CN109665982A - The synthetic method of Nefiracetam intermediate 2-Pyrrolidone - Google Patents
The synthetic method of Nefiracetam intermediate 2-Pyrrolidone Download PDFInfo
- Publication number
- CN109665982A CN109665982A CN201910058445.8A CN201910058445A CN109665982A CN 109665982 A CN109665982 A CN 109665982A CN 201910058445 A CN201910058445 A CN 201910058445A CN 109665982 A CN109665982 A CN 109665982A
- Authority
- CN
- China
- Prior art keywords
- solvent
- pyrrolidone
- pressure
- butyl chloride
- nefiracetam
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
-
- 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
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a kind of synthetic methods of Nefiracetam intermediate 2-Pyrrolidone, react the halogenated butyl chloride of 4- to obtain 2-Pyrrolidone under the effect of the catalyst with carbamate；1) the halogenated butyl chloride of 4-, catalysts and solvents A will be mixed under gas by protecting; temperature is increased to 100~125 DEG C; pressure rise is to 3~5 atmospheric pressure; the solution of carbamate and solvent B is added dropwise; time for adding is 40~60min; after; maintenance condition the reaction was continued 5~7h, then temperature is increased to 135~160 DEG C, pressure rise to 5~7 atmospheric pressure; react 6~8h; 40~60 DEG C are subsequently cooled to, normal pressure is down to, drips 20~30min buck; temperature is increased to 120~140 DEG C, reacts 3~6h；Temperature is risen to 140~160 DEG C, pressure to 7~10 atmospheric pressure, 4~6h of reaction terminates；2) it is poured into the water of 3~4 times of volumes after cooling, solubilizer C extracts layering, and after organic layer is washed, dried, concentration is evaporated off solvent and obtains product.Cost is relatively low, yield is high.
Description
Technical field
The invention belongs to pharmaceutical fields, and in particular to a kind of synthetic method of Nefiracetam intermediate 2-Pyrrolidone.
Background technique
In recent years, being increasing with elderly population, China's senile dementia disease incidence constantly rise.Senile dementia
The disease cause of disease is different, and treatment method and medicament selection are also different.According to conservative estimation, the senile dementia patients in China have 6,000,000
Left and right.Senile dementia is a kind of disease for carrying out sexual development, there is no specific medicament and cure method at present.But still needs pair
Patient carries out drug therapy appropriate, delays dull-witted development, improves the quality of life of patient, reduce the generation of complication and prolong
Long-life.The drug for treating Alzheimer's disease since the 1990s continues to bring out, and has the clinic of several drugs
Experiment achieves curative effect.Wherein the drug of aminobutyric acid class has Alzheimer's disease and cerebrovascular sequelae good clinical
Therapeutic value can promote Phosphorylcholine and phosphatidyl ethanolamine synthesis, how promote brain metabolism for enhancing metabolism and learning ability
Fei Xitan is considered more effective, safety.The clinical trial carried out in the dementia patients of secondary cerebrovascular disease shows, Nai Feixi
Smooth certain symptoms that cognitive function can be enhanced and improve spirit aspect.
Entitled N- (2,6- 3,5-dimethylphenyl) -2- (the 2- oxo-1-pyrrolidine base) acetamide of Nefiracetam chemistry is acetyl
Cholinesterase agonist is the new pyrrole ketone drug developed by Japanese Daiich Seiyaku company, chemistry knot
Structure is as follows:
Existing literature reports the synthetic route of Nefiracetam, and the mainly catalysis using 2-Pyrrolidone in sodium hydride is made
Under, it is alkylated and reacts with ethyl chloroacetate, resulting intermediate passes through esterlysis, obtains 2- oxo-pyrrolidine acetic acid, then 2-
Oxo-pyrrolidine acetic acid again with 2,6- dimethylaniline under the action of condensing agent dicyclohexyl carbodiimide (DCC) amide
Change, synthesize Nefiracetam, reaction route is as follows:
From the above equation, we can see that 2-Pyrrolidone is the main intermediate for synthesizing Nefiracetam.
