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[ CAS No. 1334298-90-6 ] {[proInfo.proName]}

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Chemical Structure| 1334298-90-6
Chemical Structure| 1334298-90-6
Structure of 1334298-90-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1334298-90-6 ]

CAS No. :1334298-90-6 MDL No. :MFCD28579595
Formula : C26H23F4N9O Boiling Point : -
Linear Structure Formula :- InChI Key :KTBSXLIQKWEBRB-UHFFFAOYSA-N
M.W : 553.51 Pubchem ID :53380437
Synonyms :
INCB039110;INCB39110;1334298-96-2

Calculated chemistry of [ 1334298-90-6 ]

Physicochemical Properties

Num. heavy atoms : 40
Num. arom. heavy atoms : 20
Fraction Csp3 : 0.38
Num. rotatable bonds : 7
Num. H-bond acceptors : 11.0
Num. H-bond donors : 1.0
Molar Refractivity : 141.13
TPSA : 119.62 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -8.55 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.89
Log Po/w (XLOGP3) : 1.59
Log Po/w (WLOGP) : 4.41
Log Po/w (MLOGP) : 1.52
Log Po/w (SILICOS-IT) : 3.36
Consensus Log Po/w : 2.75

Druglikeness

Lipinski : 1.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -4.18
Solubility : 0.0364 mg/ml ; 0.0000658 mol/l
Class : Moderately soluble
Log S (Ali) : -3.71
Solubility : 0.107 mg/ml ; 0.000194 mol/l
Class : Soluble
Log S (SILICOS-IT) : -7.22
Solubility : 0.000033 mg/ml ; 0.0000000596 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 4.6

Safety of [ 1334298-90-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1334298-90-6 ]

* 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.

  • Upstream synthesis route of [ 1334298-90-6 ]
  • Downstream synthetic route of [ 1334298-90-6 ]

