Chloromethyl chloroformate → HCID 178476677, compound

HRID 1422568Notes

Reaction equation

HRID 1422568 reaction equation
F[C:2](F)(F)[C:3]([OH:5])=[O:4].[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[C:17]([CH2:19][NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]4[N:33]=[C:32](/[CH:34]=[C:35]5/[C:36](=[O:41])[NH:37][C:38](=[O:40])[S:39]/5)[CH:31]=[CH:30][N:29]=4)[CH2:23][CH2:22]3)[CH:16]=[CH:15][CH:14]=2)=[CH:9]1.CCN(C(C)C)C(C)C.Cl[C:52]([O:54][CH2:55]Cl)=[O:53]>CN(C=O)C.C([O-])(=O)C.[Ag+]>[C:3]([O:5][CH2:55][O:54][C:52](=[O:53])[N:20]([C@H:21]1[CH2:22][CH2:23][C@H:24]([NH:27][C:28]2[N:33]=[C:32](/[CH:34]=[C:35]3/[C:36](=[O:41])[NH:37][C:38](=[O:40])[S:39]/3)[CH:31]=[CH:30][N:29]=2)[CH2:25][CH2:26]1)[CH2:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][S:8][CH:9]=2)[N:18]=1)(=[O:4])[CH3:2]

Participants

6

Reactant 3

HCID 62754Chloromethyl chloroformateHCID 81531DiisopropylethylamineHCID 178525671HCID 178525671, compound

Product 1

HCID 178476677HCID 178476677, compoundYield 1.5%

Reagents, catalysts & solvents 2

HCID 11246Silver acetateCatalystHCID 6228DimethylformamideSolvent

Procedure

(Z)-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione trifluoroacetate salt (73.6 mg, 0.12 mmol, 1 equiv.) was dissolved in DMF (2 mL) and DIEA (63 μL, 0.36 mmol, 3 equiv.) was added at once. Chloromethyl chloroformate (10.7 μL, 0.12 mmol, 1.0 equiv.) was added at once and the reaction mixture was stirred at RT for 1 h. Silver acetate (61 mg, 0.36 mmol, 3 equiv.) was added at once and the reaction mixture was shaken for 1 h at 85° C. The desired carbamate was purified by preparative HPLC (TFA method). The purest fractions were pooled and evaporated. The residue was re-dissolved in a 1:1 mixture of methanol/1% NH4OH aqueous solution and the solvents were evaporated under reduced pressure. The free base was purified on silica gel (CH2Cl2/MeOH 95:5) to give the desired product as a yellow solid (1.1 mg, 73.7 mg theoretical, 1.5%). LC-MS m/z 609 (M+1).

Workup

  1. stirringwas shaken for 1 h at 85° C
  2. customThe desired carbamate was purified by preparative HPLC (TFA method)
  3. customevaporated
  4. dissolutionThe residue was re-dissolved in a 1:1 mixture of methanol/1% NH4OH aqueous solution
  5. customthe solvents were evaporated under reduced pressure
  6. customThe free base was purified on silica gel (CH2Cl2/MeOH 95:5)

Sources & evidence

ORD record
ord-2aba803a9c10408e9db71b2d5908306b
Source dataset
uspto-grants-2015_01
Patent number
US08927525B2

Reaction notes

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