The preparation of 2-Pyrrolidone is in some documents it has been reported that mainly having: Lee, Han Won etc. is in US2014/
296466 report gamma-butyrolacton and ammonium hydroxide generation 2-Pyrrolidone；Gellrich, Urs etc. are in J.Am.Chem.Soc.
[2015,137 (14), 4851] report nafoxidine in the in the mixed solvent of dioxanes and toluene, (AcrPNPiPr)RuH(CO)
Lower react with sodium hydroxide solution of Cl catalysis generates 2-Pyrrolidone；Myriant corporation is reported in WO2013/33649
Road succinimide, which is reacted with hydrogen under glycol dimethyl ether high temperature, high pressure, generates 2-Pyrrolidone.Generally speaking, with
On prepare the method for 2-Pyrrolidone, there are raw material, expensive catalyst, yield are relatively low etc. be unfavorable for industrialized production the shortcomings that,
Therefore, it is necessary to develop the method for new synthesis 2-Pyrrolidone.
Summary of the invention
The purpose of the present invention is to provide a kind of synthetic method of Nefiracetam intermediate 2-Pyrrolidone, this method costs
It is lower, yield is higher.
To achieve the above object, the present invention adopts the following technical scheme:
X=Cl or or Br R=Me or or Et
The synthetic method of Nefiracetam intermediate 2-Pyrrolidone, which is characterized in that by the halogenated butyl chloride of 4- and amino first
Acid esters reacts under the effect of the catalyst obtains 2-Pyrrolidone, the reaction process are as follows:
1) under protective gas, the halogenated butyl chloride of 4-, catalysts and solvents A will be mixed, control reaction temperature is increased to 100
~125 DEG C, the solution of carbamate and solvent B is added dropwise in pressure rise to 3~5 atmospheric pressure, and control time for adding is 40
~60min, after completion of dropwise addition, maintenance condition the reaction was continued 5~7h, then temperature is increased to 135~160 DEG C, pressure rise to 5
~7 atmospheric pressure react 6~8h, are subsequently cooled to 40~60 DEG C, and pressure is down to normal pressure, and buck is added dropwise, and control time for adding 20
~30min, then temperature is increased to 120~140 DEG C, reacts 3~6h, then controls temperature and rises to 140~160 DEG C, pressure liter
To 7~10 atmospheric pressure, reacting 4~6h terminates；
2) by system it is cooling after, pour into the water of 3~4 times of volumes, solvent C be added and extracts, layering, organic layer through washing,
After desiccant dryness, concentration is evaporated off solvent and obtains product.
The halogenated butyl chloride of 4- is 4- chlorobutanoylchloride or 4- bromobutanoylchloride；The carbamate is carbamic acid first
Ester or urethanes.
The catalyst the preparation method comprises the following steps: organic base is dissolved in organic solvent D, the silica gel of 300~500 mesh is added,
30~50min is stirred at 40~50 DEG C, and solvent evaporated is concentrated after cooling, remaining solid is ground into uniform 200~300 mesh of mistake
After obtain；The amount ratio of the organic base, silica gel and organic solvent D is 1mol:(200~300) g:(900~1000) mL；Institute
Stating organic base is sodium methoxide or sodium ethoxide；The organic solvent D is anhydrous methanol or dehydrated alcohol.
The molar ratio of the halogenated butyl chloride of the 4- and carbamate is 1:(1.02~1.1)；The halogenated butyl chloride of 4- with urge
The weight ratio of agent is 1:(0.05~0.12)；The amount ratio of the halogenated butyl chloride of the 4- and solvent A is 1g:(3.5~5.5)
mL；The amount ratio of the carbamate and solvent B are 1g:(4~6) mL；The amount ratio of the 4- halogenated butyl chloride and solvent C
For 1g:(3~5) mL.
