CN103242152B - The synthetic method of compound 3-(benzyloxy)-1-cyclobutanone - Google Patents
The synthetic method of compound 3-(benzyloxy)-1-cyclobutanone Download PDFInfo
- Publication number
- CN103242152B CN103242152B CN201310163920.0A CN201310163920A CN103242152B CN 103242152 B CN103242152 B CN 103242152B CN 201310163920 A CN201310163920 A CN 201310163920A CN 103242152 B CN103242152 B CN 103242152B
- Authority
- CN
- China
- Prior art keywords
- benzyloxy
- cyclobutanone
- ether
- compound
- synthetic method
- 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.)
- Expired - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of novel method of synthetic compound 3-(benzyloxy)-1-cyclobutanone, belong to technical field of organic synthesis.The method take halogeno-toluene as starting raw material, pass through into ether, halo, elimination, Guan Huan, the reaction of dechlorination five step, high yield, high purity have synthesized target product 3-(benzyloxy)-1-cyclobutanone, its cheaper starting materials is easy to get, reaction conditions gentleness (particularly ring closure reaction at room temperature carries out), effectively reduce synthesis cost, reduce the requirement to equipment simultaneously, there is the prospect of good suitability for industrialized production.
Description
Technical field
The invention belongs to organic chemical synthesis field, relate to a kind of synthetic method of compound 3-(benzyloxy)-1-cyclobutanone.
Background technology
Compound 3-(benzyloxy)-1-cyclobutanone is important organic synthesis intermediate, is the synthesis material of a lot of medicine and auxiliary, the such as preparation of HIV1-RT inhibitor, PLK inhibitor etc.; Also can be used for the preparation of medicine and medical developer.Its structural formula is:
For the synthesis of 3-(benzyloxy)-1-cyclobutanone, domestic do not have bibliographical information, external more existing documents or patent report,
Bioorganic & MedicinalChemistryLetters(biology and pharmaceutical chemistry bulletin), 22 (12), 4064-4067; 2012 synthetic methods reporting 3-(benzyloxy)-1-cyclobutanone; with semi-synthetic intermediate 2-benzyloxy-1; 3-dibromopropane and methyl thio MSM are raw material; under butyllithium effect; subzero 78 DEG C of degree reactions; obtained 1-methylsulfinyl-1-methylthio group-3-benzyloxy tetramethylene, is then obtained 3-(benzyloxy)-1-cyclobutanone by perchloric acid oxidation.Because semi-synthetic intermediate 2-benzyloxy-1,3-dibromopropane and methyl sulfo-MSM are commercially difficult to buy, cost is higher, and condition is harsh, is not easy to amplify and produces; Total recovery is not high yet.Its circuit is as follows:
WO2009114512 provides a kind of method of synthesis 3-(benzyloxy)-1-cyclobutanone, with brooethyl propylene oxide and cylite for raw material, under the effect of mercury chloride, at 160 DEG C, reaction obtains 2-benzyloxy-1, 3-dibromopropane, again under butyllithium effect, 2-benzyloxy-1, 3-dibromopropane and methyl sulfo-MSM react at-78 DEG C, obtained 1-methylsulfinyl-1-methylthio group-3-benzyloxy tetramethylene, then 3-(benzyloxy)-1-cyclobutanone is obtained by perchloric acid oxidation, the method completes reaction by three steps, purifying products uses column chromatography, cost is high, yield is low, be unfavorable for suitability for industrialized production.Its synthetic line is as follows:
Summary of the invention
The object of the invention is for prior art Problems existing, the novel method of synthetic compound 3-(the benzyloxy)-1-cyclobutanone that a kind of cost is low, yield is high is provided.
