CN111362935B - Synthesis method of N-hydroxy tropisetron - Google Patents
Synthesis method of N-hydroxy tropisetron Download PDFInfo
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- CN111362935B CN111362935B CN202010337316.5A CN202010337316A CN111362935B CN 111362935 B CN111362935 B CN 111362935B CN 202010337316 A CN202010337316 A CN 202010337316A CN 111362935 B CN111362935 B CN 111362935B
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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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a method for synthesizing tropisetron oxide N-hydroxy tropisetron, belonging to the field of medicine synthesis. The method takes 2-nitrophenylacetic ester as a raw material, realizes the synthesis of tropisetron oxide N-hydroxy tropisetron through a six-step reaction, screens out optimal preparation steps and reaction conditions through a large number of experiments, obtains a target product with the purity of over 99 percent, does not contain the tropisetron serving as a raw material medicine, can be used for researches such as pharmacokinetics, raw material medicine impurity identification and the like, and has important application value for impurity identification, metabolic mechanism and new medicine research and design of the tropisetron.
Description
Technical Field
The invention belongs to a medicine synthesis technology, and particularly relates to a method for synthesizing tropisetron oxide N-hydroxy tropisetron.
Background
Anticancer drugs or radiotherapy can stimulate chromaffin cells of small intestinal mucosa to release serotonin (5-HT), induce vomiting reflex, and cause nausea and vomiting. Tropisetron is a high-efficiency and selective 5-HT3 receptor antagonist, is a high-selectivity inhibitor of 5-HT3 receptors in peripheral neurons and the central nervous system, can selectively inhibit excitation of presynaptic 5-HT3 receptors of peripheral neurons in the reflex, and can have direct influence on the vagal afferent posterior region transmitted by the 5-HT3 receptors of the central nervous system. The dual action blocks the chemical transmission of nerve mediators during the vomiting reflex, thus having therapeutic effect on vomiting caused by chemotherapy and radiotherapy. Clinical research shows that the curative effect of the medicine is not reduced when the medicine is continuously used in 2-3 cancer chemotherapy cycles.
Oxidation reaction inevitably occurs in the synthetic process and the in vivo metabolic process, and the oxidation reaction has important influence on impurity control, identification and the like in the synthetic process of the raw material medicine; the latter has important significance for the research of metabolic process, approach and the like of the medicine, so that the oxide of the bulk drug is a special medicine impurity, and has practical application value for synthesizing and confirming the structure.
According to the related publication (CN 110638819A), a mixture of N-hydroxytryptosetron and other analogues can produce synergistic antitumor effects with extracts of Camellia Chysantha, Celastrus orbiculatus, pinellia Tuber, Hedyotis diffusa, Cudrania tricuspidata, Anthriscus sylvestris, etc.
The synthesis method of the N-hydroxy tropisetron provided by the invention has no report at present.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the prior art, the invention provides the synthesis method of the N-hydroxy tropisetron, which has the advantages of reasonable process design, strong operability, easy purification of products, high purity and capability of realizing repeated production.
The technical scheme is as follows: the synthetic method of the N-hydroxy tropisetron is characterized in that the synthetic route is as follows:
the method specifically comprises the following steps:
(1) dissolving a compound I2-nitrophenyl acetate in an organic solvent, and reacting with formaldehyde, quaternary ammonium base and alkali to obtain a compound II;
in the compounds I and II, R1 is methyl ester, ethyl ester, tert-butyl ester or benzyl ester;
(2) dissolving the compound II obtained in the step (1) in an organic solvent, and reacting with a reducing agent and salt to obtain a compound III;
(3) dissolving the compound III obtained in the step (2) in an organic solvent, adding an organic reagent for reaction, and protecting hydroxyl to obtain a compound IV;
(4) dissolving the compound IV obtained in the step (3) in a solvent, and reducing by using a metal catalyst or hydrolyzing by using acid and alkali to obtain a compound V;
(5) dissolving the compound V obtained in the step (4) in an organic solvent, and reacting the compound V with a compound VI in the presence of alkali or a condensing agent to obtain a compound VII;
in the compound VI, R3 is chlorine, bromine or hydroxyl;
(6) dissolving the compound VII obtained in the step (5) in an organic solvent, and reacting with a deprotection reagent to obtain a compound VIII;
in the step (1), R1 in the compounds I and II is preferably benzyl ester.
