Triethylamine → 2-[1-[(3,5-dichloro-1H-pyrazol-1-yl)acetyl]-4-piperidinyl]-N-methyl-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide

HRID 2043741Notes

Reaction equation

HRID 2043741 reaction equation
[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([OH:11])=O)[N:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][N:20]([C@H:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36][CH2:35]1)[C:21]([C:23]1[N:24]=[C:25]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:26][CH:27]=1)=[O:22].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([N:31]2[CH2:32][CH2:33][CH:28]([C:25]3[S:26][CH:27]=[C:23]([C:21]([N:20]([CH3:19])[C@H:34]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH2:37][CH2:36][CH2:35]4)=[O:22])[N:24]=3)[CH2:29][CH2:30]2)=[O:11])[N:3]=1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 65578Oxalyl chlorideHCID 67460000HCID 67460000, compound2×HCID 67463124N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride2×

Product 1

HCID 667962142-[1-[(3,5-dichloro-1H-pyrazol-1-yl)acetyl]-4-piperidinyl]-N-methyl-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Procedure

A solution of 3,5-dichloro-1H-pyrazol-1-acetic acid (70 mg, 0.36 mmol) (i.e. the product of Example 12, Step F) in dichloromethane (1 mL) and a catalytic amount of N,N-dimethylformamide (1 drop) was treated with oxalyl chloride (0.1 mL, 1.1 mmol) and stirred at ambient temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure and re-dissolved in dichloromethane (1 mL). The reaction mixture was added to a stirred suspension of N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride (i.e. the product of Example 6, Step C) (100 mg, 0.26 mmol), triethylamine (0.1 mL, 0.72 mmol), and potassium carbonate (150 mg, 1 mmol) in dichloromethane (2 mL). The reaction mixture was then heated to reflux for 2 h, and then cooled to ambient temperature. The resulting suspension was diluted with dichloromethane (10 mL), filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography using 50-100% ethyl acetate in hexanes as eluant to give 80 mg of the title product, a compound of the present invention as an oil.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. dissolutionre-dissolved in dichloromethane (1 mL)
  3. temperatureThe reaction mixture was then heated
  4. temperatureto reflux for 2 h
  5. temperaturecooled to ambient temperature
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by silica gel chromatography

Sources & evidence

ORD record
ord-6fd65119812a41d4b6621d681a516791
Source dataset
uspto-grants-2013_11
Patent number
US08586611B2

Reaction notes

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