CN113979913B - Method for synthesizing virus treatment drug N, N-dimethyl-5-hydroxytryptamine-N12-oxide - Google Patents
Method for synthesizing virus treatment drug N, N-dimethyl-5-hydroxytryptamine-N12-oxide Download PDFInfo
- Publication number
- CN113979913B CN113979913B CN202111375754.1A CN202111375754A CN113979913B CN 113979913 B CN113979913 B CN 113979913B CN 202111375754 A CN202111375754 A CN 202111375754A CN 113979913 B CN113979913 B CN 113979913B
- Authority
- CN
- China
- Prior art keywords
- ethanol
- dimethyl
- hydroxytryptamine
- keeping
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The invention relates to the technical field of pharmaceutical chemistry synthesis, and provides a synthetic therapeutic virus drug N, N-dimethyl-5-hydroxytryptamine-N 12 -a process for oxidizing comprising the steps of: s1, adding N, N-dimethyl-5-hydroxytryptamine and a phase transfer catalyst into ethanol, and stirring to obtain a uniform solution; s2, dropwise adding a hydrogen peroxide ethanol solution, controlling the dropwise adding temperature to be 0-5 ℃, and continuing to react after the dropwise adding is finished; and S3, post-processing. Through the technical scheme, the problems of complex synthesis process, more used chemical raw materials, low yield and high cost in the prior art are solved.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a synthetic therapeutic virus drug N, N-dimethyl-5-hydroxytryptamine-N 12 -a method of oxidizing.
Background
N, N-dimethyl-5-hydroxytryptamine-N 12 The oxide is a white-like solid, which is an effective drug for the treatment of hepatitis B. Hepatitis b is a potentially life-threatening liver infection caused by the Hepatitis B Virus (HBV). It can lead to chronic liver disease and put people at high risk of dying from cirrhosis and liver cancer. Although nucleoside analogs have good tolerability and exhibit early and potent antiviral effects, this is limited by the choice of resistant mutants in long-term therapy and nephrotoxicity. Due to the fact thatThus, there is an urgent need for new non-nucleoside anti-HBV drugs with different mechanisms. For the development of a therapeutic agent for viral diseases, N-dimethyl-5-hydroxytryptamine-N 12 Oxides, of practical significance.
N, N-dimethyl-5-hydroxytryptamine-N 12 The first synthesis process uses 5-methoxy indole as initial material and includes five steps of oxalylation, amination, reduction, demethylation and oxidation to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 -an oxide. The process has the problems of using a humid and flammable reducing agent lithium aluminum hydride, and having strict requirements on reaction conditions and post-treatment operation, so the process is not suitable for industrial production and is only suitable for synthesis in a laboratory. The second synthesis process (Fischer synthesis process) is to take 4-methoxy phenylhydrazine hydrochloride as an initial raw material, carry out ring closure reaction with N, N-dimethylamino butyraldehyde diethyl acetal under the action of an acid catalyst to obtain N, N-dimethyl-5-methoxy tryptamine, and then carry out demethylation and oxidation reaction to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 Oxide, yield 60%. Although the route of the method is short, the raw materials of 4-methoxyphenylhydrazine hydrochloride and N, N-dimethylamino butyraldehyde diethyl acetal are not easy to obtain and expensive, so that the production cost is high, and the industrial production of the process is not economical. The third synthesis process is to take 5-methoxy tryptamine as the initial raw material to react with formaldehyde and sodium cyanoborohydride to obtain N, N-dimethyl-5-methoxy tryptamine, and then obtain N, N-dimethyl-5-hydroxy tryptamine-N through demethylation and oxidation reactions 12 Oxide, the process has the advantages of low yield of 55-60%, high cost and uneconomical industrial production.
For example, CN103601683A patent utilizes an oxidation reaction using perbenzoic acid as an oxidizing agent, and the highest yield is 80%, and this oxidation process has problems of low yield and high cost.