The synthetic method of the compounds of this invention 3-(benzyloxy)-1-cyclobutanone, comprises following processing step:
(1) preparation of BOE
Under mineral alkali condition, halogeno-toluene and ethylene glycol are with the mol ratio of 1:2 ~ 1:10, and DEG C reaction 1 ~ 6h in room temperature ~ 70, obtains BOE---intermediate 2;
Described halogeno-toluene is chloromethylbenzene or brooethyl benzene;
Described mineral alkali is sodium hydroxide or potassium hydroxide; The molar weight of mineral alkali is 1 ~ 1.5 times of halogeno-toluene.
(2) preparation of haloethyl phenmethyl ether
In organic solvent, BOE, triphenylphosphine, halogen, with the mol ratio of 1:1:0.5 ~ 1:1.5:1.5, in room temperature reaction 1 ~ 5h, obtain haloethyl phenmethyl ether---intermediate 3;
Described halogen is chlorine, bromine or iodine;
Described organic solvent is methylene dichloride, trichloromethane or tetracol phenixin.
(3) preparation of phenmethyl vinyl ether
Take the trimethyl carbinol as solvent, haloethyl phenmethyl ether and potassium tert.-butoxide are with the mol ratio of 1:1.0 ~ 1:1.5, and DEG C reaction 2 ~ 8h in room temperature ~ 70, obtains phenmethyl vinyl ether---intermediate 4.
(4) preparation of benzyloxy-2,2-dichloro cyclobutanone
Under nitrogen protection, in organic solvent, take zinc-copper as catalyzer, phenmethyl vinyl ether and trichoroacetic chloride are with the mol ratio of 1:1 ~ 1:3, and room temperature reaction 1 ~ 3h, obtains benzyloxy-2,2-dichloro cyclobutanone---intermediate 5;
Or under nitrogen protection, in organic solvent, take zinc-copper as catalyzer, make phenmethyl vinyl ether, trichoroacetic chloride, phosphorus oxychloride with the mol ratio of 1:1:0.2 ~ 1:3:0.3, in room temperature reaction 0.5 ~ 3.0h, obtain benzyloxy-2,2-dichloro cyclobutanone---intermediate 5;
The consumption of described zinc-copper catalyzer is 0.4 ~ 1 times of phenmethyl vinyl ether molar weight;
Described organic solvent is methyl tertiary butyl ether, ether or isopropyl ether.
(5) preparation of 3-(benzyloxy)-1-cyclobutanone
Take aqueous acetic acid as solvent, benzyloxy-2,2-dichloro cyclobutanone and metallic zinc are with the mol ratio of 1:2 ~ 1:3.5, and room temperature reaction 1 ~ 3h, obtains final product 6---3-(benzyloxy)-1-cyclobutanone;
In described aqueous acetic acid, the percent by volume of acetic acid is 40 ~ 60%.
The synthetic route of 3-of the present invention (benzyloxy)-1-cyclobutanone is as follows:
Synthetic product of the present invention is through proton nmr spectra, and high resolution gas chromatography measures, and show that the finished product that the present invention synthesizes are 3-(benzyloxy)-1-cyclobutanone, purity is 95 ~ 98%, and yield is more than 50%.
The present invention take halogeno-toluene as starting raw material, pass through into ether, halo, elimination, Guan Huan, the reaction of dechlorination five step, high yield, high purity have synthesized target product 3-(benzyloxy)-1-cyclobutanone, its cheaper starting materials is easy to get, reaction conditions gentleness (particularly ring closure reaction at room temperature carries out), effectively reduce synthesis cost, reduce the requirement to equipment simultaneously, there is the prospect of good suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the gas-chromatography of synthetic product of the present invention;
Fig. 2 is the nuclear magnetic spectrogram that the present invention synthesizes.
