Pivalic acid → HCID 58456085, compound

HRID 410647Notes

Reaction equation

HRID 410647 reaction equation
F[C:2](F)(F)[CH:3]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=3)[CH:13]=[C:12]([CH3:27])[CH:11]=2)=[CH:8][N:9]=1)[OH:4].C(O)(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+].OC(C(F)(F)F)=O.[OH:50][CH2:51][C@@H:52]1[CH2:57][CH2:56][C@](C2SC=CN=2)(O)[CH2:54][C:53]1(C)[CH3:64]>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>[OH:50][CH2:51][C@@H:52]1[CH2:57][CH2:56][C@:3]([C:5]2[S:6][C:7]([C:10]3[CH:15]=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=4)[CH:13]=[C:12]([CH3:27])[CH:11]=3)=[CH:8][N:9]=2)([OH:4])[CH2:2][C:53]1([CH3:64])[CH3:54]

Participants

6

Reactant 4

HCID 6417Pivalic acidHCID 11430Potassium CarbonateHCID 58456412HCID 58456412, compound2×HCID 86658253HCID 86658253, compound

Product 1

HCID 58456085HCID 58456085, compoundYield 20.51%

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
120 °C

Procedure

A 4-mL screw-cap pressure vial was charged with N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 2, 74.8 mg, 0.225 mmol), stir bar, pivalic acid (2.61 μl, 0.023 mmol), potassium carbonate (46.7 mg, 0.338 mmol), (1S,4R)-4-(hydroxymethyl)-3,3-dimethyl-1-(thiazol-2-yl)cyclohexanol TFA salt (40 mg, 0.113 mmol), and Pd(PPh3)4 (13.01 mg, 0.011 mmol). The vial was closed, evacuated and back-filed with nitrogen 3 times. DMA (0.5 ml) (dry, over molecular sieves, Fluka) was added and the reaction mixture heated to 120° C. for 16 hours. LCMS showed product formation and some remaining starting materials. Filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (10-60% acetonitrile gradient with water+0.1% TFA) to afford (1S,4R)-4-(hydroxymethyl)-3,3-dimethyl-1-(5-(3-methyl-5-(4-(trifluoromethyl)pyrimidin-2-ylamino)-phenyl)thiazol-2-yl)cyclohexanol (14 mg, 0.023 mmol, 20.51% yield over 2 steps) as a yellow solid.

Workup

  1. customA 4-mL screw-cap pressure vial
  2. customThe vial was closed
  3. customevacuated and back-filed with nitrogen 3 times
  4. additionDMA (0.5 ml) (dry, over molecular sieves, Fluka) was added
  5. filtrationFiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by reverse phase HPLC (10-60% acetonitrile gradient with water+0.1% TFA)

Sources & evidence

ORD record
ord-e0917a03b94e472396ef92d57c0bc193
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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