CN114890936B - Synthesis method of 5, 6-dihydro-2 (1H) -pyridone - Google Patents
Synthesis method of 5, 6-dihydro-2 (1H) -pyridone Download PDFInfo
- Publication number
- CN114890936B CN114890936B CN202210013812.4A CN202210013812A CN114890936B CN 114890936 B CN114890936 B CN 114890936B CN 202210013812 A CN202210013812 A CN 202210013812A CN 114890936 B CN114890936 B CN 114890936B
- Authority
- CN
- China
- Prior art keywords
- reaction
- methoxybenzyl
- synthesis method
- acid
- pyridone
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a method for synthesizing 5, 6-dihydro-2 (1H) -pyridone; adding sodium dihydrogen phosphate, 2, 6-tetramethylpiperidine oxide TEMPO, 1- (4-methoxybenzyl) -piperidine and sodium hypochlorite into tertiary butanol for reaction, carrying out oxidation reaction at 5-140 ℃, washing and extracting after the reaction is finished to obtain an intermediate product 1- (4-methoxybenzyl) -5, 6-dihydropyridine-2 (1H) -ketone; and refluxing the intermediate product in an acid solution to remove 4-methoxybenzyl, concentrating and extracting after the reaction is finished to obtain the 5, 6-dihydro-2 (1H) -pyridone. The method has the advantages of simple and easily obtained raw materials, simple and convenient reaction conditions, greenness and energy conservation, can be widely applied to the synthesis of pharmaceutical intermediates in industry and academia, and has higher application value.
Description
Technical Field
The invention belongs to the technical field of organic intermediate synthesis, and particularly relates to a synthesis method of 5, 6-dihydro-2 (1H) -pyridone.
Background
5, 6-dihydro-2 (1H) -pyridone, which is a very important organic molecular intermediate, is widely available in natural products and synthetic compounds with biological and pharmacological activities, and can be used for treating hepatitis C virus infection. Currently, the methods for synthesizing 5, 6-dihydro-2 (1H) -pyridone are:
the method comprises the following steps: 3-butene-1-amine and 2-butenoyl chloride are used for synthesizing amide, and then an intramolecular olefin metathesis reaction is carried out under the action of a noble metal catalyst to obtain 5, 6-dihydro-2 (1H) -pyridone.
The method has the defects of high production cost and high use cost of a metal catalyst.
The second method is that 1-tert-butoxyformyl-2-piperidone is used to remove alpha-hydrogen under the action of strong alkali (such as lithium diisopropylamide), then the alpha-hydrogen reacts with diphenyl disulfide or phenyl selenium chloride, and then the product 5, 6-dihydro-2 (1H) -pyridone is produced through heating dehydrogenation and deprotection after oxidation of m-chloroperoxybenzoic acid.
The method has the defects that strong alkali is needed, the large-scale production is not facilitated, the reaction steps are more, and the pollution generated in the production process is larger.
And a third method: starting from 1-pentafluorobenzoyl-2-piperidone, palladium trifluoroacetate and zinc trifluoroacetate are used for co-catalysis, phenyl methyl sulfoxide is used as a ligand, 2, 5-di-tert-butylbenzoquinone is used as an oxidant, and the dehydrogenation is carried out under the action of Lewis acid and organic base, and then the hydrolysis is carried out to obtain the 5, 6-dihydro-2 (1H) -pyridone.
The reaction uses noble metal palladium as a catalyst, and simultaneously uses dibutyl boron triflate as Lewis acid, so that the price is high, and the reaction economy is poor; and the reaction is sensitive to water and air, and the production conditions are very severe.
Therefore, there is still a need to develop a method for synthesizing 5, 6-dihydro-2 (1H) -pyridone, which has the advantages of simple and easily available raw materials, simple and convenient operation, good economic benefit and easy popularization in industrial production.
Disclosure of Invention
Aiming at the problems, the invention aims to provide a synthesis method of 5, 6-dihydro-2 (1H) -pyridone, which is simple to operate and easy to popularize in industrial production.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: a synthesis method of 5, 6-dihydro-2 (1H) -pyridone comprises the following steps:
wherein Me is methyl, and the oxidant in the first step is 2, 6-tetramethylpiperidine oxide TEMPO; the second step of reaction is to remove protecting groups under acidic conditions: benzyl or 4-methoxybenzyl PMB.
