Triethylamine → (R)-(-)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester

HRID 1157462Notes

Reaction equation

HRID 1157462 reaction equation
[OH:1][CH2:2][C@H:3]([CH3:32])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[N:10]([CH2:24][C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[C:9]2=[O:31].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH:28]([NH:27][C:25]([CH2:24][N:10]1[C:9](=[O:31])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([O:5][CH2:4][C@@H:3]([CH3:32])[CH2:2][O:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:7]=2)[N:12]=[C:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[O:26])([CH3:29])[CH3:30]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 59511775HCID 59511775, compound

Product 1

HCID 59511753(R)-(-)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

To a suspension of (S)-(+)-2-[6-(3-hydroxy-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (0.96 g, 2.18 mmol) in dichloromethane (100 mL) cooled to −78° C. under argon was added methanesulfonyl chloride (2.50 g, 1.7 mL, 21.90 mmol) dropwise over 5 min, followed by dropwise addition (10 min) of triethylamine (2.21 g, 3.10 mL, 21.9 mmol). The reaction mixture was warmed to −30° C. over 60 min followed by warming to room temperature over 15 min after which time the reaction was found to be complete (HPLC monitoring). The reaction mixture was diluted with ethyl acetate (300 mL), poured into ice water (100 mL) and the organic phase washed with 1N HCl (aq.) (2×200 mL), sat. NaHCO3 (aq.) (1×200 mL) and brine (1×200 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to afford (R)-(−)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester as a pale yellow solid (1.13 g, 2.18 mmol, 100%, 91% purity by LC-MS).

Workup

  1. temperatureThe reaction mixture was warmed to −30° C. over 60 min
  2. temperatureby warming to room temperature over 15 min after which time the reaction
  3. washthe organic phase washed with 1N HCl (aq.) (2×200 mL), sat. NaHCO3 (aq.) (1×200 mL) and brine (1×200 mL)
  4. dry with materialThe organic phase was dried (MgSO4)
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-af2e800845a54918b98b2ec9ffe52fbc
Source dataset
uspto-grants-2010_10
Patent number
US07807686B2

Reaction notes

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