Tetrahydrofuran → HCID 86668944, compound

HRID 511813Notes

Reaction equation

HRID 511813 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].[C:25]([C:27]1[CH:28]=[C:29]([NH:34][C:35]2[C:36]3[CH:44]=[C:43]([NH2:45])[N:42]=[CH:41][C:37]=3[N:38]=[CH:39][N:40]=2)[CH:30]=[CH:31][C:32]=1[F:33])#[CH:26].C1COCC1>O.ClCCl.CO.CC(N(C)C)=O>[C:25]([C:27]1[CH:28]=[C:29]([NH:34][C:35]2[C:36]3[CH:44]=[C:43]([NH:45][C:22](=[O:24])[CH2:21][P:16](=[O:17])([O:15][CH2:13][CH3:14])[O:18][CH2:19][CH3:20])[N:42]=[CH:41][C:37]=3[N:38]=[CH:39][N:40]=2)[CH:30]=[CH:31][C:32]=1[F:33])#[CH:26]

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 36704(Diethoxyphosphinyl)acetic acidHCID 682631,1'-CarbonyldiimidazoleHCID 86668945HCID 86668945, compound

Product 1

HCID 86668944HCID 86668944, compoundYield 91.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 31374DimethylacetamideSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
40 °C

Procedure

To a stirred mixture of CDI (2.01 g, 12.4 mmol) and dry THE (9 mL), at room temperature and under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (2.18 g, 11.1 mmol) in THE (7 mL). After addition the reaction mixture was stirred further at 40° C. (bath) for 15 min (whence evolution of gases ceased). A mixture of compound 226 (1.24 g, 4.44 mmol) in a mixed solvents of dry THF (5 mL) and DMA (6 mL) was added and stirred further at 40° C. The reaction was monitored by TLC (dichloromethane-MeOH=30:1). After stirred for 22 h, it was poured into water (200 mL) and the residue washed down with MeOH. Petroleum ether (300 mL) was added and stirred at room temperature for 1 h. Petroleum ether layer was decanted. It was repeated once more with petroleum ether (150 mL). The solid was collected by suction filtration; washed with water (5×20 mL) and dried to give diethyl 2-(4-(3-ethynyl-4-fluorophenylamino)pyrido[3,4-d]-pyrimidin-6-ylamino)-2-oxoethylphosphonate (235) (1.85 g, 91%); mp 103-106° C.; 1H NMR δ [(CD3)2SO]: 10.84 (s, 1H), 10.33 (s, 1H), 9.01 (s, 1H), 8.86 (s, 1H), 8.61 (s, 1H), 8.01 (dd, J=6.4, 2.7 Hz, 1H), 7.92-7.83 (m, 1H), 7.35 (t, J=9.1 Hz, 1H), 4.51 (s, 1H), 4.17-4.03 (m, 4H), 3.32 (d, partially obscured by water peak, 2H), 1.26 (t, J=7.0 Hz, 6H). Anal. Calcd for C21H21FN3O4P.MeOH: C, 53.99; H, 5.15; N, 14.31%. Found C, 54.21; H, 4.94; N, 14.43%.

Workup

  1. customdry THE (9 mL)
  2. additionAfter addition the reaction mixture
  3. additionwas added
  4. stirringstirred further at 40° C
  5. stirringAfter stirred for 22 h
  6. washthe residue washed down with MeOH
  7. additionPetroleum ether (300 mL) was added
  8. stirringstirred at room temperature for 1 h
  9. customPetroleum ether layer was decanted
  10. filtrationThe solid was collected by suction filtration
  11. washwashed with water (5×20 mL)
  12. customdried

Sources & evidence

ORD record
ord-1788fd6bc2c148f39fb4650133f23440
Source dataset
uspto-grants-2015_08
Patent number
US09101632B2

Reaction notes

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