CN108164479A - A kind of preparation method of dinotefuran intermediate 3- amino methyl tetrahydrofurans - Google Patents
A kind of preparation method of dinotefuran intermediate 3- amino methyl tetrahydrofurans Download PDFInfo
- Publication number
- CN108164479A CN108164479A CN201711200852.5A CN201711200852A CN108164479A CN 108164479 A CN108164479 A CN 108164479A CN 201711200852 A CN201711200852 A CN 201711200852A CN 108164479 A CN108164479 A CN 108164479A
- Authority
- CN
- China
- Prior art keywords
- preparation
- cyano
- amino
- amino methyls
- methyls tetrahydrofuran
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a kind of preparation methods of 3 amino methyl tetrahydrofuran of dinotefuran intermediate, specifically it is using cyanoacetate as raw material, elder generation and 1,2 dihaloethanes carry out condensation reaction and obtain 2 halogenated ethyl of intermediate, 2 cyan-acetic ester, then further reduction obtains 2 halogenated ethyl of intermediate, 2 cyanoethanol, and then 2 halogenated ethyl of intermediate, 2 cyanoethanol cyclization obtains 3 cyano tetrahydrofuran of intermediate；Last 3 cyano tetrahydrofuran obtains 3 amino methyl tetrahydrofuran of dinotefuran intermediate through catalytic hydrogenation.The preparation method of the present invention, raw material is easy to get, easy to operate, and production cost is relatively low, so as to be suitble to industrialized production.
Description
Technical field
The invention belongs to anabasine insecticide synthesis technical fields, and in particular to a kind of intermediate 3- aminomethyls tetrahydrochysene furan
The novel synthesis muttered.
Background technology
3- aminomethyl tetrahydrofurans are the key intermediates of third generation anabasine insecticide dinotefuran.Dinotefuran is by Japan
Three well developments, in the world, multiple countries introduce to the market, with absorbability is strong, dosage is few, quick-acting low toxicities, lasting period length, desinsection
It composes the features such as wide, demand is in persistently expanding rapidly, and industrialized production dinotefuran uses 3- aminomethyl tetrahydrofurans at present
With 1,3- dimethyl -2- nitro isourea condensation process, therefore 3- aminomethyl tetrahydrofurans fairly large industrialized production exploitation tool
It is significant.
The preparation of 3- aminomethyl tetrahydrofurans is by attention, and synthetic route has at present：
(1) pass through the method for intermediate 3- hydroxymethyl tetrahydrofurans：Patent CN102276559A and CN106349196A with
Gamma-butyrolacton is starting material, obtains intermediate 3- hydroxymethyl tetrahydrofurans, using methylmethanesulfonate esterification and Gabriel
Method prepares 3- aminomethyl tetrahydrofurans.Intermediate 3- hydroxymethyl tetrahydrofurans can also be used patent WO2005065689,
CN103709126A and CN104961710A is obtained (chemical equation is as follows) by starting material of diethyl malonate.Certain 3-
Hydroxymethyl tetrahydrofuran can also be used hydroformylation method, Hydrolyze method, the dihydrofuran method that CN106316993A is mentioned and obtain.It is such
Method operating process is complex, and there are the problems such as quantity of three wastes is big, auxiliary material is more expensive, industrial production cost is higher.
(2) pass through the method for intermediate dihydrofuran -3- formaldehyde：CN106316993A passes through using dihydrofuran as raw material
Intermediate dihydrofuran -3- formaldehyde is obtained by the reaction in Vilsmeier-Haack, then obtains 3- aminomethyls by being catalyzed reduction amination
Tetrahydrofuran (chemical equation is as follows), and further condensation is prepared for dinotefuran.It is anti-although the method route is simple
Answer condition harsh, raw material dihydrofuran is expensive, and the higher method of yield is big using phosphorus oxychloride toxicity and waste water is difficult,
Industrial production cost is higher, risk is larger.
(3) pass through the method for intermediate 3- cyano tetrahydrofurans：
1), CN106749116A replaces to obtain using gamma-butyrolacton as starting material by halogenation, reduction, dehydration, cyano
Intermediate 3- cyano tetrahydrofurans obtain 3- amido tetrahydrofurans finally by catalytic hydrogenation (chemical equation is as follows).This method
Longer, the hypertoxic Cymag wastewater treatment of route is difficult, and industrial production cost is higher, risk is larger.