Disclosure of Invention
The invention provides a synthetic virus treatment drug N, N-dimethyl-5-hydroxytryptamine-N 12 The method of oxide solves the problems of complex synthesis process, more used chemical raw materials, low yield and high cost in the prior art.
The technical scheme of the invention is as follows:
synthesis of virus-treating medicine N, N-dimethyl-5-hydroxytryptamine-N 12 -a process for oxidizing comprising the steps of:
s1, adding N, N-dimethyl-5-hydroxytryptamine and a phase transfer catalyst into ethanol, and stirring to obtain a uniform solution;
s2, dropwise adding a hydrogen peroxide ethanol solution, controlling the dropwise adding temperature to be 0-5 ℃, and continuing to react after dropwise adding is finished;
and S3, post-processing.
Preferably, the mass ratio of the N, N-dimethyl-5-hydroxytryptamine to the ethanol is 1.
Preferably, the weight of the phase transfer catalyst is 0.3-0.6% of the mass of the N, N-dimethyl-5-hydroxytryptamine.
Preferably, the phase transfer catalyst is one of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate and trioctylmethylammonium chloride.
Preferably, the stirring in the step S1 is performed for 10 to 15min.
Preferably, in the step S2, the dropping time is controlled to be 30 to 40min.
Preferably, the hydrogen peroxide ethanol solution is prepared by mixing 25-30% by mass of hydrogen peroxide and ethanol according to a mass ratio of 1.
Preferably, the molar ratio of the hydrogen peroxide ethanol solution to the N, N-dimethyl-5-hydroxytryptamine is 4.
Preferably, in the step S2, the reaction is continued for 2 to 4 hours, and the temperature is kept between 20 and 25 ℃.
Preferably, the post-treatment is: and (3) after reduced pressure distillation, cooling, adding n-hexane, crystallizing, filtering, washing and drying to obtain the product.
Preferably, the post-treatment is to start a vacuum pump, keep the vacuum degree between-0.095 and-0.097 MPa, set the water bath temperature at 50-60 ℃, distill ethanol under reduced pressure, stop the reduced pressure distillation when part of ethanol water is distilled, and close the vacuum. Rapidly cooling to 0-3 deg.C with cold water, maintaining at 0-3 deg.C, stirring for 20min,then adding N-hexane, precipitating crystals, keeping for 2 hours, filtering, washing filter cakes with ethanol water solution, compacting and pumping to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 Wet oxide, and drying at 45-50 deg.C for 6 hr under vacuum to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 -an oxide product.
The beneficial effects of the invention are as follows:
1. the invention takes easily obtained N, N-dimethyl-5-hydroxytryptamine as a starting material, and obtains the N, N-dimethyl-5-hydroxytryptamine-N by one-step oxidation reaction of hydrogen peroxide under the action of a phase transfer catalyst 12 Oxide, simple synthesis process, mild process conditions, high yield of more than or equal to 95 percent, good quality and content of more than or equal to 99.5 percent. The invention provides a synthetic N, N-dimethyl-5-hydroxytryptamine-N 12 Oxide method, easy to be industrialized.
2. The invention adopts hydrogen peroxide for oxidation, and the product after the hydrogen peroxide reaction is water, so the purity of the product can be improved. Ethanol is used as a solvent, the toxicity of the ethanol is very low, the post-treatment is easy, the dosage of the ethanol needs to be increased to ensure that the N, N-dimethyl-5-hydroxytryptamine is fully dissolved, but the concentration of hydrogen peroxide in a system is reduced by increasing the dosage of the ethanol, and the final yield of the reaction can be ensured only by reasonably controlling the dosages of hydrogen peroxide and the ethanol.
3. The invention limits the quaternary ammonium salt phase transfer catalyst, and can promote the full mixing and reaction of N, N-dimethyl-5-hydroxytryptamine and hydrogen peroxide. And for the reaction temperature, the low temperature needs to be strictly controlled, otherwise, side reactions occur to influence the product quality.
Drawings
The invention is described in further detail below with reference to the drawings and the detailed description.
