Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof
a technology of venlafaxine and hydrochloride, which is applied in the preparation of amino-hyroxy compounds, organic compounds, organic chemistry, etc., can solve the problem of not describing whether venlafaxine so obtained is solid
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example 1
[0061]Sodium hydroxide, 32% aq. solution (10.0 grams, 80.0 mmol) was added to a stirred solution of venlafaxine hydrochloride (20.0 grams, 63.7 mmol) in water (100 mL) in an ice-water bath. The mixture was stirred in an ice / water bath for about 30 min and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure at about 50-60° C. (water bath). The residue was dissolved in boiling hexane (50 mL) and cooled in a freezer (−18° C).
[0062]The crystals so obtained were filtered off, washed with cold hexane (20 mL) and dried under reduced pressure to give 15.5 grams (87.7%) of venlafaxine as white crystals with about 99.3% purity by HPLC, mp 78.3-79.5° C.
example 2
Preparation of a Crystalline Venlafaxine Free Base From N,N-didesmethyl Venlafaxine Hydrochloride
[0063]
[0064]Sodium hydroxide, 32% aq. solution (2.75 gram, 0.022 mol) was added to a stirred solution of N,N-didesmethyl venlafaxine hydrochloride (5.72 gram, 0.02 mol) in water in water (13 mL) at room temperature. Formic acid, 88.5% aq. solution (4.16 gram, 0.08 mol) and formaldehyde solution 35.8% aq. solution (3.7 gram, 0.044 mol) were added to this emulsion. The obtained mixture was stirred under reflux conditions during 8 hours cooled to room temperature, adjusted to pH˜11 with 32% aq. solution of sodium hydroxide and extracted with heptane (100 mL).
[0065]An organic extract was washed with water (20 mL), dried over sodium sulfate and evaporated two volumes and filtered to give crystalline venlafaxine base.
example 3
Preparation of Venlafaxine Base
[0066]N,N-didesmethyl venlafaxine (20 mmole) was added to water (480 mL), formic acid (88.5%, 5.2 grams, ˜100 mmole), formaldehyde (35.8%, 5 grams, 62 mmole) at room temperature. The obtained mixture was stirred under reflux conditions during 21 hours and cooled to room temperature. The pH was adjusted to about 11 with 32% aqueous solution of NaOH. Potassium hydroxide can be equivalently used to adjust to pH to about 11. The pH-adjusted mixture was extracted with toluene (50 mL×5).
[0067]The combined organic phages were washed with water (50 mL), dried over sodium sulfate and evaporated to dryness to give crystalline venlafaxine base (5.4 grams, 98%). The purity determined by HPLC was about 99.5%. The material can be crystallized from hexane, pentane, petroleium-ether and the like. The melting point of crystalline venlafaxine base ranges from 78.3-79.5° C.
[0068]The present invention provides a process for the purification o...
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