2-Methoxynaphthalene → 2-Chloro-1-(6-methoxynaphthalen-2-yl)propan-1-one
Reaction equation
ClC(C1C=C(CC(C)C)C=CC=1C(C1C=CC(CC(C)C)=CC=1C(Cl)C)=O)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[CH:36][CH:35]=[CH:34]2.C(C1C=CC=CC=1)C(C)C.[Cl:51][CH:52]([CH3:56])[C:53](Cl)=[O:54]>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([C:53]([CH:52]([Cl:51])[CH3:56])=[O:54])[CH:35]=[CH:34]2Participants
Procedure
Following the procedure of Example 1, but substituting in part (a) thereof 6-methoxynaphthalene for isobutylbenzene in the reaction with the alpha-chloropropionyl chloride, there is formed 1-chloroethyl 6-methoxy-2-naphthyl ketone. Then, as in part (b) of Example 1, the 1-chloroethyl 6-methoxy-2-naphthyl ketone, in heptane, is reacted with neopentyl glycol to form the neopentyl ketal of the ketone (also named 2-(1-chloroethyl)-2-(6'-methoxynaphthyl)-5,5-dimethyl-1,3-dioxane). In step (c) this alpha-chloroketal is mixed with a solution of zinc 2-ethylhexanoate in heptane, at a temperature of from about 135° to 150° C. to distill the heptane away and to cause the rearrangement of the α-chloroketal to the 3-chloro-2,2-dimethylpropyl ester of 2-(6-methoxy-2-naphthyl)propionic acid. The resulting oil can be cooled, treated with filter aid to adsorb zinc compounds, and diluted with heptane, stirred and filtered. The filtrate can be treated with carbon and filter aid material to remove colored impurities. The chloro-ester solution, so clarified, can be mixed with aqueous base as in part (d) of Example 1 to hydrolyze the ester and to form the sodium 2-(6'-methoxy-2-naphthyl)propionate salt. Then the sodium salt intermediate product can be precipitated from the mixture by dilution with water, cooling, seeding with sodium naproxen [sodium 2-(6'-methoxy-2-naphthyl)propionate] crystals and cooled to 0° to crystallize the sodium naproxen salt from the mixture, which solid salt is filtered and washed with heptane and dried, if desired. Then, as in step (c) of Example 1, the sodium naproxen crystals can be converted to the free naproxen acid [2-(6'-methoxy-2-naphthyl)propionic acid] by dilution with water and heptane, acidified as in part (e) of Example 1, separate the aqueous and organic liquid phases and washing the organic liquid phase with an aqueous buffer solution, and the organic solvent can be distilled to leave as residue the substantially pure naproxen acid, which can be further washed and dried with nitrogen to obtain drug-quality naproxen acid for use in preparing pharmaceutical formulations thereof.
Sources & evidence
- ORD record
- ord-329f7655bbdd4d98a156a1fb2c327aa5
- Source dataset
- uspto-grants-1986_11
- Patent number
- US04623736
Reaction notes
Loading…