2), 3- cyano tetrahydrochysene furans are made by starting material and one step of reacting ethylene oxide of acrylonitrile in CN106995422A
It mutters, 3- amido tetrahydrofurans is obtained finally by catalytic hydrogenation (chemical equation is as follows).It is main former although this method step is shorter
Expect simple and easy to get, but the catalyst such as sodium methoxide used are expensive and severe reaction conditions, industrial production cost are higher.
3), CN106366056 is condensed into intermediate 2- chloroethyls -2- by starting material and 2- chloroethanols of acrylonitrile
Cyano ethyl ether, under intermediate 2- chloroethyl -2- cyano ethyl ether alkaline conditions cyclization obtain 3- cyano tetrahydrofurans, finally lead to
It crosses catalytic hydrogenation and obtains 3- amido tetrahydrofurans (chemical equation is as follows).Although this method primary raw material is simple and easy to get, make
The catalyst such as Sodamide are expensive and yield is not high, cause industrial production cost higher.
4), Liu Bue (Henan chemical industry, 2015,032, P25-27) is proposed using 3- chloroethyl nitriles as starting material and epoxy
Ethane is condensed into intermediate 2- chloromethyl -4- hydroxybutyronitriles, under intermediate 2- chloromethyl -4- hydroxybutyronitrile alkaline conditions cyclization obtain
To 3- cyano tetrahydrofurans, restore to obtain 3- aminomethyls tetrahydrofuran finally by Lithium Aluminium Hydride (chemical equation is as follows).This
Catalyst and the raw materials such as the lithium diisopropylamine (LDA) and Lithium Aluminium Hydride that are used although method primary raw material is simple and easy to get
It is expensive, cause that industrial production cost is higher, risk is larger.
(4) other methods：CN106749117 is cyclized by starting material and ethylene oxide of cyan-acetic ester in obtaining
Mesosome 3- cyano-gamma-butyrolacton, then simultaneously open loop obtains intermediate 2-amino methyl-1 for reduction, and 4- butanediols are finally dehydrated
To 3- aminomethyls tetrahydrofuran (chemical equation is as follows).Although this method primary raw material is simple and easy to get, the tert-butyl alcohol used
The catalyst such as potassium and reducing agent red aluminum amount are big, expensive, cause that industrial production cost is higher, risk is larger.
Invention content
It is insufficient present in above-mentioned existing various technologies of preparing present invention aims at solving, a kind of all raw material letters are provided
It is singly easy to get, operation is easy, and cost is relatively low, is suitble to the preparation method of the 3- aminomethyl tetrahydrofurans of large-scale industrial production.
Specifically, the preparation method of a kind of 3- amino methyls tetrahydrofuran provided herein, includes the following steps：
1. using cyanoacetate substance as raw material, first condensation reaction is carried out with 1,2- dihaloethanes and obtain intermediate 2-
Halogenated ethyl -2- cyano-acetic acid esters；
2. intermediate 2- halogenated ethyls -2- cyano-acetic acid esters restores to obtain intermediate 2- halogenated ethyls -2- cyano-ethyl alcohol；
3. intermediate 2- halogenated ethyls -2- cyano-ethyl alcohol cyclization obtains intermediate 3- cyano tetrahydrofurans；
4. 3- cyano tetrahydrofuran obtains 3- amino methyl tetrahydrofurans through catalytic hydrogenation.
Specific synthetic route is as follows：
Wherein, step 1. described in cyanoacetate substance below formula I shown in：
Wherein, R is selected from C1-C4 alkyl, methoxyethyl and ethoxyethyl.Cyanoacetate substance is preferably cyanoacetic acid
Methyl esters or cyan-acetic ester.
Step 1. described in 1,2- dihaloethane below formulas II shown in：
Wherein, X1, X2 are selected from chlorine, bromine, iodine.1,2- dihaloethane is preferably the bromo- 2- chloroethanes of 1-.
1. above-mentioned steps carry out in the presence of organic or inorganic base；Hydroxide in the preferred inorganic base of alkali
One of sodium, sodium carbonate, potassium hydroxide, potassium carbonate；Reaction process needs heat temperature raising, and reaction temperature, can between 40-140 degree
To use specific range of temperatures isothermal reaction, can also be reacted from specific temperature 1 to 2 continuous warming of specific temperature, preferably continuous liter
The mass ratio of the reaction process of temperature, reaction raw materials cyanoacetate substance and 1,2- dihaloethane is 1: 2-2: 1, heating speed
Rate be 2-60 DEG C/h, be warming up to 80-130 DEG C, the reaction time for 1h-12h between, reaction dissolvent can be N, N- dimethyl formyls
Amine equal solvent.