In the step (1), the organic solvent is tetrahydrofuran, dioxane, toluene or xylene, and the volume ratio of the solvent to the compound I is 5-30: 1. further preferably, the organic solvent is dioxane, and the volume ratio of the dioxane to the organic solvent is 20: 1.
in the step (1), the formaldehyde is in the form of 37% aqueous solution or paraformaldehyde, and the molar ratio of the formaldehyde to the compound I is 2-10: 1. more preferably, paraformaldehyde is selected and the molar ratio is 3: 1.
in the step (1), the quaternary ammonium base is tetrabutylammonium fluoride, tetrabutylammonium iodide or tetrabutylammonium hydrogen sulfate, and the molar ratio of the quaternary ammonium base to the compound I is 0.1-0.5: 1. more preferably, tetrabutylammonium hydrogen sulfate is selected and the molar ratio is 0.2: 1.
in the step (1), the alkali is potassium carbonate, sodium bicarbonate or sodium hydroxide, and the molar ratio of the alkali to the compound I is 1-5: 1. as a more preferred option, potassium carbonate is chosen, and the molar ratio is 2: 1.
the reaction temperature of the step (1) is 50-140 ℃, and the reaction time is 2-16 hours. More preferably, the reaction is carried out at 100 ℃ for 4 hours.
In the step (2), the organic solvent is tetrahydrofuran, dioxane, ethyl acetate or toluene, and the volume ratio of the solvent to the compound II is 10-100: 1. more preferably, tetrahydrofuran is selected, and the volume ratio is 40: 1.
in the step (2), the reducing agent is reduced iron powder and stannous chloride, and the molar ratio of the reducing agent to the compound II is 1-6: 1. more preferably, stannous chloride is selected and the molar ratio is 4: 1.
in the step (2), the salt is potassium acetate, sodium acetate, ammonium acetate and ammonium chloride, and the molar ratio of the salt to the compound II is 1-25: 1. as a more preferred option, potassium acetate is selected and the molar ratio is 15: 1.
in the step (2), the reaction temperature is 60-125 ℃, and the reaction time is 2-24 hours. More preferably, 80 ℃ is selected and the reaction time is 16 hours.
In the step (3), the organic solvent is N, N-dimethylformamide, acetonitrile, tetrahydrofuran or toluene, and the volume ratio of the solvent to the compound III is 5-30: 1. more preferably, tetrahydrofuran is selected, and the volume ratio is 15: 1.
in the step (3), the organic reagent is sodium hydrogen-benzyl bromide, potassium carbonate-p-methoxybenzyl chloride or diethyl azodicarboxylate-triphenylphosphine-2- (trimethylsilyl) ethanol, and the molar ratio of the reagent to the compound III is 1-3: 1. as a more preferred embodiment, diethyl azodicarboxylate-triphenylphosphine-2- (trimethylsilyl) ethanol was chosen, and the molar ratio was 1.5: 1.5: 1.2: 1.
in the step (3), the reaction temperature is-20 ℃ to 80 ℃, and the reaction time is 0.5 to 18 hours. More preferably, the reaction is carried out at 15 ℃ for 18 hours.
In the step (4), the solvent is tetrahydrofuran, methanol, ethanol or dichloromethane, and the volume ratio of the solvent to the compound IV is 5-50: 1. more preferably, tetrahydrofuran is selected, and the volume ratio is 10: 1.
in the step (4), when the reagent is a metal catalyst, palladium carbon is used; when the acid is selected, the acid is diethyl ether hydrogen chloride; when alkali is selected, the alkali is sodium hydroxide or potassium hydroxide; and the mass ratio or the molar ratio of the reagent to the compound IV is 0.1-10: 1. more preferably, the metal catalyst, i.e., palladium on carbon, is selected in a mass ratio of 0.1: 1.
in the step (4), the reaction temperature is 0-65 ℃, and the reaction time is 6-48 hours. More preferably, the reaction is carried out at 25 ℃ for 6 hours.
