Diethyl cyanophosphonate → HCID 10180725, compound

HRID 914770Notes

Reaction equation

HRID 914770 reaction equation
[C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([OH:3])=O.[NH2:13][C@@H:14]([C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19])[CH:15]([CH3:17])[CH3:16].C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[NH3:10].[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([C:1]([NH:13][C@@H:14]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:3])[CH:12]=2)[CH:8]=[CH:9]1

Participants

6

Reactant 3

HCID 76257Diethyl cyanophosphonate2×HCID 5952301H-indole-6-carboxylic acid2×HCID 69143170HCID 69143170, compound

Product 2

HCID 222AmmoniaHCID 10180725HCID 10180725, compoundYield 184.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-15 °C

Procedure

6-Carboxyindole (4.0 g, 24.8 mmol) and 1-(D-valinyl)-4-(1-methylpiperidin-4-yl)piperidine (10.1 g, 27.8 mmol) are slurried in anhydrous CH2Cl2 (250 mL) and cooled to −15° C. To this slurry is added diethyl cyanophosphonate (4.5 mL, 29.8 mmol), followed by TEA (11.1 mL, 79.4 mmol) maintaining the temperature below −10° C. The reaction is allowed to warm to room temperature overnight. The following morning, if TLC indicates starting material still present, additional 6-carboxyindole (0.5 g, 3.1 mmol) and diethyl cyanophosphonate (0.5 mL, 3.3 mmol) are added, followed by TEA (1.0 mL, 7.2 mmol). After stirring for an additional 2 h, the reaction is quenched with the addition of brine (100 mL), forming an insoluble brown oil on the sides of the flask. The layers are separated and the aqueous layer is extracted with CH2Cl2 (3×100 mL). The organic layers are combined, dried over Na2SO4, filtered and concentrated. The crude material is then purified using chromatography over silica gel, with 5% (2 M NH3 in MeOH)/CHCl3 as the eluent, to give 9.7 g (92%) of the title compound as a light yellow foam.

Workup

  1. temperaturemaintaining the temperature below −10° C
  2. temperatureto warm to room temperature overnight
  3. customthe reaction is quenched with the addition of brine (100 mL)
  4. customforming an insoluble brown oil on the sides of the flask
  5. customThe layers are separated
  6. extractionthe aqueous layer is extracted with CH2Cl2 (3×100 mL)
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude material is then purified

Sources & evidence

ORD record
ord-076c737de8e0437987f3ca86ddc5f2ae
Source dataset
uspto-grants-2007_09
Patent number
US07265121B2

Reaction notes

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