CN101787021B - High-purified tropisetron hydrochloride compound - Google Patents
High-purified tropisetron hydrochloride compound Download PDFInfo
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- CN101787021B CN101787021B CN2010101179171A CN201010117917A CN101787021B CN 101787021 B CN101787021 B CN 101787021B CN 2010101179171 A CN2010101179171 A CN 2010101179171A CN 201010117917 A CN201010117917 A CN 201010117917A CN 101787021 B CN101787021 B CN 101787021B
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- tropisetron
- tropisetron hydrochloride
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Abstract
The invention relates to a tropisetron hydrochloride compound. The purity of the tropisetron hydrochloride is greatly improved by acid-base reaction, activated carbon adsorption and separation and purification prepared chromatographic columns, thus optimizing the quality of preparation products and the safety of clinical medication. The method has simple process, low cost and high yield, and is applicable to industrial production.
Description
Technical field
The present invention relates to a kind of Tropisetron hydrochloride compound, can obtain highly purified Tropisetron hydrochloride, belong to medical technical field by method of the present invention.
Background technology
Tropisetron hydrochloride, its chemical name is: interior-the 1H-Indole-3-Carboxylic Acid-the 8-methyl-8-azabicyclo [3.2.1]
The oct-3-yl ester hydrochloride, molecular formula: C
17H
20N
2O
2HCl, molecular weight: 320.81, structural formula is:
Tropisetron hydrochloride is that a kind of peripheral nerve potent, highly selective former and central nervous system serotonin 3 (5-HT3) acceptor are competed antagonist, mainly suppresses vomiting reflex by optionally blocking the former presynaptic 5-HT3 of peripheral nerve acceptor.Be applicable to the nausea and vomiting that prevention and treatment cancer chemotherapy cause.
The synthetic method bibliographical information of Tropisetron hydrochloride is more, is exactly that the finished product purity that obtains is lower but there is a common defective, has influenced the security of pharmaceutical preparation.
Summary of the invention
The object of the present invention is to provide a kind of process for purification of Tropisetron hydrochloride compound, pass through acidification reaction, charcoal absorption and preparative chromatography column separating purification reach the purpose of refining purifying, finally obtain highly purified Tropisetron hydrochloride compound, optimize quality product, ensured safety of clinical administration.
The process for purification of Tropisetron hydrochloride compound provided by the invention comprises the steps:
(1) the Tropisetron hydrochloride crude product is soluble in water, slowly add alkali then, stirring reaction to pH value of solution is 7-10, generation tropisetron precipitation is filtered 35-50 ℃ of drying under reduced pressure, obtain tropisetron, described alkali is sodium hydroxide, potassium hydroxide, yellow soda ash or sodium bicarbonate;
(2) will go up the tropisetron that obtains of step is dissolved in the solvent of 2-10 times of weight, the gac that adds overall solution volume 0.01-0.05 (g/ml), 20-50 ℃ was stirred 0.5-1.5 hour, filtered decarburization, collect filtrate, wherein said solvent is selected from propyl carbinol, normal hexane or ethanol;
(3) will go up the filtrate that obtains of step and utilize the preparative chromatography post to carry out separation and purification to obtain the Tropisetron hydrochloride highly finished product, wherein the moving phase used of chromatographic column accounts for the methylene dichloride of moving phase 30-50% or acetone and volume as volume and accounts for the aqueous hydrochloric acid of the pH of moving phase 50-70% as 1-2; Fixed phase stuffing is selected from silica gel or aluminum oxide; Flow velocity is 4.5-6.8ml/min; Column temperature: 20-25 ℃.Collect filtrate, drying under reduced pressure obtains the purified Tropisetron hydrochloride.
As a preferred embodiment of the present invention, wherein the middle stirring reaction of step (1) is to pH value of solution value 7-9.
As a preferred embodiment of the present invention, the preferred sodium hydroxide of alkali in the step (1) wherein.
