Ethanol → 5-{4-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester

HRID 562969Notes

Reaction equation

HRID 562969 reaction equation
C(OC(N1CC2C(COC3C=C4C(C(OC5C=CC=CC=5N[C:40]([NH:42][C:43](=[O:51])[CH2:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[S:41])=NC(F)=N4)=CC=3OC)CCC2C1)=O)C1C=CC=CC=1.C1(CC(Cl)=O)C=CC=CC=1.[CH2:64]([O:71][C:72]([N:74]1[CH2:78][CH:77]2[CH2:79][CH:80]([CH2:82][O:83][C:84]3[CH:93]=[C:92]4[C:87]([C:88]([O:94][C:95]5[CH:100]=[CH:99][C:98]([NH2:101])=[CH:97][C:96]=5[F:102])=[N:89][CH:90]=[N:91]4)=[CH:86][C:85]=3[O:103][CH3:104])[CH2:81][CH:76]2[CH2:75]1)=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CCO>C1(C)C=CC=CC=1.CCOC(C)=O.C([S-])#N.[Ag+]>[CH2:64]([O:71][C:72]([N:74]1[CH2:75][CH:76]2[CH2:81][CH:80]([CH2:82][O:83][C:84]3[CH:93]=[C:92]4[C:87]([C:88]([O:94][C:95]5[CH:100]=[CH:99][C:98]([NH:101][C:40]([NH:42][C:43](=[O:51])[CH2:44][C:45]6[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=6)=[S:41])=[CH:97][C:96]=5[F:102])=[N:89][CH:90]=[N:91]4)=[CH:86][C:85]=3[O:103][CH3:104])[CH2:79][CH:77]2[CH2:78]1)=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1

Participants

8

Reactant 4

HCID 702EthanolHCID 7679Phenylacetyl chlorideHCID 666694435-[4-(4-Amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl esterHCID 866298694-[2-Fluoro-4-(3-phenylacetyl-thioureido-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester

Product 1

HCID 866298685-{4-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl esterYield 49%

Reagents, catalysts & solvents 3

HCID 74345Silver thiocyanateCatalystHCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

5-{4-[2-Fluoro-4-(3-phenylacetyl-thioureido-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester. Phenylacetyl chloride (2.65 ml, 20.00 mmol) and AgSCN (4.92 g, 29.6 mmol) were combined in dry toluene (50 ml) and heated to reflux for 2 hrs. The reaction mixture was allowed to cool to room temperature, the solids were filtered through celite and the filtrate concentrated in vacuo. The resulting oil was combined with 5-[4-(4-amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (5.6 g, 10 mmol) in 1:1 EtOH:toluene (100 ml) and the mixture stirred at room temperature for 1-2 hrs. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting oil was purified by flash chromatography (3:1 EtOAc:hexanes) to give 5-{4-[2-fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (3.61 g, 49%) as a dark brown foam. 1H-NMR (400 MHz, DMSO): 12.44 (s, 1H), 11.80 (s, 1H), 8.54 (s, 1H), 7.90 (m, 1H), 7.53 (s, 1H), 7.48 (m, 2H), 7.38 (s, 1H), 7.34 (m, 7H), 7.28 (m, 3H), 5.05 (s, 2H), 4.16 (d, 2H), 3.94 (s, 3H), 3.72 (s, 2H), 3.48 (m, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.52 (m, 1H), 2.10 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]+ 736.2, found 736.0.

Workup

  1. temperatureheated
  2. temperatureto reflux for 2 hrs
  3. filtrationthe solids were filtered through celite
  4. concentrationthe filtrate concentrated in vacuo
  5. washwashed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×)
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. customThe resulting oil was purified by flash chromatography (3:1 EtOAc:hexanes)

Sources & evidence

ORD record
ord-c12bedc9d3fd458d81fcb2ec2ec6953b
Source dataset
uspto-grants-2011_11
Patent number
US08067436B2

Reaction notes

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