CN105669655A - Synthesis method of Ramosetron - Google Patents
Synthesis method of Ramosetron Download PDFInfo
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Abstract
The invention discloses a synthesis method of Ramosetron. According to the method, 3,4-diaminobenzoic acid is used as a starting raw material for finally preparing the Ramosetron through the synthesis of benzimidazole-5-carboxylic acid, benzimidazole-5-methyl carbonate sulfate, 4,5,6,7-tetrahydro benzimidazole-5-methyl carbonate sulfate, 4,5,6,7-tetrahydro benzimidazole-5-triazolylformate sulfate, N-[(4,5,6,7-tetrahydro benzimidazole-5-yl)] pyrrole hydrochloride and 5-[(1-methylindol -3-yl) carbonyl]-4,5,6,7-tetrahydro benzimidazole. Compared with the prior art, the method provided by the invention has the advantages that the reaction conditions are optimized; after the optimization, the reaction is really feasible; the yield of the 4,5,6,7-tetrahydro benzimidazole-5-methyl carbonate sulfate, the 4,5,6,7-tetrahydro benzimidazole-5-triazolylformate sulfate, the N-[(4,5,6,7-tetrahydro benzimidazole-5-yl)] pyrrole hydrochloride and the like is improved; the reaction total yield reaches more than 30 percent; higher economic benefits are realized.
Description
Technical field:
The present invention relates to the synthetic method of a kind of ramosetron, belong to the field of chemical synthesis.
Background technology:
Ramosetron, its chemistry (R)-5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative hydrochlorates by name, are the important source material of synthetic hydrochloric acid ramosetron.
In prior art, the method for synthesis ramosetron mainly has following several:
The synthetic route that Yamanouchi company of Japan reported in nineteen ninety, this route needs cyclization rear oxidation, step is cumbersome, and adopt dichloroethanes to participate in reaction as solvent, this reagent belongs to a national class and controls reagent, and toxicity is relatively strong, is unfavorable for industrialized production, should avoiding using, present stage no longer adopts 5-methyl-3-nitro aniline to synthesize ramosetron. Its synthetic route is shown in formula one.
2005, Li Weiliang of Tianjin Kang Hong medical sci-tech Development Co., Ltd et al. reported the synthetic method of a kind of new Ramosetron HCl. It adopts the method for imidazole ring acyl group protection, prepares the Tetrahydrobenzimidazderivative derivative of acidylate, and subsequently with acetonitrile for reaction dissolvent, after aromatic carbon acidylate, acid hydrolysis Deprotection prepares ramosetron. In this method, with indole reaction in react amidatioon protection without elder generation and pyrrolidine, but pyrrolidine, indole One-step Synthesis. This synthetic method has bigger improvement compared with synthetic route before. Its synthetic route formula is shown in formula two.
Formula one:
Formula two:
The synthetic method of Jilin University Pharmaceutical Engineering Speciality Cai Xiaolin a kind of Ramosetron HCl disclosed in its master thesis in 2012 and Its Enzymatic Resolution research, be the present invention closest to prior art. This documents is in the process preparing Ramosetron HCl, in the synthesis of benzimidazole-5-carboxylic acid, the high spot reviews response time impact on reaction, it has been found that shorten the response time, reduces side reaction product. At synthesis N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-bases)] in pyrroles's process, thionyl chloride is directly adopted not only to do reaction dissolvent but also do reactant when preparing acyl chlorides, with 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate reacts, avoid using toxic solvent acetonitrile to do reaction dissolvent, facilitate post processing, and improve productivity. Simultaneously, at prepared N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-bases)] after pyrroles, not according to domestic and foreign literature report by its hydrochloric acid salt, but directly carried out the reaction of next step and N-methylindole, phosphorus oxychloride, and process after employing pours frozen water into after completion of the reaction, saturated sodium hydroxide solution is adjusted to pH9～10, filtering after precipitating out precipitation, above step simplifies synthesis technique.But its total recovery is only about 13%, and yield is low, the low difference of economic benefit.
Summary of the invention:
It is an object of the invention on the basis of existing technology, Optimizing Technical, overcome and prior art synthesizes the present situation that ramosetron synthesis yield is too low, improve ramosetron yield and industrial economic benefit.