2. ester type compound is reduced to the adoptable method of alcohol compound as hydroborations such as sodium borohydrides by above-mentioned steps
The method that object restores and ester type compound is reduced to alcohol compound by other this fields.
3. above-mentioned steps carry out in the presence of organic or inorganic base；Hydroxide in the preferred inorganic base of alkali
One of sodium, sodium carbonate, potassium hydroxide, potassium carbonate；Reaction process needs to add in solvent, in favor of the progress of molecule inner ring condensation.Institute
It can be tetrahydrofuran equal solvent to state solvent.Reaction process needs heat temperature raising, and reaction temperature is 40-80 DEG C, and the reaction time is
1h-24h.Reaction temperature and reaction time are different with the type and its ratio of inorganic base according to 2- halogenated ethyls -2- cyano-ethyl alcohol
And difference.
4. it is Raney's nickel that cyano compound catalytic hydrogen reduction is the adoptable method of aminomethyl compound by above-mentioned steps
Catalytic hydrogenation and other this fields are by method that cyano compound catalytic hydrogen reduction is aminomethyl compound.
The present invention provides a newer 3- aminomethyl tetrahydrofuran preparation methods, and this method is relative to existing
Production method has the following advantages that：1) all raw materials are all simple and easy to get, and production operation is simple.2) reaction condition is mild, at waste water
It is low to manage difficulty.3) production cost is relatively low, risk is smaller, is suitble to fairly large industrialized production.4) present invention is gone using first reduction
Fall cyclization process after carbonyl, avoid the generation of ring-opened byproducts in reducing carbonyl technique after first cyclization, while using step 3.
Rectification under vacuum purifying process with reference to the highly selective and conversion ratio of step 4. catalytic hydrogenation, ensure that the high-purity of final products
And higher yields.
Production method of the present invention is above-mentioned due to having the advantages that, the furan worm being particularly suitable for during production scale persistently expands rapidly
The production of amine.
Specific embodiment
To make technical solution of the present invention clear in further detail, the present invention is illustrated with following exemplary specific embodiment,
But the present invention is only limitted to absolutely not these examples, these examples are not also construed as limiting the invention.All spirit, originals in the present invention
Then within the scope of, any ratio done adjusts, supplementing, is complete on the operation parameter optimizations such as temperature, pressure and operating process
Kind, replacement, adjustment, improvement etc., should all be included in the protection scope of the present invention.
Embodiment 1：
The preparation method of 3- methylamino tetrahydrofurans has steps of：
1. malonic methyl ester nitrile 30.0g is added in into the 500mL four-hole boiling flasks with thermometer, reflux and agitating device
(0.30mol), the bromo- 2- chloroethanes 47.5g (0.33mol) of 1-, potassium carbonate 58g (0.42mol) and n,N-Dimethylformamide
250mL opens stirring and continuous warming, heats up 10 degree per hour, after being warming up to 120 degree, if having a starting material left the reaction was continued extremely
Completely.Reaction mixture filtering, filtrate decompression are distilled to recover after most of solvent is applied mechanically and wash, during anhydrous sodium sulfate is dried to obtain
Mesosome 2- chloroethyls -2- cyano-methyl acetate crude product 46.5g, gas chromatographic purity 98% are directly used in the next step；
2. upper step intermediate 2- chloroethyls -2- cyano-methyl acetate crude product input is filled with thermometer, reflux and stirring
The 500mL four-hole bottles put add in absolute methanol 300mL, keep temperature 40-50 degree, are slowly added to sodium borohydride 6.8g in batches
(0.18mol) is finished and is warming up to 50-60 degree continuation insulation reaction to the reaction was complete.Reaction mixture vacuum distillation recycling methanol
It applies mechanically, ethyl acetate 150mL is added in into residue, and be slowly added to adjust pH=2-3, layering, water with hydrochloric acid after 50mL water
Merge organic phase after mutually being extracted in two times with 50mL ethyl acetate.Organic phase vacuum distillation recycling ethyl acetate is applied mechanically, in obtaining
Mesosome 2- chloroethyls -2- cyano-ethyl alcohol crude product 37.5g, gas chromatographic purity 96%, more than two-step reaction merge yield 90%,
It is directly used in the next step；
3. by upper 96% intermediate 2- chloroethyls -2- cyano of step content-ethyl alcohol crude product (0.27mol) input with temperature
In the 500mL four-hole bottles of meter, reflux and agitating device, 300mL tetrahydrofurans are added in, 50-60 degree is heated to, hydrogen-oxygen is slowly added dropwise
Change 10% solution that sodium 12.0g (0.30mol) is made into, heat preservation is added dropwise to the reaction was complete.Reaction mixture sat is layered,
Water phase filtering rear enclosure is for next time with alkali, and organic phase vacuum distillation recycling tetrahydrofuran is applied mechanically, and crude product rectification and purification obtains cyclization
Intermediate 3- cyano tetrahydrofuran 22.8g, gas chromatographic purity 97%, yield 84%.
