Diethyl cyanophosphonate → HCID 178472025, compound

HRID 272227Notes

Reaction equation

HRID 272227 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](O)=[O:23])=[CH:20][CH:19]=3)[N:11]=2)[N:6]=1.NC1N=C(N)C2C(=NC=C(CN(C3C=CC(C(O)=O)=CC=3)C)N=2)N=1.O.O.C(P(=O)(OCC)OCC)#N.CCN(C(C)C)C(C)C.C(O)(=O)C.[CH2:77]([O:79][C:80](=[O:96])[C@@H:81]([N:83]([CH2:93][CH2:94][NH2:95])[PH:84]([O:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[O:85])[CH3:82])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80](=[O:96])[CH:81]([N:83]([CH2:93][CH2:94][NH:95][C:22](=[O:23])[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)[PH:84]([O:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[O:85])[CH3:82])[CH3:78]

Participants

6

Reactant 4

HCID 76257Diethyl cyanophosphonateHCID 81531DiisopropylethylamineHCID 1317271884-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrateHCID 178476472HCID 178476472, compound

Product 1

HCID 178472025HCID 178472025, compoundYield 26%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (39.6 mg, 104.0 mmol) in DMF (1.2 mL) were added diethyl cyanophosphonate (20.6 μL, 136.1 μmol) and DIEA (36.0 μL, 209.4 μmol). The solution was stirred at ambient temperature for 3 hours, when (S)-2-[(2-aminoethyl)phenoxyphosphinoylamino]propionic acid ethyl ester mono acetic acid salt (mixture of diastereomers at phosphorus; 104.0 μmol) in DMF (200 μL) was added. The solution was stirred for 30 minutes when complete consumption of the starting materials was observed. An aliquot (66%) of the reaction was purified by silica gel chromatography using MeOH—CH2Cl2 (10-30%), yielding 27.2 mg of crude product. A small amount of the product (10 mg) was repurified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 4.2 mg (26%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.11 (t, 3H, J=6.9 Hz), 1.18 (d, 3H, J=7.2 Hz), 2.06-2.17 (m, 2H), 3.20 (s, 3H), 3.51 (m, 2H), 3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80 (d, 2H, J=9 Hz), 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.59 (s, 1H) 31P (121.4 MHz, DMSO-d6) δ 29.5, 30.1. MS (m/z) 608.2 [M+H]+.

Workup

  1. stirringThe solution was stirred for 30 minutes
  2. customwhen complete consumption of the starting materials
  3. customAn aliquot (66%) of the reaction was purified by silica gel chromatography
  4. customyielding 27.2 mg of crude product
  5. customA small amount of the product (10 mg) was repurified by RP HPLC on C18 column

Sources & evidence

ORD record
ord-8103cbd8993c4006aa52a74261be18e7
Source dataset
uspto-grants-2008_11
Patent number
US07452901B2

Reaction notes

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