Diethyl cyanophosphonate → (2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonic acid diethyl ester

HRID 2378847Notes

Reaction equation

HRID 2378847 reaction equation
O.O.Cl.[NH2:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:16][N:17]([CH3:27])[C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:11]=2)[N:6]=1.NC1N=C(N)C2C(=NC=C(C[N:41]([C:43]3[CH:51]=CC(C(O)=O)=C[CH:44]=3)C)N=2)N=1.O.O.C([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])#N.CCN(C(C)C)C(C)C.C(OP(CCCN)(=O)OCC)C>CN(C=O)C>[CH2:58]([O:57][P:56]([CH2:51][CH:43]([NH:41][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([N:17]([CH2:16][C:10]2[N:11]=[C:12]3[C:7](=[N:8][CH:9]=2)[N:6]=[C:5]([NH2:4])[N:14]=[C:13]3[NH2:15])[CH3:27])=[CH:26][CH:25]=1)[CH3:44])(=[O:63])[O:60][CH2:61][CH3:62])[CH3:59]

Participants

6

Reactant 4

HCID 76257Diethyl cyanophosphonateHCID 78113Diethyl (3-aminopropyl)phosphonateHCID 81531DiisopropylethylamineHCID 1317271884-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate

Product 1

HCID 57496979(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonic acid diethyl esterYield 75%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) were added diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL, 161 μmol). The solution was stirred at ambient temperature for 3 hours, when diethyl(aminopropyl)phosphonate (34.9 mg, 122.6 μmol) was added. The solution was stirred for 2 additional hours, whereupon complete consumption of the starting materials was observed. The reaction was worked up by removal of the solvent in vacuo and purifying the residue by silica gel chromatography using MeOH—CH2Cl2 (10-30%). The product (65.5 mg) collected from this chromatography step was sufficiently pure to be carried on to the next reaction. A small amount (32.8 mg) was re-purified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 23.2 mg (75%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, 6H, J=7.2 Hz), 1.64-1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H), 3.98 (appt septet, 4H, J=7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.68 (d, 2H, J=9 Hz), 8.17 (br s, 1H), 8.70 (s, 1H); 31P (121.4 MHz, DMSO-d6) δ 31.9; MS (m/z) 503.2 [M+H]+.

Workup

  1. stirringThe solution was stirred for 2 additional hours, whereupon complete consumption of the starting materials
  2. customThe reaction was worked up by removal of the solvent in vacuo
  3. custompurifying the residue by silica gel chromatography
  4. customThe product (65.5 mg) collected from this chromatography step
  5. customto be carried on to the next reaction
  6. customA small amount (32.8 mg) was re-purified by RP HPLC on C18 column

Sources & evidence

ORD record
ord-50a5ba2e21c94704b949315a072818fc
Source dataset
uspto-grants-2008_12
Patent number
US07470724B2

Reaction notes

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