4. upper step intermediate 3- cyano tetrahydrofuran 19.0g (0.19mol) are put into 250mL autoclaves, second is added in
Alcohol 150mL, put into Raney's nickel 2.0g, nitrogen vacuum displacement air three times after, hydrogen vacuum displacement nitrogen three times, is warming up to 55-
60 degree, hydrogen is passed through to 0.1MPa and temperature and pressure is maintained to carry out hydrogenation, reaction is sampled per 2h once to anti-after 4 hours
It should be complete.Reaction mixture filtering, filtrate decompression are distilled to recover solvent and apply mechanically, and 3- amino methyl tetrahydrofuran products are obtained after precipitation
Purity 95% after a small amount of residual solvent is deducted in 20.0g, gas chromatographic analysis, and rectification under vacuum purifies to obtain gas chromatographic purity 98%
Fine work 16.1g, yield 81.6%.
Embodiment 2：
The preparation method of 3- methylamino tetrahydrofurans has steps of：
Step 1., step 2. ingredient proportion, reaction condition and last handling process with embodiment 1.
3. upper 95% intermediate 2- chloroethyls -2- cyano of step content-ethyl alcohol crude product 45.0g (0.32mol) inputs are carried
In the 500mL four-hole bottles of thermometer, reflux and agitating device, 360mL tetrahydrofurans are added in, 40-50 degree is heated to, is slowly added dropwise
10% solution that sodium hydroxide 14.0g (0.35mol) is made into, 1h are added dropwise, and are warming up to 60 degree and keep the temperature to the reaction was complete.Instead
Mixture stratification is answered, water phase filtering rear enclosure is for next time with alkali, and organic phase vacuum distillation recycling tetrahydrofuran is applied mechanically, crude product
Rectification and purification obtains cyclised intermediate 3- cyano tetrahydrofuran 27.8g, gas chromatographic purity 99%, yield 88%.
4. upper 99% intermediate 3- cyano tetrahydrofuran 25.1g (0.25mol) of step content are put into 250mL reaction under high pressures
Kettle, add in tert-butyl alcohol 150mL, put into Raney's nickel 2.0g, nitrogen vacuum displacement air three times after, hydrogen vacuum displacement nitrogen three
It is secondary, 50-55 degree is warming up to, hydrogen is passed through to 0.15MPa and temperature and pressure is maintained to carry out hydrogenation, it is every after reacting 6 hours
2h samplings are once to the reaction was complete.Reaction mixture filtering, filtrate decompression are distilled to recover solvent and apply mechanically, and product carries out water after precipitation
Steam distillation obtains 3- amino methyl tetrahydrofuran product 24.0g, gas chromatographic analysis purity 98%, yield 93%.
Embodiment 3：
The preparation method of 3- methylamino tetrahydrofurans has steps of：
1. cyan-acetic ester 34.0g is added in into the 500mL four-hole boiling flasks with thermometer, reflux and agitating device
(0.30mol), the bromo- 2- chloroethanes 47.5g (0.33mol) of 1-, potassium carbonate 58g (0.42mol) and n,N-Dimethylformamide
250mL opens stirring and continuous warming, heats up 20 degree per hour, after being warming up to 120 degree, if having a starting material left the reaction was continued extremely
Completely.Reaction mixture filtering, filtrate decompression are distilled to recover after most of solvent is applied mechanically and wash, during anhydrous sodium sulfate is dried to obtain
Mesosome 2- chloroethyl -2- cyano-acetic acid ethyl ester crude product 51.5g, gas chromatographic purity 98% are directly used in the next step；
2. upper step intermediate 2- chloroethyl -2- cyano-acetic acid ethyl esters crude product input is filled with thermometer, reflux and stirring
The 500mL four-hole bottles put add in absolute ethyl alcohol 300mL, keep temperature 40-50 degree, are slowly added to sodium borohydride 7.6g in batches
(0.20mol) is finished and is warming up to 58-62 degree close to back flow reaction to the reaction was complete.It is evaporated under reduced pressure after reaction mixture elder generation normal pressure
Recycling ethyl alcohol is applied mechanically, and ethyl acetate 150mL is added in into residue, and is slowly added to adjust pH=2-3 with hydrochloric acid after 50mL water,
Layering, water phase merge organic phase after being extracted in two times with 50mL ethyl acetate.Organic phase vacuum distillation recycling ethyl acetate is applied mechanically,
Intermediate 2- chloroethyls -2- cyano-ethyl alcohol crude product 38.0g, gas chromatographic purity 97% are obtained, more than two-step reaction merges yield
92%, it is directly used in the next step；
Step 3., step 4. ingredient proportion, reaction condition and last handling process with embodiment 2.
In actual industrial production, since 3- aminomethyl tetrahydrofuran rectifying purification process condition is harsh and is purified in rectifying
There is greater loss in journey, in above-described embodiment 2 4. the walks product 3- aminomethyl tetrahydrofurans after steam distillation, gas chromatographic purity
It is directly used in the synthesis of dinotefuran active compound enough, the specific synthetic method of dinotefuran active compound is referring to introductions such as CN106349196A
Method, for requiring to determine according to different clients concrete technology during other purposes.
Finally it should be noted that：The above embodiments are only used to illustrate the technical solution of the present invention., rather than its limitations；To the greatest extent
Pipe is described in detail the present invention with reference to foregoing embodiments, it will be understood by those of ordinary skill in the art that：Its according to
Can so modify to the technical solution recorded in foregoing embodiments either to which part or all technical features into
Row equivalent replacement；And these modifications or replacement, various embodiments of the present invention technology that it does not separate the essence of the corresponding technical solution
The range of scheme.
Claims (10)
1. a kind of preparation method of 3- amino methyls tetrahydrofuran, it is characterised in that include the following steps：
1. using cyanoacetate substance as raw material, it is halogenated first intermediate 2- to be obtained with the progress condensation reaction of 1,2- dihaloethanes
Ethyl -2- cyano-acetic acid esters；
2. intermediate 2- halogenated ethyls -2- cyano-acetic acid esters restores to obtain intermediate 2- halogenated ethyls -2- cyano-ethyl alcohol；
3. intermediate 2- halogenated ethyls -2- cyano-ethyl alcohol cyclization obtains intermediate 3- cyano tetrahydrofurans；
4. 3- cyano tetrahydrofuran obtains 3- amino methyl tetrahydrofurans through catalytic hydrogenation.
2. the preparation method of 3- amino methyls tetrahydrofuran according to claim 1, it is characterised in that：Step 1. described in
Cyanoacetate substance below formula I shown in：
Wherein, R is selected from C1-C4 alkyl, methoxyethyl and ethoxyethyl.
3. the preparation method of 3- amino methyls tetrahydrofuran according to claim 2, it is characterised in that：Step 1. described in
Cyanoacetate substance be malonic methyl ester nitrile or cyan-acetic ester.
4. the preparation method of 3- amino methyls tetrahydrofuran according to claim 1, it is characterised in that：Step 1. described in
1,2- dihaloethane below formulas II shown in：
Wherein, X1, X2 are selected from chlorine, bromine, iodine.
5. the preparation method of 3- amino methyls tetrahydrofuran according to claim 4, it is characterised in that：Step 1. described in
1,2- dihaloethanes be the bromo- 2- chloroethanes of 1-.
6. the preparation method of 3- amino methyls tetrahydrofuran according to claim 1, it is characterised in that：1. step is to have
It is carried out in the presence of machine or inorganic base.
7. the preparation method of 3- amino methyls tetrahydrofuran according to claim 6, it is characterised in that：Step 1. described in
Alkali is sodium hydroxide, sodium carbonate, potassium hydroxide and/or the potassium carbonate in inorganic base.
8. the preparation method of 3- amino methyls tetrahydrofuran according to claim 1, it is characterised in that：3. step is to have
It is carried out in the presence of machine or inorganic base.
9. the preparation method of 3- amino methyls tetrahydrofuran according to claim 8, it is characterised in that：Step 3. described in
Alkali is sodium hydroxide, sodium carbonate, potassium hydroxide and/or the potassium carbonate in inorganic base.
