2-Pyrrolidone → 4-(2-Chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one

HRID 69559Notes

Reaction equation

HRID 69559 reaction equation
[CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][N:6]2[N:5]=1.[Cl:16][C:17]([F:28])([F:27])[CH2:18][CH:19]1[CH2:23][N:22]([CH2:24]Cl)[C:21](=[O:26])[CH2:20]1.N1CCCC1=O.S1C=NN2C=CN=C12>O1CCOCC1.[Cl-].[Cl-].[Zn+2].O>[Cl:16][C:17]([F:27])([F:28])[CH2:18][CH:19]1[CH2:23][N:22]([CH2:24][C:11]2[N:6]3[C:7]([S:8][C:4]([CH2:3][O:2][CH3:1])=[N:5]3)=[N:9][C:10]=2[C:12]([F:15])([F:13])[F:14])[C:21](=[O:26])[CH2:20]1

Participants

8

Reactant 4

HCID 120252-Pyrrolidone2×HCID 18625232Imidazo(2,1-b)(1,3,4)thiadiazoleHCID 671170844-(2-Chloro-2,2-difluoroethyl)-1-(chloromethyl)pyrrolidin-2-oneHCID 67117085Imidazo (2,1-b)-1,3,4-thiadiazole, 2-(methoxymethyl)-6-(trifluoromethyl)-

Product 1

HCID 529115564-(2-Chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-oneYield 74%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
85 °C

Procedure

To a hot solution (80° C.) of ZnCl2 (0.23 g, 1.69 mmol, 10 mol %) and 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a28 (4 g, 16.96 mmol) in dioxane (200 ml) is added a solution of 4-(2-chloro-2,2-difluoroethyl)-1-(chloromethyl)pyrrolidin-2-one a18 in dioxane (5 ml). The reaction mixture is heated at 85° C. for 5 days, then a further 2 g of pyrrolidinone a18 is added in one portion and the reaction mixture is kept under agitation at 90° C. for 1 day. A further addition of pyrrolidinone a18 (2 g) in order to insure complete conversion of compound a28 and further heating of the reaction mixture at reflux for 3 days increased significatively the conversion of imidazo[2,1-b][1,3,4]thiadiazole a28. After cooling and hydrolysis (250 ml of water), the crude mixture is extracted by CH2Cl2 (2×250 ml). The cumulated organic layers are dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified over silicagel (eluent: CH2Cl2/MeOH/NH4OH 99/1/0.1) to afford 4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one 4.

Workup

  1. temperaturefurther heating of the reaction mixture
  2. temperatureat reflux for 3 days
  3. temperatureAfter cooling
  4. extractionthe crude mixture is extracted by CH2Cl2 (2×250 ml)
  5. dry with materialThe cumulated organic layers are dried over MgSO4
  6. filtrationfiltered
  7. customcondensed under reduced pressure
  8. customThe residue is purified over silicagel (eluent: CH2Cl2/MeOH/NH4OH 99/1/0.1)

Sources & evidence

ORD record
ord-0449c6b96d814aa493b8c1679b9734d1
Source dataset
uspto-grants-2014_09
Patent number
US08822508B2

Reaction notes

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