2-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl → [4-(3-{6-[(Thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester

HRID 1186564Notes

Reaction equation

HRID 1186564 reaction equation
[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1NC.[CH3:39][N:40](C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>O1CCOCC1.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]>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:40][CH2:39][C:33]5[S:32][CH:36]=[CH:35][CH:34]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 11344002N-methylthiophen-2-amineHCID 23676156Sodium t-butoxideHCID 86670921{4-[3-(6-Bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester

Product 1

HCID 68227100[4-(3-{6-[(Thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of {4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 40 supra) (0.244 g, 0.5 mmol), thiophen-2-yl-methylamine (0.113 g, 1.0 mmol), Pd2(dba)3 (30 mg), Davephos (40 mg), NaOtBu (100 mg, 0.1 mmol) in dioxane (15 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 110° C. for 16 hour. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified first by chromatography (CH2Cl2:MeOH, 100:1), then by preparative-HPLC to give [4-(3-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester. (Yield 100 mg, 38%). LC-MS: [M+H]+ 520.

Workup

  1. customwas bubbled with N2 for several minutes
  2. temperatureThe solution was then cooled to room temperature
  3. filtrationfiltered
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. customThe residue was purified first by chromatography (CH2Cl2:MeOH, 100:1)

Sources & evidence

ORD record
ord-79472b4a3c904de598b74d633c14ba9d
Source dataset
uspto-grants-2014_03
Patent number
US08673905B2

Reaction notes

Loading…