Embodiment
Be further described below by the synthetic method of specific embodiment to 3-of the present invention (benzyloxy)-1-cyclobutanone.
embodiment 1
(1) synthesis of BOE
In the reaction flask that thermometer, prolong are housed, add 800mL(15.74mol) ethylene glycol, 285.6g(7.14mol) sodium hydroxide, be stirred to dissolving in 40 DEG C, slowly add brooethyl benzene 684g(4mol), stir 1 hour, add 2000mL water, with extracted with diethyl ether, anhydrous sodium sulfate drying, precipitation, obtain BOE 556g, yield 91%;
(2) synthesis of bromo ethyl phenenyl methyl ether
Take triphenylphosphine 832g(3.58mol) be dissolved in chloroform 2000mL, drip bromine 290g(1.79mol) to solution yellowing, under room temperature, drip 400g(2.62mol) BOE, 400mL triethylamine and 600mL chloroform mixed solution, within 1 hour, drip off, react 0.5 hour, decompression precipitation, residuum adds chloroform 1000mL, wash with water, anhydrous sodium sulfate drying, distillation, obtain product bromo ethyl phenenyl methyl ether 544g, yield 97%;
(3) synthesis of phenmethyl vinyl ether
Take bromo ethyl phenenyl methyl ether 450g(2.1mol) be dissolved in the 1000mL trimethyl carbinol, add potassium tert.-butoxide 330g(2.9mol), 55 DEG C of stirring reactions 2 hours, reaction solution is poured in 3000mL water, with petroleum ether extraction, and washing, anhydrous sodium sulfate drying, precipitation, obtains phenmethyl vinyl ether 247g, yield 88%;
(4) synthesis of benzyloxy-2,2-dichloro cyclobutanone
Under nitrogen protection, by 160g(1.2mol) phenmethyl vinyl ether is dissolved in 3000mL ether, adds zinc-copper catalyzer 50g(0.77mol), 300mL(2.7mol is dripped under room temperature) trichoroacetic chloride and 30mL(0.33mol) phosphorus oxychloride, stir 1 hour, add sodium bicarbonate aqueous solution 1000mL, get with sherwood oil, washing, anhydrous sodium sulfate drying, precipitation, obtains benzyloxy-2,2-dichloro cyclobutanone 250g, yield 85%;
(5) synthesis of 3-(benzyloxy)-1-cyclobutanone
By 250g(1mol) benzyloxy-2,2-dichloro cyclobutanone is dissolved in 2000mL water and 2000mL acetic acid, slowly add zinc powder 200g(3.07mol), stirring at room temperature 1 hour, filters, filtrate extracted with diethyl ether, washing, anhydrous sodium sulfate drying, distillation, obtain 3-(benzyloxy)-1-cyclobutanone 150g, yield 84%.End product total recovery is 55.46%.
Embodiment 2
(1) synthesis of BOE
Thermometer is being housed, add 800mL(15.74mol in the reaction flask of prolong) ethylene glycol, 400g(7.14mol) potassium hydroxide, 70 DEG C are stirred to dissolving, slowly add 522.0g(4.1mol) chloromethylbenzene, stir 1 hour, add the water of 2000mL, by extracted with diethyl ether, anhydrous sodium sulfate drying, precipitation, obtains BOE 586g, yield 96%.
(2) synthesis of bromo ethyl phenenyl methyl ether
Triphenylphosphine 832g(3.58mol) be dissolved in methylene dichloride 3000mL, drip 572g(3.5mol) to solution yellowing, under room temperature, drip 400g(2.62mol) BOE, 400mL triethylamine and 600mL methylene dichloride mixed solution, within 1 hour, drip off, drip off reaction 0.5 hour, decompression precipitation, residuum adds ether 1000mL, wash with water, anhydrous sodium sulfate drying, distillation, obtain product bromo ethyl phenenyl methyl ether 521g, yield 93%.
(3) synthesis of phenmethyl vinyl ether
Take bromo ethyl phenenyl methyl ether 450g(2.1mol) be dissolved in the 1000mL trimethyl carbinol, add potassium tert.-butoxide 330g(2.9mol), 60 DEG C of stirring reactions 2 hours, reaction solution is poured in 3000mL water, with petroleum ether extraction, and washing, anhydrous sodium sulfate drying, precipitation, obtains phenmethyl vinyl ether 252g, yield 90%.
