Cesium carbonate → 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

HRID 1297297Notes

Reaction equation

HRID 1297297 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:26][CH3:27])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][NH:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:29]1[S:30][CH:31]=[CH:32][N:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)(O)[O-].[Na+]>COCCOC.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]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:26][CH3:27])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]

Participants

8

Reactant 5

HCID 10796Cesium carbonateHCID 764302-BromothiazoleHCID 516892Sodium BicarbonateHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 103098205-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

Product 1

HCID 117851775-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amineYield 50%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine (120 mg) in ethylene glycol dimethyl ether (0.586 ml) was added 2-bromo-1,3-thiazole (0.040 ml, 1.5 eq.), Cesium carbonate (144 mg, 1.5 eq.), N-[2′-(dicyclohexylphosphino)-1,1′-biphenyl-2-yl]-N,N-dimethylamine (16 mg, 0.14 eq.) and Tris(dibenzylideneacetone)dipalladium (19 mg, 0.7 eq.). The reaction mixture was heated at 100° C. for 16 h, poured into saturated sodium bicarbonate (50 ml), extracted 2×50 ml of CH2Cl2, dried MgSO4, filtered and concentrated. Purification via MPLC chromatography eluting with 10–30% ethyl acetate/heptane provided the title compound as an amorphous solid (77 mg, 50%): 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.34, 7.28–7.23, 6.53, 5.30, 4.92, 4.27, 4.02, 3.82–3.72, 3.55, 3.46, 2.72, 2.48, 1.33–1.27, 1.16; IR (liq.) 2972 (s), 2934, 2335 (w), 1564 (s), 1539 (s), 1494 (s), 1470 (s), 1396 (s), 1357, 1350, 1201, 1141, 1121 (s), 1101, 610 cm−1 HRMS (ESI) calcd for C23H27N5OSCl2+H1 492.1391. found 492.1378.

Workup

  1. extractionextracted 2×50 ml of CH2Cl2, dried MgSO4
  2. filtrationfiltered
  3. concentrationconcentrated
  4. customPurification via MPLC chromatography
  5. washeluting with 10–30% ethyl acetate/heptane

Sources & evidence

ORD record
ord-412a7802740244289aba92887dea94d1
Source dataset
uspto-grants-2007_07
Patent number
US07250418B2

Reaction notes

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