CN108148059A - The preparation method of the double indoles impurity of Tropisetron - Google Patents
The preparation method of the double indoles impurity of Tropisetron Download PDFInfo
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- CN108148059A CN108148059A CN201810127485.9A CN201810127485A CN108148059A CN 108148059 A CN108148059 A CN 108148059A CN 201810127485 A CN201810127485 A CN 201810127485A CN 108148059 A CN108148059 A CN 108148059A
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- Prior art keywords
- tropisetron
- impurity
- preparation
- indoles
- double
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/12—Oxygen atoms acylated by aromatic or heteroaromatic carboxylic acids, e.g. cocaine
Abstract
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation method of the double indoles impurity of Tropisetron.The preparation method of the double indoles impurity of the Tropisetron, step are as follows：(1) 3 indolecarboxylic acids, acylating reagent are dissolved in solvent and reacted, it is post-treated, obtain 3 indoles formyl chlorides；(2) Tropisetron is dissolved in tetrahydrofuran, is cooled to 15~20 DEG C, add in alkali, then, the tetrahydrofuran solution of 3 indoles formyl chlorides is added dropwise, is added dropwise, react at room temperature 2~10 hours, it is post-treated, obtain the double indoles impurity of Tropisetron.The preparation method of the present invention, easy to operate, reaction is mild, and yield is higher, and product purity is high, suitable for bulk pharmaceutical chemicals impurity spectrum analysis etc., has good commercial value.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation method of the double indoles impurity of Tropisetron.
Background technology
Tropisetron is efficient, Gao Xuan of a kind of peripheral neurons and central nervous system serotonin 3 (5-HT3) receptor
Sexual competition antagonist is selected, nausea and vomiting caused by for preventing and treating cancer chemotherapy.The dosage form of domestic listing has piece at present
Agent, capsule and injection.The Tropisetron bulk pharmaceutical chemicals needs for being used to prepare Tropisetron parenteral solution reach qualified purity, single
Miscellaneous content will also reach corresponding requirements.At present, the main stream approach for preparing Tropisetron bulk pharmaceutical chemicals is by indole -3-carboxylic acid and α-support
Product alcohol is condensed, this technique can generate double indoles impurity, and structure is as shown in Figure 2.
At present, for the preparation method of the double indoles impurity of Tropisetron there are no document and patent report, in order to better
Quality research is carried out to Tropisetron bulk pharmaceutical chemicals, it is ensured that product quality, determine the preparation methods of the double indoles impurity of Tropisetron into
The technical issues of being urgently to be resolved hurrily.
Invention content
To solve the above problems, the object of the present invention is to provide a kind of preparation method of the double indoles impurity of Tropisetron, tool
There is the characteristics of easily operated, reaction condition is mild, high income, high purity.
The preparation method of the double indoles impurity of Tropisetron of the present invention, step are as follows：
(1) 3- indolecarboxylic acids, acylating reagent are dissolved in solvent and reacted, it is post-treated, obtain 3- indoles formyl chlorides；
(2) Tropisetron is dissolved in tetrahydrofuran, is cooled to -15~20 DEG C, add in alkali, then, 3- indoles first is added dropwise
The tetrahydrofuran solution of acyl chlorides, is added dropwise, and reacts at room temperature 2~10 hours, post-treated, obtains the double indoles impurity of Tropisetron.
Wherein：
In step (1), the acylating reagent is oxalyl chloride or thionyl chloride, preferably oxalyl chloride.
In step (1), the solvent is ethyl acetate or dichloromethane.
In step (1), the molar ratio of the 3- indolecarboxylic acids and acylating reagent is 1:1~10.
In step (1), the reaction time is 5 hours.
In step (1), to filter, filter cake is washed with dichloromethane for the post processing.
In step (2), the alkali is in the hexane solution of n-BuLi, sodium hydride, sodium ethoxide or potassium tert-butoxide
It is a kind of.Preferably, the alkali is the hexane solution of n-BuLi, and feed postition is is added dropwise.