As a preferred embodiment of the present invention, wherein add the gac of overall solution volume 0.02-0.03 (g/ml) in the step (2), whip attachment 30-50 minute.
The process for purification of Tropisetron hydrochloride compound provided by the invention, by acid-base reaction, charcoal absorption and preparative chromatography column separating purification have improved the purity of Tropisetron hydrochloride greatly, have optimized the quality product of preparation, have ensured safety of clinical administration; Present method technology is simple, and cost is low, and the yield height is suitable for suitability for industrialized production.
Embodiment
Below further explain and describe content of the present invention by embodiment, but embodiment is not to be construed as limiting the scope of the invention.
Purity testing is undertaken by high performance liquid chromatography with reference to two appendix V of Chinese Pharmacopoeia version in 2005 D.The filling of the preparative chromatography post that uses in the treating process is undertaken by ordinary method.Determine that by nucleus magnetic resonance and infrared spectra the resulting product in refining back is a Tropisetron hydrochloride.
Making with extra care of embodiment 1 Tropisetron hydrochloride
(1) 50g Tropisetron hydrochloride crude product is dissolved in the 500ml water, slowly adds the sodium carbonate solution of 10% (g/ml) then, stirring reaction to pH value of solution is 8, produces the tropisetron precipitation, filters, and 50 ℃ of drying under reduced pressure obtain tropisetron 41.7g.
(2) will go up the tropisetron 41.7g that obtains of step and be dissolved in the 300ml propyl carbinol, and add the gac of 3.5g, stirring at room 35 minutes is filtered decarburization, collects filtrate.
(3) will go up the filtrate that obtains of step and utilize the preparative chromatography post to carry out separation and purification to obtain the Tropisetron hydrochloride highly finished product, wherein to account for the methylene dichloride of moving phase 35% and pH that volume accounts for moving phase 65% as volume be 1 aqueous hydrochloric acid to the moving phase used of chromatographic column; Fixed phase stuffing is a silica gel; Flow velocity is 4.8ml/min; Column temperature: 22 ℃.Collect filtrate, drying under reduced pressure obtains purified Tropisetron hydrochloride 45.8g, yield 91.6%, and HPLC method purity is 99.9%.
Ultimate analysis: C
17H
21ClN
2O
2
Theoretical value (%): C:63.65, H:6.60, N:8.73, Cl:11.05;
Measured value (%): C:63.55, H:6.62, N:8.75, Cl:11.08.
UV(MeOH)λ
max：214(ε38，222)，229(ε17，438)，282(ε13，405)。
IR(KCl)cm
-1：3219，2496(N-H)，3103，748(ArC-H)，2966，1428(C-H)，1692(C＝O)，1580，1525(Ar?C＝C)，1311，1128(C-N)，1033(C-O)。
1HNMR(DMSO-D
6)δ：2.10(d，2H，CH
2)，2.32(d，4H，CH
2)，2.52(m，2H，CH
2)，2.68(s，3H，CH
3)，3.88(s，2H，-CH)，5.14(s，H，CH)，8.03(m，H，CH)，8.08(d，H，CH)，10.81(s，H，HCl)，12.10(s，H，NH)。
ESI-MS；EI?m/z：285(M+H，100％)，284(M
+，21.72％)。
Making with extra care of embodiment 2 Tropisetron hydrochlorides
(1) 50g Tropisetron hydrochloride crude product is dissolved in the 500ml water, slowly adds the sodium hydroxide solution of 8% (g/ml) then, stirring reaction to pH value of solution is 9, produces the tropisetron precipitation, filters, and 40 ℃ of drying under reduced pressure obtain tropisetron 41.3g.
(2) will go up the tropisetron 41.3g that obtains of step and be dissolved in the 300ml normal hexane, and add the gac of 3.3g, stirring at room 45 minutes is filtered decarburization, collects filtrate.