The present invention provides following technical scheme:
The synthetic method of a kind of ramosetron, with 3,4-diaminobenzoic acids for initiation material, synthesizes ramosetron through 7 steps, comprises the following steps:
The first step: synthesizing benzimidazole-5-carboxylic acid
Formic acid 500ml is added 3,4-diaminobenzoic acid 40g, agitating heating backflow 4h, concentrating under reduced pressure, add water 700ml, and ammonia regulates to pH5-6, and filtration drying obtains pale solid benzimidazole-5-carboxylic acid;
Second step: synthesizing benzimidazole-5-carboxylate methyl ester sulfate
Absolute methanol 500ml is added in the benzimidazole-5-carboxylic acid that the first step prepares, drip thionyl chloride 45ml at 7-9 DEG C of temperature, drip to finish and be warming up to 50-55 DEG C of back flow reaction 5h, be down to room temperature after back flow reaction and add water 800ml, ammonia is adjusted to pH8-9, and filtration drying obtains beige solid; To add dehydrated alcohol 500ml in this beige solid, room temperature drips 98% sulphuric acid 26g, stirs 2h, and filtration drying obtains benzimidazole-5-carboxylic acid methosulfate;
3rd step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate
1800ml acetic acid is added in autoclave, add the benzimidazole-5-carboxylic acid methosulfate that second step prepares, add activated carbon and the catalyst 20g of zirconium powder mixing gained, at 70-80 DEG C of temperature, be flushed with hydrogen gas to 5.5MPa, under this condition, react 5-6h, after filtration catalizer, concentrating under reduced pressure mother solution, obtains grease 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate;
4th step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate
The hydrochloric acid that 650-700ml mass concentration is 20% is joined that above-mentioned 3rd step prepares 4,5,6, in 7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, back flow reaction 2-2.5h under stirring operation, it is concentrated into dry, add acetone 500-600ml stirring, precipitate out white solid, filter, washing with acetone gained crystal, drain solvent and obtain 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate 5-carboxylic acid sulfate;
5th step: synthesis N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrrole hydrochloride
4,5,6 that above-mentioned 4th step of the thionyl chloride of 90ml addition is prepared, in 7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate, add Raney Ni 1-1.5g mixing post-heating back flow reaction 1.5h, after decompression steams thionyl chloride, it is suspended in acetonitrile 30ml, at 0 DEG C, is dripped nafoxidine 31.5g, normal-temperature reaction 1-1.5h, decompression steams acetonitrile, dissolves with saturated sodium bicarbonate, and chloroform extracts, obtain N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-bases)] pyrrole hydrochloride;
6th step: synthesis 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative
Dry chloroform is sequentially added in above-mentioned 5th step the N-[(4 prepared, 5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrroles, N-methylindole 38.4g, phosphorus oxychloride 80g, it is warming up to 50-60 DEG C of back flow reaction 7-8h, being cooled to 20-22 DEG C after reaction, add 400-500ml frozen water, water layer mass concentration is the NaOH aqueous solution tune pH of 20% is 9-10, solid precipitates out after completely, filter, washing, drain, obtain 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivatives;
7th step: synthesis ramosetron
The 5-[(1-methylindole-3-base) carbonyl]-4 that above-mentioned 6th step is prepared, 5, 6, 7-Tetrahydrobenzimidazderivative is dissolved in 900ml methanol, stirring is lower add by 53.63gD-(+)-dibenzoyl tartaric acid is dissolved in the solution of 300ml methanol preparation, 3-4 hour is stood at 4-7 DEG C of temperature, filtering drying, obtain white solid, by this white solid DMF: water=5:1 mixed solvent recrystallization 3 times obtains white crystal tartrate, this tartrate is suspended from the hydrochloric acid solution 100ml of 2mol/L, add butyl acetate 150ml, stirring and dissolving, stratification, aqueous phase chloroform, PH to 9 is adjusted with saturated sodium carbonate solution, extract with chloroform-ethanol (3:1) mixed solvent, merge organic facies, it is spin-dried for obtain white solid ramosetron.
Preferably, absolute methanol 500ml is added in the benzimidazole-5-carboxylic acid that the first step prepares by described second step synthesizing benzimidazole-5-carboxylate methyl ester sulfate, thionyl chloride 45ml is dripped at 8 DEG C of temperature, drip to finish and be warming up to 50 DEG C of back flow reaction 5h, it is down to room temperature after back flow reaction to add water 800ml, ammonia is adjusted to pH9, and filtration drying obtains beige solid.
Preferably, in described 3rd step synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate catalyst to be 30% activated carbon prepared with the zirconium powder mixing of 70%;
5.5h is reacted when being flushed with hydrogen gas at 70 DEG C of temperature to 5.5MPa.
Preferably, described 4th step synthesis 4,5, in 6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate, the hydrochloric acid that 700ml mass concentration is 20% is joined above-mentioned 3rd step prepares 4,5, in 6,7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, back flow reaction 2.5h under stirring operation, it is concentrated into dry, adds acetone 600ml stirring, precipitate out white solid, filter, washing with acetone gained crystal, drain solvent and obtain 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate 5-carboxylic acid sulfate.
Preferably, described 5th step synthesis N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-bases)] effective ingredient Ni content >=99.5%, sulphates content≤0.03% in raney nickel catalyst in pyrrole hydrochloride, silicone content≤0.01%, iron content≤0.05%, cobalt content≤0.05%.
Preferably, described 6th step synthesis 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivatives are sequentially added in above-mentioned 5th step the N-[(4 prepared in dry chloroform, 5,6,7-Tetrahydrobenzimidazderivative-5-bases)] pyrroles, N-methylindole, phosphorus oxychloride, it is warming up to 60 DEG C of back flow reaction 7h, it is cooled to 20-22 DEG C after reaction, adding 500ml frozen water, water layer mass concentration is the NaOH aqueous solution tune pH of 20% is 10.