In the step (5), the molar ratio of the compound VI to the compound V is 0.8-2.2: 1. more preferably, the bromide (R3 ═ Br) is selected and the molar ratio is 1.3: 1.
in the step (5), the organic solvent is N, N-dimethylformamide, acetonitrile, dimethyl sulfoxide or dichloromethane, and the volume ratio of the solvent to the compound V is (5-50): 1. more preferably, N-dimethylformamide is selected and the volume ratio is 20: 1.
in the step (5), the reaction reagent (alkali or condensing agent) is potassium carbonate, cesium carbonate, dicyclohexylcarbodiimide, and EDCI, and the molar ratio of the reagent to the compound v is 1-4: 1. more preferably, cesium carbonate is chosen and the molar ratio is 1.6: 1.
in the step (5), the reaction temperature is 0-100 ℃, and the reaction time is 0.5-8 hours. More preferably, 25 ℃ is selected and the reaction time is 4 hours.
In the step (6), the organic solvent is tetrahydrofuran, dichloromethane, ethyl acetate or toluene, and the volume ratio of the solvent to the compound VII is 5-50: 1. more preferably, tetrahydrofuran is selected, and the volume ratio is 20: 1;
in the step (6), the deprotection reagent is a reagent of hydrogen chloride, tetrabutylammonium fluoride, palladium carbon or pyridine hydrochloride, and the molar ratio of the reagent to the compound VII is 0.1-5: 1. more preferably, tetrabutylammonium fluoride is selected and the molar ratio is 3: 1;
in the step (6), the reaction temperature is 0-130 ℃, and the reaction time is 0.5-24 hours. More preferably, 30 ℃ is chosen and the reaction time is 16 hours.
Has the beneficial effects that: the synthesis method of the N-hydroxy tropisetron has reasonable whole process design and strong operability, wherein the optimal reaction conditions of each reaction step are obtained by a large number of experimental screens. The N-hydroxy tropisetron prepared by the method has the advantages of high purity up to more than 99% and high yield. The N-hydroxy tropisetron prepared by the method can provide a sample for product quality control, impurity identification, drug metabolic pathway, metabolic mechanism, kinetic parameter research and the like of tropisetron, and has important significance.
Drawings
FIG. 1 is an IR spectrum of N-hydroxythiosetron VIII prepared in example 1;
FIG. 2 is an NMR spectrum of N-hydroxythiosetron VIII prepared in example 1.
Detailed Description
The present application will be described in detail with reference to specific examples.
2-nitrobenzyl nitrophenylacetate and tert-butyl 2-nitrophenylacetate are derived from 2-nitrophenylacetic acid as raw material.
Example 1
The synthesis method of the N-hydroxy tropisetron comprises the following steps:
(1) synthesis of intermediate II
The reaction process is as follows:
20 g of benzyl 2-nitrophenylacetate was dissolved in 400 ml of dioxane, and 5.01 g of tetrabutylammonium hydrogensulfate, 20.38 g of potassium carbonate and 6.64 g of paraformaldehyde were added, followed by heating the mixture to 100 ℃ for 4 hours. The reaction was cooled to room temperature, filtered, and the filtrate was partially concentrated and purified by column chromatography to give 15.65 g of an oil, intermediate ii, in 74.9% yield.
(2) Synthesis of intermediate III
The reaction process is as follows:
dissolving 15 g of the intermediate II in 600 ml of tetrahydrofuran, adding 40.16 g of anhydrous stannous chloride and 77.86 g of anhydrous potassium acetate, mechanically stirring, reacting at 80 ℃ for 16 hours, cooling to 50 ℃, adding 400 ml of ethyl acetate, carrying out suction filtration on diatomite, washing an organic phase for 3 times by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating, and purifying by using column chromatography to obtain 10.72 g of white solid, namely the intermediate III, wherein the yield is 75.7%.