FIG. 1 shows N, N-dimethyl-5-hydroxytryptamine-N in example 1 of the present invention 12 -liquid phase spectrum of the oxide product.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any inventive step, are intended to be within the scope of the present invention.
Example 1
Under the protection of nitrogen, 20.4g of N, N-dimethyl-5-hydroxytryptamine are added into a 1000ml flask, then added into 204g of ethanol, then added with 100mg of hexadecyl tributyl ammonium bromide as a catalyst, and stirred for 10min. Cooling to 0-5 ℃ under stirring, dropwise adding a solution newly prepared from 48g of 30% hydrogen peroxide and 48g of ethanol, controlling the dropwise adding temperature to be 0-5 ℃, keeping the temperature to be 20-25 ℃ after dropwise adding for 30min, continuously reacting for 2h, and performing controlled detection in sampling to obtain the residual amount of the N, N-dimethyl-5-hydroxytryptamine of 0.3%. And (3) starting vacuum, keeping the vacuum degree of-0.095 to-0.097 MPa, setting the water bath temperature at 50 ℃, distilling ethanol under reduced pressure, stopping reduced pressure distillation when 175g of ethanol water is distilled, and closing the vacuum. Rapidly cooling to 0 ℃ with cold water, keeping the temperature at 0-3 ℃, stirring for 20min, then adding 105g of N-hexane, precipitating crystals, keeping the temperature for 2 hours, filtering, washing a filter cake with ethanol water, compacting and pumping to dry to obtain the N, N-dimethyl-5-hydroxytryptamine-N 12 Wet oxide, and then drying at 50 ℃ for 6h under vacuum to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 21.00g of oxide product, 95.2% yield and 99.7% purity.
Melting point: 212-215 ℃;
Bruker AM-400 1H(400MHz)
1 H NMR(D2O):d 7.18(d,J＝8.5Hz,1H),7.11(s,1H),6.93(d,J＝2.4Hz,1H),6.68(dd,J＝8.5,2.4 2.4Hz,1H),3.53(m,2H),3.26(s,6H),3.20(m,2H)
example 2
Under the protection of nitrogen, 20.4g of N, N-dimethyl-5-hydroxytryptamine are added into a 1000ml flask, then added into 245g of ethanol, and then added with 82mg of hexadecyl tributyl ammonium bromide catalyst, and stirred and kept for 10min. Cooling to 0-5 deg.C under stirring, adding dropwise a solution prepared from 30% hydrogen peroxide 48g and 48g ethanol, controlling the temperature at 0-5 deg.C, and adding dropwise for 30minAfter the addition is finished, the temperature is kept at 20-25 ℃ for continuous reaction for 2h, and the residual quantity of the N, N-dimethyl-5-hydroxytryptamine is 0.35 percent by control detection in sampling. And (3) starting vacuum, keeping the vacuum degree of-0.095 to-0.097 MPa, setting the water bath temperature at 60 ℃, distilling ethanol under reduced pressure, stopping reduced pressure distillation when 220g of ethanol water is distilled, and closing the vacuum. Rapidly cooling to 0 deg.C with cold water, maintaining at 0-3 deg.C, stirring for 20min, adding 105g N-hexane, precipitating crystal, maintaining for 2 hr, filtering, washing filter cake with ethanol water, compacting, and draining to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 Wet oxide, and then dried at 45 ℃ for 6h under vacuum to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 21.03g of the oxide product, 95.1% yield and 99.5% purity.