The thermal-neutron capture cross-section of zirconium is little, has prominent nuclearity energy, is the development indispensable material of atomic energy industry, can make reactor core structural material. Zirconium powder is easy firing in atmosphere, can make detonating primer and cordite. Zirconium can be used for the additive of high-quality steel-deoxidizing desulfuration, is also the constituent element of armour steel, artillery steel, rustless steel and heat resisting steel. Zirconium is the important alloying element of magnesium alloy, can improve magnesium and close tensile strength and processing characteristics. Zirconium or the alterant of almag, can crystal grain thinning. The light reflective properties of zircon is strong, Heat stability is good, can make opacifier and use in pottery and glass. Zirconium can absorb the gases such as oxygen, hydrogen, ammonia in large quantities when heating, is desirable getter, makes degasifier with zirconium powder in electron tube, makes grid support, anode carrier etc. with zirconium silk zirconium sheet.Powdered ferrum mixes with zirconium nitrate, can make flashlight powder. Metal zirconium is almost completely used as in nuclear reactor the involucrum of uranium fuel element. Also it is used for manufacturing the flash lamp of photograph and corrosion resistant container and pipeline, particularly to resistance to hydrochloric acid and sulphuric acid. The chemical drugs of zirconium can make the cross-linking agent of polymer. The present invention using activated carbon with zirconium powder mix homogeneously according to weight ratio 3:7 after add as synthesize 4,5,6, the catalyst of 7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, replace using the palladium carbon of 10% as catalyst in prior art, reduce reflection cost, reduce reaction activity simultaneously, more shorten the response time, increase economic efficiency.
Zirconium powder zirconium simple substance active constituent content >=99% of the present invention, activated carbon is active fruit shell carbon.
Raney Ni is a kind of solid-state different-phase catalyst being made up of the small grains of the nickel alumin(i)um alloy with loose structure, it the earliest by American engineer Mo Lilanni in the hydrogenation process of vegetable oil, use as catalyst. Owing to " blue Buddhist nun " is the registered trade mark of Grace chemical company, so strictly speaking, the product of the Dai Weisen Division of Chemistry pupil product only having this company just can be called " Raney Ni ". The Raney Ni strong adsorptivity to hydrogen, high catalytic activity and heat stability make Raney Ni be widely used in a lot of industrial process and organic synthesis. In addition, Raney Ni is substantially insoluble in the laboratory solvent except mineral acid, has again higher density simultaneously, is conducive to after reaction separating catalyst from mixed liquor. Except as catalyst hydrogenation, Raney Ni also will serve as the reaction that reagent participates in the desulfurization generation hydro carbons of sulfur-containing organic compound such as mercaptal. The sulfuration Asia nickel generated will precipitate, by distilling, it is possible to be easily separated with volatile ethane. Raney Ni is additionally operable to rhohene desulfiirization and hydrogenates generation saturated compounds simultaneously. But the mechanism of this class reaction does not also have so far clearly to be explained, the present invention adopts Raney Ni to catalyze and synthesize N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-bases)] pyrrole hydrochloride, shortens the response time, improve yield, and have good raising effect for subsequent reactions yield.
Beneficial effects of the present invention:
1. the present invention is on the basis of existing technology, Optimizing Technical, overcomes and synthesizes the present situation that ramosetron synthesis yield is too low in prior art, improves ramosetron yield and industrial economic benefit.
2. the present invention using activated carbon with zirconium powder mix homogeneously according to weight ratio 3:7 after add as synthesize 4,5,6, the catalyst of 7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, replace using the palladium carbon of 10% as catalyst in prior art, reduce reflection cost, reduce reaction activity simultaneously, more shorten the response time, increase economic efficiency.
3. the present invention adopts Raney Ni to catalyze and synthesize N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrrole hydrochloride, shortens the response time, improves yield, and has good raising effect for subsequent reactions yield.
Detailed description of the invention:
Below embodiments of the invention being described in detail, the present embodiment is carried out under premised on inventive technique scheme, gives detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
The present invention provides following technical scheme:
Embodiment one
The synthetic method of a kind of ramosetron, with 3,4-diaminobenzoic acids for initiation material, synthesizes ramosetron through 7 steps, comprises the following steps:
The first step: synthesizing benzimidazole-5-carboxylic acid
Formic acid 500ml is added 3,4-diaminobenzoic acid 40g, agitating heating backflow 4h, concentrating under reduced pressure, add water 700ml, and ammonia regulates to pH5-6, and filtration drying obtains pale solid benzimidazole-5-carboxylic acid;
Second step: synthesizing benzimidazole-5-carboxylate methyl ester sulfate
Absolute methanol 500ml is added in the benzimidazole-5-carboxylic acid that the first step prepares, drip thionyl chloride 45ml at 7-8 DEG C of temperature, drip to finish and be warming up to 50-52 DEG C of back flow reaction 5h, be down to room temperature after back flow reaction and add water 800ml, ammonia is adjusted to pH8-9, and filtration drying obtains beige solid; To add dehydrated alcohol 500ml in this beige solid, room temperature drips 98% sulphuric acid 26g, stirs 2h, and filtration drying obtains benzimidazole-5-carboxylic acid methosulfate;
3rd step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate
1800ml acetic acid is added in autoclave, add the benzimidazole-5-carboxylic acid methosulfate that second step prepares, add activated carbon and the catalyst 20g of zirconium powder mixing gained, at 75-80 DEG C of temperature, be flushed with hydrogen gas to 5.5MPa, under this condition, react 5-6h, after filtration catalizer, concentrating under reduced pressure mother solution, obtains grease 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate;
4th step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate
The hydrochloric acid that 650-700ml mass concentration is 20% is joined that above-mentioned 3rd step prepares 4,5,6, in 7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, back flow reaction 2-2.5h under stirring operation, it is concentrated into dry, add acetone 500-600ml stirring, precipitate out white solid, filter, washing with acetone gained crystal, drain solvent and obtain 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate 5-carboxylic acid sulfate;
5th step: synthesis N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrrole hydrochloride
4,5,6 that above-mentioned 4th step of the thionyl chloride of 90ml addition is prepared, in 7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate, add Raney Ni 1g mixing post-heating back flow reaction 1.5h, after decompression steams thionyl chloride, it is suspended in acetonitrile 30ml, at 0 DEG C, is dripped nafoxidine 31.5g, normal-temperature reaction 1-1.5h, decompression steams acetonitrile, dissolves with saturated sodium bicarbonate, and chloroform extracts, obtain N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-bases)] pyrrole hydrochloride;
6th step: synthesis 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative
Dry chloroform is sequentially added in above-mentioned 5th step the N-[(4 prepared, 5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrroles, N-methylindole 38.4g, phosphorus oxychloride 80g, it is warming up to 50-55 DEG C of back flow reaction 7h, being cooled to 20-22 DEG C after reaction, add 400-500ml frozen water, water layer mass concentration is the NaOH aqueous solution tune pH of 20% is 9-10, solid precipitates out after completely, filter, washing, drain, obtain 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivatives;
7th step: synthesis ramosetron
The 5-[(1-methylindole-3-base) carbonyl]-4 that above-mentioned 6th step is prepared, 5, 6, 7-Tetrahydrobenzimidazderivative is dissolved in 900ml methanol, stirring is lower add by 53.63gD-(+)-dibenzoyl tartaric acid is dissolved in the solution of 300ml methanol preparation, 3-3.5 hour is stood at 4-5 DEG C of temperature, filtering drying, obtain white solid, by this white solid DMF: water=5:1 mixed solvent recrystallization 3 times obtains white crystal tartrate, this tartrate is suspended from the hydrochloric acid solution 100ml of 2mol/L, add butyl acetate 150ml, stirring and dissolving, stratification, aqueous phase chloroform, PH to 9 is adjusted with saturated sodium carbonate solution, extract with chloroform-ethanol (3:1) mixed solvent, merge organic facies, it is spin-dried for obtain white solid ramosetron.
Embodiment two
The synthetic method of a kind of ramosetron, with 3,4-diaminobenzoic acids for initiation material, synthesizes ramosetron through 7 steps, comprises the following steps:
The first step: synthesizing benzimidazole-5-carboxylic acid
Formic acid 500ml is added 3,4-diaminobenzoic acid 40g, agitating heating backflow 4h, concentrating under reduced pressure, add water 700ml, and ammonia regulates to pH5-6, and filtration drying obtains pale solid benzimidazole-5-carboxylic acid;
Second step: synthesizing benzimidazole-5-carboxylate methyl ester sulfate
Absolute methanol 500ml is added in the benzimidazole-5-carboxylic acid that the first step prepares, drip thionyl chloride 45ml at 8 DEG C of temperature, drip to finish and be warming up to 50 DEG C of back flow reaction 5h, be down to room temperature after back flow reaction and add water 800ml, ammonia is adjusted to pH9, and filtration drying obtains beige solid; To add dehydrated alcohol 500ml in this beige solid, room temperature drips 98% sulphuric acid 26g, stirs 2h, and filtration drying obtains benzimidazole-5-carboxylic acid methosulfate;
3rd step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate
1800ml acetic acid is added in autoclave, add the benzimidazole-5-carboxylic acid methosulfate that second step prepares, add activated carbon and the catalyst 20g of zirconium powder mixing gained, at 78-80 DEG C of temperature, be flushed with hydrogen gas to 5.5MPa, under this condition, react 5-6h, after filtration catalizer, concentrating under reduced pressure mother solution, obtains grease 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate;
4th step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate
The hydrochloric acid that 700ml mass concentration is 20% is joined that above-mentioned 3rd step prepares 4,5,6, in 7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, back flow reaction 2.5h under stirring operation, it is concentrated into dry, add acetone 600ml stirring, precipitate out white solid, filter, washing with acetone gained crystal, drain solvent and obtain 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate 5-carboxylic acid sulfate;
5th step: synthesis N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrrole hydrochloride
4,5,6 that above-mentioned 4th step of the thionyl chloride of 90ml addition is prepared, in 7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate, add Raney Ni 1g mixing post-heating back flow reaction 1.5h, after decompression steams thionyl chloride, it is suspended in acetonitrile 30ml, at 0 DEG C, is dripped nafoxidine 31.5g, normal-temperature reaction 1-1.5h, decompression steams acetonitrile, dissolves with saturated sodium bicarbonate, and chloroform extracts, obtain N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-bases)] pyrrole hydrochloride;
6th step: synthesis 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative
Dry chloroform is sequentially added in above-mentioned 5th step the N-[(4 prepared, 5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrroles, N-methylindole, phosphorus oxychloride, it is warming up to 60 DEG C of back flow reaction 7h, 20-22 DEG C it is cooled to after reaction, add 500ml frozen water, water layer mass concentration is the NaOH aqueous solution tune pH of 20% is 10, and solid precipitates out after completely, filters, washing, drain, obtain 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivatives;
7th step: synthesis ramosetron
The 5-[(1-methylindole-3-base) carbonyl]-4 that above-mentioned 6th step is prepared, 5, 6, 7-Tetrahydrobenzimidazderivative is dissolved in 900ml methanol, stirring is lower add by 53.63gD-(+)-dibenzoyl tartaric acid is dissolved in the solution of 300ml methanol preparation, 3.5-4 hour is stood at 6-7 DEG C of temperature, filtering drying, obtain white solid, by this white solid DMF: water=5:1 mixed solvent recrystallization 3 times obtains white crystal tartrate, this tartrate is suspended from the hydrochloric acid solution 100ml of 2mol/L, add butyl acetate 150ml, stirring and dissolving, stratification, aqueous phase chloroform, PH to 9 is adjusted with saturated sodium carbonate solution, extract with chloroform-ethanol (3:1) mixed solvent, merge organic facies, it is spin-dried for obtain white solid ramosetron.
