Phenyl isocyanate → HCID 68928323, compound

HRID 1394855Notes

Reaction equation

HRID 1394855 reaction equation
OC(C(F)(F)F)=O.C1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:32]([O:34]C)=[O:33])=[CH:19][C:20]=3[N:21]3[C:27]=2[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][CH2:23][CH2:22]3)CCCCC1.C1(N=C=O)C=CC=CC=1>C(N(CC)CC)C.C(Cl)Cl.CO>[CH:28]1[C:26]2[C:27]3[N:21]([C:20]4[CH:19]=[C:18]([C:32]([OH:34])=[O:33])[CH:17]=[CH:16][C:15]=4[CH:14]=3)[CH:22]=[CH:23][NH:24][C:25]=2[CH:31]=[CH:30][CH:29]=1

Participants

6

Reactant 2

HCID 7672Phenyl isocyanateHCID 131726178HCID 131726178, compound

Product 1

HCID 68928323HCID 68928323, compound

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×HCID 8471TriethylamineSolvent

Procedure

To a solution of methyl (13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)-carboxylate TFA (80 mg, 0.17 mmol) in triethylamine (0.20 mL) and CH2Cl2 (5 mL) which had been stirred for 5 min. was added phenyl isocyanate (0.20 mL, 1.84 mmol). The reaction solution was stirred for 2 h at rt, diluted with CH2Cl2 (˜10 mL) and MeOH (˜2 mL) and washed with ½ saturated aqueous NH4Cl (10 mL) and brine (10 mL). The organics were concentrated to dryness, dissolved into MeOH/THF (1:1, 3 mL) and treated with 1M aqueous NaOH (0.80 mL). The reaction mixture was stirred and heated at 80° C. with microwave irradiation for 15 min in a sealed tube. The clear solution was diluted with H2O (3 mL), neutralized with 1M aqueous HCl (0.80 mL) and concentrated to remove organic solvents. The solids were collected by filtration, washed with water and purified by preparative HPLC (MeOH/H2O with NH4OAc buffer) to yield 5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid, 13-cyclohexyl-6,7-dihydro-5-[(phenylamino)carbonyl] (21 mg, 0.044 mmol, 25%) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 8.20 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.75-7.59 (m, 5H), 7.19-6.92 (m, 5H), 4.78-4.47 (m, 2H), 4.00-3.51 (m, 2H), 3.10-2.96 (m, 1H), 2.20-1.14 (m, 10H). LCMS: m/e 480 (M+H)+, ret time 1.54 min, column A, 3 minute gradient.

Workup

  1. washwashed with ½ saturated aqueous NH4Cl (10 mL) and brine (10 mL)
  2. concentrationThe organics were concentrated to dryness
  3. dissolutiondissolved into MeOH/THF (1:1, 3 mL)
  4. additiontreated with 1M aqueous NaOH (0.80 mL)
  5. stirringThe reaction mixture was stirred
  6. temperatureheated at 80° C. with microwave irradiation for 15 min in a sealed tube
  7. additionThe clear solution was diluted with H2O (3 mL)
  8. concentrationconcentrated
  9. customto remove organic solvents
  10. filtrationThe solids were collected by filtration
  11. washwashed with water
  12. custompurified by preparative HPLC (MeOH/H2O with NH4OAc buffer)

Sources & evidence

ORD record
ord-9dc2df9fd7e64f2eb33dff456a06c9e2
Source dataset
uspto-grants-2008_03
Patent number
US07348425B2

Reaction notes

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