Example 3
Under the protection of nitrogen, 20.4g of N, N-dimethyl-5-hydroxytryptamine are added into a 1000ml flask, then added into 245g of ethanol, then added with 110mg of hexadecyl tributyl ammonium bromide as a catalyst, and stirred for 10min. Cooling to 0-5 ℃ under stirring, dropwise adding a solution newly prepared from 48g of 30% hydrogen peroxide and 48g of ethanol, controlling the dropwise adding temperature to be 0-5 ℃, keeping the temperature to be 20-25 ℃ after dropwise adding for 30min, continuously reacting for 2h, and performing controlled detection in sampling to obtain the residual amount of the N, N-dimethyl-5-hydroxytryptamine of 0.24%. And (3) starting vacuum, keeping the vacuum degree of-0.095 to-0.097 MPa, setting the water bath temperature to 55 ℃, distilling ethanol under reduced pressure, stopping reduced pressure distillation when 220g of ethanol water is distilled, and closing the vacuum. Rapidly cooling to 3 deg.C with cold water, maintaining at 0-3 deg.C, stirring for 20min, adding 105g N-hexane, precipitating crystal, maintaining for 2 hr, filtering, washing filter cake with ethanol water, compacting, and draining to obtain N, N-dimethyl-5-hydroxytryptamine-N 12- Wet oxide, and vacuum drying at 45 deg.C for 6 hr to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 21.07g of the oxide product, 95.4% yield and 99.6% purity.
Comparative example 1
Under the protection of nitrogen, 20.4g of N, N-dimethyl-5-hydroxytryptamine is added into a 1000ml flask, then added into 245g of ethanol, then added with 50mg of hexadecyl tributyl ammonium bromide catalyst, and stirred and kept for 10min. Cooling to 0-5 deg.C under stirring, and adding dropwiseAnd (2) controlling the dropping temperature of a newly prepared solution of 48g of 30% hydrogen peroxide and 48g of ethanol at 0-5 ℃, keeping the temperature at 20-25 ℃ after the dropping is finished, continuing to react for 2 hours, and detecting the residual amount of the N, N-dimethyl-5-hydroxytryptamine by controlling in sampling to be 1.9%. And (3) starting vacuum, keeping the vacuum degree of-0.095 to-0.097 MPa, setting the water bath temperature to be 60 ℃, distilling ethanol under reduced pressure, stopping the reduced pressure distillation when 220g of ethanol water is distilled, and closing the vacuum. Rapidly cooling to 0 deg.C with cold water, maintaining at 0-3 deg.C, stirring for 20min, adding 105g N-hexane, precipitating crystal, maintaining for 2 hr, filtering, washing filter cake with ethanol water, compacting, and draining to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 Wet oxide, and then dried at 45 ℃ for 6h under vacuum to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 20.40g of the oxide product, yield 90.4% and purity 97.5%.
Comparative example 2
Under the protection of nitrogen, 20.4g of N, N-dimethyl-5-hydroxytryptamine is added into a 1000ml flask, then added into 204g of ethanol, and then added with 125mg of hexadecyl tributyl ammonium bromide catalyst, and stirred and kept for 10min. Cooling to 0-5 ℃ while stirring, dropwise adding a solution newly prepared from 48g of 30% hydrogen peroxide and 48g of ethanol, controlling the dropwise adding temperature to be 0-5 ℃, dropwise adding for 30min, keeping the temperature to be 20-25 ℃ after dropwise adding, continuously reacting for 2h, and sampling and detecting to obtain the residual amount of the N, N-dimethyl-5-hydroxytryptamine of 0.22%. And (3) starting vacuum, keeping the vacuum degree of-0.095 to-0.097 MPa, setting the water bath temperature at 50 ℃, distilling ethanol under reduced pressure, stopping the reduced pressure distillation when 175g of ethanol water is distilled, and closing the vacuum. Rapidly cooling to 0 deg.C with cold water, maintaining at 0-3 deg.C, stirring for 20min, adding 105g N-hexane, precipitating crystal, maintaining for 2 hr, filtering, washing filter cake with ethanol water, compacting, and draining to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 Wet oxide, and then dried at 50 ℃ for 6h under vacuum to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 21.05g of the oxide product, 95.3% yield and 99.6% purity.