The solvent A is anhydrous methanol or dehydrated alcohol；The solvent B is anhydrous isopropyl alcohol or dry isobutanol；
The solvent C is methylene chloride or chloroform；The protection gas is nitrogen or argon gas；The desiccant be anhydrous sodium sulfate or
Person's anhydrous magnesium sulfate.
The buck is the aqueous solution of sodium hydroxide or potassium hydroxide, and concentration is mass fraction 15%；The 4- is halogenated
The molar ratio of sodium hydroxide or potassium hydroxide in butyl chloride and buck is 1:(1.5~2).
Reaction principle of the present invention is shown below:
Under the base catalyst effect of support type and heating, pressurized conditions, the halogenated butyl chloride of 4- and carbamate are being urged
Substitution reaction first occurs for the surface of agent；Because the substitution reaction with halogen atom is relatively easy to, amino is first sent out with halogen atom
Raw reaction, generates transition state 1；Reaction temperature and pressure are improved, the amino further occurrence after substitution replaces in acid chloride groups
The reaction of chlorine atom generates transition state 2, and the step condition is more harsh, and must have catalyst action to occur；Replace anti-
After answering, buck is added, further reaction generates salt 3；For salt 3 under conditions of being heated and pressurizeed, decarboxylation generates target product
2-Pyrrolidone.
Compared with the existing technology, advantages of the present invention has:
1, raw material is easy to get, and cost is relatively low；
2, reaction yield is higher；
3, disposal of pollutants is less.
Specific embodiment
Combined with specific embodiments below, the present invention is further illustrated.
Embodiment 1
The synthetic method of 2-Pyrrolidone, comprising the following steps:
1) under protection of argon gas, 4- bromobutanoylchloride, catalyst and anhydrous methanol will be mixed, control reaction temperature is increased to
120 DEG C, the solution of methyl carbamate and anhydrous isopropyl alcohol is added dropwise in pressure rise to 4 atmospheric pressure, and control time for adding is
50min, after completion of dropwise addition, maintenance condition the reaction was continued 6h, then temperature is increased to 150 DEG C, pressure rise to 6 atmospheric pressure,
7h is reacted, is subsequently cooled to 50 DEG C, pressure is down to normal pressure, and the sodium hydrate aqueous solution that concentration is mass fraction 15%, control is added dropwise
Time for adding 25min processed, then temperature is increased to 135 DEG C, reacts 5h, then controls temperature and rises to 152 DEG C, pressure rises to 9
Atmospheric pressure, reaction 5h terminate.
The molar ratio of 4- bromobutanoylchloride and methyl carbamate is 1:1.08, and the weight ratio of 4- bromobutanoylchloride and catalyst is
The amount ratio of 1:0.1,4- bromobutanoylchloride and anhydrous methanol is 1g:4.5mL, the amount ratio of methyl carbamate and anhydrous isopropyl alcohol
For 1g:5mL, the molar ratio of sodium hydroxide is 1:1.8 in 4- bromobutanoylchloride and sodium hydrate aqueous solution.
Catalyst the preparation method comprises the following steps: sodium ethoxide is dissolved in dehydrated alcohol, the silica gel of 450 mesh is added, is stirred at 46 DEG C
40min is mixed, solvent evaporated is concentrated after cooling, is obtained after remaining solid is ground uniform 250 mesh of mistake；Sodium ethoxide, silica gel and nothing
The amount ratio of water-ethanol is 1mol:260g:950mL.
2) it by after system cooling, pours into the water of 3.5 times of volumes, methylene chloride is added and extracts, 4- bromobutanoylchloride and dichloro
The amount ratio of methane is 1g:4mL, and layering after organic layer is washed, anhydrous sodium sulfate is dry, is evaporated off with Rotary Evaporators concentration
Solvent obtains product.Molar yield 98.9%, GC purity 99.3%.
