Tributylamine → 4-[[(R)-2-(3-Chloro-4-trifluoromethyl-phenylamino)-propyl]-(3,3-dimethoxy-propionyl)-amino]-butyric acid tert-butyl ester

HRID 2095506Notes

Reaction equation

HRID 2095506 reaction equation
[C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C@H:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([Cl:25])[CH:16]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[I-].ClC1C=CC=C[N+]=1C.[CH3:36][O:37][CH:38]([O:43][CH3:44])[CH2:39][C:40](O)=[O:41].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][N:10]([CH2:11][C@H:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([Cl:25])[CH:16]=1)[CH3:13])[C:40](=[O:41])[CH2:39][CH:38]([O:43][CH3:44])[O:37][CH3:36])([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 4

HCID 7622TributylamineHCID 1670692-Chloro-1-methylpyridinium iodideHCID 103745043,3-dimethoxypropanoic AcidHCID 670741654-[(R)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propylamino]-butyric acid tert-butyl ester

Product 1

HCID 670739484-[[(R)-2-(3-Chloro-4-trifluoromethyl-phenylamino)-propyl]-(3,3-dimethoxy-propionyl)-amino]-butyric acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of 1.25 g (3.20 mmol) of 4-[(R)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propylamino]-butyric acid tert-butyl ester (22% ee) in 25 ml CH2Cl2 was treated with a solution of 1.00 g (3.80 mmol) of 2-chloro-1-methylpyridinium iodide and 0.51 g (3.80 mmol) of 3,3-dimethoxy-propionic acid (synthesized from methyl 3,3-dimethoxy-propionate by hydrolysis with LiOH) in 5 ml of CH2Cl2. The suspension was cooled and treated at 0° C. with 1.89 ml (7.90 mmol) of tributylamine. The reaction was naturally warmed to RT over night. The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution and dried over Na2SO4 to yield 1.68 g (quantitative) of the title compound as a 61:39 mixture of the (R) and (S) diastereomers as light brown oil. MS: 511.22 (MH+, Cl).

Workup

  1. temperatureThe suspension was cooled
  2. extractionThe reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×)
  3. washThe organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution
  4. dry with materialdried over Na2SO4

Sources & evidence

ORD record
ord-708950477473489fb1f921a0834095cd
Source dataset
uspto-grants-2013_05
Patent number
US08445674B2

Reaction notes

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