Tetrahydrofuran → (S)-3-(2-chloro-3-fluorobenzyl)-1-(5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl)-1-methylurea

HRID 409783

Reaction equation

HRID 409783 reaction equation
[CH:1]1[C:6]([N+]([O-])=O)=[CH:5][CH:4]=[C:3]([Cl-]C([O-])=O)[CH:2]=1.Cl.[Cl:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].CCN(C(C)C)C(C)C.[OH:34][CH2:35][C@@H:36]([NH:51][CH3:52])[CH2:37][CH2:38][CH2:39][N:40]1[C:48](=[O:49])C2C(=CC=CC=2)[C:41]1=[O:50].C1C[O:56][CH2:55]C1>>[Cl:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:55](=[O:56])[N:51]([C@@H:36]([CH2:37][CH2:38][CH2:39][N:40]1[C:41](=[O:50])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:48]1=[O:49])[CH2:35][OH:34])[CH3:52]

Participants

5

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 81531DiisopropylethylamineHCID 57947589(S)-2-(5-hydroxy-4-(methylamino)pentyl)isoindoline-1,3-dioneHCID 66622557(2-Chloro-3-fluorophenyl)methanamine hydrochloride

Product 1

HCID 57947359(S)-3-(2-chloro-3-fluorobenzyl)-1-(5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl)-1-methylureaYield 47%

Procedure

To a solution of 4-nitrophenylchloroformate (460 mg, 2.29 mmol) in THF (20 mL) was added 2-chloro-3-fluorobenzylamine hydrochloride (626 mg, 2.29 mmol) and DIEA (0.76 mL, 4.58 mmol) and the mixture was stirred at RT until TLC showed complete consumption of 2-chloro-3-fluorobenzylamine. The mixture was then added into a solution of (S)-2-(5-hydroxy-4-(methylamino)pentyl)isoindoline-1,3-dione (500 mg, 1.91 mmol) in THF (10 mL). The mixture was stirred overnight, concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-3-(2-chloro-3-fluorobenzyl)-1-(5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl)-1-methylurea (401 mg, 47%). LRMS (M+H+) m/z 448.3.

Workup

  1. customconsumption of 2-chloro-3-fluorobenzylamine
  2. stirringThe mixture was stirred overnight
  3. concentrationconcentrated
  4. custompurified on RP-HPLC
  5. additiona mixture of acetonitrile and H2O

Sources & evidence

ORD record
ord-7ab9cb5912614b078c4d521bfcac1682
Source dataset
uspto-grants-2014_06
Patent number
US08759374B2

Linked notes

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