Comparative example 3
Adding 20.4g of N, N-dimethyl-5-hydroxytryptamine into a 1000ml flask under the protection of nitrogen, adding into 204g of ethanol, and adding into a catalyst100mg of cetyltributylammonium bromide was used as a reagent, and stirring was maintained for 10min. Cooling to 0-5 ℃ under stirring, dropwise adding a solution newly prepared from 48g of 30% hydrogen peroxide and 48g of ethanol, controlling the dropwise adding temperature to be 10-20 ℃, keeping the temperature to be 20-25 ℃ after dropwise adding for 30min, continuously reacting for 2h, and performing controlled detection in sampling to obtain the residual amount of the N, N-dimethyl-5-hydroxytryptamine of 2.6%. And (3) starting vacuum, keeping the vacuum degree of-0.095 to-0.097 MPa, setting the water bath temperature at 50 ℃, distilling ethanol under reduced pressure, stopping reduced pressure distillation when 175g of ethanol water is distilled, and closing the vacuum. Rapidly cooling to 0 deg.C with cold water, maintaining at 0-3 deg.C, stirring for 20min, adding 105g N-hexane, precipitating crystal, maintaining for 2 hr, filtering, washing filter cake with ethanol water, compacting, and draining to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 Wet oxide, and drying at 45 deg.C for 6 hr under vacuum to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 21.40g of the oxide product, 89.9% yield and 92.4% purity.
Comparative example 4
Under the protection of nitrogen, 20.4g of N, N-dimethyl-5-hydroxytryptamine is added into a 1000ml flask, then added into 204g of ethanol, then added with 100mg of hexadecyl tributyl ammonium bromide catalyst, and stirred and kept for 10min. Cooling to 0-5 ℃ under stirring, dropwise adding a solution newly prepared from 48g of 30% hydrogen peroxide and 48g of ethanol, controlling the dropwise adding temperature to be-5 to-2 ℃, keeping the temperature at 20-25 ℃ for continuously reacting for 2h after dropwise adding, and carrying out controlled detection in sampling to obtain the N, N-dimethyl-5-hydroxytryptamine with the residual amount of 2.8%. And (3) starting vacuum, keeping the vacuum degree of-0.095 to-0.097 MPa, setting the water bath temperature at 50-60 ℃, distilling ethanol under reduced pressure, stopping reduced pressure distillation when 175g of ethanol water is distilled, and closing the vacuum. Rapidly cooling to 0 deg.C with cold water, maintaining at 0-3 deg.C, stirring for 20min, adding 105g N-hexane, precipitating crystal, maintaining for 2 hr, filtering, washing filter cake with ethanol water, compacting, and draining to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 Wet oxide, and then drying at 50 ℃ for 6h under vacuum to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 19.59g of the oxide product, 88.5% yield and 99.4% purity.
Comparative example 5
Nitrogen gas20.4g of N, N-dimethyl-5-hydroxytryptamine is added into a 1000ml flask under protection, then 194g of ethanol is added, 100mg of hexadecyltributylammonium bromide catalyst is added, and stirring is carried out for 10min. Cooling to 0-5 ℃ under stirring, dropwise adding a solution newly prepared from 48g of 30% hydrogen peroxide and 48g of ethanol, controlling the dropwise adding temperature to be 0-5 ℃, keeping the temperature to be 20-25 ℃ after dropwise adding for 30min, continuously reacting for 2h, and performing controlled detection in sampling to obtain the residual amount of the N, N-dimethyl-5-hydroxytryptamine of 0.31%. And (3) starting vacuum, keeping the vacuum degree of-0.095 to-0.097 MPa, setting the water bath temperature at 50 ℃, distilling ethanol under reduced pressure, stopping reduced pressure distillation when 175g of ethanol water is distilled, and closing the vacuum. Rapidly cooling to 0 deg.C with cold water, maintaining at 0-3 deg.C, stirring for 20min, adding 105g N-hexane, precipitating crystal, maintaining for 2 hr, filtering, washing filter cake with ethanol water, compacting, and draining to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 Wet oxide, and then drying at 50 ℃ for 6h under vacuum to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 Oxide product 20.30g, yield 91.52%, purity 99.2%.