Embodiment 2
The synthetic method of 2-Pyrrolidone, comprising the following steps:
1) under nitrogen protection, 4- chlorobutanoylchloride, catalyst and dehydrated alcohol will be mixed, control reaction temperature is increased to
100 DEG C, the solution of urethanes and dry isobutanol is added dropwise in pressure rise to 3 atmospheric pressure, and control time for adding is
40min, after completion of dropwise addition, maintenance condition the reaction was continued 5h, temperature is increased to 135 DEG C, pressure rise to 5 atmospheric pressure, reaction
6h is subsequently cooled to 40 DEG C, and pressure is down to normal pressure, and concentration is the potassium hydroxide aqueous solution of mass fraction 15%, when control is added dropwise
Between 20min, then temperature is increased to 120 DEG C, reacts 3h, then controls temperature and rises to 140 DEG C, pressure rises to 7 atmospheric pressure, instead
4h is answered to terminate.
Catalyst the preparation method comprises the following steps: sodium methoxide is dissolved in anhydrous methanol, the silica gel of 300 mesh is added, is stirred at 40 DEG C
30min is mixed, solvent evaporated is concentrated after cooling, is obtained after remaining solid is ground uniform 200 mesh of mistake；Sodium methoxide, silica gel and nothing
The amount ratio of water methanol is 1mol:200g:900mL.
The molar ratio of 4- chlorobutanoylchloride and urethanes is 1:1.02；The weight ratio of 4- chlorobutanoylchloride and catalyst is
1:0.05；The amount ratio of 4- chlorobutanoylchloride and dehydrated alcohol is 1g:3.5mL；The dosage of urethanes and dry isobutanol
Than for 1g:4mL；The molar ratio of potassium hydroxide is 1:1.5 in 4- chlorobutanoylchloride and potassium hydroxide aqueous solution.
2) it by after system cooling, pours into the water of 3 times of volumes, chloroform recovery, the dosage of 4- chlorobutanoylchloride and chloroform is added
Than for 1g:3mL, layering, organic layer is evaporated off solvent with Rotary Evaporators concentration and obtains product after washing, anhydrous magnesium sulfate are dry.
Molar yield 97.5%, GC purity 98.5%.
Embodiment 3
The synthetic method of 2-Pyrrolidone, comprising the following steps:
1) under protection of argon gas, 4- bromobutanoylchloride, catalyst and dehydrated alcohol will be mixed, control reaction temperature is increased to
125 DEG C, the solution of carbamate and anhydrous isopropyl alcohol is added dropwise in pressure rise to 5 atmospheric pressure, and control time for adding is
60min, after completion of dropwise addition, maintenance condition the reaction was continued 7h, temperature is increased to 160 DEG C, pressure rise to 7 atmospheric pressure, reaction
8h is subsequently cooled to 60 DEG C, and pressure is down to normal pressure, and concentration is the sodium hydrate aqueous solution of mass fraction 15%, when control is added dropwise
Between 30min, then temperature is increased to 140 DEG C, reacts 6h, then controls temperature and rises to 160 DEG C, and pressure rises to 10 atmospheric pressure,
Reaction 6h terminates.
Catalyst the preparation method comprises the following steps: sodium ethoxide is dissolved in dehydrated alcohol, the silica gel of 500 mesh is added, is stirred at 50 DEG C
50min is mixed, solvent evaporated is concentrated after cooling, is obtained after remaining solid is ground uniform 300 mesh of mistake；Sodium ethoxide, silica gel and nothing
The amount ratio of water-ethanol is 1mol:300g:1000mL.
The molar ratio of 4- bromobutanoylchloride and carbamate is 1:1.1；The weight ratio of 4- bromobutanoylchloride and catalyst is 1:
0.12；The amount ratio of 4- bromobutanoylchloride and dehydrated alcohol is 1g:5.5mL；The amount ratio of carbamate and anhydrous isopropyl alcohol is
1g:6mL；The molar ratio of sodium hydroxide is 1:2 in 4- bromobutanoylchloride and sodium hydrate aqueous solution.
2) it by after system cooling, pours into the water of 4 times of volumes, methylene chloride is added and extracts, the 4- bromobutanoylchloride and two
The amount ratio of chloromethanes is 1g:5mL, and layering is concentrated with Rotary Evaporators and is steamed after organic layer is washed, anhydrous sodium sulfate is dry
Except solvent obtains product.Molar yield 98.5%, GC purity 99.1%.
Embodiment 4
Reaction pressure before addition carbamate is set as 2 atmospheric pressure, reaction temperature is set as 70 DEG C, other reaction items
Part and material are with than same embodiment 1, molar yield 45.2%, GC purity 69.3%.
Embodiment 5
Reaction pressure before addition carbamate is set as 6 atmospheric pressure, reaction temperature is set as 140 DEG C, other reactions
Condition and material are with than same embodiment 1, molar yield 73.1%, GC purity 77.2%.
Embodiment 6
The reaction pressure for finishing carbamate the reaction was continued after 5h is set as 3 atmospheric pressure, reaction temperature is set as 120
DEG C, other reaction conditions and material are with than same embodiment 1, molar yield 62.6%, GC purity 72.5%.
Embodiment 7
The reaction pressure for finishing carbamate the reaction was continued after 5h is set as 9 atmospheric pressure, reaction temperature is set as 175
DEG C, other reaction conditions and material are with than same embodiment 1, molar yield 82.6%, GC purity 89.2%.
The analysis of 8 product nucleus magnetic hydrogen spectrum of embodiment
By taking 1 product of embodiment as an example,1H-NMR (DMSO): δ 7.72 (1H), δ 3.42 (2H), δ 2.26 (2H), δ 2.13
(2H).Ownership of the various hydrogen on product structure such as following formula:
Nmr analysis, product structure meet object, i.e. 2-Pyrrolidone.
Claims (6)
1. the synthetic method of Nefiracetam intermediate 2-Pyrrolidone, which is characterized in that by the halogenated butyl chloride of 4- and carbamic acid
Ester reacts under the effect of the catalyst obtains 2-Pyrrolidone, the reaction process are as follows:
1) under protective gas, the halogenated butyl chloride of 4-, catalysts and solvents A will be mixed, control reaction temperature be increased to 100~
125 DEG C, the solution of carbamate and solvent B is added dropwise in pressure rise to 3~5 atmospheric pressure, control time for adding for 40~
60min, after completion of dropwise addition, maintenance condition the reaction was continued 5~7h, then temperature is increased to 135~160 DEG C, and pressure rise to 5~
7 atmospheric pressure react 6~8h, are subsequently cooled to 40~60 DEG C, and pressure is down to normal pressure, are added dropwise buck, and control time for adding 20~
30min, then temperature is increased to 120~140 DEG C, reacts 3~6h, then controls temperature and rises to 140~160 DEG C, pressure rises to 7
~10 atmospheric pressure, 4~6h of reaction terminate；
2) it by after system cooling, pours into the water of 3~4 times of volumes, solvent C is added and extracts, layering, organic layer is washed, dried
After agent is dry, concentration is evaporated off solvent and obtains product.
2. the synthetic method of Nefiracetam intermediate 2-Pyrrolidone as described in claim 1, which is characterized in that the 4- halogen
It is 4- chlorobutanoylchloride or 4- bromobutanoylchloride for butyl chloride；The carbamate is methyl carbamate or urethane
Ester.
3. the synthetic method of Nefiracetam intermediate 2-Pyrrolidone as described in claim 1, which is characterized in that the catalysis
Agent the preparation method comprises the following steps: organic base is dissolved in organic solvent D, the silica gel of 300~500 mesh is added, is stirred at 40~50 DEG C
30~50min is concentrated solvent evaporated after cooling, obtains after remaining solid is ground uniform 200~300 mesh of mistake；It is described organic
The amount ratio of alkali, silica gel and organic solvent D is 1mol:(200~300) g:(900~1000) mL；The organic base is sodium methoxide
Or sodium ethoxide；The organic solvent D is anhydrous methanol or dehydrated alcohol.