(3) Synthesis of intermediate IV
The reaction process is as follows:
10.5 g of intermediate III was dissolved in 157.5 ml of tetrahydrofuran, 5.57 g of 2- (trimethylsilyl) ethanol and 15.44 g of triphenylphosphine were added, 10.25 g of diethyl azodicarboxylate was slowly added dropwise in an ice bath, and then a reaction was carried out at 15 ℃ for 18 hours. The reaction was concentrated and purified by column chromatography to give 8.80 g of a yellow oil, intermediate IV, in 60.9% yield.
(4) Synthesis of intermediate V
The reaction process is as follows:
8.5 g of the intermediate IV is dissolved in 85 ml of tetrahydrofuran, 850mg of 10% palladium carbon is added under the protection of nitrogen, and then reaction is carried out for 6 hours at 25 ℃ by using a hydrogen balloon as a hydrogen source. And (3) carrying out suction filtration on the reaction solution under the protection of nitrogen, and carrying out spin drying on the filtrate to obtain 6.10 g of oily matter, namely the intermediate V, with the yield of 95.1%.
(5) Synthesis of intermediate VII
The reaction process is as follows:
dissolving 6.1 g of the intermediate V in 122 ml of N, N-dimethylformamide, adding 5.83 g of bromotropine, namely the intermediate VI and 11.46 g of cesium carbonate, reacting the reaction solution at 25 ℃ for 4 hours, adding 70 ml of water and 100 ml of ethyl acetate into the reaction solution, separating an organic phase, extracting the water phase with ethyl acetate for 3 times, 50 ml each time, combining the organic phases, washing the organic phases with saturated saline solution for 3 times, 120 ml each time, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain 5.7 g of oily matter, namely the intermediate VII with the yield of 64.7%.
(6) Synthesis of N-hydroxy tropisetron VIII
The reaction process is as follows:
5.5 g of the intermediate VII was dissolved in 110 ml of tetrahydrofuran, 16.5 g of tetrabutylammonium fluoride was added thereto, and after the mixture was stirred until it was clear, the reaction was carried out at 30 ℃ for 16 hours. Adding 300 ml of water into the system, extracting for 3 times by using dichloromethane, each time extracting for 100 ml, combining organic phases, drying by using anhydrous sodium sulfate, concentrating, purifying by using column chromatography to obtain a crude product, and recrystallizing and purifying by using dichloromethane-methanol to obtain 2.7 g of white solid, namely N-hydroxy tropisetron VIII, wherein the yield is 65.6%, and the liquid phase purity is as follows: 99.3508%, IR is shown in FIG. 1, and NMR is shown in FIG. 2.
Example 2
The synthesis method of the N-hydroxy tropisetron comprises the following steps:
(1) synthesis of intermediate IIa
The reaction process is as follows:
20 g of tert-butyl 2-nitrophenylacetate were dissolved in 120 ml of toluene, 1.56 g of tetrabutylammonium iodide, 8.94 g of sodium carbonate and 9 ml of 37% aqueous formaldehyde were added, and the mixture was heated to 115 ℃ to react for 8 hours. After cooling the reaction solution to room temperature, the reaction solution was filtered, the filtrate was extracted with ethyl acetate, dried and concentrated with anhydrous sodium sulfate as an organic phase, and purified by column chromatography to obtain 6.40 g of an oily substance, i.e., intermediate IIa, in a yield of 60.9%.
(2) Synthesis of intermediate IIIa
The reaction process is as follows:
6.4 g of intermediate IIa is dissolved in 128 ml of ethyl acetate, 3.6 g of reduced iron powder and 5.5 g of ammonium chloride are added, after reaction for 24 hours at 65 ℃, the mixture is cooled to 50 ℃, suction filtration is carried out while the mixture is hot, filtrate is washed by saturated saline solution for 3 times, dried by anhydrous sodium sulfate and concentrated, and column chromatography purification is carried out to obtain 1.81 g of white solid, namely intermediate IIIa, with the yield of 30.2%.
(3) Synthesis of intermediate IVa
The reaction process is as follows:
1.8 g of intermediate IIIa was dissolved in 27 ml of N, N-dimethylformamide, and 0.46 g of sodium hydrogen was added under ice-cooling, and after stirring at room temperature for 30 minutes, 1.98 g of benzyl bromide was added. After 2 hours of reaction at room temperature, the reaction was quenched by slowly dropping 1 ml of water under ice bath, and then extracted with 30 ml of ethyl acetate and 30 ml of saturated brine, and the aqueous phase was extracted with ethyl acetate again 2 times by 20 ml each time. The organic phase was washed 2 times with 40 ml of saturated saline solution each time. The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give 2.2 g of an oil, intermediate iva, in 88.2% yield.
