- Epinastine hydrochloride intermediate and synthesis method thereof
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The invention provides a compound shown in the formula II; the compound is used as a raw material or an intermediate for synthesizing epinastine hydrochloride, cyanogen bromide is not needed in the synthesis process, hydrogen sulfide or/and methyl mercaptan is/are not generated in the synthesis process, the operation safety is improved, the environmental protection pressure is reduced, and safetyproduction and environmental protection requirements are met. The synthetic method disclosed by the invention is short in time, the reaction can be completed within 10 hours in total in two steps, andthe synthetic method has obvious advantages in industrial production, is high in yield and is suitable for industrial production.
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Paragraph 0064-0068
(2020/07/28)
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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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Paragraph 0109; 0111; 0112; 0113; 0117
(2018/12/13)
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- Epinastine synthetic method
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The invention discloses a method for synthesizing epinastine. The method comprises the following steps: (1) reacting 6-halomethylmorphanthridine with hexamine in an organic solvent, thereby obtaining a 6-halomethylmorphanthridine quaternary ammonium salt; (2) dissolving the 6-halomethylmorphanthridine quaternary ammonium salt in the organic solvent to carry out an acid hydrolysis reaction, thereby obtaining 6-halomethylmorphanthridine hydrochloride; (3) reducing the product 6-halomethylmorphanthridine hydrochloride obtained in the step (2) by using a reducing agent, thereby obtaining 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]aza-cycloheptatrien; and (4) adding cyanogen bromide to carry out a ring-closure reaction, thereby obtaining the epinastine. According to the synthetic method disclosed by the invention, use of high-price and flammable lithium aluminum hydride or aluminum hydride is avoided, use of virulent sodium cyanide is avoided, and the security risk and production cost are effectively reduced. The method disclosed by the invention is simple in synthetic process, the reaction conditions are mild, the product is high in yield and high in purity, and industrial production is facilitated.
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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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- Synthetic method of epinastine hydrochloride impurity B
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The invention relates to the field of pharmaceutical technology and, and particularly relates to a preparation process of an epinastine hydrochloride impurity. The method comprises: firstly, using 6-(phthalimidomethyl)-6,11-dihydro-5H-dibenz[b,e]azepine (shown in the description) as a starting material, removing a protective group with hydrazine hydrate and then performing ring closure with cyanogen bromide to obtain 3- amino-9,13-dihydro-1H-dibenzo [c,f ]-imidazo [1,5-a] heterocyclic nitrogen (shown in the description) (epinastine), and finally reacting with a simple substance bromine to obtain the epinastine hydrochloride impurity B. The synthetic method of the epinastine hydrochloride impurity B has the advantages of being simple in process route, convenient to operate, good in selectivity and high in yield. The synthetic epinastine hydrochloride impurity B can be used as a control substance for testing a related substance of epinastine hydrochloride, can be applied in quality control of epinastine hydrochloride and related preparations thereof, and can be used for controlling the purity of the epinastine hydrochloride active pharmaceutical ingredients or preparations thereof.
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Paragraph 0030-0036
(2017/09/12)
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- Method of manufacturing using [...] compd. epinastine
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PROBLEM TO BE SOLVED: To provide a method for producing epinastine via a new intermediate which is safely synthesizable at a low cost.SOLUTION: Epinastine is produced by reacting 5H-dibenz[b, e]azepine-6,11-dihydro-6-methanamine with an N-(iminoalkoxymethyl)carbamic acid ester to synthesize an N-(9,13-dihydro-1H-dibenz[c, f]imidazo[1,5-a]azepin-3-yl)-carbamic acid ester as an intermediate and treating the intermediate with an acid (process A). As an alternative, epinastine is produced by reacting an acid salt of 5H-dibenz[b, e]azepine-6,11-dihydro-6-methanamine with an N-(iminoalkoxymethyl)carbamic acid ester to synthesize an {imino[N-(5H-dibenz[b, e]azepin-6-yl)methylamino]methyl}carbamic acid ester as an intermediate and treating the intermediate with an acid (process B).
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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 24
(2009/06/27)
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- Process for preparing 3-amino-9,13b-dihydro-1H-dibenz(c,f)imidazo(1,5-a)azepine-hydrochloride
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The present invention relates to a process for preparing 3-amino-9,13b-dihydro-1H-dibenz[c,f]-imidazo[1,5-a]azepine-hydrochloride, as follows: a) hydrogenating 6-phthalimidomethyl-5H-dibenz[b,e]-azepine, to produce 6-(phthalimidomethyl)-6,11-dihydro-5H-dibenz[b,e]azepine; b) reacting the 6-(phthalimidomethyl)-6,11-dihydro-5H-dibenz[b,e]azepine with hydrazine, to produce 6-aminomethyl-6,11-dihydro-5H-dibenz[b,e]azepine; c) reacting the 6-aminomethyl-6,11-dihydro-5H-dibenz[b,e]azepine with bromooyanogen, to produce 3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine; and d) precipitating the 3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine in the presence of DMF and HCl, to produce 3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine-hydrochloride.
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