Hydrochloric Acid → (1S,4R)-4-(5-{3-cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid

HRID 410649Notes

Reaction equation

HRID 410649 reaction equation
[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]3[S:22][C:21]([C@@:23]4([OH:35])[CH2:28][CH2:27][C@H:26]([C:29]([O:31]C)=[O:30])[C:25]([CH3:34])([CH3:33])[CH2:24]4)=[N:20][CH:19]=3)[CH:7]=[C:8]([NH:10][C:11]3[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=3)[CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl.CO.O>O1CCCC1.CO.O.C(O)(C)C.C(Cl)(Cl)Cl.[Cl-].[Na+].O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]3[S:22][C:21]([C@@:23]4([OH:35])[CH2:28][CH2:27][C@H:26]([C:29]([OH:31])=[O:30])[C:25]([CH3:33])([CH3:34])[CH2:24]4)=[N:20][CH:19]=3)[CH:7]=[C:8]([NH:10][C:11]3[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=3)[CH:9]=2)[CH2:3][CH2:2]1

Participants

10

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium Hydroxide2×HCID 22242641Methanol--water (1/1)HCID 67430830methyl(1S,4R)-4-(5-{3-cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate

Product 1

HCID 58456223(1S,4R)-4-(5-{3-cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acidYield 85.7%

Reagents, catalysts & solvents 5

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolventHCID 21906603Chloroform isopropyl alcoholSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of the product from Step 1 (41.3 mg, 0.084 mmol) in tetrahydrofuran (0.4 mL) and methanol (0.8 mL) was added sodium hydroxide (1 M in water, 0.153 mL, 0.153 mmol). The reaction mixture was heated to 120° C. for 10 minutes in a microwave oven. An additional charge of sodium hydroxide was added (1 M in water, 0.300 mL, 0.300 mmol) and the vessel was heated again for 10 minutes at 120° C. Upon cooling aqueous hydrogen chloride (2M in water, 0.235 mL, 0.470 mmol) was added and the resulting mixture was diluted with 10% v/v isopropanol/chloroform (20 mL), brine (10 mL), and water (1 mL). The layers were separated and the aqueous layer was re-extracted with 10% v/v isopropanol/chloroform (10 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. Lyophilization of the residue from methanol/water provided (1S,4R)-4-(5-{3-cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid (34.3 mg, 0.072 mmol, 84% yield) as an off-white solid. MS ESI: [M+H]+ m/z 461.1.

Workup

  1. temperaturethe vessel was heated again for 10 minutes at 120° C
  2. additionwas added
  3. customThe layers were separated
  4. extractionthe aqueous layer was re-extracted with 10% v/v isopropanol/chloroform (10 mL)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-374be05b8c1e48bf8b449ff760c7c948
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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