Diisopropylethylamine → [2-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-(4-methylene-3,4-dihydro-2H-quinolin-1-yl)-methanone

HRID 1877394Notes

Reaction equation

HRID 1877394 reaction equation
C(O[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[CH2:18])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:21]=1[O:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1C(O)=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>Cl.O1CCOCC1>[Cl:19][C:20]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:21]=1[O:22][C:23]1[C:24]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[CH2:18])[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=[CH:30][N:31]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 167959962-(2,5-Dichloro-phenoxy)-nicotinic acidHCID 67367966tert-butyl 4-methylene-3,4-dihydroquinoline-1(2H)-carboxylate

Product 1

HCID 46195420[2-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-(4-methylene-3,4-dihydro-2H-quinolin-1-yl)-methanoneYield 7%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 4-methylene-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (44.2 mg, 0.18 mmol, 1.2 equiv) in 4 M HCl in dioxane (4 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product redissolved in anhydrous DMF (1 mL). To this solution was added 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1), N-ethyldiisopropylamine (97 mg, 131 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (68 mg, 0.18 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture heated by microwave irradiation to 100° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 4.1 mg (7%) of the title compound. MS (ISP): 410.7 [M+H]+.

Workup

  1. customThe solvent was removed under reduced pressure
  2. dissolutionthe crude product redissolved in anhydrous DMF (1 mL)
  3. customRemoval of the solvent mixture
  4. customunder reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column
  5. customequipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps
  6. washa Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water

Sources & evidence

ORD record
ord-d088a38a50834ab99c31587c4c1d2348
Source dataset
uspto-grants-2012_11
Patent number
US08309734B2

Reaction notes

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