Nitrogen → 1-{4-[(2R,4S)-4-((3,5-bis-trifluoromethyl-benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amino)-2-ethyl-pyrrolidin-1-yl]-5-chloro-pyrimidin-2-yl}-piperidin-4-ol

HRID 409447Notes

Reaction equation

HRID 409447 reaction equation
[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[N:8]1.[F:21][C:22]([F:64])([F:63])[C:23]1[CH:24]=[C:25]([CH:56]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:58]=1)[CH2:26][N:27]([C:49]1[N:54]=[CH:53][C:52](Br)=[CH:51][N:50]=1)[C@@H:28]1[CH2:32][N:31]([C:33]2[C:38]([Cl:39])=[CH:37][N:36]=[C:35]([N:40]3[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]3)[N:34]=2)[C@H:30]([CH2:47][CH3:48])[CH2:29]1.N#N.C([O-])([O-])=O.[Na+].[Na+]>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.ClCCl.O.COCCOC>[F:62][C:59]([F:60])([F:61])[C:57]1[CH:56]=[C:25]([CH:24]=[C:23]([C:22]([F:21])([F:63])[F:64])[CH:58]=1)[CH2:26][N:27]([C:49]1[N:54]=[CH:53][C:52]([C:10]2[CH:9]=[N:8][N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:11]=2)=[CH:51][N:50]=1)[C@@H:28]1[CH2:32][N:31]([C:33]2[C:38]([Cl:39])=[CH:37][N:36]=[C:35]([N:40]3[CH2:41][CH2:42][CH:43]([OH:46])[CH2:44][CH2:45]3)[N:34]=2)[C@H:30]([CH2:47][CH3:48])[CH2:29]1

Participants

9

Reactant 4

HCID 947NitrogenHCID 10340Sodium CarbonateHCID 510003841-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 596143681-(4-{(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1-yl}-5-chloro-pyrimidin-2-yl)-piperidin-4-ol

Product 1

HCID 866483931-{4-[(2R,4S)-4-((3,5-bis-trifluoromethyl-benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amino)-2-ethyl-pyrrolidin-1-yl]-5-chloro-pyrimidin-2-yl}-piperidin-4-ol

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

A 25 ml round-bottom flask is charged with 1-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (56 mg, 0.2 mmol), 1-(4-{(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1-yl}-5-chloro-pyrimidin-2-yl)-piperidin-4-ol (110 mg, 0.15 mmol) under N2. Pd(PPh3)4 (34 mg, 0.03 mmol) is added promptly and the flask is recharged with N2. Then DME (0.5 ml), Na2CO3 (1 M in H2O, 0.3 ml, 0.3 mmol) are added. The mixture is then heated to 95 degree for 2 hours. After cooling down to rt, NaIO4 (103 mg, 0.48 mmol) is added into reaction mixture. Stirring is continued for 1 h to give white suspension. H2O and dichloromethane are added, then organic layer is collected with phase separator. Removal of solvent gave 1-{4-[(2R,4S)-4-((3,5-bis-trifluoromethyl-benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amino)-2-ethyl-pyrrolidin-1-yl]-5-chloro-pyrimidin-2-yl}-piperidin-4-ol which is used without further purification.

Workup

  1. temperatureThe mixture is then heated to 95 degree for 2 hours
  2. customto give white suspension
  3. customorganic layer is collected with phase separator
  4. customRemoval of solvent

Sources & evidence

ORD record
ord-f5fe2892d37c43beadd17ceaeb6aa81d
Source dataset
uspto-grants-2014_06
Patent number
US08759365B2

Reaction notes

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