Dimethylformamide → 2-Amino-6-chloro-9-(2-diethoxyphosphonomethoxyethyl)purine

HRID 363714Notes

Reaction equation

HRID 363714 reaction equation
[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.O[CH2:13][CH2:14][O:15][CH2:16][P:17]([O:22]CC)(=[O:21])[O:18]CC.C1(P([C:38]2[CH:43]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O:48][CH2:49][CH3:50])=O.CN(C=[O:60])C>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:13][CH2:14][O:15][CH2:16][P:17]([O:18][O:60][CH2:43][CH3:38])([O:22][O:48][CH2:49][CH3:50])=[O:21])=[C:4]([Cl:11])[N:3]=1

Participants

6

Reactant 5

HCID 6228Dimethylformamide2×HCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 53603492-Amino-6-chloropurineHCID 10262588Diethyl 2-hydroxyethoxymethanephosphonate

Product 1

HCID 542406682-Amino-6-chloro-9-(2-diethoxyphosphonomethoxyethyl)purineYield 42%

Procedure

A mixture of 2-amino-6-chloropurine (890 mg, 4.2 mmol), diethyl 2-hydroxyethoxymethane-phosphonate 2b (710 mg, 4.2 mmol) and triphenylphosphine (1.65 g, 6.3 mmol) in anhydrous DMF (10 mL) was stirred at ambient temperature under N2 for 30 min. The reaction mixture was then cooled to -10° C. and diethyl azodicarboxylate (0.67 mL, 4.2 mmol) in DMF (2 mL) was added dropwise at such a rate that the reaction temperature was maintained at -10° C. The reaction mixture was stirred at that temperature for 2 h and then allowed to warm to ambient temperature gradually and stirred for 5 h. Any unreacted 2-amino-6-chloropurine was removed by filtration and the solvent removed under vacuum. The crude product was purified by silica gel column chromatography, eluting with CH2Cl2 /MeOH (9:1), to afford 650 mg (42 % yield) of the desired N9 -product 1d. 1H NMR (CDCl3) δ 7.90 (s, 1 H, H-8), 5.20 (s, broad, 2 H, NH2), 4.30 (t, J=4.8 Hz, 2 H, CH2N), 4.12 (dq, J=8.4 Hz, J=7.0 Hz, 4 H, 2 OCH2CH3), 3.92 (t, J=5.0 Hz, 2 H, CH2O), 3.79 (d, J=8.4 Hz, 2 H, CH2O), 1.30 (t, J=7.1 Hz, 6 H, 2 CH3); 13C NMR (CDCl3) δ 159.20, 153.78, 151.20, 143.29, 124.99 (purine ring carbons), 70.82 (d, 2JC,P=10.3 Hz, OCH2CH3), 65.17 (d, 1JC,P=166.0 Hz, CH2P), 62.42 (d, 3JC,P=5.7 Hz, CH2O), 43.19 (CH2N), 16.27 (d, 3J,P=5.7 Hz, CH3); UV (MeOH) λmax 247 (14,600), 310 (18,300) nm; IR (KBr, cm-1) 3327 and 3210 (m, broad, NH2), 1612 and 1562 (vs, purine ring), 1229 (s, P=O), 1026 (s, P--O--C); MS (CI) m/e 366 and 364 (40.5, 100, M+1), 3328 (22.3, M--Cl); Anal. calcd. for C12H19ClN5O4P: C, 39.63; H, 5.26; N, 19.25. Found: C, 39.53; H, 5.48; N, 18.99.

Workup

  1. temperatureThe reaction mixture was then cooled to -10° C.
  2. temperaturewas maintained at -10° C
  3. stirringThe reaction mixture was stirred at that temperature for 2 h
  4. temperatureto warm to ambient temperature gradually
  5. stirringstirred for 5 h
  6. customAny unreacted 2-amino-6-chloropurine was removed by filtration
  7. customthe solvent removed under vacuum
  8. customThe crude product was purified by silica gel column chromatography
  9. washeluting with CH2Cl2 /MeOH (9:1)

Sources & evidence

ORD record
ord-c1542ae617884c6691a57f3bdf5b7e14
Source dataset
uspto-grants-1999_02
Patent number
US05874577

Reaction notes

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