4. the synthetic method of Nefiracetam intermediate 2-Pyrrolidone as described in claim 1, which is characterized in that the 4- halogen
It is 1:(1.02~1.1 for the molar ratio of butyl chloride and carbamate)；The weight ratio of the halogenated butyl chloride of 4- and catalyst is 1:
(0.05~0.12)；The amount ratio of the halogenated butyl chloride of the 4- and solvent A is 1g:(3.5~5.5) mL；The carbamate
Amount ratio with solvent B is 1g:(4~6) mL；The halogenated butyl chloride of the 4- and the amount ratio of solvent C are 1g:(3~5) mL.
5. the synthetic method of Nefiracetam intermediate 2-Pyrrolidone as described in claim 1, which is characterized in that the solvent
A is anhydrous methanol or dehydrated alcohol；The solvent B is anhydrous isopropyl alcohol or dry isobutanol；The solvent C is dichloromethane
Alkane or chloroform；The protection gas is nitrogen or argon gas；The desiccant is anhydrous sodium sulfate or anhydrous magnesium sulfate.
6. the synthetic method of Nefiracetam intermediate 2-Pyrrolidone as described in claim 1, which is characterized in that the buck
For sodium hydroxide or the aqueous solution of potassium hydroxide, concentration is mass fraction 15%；In the halogenated butyl chloride of 4- and buck
The molar ratio of sodium hydroxide or potassium hydroxide is 1:(1.5~2).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910058445.8A CN109665982B (en) | 2019-01-22 | 2019-01-22 | Synthetic method of nefiracetam intermediate 2-pyrrolidone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910058445.8A CN109665982B (en) | 2019-01-22 | 2019-01-22 | Synthetic method of nefiracetam intermediate 2-pyrrolidone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109665982A true CN109665982A (en) | 2019-04-23 |
| CN109665982B CN109665982B (en) | 2022-07-08 |
Family
ID=66149733
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910058445.8A Active CN109665982B (en) | 2019-01-22 | 2019-01-22 | Synthetic method of nefiracetam intermediate 2-pyrrolidone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109665982B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617436A (en) * | 2012-03-20 | 2012-08-01 | 浙江洪波化工有限公司 | Preparation method for 2-(2-oxo-pyrrolidyl) butanamide |
| CN103608332A (en) * | 2011-06-10 | 2014-02-26 | 霍夫曼-拉罗奇有限公司 | Pyridin-2-amides useful as CB2 agonists |
| CN106397294A (en) * | 2016-08-30 | 2017-02-15 | 山东默得森生物制药有限公司 | Preparation method of nootropic of (S)-oxiracetam |
| CN109053553A (en) * | 2018-10-16 | 2018-12-21 | 山东省农药科学研究院 | The synthetic method of insecticide sulfoxaflor intermediate 3- [1- (methyl mercapto) ethyl] -6 (trifluoromethyl) pyridines |
| CN109053491A (en) * | 2018-10-16 | 2018-12-21 | 山东省农药科学研究院 | Synthetic method of the acaricide cyflumetofen intermediate to tert-butyl benzene acetonitrile |
| CN109180574A (en) * | 2018-10-16 | 2019-01-11 | 山东省农药科学研究院 | The synthetic method of insecticide flonicamid intermediate o-trifluoromethyl nicotinoyl chlorine |
| CN109232425A (en) * | 2018-10-16 | 2019-01-18 | 山东省农药科学研究院 | A kind of synthetic method of propenyl benzene fluorine bacterium azoles intermediate 3- (difluoromethyl) -1- methyl-1 H- pyrazoles -4- carboxylic acid |
-
2019
- 2019-01-22 CN CN201910058445.8A patent/CN109665982B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103608332A (en) * | 2011-06-10 | 2014-02-26 | 霍夫曼-拉罗奇有限公司 | Pyridin-2-amides useful as CB2 agonists |
