Acetic Acid → (2S,4R)-1-[3-(5-Bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidine-3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

HRID 69529Notes

Reaction equation

HRID 69529 reaction equation
[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])(=[O:16])=[O:15])[CH2:11][N:10]2[C:24]([C:26]2([C:30]3[C:35]([F:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]=3)[CH2:29][NH:28][CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:38]([O-])(=O)C.[Na+].C(O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])(=[O:15])=[O:16])[CH2:11][N:10]2[C:24]([C:26]2([C:30]3[C:35]([F:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]=3)[CH2:29][N:28]([CH3:38])[CH2:27]2)=[O:25])=[O:8])[CH2:4][CH2:5]1)#[N:2]

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 712FormaldehydeHCID 517045Sodium AcetateHCID 5049666Sodium triacetoxyborohydrideHCID 71679559(2S,4R)-1-[3-(5-Bromo-3-fluoro-pyridin-2-yl)-azetidine-3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Product 1

HCID 71679560(2S,4R)-1-[3-(5-Bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidine-3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amideYield 40.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a mixture of example 13 (0.05 g, 81.8 μmol, Eq: 1.00), sodium acetate (14.8 mg, 180 μmol, Eq: 2.2) and acetic acid (10.8 mg, 10.3 μl, 180 μmol, Eq: 2.2) in dichloromethane (0.5 ml) was added at 25° C. aqueous formaldehyde solution (36%; 19.1 mg, 17.5 μl, 229 μmol, Eq: 2.8). The mixture was stirred for 45 min, then sodium triacetoxyborohydride (55.5 mg, 262 μmol, Eq: 3.2) was added in one portion at 0-5° C. The cooling bath was removed after 10 min and stirring was continued at 25° C. for further 18 h. The reaction mixture was quenched with aqueous 0.5 M NaOH-solution (2 ml), stirred for 2 min, then the layers were separated. The aqueous layer was extracted with three portions of AcOEt (each 5 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative HPLC to yield the title compound as a colorless amorphous solid (0.0206 g; 40%). m/z=626.1 [M+H]+.

Workup

  1. customThe cooling bath was removed after 10 min
  2. stirringstirring
  3. waitwas continued at 25° C. for further 18 h
  4. customThe reaction mixture was quenched with aqueous 0.5 M NaOH-solution (2 ml)
  5. stirringstirred for 2 min
  6. customthe layers were separated
  7. extractionThe aqueous layer was extracted with three portions of AcOEt (each 5 ml)
  8. washThe combined organic layers were washed with brine
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated in vacuo
  11. customThe crude material was purified by preparative HPLC

Sources & evidence

ORD record
ord-428e008081b942ec8ef1121f46cbb07f
Source dataset
uspto-grants-2014_09
Patent number
US08822505B2

Reaction notes

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