(4) Synthesis of intermediate Va
The reaction process is as follows:
2.2 g of intermediate IVa were dissolved in 22 ml of dichloromethane, 10 ml of ethereal hydrogen chloride solution were added under ice-bath, and then reacted at 15 ℃ for 4 hours. The reaction was concentrated, slurried with diethyl ether and purified to give 1.70g of a white solid, intermediate Va, in 93.5% yield.
(5) Synthesis of intermediate VIIa
The reaction process is as follows:
0.5 g of the intermediate Va is dissolved in 122 ml of dichloromethane, 0.3 g of tropine, namely the intermediate Via, 0.42 g of dicyclohexylcarbodiimide and 0.05 g of 4-dimethylaminopyridine are added, and the reaction solution reacts for 6 hours at 40 ℃. The reaction solution was cooled and filtered, and the filtrate was concentrated and purified by column chromatography to give 0.14 g of an oil, i.e., intermediate VIIa, in 19.2% yield.
(6) Synthesis of N-hydroxy tropisetron VIII
The reaction process is as follows:
100 mg of the intermediate VIIa is dissolved in 2 ml of ethyl acetate, 20 mg of palladium-carbon is added under the protection of nitrogen, and a hydrogen balloon is used as a hydrogen source to react for 12 hours at 25 ℃. And (3) carrying out suction filtration on the reaction solution under the protection of nitrogen, and concentrating the filtrate to obtain 62 mg of white solid, namely N-hydroxy tropisetron VIII, wherein the yield is 81.6%, and the liquid phase purity is 99.9899%.
Claims (10)
1. A synthetic method of N-hydroxy tropisetron is characterized by comprising the following steps:
(1) dissolving a compound I2-nitrophenyl acetate in an organic solvent, and reacting with formaldehyde, quaternary ammonium base and alkali to obtain a compound II;
wherein in compounds I and II, R 1 Is methyl, ethyl, tert-butyl or benzyl;
(2) dissolving the compound II obtained in the step (1) in an organic solvent, and reacting with a reducing agent and a salt to obtain a compound III, R 1 Is methyl, ethyl, tert-butyl or benzyl;
(3) dissolving the compound III obtained in the step (2) in an organic solvent, adding an organic reagent for reaction, and protecting hydroxyl to obtain a compound IV, R 1 Is methyl, ethyl, tert-butyl or benzyl, R 2 Is a hydroxyl protecting group;
(4) dissolving the compound IV obtained in the step (3) in a solvent, and reducing by using a metal catalyst or hydrolyzing by using acid and alkali to obtain a compound V, R 2 Is a hydroxyl protecting group;
(5) dissolving the compound V obtained in the step (4) in an organic solvent, and reacting the compound V with a compound VI in the presence of alkali or a condensing agent to obtain a compound VII;
wherein in the compound VI, R 3 Is chlorine, bromine or hydroxyl, in compound V and compound VII, R 2 Is a hydroxyl protecting group;
(6) dissolving the compound VII obtained in the step (5) in an organic solvent, and reacting with a deprotection reagent to obtain a compound VIII;
2. the method for synthesizing N-hydroxythiosetron as claimed in claim 1, wherein in step (1), the organic solvent is tetrahydrofuran, dioxane, toluene or xylene, and the volume ratio of the organic solvent to the compound I is 5-30: 1; the formaldehyde is a 37% aqueous solution or paraformaldehyde, and the molar ratio of the formaldehyde to the compound I is 2-10: 1; the quaternary ammonium base is tetrabutylammonium fluoride, tetrabutylammonium iodide or tetrabutylammonium hydrogen sulfate, and the molar ratio of the quaternary ammonium base to the compound I is 0.1-0.5: 1; the alkali is potassium carbonate, sodium bicarbonate or sodium hydroxide, and the molar ratio of the alkali to the compound I is (1-5): 1.
