Diethyl cyanophosphonate → 2-[(2-{4-[(2,4-Diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)phenoxy-phosphinoyloxy]propionic acid ethyl ester

HRID 2378849Notes

Reaction equation

HRID 2378849 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(O)=O)=[CH:20][CH:19]=3)[N:11]=2)[N:6]=1.NC1N=C(N)C2C(=NC=C(CN(C3C=CC([C:47](O)=[O:48])=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]([O:83][P:84]([CH2:93][CH2:94][NH2:95])([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]([O:83][P:84]([CH2:93][CH2:94][NH:95][C:47](=[O:48])[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)([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 131727189(S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]propionic acid ethyl ester mono acetic acid salt

Product 1

HCID 729847782-[(2-{4-[(2,4-Diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)phenoxy-phosphinoyloxy]propionic acid ethyl esterYield 65%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (60.0 mg, 158.3 μmol) in DMF (2.5 mL) were added diethyl cyanophosphonate (31.2 μL, 205.7 μmol) and DIEA (81.8 μL, 474.9 μmol). The solution was stirred at ambient temperature for 3.5 hours, when a solution of (S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]-propionic acid ethyl ester mono acetic acid salt (57.1 mg, 158.3 μmol; mixture of diastereomers at phosphorus) in DMF (200 μL) was added. The solution was stirred for 1.5 additional hours, whereupon complete consumption of the starting materials was observed. The solvent was removed in vacuo and the crude material was purified by silica gel chromatography using MeOH—CH2Cl2 (10-30%). A small amount of the product (24.8 mg) was repurified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 15.8 mg (65%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.17-1.27 (m, 3H), 1.32 (d, 2H, J=7.5 Hz), 1.42 (d, 1H, J=7.5 Hz) 2.27 (m, 2H), 3.19 (s, 3H), 3.53 (m, 2H), 4.08-4.14 (m, 2H), 4.77 (s, 2H), 4.98 (m, 1H), 6.72 (br s, 1H), 6.81 (d, 2H, J=9 Hz), 7.21 (m, 3H), 7.36 (m, 2H), 7.66 (d, 2H, J=9 Hz), 8.26 (br s, 1H), 8.56 (s, 1H); 31P (121.4 MHz, DMSO-d6) δ 26.6, 27.4. MS (m/z) 609.2 [M+H]+.

Workup

  1. stirringThe solution was stirred for 1.5 additional hours, whereupon complete consumption of the starting materials
  2. customThe solvent was removed in vacuo
  3. customthe crude material was purified by silica gel chromatography
  4. customA small amount of the product (24.8 mg) was repurified by RP HPLC on C18 column

Sources & evidence

ORD record
ord-02abf2b6aa49403cb482c173fff7b229
Source dataset
uspto-grants-2008_12
Patent number
US07470724B2

Reaction notes

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