid (20 μL). The reaction was stirred at room temperature for 1 hour before additional 85% phosphoric acid (30 μL) was added. After 1 hour stirring at room temperature, additional 85% phosphoric acid (50 μL) was added. The reaction was allowed to stir overnight at room temperature. After stirring overnight, reaction progress was monitored by LCMS. The reaction was determined to have proceeded to 77% conversion by UV. The crude cyclization mixture was quenched with water with saturated aqueous potassium carbonate. The quenched reaction was then extracted with DCM, dried over sodium sulfate, and the solvent was evaporated. The crude product was evaluated with chiral HPLC. Chiral HPLC (AD-H column, 1 mL/min flow, 50:50 MeOH:EtOH with 0.1% diethylamine) showed an enantiomeric ratio of 97:3, ruxolitinib to ruxolitinib-X (undesired enantiomer).
  • 85
  • [ 2469103-69-1 ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
Stage #1: tert-butyl (R)-(6-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol- 4-yl)-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate With trifluoroacetic acid In toluene at 100℃; for 0.25h; Stage #2: With trifluoroacetic anhydride In toluene at 40℃; for 0.25h; 5B Step 5B: Preparation of (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1- yl)-3-cyclopentylpropanenitrile (ruxolitinib): To an HPLC vial containing the amino acetal (50 mg, 0.108 mmol) was added toluene (0.508 mL, 10 volumes) to dissolve the material. To the flask was then added trifluoroacetic acid (0.0508 mL, 1 volume) and the plate was set to 100 °C and reaction allowed to stir. Reaction was monitored by HPLC. After 15 minutes, a sample was taken which showed >90% conversion to product. The reaction was allowed to cool to 40 °C and then to the vial was added trifluoroacetic anhydride (0.0508 mL, 1 volume). After 15 minutes, the reaction had gone to completion.Triethyl amine (0.0508 mL, 1 volume) was added to neutralize the reaction. The mixture was then diluted with EtOAc and the organic phase washed twice with 10 volumes water. The crude product was dried over sodium sulfate and concentrated to yield the product as a white foam. Chiral HPLC (AD-H column, 1 mL/min flow, 50:50 MeOH:EtOH with 0.1% diethylamine) showed an enantiometic ratio of 99.6:0.4, ruxolitinib to the undesired enantiomer.1H NMR (400 MHz, Methanol-d4) d 8.69 (s, 1H), 8.66 (d, J = 0.8 Hz, 1H), 8.39 (s, 1H), 7.55 (d, J = 3.7 Hz, 1H), 6.99 (d, J = 3.7 Hz, 1H), 4.50 (ddd, J = 9.8, 9.8, 4.0 Hz, 1H), 3.23 (dd, J = 17.1, 9.6 Hz, 1H), 3.12 (dd, J = 17.2, 4.1 Hz, 1H), 2.55 (m, 1H), 1.95 (m, J = 12.0, 7.6, 4.1 Hz, 1H), 1.82 - 1.17 (overlap, 7H).
Stage #1: tert-butyl (R)-(6-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol- 4-yl)-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate With trifluoroacetic acid In toluene at 100℃; for 0.25h; Stage #2: With trifluoroacetic anhydride In toluene at 40℃; for 0.25h; 5B Step 5B: Preparation of (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1- yl)-3-cyclopentylpropanenitrile (ruxolitinib): To an HPLC vial containing the amino acetal (50 mg, 0.108 mmol) was added toluene (0.508 mL, 10 volumes) to dissolve the material. To the flask was then added trifluoroacetic acid (0.0508 mL, 1 volume) and the plate was set to 100 °C and reaction allowed to stir. Reaction was monitored by HPLC. After 15 minutes, a sample was taken which showed >90% conversion to product. The reaction was allowed to cool to 40 °C and then to the vial was added trifluoroacetic anhydride (0.0508 mL, 1 volume). After 15 minutes, the reaction had gone to completion.Triethyl amine (0.0508 mL, 1 volume) was added to neutralize the reaction. The mixture was then diluted with EtOAc and the organic phase washed twice with 10 volumes water. The crude product was dried over sodium sulfate and concentrated to yield the product as a white foam. Chiral HPLC (AD-H column, 1 mL/min flow, 50:50 MeOH:EtOH with 0.1% diethylamine) showed an enantiometic ratio of 99.6:0.4, ruxolitinib to the undesired enantiomer.1H NMR (400 MHz, Methanol-d4) d 8.69 (s, 1H), 8.66 (d, J = 0.8 Hz, 1H), 8.39 (s, 1H), 7.55 (d, J = 3.7 Hz, 1H), 6.99 (d, J = 3.7 Hz, 1H), 4.50 (ddd, J = 9.8, 9.8, 4.0 Hz, 1H), 3.23 (dd, J = 17.1, 9.6 Hz, 1H), 3.12 (dd, J = 17.2, 4.1 Hz, 1H), 2.55 (m, 1H), 1.95 (m, J = 12.0, 7.6, 4.1 Hz, 1H), 1.82 - 1.17 (overlap, 7H).