(4) synthesis of 3-(benzyloxy)-1-cyclobutanone
Under nitrogen protection, by 160g(1.2mol) phenmethyl vinyl ether is dissolved in 3000mL ether, adds zinc-copper catalyzer 50g(0.77mol), 300mL(2.7mol is dripped under room temperature) trichoroacetic chloride, stir 1 hour, add sodium bicarbonate aqueous solution 1000mL, get with sherwood oil, washing, anhydrous sodium sulfate drying, precipitation, obtains benzyloxy-2,2-dichloro cyclobutanone 232g, yield 79%;
(5) synthesis of 3-(benzyloxy)-1-cyclobutanone
By 125g(0.5mol) benzyloxy-2,2-dichloro cyclobutanone is dissolved in 1000mL water and 1000mL acetic acid, slowly add zinc powder 100g(1.5mol), stirring at room temperature 1 hour, filters, filtrate extracted with diethyl ether, washing, anhydrous sodium sulfate drying, distillation, obtain 3-(benzyloxy)-1-cyclobutanone 77.6g, yield 87%.End product total recovery is 55.22%.
Embodiment 3
(1) synthesis of BOE
Thermometer is being housed, add 800mL(15.74mol in the reaction flask of prolong) ethylene glycol, 400g(7.14mol) potassium hydroxide, stirring at room temperature to dissolve, slowly add 522.0g(4.1mol) chloromethylbenzene, stir 6 hours, add the water of 2000mL, by extracted with diethyl ether, anhydrous sodium sulfate drying, precipitation, obtains BOE 525g, yield 86%.
(2) synthesis of bromo ethyl phenenyl methyl ether
Triphenylphosphine 832g(3.58mol) be dissolved in methylene dichloride 3000mL, drip 572g(3.5mol) to solution yellowing, under room temperature, drip 400g(2.62mol) BOE, 400mL triethylamine and 600mL methylene dichloride mixed solution, within 1 hour, drip off, drip off reaction 0.5 hour, decompression precipitation, residuum adds ether 1000mL, wash with water, anhydrous sodium sulfate drying, distillation, obtain product bromo ethyl phenenyl methyl ether 521g, yield 93%.
(3) synthesis of phenmethyl vinyl ether
Take bromo ethyl phenenyl methyl ether 450g(2.1mol) be dissolved in the 1000mL trimethyl carbinol, add potassium tert.-butoxide 330g(2.9mol), stirring at room temperature reacts 8 hours, reaction solution is poured in 3000mL water, with petroleum ether extraction, and washing, anhydrous sodium sulfate drying, precipitation, obtains phenmethyl vinyl ether 246g, yield 88%.
(4) synthesis of benzyloxy-2,2-dichloro cyclobutanone
Under nitrogen protection, by 160g(1.2mol) phenmethyl vinyl ether is dissolved in 3000mL ether, adds zinc-copper catalyzer 78g(1.2mol), 300mL(2.7mol is dripped under room temperature) trichoroacetic chloride, stir 1 hour, add sodium bicarbonate aqueous solution 1000mL, get with sherwood oil, washing, anhydrous sodium sulfate drying, precipitation, obtains benzyloxy-2,2-dichloro cyclobutanone 246g, yield 84%;
(5) synthesis of 3-(benzyloxy)-1-cyclobutanone
By 125g(0.5mol) benzyloxy-2,2-dichloro cyclobutanone is dissolved in 1000mL water and 1000mL acetic acid, slowly add zinc powder 112g(1.75mol), stirring at room temperature 1.5 hours, filters, filtrate extracted with diethyl ether, washing, anhydrous sodium sulfate drying, distillation, obtain 3-(benzyloxy)-1-cyclobutanone 78.5g, yield 88%.End product total recovery is 52%.
