Water → HCID 136395964, compound

HRID 1940019Notes

Reaction equation

HRID 1940019 reaction equation
[NH2:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[N:5][C:6]([NH2:25])=[C:7]([CH2:13][N:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH3:15])[N:8]=2)[N:3]=1.C(P(=O)([O-])OCC)#[N:27].C(N(CC)CC)C.Cl.[NH2:42][C@H:43]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47].[OH2:56]>CN(C=O)C>[NH2:27][CH:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:44][C@@H:43]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[NH:42][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([N:14]([CH3:15])[CH2:13][C:7]2[N:8]=[C:9]3[C:4]([N:3]=[C:2]([NH:11][C:10]3=[O:56])[NH2:1])=[N:5][C:6]=2[NH2:25])=[CH:17][CH:18]=1

Participants

7

Reactant 5

HCID 962WaterHCID 8471Triethylamine2×HCID 73960Glutamic acid diethyl ester hydrochlorideHCID 21465278HCID 21465278, compoundHCID 86180093Ethyl cyanophosphate

Product 1

HCID 136395964HCID 136395964, compoundYield 40%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

Compound 7a (1.02 g, 3.0 mmole) was dissolved in 30 ml of DMF. To this solution were added ethyl cyanophosphonate (1.62 ml, 9 mmole) and triethylamine (1.23 ml, 9.0 mmole). The mixture was heated to 80° C. for 2 minutes. After the mixture had been cooled to room temperature, a solution of diethyl L-glutamate hydrochloride (0.72 gm, 3.0 mmole) in triethylamine (0.42 ml, 3.0 mmole) was added to the mixture which was then stirred at room temperature for 48 hours. At the end of 48 hours, 150 ml of water was added to the mixture which was then extracted several times with chloroform. The organic layers were combined and dried over Na2 SO4. The chloroform solution was filtered, and the filtrate was evaporated to dryness. The residue was chromatographed on a silica gel column which was eluted with CHCl3 :ethanol (4:1). After the eluent was evaporated, the crude product, diethyl 4,7-diamino-N-10-methylpteroylglutamate was obtained as a yellow solid. Recrystallization from ethanol gave 0.5 g, corresponding to a 40% yield, of diethyl ester of 7-aminomethotrexate. The melting point of this compound was 210°-213° C. The IR spectrum (KBr) showed absorption signals corresponding to NH2 at 3108-3451.2 cm-1, aliphatic --CH at 2986.0 cm-1, --C(=O)O-- at 1727.9 cm-1, and --C=N-- at 1605.5 cm-1. The nmr spectrum (DMSO-d6) revealed signals at 8.30 δ (1H,d,CONH), 7.78 δ (2H,d,arom), 7.18 δ (2H, s,NH2), 6.50-7.0 δ (2H,b,NH2), 6.80 δ (2H,d,arom), 6.60 δ (2H,s,NH2), 4.65 δ (2H,s,CH2N), 4.30 δ (1H,m,NCH--), 4.10 δ (4H,q,COOCH2CH3 ×2), 3.20 δ (3H, s,NCH3), 2.45 δ (2H,m,CH2 CH2COOEt), 2.10 δ (2H,m,CH2CH2COOEt), and 1.20 δ (6H,t,OCH2CH3 ×2). The FAB mass spectrum showed a molecular ion peak at m/z 526. This peak confirmed that the molecular weight of this compound was 526. Elemental analysis of 4,7-diamino-N-10 methylpteroylglutamate confirmed a chemical structure corresponding to C24H31N9O5.H2O.

Workup

  1. temperatureAfter the mixture had been cooled to room temperature
  2. extractionwas then extracted several times with chloroform
  3. customdried over Na2 SO4
  4. filtrationThe chloroform solution was filtered
  5. customthe filtrate was evaporated to dryness
  6. customThe residue was chromatographed on a silica gel column which
  7. washwas eluted with CHCl3 :ethanol (4:1)
  8. customAfter the eluent was evaporated

Sources & evidence

ORD record
ord-97347ab889b748c6b553082c4ad11885
Source dataset
uspto-grants-1997_12
Patent number
US05698556

Reaction notes

Loading…