| CN102617436A (en) * | 2012-03-20 | 2012-08-01 | 浙江洪波化工有限公司 | Preparation method for 2-(2-oxo-pyrrolidyl) butanamide |
| CN106397294A (en) * | 2016-08-30 | 2017-02-15 | 山东默得森生物制药有限公司 | Preparation method of nootropic of (S)-oxiracetam |
| CN109053553A (en) * | 2018-10-16 | 2018-12-21 | 山东省农药科学研究院 | The synthetic method of insecticide sulfoxaflor intermediate 3- [1- (methyl mercapto) ethyl] -6 (trifluoromethyl) pyridines |
| CN109053491A (en) * | 2018-10-16 | 2018-12-21 | 山东省农药科学研究院 | Synthetic method of the acaricide cyflumetofen intermediate to tert-butyl benzene acetonitrile |
| CN109180574A (en) * | 2018-10-16 | 2019-01-11 | 山东省农药科学研究院 | The synthetic method of insecticide flonicamid intermediate o-trifluoromethyl nicotinoyl chlorine |
| CN109232425A (en) * | 2018-10-16 | 2019-01-18 | 山东省农药科学研究院 | A kind of synthetic method of propenyl benzene fluorine bacterium azoles intermediate 3- (difluoromethyl) -1- methyl-1 H- pyrazoles -4- carboxylic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109665982B (en) | 2022-07-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2012350482B2 (en) | Imidazolidinedione compounds and their uses | |
| AU2018102141A4 (en) | Method for preparing Baricitinib | |
| CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| CN111225907B (en) | Process for preparing benzothien-2 yl boric acid/borate | |
| EP3434671B1 (en) | Sultam compound and application method thereof | |
| CN106946880B (en) | A method of preparing Rui Boxini intermediate | |
| CN107118215B (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediate | |
| CN112243437B (en) | Acryl-containing nuclear transport regulator and use thereof | |
| CN109665982A (en) | The synthetic method of Nefiracetam intermediate 2-Pyrrolidone | |
| CN104130146B (en) | (4S) preparation method of-3,6,9-tri-azepine-3,6,9-tri-(carboxymethyl)-4-(4-ethoxy benzyl) undecane diacids | |
| CN105906622A (en) | Preparation method of palbociclib for treating breast cancer | |
| CN105968109B (en) | A kind of method for preparing Pa Boxini intermediates | |
| CN113072514B (en) | Preparation method of Xuanjinning and intermediate thereof | |
| CN113121417A (en) | Novel piperidine derivative and pharmaceutical application thereof | |
| CN109761817A (en) | The synthetic method of Nefiracetam intermediate 2,6- dimethylaniline | |
| CN112194602A (en) | Synthesis method of ketamine and its derivatives and intermediates | |
| CN108440438B (en) | Method for constructing 2, 4-diaryl oxazole by acetophenone compounds, ammonium persulfate and dimethyl sulfoxide | |
| CN112500345A (en) | Synthetic method of alpha-cyano quaternary carbon substituted tetrahydroisoquinoline compound | |
| Takashima-Hirano et al. | Efficient synthesis of [11C] ramelteon as a positron emission tomography probe for imaging melatonin receptors involved in circadian rhythms | |
| CN106117104B (en) | A kind of preparation method of vildagliptin | |
| CN104341360A (en) | A rufinamide preparing method | |
| CN114181133B (en) | Preparation method of glycine derivative acetamide compound | |
| CN107304171A (en) | A kind of synthetic method of Oseltamivir | |
| CN111018734B (en) | Synthesis method of cinacalcet hydrochloride intermediate | |
| CN103848756B (en) | Preparation method of teriflunomide 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 |