99.2 % ee Stage #1: tert-butyl (R)-(6-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol- 4-yl)-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate With trifluoroacetic acid In toluene at 100℃; for 0.25h; Stage #2: With trifluoroacetic anhydride In toluene at 40℃; for 0.25h; 1.5B Step 5B: Preparation of (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (ruxolitinib) To an HPLC vial containing the amino acetal (50 mg, 0.108 mmol) was added toluene (0.508 mL, 10 volumes) to dissolve the material. To the flask was then added trifluoroacetic acid (0.0508 mL, 1 volume) and the plate was set to 100° C. and reaction allowed to stir. Reaction was monitored by HPLC. After 15 minutes, a sample was taken which showed >90% conversion to product. The reaction was allowed to cool to 40° C. and then to the vial was added trifluoroacetic anhydride (0.0508 mL, 1 volume). After 15 minutes, the reaction had gone to completion. Triethyl amine (0.0508 mL, 1 volume) was added to neutralize the reaction. The mixture was then diluted with EtOAc and the organic phase washed twice with 10 volumes water. The crude product was dried over sodium sulfate and concentrated to yield the product as a white foam. Chiral HPLC (AD-H column, 1 mL/min flow, 50:50 MeOH:EtOH with 0.1% diethylamine) showed an enantiometic ratio of 99.6:0.4, ruxolitinib to the undesired enantiomer. 1H NMR (400 MHz, Methanol-d4) δ 8.69 (s, 1H), 8.66 (d, J=0.8 Hz, 1H), 8.39 (s, 1H), 7.55 (d, J=3.7 Hz, 1H), 6.99 (d, J=3.7 Hz, 1H), 4.50 (ddd, J=9.8, 9.8, 4.0 Hz, 1H), 3.23 (dd, J=17.1, 9.6 Hz, 1H), 3.12 (dd, J=17.2, 4.1 Hz, 1H), 2.55 (m, 1H), 1.95 (m, J=12.0, 7.6, 4.1 Hz, 1H), 1.82-1.17 (overlap, 7H).
  • 86
  • [ 2469103-39-5 ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
61% With trifluoroacetic acid; trifluoroacetic anhydride In toluene at 100℃; for 1h; 1.6 Step 6: Preparation of Ruxolitinib (free base): To a solution of the amino acetal E-6 (230 mg, 0.621 mmol) in toluene (2.3 mL, 10 volumes) was added trifluoroacetic acid (0.23 mL, 1 volume) and trifluoroacetic anhydride (0.023 mL, 0.1 volume). The plate was set to 100 °C, and reaction allowed to stir. Reaction was monitored by HPLC. After 30 minutes, a sample was taken which showed >90% conversion to product. The reaction was allowed to stir for an additional 30 min before the heat turned off. Once the reaction had reached 30 °C, triethyl amine (0.46 mL, 2 volumes) was added to neutralize the reaction. The mixture was then diluted with EtOAc and washed 2x with water. The organic phase was concentrated and the crude product was purified by flash chromatography (elution with 20-100% EtOAc in heptane) to yield the product as a white foam (61% yield).1H NMR (400 MHz, DMSO-d6) d 12.10 (s, NH), 8.79 (s, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 7.59 (dd, J = 3.6, 2.4 Hz, 1H), 6.98 (dd, J = 3.6, 1.7 Hz, 1H), 4.54 (ddd, J = 9.7, 9.7, 4.2 Hz, 1H), 3.27 (dd, J = 17.2, 9.6 Hz, 1H), 3.18 (dd, J = 17.1, 4.2 Hz, 1H), 2.42 (m, 1H), 1.81 (m, 1H), 1.67- 1.13 (overlap, 7H).