Comparative example 6
Under the protection of nitrogen, 20.4g of N, N-dimethyl-5-hydroxytryptamine was added to a 1000ml flask, and then added to 316.2g of ethanol, and then 100mg of cetyltributylammonium bromide as a catalyst was added thereto, and the mixture was stirred and maintained for 10min. Cooling to 0-5 ℃ while stirring, dropwise adding a solution newly prepared from 48g of 30% hydrogen peroxide and 48g of ethanol, controlling the dropwise adding temperature to be 0-5 ℃, dropwise adding for 30min, keeping the temperature to be 20-25 ℃ after dropwise adding, continuously reacting for 2h, and sampling and detecting to obtain 1.4% of the residual amount of the N, N-dimethyl-5-hydroxytryptamine. And (3) starting vacuum, keeping the vacuum degree of-0.095 to-0.097 MPa, setting the water bath temperature at 50-60 ℃, distilling ethanol under reduced pressure, stopping reduced pressure distillation when 175g of ethanol water is distilled, and closing the vacuum. Rapidly cooling to 0 deg.C with cold water, maintaining at 0-3 deg.C, stirring for 20min, adding 105g N-hexane, precipitating crystal, maintaining for 2 hr, filtering, washing filter cake with ethanol water, compacting, and draining to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 Wet oxide, and drying at 45 deg.C for 6 hr under vacuum to obtain N, N-dimethyl-5-hydroxytryptamine-N 12 Oxide product 20.62g, yield 92.9%And the purity is 99.1%.
The invention has simple synthesis process, mild process conditions, high yield of more than or equal to 95 percent, good quality and content of more than or equal to 99.5 percent. The catalyst addition in comparative example 1 was less and the product yield and purity were decreased, but the present inventors found that the purity and yield of the product were almost unchanged by increasing the amount of the catalyst in comparative example 2. In comparative example 3, the product purity is greatly reduced and impurities are increased by increasing the dropping temperature, while in comparative example 4, the reaction is not facilitated by reducing the temperature, the product yield is reduced, and in comparative example 5 and comparative example 6, the yield and purity are reduced by changing the adding amount of ethanol.
The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. A method of synthesizing a compound of formula I, wherein said compound of formula I is:
the method comprises the following specific steps:
adding 20.4g of N, N-dimethyl-5-hydroxytryptamine into a 1000ml flask under the protection of nitrogen, then adding 204g of ethanol, adding 100mg of hexadecyl tributyl ammonium bromide serving as a catalyst, and stirring for 10min; cooling to 0-5 ℃ while stirring, dropwise adding a solution newly prepared from 48g of 30% hydrogen peroxide and 48g of ethanol, controlling the dropwise adding temperature to be 0-5 ℃, dropwise adding for 30min, keeping the temperature to be 20-25 ℃ after dropwise adding, continuously reacting for 2h, and sampling and detecting, wherein the residual quantity of the N, N-dimethyl-5-hydroxytryptamine is 0.3%; starting vacuum, keeping the vacuum degree between-0.095 and-0.097 MPa, setting the water bath temperature at 50 ℃, distilling ethanol under reduced pressure to obtain 175g of ethanol water, stopping the reduced pressure distillation, and closing the vacuum; rapidly cooling to 0 ℃ with cold water, keeping the temperature at 0-3 ℃, stirring for 20min, then adding 105g of n-hexane, precipitating crystals, keeping the temperature for 2 hours, filtering, washing a filter cake with ethanol water, compacting and pumping to dryness to obtain a wet product of the compound shown in the formula I, and then drying for 6 hours at 50 ℃ under vacuum to obtain the compound shown in the formula I.
