Citric Acid → trans-2-[N'-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(S)-pyrrolidin-1-carboxylic acid tert-butyl ester

HRID 2276508Notes

Reaction equation

HRID 2276508 reaction equation
[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH:33]1[CH:34]=[CH:35][C:36]2[N:41](O)[N:40]=[N:39][C:37]=2C=1.[C:43]([O:47][C:48](N(C([C@@H]1CCCN1)=O)N)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:71]>CN(C)C=O>[C:43]([O:47][C:48]([N:41]1[CH2:33][CH2:34][CH2:35][C@H:36]1[C:37]([NH:39][NH:40][C:18]([C@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])=[O:71])=[O:49])([CH3:46])([CH3:45])[CH3:44]

Participants

8

Reactant 6

HCID 311Citric AcidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68761009HCID 68761009, compoundHCID 71283665HCID 71283665, compound

Product 1

HCID 86719958trans-2-[N'-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(S)-pyrrolidin-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a clear solution of trans-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (15 gm, 0.054 mol) in N,N-dimethyl formamide (150 ml), was added EDC hydrochloride (15.57 gm, 0.082 mol) followed by HOBt (11.0 gm, 0.082 mol) at about 25° C. to 35° C. under stirring. The reaction mixture was stirred for 15 minutes and a solution of (S)—N-tert-butoxycarbonyl-pyrrolidin-2-carboxylic acid hydrazide (14.93 gm, 0.065 mol) dissolved in N,N-dimethyl formamide (75 ml), followed by N,N-di-isopropyl ethylamine (28.4 ml, 0.163 mol) were added. The reaction mixture was stirred at a temperature between 25° C. to 35° C. for 16 hours. The reaction mixture was poured under stirring into 10% aqueous citric acid solution (2250 ml). The resulting mixture was extracted with diethyl ether (1000 ml×3). Combined organic layer was washed with water (1000 ml) followed by brine solution (500 ml) and dried over sodium sulfate. Concentration of organic layer under vacuum afforded the crude residue in 13 gm quantity. The residue was purified using silica gel column chromatography to provide the product (trans-2-[N′-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(S)-pyrrolidin-1-carboxylic acid tert-butyl ester) in 6.3 gm quantity as a white powder.

Workup

  1. stirringThe reaction mixture was stirred for 15 minutes
  2. additionwere added
  3. stirringThe reaction mixture was stirred at a temperature between 25° C. to 35° C. for 16 hours
  4. additionThe reaction mixture was poured
  5. extractionThe resulting mixture was extracted with diethyl ether (1000 ml×3)
  6. washCombined organic layer was washed with water (1000 ml)
  7. dry with materialdried over sodium sulfate
  8. customConcentration of organic layer under vacuum afforded the crude residue in 13 gm quantity
  9. customThe residue was purified

Sources & evidence

ORD record
ord-73ff11ef7f2e45e386a50f6591d70c3f
Source dataset
uspto-grants-2015_09
Patent number
US09132133B2

Reaction notes

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