Triethylamine → 3(R,S)-[2(R)-(tert-Butyloxycarbonvl)amino-3-phenylpropionylamino]-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one

HRID 1655008Notes

Reaction equation

HRID 1655008 reaction equation
[NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]([NH:28][C@@H:29]([C:37](O)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O.O.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[C:24]([O:23][C:21]([NH:28][C@H:29]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]([NH:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20])=[O:38])=[O:22])([CH3:27])([CH3:25])[CH3:26]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 637610Boc-D-phenylalanineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 111191973(R,S)-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-oneHCID 214804841-Hydroxybenzotriazole trihydrate

Product 1

HCID 1317187683(R,S)-[2(R)-(tert-Butyloxycarbonvl)amino-3-phenylpropionylamino]-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3(R,S)-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (4 g, 14.8 mmol) in anhydrous dimethylformamide (35 ml), under an atmosphere of nitrogen, was added in succession Boc-D-phenylalanine (4.11 g, 15.4 mmol), 1-hydroxybenzotriazole trihydrate (2.09 g, 15.4 mmol) and 1- ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (2.97 g, 15.4 mmol). Triethylamine (2.16 ml, 15.4 mmol) was then added and the resulting suspension was stirred at ambient temperature for 20 min. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (50 ml) and 10% citric acid solution (50 ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with 10% sodium hydroxide solution (50 ml), water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, using 1:1 petrol:ethyl acetate as the eluant, to afford the product (7.26, 95%) as a pale yellow solid. mp 95°-98° C. 1H NMR (360MHz, CDCl3) δ0.99-1.11 (1H, m), 1.16-1.72 (7H, m), 1.40 (9H, s), 1.83-1.92 (1H, m), 1.98-2.06 (1H, m), 2.73-2.83 (1H, m), 3.10-3.24) (2H, m), 3.38 (3H, s), 4.53 (1H, brs), 4.98 (1H, brs), 5.28-5.34 (2H, m), 7.19-7.32 (7H, m), 7.49-7.58 (2H, m).

Workup

  1. customThe solvent was removed under reduced pressure
  2. customthe residue was partitioned between ethyl acetate (50 ml) and 10% citric acid solution (50 ml)
  3. customThe organic phase was separated
  4. extractionthe aqueous phase extracted with ethyl acetate (3×50 ml)
  5. washThe combined organic phases were washed with 10% sodium hydroxide solution (50 ml), water (50 ml) and brine (50 ml)
  6. dry with materialdried (MgSO4)
  7. customevaporated in vacuo
  8. customThe residue was chromatographed on silica gel
  9. customethyl acetate as the eluant, to afford the product (7.26, 95%) as a pale yellow solid

Sources & evidence

ORD record
ord-781c43fb1ab7497f83a8edb751e19e23
Source dataset
uspto-grants-1995_04
Patent number
US05410049

Reaction notes

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