The synthesis method of the invention comprises the following steps:
1) Sodium dihydrogen phosphate, 2, 6-tetramethyl piperidine oxide (TEMPO) and 1- (4-methoxybenzyl) -piperidine are stirred in air at normal temperature for 5 minutes, sodium hypochlorite solution is dropwise added, the reaction temperature is 5 ℃ for 2 hours, the reaction is heated to 140 ℃ and the reaction time is 19 hours at 140 ℃, after the reaction is completed, the unreacted sodium hypochlorite is removed by saturated sodium thiosulfate and saturated sodium hydroxide, the mixture is extracted three times by ethyl acetate, and the mixture is subjected to column chromatography to obtain 1- (4-methoxybenzyl) -5, 6-dihydropyridin-2 (1H) -one.
2) Refluxing 1- (4-methoxybenzyl) -5, 6-dihydropyridine-2 (1H) -ketone in an acid solution to remove benzyl or 4-methoxybenzyl, wherein the reflux temperature is 75 ℃, and the reaction time is 8-12H; after the reaction, the reaction solution was concentrated and extracted three times with methylene chloride, and the 5, 6-dihydro-2 (1H) -pyridone was obtained by column chromatography.
The molar ratio of TEMPO to the reaction initiator of formula (1) in the first reaction step is 1-2: 1, a step of; preferably the molar ratio is 1.5:1; when the molar ratio of TEMPO to the reaction initiator of formula (1) is 1.5:1, the product yield of the first reaction step is high.
The molar ratio of the sodium dihydrogen phosphate to the reaction initiator in the first step reaction is 2.5-3.5: 1, a step of; the preferred molar ratio is 3.2:1.
The first step of reaction solvent is tertiary butanol; the t-butanol was used in such an amount that the molar concentration of the reaction initiator 1- (4-methoxybenzyl) -piperidine was 0.15mol/L.
The acid in the second step reaction solvent comprises acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid or sulfuric acid, and the preferred acid is trifluoroacetic acid; the amount of acid used was such that the molar concentration of the starting materials for the second reaction was 0.1mmol/mL.
The invention has the advantages that: the invention takes the 1- (4-methoxybenzyl) -piperidine which is easy to obtain as a reaction substrate and is not easy to be sensitive to air. Compared with other methods for synthesizing 5, 6-dihydro-2 (1H) -pyridone, the method has the characteristics of mild reaction conditions, low price and easy obtainment of the used reaction raw materials, no need of using a metal catalyst, cost saving, environmental friendliness and industrial popularization.
The invention can be widely applied to the drug synthesis in industry and academia and the total synthesis of natural products, and has higher application value.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of the product 1-benzyl-5, 6-dihydropyridin-2 (1H) -one of example 1 of the present invention;
FIG. 2 is a nuclear magnetic carbon spectrum of the product 1-benzyl-5, 6-dihydropyridin-2 (1H) -one of example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance spectrum of the product 1- (4-methoxybenzyl) -5, 6-dihydropyridin-2 (1H) -one of example 2 according to the invention;
FIG. 4 is a nuclear magnetic carbon spectrum of the product 1- (4-methoxybenzyl) -5, 6-dihydropyridin-2 (1H) -one of example 2 according to the invention;
FIG. 5 is a nuclear magnetic resonance spectrum of the product 5, 6-dihydro-2 (1H) -pyridone in the examples of the present invention;
FIG. 6 is a nuclear magnetic carbon spectrum of the product 5, 6-dihydro-2 (1H) -pyridone in the examples of the present invention.
Wherein the abscissa in FIGS. 1-4 is signal absorption and the ordinate is chemical shift in ppm.
Detailed Description
The invention is described in further detail below with reference to the accompanying drawings and detailed description.
The synthesis method of the related 5, 6-dihydro-2 (1H) -pyridone according to the present invention will be described in detail. It should be noted that the following specific examples are intended only to further illustrate specific embodiments of the invention and to make it easier for the skilled person to understand the invention, without limiting the scope of the claims.
The starting materials used in the following specific examples were commercially available or synthesized by simple procedures.
1 H NMR 13 C NMR was measured using a Bruker Avance 400spectrometer instrument. The test temperature was room temperature and the solvent was deuterated chloroform, and the reference was selected: 1 H NMR:CHCl 3 7.260ppm; 13 C NMR:CHCl 3 77.000ppm.
Examples 1-2 synthetic route
Example 1: synthesis method of 1- (4-methoxybenzyl) -5, 6-dihydropyridin-2 (1H) -one, wherein R=H
After completion of the reaction of step 1), the mixture was diluted with ethyl acetate and extracted twice with water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution in anhydrous Na 2 SO 4 The mixture was purified by column chromatography on silica gel using a dichloromethane/methanol mixture as eluent to give 1- (4-methoxybenzyl) -piperidine.
Step 2) sodium dihydrogen phosphate, 2, 6-tetramethylpiperidine oxide (TEMPO), 1- (4-methoxybenzyl) -piperidine, t-butanol were added to a thick-walled pressure-resistant bottle equipped with a magnetic stirrer, stirred in air at room temperature for 5 minutes, then sodium hypochlorite solution (0.6 ml of 3% aqueous solution) was added, and the mixture was stirred at 5 ℃ for 2 hours. Then, the tube was capped with a polytetrafluoroethylene screw cap and heated in an oil bath at 140℃for 19 hours.
After the reaction of step 3) is completed, the post-treatment and purification are carried out according to a conventional method. For example, the reaction mixture is cooled to room temperature, a proper amount of saturated sodium thiosulfate solution and saturated sodium hydroxide solution are added, respectively, and then ethyl acetate and a saturated aqueous solution of ammonium chloride are added, and the aqueous phase is extracted with ethyl acetate. The combined organic phases were dried and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography using petroleum ether/ethyl acetate mixture as eluent to give 1- (4-methoxybenzyl) -5, 6-dihydropyridin-2 (1H) -one.
1- (4-methoxybenzyl) -5, 6-dihydropyridin-2 (1H) -one: 1 H NMR(400MHz,Chloroform-d)δ7.22–7.20 (m,2H),6.86–6.84(m,2H),6.55–6.51(m,1H),5.98–5.96(m,1H),4.55(s,2H),3.78(s,3H), 3.29(t,J＝7.2Hz,2H),2.32–2.27(m,2H). 13 C NMR(101MHz,Chloroform-d)δ164.5,158.9, 129.4,129.5,129.4,125.4,113.9,55.3,49.0,44.4,24.2.
step 4) 1- (4-methoxybenzyl) -5, 6-dihydropyridin-2 (1H) -one, trifluoroacetic acid, was added to a round bottom flask equipped with a magnetic stirrer and heated to 75℃in an oil bath for reflux for 12 hours.
After the completion of the reaction of step 5), the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The organic layer was washed with water (2X 25 mL), dried (MgSO 4 ) Concentrating under reduced pressure, and purifying the crude mixture by silica gel chromatography with dichloromethane/methanol mixture as eluent to obtain the target product 5, 6-dihydro-2 (1H) -pyridone.
Target product 5, 6-dihydro-2 (1H) -pyridone: 1 H NMR(400MHz,Chloroform-d)δ6.99(br,1H),6.67–6.63(m,1H),5.91(dd,J＝9.6,2.0Hz,1H),3.44–3.40(m,2H),2.37–2.32(m,2H). 13 C NMR (101MHz,Chloroform-d)δ166.9,141.8,124.8,39.5,23.8.
example 2: synthesis method of 1-benzyl-5, 6-dihydropyridin-2 (1H) -one, wherein R=MeO
After completion of the reaction of step 1), the mixture was diluted with ethyl acetate and extracted twice with water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution in anhydrous Na 2 SO 4 Drying above, evaporating solvent, and purifying the crude mixture with silica gel column chromatography using dichloromethane/methanol mixture as eluent to obtain 1-benzyl-piperidine.
Step 2) sodium dihydrogen phosphate, 2, 6-tetramethylpiperidine oxide (TEMPO), 1-benzyl-piperidine, t-butanol were placed in a thick-walled pressure-resistant bottle equipped with a magnetic stirrer, stirred in air at room temperature for 5 minutes, then sodium hypochlorite solution (0.6 mL of 3% aqueous solution) was added, and the mixture was stirred at 5 ℃ for 2 hours. Then, the tube was capped with a polytetrafluoroethylene screw cap and heated in an oil bath at 140℃for 19 hours.
After the reaction of step 3) is completed, the post-treatment and purification are carried out according to a conventional method. For example, the reaction mixture is cooled to room temperature, a proper amount of saturated sodium thiosulfate solution and saturated sodium hydroxide solution are added, respectively, and then ethyl acetate and a saturated aqueous solution of ammonium chloride are added, and the aqueous phase is extracted with ethyl acetate. The combined organic phases were dried and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography using petroleum ether/ethyl acetate mixture as eluent to give 1-benzyl-5, 6-dihydropyridin-2 (1H) -one.
