Triethylamine → (1S,2R,3S,4S,5R,6R)-2-[(Tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid

HRID 2173012Notes

Reaction equation

HRID 2173012 reaction equation
C(N(CC)CC)C.[C:8]([O:12][C:13](ON=C(C1C=CC=CC=1)C#N)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[NH2:27][C@@:28]1([C:48]([OH:50])=[O:49])[C@H:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[C@@H:32]([OH:44])[C@@H:31]2[C@H:29]1[C@H:30]2[C:45]([OH:47])=[O:46]>O1CCOCC1.O>[C:8]([O:12][C:13]([NH:27][C@@:28]1([C:48]([OH:50])=[O:49])[C@H:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[C@@H:32]([OH:44])[C@@H:31]2[C@H:29]1[C@H:30]2[C:45]([OH:47])=[O:46])=[O:14])([CH3:11])([CH3:10])[CH3:9]

Participants

6

Reactant 3

HCID 8471Triethylamine2×HCID 938652-(tert-Butoxycarbonyloxyimino)-2-phenylacetonitrile2×HCID 86695987(1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride

Product 1

HCID 69676136(1S,2R,3S,4S,5R,6R)-2-[(Tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acidYield 92%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
50 °C

Procedure

Triethylamine (212.80 mL, 154.49 g, 1.53 mol) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (125.33 g, 508.90 mmol) are added sequentially to a suspension of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (140 g, 339 mmol) in 1,4-dioxane (203.56 mL), and water (0.6 mL/mmol-pure-LR, 203.56 mL), at ambient temperature. After 4.5 hours, add additional 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (25.07 g, 101.78 mmol) and triethylamine (23.64 mL, 17.17 g, 169.63 mmol) to the reaction and stir at 50° C. overnight. Cool to 23° C., dilute with water (500 mL), and wash with methyl tert-butyl ether (6×500 mL). Dilute the aqueous phase with 10% aq. HCl (300 mL; final pH=2) and extract with ethyl acetate (2×500 mL). The ethyl acetate extracts are dried over MgSO4 and concentrated in vacuo to yield the title compound (148.3 g, 92% yield).

Workup

  1. customto the reaction
  2. temperatureCool to 23° C.
  3. washwash with methyl tert-butyl ether (6×500 mL)
  4. additionDilute the aqueous phase with 10% aq. HCl (300 mL
  5. extractionfinal pH=2) and extract with ethyl acetate (2×500 mL)
  6. dry with materialThe ethyl acetate extracts are dried over MgSO4
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-66441c8f28ff4f8b936ad08cdfac5eb5
Source dataset
uspto-grants-2015_06
Patent number
US09056844B2

Reaction notes

Loading…