Claims (8)
1. the synthetic method of compound 3-(benzyloxy)-1-cyclobutanone, comprises following processing step:
(1) preparation of BOE: under mineral alkali condition, halogeno-toluene and ethylene glycol are with the mol ratio of 1:2 ~ 1:10, and in room temperature ~ 70, DEG C reaction 1 ~ 6h, obtains BOE;
(2) preparation of haloethyl phenmethyl ether: in organic solvent, BOE, triphenylphosphine, halogen, with the mol ratio of 1:1:0.5 ~ 1:1.5:1.5, in room temperature reaction 1 ~ 5h, obtain haloethyl phenmethyl ether;
(3) preparation of phenmethyl vinyl ether: take the trimethyl carbinol as solvent, haloethyl phenmethyl ether and potassium tert.-butoxide are with the mol ratio of 1:1.0 ~ 1:1.5, and in room temperature ~ 70, DEG C reaction 2 ~ 8h, obtains phenmethyl vinyl ether;
(4) preparation of benzyloxy-2,2-dichloro cyclobutanone: under nitrogen protection, in organic solvent take zinc-copper as catalyzer, and phenmethyl vinyl ether and trichoroacetic chloride are with the mol ratio of 1:1 ~ 1:3, and room temperature reaction 1 ~ 3h, obtains benzyloxy-2,2-dichloro cyclobutanone;
(5) preparation of 3-(benzyloxy)-1-cyclobutanone: take aqueous acetic acid as solvent, benzyloxy-2,2-dichloro cyclobutanone and metallic zinc are with the mol ratio of 1:2 ~ 1:3.5, and room temperature reaction 1 ~ 3h, obtains end product 3-(benzyloxy)-1-cyclobutanone.
2. the synthetic method of compound 3-(benzyloxy)-1-cyclobutanone as claimed in claim 1, is characterized in that: step (1) described halogeno-toluene is chloromethylbenzene or brooethyl benzene.
3. the synthetic method of compound 3-(benzyloxy)-1-cyclobutanone as claimed in claim 1, is characterized in that: step (1) described mineral alkali is sodium hydroxide or potassium hydroxide; The molar weight of mineral alkali is 1 ~ 1.5 times of halogeno-toluene.
4. the synthetic method of compound 3-(benzyloxy)-1-cyclobutanone as claimed in claim 1, is characterized in that: step (2) described halogen is chlorine, bromine or iodine.
5. the synthetic method of compound 3-(benzyloxy)-1-cyclobutanone as claimed in claim 1, is characterized in that: step (2) described organic solvent is methylene dichloride, trichloromethane or tetracol phenixin.
6. the synthetic method of compound 3-(benzyloxy)-1-cyclobutanone as claimed in claim 1, is characterized in that: the consumption of the described zinc-copper catalyzer of step (4) is 0.4 ~ 1 times of phenmethyl vinyl ether molar weight.
7. the synthetic method of compound 3-(benzyloxy)-1-cyclobutanone as claimed in claim 1, is characterized in that: step (4) described organic solvent is methyl tertiary butyl ether, ether or isopropyl ether.