[ 1334298-90-6 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 1334303-20-6 ]
  • [ 1334298-90-6 ]
YieldReaction ConditionsOperation in experiment
93.5%
Stage #1: With boron trifluoride diethyl etherate In acetonitrile at 5 - 20℃; for 23 h;
Stage #2: With water In acetonitrile at 5 - 20℃; for 2 h;
Stage #3: With ammonium hydroxide In water; acetonitrile at 5 - 20℃; for 20 h;
Example 7. 2-(3-(4-(7H-P rrolo[2,3-rflpyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(l-(3- fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (22) 21 22 C32H37F4N902Si C26H23F4N9O Mol. Wt: 683.77 Mol. Wt: 553.51 To a 250 mL 4-necked round bottom flask equipped with a mechanical stirrer, a thermocouple, an addition funnel and a nitrogen inlet was added compound 21 (9.25 g, 13.52 mmol, F water content 3.50percent) and acetonitrile (74 mL) at 20 ± 5 °C. The resulting white slurry was cooled to below 5 °C. Boron trifluoride diethyl etherate (BF3-OEt2, 6.46 mL, 51.37 mmol, 3.80 equiv) was then added at a rate while the internal temperature was kept at.below 5.0 °C. The reaction mixture was then warmed to 20 ± 5 °C. After stirring at 20 ± 5 °C for 18 hours, the reaction mixture was cooled to 0 - 5 °C and an additional amount of BF3 OE12 (0.34 mL, 2.70 mmol, 0.2 equiv) was introduced to the reaction mixture at below 5.0 °C. The resulting reaction mixture was warmed to 20 ± 5 °C, and kept stirring at room temperature for an additional 5 hours. The reaction mixture was then cooled to 0 - 5 °C before water (12.17 mL, 0.676 mol, 50 equiv) was added. The internal temperature was kept at below 5.0 °C during addition of water. The resultant mixture was warmed to 20 ± 5 °C and kept stirring at room temperature for 2 hours. The reaction mixture was then cooled to 0 - 5 °C and aqueous ammonium hydroxide (NH4OH, 5 N, 121.7 mmol, 9.0 equiv) was added. During addition of aqueous ammonium hydroxide solution, the internal temperature was kept at below 5.0 °C. The resulting reaction mixture was warmed to 20 ± 5 °C and stirred at room temperature for 20 hours. Once the SEM-deprotection was deemed complete, the reaction mixture was filtered, and the solids were washed with EtOAc (9.25 mL). The filtrates were combined and diluted with EtOAc (74 mL). The diluted organic solution was washed with 13percent aqueous sodium chloride solution (46.2 mL). The organic phase was then diluted with EtOAc (55.5 mL) before being concentrated to a minimum volume under reduced pressure. EtOAc (120 mL) was added to the residue, and the resulting solution was stirred at 20 ± 5 °C for 30 minutes. The solution was then washed with 7percent aqueous sodium bicarbonate solution (2 x 46 mL) and 13percent aqueous sodium bicarbonate solution (46 mL). The resultant organic phase was diluted with EtOAc (46 mL) and treated with water (64 mL) at 50 ± 5 °C for 30 minutes. The mixture was cooled to 20 ± 5 °C and the two phases were separated. The organic phase was treated with water (64 mL) at 50 ± 5 °C for 30 minutes for the second time. The mixture was cooled to 20 ± 5 °C and the two phases were separated. The resultant organic phase was concentrated to afford crude compound 22 (free base), which was further purified by column chromatography (S1O2, 330 g, gradient elution with 0 - 10percent of MeOH in EtOAc) to afford analytically pure free base (22, 7.00 g, 93.5 percent) as an off-white solid. For 22: NMR (400 MHz, (CD3)2SO)812.17 (d, J = 2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, .7=4.7 Hz, 1H), 7.63 (dd, J= 3.6, 2.3 Hz, 1H), 7.09 (dd,J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d,J=7.9Hz, 2H), 3.61 (t,J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t,J= 10.5 Hz, 1H),3.09 (ddd,J= 13.2, 9.5,3.1 Hz, 1H), 2.58 (m, 1H), 1.83- 1.75 (m, 1H), 1.70 - 1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; l3C NMR (101 MHz, (CD3)2SO)5160.28,(153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48,(134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04,(124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4 9O (MW, 553.51), LCMS (EI)m/e 554.1 (M+ + H).
Reference: [1] Patent: WO2013/36611, 2013, A1, . Location in patent: Page/Page column 36; 37
[2] Patent: US2011/224190, 2011, A1, . Location in patent: Page/Page column 40
[3] Patent: US2015/246046, 2015, A1, . Location in patent: Paragraph 0139
  • 2
  • [ 3680-69-1 ]
  • [ 1334298-90-6 ]
YieldReaction ConditionsOperation in experiment
44.6% With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,4-dioxane; water at 85℃; Inert atmosphere 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8) [0148] To a 25-mL flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a magnetic stirrer were added 2-(1-(1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (11, 307 mg, 0.546 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4, 84.8 mg, 0.548 mmol, 1.0 equiv), sodium bicarbonate (NaHCO3, 229 mg, 2.72 mmol, 5.0 equiv), water (1.6 mL), and 1,4-dioxane (1.6 mL) at ambient temperature. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (12.8 mg, 0.011 mmol, 0.02 equiv) at ambient temperature and the resulting reaction mixture was de-gassed and refilled with nitrogen for 3 times before being heated to 85° C. The reaction mixture was stirred at 85° C. under nitrogen for overnight. When the reaction was complete as monitored by HPLC, the reaction mixture was concentrated to dryness under reduced pressure and the desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base, 135 mg, 302.2 mg theoretical, 44.6percent), was obtained as off-white solids by direct silica gel (SiO2) column chromatography (0-10percent of ethyl acetate in hexane gradient elution) purification of the dried reaction mixture. The compound obtained by this synthetic approach is identical in every comparable aspect to the compound 8 manufactured by the synthetic method as described above in Example 1.
Reference: [1] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0148
  • 3
  • [ 1334303-99-9 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0142
  • 4
  • [ 1153949-11-1 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: US2014/256941, 2014, A1,
[3] Patent: US2015/246046, 2015, A1,
  • 5
  • [ 3680-69-1 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: US2014/256941, 2014, A1,
[3] Patent: US2015/246046, 2015, A1,
  • 6
  • [ 177-11-7 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: US2014/256941, 2014, A1,
[3] Patent: US2014/256941, 2014, A1,
  • 7
  • [ 1426436-72-7 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: US2014/256941, 2014, A1,
[3] Patent: US2014/256941, 2014, A1,
  • 8
  • [ 941685-27-4 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: US2015/246046, 2015, A1,
  • 9
  • [ 1334303-99-9 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: US2014/256941, 2014, A1,
  • 10
  • [ 1187594-11-1 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: US2015/246046, 2015, A1,
  • 11
  • [ 941685-26-3 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: WO2013/36611, 2013, A1,
[2] Patent: US2015/246046, 2015, A1,
  • 12
  • [ 886510-09-4 ]
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Reference: [1] Patent: US2011/224190, 2011, A1,
  • 13
  • [ 1187595-88-5 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: WO2013/36611, 2013, A1,
  • 14
  • [ 1153949-15-5 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: US2014/256941, 2014, A1,
  • 15
  • [ 1334303-18-2 ]
  • [ 1334298-90-6 ]
Reference: [1] Patent: US2015/246046, 2015, A1,
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