Hydrochloric Acid → HCID 67386579, compound

HRID 1971905Notes

Reaction equation

HRID 1971905 reaction equation
[ClH:1].Cl.C([O:5][C:6](=O)[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[N:17]=[N:18][C:19]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[CH:21]=2)[CH2:11][CH2:10]1)C.[Li+].[OH-].Cl.[CH3:43][NH:44][CH3:45].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C1COCC1.CO.O.O.CCOC(C)=O.C(O)(=O)C.CN(C=O)C.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[CH2:35]([C:19]1[N:18]=[N:17][C:16]([O:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]([N:44]([CH3:45])[CH3:43])=[O:5])[CH2:14][CH2:13]2)=[CH:21][C:20]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:26][CH:27]=1)[CH2:36][CH2:37][CH3:38]

Participants

13

Reactant 6

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 10473Dimethylamine, hydrochlorideHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67373658HCID 67373658, compound

Product 1

HCID 67386579HCID 67386579, compoundYield 95.9%

Reagents, catalysts & solvents 6

HCID 176Acetic AcidSolvent2×HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 21892291Methanol tetrahydrofuran waterSolventHCID 22728543Water ethylacetateSolvent2×

Conditions

Temperature
100 °C

Procedure

To a solution of 3-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidin-1-yl}-propionic acid ethyl ester dihydrochloride (Example 15, 1.0 mmol, 583 mg) in THF-MeOH—H2O (1:1:1, 3 mL) was added LiOH (20 mmol, 480 mg). The mixture was stirred at 100° C. for 10 min. The mixture was then diluted with water/EtOAc and neutralized with acetic acid. The organic layers combined, dried, and condensed in vacuo, and the residue was dissolved in DMF (2 mL). Dimethylamine hydrochloride (3.0 mmol, 245 mg), HBTU (3.0 mmol, 1.14 g), DIEA (3.0 mmol, 0.53 mL) were added to the mixture, and the mixture was stirred at 100° C. for 2 hours. It was then diluted with water/EtOAc and neutralized with acetic acid. The organic layers were combined, dried, and condensed in vacuo, and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N ammonia in MeOH) to give a colorless sticky solid, which was dissolved in DCM (2 mL), 2N HCl in ether (2 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (279 mg). LCMS: m/z 510 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.31-7.35 (2H, m), 7.01-7.07 (3H, m), 5.46-5.52 (1H, m), 4.37-4.43 (1H, m), 3.35-3.50 (5H, m), 3.03 (6H, s), 2.87-2.95 (5H, m), 2.20-2.35 (4H, m), 1.96-2.03 (2H, m), 1.78-1.84 (2H, m), 1.27-1.63 (8H, m), 1.20-1.24 (2H, m), 0.80 (3H, t).

Workup

  1. customdried
  2. customcondensed in vacuo
  3. stirringthe mixture was stirred at 100° C. for 2 hours
  4. customdried
  5. customcondensed in vacuo
  6. customthe residue was purified by silica gel chromatography (DCM to DCM+10% 2N ammonia in MeOH)
  7. customto give a colorless sticky solid, which
  8. waitkept at room temperature for 10 min
  9. customcondensed
  10. customtriturated with hexanes

Sources & evidence

ORD record
ord-7a42211582624862821d7a188b570df0
Source dataset
uspto-grants-2013_04
Patent number
US08431575B2

Reaction notes

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