Triethylamine → (2S,6R,8aR)-2-(3-chloro-5-fluorophenylamino)-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one

HRID 919635Notes

Reaction equation

HRID 919635 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[NH2:19][C@@H:20]1[C:28](=[O:29])[N:27]2[C@H:22]([CH2:23][CH2:24][C@@H:25]([NH:30][C:31]3[C:32]4[CH:39]=[CH:38][N:37]([S:40]([C:43]5[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=5)(=[O:42])=[O:41])[C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:26]2)[CH2:21]1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C@@H:20]2[C:28](=[O:29])[N:27]3[C@H:22]([CH2:23][CH2:24][C@@H:25]([NH:30][C:31]4[C:32]5[CH:39]=[CH:38][N:37]([S:40]([C:43]6[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=6)(=[O:42])=[O:41])[C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:26]3)[CH2:21]2)[CH:5]=[C:6]([F:8])[CH:7]=1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 15391287(3-Chloro-5-fluorophenyl)boronic acidHCID 68070553(2S,6R,8aR)-2-amino-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one

Product 1

HCID 68070556(2S,6R,8aR)-2-(3-chloro-5-fluorophenylamino)-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-oneYield 15%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 3-chloro-5-fluorophenylboronic acid (44 mg, 0.25 mmole) 127.b, powdered 4 Å molecular sieves (0.3 g), cupric acetate (83 mg, 0.45 mmole), triethylamine (69 μL (0.68 mmole), and anhydrous THF (3 mL) was stirred under a N2 atmosphere for 5 min. A solution of (2S,6R,8aR)-2-amino-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one (0.1 g) 127.5 in anhydrous THF (1.5 mL) was added and the reaction mixture was stirred at room temperature for 24 hr and then heated at 60° C. for 48 hr. The mixture was diluted with EtOAc and filtered through a celite plug. The filtrate was concentrated in vacuo, absorbing onto 3 g silica gel. Purification by flash column chromatography (ISCO 24 g SiO2, 40% EtOAc/hex then gradient to 100% EtOAc) afforded 19.4 mg of (2S,6R,8aR)-2-(3-chloro-5-fluorophenylamino)-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one 127.6 as a white solid. LCMS (ESI) m/z: 569.2 [M+H]+.

Workup

  1. stirringthe reaction mixture was stirred at room temperature for 24 hr
  2. filtrationfiltered through a celite plug
  3. concentrationThe filtrate was concentrated in vacuo
  4. customabsorbing onto 3 g silica gel
  5. customPurification by flash column chromatography (ISCO 24 g SiO2, 40% EtOAc/hex

Sources & evidence

ORD record
ord-ef941973c1cf4d07abc285592c01f376
Source dataset
uspto-grants-2016_03
Patent number
US09273028B2

Reaction notes

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