Chloroform → 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one

HRID 242335Notes

Reaction equation

HRID 242335 reaction equation
[N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]=2[C:4]([O:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:13]2)=[N:3][CH:2]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(Cl)(Cl)Cl.Br[C:60]1[CH:61]=[C:62]([C:68]([F:71])([F:70])[F:69])[C:63]([O:66][CH3:67])=[N:64][CH:65]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:67][O:66][C:63]1[N:64]=[CH:65][C:60]([N:9]2[CH2:8][CH2:7][C:6]3[N:1]=[CH:2][N:3]=[C:4]([O:11][C@H:12]4[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:13]4)[C:5]=3[CH2:10]2)=[CH:61][C:62]=1[C:68]([F:71])([F:69])[F:70]

Participants

7

Reactant 5

HCID 6212ChloroformHCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 533931825-Bromo-2-methoxy-3-(trifluoromethyl)pyridine2×HCID 574953481-[(S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-propan-1-one

Product 1

HCID 574952871-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-oneYield 33.3%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
150 °C

Procedure

1-[(S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-propan-1-one (47.8 mg, 0.173 mmol), X-Phos (28 mg, 0.059 mmol) and Pd2(dba)3.CHCl3 (17.90 mg, 0.017 mmol) were combined and flushed with argon during several min before addition of degassed dioxane. 5-Bromo-2-methoxy-3-trifluoromethyl-pyridine (intermediate 1) (54.5 mg, 0.213 mmol) and Cs2CO3 (113 mg, 0.346 mmol) were then added to the reaction mixture and the resulting mixture flushed with argon and heated at 150° C. for 30 min. in a sealed tube. The reaction mixture was cooled to rt, filtered over Hyflo and evaporated. Purification by preparative reverse phase Gilson HPLC and subsequent neutralization of the combined fractions over PL-HCO3 MP gave 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one (26 mg, 33% yield) 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 0.94-1.00 (m, 3H) 2.05-2.17 (m, 4H) 2.95-3.0 (m, 2H) 3.45-3.97 (m, 9H) 4.07-4.11 (m, 2H) 5.58-5.72 (m, 1H) 7.81-7.86 (m, 1H) 8.18-8.23 (m, 1H) 8.62 (s, 1H). MS: [M+H]+=452.2, Rt(1)=1.74 min.

Workup

  1. customflushed with argon during several min before addition of degassed dioxane
  2. customthe resulting mixture flushed with argon
  3. temperatureThe reaction mixture was cooled to rt
  4. filtrationfiltered over Hyflo
  5. customevaporated
  6. customPurification by preparative reverse phase Gilson HPLC and subsequent neutralization of the combined fractions over PL-HCO3 MP

Sources & evidence

ORD record
ord-70182c6b2cb04384b043c470274152d6
Source dataset
uspto-grants-2014_02
Patent number
US08653092B2

Reaction notes

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