61% With trifluoroacetic acid; trifluoroacetic anhydride In toluene at 100℃; for 1h; 1.6 Step 6: Preparation of Ruxolitinib (free base): To a solution of the amino acetal E-6 (230 mg, 0.621 mmol) in toluene (2.3 mL, 10 volumes) was added trifluoroacetic acid (0.23 mL, 1 volume) and trifluoroacetic anhydride (0.023 mL, 0.1 volume). The plate was set to 100 °C, and reaction allowed to stir. Reaction was monitored by HPLC. After 30 minutes, a sample was taken which showed >90% conversion to product. The reaction was allowed to stir for an additional 30 min before the heat turned off. Once the reaction had reached 30 °C, triethyl amine (0.46 mL, 2 volumes) was added to neutralize the reaction. The mixture was then diluted with EtOAc and washed 2x with water. The organic phase was concentrated and the crude product was purified by flash chromatography (elution with 20-100% EtOAc in heptane) to yield the product as a white foam (61% yield).1H NMR (400 MHz, DMSO-d6) d 12.10 (s, NH), 8.79 (s, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 7.59 (dd, J = 3.6, 2.4 Hz, 1H), 6.98 (dd, J = 3.6, 1.7 Hz, 1H), 4.54 (ddd, J = 9.7, 9.7, 4.2 Hz, 1H), 3.27 (dd, J = 17.2, 9.6 Hz, 1H), 3.18 (dd, J = 17.1, 4.2 Hz, 1H), 2.42 (m, 1H), 1.81 (m, 1H), 1.67- 1.13 (overlap, 7H).
61% With trifluoroacetic acid; trifluoroacetic anhydride In toluene at 100℃; for 0.5h; 1.6 Step 6: Preparation of Ruxolitinib (Free Base) To a solution of the amino acetal E-6 (230 mg, 0.621 mmol) in toluene (2.3 mL, 10 volumes) was added trifluoroacetic acid (0.23 mL, 1 volume) and trifluoroacetic anhydride (0.023 mL, 0.1 volume). The plate was set to 100° C., and reaction allowed to stir. Reaction was monitored by HPLC. After 30 minutes, a sample was taken which showed >90% conversion to product. The reaction was allowed to stir for an additional 30 min before the heat turned off. Once the reaction had reached 30° C., triethyl amine (0.46 mL, 2 volumes) was added to neutralize the reaction. The mixture was then diluted with EtOAc and washed 2× with water. The organic phase was concentrated and the crude product was purified by flash chromatography (elution with 20-100% EtOAc in heptane) to yield the product as a white foam (61% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, NH), 8.79 (s, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 7.59 (dd, J=3.6, 2.4 Hz, 1H), 6.98 (dd, J=3.6, 1.7 Hz, 1H), 4.54 (ddd, J=9.7, 9.7, 4.2 Hz, 1H), 3.27 (dd, J=17.2, 9.6 Hz, 1H), 3.18 (dd, J=17.1, 4.2 Hz, 1H), 2.42 (m, 1H), 1.81 (m, 1H), 1.67-1.13 (overlap, 7H).
  • 87
  • [ 941678-49-5 ]
  • [ 67-63-0 ]
  • [ 1092939-17-7 ]
YieldReaction ConditionsOperation in experiment
13 (3R)-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrilephosphate (Compound 1 Phosphate) (3R)-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrilephosphate (Compound 1 Phosphate) A suspension of the crude Compound 1 phosphate (40.0 g, 100 mmol) in methanol (MeOH, 520 mL) is heated to 50-60° C. to generate a homogenous solution. The solution is polish filtered at 50-60° C. Methanol (287 mL) is partially distilled at atmosphere pressure at 60-70° C. before IPA (320 mL) is added to the mixture at the same temperature to initiate crystallization of the final product (Compound 1 phosphate). n-Heptane (1000 mL) is then added to the mixture at 60-70° C. and the distillation is continued at atmospheric pressure at 60-70° C. Once the distillation is complete, the mixture is stirred at 60-70° C. for 10-60 minutes before being gradually cooled to room temperature and stirred at room temperature for 3-6 hours. The solids are collected by filtration, washed sequentially with a mixture of IPA and n-heptane and n-heptane, and dried at 40-50° C. under vacuum to afford the final product, (Compound 1 phosphate, 39.4 g, 98.5%) as white crystalline powders. For Compound 1 phosphate mp. 197.6° C.; 1H NMR (DMSO-d6, 500 MHz) δ ppm 12.10 (s, 1H), 8.78 (s, 1H), 8.68 (s, 1H), 8.36 (s 1H), 7.58 (dd, 1H, J=1.9, 3.5 Hz), 6.97 (d, 1H, J=3.6 Hz), 4.52 (td, 1H, J=3.9, 9.7 Hz), 3.25 (dd, 1H, J=9.8, 17.2 Hz), 3.16 (dd, 1H, J=4.0, 17.0 Hz), 2.41, (m, 1H), 1.79 (m, 1H), 1.59 (m, 1H), 1.51 (m, 2H), 1.42 (m, 1H), 1.29 (m, 2H), 1.18 (m, 1H); 13C NMR (DMSO-d6, 125 MHz) δ ppm 152.1, 150.8, 149.8, 139.2, 131.0, 126.8, 120.4, 118.1, 112.8, 99.8, 62.5, 44.3, 29.1, 29.0, 24.9, 24.3, 22.5; C17H18N6 (MW, 306.37 for free base) LCMS (EI) m/e 307 (M++H, base peak), 329.1 (M++Na).
