Background and overview[1-2]
Methyl o-toluate can be widely used as an intermediate in pharmaceutical synthesis, such as the synthesis of doxepin hydrochloride. Doxepin hydrochloride is a drug used to treat depression and anxiety neurosis. Its function is to inhibit the reuptake of 5-hydroxytryptamine and norepinephrine in the central nervous system, thereby reducing the reuptake of these two neurotransmitters in the synaptic cleft. Increased concentrations exert antidepressant effects, and also have anti-anxiety and sedative effects.
Apply[1-2]
Application 1,
CN201510835666.3 discloses a synthesis method of doxepin hydrochloride using methyl o-toluate as raw material. A preparation method of doxepin hydrochloride, including the following steps:
(1) Carry out benzyl halogenation reaction between methyl o-toluic acid and N-halosuccinimide in petroleum ether solvent under light conditions to obtain methyl o-halomethyl benzoate. (Compound J), the reaction formula is as follows,
(2) Perform a substitution reaction between methyl o-halomethyl benzoate and phenol in an alcohol solvent of sodium methoxide to obtain compound H. The reaction formula is as follows,
(3) The compound H is subjected to a hydrolysis reaction to obtain compound I. The reaction formula is as follows,
(4) The compound I is cyclized in DMSO solvent under the catalysis of anhydrous aluminum chloride to obtain 6,11-dihydrodibenzo[b,e]oxeppine-11- Ketone (compound A), the reaction formula is as follows,
(5) Add magnesium powder to 6,11-dihydrodibenzo[b,e]oxepin-11-one (compound A) and 3-chloropropyl tert-butyl ether (compound B) And perform a nucleophilic addition reaction using THF and/or anhydrous ether as solvents to obtain a hydroxyl compound (compound C). The reaction formula is as follows,
(6) The hydroxyl compound is heated in a strong alkaline alcohol solvent to perform an elimination reaction to obtain an olefin compound (compound D). The reaction formula is as follows,
(7) The olefin compound is subjected to a nucleophilic substitution reaction under a hydrohalic acid to obtain a halide (compound E). The reaction formula is as follows, where X in compound E is -Cl, -Br or -I ;
(8) Perform a nucleophilic substitution reaction between the halide and dimethylamine by adding an organic lithium compound in an ether solvent to obtain doxepin (compound F).
Application 2,
CN201410514898.4 discloses a preparation method of 1-isoindolinone. (1) Weigh methyl o-toluate and dissolve it in carbon tetrachloride, add NBS and benzoyl peroxide, and perform a reflux reaction 2h. After TLC detects that the reaction is complete, cool, filter, and spin the filtrate to dryness to obtain the intermediate methyl o-bromomethyl benzoate. ⑵ Dissolve methyl o-bromomethyl benzoate in tetrahydrofuran solution, add concentrated ammonia dropwise, and stir at room temperature overnight. After TLC detection of complete reaction, spin dry. The solid was dissolved in water and ethyl acetate, extracted, and the organic phase was dried over anhydrous sodium sulfate and spun to dryness to obtain the product 1-isoindolinone. The present invention uses methyl o-toluate, NBS, benzoyl peroxide and other raw materials to synthesize compound 1-isoindolinone with a complex structure. The product has high yield, good crystallization effect and high purity. Provide high-purity standards or samples for subsequent chemical and biological experiments.
References
[1]CN201510835666.3 Synthesis method of doxepin hydrochloride using methyl o-halomethyl benzoate as raw material
[2] Preparation method of CN201410514898.41-isoindolinone