8. the synthetic method of compound 3-(benzyloxy)-1-cyclobutanone as claimed in claim 1, it is characterized in that: in step (5) described aqueous acetic acid, the percent by volume of acetic acid is 40 ~ 60%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310163920.0A CN103242152B (en) | 2013-05-07 | 2013-05-07 | The synthetic method of compound 3-(benzyloxy)-1-cyclobutanone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310163920.0A CN103242152B (en) | 2013-05-07 | 2013-05-07 | The synthetic method of compound 3-(benzyloxy)-1-cyclobutanone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103242152A CN103242152A (en) | 2013-08-14 |
| CN103242152B true CN103242152B (en) | 2015-12-02 |
Family
ID=48922061
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310163920.0A Expired - Fee Related CN103242152B (en) | 2013-05-07 | 2013-05-07 | The synthetic method of compound 3-(benzyloxy)-1-cyclobutanone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103242152B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002060362A (en) * | 2000-08-17 | 2002-02-26 | Nippon Synthetic Chem Ind Co Ltd:The | Method for producing ethylene glycol monobenzyl ether |
| GB0229695D0 (en) * | 2002-12-20 | 2003-01-29 | Amersham Plc | Solid-phase preparation of 18F-labelled amino acids |
| WO2011006000A1 (en) * | 2009-07-08 | 2011-01-13 | Haiyan Liu | Berberine derivatives useful for modulating lipid levels and their methods of synthesis |
-
2013
- 2013-05-07 CN CN201310163920.0A patent/CN103242152B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN103242152A (en) | 2013-08-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2015049360A1 (en) | Selective hydrolysis and alcoholysis of chlorinated benzenes | |
| CN102850325B (en) | Preparation method of Dabigatran etexilate key intermediate | |
| CN105367526B (en) | A kind of preparation method of high-purity n butylphthalide | |
| CN103242152B (en) | The synthetic method of compound 3-(benzyloxy)-1-cyclobutanone | |
| CN108558916B (en) | Synthesis process of p-phenylbutoxy benzoic acid | |
| CN104447621A (en) | Preparation method of Vortioxetine | |
| CN109956884A (en) | A kind of preparation method of Phenylmethoxyamine hydrochloride | |
| CN105481695A (en) | Method for preparing carboxylate compounds | |
| CN104788483A (en) | A method of preparing phenylboronic acid ortho- meta- and para-substituted with hydroxy and mercapto | |
| CN105294415A (en) | Preparation method of 3-halogenated fluorenone compound | |
| CN107118224B (en) | A kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and preparation method thereof | |
| CN110041176B (en) | Preparation method of thermosensitive paper sensitizer ethylene glycol diphenyl ether | |
| CN103145540B (en) | The preparation method of a kind of optical activity 7-halo-6-hydroxyl-heptan-3-alkene-2-ketone | |
| CN105330525A (en) | Preparation method of 7-hydroxy-1-indanone | |
| CN102127061B (en) | One prepares improving one's methods of fluoro-3, the 4-dihydro-2 H-1-benzopyran-2-epoxy ethanes of 6- | |
| CN103539666B (en) | Preparation method of 2-methyl-3-butenoic acid ester | |
| CN102936209A (en) | Synthetic method of 2-hydroxy propanedinitrile | |
| CN103254111B (en) | Preparation method of 2,5-dihydropyrrole | |
| CN104387259B (en) | One is prepared the method for 2,4,5-trifluoro benzene acetic acid | |
| CN104262450A (en) | Method for preparing and refining eplerenone | |
| CN104557653A (en) | Preparation method for 7-methyl-aza-bicyclo[4,1,0]heptane | |
| CN103242276B (en) | Synthesis method of 2, 2-dimethyltetrahydro-2H-pyran-4-carboxylic acid | |
| CN103193729B (en) | Preparation method of (2-hydrocarbon sulfenyl thiazoline-5-yl) methanol and carboxylic ester thereof | |
| CN105566201A (en) | Green synthesis method of carbazole oxime ester photoinitiator | |
| CN101811941A (en) | Preparation method for o-hydroxy-phenyl alkyl ether |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20150915 Address after: 730010 Gansu Province Chengguan District of Lanzhou City Yantan Power Plant Road Building Room 2404 Applicant after: LANZHOU AGLI BIOCHEMICAL TECHNOLOGY Co.,Ltd. Address before: 730020, Gansu Province, Chengguan District, Lanzhou Province, 177 section 7, 3 floor, 301 Jia Lu Road House Applicant before: LANZHOU SHUYA BIOCHEMICAL TECHNOLOGY Co.,Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20151202 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |