Hydrochloric Acid → rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylic acid

HRID 1482900Notes

Reaction equation

HRID 1482900 reaction equation
[F:1][CH:2]([F:37])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][C:20]([CH:23]([CH:25]4[CH2:30][CH2:29][C@@H:28]([C:31]([O:33]CC)=[O:32])[C@@H:27]([CH3:36])[CH2:26]4)[CH3:24])=[N:21][CH:22]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1.O.[OH-].[Li+].Cl>C1COCC1.O.[Cl-].[Na+].O>[F:37][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:22]=[N:21][C:20]([CH:23]([CH:25]4[CH2:30][CH2:29][C@@H:28]([C:31]([OH:33])=[O:32])[C@@H:27]([CH3:36])[CH2:26]4)[CH3:24])=[N:19][CH:18]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1

Participants

7

Reactant 3

HCID 313Hydrochloric AcidHCID 168937Lithium hydroxide, monohydrateHCID 118126847ethyl rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylate

Product 1

HCID 118126845rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylic acid

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of ethyl rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylate, isomer 1 (22 mg, 0.044 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (5.0 mg, 0.13 mmol). The reaction mixture was stirred for 8 hours at 60° C. and then cooled to room temperature. The pH of the mixture was adjusted to pH 2 by adding aqueous hydrochloric acid, and then the mixture was diluted with brine and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylic acid. MS ESI calc'd. for C26H30F2N5O2 [M+H]+ 482. found 482. 1H NMR: (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.97 (s, 2H), 8.72 (s, 1H), 8.00 (s, 1H), 7.59 (s, 1H), 7.22 (s, 1H), 7.08-7.07 (m, 1H), 6.88 (t, J=54.4 Hz, 1H), 2.79-2.76 (m, 1H), 2.36 (s, 3H), 2.07-1.43 (m, 8H), 1.24-1.23 (m, 3H), 0.92-0.91 (m, 1H), 0.85-0.83 (m, 3H).

Workup

  1. temperaturecooled to room temperature
  2. extractionextracted with ethyl acetate (3×100 mL)
  3. dry with materialThe combined organic layers were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by prep-HPLC

Sources & evidence

ORD record
ord-dbd7492f32584ddbb0f31fcf60b19a5e
Source dataset
uspto-grants-2016_08
Patent number
US09416111B2

Reaction notes

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