Tetrahydrofuran → tert-butyl 1-(6-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2-fluorobenzyl)cyclopropanecarboxylate

HRID 1475664Notes

Reaction equation

HRID 1475664 reaction equation
NC1C(F)=C(C=CC=1Cl)CC1(C(OC(C)(C)C)=O)CC1.[NH2:21][C:22]1[C:23]([F:40])=[C:24]([C:36]([Cl:39])=[CH:37][CH:38]=1)[CH2:25][C:26]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]1.C1COCC1.[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([C@H:53]([C@@H:57]([CH3:62])[C:58]([F:61])([F:60])[F:59])[C:54](Cl)=[O:55])=[CH:49][CH:48]=1>O>[Cl:39][C:36]1[C:24]([CH2:25][C:26]2([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]2)=[C:23]([F:40])[C:22]([NH:21][C:54](=[O:55])[C@H:53]([C:50]2[CH:49]=[CH:48][C:47]([Cl:46])=[CH:52][CH:51]=2)[C@@H:57]([CH3:62])[C:58]([F:59])([F:60])[F:61])=[CH:38][CH:37]=1

Participants

6

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 58288266(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl chlorideHCID 67958472Tert-butyl 1-(3-amino-6-chloro-2-fluorobenzyl)cyclopropanecarboxylateHCID 68007253Tert-butyl 1-(3-amino-4-chloro-2-fluorobenzyl)cyclopropanecarboxylate

Product 1

HCID 86667525tert-butyl 1-(6-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2-fluorobenzyl)cyclopropanecarboxylate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

33.0 mg of a mixture of tert-butyl 1-(3-amino-4-chloro-2-fluorobenzyl)cyclopropanecarboxylate and tert-butyl 1-(3-amino-6-chloro-2-fluorobenzyl)cyclopropanecarboxylate (Example 24A/25A, ratio about 1.5:1) were dissolved in 0.16 ml of abs. THF, the solution was cooled to −10° C. and a solution of 38 mg (0.132 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl chloride in about 0.1 ml of abs. THF was added dropwise. After the addition had ended, the mixture was slowly warmed to RT, and after 2 h, water was added. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with 1 N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The product mixture obtained was separated by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 23.2 mg (38% of theory) of tert-butyl 1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2-fluorobenzyl)cyclopropanecarboxylate (Example 186A) and 18.7 mg (31% of theory) of tert-butyl 1-(6-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}-2-fluorobenzyl)cyclopropanecarboxylate (Example 187A).

Workup

  1. additionAfter the addition
  2. extractionThe mixture was extracted three times with ethyl acetate
  3. washthe combined organic phases were washed with 1 N hydrochloric acid and saturated sodium chloride solution
  4. dry with materialdried over magnesium sulphate
  5. concentrationconcentrated under reduced pressure
  6. customThe product mixture obtained
  7. customwas separated by preparative RP-HPLC (mobile phase acetonitrile/water)

Sources & evidence

ORD record
ord-1d7d7dfb783f42d1ac002924a4adc955
Source dataset
uspto-grants-2015_04
Patent number
US09018258B2

Reaction notes

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