In step (2), the post processing is evaporated under reduced pressure filtrate, is then extracted, had using ethyl acetate and water to filter
It after machine is added to anhydrous sodium sulfate drying, filters, vacuum distillation obtains crude product, purifies to obtain product.The purifying is post separation,
The eluant, eluent used for dichloromethane and the mixed liquor of methanol, wherein, the volume ratio of dichloromethane and methanol is 5~20：1, it is excellent
Select 10：1.
Beneficial effects of the present invention are as follows：
The preparation method of the present invention, easy to operate, reaction is mild, and yield is higher, and product purity is high, miscellaneous suitable for bulk pharmaceutical chemicals
Mass spectral analysis etc. has good commercial value.
Description of the drawings
Fig. 1 is the mass spectrogram of the double indoles impurity of Tropisetron of the present invention；
Fig. 2 is the structure chart of the double indoles impurity of Tropisetron of the present invention.
Specific embodiment
The present invention is described further with reference to embodiments.
The raw material used in embodiment is marketable material unless otherwise specified.
Embodiment 1
3- indolecarboxylic acids (5.0g, 31mmol) are added in 100mL reaction bulbs, add in 25mL dichloromethane, add in oxalyl
Raw material is reacted finishes (dichloromethane for chlorine (5.3mL, 62mmol) normal-temperature reaction 5h, TLC detection：Methanol=10:1).After
Reason：Filtering removes filtrate, and filter cake is washed twice with dichloromethane, is dried in vacuo to obtain yellow solid powder 4.5g, yield
81.2%.
Embodiment 2
3- indolecarboxylic acids (5.0g, 31mmol) are added in 100mL reaction bulbs, add in 25mL dichloromethane, add in chlorination
Sulfoxide (9.2mL, 124mmol) normal-temperature reaction 4h.Raw material is reacted finishes (dichloromethane for TLC detections：Methanol=10:1).Afterwards
Processing：Filtering removes filtrate, and filter cake is washed twice with dichloromethane, is dried in vacuo to obtain yellow solid powder 4.3g, yield
78.2%.
Embodiment 3
3- indolecarboxylic acids (5.0g, 31mmol) are added in 100mL reaction bulbs, add in 25mL ethyl acetate, add in oxalyl
Chlorine (15.9mL, 186mmol) normal-temperature reaction 3h.Raw material is reacted finishes (dichloromethane for TLC detections：Methanol=10:1).Afterwards
Processing：Vacuum distillation removes solvent, obtains thick solid, adds in 10mL dichloromethane, is beaten 1 hour, and filtering removes filter
Liquid, filter cake are washed twice with dichloromethane, are dried in vacuo to obtain yellow solid powder 3.9g, yield 70.9%.
Embodiment 4
Tropisetron (2.0g, 7mmol) is added in 100mL there-necked flasks, 10mL tetrahydrofurans is added in, is cooled to -5
DEG C, the hexane solution (6mL, 15mmol) of n-BuLi is added dropwise, is added dropwise, by 3- indoles formyl chloride (1.8g, 10mmol)
It is dissolved in 5mL tetrahydrofurans, is added dropwise in reaction solution, be added dropwise, react at room temperature 2 hours, TLC detection raw materials are reacted complete
Finish (dichloromethane：Methanol=10:1).Post processing：Reaction solution is filtered, removes insoluble matter, vacuum distillation adds in second except solvent
Acetoacetic ester and water, extraction is organic to be added to anhydrous sodium sulfate drying, filters, vacuum distillation obtains crude material.Column chromatography for separation
Purifying, eluant, eluent is dichloromethane：Methanol=10：1, obtain product 895mg, yield 32.1%, purity 97.5%.
Embodiment 5
Tropisetron (2.0g, 7mmol) is added in 100mL there-necked flasks, 10mL tetrahydrofurans is added in, is cooled to 5 DEG C,
Sodium hydride (0.3g, 14mmol) is added in, 3- indoles formyl chloride (1.8g, 10mmol) is dissolved in 5mL tetrahydrofurans, is added dropwise to anti-
It answers in liquid, is added dropwise, react at room temperature 6 hours, raw material is reacted finishes (dichloromethane for TLC detections：Methanol=15:1) after,
Processing：Reaction solution is filtered, removes insoluble matter, vacuum distillation adds in ethyl acetate and water, extraction is organic to be added to except solvent
Anhydrous sodium sulfate is dried, and is filtered, and vacuum distillation obtains crude material.Column chromatographic isolation and purification, eluant, eluent are dichloromethane：Methanol
=15:1, obtain product 623mg, yield 22.3%, purity 98.3%.
The double indoles impurity mass spectrums of Tropisetron are：M/Z=428.2 is shown in attached drawing 1.
Claims (10)
1. a kind of preparation method of the double indoles impurity of Tropisetron, it is characterised in that：Step is as follows：
(1) 3- indolecarboxylic acids, acylating reagent are dissolved in solvent and reacted, it is post-treated, obtain 3- indoles formyl chlorides；
(2) Tropisetron is dissolved in tetrahydrofuran, is cooled to -15~20 DEG C, add in alkali, then, 3- indoles formyl chlorides are added dropwise
Tetrahydrofuran solution, be added dropwise, react at room temperature 2~10 hours, it is post-treated, obtain the double indoles impurity of Tropisetron.
2. the preparation method of the double indoles impurity of Tropisetron according to claim 1, it is characterised in that：In step (1), institute
The acylating reagent stated is oxalyl chloride or thionyl chloride.
3. the preparation method of the double indoles impurity of Tropisetron according to claim 2, it is characterised in that：In step (1), institute
The acylating reagent stated is oxalyl chloride.
4. the preparation method of the double indoles impurity of Tropisetron according to claim 1, it is characterised in that：In step (1), institute
The solvent stated is ethyl acetate or dichloromethane.
5. the preparation method of the double indoles impurity of Tropisetron according to claim 1, it is characterised in that：In step (1), institute
The 3- indolecarboxylic acids and the molar ratio of acylating reagent stated are 1:1~10.
6. the preparation method of the double indoles impurity of Tropisetron according to claim 1, it is characterised in that：In step (1), institute
To filter, filter cake is washed with dichloromethane for the post processing stated.
7. the preparation method of the double indoles impurity of Tropisetron according to claim 1, it is characterised in that：In step (2), institute
The alkali stated is one kind in the hexane solution of n-BuLi, sodium hydride, sodium ethoxide or potassium tert-butoxide.
8. the preparation method of the double indoles impurity of Tropisetron according to claim 7, it is characterised in that：In step (2), institute
The alkali stated is the hexane solution of n-BuLi, and feed postition is is added dropwise.
9. the preparation method of the double indoles impurity of Tropisetron according to claim 1, it is characterised in that：In step (2), institute
The post processing stated is evaporated under reduced pressure filtrate, is then extracted using ethyl acetate and water, organic anhydrous sodium sulfate that is added to is done to filter
It after dry, filters, vacuum distillation obtains crude product, purifies to obtain product.
10. the preparation method of the double indoles impurity of Tropisetron according to claim 9, it is characterised in that：The purifying
For post separation, the eluant, eluent used for dichloromethane and the mixed liquor of methanol, wherein, the volume ratio of dichloromethane and methanol is 5
~20：1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5124324A (en) * | 1989-11-17 | 1992-06-23 | Nisshin Flour Milling Co., Ltd. | Indole derivatives |
| CN101838266A (en) * | 2009-02-17 | 2010-09-22 | 回音必集团抚州制药有限公司 | Citric acid tropisetron raw material medicine and preparation technology of raw material medicine and injection liquid |
| CN102507796A (en) * | 2011-11-26 | 2012-06-20 | 山东齐都药业有限公司 | Detecting method for indole-3-carboxylic acid of impurities in tropisetron hydrochloride raw materials and preparations |
-
2018
- 2018-02-08 CN CN201810127485.9A patent/CN108148059A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5124324A (en) * | 1989-11-17 | 1992-06-23 | Nisshin Flour Milling Co., Ltd. | Indole derivatives |
| CN101838266A (en) * | 2009-02-17 | 2010-09-22 | 回音必集团抚州制药有限公司 | Citric acid tropisetron raw material medicine and preparation technology of raw material medicine and injection liquid |
| CN102507796A (en) * | 2011-11-26 | 2012-06-20 | 山东齐都药业有限公司 | Detecting method for indole-3-carboxylic acid of impurities in tropisetron hydrochloride raw materials and preparations |
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Application publication date: 20180612 |