  • 88
  • [ 941678-49-5 ]
  • [ 98-59-9 ]
  • [ 2700217-69-0 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In dichloromethane at 0 - 23℃; for 16h; Inert atmosphere;
80 % With triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; 9 [Preparation Example 9] Preparation of N-Tosyl-ruxolitinib (S9) Stirring bar, ruxolitinib (1022 mg, 3.336 mmol, 1.0 equiv), and anhydrous dichloromethane (15 mL) were charged to an oven-dried 50 mL round bottom flask under an argon atmosphere. To the stirred mixture was added triethylamine (1.53 mL, 1.11 g, 11.0 mmol, 3.3 equiv) via syringe, the mixture was cooled to 0 °C, and 4-methylbenzenesulfonyl chloride (2099 mg, 11.01 mmol, 3.3 equiv) was added. did The mixture was warmed to 23° C. over 5 minutes and then stirred at the same temperature for 16 hours. After adding dichloromethane (50 mL) and saturated aqueous ammonium chloride solution (50 mL), the organic layer was separated. The aqueous layer was extracted with dichloromethane (50 mL × 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a solvent mixture of dichloromethane/methanol (100/0 to 90/10 (v/v)) to give the desired compound S9 as a brown solid (1.23 g, 80% yield). .
  • 89
  • [ 870-46-2 ]
  • [ 941678-49-5 ]
  • [ 5070-13-3 ]
  • [ 2758775-38-9 ]
YieldReaction ConditionsOperation in experiment
54.9% Stage #1: (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile; bis-(p-nitrophenyl) carbonate With triethylamine In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: t-butoxycarbonylhydrazine In dimethyl sulfoxide at 20℃; for 16h; Inert atmosphere; 67.1 Step 1: Preparation of tert-butyl N- [[4- [1- [(1R) -2-cyano-1-cyclopentyl-ethyl] pyrazol-4-yl] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] carbamate A mixture of 2- [1-ethylsulfonyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl] acetonitrile (1617 mg, 4 mmol), triethylamine (1.67 mL, 12 mmol) and bis (4-nitrophenyl) carbonate (1337.6 mg, 4.4 mmol) in DMSO (20 mL) was stirred at room temperature for 7 hours. Then tert-Butyl hydrazinecarboxylate (634.4 mg, 4.8 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated Na 2CO 3 solution. The mixture was filtered. The filter cake was washed with saturated NaHCO 3 solution and water. Then the filter cake was dissolved in DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=100: 1) to afford the title compound (1.02 g, Yield: 54.9%). MS (m/z) : [M+H] + calcd for C 23H 28N 8O 3, 465.22; found, 465.2. 1H NMR (400 MHz, CDCl3) δ ppm 10.97 (d, J = 1.9 Hz, 1H), 8.86 (s, 1H), 8.31 (d, J = 15.2 Hz, 2H), 7.97 (d, J = 4.0 Hz, 1H), 6.87-6.84 (m, 1H), 6.62 (s, 1H), 4.27 (td, J = 10.0, 3.9 Hz, 1H), 3.14 (dd, J = 17.0, 8.6 Hz, 1H), 2.97 (dd, J = 17.0, 3.9 Hz, 1H), 2.61 (dt, J = 17.0, 8.6 Hz, 1H), 2.04-1.92 (m, 1H), 1.79-1.62 (m, 5H), 1.54 (d, J = 13.3 Hz, 9H), 1.35-1.19 (m, 3H).