(3) will go up the filtrate that obtains of step and utilize the preparative chromatography post to carry out separation and purification to obtain the Tropisetron hydrochloride highly finished product, wherein to account for the methylene dichloride of moving phase 45% and pH that volume accounts for moving phase 55% as volume be 1 aqueous hydrochloric acid to the moving phase used of chromatographic column; Fixed phase stuffing is a silica gel; Flow velocity is 5.2ml/min; Column temperature: 20 ℃.Collect filtrate, drying under reduced pressure obtains purified Tropisetron hydrochloride 46.2g, yield 92.4%, and HPLC method purity is 99.8%.
Ultimate analysis: C
17H
21ClN
2O
2
Theoretical value (%): C:63.65, H:6.60, N:8.73, Cl:11.05;
Measured value (%): C:63.58, H:6.61, N:8.70, Cl:11.06.
UV(MeOH)λ
max：214(ε38，222)，229(ε17，438)，282(ε13，405)。
IR(KCl)cm
-1：3219，2496(N-H)，3103，748(ArC-H)，2966，1428(C-H)，1692(C＝O)，1580，1525(Ar?C＝C)，1311，1128(C-N)，1033(C-O)。
1HNMR(DMSO-D
6)δ：2.10(d，2H，CH
2)，2.32(d，4H，CH
2)，2.52(m，2H，CH
2)，2.68(s，3H，CH
3)，3.88(s，2H，-CH)，5.14(s，H，CH)，8.03(m，H，CH)，8.08(d，H，CH)，10.81(s，H，HCl)，12.10(s，H，NH)。
ESI-MS；EI?m/z：285(M+H，100％)，284(M
+，21.72％)。
Making with extra care of embodiment 3 Tropisetron hydrochlorides
(1) 50g Tropisetron hydrochloride crude product is dissolved in the 500ml water, slowly adds the sodium hydrogen carbonate solution of 12% (g/ml) then, stirring reaction to pH value of solution is 7, produces the tropisetron precipitation, filters, and 40 ℃ of drying under reduced pressure obtain tropisetron 42.0g.
(2) will go up the tropisetron 42.0g that obtains of step and be dissolved in the 300ml normal hexane, and add the gac of 3.2g, stirring at room 40 minutes is filtered decarburization, collects filtrate.
(3) will go up the filtrate that obtains of step and utilize the preparative chromatography post to carry out separation and purification to obtain the Tropisetron hydrochloride highly finished product, wherein to account for the methylene dichloride of moving phase 40% and pH that volume accounts for moving phase 60% as volume be 1 aqueous hydrochloric acid to the moving phase used of chromatographic column; Fixed phase stuffing is a silica gel; Flow velocity is 5.4ml/min; Column temperature: 25 ℃.Collect filtrate, drying under reduced pressure obtains purified Tropisetron hydrochloride 45.4g, yield 90.8%, and HPLC method purity is 99.7%.
Ultimate analysis: C
17H
21ClN
2O
2
Theoretical value (%): C:63.65, H:6.60, N:8.73, Cl:11.05;
Measured value (%): C:63.59, H:6.63, N:8.74, Cl:11.03.
UV(MeOH)λ
max：214(ε38，222)，229(ε17，438)，282(ε13，405)。
IR(KCl)cm
-1：3219，2496(N-H)，3103，748(Ar?C-H)，2966，1428(C-H)，1692(C＝O)，1580，1525(Ar?C＝C)，1311，1128(C-N)，1033(C-O)。
1HNMR(DMSO-D
6)δ：2.10(d，2H，CH
2)，2.32(d，4H，CH
2)，2.52(m，2H，CH
2)，2.68(s，3H，CH
3)，3.88(s，2H，-CH)，5.14(s，H，CH)，8.03(m，H，CH)，8.08(d，H，CH)，10.81(s，H，HCl)，12.10(s，H，NH)。
ESI-MS；EIm/z：285(M+H，100％)，284(M
+，21.72％)。
Making with extra care of embodiment 4 Tropisetron hydrochlorides
(1) 50g Tropisetron hydrochloride crude product is dissolved in the 500ml water, slowly adds the sodium hydrogen carbonate solution of 8% (g/ml) then, stirring reaction to pH value of solution is 9, produces the tropisetron precipitation, filters, and 45 ℃ of drying under reduced pressure obtain tropisetron 42.2g.
