Potassium Phosphate, Tribasic → 6-Cyclopropyl-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

HRID 1777910Notes

Reaction equation

Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[CH:17]1(B(O)O)[CH2:19][CH2:18]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH:17]1([C:2]2[CH:3]=[C:4]3[C:9](=[N:10][C:11]=2[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]3)[CH2:19][CH2:18]1

Participants

Conditions

Temperature: 100 °C

Procedure

A tube was charged with 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12, 670 mg, 2.333 mmol), cyclopropylboronic acid (401 mg, 4.67 mmol), tricyclohexylphosphine (6.54 mg, 0.023 mmol), K3PO4 (1733 mg, 8.17 mmol) and dioxane (10 ml) and flushed with argon. Then Pd(OAc)2 (26.2 mg, 0.117 mmol) was added, the tube was sealed and the reaction mixture was stirred at 100° C. for 1 day. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed twice with water. The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified twice by normal phase chromatography (40 g silica gel cartridge, DCM/(DCM/(7 M NH3 in MeOH) 9/1) 100:0 to 50:50) to give the title compound as an orange solid. (UPLC-MS 3) tR 0.64 min; ESI-MS 249.2 [M+H]+.

Workup

customflushed with argon
customthe tube was sealed
temperatureThe reaction mixture was cooled to room temperature
washwashed twice with water
dry with materialThe organic phase was then dried over Na2SO4
filtrationfiltered
customevaporated
customThe crude material was purified twice by normal phase chromatography (40 g silica gel cartridge, DCM/(DCM/(7 M NH3 in MeOH) 9/1) 100:0 to 50:50)

Sources & evidence

ORD record: ord-b715c1cd32644db7b60a227d9754dd1e
Source dataset: uspto-grants-2016_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09266883B2

Reaction notes

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