54.9% Stage #1: (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile; bis-(p-nitrophenyl) carbonate With triethylamine In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: t-butoxycarbonylhydrazine In dimethyl sulfoxide at 20℃; for 16h; Inert atmosphere; 67.1 Step 1: Preparation of tert-butyl N- [[4- [1- [(1R) -2-cyano-1-cyclopentyl-ethyl] pyrazol-4-yl] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] carbamate A mixture of 2- [1-ethylsulfonyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl] acetonitrile (1617 mg, 4 mmol), triethylamine (1.67 mL, 12 mmol) and bis (4-nitrophenyl) carbonate (1337.6 mg, 4.4 mmol) in DMSO (20 mL) was stirred at room temperature for 7 hours. Then tert-Butyl hydrazinecarboxylate (634.4 mg, 4.8 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated Na 2CO 3 solution. The mixture was filtered. The filter cake was washed with saturated NaHCO 3 solution and water. Then the filter cake was dissolved in DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=100: 1) to afford the title compound (1.02 g, Yield: 54.9%). MS (m/z) : [M+H] + calcd for C 23H 28N 8O 3, 465.22; found, 465.2. 1H NMR (400 MHz, CDCl3) δ ppm 10.97 (d, J = 1.9 Hz, 1H), 8.86 (s, 1H), 8.31 (d, J = 15.2 Hz, 2H), 7.97 (d, J = 4.0 Hz, 1H), 6.87-6.84 (m, 1H), 6.62 (s, 1H), 4.27 (td, J = 10.0, 3.9 Hz, 1H), 3.14 (dd, J = 17.0, 8.6 Hz, 1H), 2.97 (dd, J = 17.0, 3.9 Hz, 1H), 2.61 (dt, J = 17.0, 8.6 Hz, 1H), 2.04-1.92 (m, 1H), 1.79-1.62 (m, 5H), 1.54 (d, J = 13.3 Hz, 9H), 1.35-1.19 (m, 3H).
  • 90
  • [ 941678-49-5 ]
  • [ 5070-13-3 ]
  • [ 3017-32-1 ]
  • methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[4-[1-[(1R)-2-cyano-1-cyclopentylethyl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidine-7-carbonyl]amino]hexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
34.9% Stage #1: (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dimethyl sulfoxide at 20℃; for 16h; Inert atmosphere; 66.1 Step 1: Preparation of methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[4- [1- [(1R) -2-cyano-1-cyclopentyl-ethyl] pyrazol-4-yl] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] hexanoate A mixture of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile (1486 mg, 4 mmol) and bis (4-nitrophenyl) carbonate (1141 mg, 3.754 mmol) in DMSO (12 mL) was stirred at room temperature for 7 hours. Then (S) -methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (1448 mg, 4.88 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated Na 2CO 3 solution. The mixture was filtered. The filter cake was washed with saturated NaHCO 3 solution and water. Then the filter cake was dissolved in DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol =150: 1) to afford the title compound (0.828 g, Yield: 34.9%). MS (m/z) : [M+H] + calcd for C 30H 40N 8O 5, 593.31; found, 593.2. 1H NMR (400 MHz, CDCl3) δ ppm 9.95 (d, J = 7.5 Hz, 1H), 8.91 (s, 1H), 8.32 (d, J = 11.9 Hz, 2H), 7.99 (d, J = 4.0 Hz, 1H), 6.82 (d, J = 4.0 Hz, 1H), 4.76 (dd, J = 12.8, 7.5 Hz, 1H), 4.60 (s, 1H), 4.28 (td, J = 9.9, 3.8 Hz, 1H), 3.81 (s, 3H), 3.22-3.05 (m, 3H), 2.97 (dd, J = 17.0, 3.8 Hz, 1H), 2.61 (dt, J = 16.5, 8.4 Hz, 1H), 2.13-1.88 (m, 3H), 1.65-1.50 (m, 7H), 1.44-1.35 (m, 9H), 1.27 (d, J = 12.8 Hz, 4H).