10. the 3- amino prepared by a kind of preparation method of 3- amino methyls tetrahydrofuran of claim 1-9 any one of them
Application of the methyltetrahydrofuran in dinotefuran production.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711200852.5A CN108164479A (en) | 2017-11-24 | 2017-11-24 | A kind of preparation method of dinotefuran intermediate 3- amino methyl tetrahydrofurans |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711200852.5A CN108164479A (en) | 2017-11-24 | 2017-11-24 | A kind of preparation method of dinotefuran intermediate 3- amino methyl tetrahydrofurans |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108164479A true CN108164479A (en) | 2018-06-15 |
Family
ID=62527689
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711200852.5A Pending CN108164479A (en) | 2017-11-24 | 2017-11-24 | A kind of preparation method of dinotefuran intermediate 3- amino methyl tetrahydrofurans |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108164479A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150023913A1 (en) * | 2013-07-02 | 2015-01-22 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
| CN105517574A (en) * | 2013-07-09 | 2016-04-20 | 百时美施贵宝公司 | Combinations of hepatitis c virus inhibitors |
| CN106749117A (en) * | 2016-11-29 | 2017-05-31 | 北京怡力生物科技有限公司 | A kind of preparation method of 3 amino methyl tetrahydrofuran |
-
2017
- 2017-11-24 CN CN201711200852.5A patent/CN108164479A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150023913A1 (en) * | 2013-07-02 | 2015-01-22 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
| CN105517574A (en) * | 2013-07-09 | 2016-04-20 | 百时美施贵宝公司 | Combinations of hepatitis c virus inhibitors |
| CN106749117A (en) * | 2016-11-29 | 2017-05-31 | 北京怡力生物科技有限公司 | A kind of preparation method of 3 amino methyl tetrahydrofuran |
Non-Patent Citations (2)
| Title |
|---|
| SEO-JUNG HAN ET AL.: "Nickel-Catalyzed Intramolecular C¢O Bond Formation: Synthesis of Cyclic Enol Ethers", 《ANGEW. CHEM. INT. ED.》 * |
| 刘补娥: "呋虫胺的合成", 《河南化工》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| CN109369545B (en) | Synthesis process of 2-methyl-5-pyrazine formate | |
| CN107337634B (en) | A kind of preparation method of Abbe Seeley midbody compound | |
| CN112062712A (en) | Preparation method of 2- (5-bromo-3-methylpyridin-2-yl) acetic acid hydrochloride | |
| CN105330598A (en) | Preparing method for pirfenidone | |
| CN102020543B (en) | Method for producing 9-fluorenone | |
| CN105358529A (en) | Novel method for synthesizing key intermediate of apixaban | |
| CN103896858A (en) | Technology for preparing cytosine | |
| CN108164479A (en) | A kind of preparation method of dinotefuran intermediate 3- amino methyl tetrahydrofurans | |
| CN107652226B (en) | Preparation method of N-Boc-4-piperidine formaldehyde | |
| CN108314688B (en) | A kind of synthetic method of sitagliptin | |
| CN110218189B (en) | Abelide intermediate and simple preparation method of Abelide | |
| CN106749116B (en) | A kind of preparation method of 3- amino methyls tetrahydrofuran | |
| CN101967102B (en) | Synthesizing method of N,N-diethyl-3,7-dimethyl-(E)-2,6-octadiene-1-amine | |
| CN103524305A (en) | Preparation method of 1,3-propanediol derivatives and intermediates | |
| JP2017502009A (en) | Method for producing silodosin and its intermediate | |
| CN109369618B (en) | Method for preparing 2-chloro-5- ((2- (nitromethylene) imidazoline-1-yl) methyl) pyridine in one pot | |
| CN106008363B (en) | The preparation method of 2- methyl -4- amino-5-cyanopyrimidines | |
| CN106749133B (en) | A method of preparing Ta Simeiqiong | |
| CN106243022A (en) | A kind of preparation method of nevirapine intermediate | |
| CN116730832B (en) | Preparation method of 2-propyl caproic acid | |
| CN106883185B (en) | Preparation method of 4-chloro-2-trifluoromethylpyrimidine | |
| CN110790650A (en) | Synthesis method of trans-4 '- (4-alkyl phenyl) (1, 1' -dicyclohexyl) -4-ketone | |
| CN103833530A (en) | Preparation method of organic intermediate 3-phenoxyl-1, 2-propylene glycol | |
| CN113087669B (en) | Preparation method of 4-cyano-5-bromopyrimidine |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180615 |