(2) will go up the tropisetron 42.2g that obtains of step and be dissolved in the 300ml ethanol, and add the gac of 3.6g, stirring at room 40 minutes is filtered decarburization, collects filtrate.
(3) will go up the filtrate that obtains of step and utilize the preparative chromatography post to carry out separation and purification to obtain the Tropisetron hydrochloride highly finished product, wherein to account for the methylene dichloride of moving phase 38% and pH that volume accounts for moving phase 62% as volume be 2 aqueous hydrochloric acid to the moving phase used of chromatographic column; Fixed phase stuffing is a silica gel; Flow velocity is 5.6ml/min; Column temperature: 25 ℃.Collect filtrate, drying under reduced pressure obtains purified Tropisetron hydrochloride 44.8g, yield 89.6%, and HPLC method purity is 99.9%.
Ultimate analysis: C
17H
21ClN
2O
2
Theoretical value (%): C:63.65, H:6.60, N:8.73, Cl:11.05;
Measured value (%): C:63.61, H:6.61, N:8.76, Cl:11.04.
UV(MeOH)λ
max：214(ε38，222)，229(ε17，438)，282(ε13，405)。
IR(KCl)cm
-1：3219，2496(N-H)，3103，748(Ar?C-H)，2966，1428(C-H)，1692(C＝O)，1580，1525(Ar?C＝C)，1311，1128(C-N)，1033(C-O)。
1HNMR(DMSO-D
6)δ：2.10(d，2H，CH
2)，2.32(d，4H，CH
2)，2.52(m，2H，CH
2)，2.68(s，3H，CH
3)，3.88(s，2H，-CH)，5.14(s，H，CH)，8.03(m，H，CH)，8.08(d，H，CH)，10.81(s，H，HCl)，12.10(s，H，NH)。
ESI-MS；EI?m/z：285(M+H，100％)，284(M
+，21.72％)。
Making with extra care of embodiment 5 Tropisetron hydrochlorides
(1) 100g Tropisetron hydrochloride crude product is dissolved in the 500ml water, slowly adds the sodium carbonate solution of 12% (g/ml) then, stirring reaction to pH value of solution is 8, produces the tropisetron precipitation, filters, and 40 ℃ of drying under reduced pressure obtain tropisetron 84.1g.
(2) will go up the tropisetron 84.1g that obtains of step and be dissolved in the 400ml ethanol, and add the gac of 5.2g, stirring at room 40 minutes is filtered decarburization, collects filtrate.
(3) will go up the filtrate that obtains of step and utilize the preparative chromatography post to carry out separation and purification to obtain the Tropisetron hydrochloride highly finished product, wherein to account for the methylene dichloride of moving phase 32% and pH that volume accounts for moving phase 68% as volume be 1 aqueous hydrochloric acid to the moving phase used of chromatographic column; Fixed phase stuffing is a silica gel; Flow velocity is 6.2ml/min; Column temperature: 25 ℃.Collect filtrate, drying under reduced pressure obtains purified Tropisetron hydrochloride 91.7g, yield 91.7%, and HPLC method purity is 99.9%.
Ultimate analysis: C
17H
21ClN
2O
2
Theoretical value (%): C:63.65, H:6.60, N:8.73, Cl:11.05;
Measured value (%): C:63.62, H:6.64, N:8.74, Cl:11.06.
