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Nitrogen → tert-Butyl ((5-methyl-1,3,4-thiadiazol-2-yl)methyl)(2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-yl)carbamate

HRID 2175404
Notes
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Reaction equation

HRID 2175404 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:12][C@@H:11]2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[N:5]=[C:4]([CH3:20])[N:3]=1.[CH3:21][C:22]1[S:26][C:25]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:24][N:23]=1.CC(C)([O-])C.[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.N#N>CC(O)(CC)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:21][C:22]1[S:26][C:25]([CH2:27][N:28]([C:2]2[CH:7]=[C:6]([O:8][CH2:9][C@H:10]3[CH2:12][C@@H:11]3[C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=3)[N:5]=[C:4]([CH3:20])[N:3]=2)[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[N:24][N:23]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

10

Reactant 5

HCID 947NitrogenHCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphaneHCID 23665647Potassium tert-butoxideHCID 59892191Tert-butyl ((5-methyl-1,3,4-thiadiazol-2-yl)methyl)carbamateHCID 867295664-chloro-2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidine

Product 1

HCID 86729565
tert-Butyl ((5-methyl-1,3,4-thiadiazol-2-yl)methyl)(2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-yl)carbamate
Yield 70%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 64052-Methyl-2-butanolSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
60 °C

Procedure

A solution of 2-1 (100 mg, 0.35 mmol), tert-butyl ((5-methyl-1,3,4-thiadiazol-2-yl)methyl)carbamate (119 mg, 0.52 mmol; for preparation, see D. C. Pryde et al. J. Med. Chem. 2006, 49, 4409-4424), 1 M potassium tert-butoxide (1.03 mL in THF) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (14.6 mg, 0.035 mmol) in 2-Methyl-2-butanol (1.7 ml) was purged with N2 for 5 min. Tris(dibenzylideneacetone)-dipalladium(0) (31.6 mg, 0.035 mmol) was added and the mixture was heated at 60° C. for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate and sat. NaHCO3. The organic phase was washed with water, brine and concentrated. The residue was purified by flash column chromatography using a 20-60% ethyl acetate/hexane gradient gave 2-2 as a colorless oil (117 mg, 70%). MS (M+H)+: observed=483.10, calculated=483.21.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. washThe organic phase was washed with water, brine
  3. concentrationconcentrated
  4. customThe residue was purified by flash column chromatography

Sources & evidence

ORD record
ord-3d4ea472d1e340ac8194fd53250034c1
Source dataset
uspto-grants-2015_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09062059B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes