CN110423224B - Synthesis method of 2-aminopyrimidine type antiplatelet compound - Google Patents
Synthesis method of 2-aminopyrimidine type antiplatelet compound Download PDFInfo
- Publication number
- CN110423224B CN110423224B CN201910810281.XA CN201910810281A CN110423224B CN 110423224 B CN110423224 B CN 110423224B CN 201910810281 A CN201910810281 A CN 201910810281A CN 110423224 B CN110423224 B CN 110423224B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- hydroxybenzaldehyde
- antiplatelet
- aminopyrimidine
- 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
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for synthesizing a 2-aminopyrimidine type antiplatelet compound, which comprises the steps of selecting o-hydroxybenzaldehyde A and 2-bromoacetophenone B containing different substituents as raw materials, taking N-heterocyclic carbene as a reaction catalyst, synthesizing an intermediate 1, 3-diketone compound C of a novel antiplatelet drug under an alkaline condition, synthesizing a flavonoid compound D from the 1, 3-diketone compound C under an acidic condition, and finally generating a final product 2-aminopyrimidine type antiplatelet compound E from the flavonoid compound D and guanidine hydrochloride under an alkaline condition. The invention simplifies the original synthesis method from four steps to three steps, thereby greatly simplifying the original synthesis method, effectively reducing the production cost and the price of medicines and improving the possibility of industrial production.
Description
Technical Field
The invention belongs to the technical field of compound preparation, and particularly relates to a synthesis method of a 2-aminopyrimidine type antiplatelet compound.
Background
In western countries, the incidence and mortality rate of atherosclerotic thrombotic vascular disease is about 40%. Platelets play a key role in thrombosis and hemostasis, with the primary physiological role being to maintain the integrity of the circulatory system and to respond rapidly and forcefully at the site of vascular injury. Platelets are activated when they come into contact with drugs such as collagen, thrombin and ADP. This activation plays a key role in arterial thrombosis, mainly involving platelet aggregation, densification, particle secretion and procoagulant activity. At present, nearly 50% of the world population is resistant to common antiplatelet drugs, such as: aspirin and thiophenepyridine drugs, increasing the risk of recurrent myocardial infarction and stroke. Therefore, the development of novel antiplatelet drugs and the research of the synthesis method thereof are of great significance.
Recent studies have shown that pyrimidine derivatives are an effective antiplatelet agent. Pyrimidine plays an important role in many biological processes, and pyrimidine rings are found in nucleoside anti-alkaloids to have important chemical and pharmacological significance. Pyrimidines, in particular alkylthio-substituted pyrimidines, such as 2-propylthiotriazolopyrimidines and thiophenopyrimidines, are of great interest because of their high resistance to drugs. The dual antiplatelet method in which aspirin and a thiopyridine drug are used in combination, is one of the main causes of morbidity and mortality in the acute and secondary prevention stages, despite recent progress in the treatment of coronary syndromes. In addition, indobufen is used as a new generation of anti-platelet aggregation medicine, and can inhibit platelet aggregation caused by epinephrine, platelet activating factor, collagen and arachidonic acid. Clinical uses include the treatment of ischemic stroke, myocardial infarction, non-rheumatic atrial fibrillation, venous thrombosis, in particular the prevention and treatment of arterial thrombosis, but studies on its anticoagulation have not been adequate.
The limitations of currently available antiplatelet drugs have led to the development of new drugs. Wherein the compounds extracted from the 2-aminopyrimidine provide basis for different pharmaceutical applications. The preparation method of the pyrimidine type antiplatelet medicine at present mainly comprises the following steps:
1) In 2011, the Du Hongguang problem was to combine 6-alkylamine-2, 4-dialkylated (aryl) thiopyridine and to examine the activity of the synthesized compound. The results show that some compounds have an anti-platelet aggregation effect.
2) Giridhar's subject group in 2012 synthesized 4, 6-diaryl-2-aminopyrimidine compounds in a four-step reaction. In vitro experiments show that the efficacy of aspirin is only half that of 4- (2 '-hydroxy-4' -methoxyphenyl) -6- (2 ', 4' -dichlorophenyl) -2-aminopyridine.
3) The Okuda problem combines a number of tricyclic 2-substituted 4-alkylamino-5, 6-dihydrobenzazepine [5,4-d ] pyrimidines, a wide variety of alkyl and aryl groups of which can be used as substituents at the 2-position. And the antiplatelet activity of the synthesized pentacyclic pyrimidine compound is evaluated, and the research results show that some products have equivalent effects to aspirin. By examining this group of subjects, it was found that the effect of the newly synthesized compound on collagen-induced platelet aggregation gave several effects superior to aspirin, and was expected to be an antiplatelet compound.
However, the above preparation process requires multiple steps, and in the multi-step organic synthesis, since the yield of each step reaction is lower than the theoretical yield, the total yield is necessarily affected by the accumulation every one more reaction step. Thus, the reduction of the reaction steps has a great effect on the improvement of the yield of the final product.
Disclosure of Invention
The invention aims to provide a synthesis method of a 2-aminopyrimidine type antiplatelet compound, which greatly simplifies the original four-step reaction synthesis method, can effectively reduce the production cost and the price of medicines, and improves the possibility for industrial production.
The invention is realized by the following technical scheme:
a process for synthesizing 2-aminopyrimidine type antiplatelet compound includes such steps as dissolving flavonoid, guanidine hydrochloride and alkali in solvent, stirring at 65 deg.C for reaction, pouring the reaction liquid in crushed ice containing acetic acid, filtering to obtain yellow solid, washing with water, and recrystallizing in methanol.
The alkali is selected from potassium hydroxide, and the solvent is selected from methanol.
In another aspect of the invention, the preparation method of the flavonoid compound is provided, the 1, 3-diketone compound and concentrated sulfuric acid are dissolved in a solvent, the mixture is stirred and reacted at the temperature of 100 ℃, after the reaction is finished, the temperature of the reaction solution is reduced to room temperature, the reaction solution is poured into crushed ice, and the flavonoid compound is obtained through filtration.
The solvent is selected from glacial acetic acid.
In another aspect of the invention, the preparation method of the 1, 3-diketone compound is provided, wherein the o-hydroxybenzaldehyde, the 2-bromoacetophenone, the N-heterocyclic carbene precursor and the alkali are dissolved in a solvent, stirred and reacted at the temperature of 80-130 ℃, and after the reaction is finished, the crude product is concentrated under reduced pressure, and purified by a silica gel column chromatography to obtain the 1, 3-diketone compound.
The o-hydroxybenzaldehyde and the 2-bromoacetophenone contain different substituents; the molar ratio of the o-hydroxybenzaldehyde to the 2-bromoacetophenone is 1:1-1:1.3.
The solvent is selected from one of acetonitrile, toluene, DMF, THF or paraxylene.
The alkali is selected from one of potassium hydroxide, sodium hydroxide, cesium carbonate, triethylamine or pyridine; the molar ratio of the alkali to the o-hydroxybenzaldehyde is 0.5-1.
The N-heterocyclic carbene precursor is selected from one of L1-L4, the molar ratio of the N-heterocyclic carbene precursor to o-hydroxybenzaldehyde is 0.02-0.2, and the preferable molar ratio is 0.02, 0.05, 0.1 or 0.2, wherein the structural formula of L1-L4 is as follows:
the beneficial effects of the invention are as follows:
the method of the invention can simplify the original four-step reaction synthesis method to a great extent, and can effectively reduce the production cost and the price of medicines.
Detailed Description
The following description of the present invention will be made more complete and clear in view of the detailed description of the invention, which is to be taken in conjunction with the accompanying drawings that illustrate only some, but not all, of the embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides a novel method for synthesizing a novel 2-aminopyrimidine type antiplatelet compound, which comprises the steps of reacting o-hydroxybenzaldehyde and a 2-bromoacetophenone compound under the catalysis of an N-heterocyclic carbene to obtain a 1, 3-diketone compound, synthesizing the 1, 3-diketone compound into a flavonoid compound under an acidic condition, and finally generating a final product of the 2-aminopyrimidine type antiplatelet compound under an alkaline condition by the flavonoid compound and guanidine hydrochloride.
The specific reaction formula is as follows:
example 1
The reaction route is as follows:
to a 50mL pressure-resistant flask were successively added 2-hydroxy-5-methoxybenzaldehyde (4.0 mmol), 2-bromo-1- (4-methoxyphenyl) ethane (4.8 mmol) and L1 (0.2 mmol), KOH and toluene (10 mL), and the mixture was refluxed at 110℃in air and reacted for 5 hours. Concentrating the obtained solid under reduced pressure by a rotary evaporator after the reaction is finished, and purifying the crude product in a mixed solvent of ethyl acetate/n-hexane which is 1:8 by a silica gel column chromatography to obtain a 1, 3-diketone compound C1 with the yield of 83%; dissolving C1 (3.0 mmol) and concentrated sulfuric acid (3.0 ml) in glacial acetic acid (15.0 ml), stirring at 100 ℃ for reaction, cooling the reaction liquid to room temperature after the reaction is finished, pouring the reaction liquid into crushed ice, and filtering to obtain an intermediate flavonoid compound D1, wherein the yield is 65%; d1 (1.5 mmol), guanidine hydrochloride (7.5 mmol) and potassium hydroxide (0.8 g) were dissolved in methanol (25 ml), and reacted at 65℃with stirring, after the reaction was completed, the reaction solution was poured into crushed ice containing acetic acid, and a yellow solid was obtained by filtration, and the final product E1 was obtained by washing with water and recrystallization from methanol. And finally weighing the obtained target product and recording data. The final yield of the product was 67%.
The nuclear magnetic data of the compound prepared in example 1 are characterized as:
1 H NMR(CDCl 3 ,400MHz):δ3.86(s,6H,OCH 3 ),5.48(s,2H,NH 2 ),7.24-7.26(d,2H,ArH),7.30-7.32(d,2H,ArH),7.36-7.38(d,2H,ArH),7.49(s,1H,ArH),8.06(s,1H,pyri).MS m/z；324.05(M+1).Anal.Calcd for C 18 H 17 N 3 O 3 :C,66.86；H,5.30；N,13.0.Found:C,66.84；H,5.32；N,13.10。
example 2
The reaction route is as follows:
to a 50mL pressure-resistant flask were successively added 2-hydroxy-5 methoxybenzaldehyde (4.0 mmol), 2-bromo-1- (2-chlorophenyl) ethane (4.8 mmol) and L1 (0.2 mmol), KOH and toluene (10 mL), and the mixture was refluxed at 110℃in air and reacted for 5 hours. Concentrating the obtained solid under reduced pressure by a rotary evaporator after the reaction is finished, and purifying the crude product in a mixed solvent of ethyl acetate/n-hexane which is 1:8 by a silica gel column chromatography to obtain a 1, 3-diketone compound C2 with the yield of 76%; dissolving C2 (3.0 mmol) and concentrated sulfuric acid (3.0 ml) in glacial acetic acid (15.0 ml), stirring at 100 ℃ for reaction, cooling the reaction liquid to room temperature after the reaction is finished, pouring the reaction liquid into crushed ice, and filtering to obtain an intermediate flavonoid compound D2 with the yield of 60%; d2 (1.5 mmol), guanidine hydrochloride (7.5 mmol) and potassium hydroxide (0.8 g) were dissolved in methanol (25 ml), and reacted at 65℃with stirring, after the reaction was completed, the reaction solution was poured into crushed ice containing acetic acid, and a yellow solid was obtained by filtration, and the final product E2 was obtained by washing with water and recrystallization from methanol in 61% yield.
The nuclear magnetic data of the compound prepared in example 2 are characterized as:
1 H NMR(CDCl 3 ,400MHz):δ3.81(s,3H,OCH 3 ),5.24(s,2H,NH2),6.97(s,1H,ArH),7.0-7.02(m,1H,ArH),7.39-7.42(m,3H,ArH),7.50-7.52(m,1H,ArH),7.60-7.62(m,1H,ArH),7.83(s,1H,pyri),13.09(br,1H,OH)；MS m/z；328.1(M+1)；Anal.Calcd for C 17 H 14 ClN 3 O 2 :C,62.30；H,4.31；N,12.82.Found:C,62.33；4.38；N,12.86.
example 3
The reaction route is as follows:
in a 50mL pressure-resistant flask were successively added 2-hydroxy-4-methoxybenzaldehyde (4.0 mmol), 2-bromo-1- (2, 4-dichlorophenyl) ethane (4.8 mmol), L1 (0.2 mmol), KOH and toluene (10 mL), and the mixture was refluxed at 110℃in air and reacted for 5 hours. Concentrating the obtained solid under reduced pressure by a rotary evaporator after the reaction is finished, and purifying the crude product in a mixed solvent of ethyl acetate/n-hexane which is 1:8 by a silica gel column chromatography to obtain a 1, 3-diketone compound C3 with the yield of 90%; dissolving C3 (3.0 mmol) and concentrated sulfuric acid (3.0 ml) in glacial acetic acid (15.0 ml), stirring at 100 ℃ for reaction, cooling the reaction liquid to room temperature after the reaction is finished, pouring the reaction liquid into crushed ice, and filtering to obtain an intermediate flavonoid compound D3 with the yield of 71%; d3 (1.5 mmol), guanidine hydrochloride (7.5 mmol) and potassium hydroxide (0.8 g) were dissolved in methanol (25 ml), and reacted at 65℃with stirring, after the reaction was completed, the reaction solution was poured into crushed ice containing acetic acid, and a yellow solid was obtained by filtration, and the final product E3 was obtained by washing with water and recrystallization from methanol. And finally weighing the obtained target product and recording data. The final yield of the product was 74%.
The nuclear magnetic data of the compound prepared in example 3 are characterized as:
1 H NMR(CDCl 3 ,400MHz):δ3.84(s,3H,OCH 3 ),5.15(s,2H,NH 2 ),6.48-6.51(m,2H,ArH),7.33(s,1H,pyri),7.36e7.38(dd,1H,ArH),7.52-7.53(m,1H,ArH),7.56-7.58(d,1H,ArH),7.67-7.69(dd,1H,ArH),13.19(s,1H,OH)； 13 C NMR(CDCl 3 ,400MHz):δ55.48,101.89,105.84,107.69,110.34,127.60,128.66,130.28,131.79,132.94,135.56,136.12,160.05,163.19,163.90,164.05,165.55；MS m/z；362.1(M+1)；Anal.Calcd for C 17 H 13 Cl 2 N 3 O 2 :C,56.37；H,3.62；N,11.60.Found:C,56.44；H,3.56；N,11.68.
example 4
The reaction route is as follows:
the same as in example 1, except that 2-bromo-1- (3-chlorophenyl) ethane was used instead of 2-bromo-1- (4-methoxyphenyl) ethane, the three-step reaction yields were 92%, 75% and 77% in this order, and the nuclear magnetic resonance and mass spectrometry data were identical to those of the prior art.
Example 5
The reaction route is as follows:
the same as in example 1, except that 2-bromo-1- (4-fluorophenyl) ethane was used instead of 2-bromo-1- (4-methoxyphenyl) ethane, the three-step reaction yield was 62%, 55% and 15% in this order, and the nuclear magnetic resonance and mass spectrometry data were identical to those of the prior art.
Example 6
The reaction route is as follows:
the same as in example 3, except that 2-bromo-1- (3-methylphenyl) ethane was used instead of 2-bromo-1- (2, 4-dichlorophenyl) ethane, the three-step reaction yields were 62%, 55% and 15% in this order, and the nuclear magnetic resonance and mass spectrometry data were consistent with those of the prior art.
Example 7
The reaction route is as follows:
the same as in example 3, except that 2-bromo-1- (3-chlorophenyl) ethane was used instead of 2-bromo-1- (2, 4-dichlorophenyl) ethane, the three-step reaction yields were 72%, 65% and 65% in order, and the nuclear magnetic resonance and mass spectrometry data were identical to those of the prior art.
Example 8
The reaction route is as follows:
the same as in example 3, except that 2-bromo-1- (4-fluorophenyl) ethane was used instead of 2-bromo-1- (2, 4-dichlorophenyl) ethane, the three-step reaction yields were 70%, 60% and 62% in this order, and the nuclear magnetic resonance and mass spectrometry data were in accordance with the present.
Example 9
The reaction route is as follows:
the same as in example 3, except that 2-bromo-1- (3-methoxyphenyl) ethane was used instead of 2-bromo-1- (2, 4-dichlorophenyl) ethane, the three-step reaction yields were 60%, 65% and 52% in this order, and the nuclear magnetic resonance and mass spectrometry data were in accordance with the present.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (2)
1. A synthesis method of 2-aminopyrimidine type antiplatelet compound is characterized in that flavonoid compound, guanidine hydrochloride and potassium hydroxide are dissolved in methanol, stirred at 65 ℃ for reaction, after the reaction is finished, reaction liquid is poured into crushed ice containing acetic acid, yellow solid is obtained by filtration, and target product is obtained by water washing and methanol recrystallization;
the preparation method of the flavonoid compound comprises the following steps:
1) Dissolving o-hydroxybenzaldehyde, 2-bromoacetophenone, an N-heterocyclic carbene precursor and alkali in a solvent, stirring at the temperature of 80-130 ℃ for reaction, concentrating under reduced pressure after the reaction is finished, and purifying the crude product by a silica gel column chromatography to obtain a 1, 3-diketone compound; the solvent is selected from one of acetonitrile, toluene, DMF, THF or paraxylene; the alkali is selected from one of potassium hydroxide, sodium hydroxide, cesium carbonate, triethylamine or pyridine; the molar ratio of the alkali to the o-hydroxybenzaldehyde is 0.5-1;
the N-heterocyclic carbene precursor is one of L1-L4, and the molar ratio of the N-heterocyclic carbene precursor to the o-hydroxybenzaldehyde is 0.02-0.2;
wherein the structural formulas of L1 to L4 are as follows:
2) Dissolving 1, 3-diketone compound and concentrated sulfuric acid in glacial acetic acid, stirring at 100 ℃ for reaction, cooling the reaction liquid to room temperature after the reaction is finished, pouring the reaction liquid into crushed ice, and filtering to obtain flavonoid compound;
the molar ratio of the o-hydroxybenzaldehyde to the 2-bromoacetophenone is 1:1-1:1.3.
2. The method of claim 1, wherein the molar ratio of the N-heterocyclic carbene precursor to o-hydroxybenzaldehyde is 0.02, 0.05, 0.1 or 0.2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910810281.XA CN110423224B (en) | 2019-08-29 | 2019-08-29 | Synthesis method of 2-aminopyrimidine type antiplatelet compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910810281.XA CN110423224B (en) | 2019-08-29 | 2019-08-29 | Synthesis method of 2-aminopyrimidine type antiplatelet compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110423224A CN110423224A (en) | 2019-11-08 |
| CN110423224B true CN110423224B (en) | 2023-08-11 |
Family
ID=68418199
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910810281.XA Active CN110423224B (en) | 2019-08-29 | 2019-08-29 | Synthesis method of 2-aminopyrimidine type antiplatelet compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110423224B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085433A (en) * | 2014-05-19 | 2015-11-25 | 中国科学院上海药物研究所 | Substituted-amide phenolic compound, preparation method, pharmaceutical composition and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1343048A3 (en) * | 2002-03-08 | 2004-01-14 | JSR Corporation | Anthracene derivative and radiation-sensitive resin composition |
-
2019
- 2019-08-29 CN CN201910810281.XA patent/CN110423224B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085433A (en) * | 2014-05-19 | 2015-11-25 | 中国科学院上海药物研究所 | Substituted-amide phenolic compound, preparation method, pharmaceutical composition and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| Assessment of antiplatelet activity of 2-aminopyrimidines;Rajani Giridhar，等;《European Journal of Medicinal Chemistry》;20120124;第50卷;第428-432页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110423224A (en) | 2019-11-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| EP3712130A1 (en) | Method for synthesis of roxadustat and intermediate compounds thereof | |
| CN105801575A (en) | Synthetic method of imidazo[1,2-a]pyridine | |
| JPS6139949B2 (en) | ||
| CN114315823B (en) | Intermediate of berberine hydrochloride and analogues thereof and preparation method thereof | |
| CN107540678B (en) | Method for preparing coumarin heteroaromatic ring compound and derivative thereof through intramolecular cross dehydrogenation coupling | |
| CN110423224B (en) | Synthesis method of 2-aminopyrimidine type antiplatelet compound | |
| JPH0261476B2 (en) | ||
| US9512155B2 (en) | Chiral phosphines for palladium-catalyzed asymmetric α-arylation of ester enolates to produce tertiary stereocenters in high enantioselectivity | |
| CN110256451B (en) | Synthetic method of benzofuro [2,3-b ] quinoline derivative | |
| CN105153029A (en) | Method for synthesizing isoquinoline ketone compounds | |
| CN103351333B (en) | A kind of Aryl pyridine derivative compound and preparation method thereof | |
| RU2806043C1 (en) | Method for preparation of 1-methyl-n-aryl-3-oxo-8-phenyl-2-oxa-6-thiabicyclo[2.2.2]octane-5-carboxamides | |
| KR102327657B1 (en) | Novel azulene compounds and its preparation method | |
| CN115894303B (en) | Preparation method of (3-amino bicyclo [1.1.1] pentane-1-yl) carbamic acid tert-butyl ester and intermediate thereof | |
| CN115043845B (en) | Synthesis method of sildenafil | |
| CN114573551A (en) | Preparation method of benzo-cyclopentenothiophene compound | |
| CN108164435B (en) | Green and efficient synthesis method of aryl acrylonitrile compound | |
| CN117343007A (en) | Preparation method of lenvatinib | |
| CN116496201A (en) | Preparation method of aza spirocyclic ketone compound and dihydroxyl hydroindole compound | |
| JP2907475B2 (en) | Process for producing (1,2,3-thiadiazol-4-yl) carbaldehyde and intermediate | |
| CN113582933A (en) | Preparation method of medical intermediate 4-chloro-5-cyanopyrimidine | |
| CN118005593A (en) | Preparation method of 2, 3-disubstituted chromone compound | |
| CN105111217A (en) | Method for synthesizing isoindole dihyroquinazoline derivative | |
| CN116731087A (en) | Preparation method of monabivalir and intermediate thereof |
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 |