1-benzyl-5, 6-dihydropyridin-2 (1H) -one: 1H NMR (400 MHz, chloroform-d) delta 7.37-7.28 (m, 5H), 6.60-6.55 (m, 1H), 6.04-6.01 (m, 1H), 4.65 (s, 2H), 3.34 (t, J=7.2 Hz, 2H), 2.37-2.32 (m, 2H) 13C NMR (101 MHz, chloroform-d) delta 164.7,139.6,137.6,128.7,128.1,127.5,125.5,49.8,44.7,24.3.
Step 4) 1-benzyl-5, 6-dihydropyridin-2 (1H) -one, trifluoroacetic acid, was added to a round bottom flask equipped with a magnetic stirrer and heated to 75℃in an oil bath for reflux for 12 hours.
After the completion of the reaction of step 5), the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The organic layer was washed with water (2X 25 mL), dried (MgSO 4 ) Concentrating under reduced pressure, and purifying the crude mixture by silica gel chromatography with dichloromethane/methanol mixture as eluent to obtain the target product 5, 6-dihydro-2 (1H) -pyridone.
Target product 5, 6-dihydro-2 (1H) -pyridone: 1 H NMR(400MHz,Chloroform-d)δ6.99(br,1H),6.67– 6.63(m,1H),5.91(dd,J＝9.6,2.0Hz,1H),3.44–3.40(m,2H),2.37–2.32(m,2H). 13 C NMR (101MHz,Chloroform-d)δ166.9,141.8,124.8,39.5,23.8.
the method is not only suitable for preparing the 5, 6-dihydro-2 (1H) -pyridone in a small scale in a laboratory, but also suitable for industrialized mass production in a chemical plant. The specific reaction parameters at the time of industrial mass production can be determined by one skilled in the art through routine experiments.
From the reaction process, the method of the invention is characterized in that from 1-benzyl-piperidine or 1- (4-methoxybenzyl) -piperidine which is easy to obtain, in tertiary butanol, under the combined action of sodium dihydrogen phosphate, 2, 6-tetramethylpiperidine oxide (TEMPO) and sodium hypochlorite, the oxidation reaction is carried out at the temperature of 5 ℃ to 140 ℃ to obtain 5, 6-dihydro-2 (1H) -pyridone. The method is a synthesis method of 5, 6-dihydro-2 (1H) -pyridone with mild conditions and simple operation.
It should be noted that the foregoing is merely a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and any combination or equivalent transformation made on the basis of the foregoing embodiment falls within the scope of the present invention.
Claims (8)
1. A synthesis method of 5, 6-dihydro-2 (1H) -pyridone is characterized by comprising the following steps:
wherein Me is methyl, and the oxidant in the first step is 2, 6-tetramethylpiperidine oxide TEMPO; the second step of reaction is to remove protecting groups under acidic conditions: 4-methoxybenzyl PMB.
2. The synthesis method according to claim 1, characterized in that the synthesis method is as follows:
1) Adding sodium dihydrogen phosphate, 2, 6-tetramethylpiperidine oxide TEMPO, 1- (4-methoxybenzyl) -piperidine and sodium hypochlorite into tertiary butanol for reaction, carrying out oxidation reaction at 5-140 ℃, washing and extracting after the reaction is finished to obtain an intermediate product 1- (4-methoxybenzyl) -5, 6-dihydropyridin-2 (1H) -one;
2) Reflux-removing 4-methoxybenzyl from intermediate 1- (4-methoxybenzyl) -5, 6-dihydropyridin-2 (1H) -one in acid solution, concentrating and extracting after the reaction is completed to obtain 5, 6-dihydro-2 (1H) -pyridone.
3. The synthesis according to claim 1 or 2, wherein the molar ratio of TEMPO to the reaction initiator formula (1) in the first reaction step is 1-2: 1.
4. the synthesis method according to claim 1 or 2, wherein the molar ratio of sodium dihydrogen phosphate to the reaction initiator of formula (1) in the first reaction step is 2.5 to 3.5:1.
5. the synthetic method according to claim 1 or 2, wherein the first-step reaction solvent is t-butanol; the t-butanol was used in such an amount that the molar concentration of the reaction initiator 1- (4-methoxybenzyl) -piperidine was 0.15mol/L.
6. The synthesis method according to claim 1 or 2, wherein the acid in the second reaction solvent is acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid or sulfuric acid; the amount of acid used was such that the molar concentration of the starting materials for the second reaction was 0.1mmol/mL.
