Font Size: a A A

The Development Of New Drug Atomoxetine Hydrochloride For The Treatment Of Children With ADHD

Posted on:2014-09-19Degree:MasterType:Thesis
Country:ChinaCandidate:L WangFull Text:PDF
GTID:2251330425461696Subject:Pharmaceutical engineering
Abstract/Summary:PDF Full Text Request
Atomoxetine hydrochloride is the non-stimulating drug which was firstly used to treat attention deficit hyperactivity disorder(ADHD). ADHD with morbidity is about5%to7%. which pathogenesis most frequently related to the decrease of catecholamine neurotransmitters dopamine and NE flip effect. The exact therapeutic mechanism of atomoxetine hydrochloride for ADHD is not clear at present, and it is considered that the therapeutical action is related with the effect of selective inhibitor of presynaptic amine pump on the NE reuptaking, which can enhance the effect of NE flip to relieve the symptoms of ADHD, which may indirectly promote completing the and focusing attention.On the basis of the well-studied research on the literature information, this paper comprehensively considered the basic requirements on the industrialization, taking3-chloropropiophenone as raw material, and target compound is obtained through five reactions. Racemic alcohol is obtained from the synthesis of halogenate proplophenone, then racemic form is obtained by etherification, racemic amine is obtained by methylamination, finally R(-)-atomoxetine hydrochloride is obtained by the seperation of racemic amine mandelate. A.nd racemic3-chloro-phenyl propanol is obtained by the reduction of3-chloro-phenyl acetone, and the racemic either3-(o-tolyloxy)-3-phenyl-1-chloro-propane is prepared by the Mitsunobu reaction, after the amine substituting for the chlorine atom, and also separation with L(+)-mandelic acid, R-atomoxetine-S-mandelic acid salt is obtained, and then collect free base after alkalization, and finally R(-)-atomoxetine hydrochloride is obtained after hydrochlorination.The reaction conditions were optimized to obtain the optimal synthesis conditions with single factor and orthogonal experiments. The total yield of the five reaction steps reach up to16.3%, the purity of the product is more than99.5%, and none of the related substance A, B, C and S-isomer is more than0.1%(taking reference of USP in-process revision limit control as no more than0.15%).The the structure of the sample product were characterized through UV,FT-IR, NMR, MS and XRD such as reported in the literature reported; according to relative quality research on the impurity profile, the starting materials and the quality of the key intermediate were researched, the appropriate quality standards and control methods were established. Reference to the U.S. Pharmacopeia, the analysis methods of related substances and the content assay have been self-developed, and the analytical method validations have passed, which may indicating that quality of the target product can effectively controlled by the quality standards.
Keywords/Search Tags:aomoxetine hydrochloride, Mitsunobu reaction, resolution, impurityprofile
PDF Full Text Request
Related items