Formaldehyde → HCID 60036683, compound

HRID 1948957Notes

Reaction equation

HRID 1948957 reaction equation
[Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:37][CH3:38])=[C:13]([O:16][C@H:17]3[CH2:21][N:20]([C:22](OC(C)(C)C)=O)[C@H:19]([C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C=O>C(O)=O>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:37][CH3:38])=[C:13]([O:16][C@H:17]3[CH2:21][N:20]([CH3:22])[CH:19]([C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1

Participants

4

Reactant 2

HCID 712FormaldehydeHCID 60036701HCID 60036701, compound

Product 1

HCID 60036683HCID 60036683, compoundYield 22.6%

Reagents, catalysts & solvents 1

HCID 284Formic AcidSolvent

Procedure

A solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S,4R)-1-(tert-butoxycarbonyl)-2-(morpholinocarbonyl)pyrrolidin-4-yloxy]quinazoline (0.3 g), formic acid (3.0 ml) and paraformaldehyde (0.047 mg) was stirred at 80° C. for 8 hours. The reaction was cooled, reduced under vacuum and adsorbed onto silica. The product was eluted with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the desired product were combined and evaporated under vacuum. The product was then re-purified by preparative HPLC on a reverse phase Hi-Chrom HIRPB column. The product was eluted with decreasingly polar mixtures of acetonitrile/water (0.1% trifluoroacetic acid) (20/80 to 50150). The fractions containing the desired product were combined and evaporated under vacuum and the residue dissolved in methylene chloride/methanol (saturated with ammonia) and adsorbed onto silica. The product was eluted with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 90/10). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a colourless foam (0.058 g); 1H NMR Spectrum: (DMSO d6) 2.10-2.18 (m, 1H), 2.31 (s, 3H), 2.53-2.60 (m, 1H), 3.44-3.67 (m, 10H), 3.72 (t, 1H), 3.92 (s, 3H), 5.10 (m, 1H), 7.21 (s, 1H), 7.28 (t, 1H), 7467.56 (m, 2H), 7.71 (s, 1H), 8.36 (s, 1H), 9.64 (s, 1H); Mass Spectrum: (M+H)+ 516.

Workup

  1. temperatureThe reaction was cooled
  2. washThe product was eluted
  3. temperaturewith increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10)
  4. additionThe fractions containing the desired product
  5. customevaporated under vacuum
  6. customThe product was then re-purified by preparative HPLC on a reverse phase Hi-Chrom HIRPB column
  7. washThe product was eluted with decreasingly polar mixtures of acetonitrile/water (0.1% trifluoroacetic acid) (20/80 to 50150)
  8. additionThe fractions containing the desired product
  9. customevaporated under vacuum
  10. dissolutionthe residue dissolved in methylene chloride/methanol (saturated with ammonia)
  11. washThe product was eluted
  12. temperaturewith increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 90/10)
  13. additionThe fractions containing the desired product
  14. customevaporated under vacuum

Sources & evidence

ORD record
ord-e09e3c17d06343a1a15cb55f104ad173
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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