7. The synthesis method according to claim 2, wherein in the first reaction, sodium dihydrogen phosphate, 2, 6-tetramethylpiperidine oxide, 1- (4-methoxybenzyl) -piperidine and tert-butanol as a solvent are stirred at room temperature in air for 5 minutes, then sodium hypochlorite solution is added dropwise, and the mixture is reacted at a reaction temperature of 5 ℃ for 2 hours and then heated to 140 ℃ for 19 hours at 140 ℃.
8. The synthesis method according to claim 2, wherein in the second reaction, the reflux temperature is 75 ℃ and the reaction time is 8-12 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210013812.4A CN114890936B (en) | 2022-01-06 | 2022-01-06 | Synthesis method of 5, 6-dihydro-2 (1H) -pyridone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210013812.4A CN114890936B (en) | 2022-01-06 | 2022-01-06 | Synthesis method of 5, 6-dihydro-2 (1H) -pyridone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114890936A CN114890936A (en) | 2022-08-12 |
| CN114890936B true CN114890936B (en) | 2023-10-03 |
Family
ID=82716006
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210013812.4A Active CN114890936B (en) | 2022-01-06 | 2022-01-06 | Synthesis method of 5, 6-dihydro-2 (1H) -pyridone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114890936B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110734394A (en) * | 2018-12-21 | 2020-01-31 | 江西省科学院应用化学研究所 | Synthesis method of 3, 6-dihydropyridone compounds |
| CN111100069A (en) * | 2019-08-28 | 2020-05-05 | 遵义医科大学 | 3, 3-difluoro-3, 4-dihydroquinoline-2 (1H) -ketone compound and preparation method thereof |
-
2022
- 2022-01-06 CN CN202210013812.4A patent/CN114890936B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110734394A (en) * | 2018-12-21 | 2020-01-31 | 江西省科学院应用化学研究所 | Synthesis method of 3, 6-dihydropyridone compounds |
| CN111100069A (en) * | 2019-08-28 | 2020-05-05 | 遵义医科大学 | 3, 3-difluoro-3, 4-dihydroquinoline-2 (1H) -ketone compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Delfino Chamorro-Arenas 等.Transition-Metal-Free Multiple Functionalization of Piperidines to 4-Substituted and 3,4-Disubstituted 2-Piperidinones.《Chemistry - A European Journal》.2020,第26卷(第21期),4671-4676. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114890936A (en) | 2022-08-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110317189B (en) | Method for synthesizing 5-chlorothiophene-2-formic acid by taking thiophene-2-formic acid as raw material | |
| CN108976243B (en) | Synthesis method of spiro-chroman-4, 3' -oxindole through dimethyl furan and oxoindole o-hydroxy benzyl alcohol | |
| CN114890936B (en) | Synthesis method of 5, 6-dihydro-2 (1H) -pyridone | |
| CN113416150A (en) | Novel synthesis method of lobaplatin intermediate | |
| CN115490657B (en) | Preparation method of 3,3', 4' -benzophenone tetracarboxylic dianhydride | |
| CN110078622B (en) | Synthetic method of 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-benzoate | |
| CN102140103A (en) | Method for preparing 7-amino-3-hydro cephalosporanic acid by taking penicillin G/K as raw material | |
| CN111533689B (en) | 2,2' -biquinoline compound and one-pot preparation method thereof | |
| CN101575329B (en) | Preparation method of tetrahydrothiophene-3-ketone and intermediate | |
| CN109721604B (en) | Preparation method of pemetrexed acid | |
| CN103012507A (en) | Synthetic method of 3-deoxidized-D-sweet dew-2-octulosonic ammonium salt | |
| CN108299466B (en) | Improved dolutegravir synthesis method | |
| CN113501771A (en) | Preparation method of N- (2-aminoethyl) glycine derivative | |
| CN111704559A (en) | Method for preparing 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride | |
| CN111499504A (en) | Preparation method of α -naphthylacetic acid | |
| CN114702451B (en) | Preparation method of clonazepam and intermediate thereof | |
| CN113968842B (en) | Ibutinib intermediate compound | |
| CN115677711B (en) | Method for preparing spiro oxindole natural product Spirotryprostatin A | |
| CN115304477B (en) | Preparation method of aromatic carboxylic ester | |
| CN112851494B (en) | Preparation method of 1-pyrene butyric acid | |
| CN116253675B (en) | Synthesis method of N-substituted-2-piperidone | |
| CN115385850B (en) | Preparation method of 1, 4-dihydropyridine compound | |
| CN110028469B (en) | Preparation method and application of key intermediate of non-opioid analgesic | |
| CN115403555A (en) | Synthetic method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |