Lithium Hydroxide → HCID 178437771, compound

HRID 1620308Notes

Reaction equation

HRID 1620308 reaction equation
[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[C:22]([NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1)=[CH:26][CH:25]=2.[Li+].[OH-]>C1COCC1>[CH:33]1([CH2:32][O:31][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41])[C:21]([CH2:20][C:6]2[C:7]4[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=4)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=2[OH:17])=[CH:30]3)[CH2:34][CH2:35]1

Participants

5

Reactant 3

HCID 3939Lithium HydroxideHCID 68182271N-(2-(3-(Chloromethyl)-6-(cyclopropylmethoxy)quinolin-2-ylamino)ethyl)acetamide hydrochloride2×HCID 178437769HCID 178437769, compound

Product 1

HCID 178437771HCID 178437771, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
160 °C

Procedure

To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 47022 (128 mg, 0.55 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-(2-(3-(chloromethyl)-6-(cyclopropylmethoxy)quinolin-2-ylamino)ethyl)acetamide hydrochloride SLA 47096B (211 mg, 0.55 mmol) and 2 N aq. LiOH solution (0.55 mL, 1.10 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was then removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 27 mg of N-(2-(6-(cyclopropylmethoxy)-3-((1-ethyl-3-hydroxy-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to give N-(2-(6-(cyclopropylmethoxy)-3-((1-ethyl-3-hydroxy-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide dihydrochloride 87 as a brown solid (28.9 mg, 8% yield).

Workup

  1. temperatureAfter cooling to RT
  2. customTHF was then removed at 40° C. under vacuum
  3. washwashed with brine (10 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customPurification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7)
  8. customfollowed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5)

Sources & evidence

ORD record
ord-b4772243387c489d88c4318b99839692
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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