Dimethylacetamide → HCID 86663604, compound

HRID 1520740Notes

Reaction equation

HRID 1520740 reaction equation
C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[Br:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:35]3[CH:43]=[C:42]([NH2:44])[N:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[F:32].CC(N(C)C)=O>C1COCC1.O.C(OCC)(=O)C>[Br:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:35]3[CH:43]=[C:42]([NH:44][C:22](=[O:24])[CH2:21][P:16](=[O:17])([O:15][CH2:13][CH3:14])[O:18][CH2:19][CH3:20])[N:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[F:32]

Participants

8

Reactant 4

HCID 31374DimethylacetamideHCID 36704(Diethoxyphosphinyl)acetic acid2×HCID 682631,1'-Carbonyldiimidazole2×HCID 10640427HCID 10640427, compound

Product 1

HCID 86663604HCID 86663604, compoundYield 98.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent5×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

To a stirred mixture of CDI (8.44 g, 52.0 mmol) and dry THF (32 mL), at room temperature under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (10.2 g, 52.0 mmol) in THF (28 mL). After addition the reaction mixture was stirred further at 40° C. (bath) for 20 min (whence evolution of gases ceased). A solution of compound 159 (13.4 g, 40.0 mmol) in a mixture of dry THF (45 mL) and DMA (50 mL) was added and the reaction was stirred further at 40° C. The reaction was monitored by TLC (ethyl acetate) and found to be only ca. 70% complete after 1.5 hours. Thus, another batch of reagent was prepared by adding CDI (4.22 g, 26.0 mmol) in dry THF (16 mL) to 2-(diethoxyphosphoryl)acetic acid (5.10 g, 26.0 mmol) in dry THF (7 mL). This additional reagent was added to the reaction mixture before it was stirred further for 2 h at 40° C. and then poured into water (1,000 mL) and stirred with petroleum ether (1,500 mL) at room temperature for 16 h. The petroleum ether layer was then decanted. More petroleum ether (800 mL) was added and the mixture was stirred for 15 min. The solid was collected by filtration, washed with water (5×200 mL) and dried to give diethyl 2-(4-(3-bromo-4-fluorophenylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate (160) (20.1 g, 98%), m.p. 214-217° C. 1H NMR δ (CDCl3) 9.45 (s, 1H), 9.03 (s, 1H), 8.73 (s, 1H), 8.55 (s, 1H), 8.13 (dd, J=6.0, 2.6 Hz, 1H), 7.77 (s, 1H), 7.70-7.63 (m, 1H), 7.18 (dd, J=8.7, 8.2 Hz, 1H), 4.31-4.18 (m, 4H), 3.15 (d, J=21.0 Hz, 2H), 1.39 (t, J=7.1 Hz, 6H). Anal. Calcd for C19H20BrFN5O4P.0.2H2O: C, 44.24; H, 3.99; N, 13.58%. Found C, 44.00; H, 4.09; N, 13.42%.

Workup

  1. additionAfter addition the reaction mixture
  2. additionwas added
  3. stirringthe reaction was stirred further at 40° C
  4. customcomplete after 1.5 hours
  5. customThus, another batch of reagent was prepared
  6. additionThis additional reagent was added to the reaction mixture before it
  7. stirringwas stirred further for 2 h at 40° C.
  8. customThe petroleum ether layer was then decanted
  9. additionMore petroleum ether (800 mL) was added
  10. stirringthe mixture was stirred for 15 min
  11. filtrationThe solid was collected by filtration
  12. washwashed with water (5×200 mL)
  13. customdried

Sources & evidence

ORD record
ord-ac9557c46d1c4bada15e2fa342473edb
Source dataset
uspto-grants-2015_07
Patent number
US09073916B2

Reaction notes

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