Dolasetron isomer or salt thereof, preparation method for the Dolasetron isomer or salt thereof and application of the Dolasetron isomer or salt thereof

Abstract

The invention relates to a Dolasetron isomer or salt thereof, a preparation method for the Dolasetron isomer or salt thereof and application of the Dolasetron isomer or salt thereof. In the preparation method, the Dolasetron isomer or salt thereof is prepared from outside-hexahydro-8-hydroxy-2,6-methylene-2H-quinolizidine-3(4H)-ketone or salt thereof serving as a raw material by esterifying and salifying. The invention also provides two methods for synthesizing outside-hexahydro-8-hydroxy-2,6-methylene-2H-quinolizidine-3(4H)-ketone. The outside-hexahydro-8-hydroxy-2,6-methylene-2H-quinolizidine-3(4H)-ketone is prepared from the compound (6) shown in the specification and serving as a raw material by the steps of reducing, protecting hydroxyl, performing Dieckmann condensation and performing hydrolysis and decarboxylation, or by the steps of reducing, performing Mitsunbu esterification, performing hydrolysis, protecting hydroxyl, performing Dieckmann condensation and performing hydrolysis and decarboxylation. The invention also relates to application of the Dolasetron isomer or the salt thereof to preparation of Dolasetron, or application of the salt of the Dolasetron isomer to preparation of control products for detection.

Description

technical field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to dolasetron isomers or salts thereof, preparation methods and applications thereof. Background technique

[0002] In recent years, the market sales of antiemetic drugs have been increasing year by year, and their market share in digestive system drugs ranks second only to antiulcer drugs.

[0003] Dolasetron and its salts are potent and highly selective 5-HT 3 Receptor antagonists are clinically used to prevent and treat nausea and vomiting in tumor patients during chemotherapy and after gynecological operations and surgical operations, with mild adverse reactions. Specifically, the clinical therapeutic applications of dolasetron and its salts mainly include: 1) prevention of nausea and vomiting associated with naïve and re-treated emetogenic tumor chemotherapy (including high-dose cisplatin), strongly inhibiting cisplatin, adriamycin 2) Prevention of postoperative naus...

Examples

Embodiment 1

[0061] Example 1 Preparation of cis-7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3,3,1]nonan-3-ol

[0062] Put 100g of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3,3,1]non-3-one, 500ml of tetrahydrofuran and 10g of Raney nickel into the autoclave , feed hydrogen to a pressure of 0.1Mpa; slowly heat up to 90-100°C, adjust the hydrogen pressure to 0.5-0.6Mpa, stir until the reaction is complete, cool to room temperature, and filter the reaction solution through diatomaceous earth to remove Raney nickel , after the obtained filtrate was concentrated and dried under reduced pressure, the obtained brown-yellow oil was purified through a silica gel column (980 g of 200-300 mesh silica gel, packed with petroleum ether, washed with ethyl acetate / petroleum ether (1 / 10-1 / 5) deagent), to obtain light yellow oil 12g.

Embodiment 2

[0063] Example 2 Preparation of cis-7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3,3,1]nonan-3-ol

[0064]Dissolve 100g of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3,3,1]nonan-3-one with 500ml of absolute ethanol and add 12.5g in batches Sodium borohydride, heating to reflux, stirring, until the reaction is complete, add concentrated hydrochloric acid dropwise, adjust the pH of the reaction solution to 7~8, recover ethanol under reduced pressure, add water to dissolve the obtained concentrate after cooling, and extract to the water phase with ethyl acetate There was no product, the ethyl acetate layers were combined and dried with anhydrous sodium sulfate, anhydrous sodium sulfate was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the obtained concentrate was purified on a silica gel column (950 g of 200-300 mesh silica gel, packed in petroleum ether, washed The deagent is ethyl acetate / petroleum ether (1 / 10~1 / 5))...

Embodiment 3

[0065] Example 3 Preparation of cis-7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo[3,3,1]nonan-3-ol-2-tetrahydropyranyl ether

[0066] Dissolve 20 g of cis-7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3,3,1]nonan-3-ol in 100 ml of dichloromethane, cool in an ice bath, Slowly add 6g of methanesulfonic acid dropwise, then add 6g of 3,4-dihydropyran dropwise, stir until the reaction is complete, transfer the reaction solution into 200g of 40% potassium carbonate solution, extract with ethyl acetate, take the ethyl acetate layer It was dried with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure to obtain 24 g of brown-yellow oil.

technical field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to dolasetron isomers or salts thereof, preparation methods and applications thereof. Background technique

[0002] In recent years, the market sales of antiemetic drugs have been increasing year by year, and their market share in digestive system drugs ranks second only to antiulcer drugs.

[0003] Dolasetron and its salts are potent and highly selective 5-HT 3 Receptor antagonists are clinically used to prevent and treat nausea and vomiting in tumor patients during chemotherapy and after gynecological operations and surgical operations, with mild adverse reactions. Specifically, the clinical therapeutic applications of dolasetron and its salts mainly include: 1) prevention of nausea and vomiting associated with naïve and re-treated emetogenic tumor chemotherapy (including high-dose cisplatin), strongly inhibiting cisplatin, adriamycin 2) Prevention of postoperative naus...

Examples

Embodiment 1

[0061] Example 1 Preparation of cis-7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3,3,1]nonan-3-ol

[0062] Put 100g of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3,3,1]non-3-one, 500ml of tetrahydrofuran and 10g of Raney nickel into the autoclave , feed hydrogen to a pressure of 0.1Mpa; slowly heat up to 90-100°C, adjust the hydrogen pressure to 0.5-0.6Mpa, stir until the reaction is complete, cool to room temperature, and filter the reaction solution through diatomaceous earth to remove Raney nickel , after the obtained filtrate was concentrated and dried under reduced pressure, the obtained brown-yellow oil was purified through a silica gel column (980 g of 200-300 mesh silica gel, packed with petroleum ether, washed with ethyl acetate / petroleum ether (1 / 10-1 / 5) deagent), to obtain light yellow oil 12g.

Embodiment 2

[0063] Example 2 Preparation of cis-7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3,3,1]nonan-3-ol

[0064]Dissolve 100g of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3,3,1]nonan-3-one with 500ml of absolute ethanol and add 12.5g in batches Sodium borohydride, heating to reflux, stirring, until the reaction is complete, add concentrated hydrochloric acid dropwise, adjust the pH of the reaction solution to 7~8, recover ethanol under reduced pressure, add water to dissolve the obtained concentrate after cooling, and extract to the water phase with ethyl acetate There was no product, the ethyl acetate layers were combined and dried with anhydrous sodium sulfate, anhydrous sodium sulfate was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the obtained concentrate was purified on a silica gel column (950 g of 200-300 mesh silica gel, packed in petroleum ether, washed The deagent is ethyl acetate / petroleum ether (1 / 10~1 / 5))...

Embodiment 3

[0065] Example 3 Preparation of cis-7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo[3,3,1]nonan-3-ol-2-tetrahydropyranyl ether

[0066] Dissolve 20 g of cis-7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3,3,1]nonan-3-ol in 100 ml of dichloromethane, cool in an ice bath, Slowly add 6g of methanesulfonic acid dropwise, then add 6g of 3,4-dihydropyran dropwise, stir until the reaction is complete, transfer the reaction solution into 200g of 40% potassium carbonate solution, extract with ethyl acetate, take the ethyl acetate layer It was dried with anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure to obtain 24 g of brown-yellow oil.

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