- A facile synthesis of epinastine HCl via dehydroepinastine intermediate
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Epinastine is a second generation histamine H1 receptor antagonist used as a non-sedative antiallergic drug. When given orally, epinastine poorly penetrates blood-brain barrier (BBB) and appears to be free of cardiac toxicity as compared to other antihistamine drugs. A couple of synthetic approaches for epinastine HCl have been reported so far. They hold several problems such as explosive, highly toxic or expensive reagents. Moreover, they usually do not offer concise synthetic steps. In our synthesis shown here, a commonly used starting material, 6-(chloromethyl)-11H-dibenzo[b,e]azepine is treated with cyanamide to afford dehydroepinastine (14) in significantly high yield, which is subsequently reduced in the presence of aqueous HCl to give epinastine HCl in only two steps (75% overall yield for two steps). The problems associated with the reported processes such as using toxic and dangerous chemicals, lengthy synthetic steps or low overall product yields can be overcome by utilizing this new route. We believe our synthetic scheme might provide a breakthrough to reduce the cost of the production of epinastine HCl.
- Park, Sang Won,Kang, Han Eol,Yun, Wheesahng,Lee, Sang Yeul,Nam, Tae-gyu
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- Novel method of preparing Epinastine
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The present invention relates to a novel manufacturing method for synthesizing an anti-histamine pharmaceutical medicine, epinastine. The novel manufacturing method for synthesizing epinastine according to the present invention has fewer synthesizing steps than a conventional epinastine manufacturing method, and is a safe synthesis method, thereby being expected to be used for inexpensively synthesizing the anti-histamine pharmaceutical medicine, epinastine by the manufacturing method, and supplying the same to the market.COPYRIGHT KIPO 2020
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Paragraph 0068; 0081; 0086-0090; 0098; 0100
(2020/05/13)
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- A synthesis method of epinastine hydrochloride
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The invention discloses a synthesis method for epinastine hydrochloride. With a compound (6-aminomethyl-6,11-dihydro-5H-dibenzo [b, e] azepine maleate), shown in the formula II, being the initial raw material, epinastine hydrochloride is synthesized. By the utilization of the synthesis method for epinastine hydrochloride, epinsastine hydrochloride can be effectively synthesized, and the method has the advantages of being high in synthesis efficiency, safe in production, simple in technology operation, short in production period and the like and is more suitable for large-scale and industrialized production of epinastine hydrochloride.
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- Synthesis method of epinastine hydrochloride
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The invention discloses a synthesis method of epinastine hydrochloride and relates to the technical field of medicines. The synthesis method comprises the following steps of: adopting 6-cyano-6,111H-dibenzo[b,e]azacycloheptatriene as a raw material, under the existence of RaneyNi, adopting methanol solution of ammonia as a solvent, introducing hydrogen to generate reduction reaction, and then obtaining 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e]azacycloheptatriene; leading the 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e]azacycloheptatriene and cyanogen bromide to generate cyclization reaction, then using alkaline for neutralization, and obtaining 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5a]azacycloheptatriene; leading the 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5a]azacycloheptatriene and hydrochloric acid to form a salt, and obtaining the epinastine hydrochloride. The synthesis method disclosed by the invention has the beneficial effects that in the reduction step, the RaneyNi is adopted as a catalyst, catalytic hydrogenation reaction is carried out in the methanol solution of the ammonia, the reaction conditions are moderate, the reaction time is shorter, the yield of reduction products can reach 90% or more, the whole synthesis process is stable, the reaction steps are simple, the consumed time is short and the prepared epinastine hydrochloride is high in purityand yield.
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Paragraph 0027; 0030-0031; 0035-0036; 0040-0041; 0045-0046
(2018/09/08)
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- Synthetic method of epinastine hydrochloride
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The invention discloses a synthetic method of epinastine hydrochloride. The synthetic method comprises the following steps: enabling a substance A to react with a substance B to obtain a substance C; enabling the substance C to be subjected to ring closing reaction with polyphosphoric acid to obtain a substance D; enabling the substance D to react with a de-protection reagent to obtain a substance E; enabling the substance E to react with cyanogen bromide to obtain epinastine and then salifying with hydrochloric acids to obtain the epinastine hydrochloride. The synthetic method disclosed by the invention is easily-available in raw materials, mild in reaction conditions, low in energy consumption, low in production cost, simple to operate, short in preparation period and suitable for large-scale industrial production; the prepared epinastine hydrochloride is high in purity and relatively high in yield in each step of reaction.
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- NOVEL CRYSTAL MODIFICATION OF EPINASTINE OR SALTS THEREOF AND PROCESS FOR PREPARATION THEREOF
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The present invention provides novel crystalline forms of 3-amino-9,13b-dihydro-lH- dibenzo[c,f]imidazo[l55-a] azepine or salts thereof and process for preparation thereof.
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Page/Page column 25
(2009/06/27)
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- New tetracyclic guanidine derivatives with H1-antihistaminic properties. Chemistry of epinastine
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A series of new tetracyclic guanides were synthesized by various methods. Specific binding of the described compounds to histamine-1 and histamine-2 receptors was determined. The compound 3-amino-9, 13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine (epinastine, WAL 801) combines high selectivity with high affinity for the H1 receptor and was selected from the compounds studied for further pharmacological and clinical investigations. Experimentally determined physicochemical parameters (pk(a)-value, partition coefficient) and the hydrogen-bonding ability of epinastine are indications that this compound will not easily cross the blood-brain barrier. This explains the absence of CNS side-effects of epinastine in pharmacological and clinical studies.
- Walther,Daniel,Bechtel,Brandt
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p. 440 - 446
(2007/10/02)
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- FUSED DIBENZO IMIDAZOLO COMPOUNDS, COMPOSITIONS AND USE
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This invention relates to a compound of the formula wherein R1, R2, R3, and R4, which may be the same or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy group of from 1 to 6 carbon atoms; R5 and R6, which may be the same or different, each represent a hydrogen atom, an alkyl group of from 1 to 6 carbon atoms, or an alkenyl group of from 3 to 6 carbon atoms, or R5 and R6 together with the nitrogen atom to which they are attached represent a pyrrolidino, piperidino, or morpholino group; and X represents oxygen, sulfur, or a methylene group, or a non-toxic, pharmacologically acceptable acid addition salt thereof, or a racemate, enantiomer, or mixture of enantiomers thereof. The compounds of Formula I are useful in pharmaceutical compositions for treating bronchial asthma and allergic bronchitis
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