Triethylamine → 2-(3,5-dichloro-1H-1,2,4-triazol-1-yl)-1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-ethanone

HRID 2096032Notes

Reaction equation

HRID 2096032 reaction equation
[Cl:1][C:2]1[N:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([OH:11])=O)[N:3]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:21]1[O:25][N:24]=[C:23]([C:26]2[N:27]=[C:28]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH2:22]1.C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl>[Cl:1][C:2]1[N:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([N:34]2[CH2:35][CH2:36][CH:31]([C:28]3[S:29][CH:30]=[C:26]([C:23]4[CH2:22][CH:21]([C:15]5[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=5[F:20])[O:25][N:24]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:11])[N:3]=1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 687435873,5-dichloro-1H-1,2,4-triazole-1-acetic acid2×HCID 687443094-[4-[4,5-Dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl]-2-thiazolyl]piperidine hydrochloride

Product 1

HCID 687436602-(3,5-dichloro-1H-1,2,4-triazol-1-yl)-1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-ethanone

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 24386Thionyl ChlorideSolvent

Procedure

A mixture of 3,5-dichloro-1H-1,2,4-triazole-1-acetic acid (i.e. the product of Example 16, Step B), (114 mg, 0.58 mmol) in thionyl chloride (5 mL) was heated at reflux for 1 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting crude acid chloride was dissolved in dichloromethane (5 mL) and added to a solution of 4-[4-[4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl]-2-thiazolyl]piperidine hydrochloride (196 mg, 0.51 mmol) and triethylamine (0.5 mL) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 3 h, diluted with dichloromethane, washed with 1 N hydrochloric acid, aqueous sodium chloride, and dried (MgSO4). The reaction mixture was concentrated under reduced pressure and further purified by medium-pressure liquid chromatography to give 80 mg of the title product as a white solid melting at 147-150° C.

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 1 h
  3. concentrationconcentrated under reduced pressure
  4. dissolutionThe resulting crude acid chloride was dissolved in dichloromethane (5 mL)
  5. washwashed with 1 N hydrochloric acid, aqueous sodium chloride
  6. dry with materialdried (MgSO4)
  7. concentrationThe reaction mixture was concentrated under reduced pressure
  8. customfurther purified by medium-pressure liquid chromatography

Sources & evidence

ORD record
ord-819c75dab34b4d0d9171cc0b48258f06
Source dataset
uspto-grants-2013_05
Patent number
US08449898B2

Reaction notes

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