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Chloride → Tert-butyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate

HRID 1040048
Notes
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Reaction equation

HRID 1040048 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[CH:7]=1.[Li+].CC([N-]C(C)C)C.[O:32]=[C:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.[Cl-]>C1COCC1>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][C:33]([OH:32])([C:11]2[S:12][C:8]([C:6]3[CH:5]=[C:4]([NH:13][C:14]4[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=4)[CH:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:9][N:10]=2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 312ChlorideHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 2724682Lithium diisopropylamideHCID 58456403N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine

Product 1

HCID 58456305Tert-butyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate
Yield 82%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

At −78° C., INTERMEDIATE 4 (200 mg, 0.595 mmol) in THF (3.0 mL) was added to LDA (892 μL, 1.784 mmol) and the reaction aged for 10 min followed by addition of tert-butyl 4-oxo-piperidine-1-carboxylate (474 mg, 2.379 mmol). The reaction was allowed to slowly warm to −20° C. over 4 hrs. To the mixture was added saturated aqueousammonium chloride solution and the product was extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layer was dried, filtered and solvent reduced by rotovap. The residue was purified by column chromatography on silica gel (0-50% ethyl acetate in DCM) to give 260 mg (0.485 mmol, 82%) tert-butyl-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate as off-white solid. MS ESI: [M+H]+ m/z 536.2. 1H NMR (600 MHz, CDCl3): δ 8.60 (d, J=4.8 Hz, 1H); 7.81 (appr s, 2H); 7.74 (br s, 1H); 7.28 (s, 1H); 7.02 (s, 1H); 7.00 (d, J=4.8 Hz, 1H); 4.0 (br s, 2H); 3.28 (br s, 2H); 2.34 (s, 3H); 2.09 (m, 2H); 1.88 (m, 2H); 1.41 (s, 9H). rhSYK=++

Workup

  1. extractionthe product was extracted with ethyl acetate
  2. washThe organic layer was washed with water and brine
  3. customThe combined organic layer was dried
  4. filtrationfiltered
  5. customThe residue was purified by column chromatography on silica gel (0-50% ethyl acetate in DCM)

Sources & evidence

ORD record
ord-cf61480ecc664f7d84af09617617256e
Source dataset
uspto-grants-2013_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08551984B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes