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Dimethylacetamide → Diethyl 2-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate

HRID 511796
Notes
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Reaction equation

HRID 511796 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].[Cl:25][C:26]1[CH:27]=[C:28]([NH:40][C:41]2[C:42]3[CH:50]=[C:49]([NH2:51])[N:48]=[CH:47][C:43]=3[N:44]=[CH:45][N:46]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.CC(N(C)C)=O>C1COCC1.O.ClCCl.CO>[Cl:25][C:26]1[CH:27]=[C:28]([NH:40][C:41]2[C:42]3[CH:50]=[C:49]([NH:51][C:22](=[O:24])[CH2:21][P:16](=[O:17])([O:15][CH2:13][CH3:14])[O:18][CH2:19][CH3:20])[N:48]=[CH:47][C:43]=3[N:44]=[CH:45][N:46]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 31374DimethylacetamideHCID 36704(Diethoxyphosphinyl)acetic acidHCID 682631,1'-CarbonyldiimidazoleHCID 86668932N4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrido[3,4-d]-pyrimidine-4,6-diamine

Product 1

HCID 86668933Diethyl 2-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate
Yield 93%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×HCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
40 °C

Procedure

To a stirred mixture of CDI (2.25 g, 13.9 mmol) and dry THF (9 mL), at room temperature and under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (2.43 g, 12.4 mmol) in THF (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 221 (1.88 g, 4.96 mmol) in a mixed solvents of dry THF (10 mL) and DMA (16 mL) was added and stirred further at 40° C. The reaction was monitored by TLC (dichloromethane-MeOH=15:1). After stirred for 17 h, it was poured into water (300 mL) and stirred with petroleum ether (300 mL) at room temperature for 30 min. Petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by suction filtration; washed with water (5×20 mL) and dried to give diethyl 2-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate (230) (2.56 g, 93%); mp 113-116° C.; 1H NMR δ [(CD3)2SO]: 10.82 (s, 1H), 10.25 (s, 1H), 8.99 (s, 1H), 8.84 (s, 1H), 8.63-8.56 (m, 214), 7.96 (d, J=2.6 Hz, 1H), 7.88 (td, J=7.7, 1.8 Hz, 1H), 7.70 (dd, J=8.9, 2.6 Hz, 1H), 7.59 (br d, J=7.8 Hz, 1H), 7.41-7.34 (m, 1H), 7.28 (d, J=9.0 Hz, 4.16-4.03 (m, 4H), 3.31 (d, partially obscured by water peak, 211), 1.26 (t, J=7.0 Hz, 6H). Anal. Calcd for C25H26ClN6O5P.1.2H2O: C, 51.90; H, 4.95; N, 14.53%. Found C, 51.85; H, 4.94; N, 14.52%.

Workup

  1. additionAfter addition the reaction mixture
  2. additionwas added
  3. stirringstirred further at 40° C
  4. stirringAfter stirred for 17 h
  5. customPetroleum ether layer was decanted
  6. filtrationThe solid was collected by suction filtration
  7. washwashed with water (5×20 mL)
  8. customdried

Sources & evidence

ORD record
ord-a55c3d9ab1924f1b8a6a2a9ba75cf342
Source dataset
uspto-grants-2015_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09101632B2

Reaction notes

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