CN108690073A - [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid - Google Patents
[Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid Download PDFInfo
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- CN108690073A CN108690073A CN201810679850.7A CN201810679850A CN108690073A CN 108690073 A CN108690073 A CN 108690073A CN 201810679850 A CN201810679850 A CN 201810679850A CN 108690073 A CN108690073 A CN 108690073A
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- bis
- linji
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- acetic acid
- trifluoro ethoxies
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title claims abstract description 99
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 42
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims abstract description 11
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 239000011259 mixed solution Substances 0.000 claims abstract description 8
- 238000000746 purification Methods 0.000 claims abstract description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 12
- 239000002253 acid Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000000638 solvent extraction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 235000015277 pork Nutrition 0.000 description 3
- 150000002240 furans Chemical class 0.000 description 2
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical class [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses Yi Zhong [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid, includes the following steps:[Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Methyl acetate is dissolved in organic solvent, is cooled to -50 DEG C to -80 DEG C, and the mixed solution of tetrahydrofuran/water of alkali is added dropwise, is stirred to react, by adjusting acid, organic solvent extraction and column purification get Dao [ after the completion of reaction;Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Acetic acid.This method is simple and easy to do, and cost is controllable, is suitable for industrialized production.
Description
Technical field
The present invention relates to organic synthesis fields more particularly to organic drug to synthesize field ,Ju Tisheji [Bis- (2,2,2- tri-
Fluorine ethyoxyl) Yang Linji ]The synthetic method of acetic acid.
Background technology
[Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Acetic acid is the important intermediate of synthesizing cis double bond, is synthesized at present
[Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]There are mainly three types of the methods of acetic acid.
Method one:As shown in formula (one), this method has three steps, and final step is hydrogenation, more special to equipment requirement, is put
There is certain danger greatly, and reagent cost includes that palladium carbon is all more expensive.Three step total recoverys of document report are about 50% or so.
Method two:As shown in formula (two), this method has two steps, prepares that atmospheric carbon dioxide is comparatively laborious, the dioxy of preparation
The moisture for changing carbon or the carbon dioxide of purchase needs to re-scale, and data are shown, the moisture of carbon dioxide increases, the receipts of final product
Rate can have a greatly reduced quality, and two step total recoverys of document report are about 40% or so.
Method three:As shown in formula (three), although this method only step, domestic pork liver enzyme purchase is difficult, and reagent
Costliness, the order cycle time is very long, and cost is very high.
[Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Acetic acid is the important intermediate of synthesizing cis double bond, ready-made at present
Method Shi Duo Walk reaction, such as the synthetic method of formula (one) and (two), cost is generally higher, operates relatively difficult or to equipment
Have particular/special requirement, formula (three) although shown in synthetic method only single step reaction, the purchase of pork liver enzyme is difficult at home, not only purchases
It is very long to buy the period, and reagent is very expensive.
In order to solve problem above, we by experimental design and put into practice and optimize the present invention.
Invention content
The technical problem to be solved in the present invention is to provide Yi Zhong [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The conjunction of acetic acid
At method, this method is simple and easy to do.
To realize above-mentioned target, present invention employs following technical schemes:
The present invention provides Yi Zhong [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid, including following step
Suddenly:Under atmosphere of inert gases, by [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Methyl acetate is dissolved in organic solvent, drop
Temperature is added dropwise the mixed solution of tetrahydrofuran/water of alkali, is stirred to react to -50 DEG C to -80 DEG C, get Dao [ after the completion of reaction;Bis- (2,
2,2- trifluoro ethoxies) Yang Linji ]Acetic acid.
Further, reaction temperature is -60 DEG C to -78 DEG C
Further , [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The molar ratio of methyl acetate and alkali is 1:0.8-1:1.
Preferably , [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The molar ratio of methyl acetate and alkali is 1:0.9.
Further, organic solvent is methanol, ethyl alcohol, tetrahydrofuran, methyl tertiary butyl ether(MTBE) or acetone.
Preferably, organic solvent is tetrahydrofuran or acetone.
Further, the dosage dosage [ of organic solvent;Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The mass ratio of acetic acid is
25:1 to 50:1.
Preferably, the dosage dosage [ of organic solvent;Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The mass ratio of acetic acid is 40:1
To 45:1.
Further, inert gas is argon gas, nitrogen or helium.
Further, alkali is sodium bicarbonate or saleratus.