34.9% Stage #1: (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dimethyl sulfoxide at 20℃; for 16h; Inert atmosphere; 66.1 Step 1: Preparation of methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[4- [1- [(1R) -2-cyano-1-cyclopentyl-ethyl] pyrazol-4-yl] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] hexanoate A mixture of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile (1486 mg, 4 mmol) and bis (4-nitrophenyl) carbonate (1141 mg, 3.754 mmol) in DMSO (12 mL) was stirred at room temperature for 7 hours. Then (S) -methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (1448 mg, 4.88 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated Na 2CO 3 solution. The mixture was filtered. The filter cake was washed with saturated NaHCO 3 solution and water. Then the filter cake was dissolved in DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol =150: 1) to afford the title compound (0.828 g, Yield: 34.9%). MS (m/z) : [M+H] + calcd for C 30H 40N 8O 5, 593.31; found, 593.2. 1H NMR (400 MHz, CDCl3) δ ppm 9.95 (d, J = 7.5 Hz, 1H), 8.91 (s, 1H), 8.32 (d, J = 11.9 Hz, 2H), 7.99 (d, J = 4.0 Hz, 1H), 6.82 (d, J = 4.0 Hz, 1H), 4.76 (dd, J = 12.8, 7.5 Hz, 1H), 4.60 (s, 1H), 4.28 (td, J = 9.9, 3.8 Hz, 1H), 3.81 (s, 3H), 3.22-3.05 (m, 3H), 2.97 (dd, J = 17.0, 3.8 Hz, 1H), 2.61 (dt, J = 16.5, 8.4 Hz, 1H), 2.13-1.88 (m, 3H), 1.65-1.50 (m, 7H), 1.44-1.35 (m, 9H), 1.27 (d, J = 12.8 Hz, 4H).
  • 91
  • [ 2469103-65-7 ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
62.9% With trifluoroacetic acid; trifluoroacetic anhydride In toluene at 100℃; for 0.25h; 1.7A Step 7A: Preparation of (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (Ruxolitinib Free Base) To an HPLC vial containing the amino acetal (80 mg, 0.140 mmol) was added toluene (0.80 mL, 10 volumes) to dissolve the material. To the flask was then added trifluoroacetic acid (0.08 mL, 1 volume) and the plate was set to 100° C. and reaction allowed to stir. Reaction was monitored by HPLC. After 15 minutes, a sample was taken which showed >90% conversion to product. The reaction was allowed to cool to 40° C. and then to the vial was added trifluoroacetic anhydride (0.08 mL, 1 volume). After 15 minutes, the reaction had gone to completion. Water (0.80 mL, 10 volumes) was added to quench the reaction. The mixture was neutralized with Na2CO3 and extracted with EtOAc. The crude product was dried over sodium sulfate and concentrated to yield the product as a white foam (27 mg, 62.9% yield).
  • 92
  • [ 2892268-90-3 ]
  • [ 941678-49-5 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride; methanol; lithium hydroxide monohydrate for 12h; 8 Synthesis of target compound ructinib Add 100 mL of methanol and compound b (20 g, 0.049 mol) to a 500 mL three-necked flask, stir and mix well, add 25 mL of 10% hydrochloric acid dropwise, and continue to stir for 12 h after the dropwise addition.The pH value was adjusted to 7-8 with 5% sodium hydroxide, a large amount of solid was precipitated, suction filtration, and the filter cake was air-dried at 50°C to obtain the final product, 13.5 g, yield 90%, HPLC purity 99.8%.
  • 93
  • [ 941678-49-5 ]
  • [ 51146-56-6 ]
  • [ 2893771-88-3 ]
YieldReaction ConditionsOperation in experiment
85 % With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; 28 (R)-3-cyclopentyl-3-(4-(7-(S)-2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile Combine (R)-3-(4-(7H-pyrrole[2,3-d]pyridine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropane (ruxotinib, 306 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 12 mg, 0.1 mmol), (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 247 mg, 1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) was dissolved in dichloromethane (10 mL) and stirred for 5 h at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. After silica gel column chromatography (petroleum ether/ethyl acetate = 51 to 31), the target compound was obtained, white solid, 0.42 g, yield 85%.
Same Skeleton Products
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Similar Product of
[ 941678-49-5 ]

Chemical Structure| 1092939-16-6

A567765[ 1092939-16-6 ]

(R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile sulfate

Reason: Free-salt