Water → Itacitinib

HRID 1508355Notes

Reaction equation

HRID 1508355 reaction equation
[F:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[N:35][CH:34]=[CH:33][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:15][C:14]([CH2:30][C:31]#[N:32])([N:16]3[CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=[N:17]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5].Cl[C:42]1[C:43]2[CH:50]=[CH:49][NH:48][C:44]=2[N:45]=[CH:46][N:47]=1.C(=O)(O)[O-].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[N:45]1[C:44]2[NH:48][CH:49]=[CH:50][C:43]=2[C:42]([C:19]2[CH:18]=[N:17][N:16]([C:14]3([CH2:30][C:31]#[N:32])[CH2:13][N:12]([CH:9]4[CH2:8][CH2:7][N:6]([C:4](=[O:5])[C:3]5[CH:33]=[CH:34][N:35]=[C:36]([C:37]([F:40])([F:38])[F:39])[C:2]=5[F:1])[CH2:11][CH2:10]4)[CH2:15]3)[CH:20]=2)=[N:47][CH:46]=1

Participants

7

Reactant 4

HCID 962WaterHCID 516892Sodium BicarbonateHCID 53566827H-Pyrrolo(2,3-d)pyrimidine, 4-chloro-HCID 783236422-(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

Product 1

HCID 53380437ItacitinibYield 44.7%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

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, 44.6%), was obtained as off-white solids by direct silica gel (SiO2) column chromatography (0-10% 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.

Workup

  1. customTo a 25-mL flask equipped with a nitrogen inlet
  2. customthe resulting reaction mixture
  3. customwas de-gassed
  4. additionrefilled with nitrogen for 3 times
  5. concentrationthe reaction mixture was concentrated to dryness under reduced pressure

Sources & evidence

ORD record
ord-da80ace4320f4908a9c14069ccd25610
Source dataset
uspto-grants-2015_12
Patent number
US09221845B2

Reaction notes

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