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 848530Notes

Reaction equation

HRID 848530 reaction equation
C(Cl)(Cl)=O.NC1C=CC2N(C)[C:14](=[O:17])[C@H:13](C)[N:12]=C(C3C=CC=CC=3F)C=2C=1Cl.[Cl:28][C:29]1[C:34]2[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])=[N:36][C@@H:37]([CH3:42])[C:38](=[O:41])[N:39]([CH3:40])[C:33]=2[CH:32]=[CH:31][C:30]=1[N:50]=[C:51]=[O:52].NCCO>ClCCCl.C(N(CC)CC)C>[Cl:28][C:29]1[C:34]2[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])=[N:36][C@@H:37]([CH3:42])[C:38](=[O:41])[N:39]([CH3:40])[C:33]=2[CH:32]=[CH:31][C:30]=1[NH:50][C:51]([NH:12][CH2:13][CH2:14][OH:17])=[O:52]

Participants

7

Reactant 4

HCID 700EthanolamineHCID 6371PhosgeneHCID 53915665(S)-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanateHCID 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 2

HCID 111,2-DichloroethaneSolvent2×HCID 8471TriethylamineSolvent

Procedure

A solution of 2 g 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-benzodiazepin-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-8630b3c443e14462afe9021e5ba3328c
Source dataset
uspto-grants-1981_10
Patent number
US04296031

Reaction notes

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