Still further, the time that the mixed solution of tetrahydrofuran/water of alkali is added dropwise is 3-10 hours.
Preferably, the time that the mixed solution of tetrahydrofuran/water of alkali is added dropwise is 8-10 hours.
Further, the volume ratio of the mixed solution of tetrahydrofuran/water is tetrahydrofuran:Water=1:1-3:1.
Preferably, the volume ratio of the mixed solution of tetrahydrofuran/water is tetrahydrofuran:Water=1:1.
Further, the time being stirred to react is 10-24 hours.
Preferably, the time being stirred to react is 18-24 hours.
Further, after the completion of reaction, pass through acidification, extraction and column purification get Dao [Bis- (2,2,2- trifluoro ethoxies) oxygen
Lin Ji ]Acetic acid.
Further, extraction organic solvent is ethyl acetate, dichloromethane, methyl tertiary butyl ether(MTBE) or tetrahydrofuran.
Preferably, extraction organic solvent is ethyl acetate or dichloromethane.
Compared with prior art, the present invention has the following advantages:The present invention synthesizes [ by easy-to-use method;Bis- (2,
2,2- trifluoro ethoxies) Yang Linji ]Acetic acid does not need Duo Walk reactions, need not be hydrolyzed in buffer solution with pork liver enzyme, pig yet
Liver enzyme is difficult to buy, thus be easier to operate to, it can be achieved that industrialization meaning at home.
Specific implementation mode
The present invention is further explained in the light of specific embodiments, so that those skilled in the art can be preferably
Understand the present invention and can be practiced, but illustrated embodiment is not as a limitation of the invention.
Embodiment 1
Under nitrogen protection, by [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Methyl acetate (6.22g, 0.01mol) dissolves
It in tetrahydrofuran (50 times), is cooled to -80 DEG C, sodium bicarbonate is slowly added dropwise (0.67g, 0.08mol are dripped off for about 3 hours)
Tetrahydrofuran/water (1:1) after, being added dropwise, the reaction was continued at such a temperature 10 hours, after the completion of reaction, adjusts acid, uses acetic acid
Three times, after removing organic solvent under reduced pressure, column purification obtains Bai Seguti [ to ethyl ester aqueous phase extracted;Bis- (2,2,2- trifluoro ethoxies) phosphine oxides
Ji ]Acetic acid (1.52g).
Embodiment 2
Under nitrogen protection, by [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Methyl acetate (6.22g, 0.01mol) dissolves
In ethyl alcohol (25 times), -50 DEG C are cooled to, the tetrahydrochysene of saleratus (0.9g, 0.9mol are dripped off for about 10 hours) is slowly added dropwise
Furans/water (2:1) after, being added dropwise, the reaction was continued at such a temperature 24 hours, after the completion of reaction, adjusts acid, is extracted with ethyl acetate
Mutually three times, after removing organic solvent under reduced pressure, column purification obtains Bai Seguti [ for water intaking;Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Second
Sour (1.17g).
Embodiment 3
Under nitrogen protection, by [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Methyl acetate (6.22g, 0.01mol) dissolves
In methyl tertiary butyl ether(MTBE) (45 times), -75 DEG C are cooled to, sodium bicarbonate is slowly added dropwise, and (0.84g, 1.0mol drip for about 8 hours
It is complete) tetrahydrofuran/water (3:1) after, being added dropwise, the reaction was continued at such a temperature 18 hours, after the completion of reaction, adjusts acid, uses
Three times, after removing organic solvent under reduced pressure, column purification obtains Bai Seguti [ to ethyl acetate aqueous phase extracted;Bis- (2,2,2- trifluoro ethoxies)
Yang Linji ]Acetic acid (1.38g).
Embodiment 4
Under nitrogen protection, by [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Methyl acetate (6.22g, 0.01mol) dissolves
In acetone (40 times), -75 DEG C are cooled to, the tetrahydrochysene of sodium bicarbonate (0.77g, 0.9mol are dripped off for about 8 hours) is slowly added dropwise
Furans/water (1:1) after, being added dropwise, the reaction was continued at such a temperature 18 hours, after the completion of reaction, adjusts acid, is extracted with ethyl acetate
Mutually three times, after removing organic solvent under reduced pressure, column purification obtains Bai Seguti [ for water intaking;Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Second
Sour (1.91g).
