Acetic Acid → 4-[(R)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propylamino]-butyric acid tert-butyl ester

HRID 2095505Notes

Reaction equation

HRID 2095505 reaction equation
[C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.Cl[C:12]1[CH:13]=[C:14]([NH:22][C@H:23]([CH3:26])[CH2:24]O)[CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19].C([N:29]([CH2:32][CH3:33])CC)C.[C:34]([O:38]C(=O)CCCN)([CH3:37])([CH3:36])[CH3:35].[ClH:45].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(Cl)Cl>CCOC(C)=O.CCCCCCC>[C:34]([O:38][C:1](=[O:5])[CH2:2][CH2:33][CH2:32][NH:29][CH2:24][C@H:23]([NH:22][C:14]1[CH:15]=[CH:16][C:17]([C:18]([F:21])([F:20])[F:19])=[C:12]([Cl:45])[CH:13]=1)[CH3:26])([CH3:37])([CH3:36])[CH3:35]

Participants

12

Reactant 10

HCID 176Acetic AcidHCID 313Hydrochloric AcidHCID 679Dimethyl SulfoxideHCID 6344Dichloromethane3×HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 7020335Tert-butyl 4-aminobutanoateHCID 67074173(R)-2-(3-Chloro-4-trifluoromethyl-phenylamino)-propan-1-ol

Product 1

HCID 670741654-[(R)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propylamino]-butyric acid tert-butyl esterYield 94%

Reagents, catalysts & solvents 1

HCID 21899848Ethylacetate heptaneSolvent

Procedure

To a solution of 0.36 ml (4.10 mmol) of oxalyl chloride in 10 ml CH2Cl2 at −50 to −60° C. was added a solution of 0.60 ml (8.50 mmol) dimethylsulfoxide in 2.4 ml of CH2Cl2 within 10 min. The solution was stirred for 5 min and a solution of 0.90 (3.50 mmol) (R)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propan-1-ol (22% ee) in 10 ml of CH2Cl2 was added within 10 min. The mixture was stirred for 15 min and 2.47 ml (17.70 mmol) of triethylamine were added within 20 min. The suspension was stirred for 75 min and slowly warmed to 0° C. (complete oxidation followed by TLC, SiO2, EtOAc:n-heptane 1:1). 0.73 g (3.70 mmol) of 4-aminobutyric acid tert-butyl ester; hydrochlorid was added and 0.41 ml (7.10 mmol) of acetic acid to adjust the pH to 5 followed by 0.85 g (3.90 mmol) of sodium triacetoxyborohydride. After 5 min at 0° C. and 1.5 h at RT, the reaction was poured on a solution of sat. aq. NaHCO3 solution and extracted with EtOAc (3 times). The organic phases were washed with a solution of 10% aq. NaCl solution. The combined organic phases were dried over Na2SO4 and the solvent was removed under vacuum to give 1.31 g (94%) of the title compound as a 61:39 mixture of the (R) and (S) diastereomers as orange oil. MS: 395.17 (MH+, Cl).

Workup

  1. stirringThe mixture was stirred for 15 min
  2. stirringThe suspension was stirred for 75 min
  3. waitAfter 5 min at 0° C.
  4. extractionextracted with EtOAc (3 times)
  5. washThe organic phases were washed with a solution of 10% aq. NaCl solution
  6. dry with materialThe combined organic phases were dried over Na2SO4
  7. customthe solvent was removed under vacuum

Sources & evidence

ORD record
ord-a2cdb1319eb84d418af8a9f6800a0cb7
Source dataset
uspto-grants-2013_05
Patent number
US08445674B2

Reaction notes

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