Embodiment three
The synthetic method of a kind of ramosetron, with 3,4-diaminobenzoic acids for initiation material, synthesizes ramosetron through 7 steps, comprises the following steps:
The first step: synthesizing benzimidazole-5-carboxylic acid
Formic acid 500ml is added 3,4-diaminobenzoic acid 40g, agitating heating backflow 4h, concentrating under reduced pressure, add water 700ml, and ammonia regulates to pH5-6, and filtration drying obtains pale solid benzimidazole-5-carboxylic acid;
Second step: synthesizing benzimidazole-5-carboxylate methyl ester sulfate
Absolute methanol 500ml is added in the benzimidazole-5-carboxylic acid that the first step prepares, drip thionyl chloride 45ml at 7-8 DEG C of temperature, drip to finish and be warming up to 53-55 DEG C of back flow reaction 5h, be down to room temperature after back flow reaction and add water 800ml, ammonia is adjusted to pH8-9, and filtration drying obtains beige solid; To add dehydrated alcohol 500ml in this beige solid, room temperature drips 98% sulphuric acid 26g, stirs 2h, and filtration drying obtains benzimidazole-5-carboxylic acid methosulfate;
3rd step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate
1800ml acetic acid is added in autoclave, add the benzimidazole-5-carboxylic acid methosulfate that second step prepares, add activated carbon and the catalyst 20g of zirconium powder mixing gained, at 70-73 DEG C of temperature, be flushed with hydrogen gas to 5.5MPa, under this condition, react 5-6h, after filtration catalizer, concentrating under reduced pressure mother solution, obtains grease 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate;
4th step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate
The hydrochloric acid that 680-700ml mass concentration is 20% is joined that above-mentioned 3rd step prepares 4,5,6, in 7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, back flow reaction 2-2.5h under stirring operation, it is concentrated into dry, add acetone 500-600ml stirring, precipitate out white solid, filter, washing with acetone gained crystal, drain solvent and obtain 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate 5-carboxylic acid sulfate;
5th step: synthesis N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrrole hydrochloride
4,5,6 that above-mentioned 4th step of the thionyl chloride of 90ml addition is prepared, in 7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate, add Raney Ni 1.5g mixing post-heating back flow reaction 1.5h, after decompression steams thionyl chloride, it is suspended in acetonitrile 30ml, at 0 DEG C, is dripped nafoxidine 31.5g, normal-temperature reaction 1h, decompression steams acetonitrile, dissolves with saturated sodium bicarbonate, and chloroform extracts, obtain N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-bases)] pyrrole hydrochloride;
6th step: synthesis 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative
Dry chloroform is sequentially added in above-mentioned 5th step the N-[(4 prepared, 5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrroles, N-methylindole 38.4g, phosphorus oxychloride 80g, it is warming up to 50-55 DEG C of back flow reaction 7-8h, being cooled to 20-22 DEG C after reaction, add 400-500ml frozen water, water layer mass concentration is the NaOH aqueous solution tune pH of 20% is 9-10, solid precipitates out after completely, filter, washing, drain, obtain 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivatives;
7th step: synthesis ramosetron
The 5-[(1-methylindole-3-base) carbonyl]-4 that above-mentioned 6th step is prepared, 5, 6, 7-Tetrahydrobenzimidazderivative is dissolved in 900ml methanol, stirring is lower add by 53.63gD-(+)-dibenzoyl tartaric acid is dissolved in the solution of 300ml methanol preparation, 3-4 hour is stood at 4-5 DEG C of temperature, filtering drying, obtain white solid, by this white solid DMF: water=5:1 mixed solvent recrystallization 3 times obtains white crystal tartrate, this tartrate is suspended from the hydrochloric acid solution 100ml of 2mol/L, add butyl acetate 150ml, stirring and dissolving, stratification, aqueous phase chloroform, PH to 9 is adjusted with saturated sodium carbonate solution, extract with chloroform-ethanol (3:1) mixed solvent, merge organic facies, it is spin-dried for obtain white solid ramosetron.