3. the method for synthesizing N-hydroxythiosetron as claimed in claim 1, wherein the reaction temperature in step (1) is 50-140 ℃ and the reaction time is 2-16 hours.
4. The method for synthesizing N-hydroxythiosetron as claimed in claim 1, wherein in step (2), the organic solvent is tetrahydrofuran, dioxane, ethyl acetate or toluene, and the volume ratio of the organic solvent to the compound II is 10-100: 1; the reducing agent is reduced iron powder and stannous chloride, and the molar ratio of the reagent to the compound II is 1-6: 1; the salt is potassium acetate, sodium acetate, ammonium acetate and ammonium chloride, and the molar ratio of the reagent to the compound II is 1-25: 1.
5. the method for synthesizing N-hydroxythiosetron as claimed in claim 1, wherein in step (2), the reaction temperature is 60-125 ℃ and the reaction time is 2-24 hours.
6. The method for synthesizing N-hydroxythiosetron as claimed in claim 1, wherein in step (3), the organic solvent is N, N-dimethylformamide, acetonitrile, tetrahydrofuran or toluene, and the volume ratio of the organic solvent to the compound III is 5-30: 1; the organic reagent is sodium hydrogen-benzyl bromide, potassium carbonate-p-methoxybenzyl chloride or diethyl azodicarboxylate-triphenylphosphine-2- (trimethylsilyl) ethanol, and the molar ratio of the reagent to the compound III is (1-3): 1.
7. the method for synthesizing N-hydroxythiosetron as claimed in claim 1, wherein in step (3), the reaction temperature is-20 ℃ to 80 ℃ and the reaction time is 0.5 to 18 hours.
8. The method for synthesizing N-hydroxythiosetron as claimed in claim 1, wherein in step (4), the solvent is tetrahydrofuran, methanol, ethanol or dichloromethane, and the volume ratio of the solvent to the compound IV is 5-50: 1; the metal catalyst is palladium carbon, the acid is diethyl ether hydrogen chloride, the alkali is sodium hydroxide or potassium hydroxide, and the mass ratio or the molar ratio of the solvent to the compound IV is 0.1-10: 1; the reaction temperature is 0-65 ℃, and the reaction time is 6-48 hours.
9. The method for synthesizing N-hydroxythiosetron as claimed in claim 1, wherein in step (5), the molar ratio of the compound VI to the compound V is 0.8-2.2: 1; the organic solvent is N, N-dimethylformamide, acetonitrile, dimethyl sulfoxide or dichloromethane, and the volume ratio of the organic solvent to the compound V is 5-50: 1; the condensing agent is potassium carbonate, cesium carbonate, dicyclohexylcarbodiimide and EDCI, and the molar ratio of the reagent to the compound V is (1-4): 1.
10. the method for synthesizing N-hydroxythiosetron as claimed in claim 1, wherein in step (6), the organic solvent is tetrahydrofuran, dichloromethane, ethyl acetate or toluene, and the volume ratio of the organic solvent to the compound VII is 5-50: 1; the deprotection reagent is a reagent of hydrogen chloride, tetrabutylammonium fluoride, palladium carbon or pyridine hydrochloride, and the molar ratio of the reagent to the compound VII is 0.1-5: 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015009977A1 (en) * | 2013-07-18 | 2015-01-22 | Novartis Ag | Aminomethyl-biaryl derivatives as complement factor d inhibitors and uses thereof |
| CN110638819A (en) * | 2019-10-21 | 2020-01-03 | 黄泳华 | Compositions containing azabicyclo derivatives and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015009977A1 (en) * | 2013-07-18 | 2015-01-22 | Novartis Ag | Aminomethyl-biaryl derivatives as complement factor d inhibitors and uses thereof |
| CN110638819A (en) * | 2019-10-21 | 2020-01-03 | 黄泳华 | Compositions containing azabicyclo derivatives and uses thereof |
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| Title |
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| SIMPLE SYNTHESES OF ANALOGS OF A WASABI PHYTOALEXIN;Fumio Yamada 等;《HETEROCYCLES》;20011231;第55卷(第12期);第2361-2368页 * |
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