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}-piperidine-4-carboxylic acid ethyl ester

HRID 409449Notes

Reaction equation

HRID 409449 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.[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[C:36]([N:38]3[CH2:42][C@@H:41]([N:43]([CH2:51][C:52]4[CH:57]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:55]=[C:54]([C:62]([F:65])([F:64])[F:63])[CH:53]=4)[C:44]4[N:49]=[CH:48][C:47](Br)=[CH:46][N:45]=4)[CH2:40][C@H:39]3[CH2:66][CH3:67])[C:35]([Cl:68])=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22].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>[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[C:36]([N:38]3[CH2:42][C@@H:41]([N:43]([CH2:51][C:52]4[CH:57]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:55]=[C:54]([C:62]([F:65])([F:63])[F:64])[CH:53]=4)[C:44]4[N:49]=[CH:48][C:47]([C:10]5[CH:9]=[N:8][N:7]([CH:2]6[CH2:3][CH2:4][CH2:5][CH2:6][O:1]6)[CH:11]=5)=[CH:46][N:45]=4)[CH2:40][C@H:39]3[CH2:66][CH3:67])[C:35]([Cl:68])=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]

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 596143621-(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)-piperidine-4-carboxylic acid ethyl ester

Product 1

HCID 596143501-{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}-piperidine-4-carboxylic acid ethyl ester

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 (83 mg, 0.3 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)-piperidine-4-carboxylic acid ethyl ester (178 mg, 0.23 mmol) under N2. Pd(PPh3)4 (57 mg, 0.05 mmol) is added promptly and the flask is recharged with N2. Then DME (1 ml), Na2CO3 (1 M in H2O, 0.45 ml, 0.45 mmol) are added. The mixture is then heated to 95 degree for 2 hrs. After cooling down to rt, NaIO4 (140 mg, 0.72 mmol) is added into reaction mixture. Stirring is continued for 1 h to give white suspension. H2O and dichloromethane are added, and then organic layer is collected. Removal of solvent give 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}-piperidine-4-carboxylic acid ethyl ester which is used without further purification.

Workup

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

Sources & evidence

ORD record
ord-913ae3525efd448aa0e5bfd4a922d125
Source dataset
uspto-grants-2014_06
Patent number
US08759365B2

Reaction notes

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