Hydrochloric Acid → 6-Methoxy-1-methyl-1-trifluoromethylisochroman

HRID 1019362Notes

Reaction equation

HRID 1019362 reaction equation
[F:1][C:2]([F:18])([F:17])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH2:14][CH2:15][OH:16])(O)[CH3:4].C(N(CC)CC)C.CS(Cl)(=O)=O.COC1C=CC(C(O)(C)C(F)(F)F)=C(CCOS(C)(=O)=O)C=1.Cl>ClCCl.CC#N>[CH3:13][O:12][C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[C:3]([CH3:4])([C:2]([F:18])([F:17])[F:1])[O:16][CH2:15][CH2:14]2

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 18401029HCID 18401029, compoundHCID 59921411HCID 59921411, compound

Product 1

HCID 102205196-Methoxy-1-methyl-1-trifluoromethylisochromanYield 73.1%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 1,1,1-trifluoro-2-[2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-propan-2-ol (5.00 g, 18.9 mmol) in dichloromethane (30 mL) was added triethylamine (9.20 mL, 66.3 mmol). The solution was cooled to 0° C. and methanesulfonyl chloride (1.61 mL, 20.8 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred 12 hours. The formation of methanesulfonic acid 2-[5-methoxy-2-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl ester is rapid and its disappearance was monitored by HPLC (retention time=4.5 minutes, Zorbax Rx-C6 column 4.6×150 mm, 40° C., 50% CH3CN/50% (0.2% Et3N, 0.1% H3PO4 aqueous pH=3.2 buffer), 1 mL/min). At the end of the reaction, the mixture was poured into 1N aqueous hydrochloric acid (30 mL) and was extracted with dichloromethane (20 mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman as an oil (3.40 g, 73%). 1H NMR (300 MHz, CDCl3) δ1.69 (s, 3), 2.85-2.90 (m, 2), 3.85 (s, 3), 3.90-3.98 (m, 1), 4.14-4.21 (m, 1), 6.72 (d, 1, J=2.6), 6.85 (dd, 1, J=8.7, 2.6), 7.31 (d, 1, J=8.7). 13C NMR (100 MHz, CDCl3) δ23.25, 29.42, 55.19, 61.37, 76.10 (q, J=27.4), 112.84, 113.43, 124.85, 125.96 (q, J=289), 127.86, 136.49, 158.98. IR 2946, 2839, 1738, 1611, 1505, 1162, 1137, 1101 cm−1. Analysis calculated for C12H13F3O2: C, 58.54; H, 5.32. Found: C, 58.27; H, 5.35.

Workup

  1. temperatureto warm to room temperature
  2. customAt the end of the reaction
  3. extractionwas extracted with dichloromethane (20 mL)
  4. dry with materialThe organic extracts were dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-9948d650f1a848b1933c19f3120f5a53
Source dataset
uspto-grants-2002_11
Patent number
US06486325B1

Reaction notes

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