UV(MeOH)λ
max：214(ε38，222)，229(ε17，438)，282(ε13，405)。
IR(KCl)cm
-1：3219，2496(N-H)，3103，748(Ar?C-H)，2966，1428(C-H)，1692(C＝O)，1580，1525(Ar?C＝C)，1311，1128(C-N)，1033(C-O)。
1HNMR(DMSO-D
6)δ：2.10(d，2H，CH
2)，2.32(d，4H，CH
2)，2.52(m，2H，CH
2)，2.68(s，3H，CH
3)，3.88(s，2H，-CH)，5.14(s，H，CH)，8.03(m，H，CH)，8.08(d，H，CH)，10.81(s，H，HCl)，12.10(s，H，NH)。
ESI-MS；EI?m/z：285(M+H，100％)，284(M
+，21.72％)。
Claims (4)
1. the purification process of the Tropisetron hydrochloride compound shown in the formula (I) comprises the steps:
(1) the Tropisetron hydrochloride crude product is soluble in water, slowly add alkali then, stirring reaction to pH value of solution is 7-10, generation tropisetron precipitation is filtered 35-50 ℃ of drying under reduced pressure, obtain tropisetron, described alkali is sodium hydroxide, potassium hydroxide, yellow soda ash or sodium bicarbonate;
(2) will go up the tropisetron that obtains of step is dissolved in the solvent of 2-10 times of weight, the gac that adds overall solution volume 0.01-0.05g/ml, 20-50 ℃ was stirred 0.5-1.5 hour, filtered decarburization, collect filtrate, wherein said solvent is selected from propyl carbinol, normal hexane or ethanol;
(3) will go up the filtrate that obtains of step utilizes the preparative chromatography post to carry out separation and purification to obtain the Tropisetron hydrochloride highly finished product, wherein the moving phase used of chromatographic column accounts for the methylene dichloride of moving phase 30-50% or acetone and volume as volume and accounts for the aqueous hydrochloric acid of the pH of moving phase 50-70% as 1-2, fixed phase stuffing is selected from silica gel or aluminum oxide, flow velocity is 4.5-6.8ml/min, column temperature 20-25 ℃, collect filtrate, drying under reduced pressure obtains the purified Tropisetron hydrochloride.
2. purification process according to claim 1 is characterized in that stirring reaction is to pH value of solution value 7-9 in the step (1).
3. purification process according to claim 1 is characterized in that the middle gac that adds overall solution volume 0.02-0.03g/ml of step (2), whip attachment 30-50 minute.
4. purification process according to claim 1 is characterized in that the alkali described in the step (1) is sodium hydroxide.
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|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159765A (en) * | 2011-12-15 | 2013-06-19 | 北京嘉林药业股份有限公司 | Indisetron purification method suitable for industrialization |
| CN104844591A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form II substance, preparation method, composition and uses thereof |
| CN104844592A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form III substance, preparation method, composition and uses thereof |
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| CN102532128B (en) * | 2010-12-17 | 2014-11-12 | 北大方正集团有限公司 | Synthetic method of tropisetron and prepare method of hydrochloric acid tropisetron |
| CN102351857B (en) * | 2011-08-23 | 2013-06-12 | 天津市汉康医药生物技术有限公司 | Tropiseiron hydrochloride compound |
| CN102367252A (en) * | 2011-11-03 | 2012-03-07 | 天津市汉康医药生物技术有限公司 | Tropisetron hydrochloride compound |
| CN103408543B (en) * | 2013-08-12 | 2014-02-12 | 回音必集团抚州制药有限公司 | High purity citric acid and navoban compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100503601C (en) * | 2007-04-02 | 2009-06-24 | 北京成宇化工有限公司 | Process of preparing troipisetron |
-
2010
- 2010-03-05 CN CN2010101179171A patent/CN101787021B/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159765A (en) * | 2011-12-15 | 2013-06-19 | 北京嘉林药业股份有限公司 | Indisetron purification method suitable for industrialization |
| CN103159765B (en) * | 2011-12-15 | 2015-06-24 | 北京嘉林药业股份有限公司 | Indisetron purification method suitable for industrialization |
| CN104844591A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form II substance, preparation method, composition and uses thereof |
| CN104844592A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form III substance, preparation method, composition and uses thereof |
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