2-Bromopyridine → 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-1-pyridin-2-yl-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

HRID 242338Notes

Reaction equation

HRID 242338 reaction equation
Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(N(CC)C(C)C)(C)C>>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:28])[F:29]

Participants

4

Reactant 3

HCID 79732-BromopyridineHCID 81531DiisopropylethylamineHCID 57495351HCID 57495351, compound2×

Product 1

HCID 574953506-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-1-pyridin-2-yl-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidineYield 25.1%

Conditions

Temperature
160 °C

Procedure

To a glass vial was added 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride (prepared using step 1 of example 91 from intermediate 13) (75 mg, 0.16 mmol), 2-bromopyridine (1 mL, 10.25 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol). The vial was capped and the mixture heated in the microwave at 160° C. for 20 min. Purification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HCO3 MP to give 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-1-pyridin-2-yl-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a light brown solid (19 mg, 25% yield) 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.24-2.44 (m, 2 H) 2.92 (t, 2 H) 3.47-3.69 (m, 5 H) 3.77-3.85 (m, 1H) 3.88-3.93 (m, 3 H) 4.12-17 (m, 2 H) 5.73-5.81 (m, 1 H) 6.40-6.52 (d, 1 H) 6.56-6.58 (m, 1 H) 7.43-7.54 (m, 1 H) 7.77-7.84 (m, 1 H) 8.02-8.09 (m, 1 H) 8.13-8.20 (m, 1 H) 8.61-8.66 (m, 1 H) LCMS: [M+H]+=473.0, Rt(4)=0.85 min.

Workup

  1. customThe vial was capped
  2. customPurification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HCO3 MP

Sources & evidence

ORD record
ord-5d367c06c60c488581820a60f8501f75
Source dataset
uspto-grants-2014_02
Patent number
US08653092B2

Reaction notes

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