Embodiment 5
Under nitrogen protection, by [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Methyl acetate (6.22g, 0.01mol) dissolves
It in tetrahydrofuran (40 times), is cooled to -75 DEG C, sodium bicarbonate is slowly added dropwise (0.77g, 0.9mol are dripped off for about 8 hours)
Tetrahydrofuran/water (1:1) after, being added dropwise, the reaction was continued at such a temperature 18 hours, after the completion of reaction, acid is adjusted, with acetic acid second
Three times, after removing organic solvent under reduced pressure, column purification obtains Bai Seguti [ to ester aqueous phase extracted;Bis- (2,2,2- trifluoro ethoxies) phosphine oxides
Ji ]Acetic acid (2.32g).
Embodiment described above is only to absolutely prove preferred embodiment that is of the invention and being lifted, protection model of the invention
It encloses without being limited thereto.Those skilled in the art on the basis of the present invention made by equivalent substitute or transformation, in the present invention
Protection domain within.Protection scope of the present invention is subject to claims.
Claims (10)
1. Yi Zhong [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid, which is characterized in that include the following steps:
Under atmosphere of inert gases, by [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Methyl acetate is dissolved in organic solvent, be cooled to-
50 DEG C to -80 DEG C, the mixed solution of tetrahydrofuran/water of alkali is added dropwise, is stirred to react, get Dao [ after the completion of reaction;Bis- (2,2,2- tri-
Fluorine ethyoxyl) Yang Linji ]Acetic acid.
2. Ru Quanliyaoqiu1Suo Shu [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid, it is characterised in that:
[Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The molar ratio of methyl acetate and alkali is 1:0.8-1:1.
3. Ru Quanliyaoqiu1Suo Shu [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The synthetic method of acetic acid, it is characterised in that:
The organic solvent is methanol, ethyl alcohol, tetrahydrofuran, methyl tertiary butyl ether(MTBE) or acetone.
4. the [ as described in claim 1 or 3;Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The synthetic method of acetic acid, feature exist
In:The organic solvent organic solvent [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The mass ratio of acetic acid is
25:1 to 50:1.
5. Ru Quanliyaoqiu1Suo Shu [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid, it is characterised in that:
The inert gas is argon gas, nitrogen or helium.
6. Ru Quanliyaoqiu1Suo Shu [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid, it is characterised in that:
The alkali is sodium bicarbonate or saleratus.
7. Ru Quanliyaoqiu1Suo Shu [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid, it is characterised in that:
The time that the mixed solution of tetrahydrofuran/water of the alkali is added dropwise is 3-10 hours.
8. Ru Quanliyaoqiu1Suo Shu [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid, it is characterised in that:
The volume ratio of the mixed solvent of the tetrahydrofuran/water is tetrahydrofuran:Water=1:1-3:1.
9. Ru Quanliyaoqiu1Suo Shu [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid, it is characterised in that:
The time being stirred to react is 10-24 hours.
10. Ru Quanliyaoqiu1Suo Shu [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid, feature exist
In:After the completion of reaction, pass through acidification, extraction and column purification get Dao [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]Acetic acid.
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| CN201810679850.7A CN108690073A (en) | 2018-06-27 | 2018-06-27 | [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid |
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| CN201810679850.7A CN108690073A (en) | 2018-06-27 | 2018-06-27 | [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid |
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| CN108690073A true CN108690073A (en) | 2018-10-23 |
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| CN201810679850.7A Withdrawn CN108690073A (en) | 2018-06-27 | 2018-06-27 | [Bis- (2,2,2- trifluoro ethoxies) Yang Linji ]The preparation method of acetic acid |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030779A2 (en) * | 2003-09-23 | 2005-04-07 | Eisai Co. Ltd. | Laulimalide analogs with anti-cancer activitity |
-
2018
- 2018-06-27 CN CN201810679850.7A patent/CN108690073A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030779A2 (en) * | 2003-09-23 | 2005-04-07 | Eisai Co. Ltd. | Laulimalide analogs with anti-cancer activitity |
Non-Patent Citations (2)
| Title |
|---|
| ADAM D. BROOKS ET AL.: "Design, Synthesis, and Characterization of Small-Molecule Reagents That Cooperatively Provide Dual Readouts for Triaging and, When Necessary, Quantifying Point-of-Need Enzyme Assays", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| SAMIA GUEZANE LAKOUD ET AL.: "Synthesis of chiral phosphonoacetamides and their toxic effects on Paramecium sp", 《ORGANIC COMMUNICATIONS》 * |
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