2. A method of synthesizing a compound of formula I, wherein said compound of formula I is:
the method comprises the following specific steps:
adding 20.4g of N, N-dimethyl-5-hydroxytryptamine into a 1000ml flask under the protection of nitrogen, then adding 245g of ethanol, adding 82mg of hexadecyl tributyl ammonium bromide serving as a catalyst, and stirring for 10min; cooling to 0-5 ℃ under stirring, dropwise adding a solution newly prepared from 48g of 30% hydrogen peroxide and 48g of ethanol, controlling the dropwise adding temperature to be 0-5 ℃, keeping the temperature to be 20-25 ℃ after dropwise adding for 30min, continuously reacting for 2h, and performing controlled detection in sampling, wherein the residual amount of the N, N-dimethyl-5-hydroxytryptamine is 0.35%; starting vacuum, keeping the vacuum degree of-0.095 to-0.097 MPa, setting the water bath temperature at 60 ℃, distilling ethanol under reduced pressure to obtain 220g of ethanol water, stopping the reduced pressure distillation, and closing the vacuum; rapidly cooling to 0 ℃ with cold water, keeping the temperature at 0-3 ℃, stirring for 20min, then adding 105g of n-hexane, precipitating crystals, keeping the crystals for 2 hours, filtering, washing a filter cake with ethanol water, compacting, pumping to dryness to obtain a wet product of the compound shown in the formula I, and then drying for 6 hours at 45 ℃ under vacuum to obtain the compound shown in the formula I.
3. A method of synthesizing a compound of formula I, wherein said compound of formula I is:
the method comprises the following specific steps:
adding 20.4g of N, N-dimethyl-5-hydroxytryptamine into a 1000ml flask under the protection of nitrogen, then adding 245g of ethanol, adding 110mg of hexadecyl tributyl ammonium bromide serving as a catalyst, and stirring for 10min; cooling to 0-5 ℃ under stirring, dropwise adding a solution newly prepared from 48g of 30% hydrogen peroxide and 48g of ethanol, controlling the dropwise adding temperature to be 0-5 ℃, keeping the temperature to be 20-25 ℃ after dropwise adding for 30min, continuously reacting for 2h, and performing controlled detection in sampling, wherein the residual amount of the N, N-dimethyl-5-hydroxytryptamine is 0.24%; starting vacuum, keeping the vacuum degree of-0.095 to-0.097 MPa, setting the water bath temperature to 55 ℃, distilling ethanol under reduced pressure to obtain 220g of ethanol water, stopping the reduced pressure distillation, and closing the vacuum; rapidly cooling to 3 ℃ with cold water, keeping the temperature at 0-3 ℃, stirring for 20min, then adding 105g of n-hexane, precipitating crystals, keeping for 2 hours, filtering, washing filter cakes with ethanol water, compacting, pumping to dry to obtain a wet product of the compound of the formula I, and then drying at 45 ℃ under vacuum for 6 hours to obtain the compound of the formula I.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111375754.1A CN113979913B (en) | 2021-11-19 | 2021-11-19 | Method for synthesizing virus treatment drug N, N-dimethyl-5-hydroxytryptamine-N12-oxide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111375754.1A CN113979913B (en) | 2021-11-19 | 2021-11-19 | Method for synthesizing virus treatment drug N, N-dimethyl-5-hydroxytryptamine-N12-oxide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113979913A CN113979913A (en) | 2022-01-28 |
| CN113979913B true CN113979913B (en) | 2023-02-03 |
Family
ID=79749511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111375754.1A Active CN113979913B (en) | 2021-11-19 | 2021-11-19 | Method for synthesizing virus treatment drug N, N-dimethyl-5-hydroxytryptamine-N12-oxide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113979913B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101108814A (en) * | 2007-07-24 | 2008-01-23 | 王伟松 | Method of synthesizing axungia alkyl dimethyl group amine oxide |
| CN102219725A (en) * | 2010-04-16 | 2011-10-19 | 中国科学院上海药物研究所 | Benzohetercyclic compound as well as preparation method and applications thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI786519B (en) * | 2020-01-29 | 2022-12-11 | 美商艾德凡斯化學公司 | Amino acid surfactants |
