Trimethyl orthoformate → 1-(3-Carbamoyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)thiophen-2-yl)urea

HRID 2421366Notes

Reaction equation

HRID 2421366 reaction equation
[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(OC)(OC)OC.C([BH3-])#N.[N-]=C=O>COCCOC.CN(C)C(=O)C.C(O)(=O)C>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]

Participants

9

Reactant 5

HCID 9005Trimethyl orthoformateHCID 531671-MethylpiperazineHCID 105034IsocyanateHCID 498716Cyano-borohydrideHCID 219143262-[(Aminocarbonyl)amino]-5-[4-formylphenyl]thiophene-3-carboxamide

Product 1

HCID 219143981-(3-Carbamoyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)thiophen-2-yl)ureaYield 12.4%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 80711,2-DimethoxyethaneSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
80 °C

Procedure

2-[(Aminocarbonyl)amino]-5-(4-formylphenyl)-3-thiophenecarboxamide (100 mg) was stirred in a mixture of 1,2-dimethoxyethane (10 ml) and N,N-dimethylacetamide (5 ml). 1-Methyl piperazine (0.16 g) was added, followed by trimethyl orthoformate (5 ml) and acetic acid (0.5 ml). The reaction was stirred at 80° C. for 20 minutes, and then polymer-supported cyanoborohydride (0.45 g) was added. The reaction was stirred at 80° C. for a further 2 h, and then polymer-supported isocyanate (0.5 g) was added. The resins were removed by filtration, and the filtrate was then passed through a 5 g SCX column, washing with methanol (25 ml). The product was eluted using 1M methanolic ammonia (45 ml), and this solution was then evaporated to dryness under reduced pressure and the residue purified by chromatography on silica, eluting with dichloromethane/methanol (9:1), to give the product as an off-white solid (16 mg).

Workup

  1. stirringThe reaction was stirred at 80° C. for a further 2 h
  2. customThe resins were removed by filtration
  3. washwashing with methanol (25 ml)
  4. washThe product was eluted
  5. customthis solution was then evaporated to dryness under reduced pressure
  6. customthe residue purified by chromatography on silica
  7. washeluting with dichloromethane/methanol (9:1)

Sources & evidence

ORD record
ord-1c13bf2b11904283bef6836d7d418ca2
Source dataset
uspto-grants-2011_06
Patent number
US07956084B2

Reaction notes

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