Ethanolamine → (S)-1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea

HRID 1155118Notes

Reaction equation

HRID 1155118 reaction equation
[C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[C@H:13]([CH3:18])[N:12]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:10]=2[C:26]=1[Cl:27].C(N(CC)CC)C.[NH2:35][CH2:36][CH2:37][OH:38]>ClCCCl>[Cl:27][C:26]1[C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:12][C@@H:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:9]=2[CH:8]=[CH:7][C:6]=1[NH:5][C:1]([NH:35][CH2:36][CH2:37][OH:38])=[O:2]

Participants

6

Reactant 4

HCID 700EthanolamineHCID 6371PhosgeneHCID 8471TriethylamineHCID 54545945(S)-7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one

Product 1

HCID 54551834(S)-1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent2×

Procedure

A solution of 2g of phosgene in 20 ml of ice-cold 1,2-dichloroethane is placed in a sulphonation flask. There is added dropwise thereto a solution of 4 g (0.012 M) of (S)-7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one in 40 ml of 1,2-dichloroethane while cooling with ice and stirring in such a manner that the temperature does not exceed 10° C. The mixture is then stirred at room temperature for 45 minutes. The resulting solution of (S)-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodizepin-7-yl]isocyanate is cooled with ice and slowly made alkaline with 6 ml of triethylamine. A solution of 2 ml of 2-aminoethanol in 20 ml of 1,2-dichloroethane is treated with the foregoing pre-prepared solution, the mixture is stirred at room temperature for 30 minutes and then concentrated. The residue is purified on a 300 g silica gel column using methylene chloride and then methylene chloride/ethanol (20:1) as the eluting agent and crystallised from a small amount of ethyl acetate/n-hexane. There is obtained (S)-1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which melts above 147° C. with decomposition; [α]25D =+192.2° (in dioxan; 1%).

Workup

  1. additionThere is added dropwise
  2. customdoes not exceed 10° C
  3. stirringThe mixture is then stirred at room temperature for 45 minutes
  4. stirringthe mixture is stirred at room temperature for 30 minutes
  5. concentrationconcentrated
  6. customThe residue is purified on a 300 g silica gel column
  7. custommethylene chloride/ethanol (20:1) as the eluting agent and crystallised from a small amount of ethyl acetate/n-hexane

Sources & evidence

ORD record
ord-6c7b261c0f7340e4901d0edd16ddca8c
Source dataset
uspto-grants-1981_11
Patent number
US04299767

Reaction notes

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