| CN113214133B (en) * | 2021-05-08 | 2023-03-07 | 河北维达康生物科技有限公司 | Synthesis method of melatonin |
| CN113402437B (en) * | 2021-06-29 | 2023-07-14 | 河北维达康生物科技有限公司 | Novel method for synthesizing dietary supplement melatonin |
-
2021
- 2021-11-19 CN CN202111375754.1A patent/CN113979913B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101108814A (en) * | 2007-07-24 | 2008-01-23 | 王伟松 | Method of synthesizing axungia alkyl dimethyl group amine oxide |
| CN102219725A (en) * | 2010-04-16 | 2011-10-19 | 中国科学院上海药物研究所 | Benzohetercyclic compound as well as preparation method and applications thereof |
Non-Patent Citations (4)
| Title |
|---|
| Gramine Derivatives Targeting Ca2+ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases;Rocío Lajarín-Cuesta et al;《J. Med. Chem.》;20160609;第59卷;第6265-6280页 * |
| N-phosphonomethyl iminodiacetic acid N-oxide synthesis in the presence of bifunctional catalysts based on tungsten complexes;Z.P. Pai et al;《Catalysis Communications》;20150829;第71卷;第102-105页 * |
| Synthesis and Characterization of 5‑MeO-DMT Succinate for Clinical Use;Alexander M. Sherwood et al;《ACS Omega》;20201231;第5卷;第32067-32075页 * |
| Tryptamine derivatives as novel non-nucleosidic inhibitors against hepatitis B virus;Shi-Jin Qu et al.;《Bioorganic & Medicinal Chemistry》;20110406;第19卷;第3120-3127页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113979913A (en) | 2022-01-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU595827B2 (en) | Novel platinum complexes | |
| JP2019505499A (en) | Voriconazole intermediate and method for synthesizing voriconazole | |
| JP2010254710A (en) | Production of platinum (ii) complex | |
| CN114315534A (en) | Preparation method of dapagliflozin intermediate | |
| CN111018803B (en) | Preparation method of Barosavir intermediate | |
| CN113979913B (en) | Method for synthesizing virus treatment drug N, N-dimethyl-5-hydroxytryptamine-N12-oxide | |
| CN110615448B (en) | Method for preparing sodium nitroprusside | |
| CN112812107A (en) | Preparation method of SGLT-2 inhibitor and intermediate | |
| IL139528A (en) | Platinum complexes, processes for the preparation thereof and pharmaceutical compositions containing the same | |
| US20110190391A1 (en) | Ferrocene derivatives with anticancer activity | |
| CN110229111B (en) | Ambroxol impurity and preparation method and application thereof | |
| JP5327751B2 (en) | Platinum complex compounds and uses thereof | |
| CN108148061A (en) | The industrialized process for preparing of Entecavir | |
| CN111072450B (en) | Synthesis method of allyl alcohol derivative | |
| CN109721523B (en) | Indoline derivative and preparation method thereof | |
| EP0258655B1 (en) | Complexes of platinum (ii) 2,3-dinitrilo-2-butene-2,3-dithiolate, a process for preparing them and pharmaceutical compositions containing them | |
| CN113372281A (en) | Synthetic method of metronidazole | |
| CN111138293B (en) | Method for synthesizing ibutilide fumarate intermediate by using microchannel reactor | |
| CN109053847B (en) | 17 β -imidazolidinyl bromide-dehydroepiandrostane derivative and preparation method and application thereof | |
| CN103857679A (en) | Methods for the preparation of 5-[2-[7-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]ethynyl]-2-pyridinamine | |
| JPS6145989B2 (en) | ||
| CN114751853B (en) | Process for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane compounds | |
| CN109988297A (en) | A kind of preparation method of alkyl pegylation oxaliplatin precursor | |
| CN111196781B (en) | Improved method for preparing pentafluoride | |
| WO2023217058A1 (en) | Method for preparing glucopyranosyl-containing compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zhao Yunxian Inventor after: Cui Jinwang Inventor after: Yang Zhibin Inventor before: Cui Jinwang Inventor before: Zhang Ben Inventor before: Zhao Zejia Inventor before: Tian Junbo Inventor before: Li Qian Inventor before: Yang Zhibin Inventor before: Tian Haobo Inventor before: Liu Gang Inventor before: Jia Boshuo Inventor before: Wang Can Inventor before: Xing Ruijing |
|
| CB03 | Change of inventor or designer information | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |