5-Bromopyrimidine → HCID 16069044, compound

HRID 2047569Notes

Reaction equation

HRID 2047569 reaction equation
[N:1]1([C@@H:7]2[CH2:10][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O.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].C1(C)C=CC=CC=1>[N:1]1([CH:7]2[CH2:10][CH:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([NH:20][C:22]5[CH:23]=[N:24][CH:25]=[N:26][CH:27]=5)[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

8

Reactant 4

HCID 783445-BromopyrimidineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 178507336HCID 178507336, compound

Product 1

HCID 16069044HCID 16069044, compound

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
145 °C

Procedure

The product of Example 101A (cis-2-(3-piperidin-1-yl-cyclobutyl)-benzothiazole-6-ylamine) (50 mg, 0.174 mmole), 5-bromopyrimidine (42 mg, 0.264 mmole), tris(dibenzylideneacetone)dipalladium (0) (6.5 mg, 0.007 mmole), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 8.7 mg, 0.014 mmole) and sodium tert-butoxide (23 mg, 0.242 mmole) were charged in a tube and sealed. The tube was placed on high vacuum for 2 hours and refilled with nitrogen. Toluene (2 mL) was added and the reaction vessel was placed in a microwave reactor and heated at 145° C. for 15 minutes. After cooling to room temperature, the mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were concentrated and the crude product was purified by column chromatography (0.4% ammonium hydroxide and 4% methanol in dichloromethane). The product collected was a mixture of cis and trans isomers. 1H NMR (400 MHz, CDCl3) δ ppm 8.79 (s, 1H) 8.50-8.56 (m, 2H) 7.89 (d, J=8.90 Hz, 1H) 7.58 (d, J=2.15 Hz, 1H) 7.18 (dd, J=8.59, 2.15 Hz, 1H) 5.83 (s, 1H) 3.48-3.63 (m, 1H) 2.73-2.85 (m, 1H) 2.59-2.71 (m, 2H) 2.23-2.39 (m, 6H) 1.54-1.66 (m, 4H) 1.41-1.51 (m, 2H). MS: (M+H)+=366.

Workup

  1. customsealed
  2. additionrefilled with nitrogen
  3. customthe reaction vessel was placed in a microwave reactor
  4. temperatureAfter cooling to room temperature
  5. extractionextracted three times with dichloromethane
  6. concentrationThe combined organic layers were concentrated
  7. customthe crude product was purified by column chromatography (0.4% ammonium hydroxide and 4% methanol in dichloromethane)
  8. customThe product collected
  9. additiona mixture of cis and trans isomers

Sources & evidence

ORD record
ord-585622fd7f2b40a097960c915a0eeac0
Source dataset
uspto-grants-2013_11
Patent number
US08592467B2

Reaction notes

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