Embodiment four
The synthetic method of a kind of ramosetron, with 3,4-diaminobenzoic acids for initiation material, synthesizes ramosetron through 7 steps, comprises the following steps:
The first step: synthesizing benzimidazole-5-carboxylic acid
Formic acid 500ml is added 3,4-diaminobenzoic acid 40g, agitating heating backflow 4h, concentrating under reduced pressure, add water 700ml, and ammonia regulates to pH5-6, and filtration drying obtains pale solid benzimidazole-5-carboxylic acid;
Second step: synthesizing benzimidazole-5-carboxylate methyl ester sulfate
Absolute methanol 500ml is added in the benzimidazole-5-carboxylic acid that the first step prepares, drip thionyl chloride 45ml at 7-8 DEG C of temperature, drip to finish and be warming up to 53-55 DEG C of back flow reaction 5h, be down to room temperature after back flow reaction and add water 800ml, ammonia is adjusted to pH8-9, and filtration drying obtains beige solid; To add dehydrated alcohol 500ml in this beige solid, room temperature drips 98% sulphuric acid 26g, stirs 2h, and filtration drying obtains benzimidazole-5-carboxylic acid methosulfate;
3rd step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate
1800ml acetic acid is added in autoclave, add the benzimidazole-5-carboxylic acid methosulfate that second step prepares, add activated carbon and the catalyst 20g of zirconium powder mixing gained, at 70-80 DEG C of temperature, be flushed with hydrogen gas to 5.5MPa, under this condition, react 5-6h, after filtration catalizer, concentrating under reduced pressure mother solution, obtains grease 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate;
4th step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate
The hydrochloric acid that 650-700ml mass concentration is 20% is joined that above-mentioned 3rd step prepares 4,5,6, in 7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, back flow reaction 2-2.5h under stirring operation, it is concentrated into dry, add acetone 500-600ml stirring, precipitate out white solid, filter, washing with acetone gained crystal, drain solvent and obtain 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate 5-carboxylic acid sulfate;
5th step: synthesis N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrrole hydrochloride
4,5,6 that above-mentioned 4th step of the thionyl chloride of 90ml addition is prepared, in 7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate, add Raney Ni 1.3g mixing post-heating back flow reaction 1.5h, after decompression steams thionyl chloride, it is suspended in acetonitrile 30ml, at 0 DEG C, is dripped nafoxidine 31.5g, normal-temperature reaction 1.5h, decompression steams acetonitrile, dissolves with saturated sodium bicarbonate, and chloroform extracts, obtain N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-bases)] pyrrole hydrochloride;
6th step: synthesis 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative
Dry chloroform is sequentially added in above-mentioned 5th step the N-[(4 prepared, 5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrroles, N-methylindole 38.4g, phosphorus oxychloride 80g, it is warming up to 55-60 DEG C of back flow reaction 7-8h, being cooled to 20-22 DEG C after reaction, add 400ml frozen water, water layer mass concentration is the NaOH aqueous solution tune pH of 20% is 9-10, solid precipitates out after completely, filter, washing, drain, obtain 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivatives;
7th step: synthesis ramosetron
The 5-[(1-methylindole-3-base) carbonyl]-4 that above-mentioned 6th step is prepared, 5, 6, 7-Tetrahydrobenzimidazderivative is dissolved in 900ml methanol, stirring is lower add by 53.63gD-(+)-dibenzoyl tartaric acid is dissolved in the solution of 300ml methanol preparation, stand 3 hours at 6-7 DEG C of temperature, filtering drying, obtain white solid, by this white solid DMF: water=5:1 mixed solvent recrystallization 3 times obtains white crystal tartrate, this tartrate is suspended from the hydrochloric acid solution 100ml of 2mol/L, add butyl acetate 150ml, stirring and dissolving, stratification, aqueous phase chloroform, PH to 9 is adjusted with saturated sodium carbonate solution, extract with chloroform-ethanol (3:1) mixed solvent, merge organic facies, it is spin-dried for obtain white solid ramosetron.
Embodiment five
The synthetic method of a kind of ramosetron, with 3,4-diaminobenzoic acids for initiation material, synthesizes ramosetron through 7 steps, comprises the following steps:
The first step: synthesizing benzimidazole-5-carboxylic acid
Formic acid 500ml is added 3,4-diaminobenzoic acid 40g, agitating heating backflow 4h, concentrating under reduced pressure, add water 700ml, and ammonia regulates to pH5-6, and filtration drying obtains pale solid benzimidazole-5-carboxylic acid;
Second step: synthesizing benzimidazole-5-carboxylate methyl ester sulfate
Absolute methanol 500ml is added in the benzimidazole-5-carboxylic acid that the first step prepares, drip thionyl chloride 45ml at 7-9 DEG C of temperature, drip to finish and be warming up to 50-52 DEG C of back flow reaction 5h, be down to room temperature after back flow reaction and add water 800ml, ammonia is adjusted to pH8-9, and filtration drying obtains beige solid; To add dehydrated alcohol 500ml in this beige solid, room temperature drips 98% sulphuric acid 26g, stirs 2h, and filtration drying obtains benzimidazole-5-carboxylic acid methosulfate;
3rd step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate
1800ml acetic acid is added in autoclave, add the benzimidazole-5-carboxylic acid methosulfate that second step prepares, add the catalyst 20g of activated carbon and zirconium powder mixing gained, 5.5-6h is reacted when being flushed with hydrogen gas at 70-72 DEG C of temperature to 5.5MPa, after filtration catalizer, concentrating under reduced pressure mother solution, obtain grease 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate;
4th step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate
The hydrochloric acid that 650-680ml mass concentration is 20% is joined that above-mentioned 3rd step prepares 4,5,6, in 7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, back flow reaction 2h under stirring operation, it is concentrated into dry, add acetone 500ml stirring, precipitate out white solid, filter, washing with acetone gained crystal, drain solvent and obtain 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate 5-carboxylic acid sulfate;
5th step: synthesis N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrrole hydrochloride
4,5,6 that above-mentioned 4th step of the thionyl chloride of 90ml addition is prepared, in 7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate, add Raney Ni 1.2g mixing post-heating back flow reaction 1.5h, after decompression steams thionyl chloride, it is suspended in acetonitrile 30ml, at 0 DEG C, is dripped nafoxidine 31.5g, normal-temperature reaction 1.5h, decompression steams acetonitrile, dissolves with saturated sodium bicarbonate, and chloroform extracts, obtain N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-bases)] pyrrole hydrochloride;
6th step: synthesis 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative
Dry chloroform is sequentially added in the 5th step the N-[(4 prepared, 5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrroles, N-methylindole 38.4g, phosphorus oxychloride 80g, it is warming up to 55 DEG C of back flow reaction 8h, being cooled to 20-22 DEG C after reaction, add 500ml frozen water, water layer mass concentration is the NaOH aqueous solution tune pH of 20% is 9-10, solid precipitates out after completely, filter, washing, drain, obtain 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivatives;
7th step: synthesis ramosetron
The 5-[(1-methylindole-3-base) carbonyl]-4 that above-mentioned 6th step is prepared, 5, 6, 7-Tetrahydrobenzimidazderivative is dissolved in 900ml methanol, stirring is lower add by 53.63gD-(+)-dibenzoyl tartaric acid is dissolved in the solution of 300ml methanol preparation, stand 3.5 hours at 4-6 DEG C of temperature, filtering drying, obtain white solid, by this white solid DMF: water=5:1 mixed solvent recrystallization 3 times obtains white crystal tartrate, this tartrate is suspended from the hydrochloric acid solution 100ml of 2mol/L, add butyl acetate 150ml, stirring and dissolving, stratification, aqueous phase chloroform, PH to 9 is adjusted with saturated sodium carbonate solution, extract with chloroform-ethanol (3:1) mixed solvent, merge organic facies, it is spin-dried for obtain white solid ramosetron.
Catalyst described in above-described embodiment be 30% activated carbon and 70% zirconium powder mixing prepare; Wherein zirconium powder zirconium simple substance active constituent content >=99%, activated carbon is active fruit shell carbon.
Effective ingredient Ni content >=99.5%, sulphates content≤0.03%, silicone content≤0.01%, iron content≤0.05%, cobalt content≤0.05% in raney nickel catalyst.
What table one table two represented respectively is that each step prepares weight and the yield of product by way of example, unit is g and % respectively, wherein first step product is benzimidazole-5-carboxylic acid, second step product is benzimidazole-5-carboxylic acid methosulfate, 3rd step product is 4, 5, 6, 7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, 4th step product is 4, 5, 6, 7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate, 5th step product is N-[(4, 5, 6, 7-Tetrahydrobenzimidazderivative-5-base)] pyrrole hydrochloride, 6th step product is 5-[(1-methylindole-3-base) carbonyl]-4, 5, 6, 7-Tetrahydrobenzimidazderivative, 7th step product is ramosetron.
Table one: each step Product yields of way of example.
Table two: each step products collection efficiency of way of example and total recovery.
Above content is only the better embodiment of the present invention, for those of ordinary skill in the art, according to the thought of the present invention, all will change in specific embodiments and applications, and this specification content should not be construed as limitation of the present invention.
Claims (6)
1. a synthetic method for ramosetron, with 3,4-diaminobenzoic acids for initiation material, synthesizes ramosetron through 7 steps, it is characterised in that comprise the following steps:
The first step: synthesizing benzimidazole-5-carboxylic acid
Formic acid 500ml is added 3,4-diaminobenzoic acid 40g, agitating heating backflow 4h, concentrating under reduced pressure, add water 700ml, and ammonia regulates to pH5-6, and filtration drying obtains pale solid benzimidazole-5-carboxylic acid;
Second step: synthesizing benzimidazole-5-carboxylate methyl ester sulfate
Absolute methanol 500ml is added in the benzimidazole-5-carboxylic acid that the first step prepares, drip thionyl chloride 45ml at 7-9 DEG C of temperature, drip to finish and be warming up to 50-55 DEG C of back flow reaction 5h, be down to room temperature after back flow reaction and add water 800ml, ammonia is adjusted to pH8-9, and filtration drying obtains beige solid; To add dehydrated alcohol 500ml in this beige solid, room temperature drips 98% sulphuric acid 26g, stirs 2h, and filtration drying obtains benzimidazole-5-carboxylic acid methosulfate;
3rd step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate
1800ml acetic acid is added in autoclave, add the benzimidazole-5-carboxylic acid methosulfate that second step prepares, add activated carbon and the catalyst 20g of zirconium powder mixing gained, at 70-80 DEG C of temperature, be flushed with hydrogen gas to 5.5MPa, under this condition, react 5-6h, after filtration catalizer, concentrating under reduced pressure mother solution, obtains grease 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate;
4th step: synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate
The hydrochloric acid that 650-700ml mass concentration is 20% is joined that above-mentioned 3rd step prepares 4,5,6, in 7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, back flow reaction 2-2.5h under stirring operation, it is concentrated into dry, add acetone 500-600ml stirring, precipitate out white solid, filter, washing with acetone gained crystal, drain solvent and obtain 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate 5-carboxylic acid sulfate;
5th step: synthesis N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrrole hydrochloride
4,5,6 that above-mentioned 4th step of the thionyl chloride of 90ml addition is prepared, in 7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate, add Raney Ni 1-1.5g mixing post-heating back flow reaction 1.5h, after decompression steams thionyl chloride, it is suspended in acetonitrile 30ml, at 0 DEG C, is dripped nafoxidine 31.5g, normal-temperature reaction 1-1.5h, decompression steams acetonitrile, dissolves with saturated sodium bicarbonate, and chloroform extracts, obtain N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-bases)] pyrrole hydrochloride;
6th step: synthesis 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative
Dry chloroform is sequentially added in above-mentioned 5th step the N-[(4 prepared, 5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrroles, N-methylindole 38.4g, phosphorus oxychloride 80g, it is warming up to 50-60 DEG C of back flow reaction 7-8h, being cooled to 20-22 DEG C after reaction, add 400-500ml frozen water, water layer mass concentration is the NaOH aqueous solution tune pH of 20% is 9-10, solid precipitates out after completely, filter, washing, drain, obtain 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivatives;
7th step: synthesis ramosetron
The 5-[(1-methylindole-3-base) carbonyl]-4 that above-mentioned 6th step is prepared, 5, 6, 7-Tetrahydrobenzimidazderivative is dissolved in 900ml methanol, stirring is lower add by 53.63gD-(+)-dibenzoyl tartaric acid is dissolved in the solution of 300ml methanol preparation, 3-4 hour is stood at 4-7 DEG C of temperature, filtering drying, obtain white solid, by this white solid DMF: water=5:1 mixed solvent recrystallization 3 times obtains white crystal tartrate, this tartrate is suspended from the hydrochloric acid solution 100ml of 2mol/L, add butyl acetate 150ml, stirring and dissolving, stratification, aqueous phase chloroform, PH to 9 is adjusted with saturated sodium carbonate solution, extract with chloroform-ethanol (3:1) mixed solvent, merge organic facies, it is spin-dried for obtain white solid ramosetron.
2. the synthetic method of a kind of ramosetron according to claim 1, it is characterized in that: absolute methanol 500ml is added in the benzimidazole-5-carboxylic acid that the first step prepares by described second step synthesizing benzimidazole-5-carboxylate methyl ester sulfate, thionyl chloride 45ml is dripped at 8 DEG C of temperature, drip to finish and be warming up to 50 DEG C of back flow reaction 5h, it is down to room temperature after back flow reaction to add water 800ml, ammonia is adjusted to pH9, and filtration drying obtains beige solid.
3. the synthetic method of a kind of ramosetron according to claim 1, it is characterised in that: in described 3rd step synthesis 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, to be 30% activated carbon prepared with the zirconium powder mixing of 70% for catalyst; 5.5h is reacted when being flushed with hydrogen gas at 70 DEG C of temperature to 5.5MPa.
4. the synthetic method of a kind of ramosetron according to claim 1, it is characterized in that: described 4th step synthesis 4,5, in 6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate, the hydrochloric acid that 700ml mass concentration is 20% is joined above-mentioned 3rd step prepares 4,5,6, in 7-Tetrahydrobenzimidazderivative-5-carboxylate methyl ester sulfate, back flow reaction 2.5h under stirring operation, it is concentrated into dry, add acetone 600ml stirring, precipitate out white solid, filter, washing with acetone gained crystal, drain solvent and obtain 4,5,6,7-Tetrahydrobenzimidazderivative-5-carboxylic acid sulfate 5-carboxylic acid sulfate.
5. the synthetic method of a kind of ramosetron according to claim 1, it is characterized in that: described 5th step synthesis N-[(4,5,6,7-Tetrahydrobenzimidazderivative-5-base)] effective ingredient Ni content >=99.5%, sulphates content≤0.03%, silicone content≤0.01% in raney nickel catalyst in pyrrole hydrochloride, iron content≤0.05%, cobalt content≤0.05%.
6. the synthetic method of a kind of ramosetron according to claim 1, it is characterized in that: described 6th step synthesis 5-[(1-methylindole-3-base) carbonyl]-4,5,6,7-Tetrahydrobenzimidazderivative is sequentially added in above-mentioned 5th step the N-[(4 prepared in dry chloroform, 5,6,7-Tetrahydrobenzimidazderivative-5-base)] pyrroles, N-methylindole, phosphorus oxychloride, it is warming up to 60 DEG C of back flow reaction 7h, 20-22 DEG C it is cooled to after reaction, adding 500ml frozen water, water layer mass concentration is the NaOH aqueous solution tune pH of 20% is 10.
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| CN117229266A (en) * | 2023-11-13 | 2023-12-15 | 成都通德药业有限公司 | Method for synthesizing ramosetron racemate and salt thereof |
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| CN1045583A (en) * | 1989-02-02 | 1990-09-26 | 山之内制药株式会社 | Tetrahydrobenzimidazderivative derivative |
| CN1696128A (en) * | 2004-11-02 | 2005-11-16 | 天津康鸿医药科技发展有限公司 | New method for synthesizing Ramosetron Hydrochloride |
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| CN1696128A (en) * | 2004-11-02 | 2005-11-16 | 天津康鸿医药科技发展有限公司 | New method for synthesizing Ramosetron Hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117229266A (en) * | 2023-11-13 | 2023-12-15 | 成都通德药业有限公司 | Method for synthesizing ramosetron racemate and salt thereof |
| CN117229266B (en) * | 2023-11-13 | 2024-03-01 | 成都通德药业有限公司 | Method for synthesizing ramosetron racemate and salt thereof |
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