Acetyl chloride → (11aS)-8-Benzyloxy-7-methoxy-2-methylidene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one

HRID 1695313Notes

Reaction equation

HRID 1695313 reaction equation
[CH2:1]=[C:2]1[CH2:6][N:5]([C:7](=[O:27])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][C:9]=2[N+:24]([O-])=O)[C@H:4]([CH:28]=O)[CH2:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(Cl)Cl.CO.C(Cl)(C)=O>C1COCC1.O>[CH3:15][O:14][C:12]1[C:11]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][C:9]2[N:24]=[CH:28][C@@H:4]3[CH2:3][C:2](=[CH2:1])[CH2:6][N:5]3[C:7](=[O:27])[C:8]=2[CH:13]=1

Participants

6

Reactant 4

HCID 6367Acetyl chlorideHCID 24489Sodium DithioniteHCID 21226129Dichloromethane methanolHCID 57570988(2S)-4-(methylene)-1-[5-methoxy-2-nitro-4-(phenylmethoxy)benzoyl]-2-pyrrolidinecarboxaldehyde

Product 1

HCID 9884692(11aS)-8-Benzyloxy-7-methoxy-2-methylidene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-oneYield 70%

Reagents, catalysts & solvents 1

HCID 21881883Oxolane--water (1/1)Solvent

Procedure

To a solution of (2S)-4-(methylene)-1-[5-methoxy-2-nitro-4-(phenylmethoxy)benzoyl]-2-pyrrolidinecarboxaldehyde (1.0 equivalent) in THF/H2O (v/v, 1.7:1, 0.03 M) was added sodium hydrosulfite (5˜8 equivalent) in portions within 2 minutes at room temperature. The mixture was further stirred for 6˜20 hours and monitored by TLC (hexanes/AcOEt 1:2 and CH2Cl2/MeOH 5:1). After the aldehyde was almost consumed, the reaction was quenched with methanol (about same volume as THF used). The solvents were removed by rotary evaporation in vacuo (temperature <40° C.) and the remainder solid was put on high vacuum to make it completely dry. The solid was suspended in anhydrous methanol (0.03 M) and AcCl (8˜10 equivalent) was added dropwise at room temperature. After stirred for 15 minutes, the cloudy solution was filtered and the solid was washed with anhydrous methanol. The clear yellow filtrate was stirred at room temperature for 1 to 2 hours and was quenched with saturated sodium bicarbonate. After most of the methanol was removed by rotary evaporation, the remainder was diluted with dichloromethane and water. The aqueous layer was extracted with AcOEt. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvents were removed and the residue was purified by flash chromatography (hexanes/AcOEt, 1:3, 1:5) to give (11aS)-7-methoxy-2-methylene-8-(phenylmethoxy)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one in 70% to 85% yield. The NMR spectra are consistent with the literature reported. MS (ESI): m/z 371.2 (M+Na)+. MS (ESI, with CH3OH): m/z 403.3 (M+CH3OH+Na)+. MS (ESI, with H2O): m/z 389.2 (M+H2O+Na)+.

Workup

  1. customAfter the aldehyde was almost consumed
  2. customthe reaction was quenched with methanol (about same volume as THF used)
  3. customThe solvents were removed by rotary evaporation in vacuo (temperature <40° C.)
  4. customcompletely dry
  5. stirringAfter stirred for 15 minutes
  6. filtrationthe cloudy solution was filtered
  7. washthe solid was washed with anhydrous methanol
  8. stirringThe clear yellow filtrate was stirred at room temperature for 1 to 2 hours
  9. customwas quenched with saturated sodium bicarbonate
  10. customAfter most of the methanol was removed by rotary evaporation
  11. additionthe remainder was diluted with dichloromethane and water
  12. extractionThe aqueous layer was extracted with AcOEt
  13. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  14. filtrationfiltered
  15. customThe solvents were removed
  16. customthe residue was purified by flash chromatography (hexanes/AcOEt, 1:3, 1:5)

Sources & evidence

ORD record
ord-681e67464f7e489bbca41eae4f0b92de
Source dataset
uspto-grants-2012_04
Patent number
US08163736B2

Reaction notes

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