CN104496858A - Method for synthesizing 4-oxotetrahydro-2H-pyran-3-carboxylic acid ethyl ester - Google Patents
Method for synthesizing 4-oxotetrahydro-2H-pyran-3-carboxylic acid ethyl ester Download PDFInfo
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- CN104496858A CN104496858A CN201410818720.9A CN201410818720A CN104496858A CN 104496858 A CN104496858 A CN 104496858A CN 201410818720 A CN201410818720 A CN 201410818720A CN 104496858 A CN104496858 A CN 104496858A
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- CN
- China
- Prior art keywords
- carboxylic acid
- ethyl ester
- pyrans
- synthesizing
- oxo tetrahydrochysene
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- ZUJSLBBFQOCMFB-UHFFFAOYSA-N ethyl 4-oxooxane-3-carboxylate Chemical compound CCOC(=O)C1COCCC1=O ZUJSLBBFQOCMFB-UHFFFAOYSA-N 0.000 title abstract 3
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims abstract description 7
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- 125000004494 ethyl ester group Chemical group 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for synthesizing 4-oxotetrahydro-2H-pyran-3-carboxylic acid ethyl ester. The method is characterized in that firstly, ethyl hydroxyropanoate and ethyl acrylate are dissolved into a solvent for reacting under an alkaline condition to obtain 4-oxa-1,7-diethyl pimelate, and then adding a strong base at a low temperature and performing Ducommun condensation to obtain the 4-oxotetrahydro-2H-pyran-3-carboxylic acid ethyl ester. Compared with the existing methods, the method is simple in process, mild in condition, simple in after-treatment and relatively high in yield.
Description
Technical field
The present invention relates to synthesis field of medicaments, particularly relate to a kind of method of synthesizing 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester.
Background technology
4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester is a kind of important intermediate of synthesis field of medicaments, at present its synthetic method is mainly reacted under certain condition with to tetrahydro pyrone and diethyl carbonate or itrile group four acetoacetic ester and is obtained, the 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester that these two kinds of methods obtain, one is that reaction conditions requirement is harsher, two is that yield is very low, and cost is high.
Summary of the invention
The present invention, in order to solve the above problems, provides a kind of method of synthesizing 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester, and compared with the conventional method, present invention process is simple, mild condition, and aftertreatment is simple, and yield is higher.
Concrete technology of the present invention is, a kind of method of synthesizing 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester, it is characterized in that, first hydroxypropionate and ethyl propenoate are dissolved in solvent, be obtained by reacting 4-oxa--1 in the basic conditions, 7-pimelic acid diethyl ester, then adds highly basic at low temperatures, carries out Di Keman condensation and obtains 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester.
Concrete route is as follows:
Be dissolved in solvent by hydroxypropionate and ethyl propenoate, be obtained by reacting 4-oxa--1,7-pimelic acid diethyl ester in the basic conditions, described solvent is tetrahydrofuran (THF) or DMF, and described alkaline condition is Na
2cO
3, K
2cO
3, in NaOH or KOH any one.
Because aforesaid method carries out continuously, the optimum mole ratio of hydroxypropionate and ethyl propenoate is 1:1.
Add highly basic at low temperatures, carry out Di Keman condensation and obtain 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester, described cryogenic temperature is-10 ~ 0 DEG C, and described highly basic is sodium ethylate or sodium hydrogen.
Beneficial effect: the method for synthesis 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester provided by the invention is " one kettle way " operation, convenient and simple, and the 4-oxa--1 obtained, during 7-pimelic acid diethyl ester intermediate, purity is higher, do not need extraction purification, directly can add highly basic and carry out Di Keman condensation reaction, such reaction just avoids and generates a large amount of by product and make purification difficult.Yield of the present invention is higher, and condition is gentleer.
Embodiment
In order to clearly understand advantage of the present invention and creativeness, being further elaborated below in conjunction with specific embodiment and illustrating.
Hydroxypropionate (10.00g, 96mmol, 1eq) and ethyl propenoate (9.61g, 96 mmol, 1eq) join and fill in 250 ml, tri-mouthfuls of reaction flasks of 50 ml tetrahydrofuran (THF)s by embodiment 1, then add K
2cO
3(1.32g, 9.6mmol, 0.1eq) catalysis, stirred at ambient temperature 24 hours, thin plate laminate mode monitors reaction (developping agent: ethyl acetate: normal hexane=1:5), develops the color with potassium permanganate solution.After detecting and reacting completely, temperature of reaction is down to-10 ~ 0 DEG C, under nitrogen protection, 60%NaH (7.68 g are slowly dropped in reaction flask, 192mmol, 2eq), attentional manipulation temperature is at-10 ~ 0 DEG C, after input, keep this temperature to reacting end, then in reaction, instill a small amount of water to react with cancellation, add dilute hydrochloric acid and reaction is adjusted to PH=6 ~ 7, then three times are extracted with EA, each 50ml, merge organic layer, washing (20 ml) and salt with water, to wash (20ml) each once, dry, concentrated, obtain crude product 18 g, crude product FLASH is separated, (use ethyl acetate: normal hexane=1:20 ~ 1:10, collect 10 ~ 20min, 254nm, absorption peak is 1000 ~ 4500, 220nm, absorption peak 500 ~ 1500), by concentrated for eluent dry, obtain colourless oil liquid 11g, yield 68.75%.
Above-described embodiment is only in order to illustrate technical scheme of the present invention but not to limit design of the present invention and protection domain; those of ordinary skill of the present invention is modified to technical scheme of the present invention or equivalent replacement; and not departing from aim and the scope of technical scheme, it all should be encompassed in right of the present invention.
Claims (4)
1. one kind is synthesized the method for 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester, it is characterized in that, first hydroxypropionate and ethyl propenoate are dissolved in solvent, be obtained by reacting 4-oxa--1 in the basic conditions, 7-pimelic acid diethyl ester, then add highly basic at low temperatures, carry out Di Keman condensation and obtain 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester;
Concrete route is as follows:
。
2. a kind of method of synthesizing 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester according to claim 1, it is characterized in that, described solvent is tetrahydrofuran (THF) or DMF, and described alkaline condition is Na
2cO
3, K
2cO
3, in NaOH or KOH any one.
3. a kind of method of synthesizing 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester according to claim 1, is characterized in that, the optimum mole ratio of hydroxypropionate and ethyl propenoate is 1:1.
4. a kind of method of synthesizing 4-oxo tetrahydrochysene-2H-pyrans-3-carboxylic acid, ethyl ester according to claim 1, it is characterized in that, described cryogenic temperature is-10 ~ 0 DEG C, and described highly basic is sodium ethylate or sodium hydrogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410818720.9A CN104496858A (en) | 2014-12-25 | 2014-12-25 | Method for synthesizing 4-oxotetrahydro-2H-pyran-3-carboxylic acid ethyl ester |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410818720.9A CN104496858A (en) | 2014-12-25 | 2014-12-25 | Method for synthesizing 4-oxotetrahydro-2H-pyran-3-carboxylic acid ethyl ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104496858A true CN104496858A (en) | 2015-04-08 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410818720.9A Pending CN104496858A (en) | 2014-12-25 | 2014-12-25 | Method for synthesizing 4-oxotetrahydro-2H-pyran-3-carboxylic acid ethyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104496858A (en) |
-
2014
- 2014-12-25 CN CN201410818720.9A patent/CN104496858A/en active Pending
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| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150408 |