CN107673967A - A kind of preparation method of α fluoro propionyl acetic acid esters - Google Patents
A kind of preparation method of α fluoro propionyl acetic acid esters Download PDFInfo
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- CN107673967A CN107673967A CN201610616248.XA CN201610616248A CN107673967A CN 107673967 A CN107673967 A CN 107673967A CN 201610616248 A CN201610616248 A CN 201610616248A CN 107673967 A CN107673967 A CN 107673967A
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- acetic acid
- acid esters
- fluoro
- propionyl acetic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation method of α fluoro propionyl acetic acid esters.This method is reacted in the presence of the alkali such as sodium hydrogen or sodium alkoxide using the butanone of 1 fluorine 2 and carbonic ester as raw material, fluoro propionyl acetic acid esters can be obtained with higher yield, the preparation for α fluoro propionyl acetic acid esters and the fluoropyrimidine of 4 chlorine, 6 ethyl 5 provides new method.
Description
Technical field
The present invention relates to the preparation field of the chloro- 6- ethyls -5-FUs of voriconazole intermediate 4-, more particularly to fluoro third
The preparation field of ethyl sodio acetoacetic ester.
Background technology
Voriconazole（Voriconazol, formula (V)）It is a kind of New-type wide-spectrum triazole antifungal agent, it is by suppressing true
By 14 α-sterol demethylation of cytochrome P 450 mediated in bacterium, so as to suppress the biosynthesis of ergosterol.The medicine is beautiful
Pfizer of state researches and develops, and is listed first in the U.S. in 2002.Voriconazole is that current clinical treatment is serious by mould etc.
One of maximally effective medicine of fungal infection, the medical instrument it is effective in cure it is high, toxic side effect is small, better tolerance and has drug resistance advantage.
The chloro- 6- ethyls of 4- -5-FU (IV) is the key intermediate for synthesizing voriconazole (V), and it is chloro- to synthesize 4-
6- ethyls -5-FU (IV) then needs to use alpha-fluoro propionyl acetic acid esters (I), as shown in Equation 1.
Formula 1
Synthesis alpha-fluoro propionyl acetic acid esters (I) mainly has following two methods at present.
Chinese patent application CN200910224742, CN103896855B, CN102190628 etc. disclose one kind with fluoro
Acetic acid esters and propionyl chloride are raw material, and the method for alpha-fluoro propionyl acetic acid esters (I) is obtained through acylation reaction.Although this method route is simple
Buy, but yield is low, acylation reaction yield only has 30%, and propionyl chloride easily decomposes, and produces corrosive gas, and equipment is damaged
Evil is big, is unfavorable for carrying out industrialized production.The synthetic route of this method is as shown in Equation 2.
Formula 2
Chinese patent application CN201010118357 andOrg. Lett.2001,9 (13), 2392-2394 disclose another
The method of kind synthesis alpha-fluoro propionyl acetic acid esters (I), it is perfluorinated using propionyl acetic acid esters as raw material, or be fluorinated again after chlorine substitution
To alpha-fluoro propionyl acetic acid esters (I).Although this method raw material is conveniently easy to get, large excess of severe corrosive fluorine is used in reaction
Change hydrogen and hypertoxicity simple substance fluoride, production cost is high.Polyfluorinated organic accessory substance, product can be produced by carrying out fluorine substitution reaction using simple substance fluoride
Not easy purification, therefore this method is also not suitable for carrying out large-scale industrial production.The synthetic route of this method is as shown in Equation 3.
Formula 3
The content of the invention
Present invention aims at alpha-fluoro propionyl acetic acid esters (I) is provided, to synthesize alpha-fluoro third in the prior art in solution
Security is low in the method for ethyl sodio acetoacetic ester (I), and equipment requirement is high, is unfavorable for the technical problem of industrialized production.
Formula 4
The present invention develops a brand-new method for preparing alpha-fluoro propionyl acetic acid esters (I), efficient, safety, to equipment requirement
It is low.This method for raw material, in the presence of base, is occurred with the fluoro- 2- butanone (III) of 1- and carbonic ester (II) in alcohol or ether solvent
Reaction, obtains the fluoro propionyl acetic acid esters of formula (I).
In typical embodiment, alpha-fluoro propionyl acetic acid esters (I) is methyl esters or ethyl ester.
Preferably, the carbonic ester (II) used is dimethyl carbonate or diethyl carbonate.
Preferably, alkali used in reaction is sodium hydrogen or sodium alkoxide, including sodium methoxide, caustic alcohol.
Preferably, reaction temperature is 0 ~ 30 DEG C.
Preferably, alcohol or ether solvent include methanol, ethanol, tetrahydrofuran.
The fluoro- 2- butanone (III) of 1- that the present invention is easy to get with facilitating and carbonic ester (II) are raw material, safe to use, gentle anti-
The condition answered, new method is provided for synthesis alpha-fluoro propionyl acetic acid esters (I).
Embodiment
In order to be more clearly understood that the technology contents of the present invention, described in detail especially exemplified by following examples.
Embodiment 1：
Anhydrous tetrahydro furan 300mL is added in dry reaction bulb, is cooled to 0 DEG C of addition g of 60% sodium hydride 13.1, and be added dropwise
The fluoro- g of 2- butanone 45.0 of 1-, 30min is stirred in 0 DEG C；Dimethyl carbonate 60.0g is added dropwise at 0 DEG C again, is slowly warming up to room temperature
（25℃）Continue to stir 8h；GC detection raw material reactions finish.1 mol/L hydrochloric acid 100mL quenching reactions are slowly added into, decompression is steamed
Except most of tetrahydrofuran, remaining reaction solution is extracted with 300mL ethyl acetate, is divided and is taken ethyl acetate layer, uses saturated sodium-chloride
Solution is washed, and anhydrous magnesium sulfate is dried, and concentrated solvent obtains colorless oil, then is evaporated under reduced pressure to obtain colourless transparent liquid 54.3
Kg, yield 73.3%.
1H NMR (300 MHz, CDCl3) δ 5.04 (d, J = 48.5 Hz, 1H), 3.47 (s, 3H),
2.35 (q, J = 7.5 Hz, 2H), 0.68 (t, J = 7.4 Hz, 3H); 19F NMR (300 MHz, CDCl3):
δ –197.2 (d, J = 48.5Hz, 1F).
MS (ESI) m/z = 149.1 (M++1).
Embodiment 2：
Absolute ethyl alcohol 500mL is added in dry reaction bulb, is cooled to 0 DEG C of addition g of caustic alcohol 100.0, and the fluoro- 2- of 1- are added dropwise
The g of butanone 90.0,30min is stirred in 0 DEG C；Diethyl carbonate 150.0g is added dropwise at 0 DEG C again, is slowly warming up to room temperature（25℃）
Continue to stir 12h；GC detection raw material reactions finish.1 mol/L hydrochloric acid 100mL quenching reactions are slowly added into, are removed under reduced pressure big
Part ethanol, remaining reaction solution are extracted with 500mL ethyl acetate, are divided and are taken ethyl acetate layer, are washed with saturated nacl aqueous solution,
Anhydrous magnesium sulfate is dried, and concentrated solvent obtains colorless oil, then is evaporated under reduced pressure to obtain the g of colourless transparent liquid 82.9, yield
65.7%。
1H NMR (300 MHz, CDCl3) δ 5.20 (d, J = 49.3 Hz, 1H), 4.29 (q, J = 7.2
Hz, 2H), 2.80-2.54 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H) , 1.09 (t, J = 7.2 Hz,
3H); 19F NMR (300 MHz, CDCl3): δ –195.2 (d, J = 49.3Hz, 1F).
MS (ESI) m/z = 163.1 (M++1).
In this description, the present invention is described with reference to its specific embodiment.But it is clear that it can still make various
Modification and conversion are without departing from the spirit and scope of the present invention.Therefore, specification is considered as illustrative and non-limiting
's.
Claims (4)
1. a kind of preparation method of alpha-fluoro propionyl acetic acid esters (I), it is characterised in that with the fluoro- 2- butanone (III) of 1- and carbonic ester
(II) it is raw material, in the presence of base, is reacted in alcohol or ether solvent, obtains the fluoro propionyl acetic acid esters of formula (I)：
Wherein, R is methyl or ethyl.
2. according to the method for claim 1, it is characterised in that described alkali is sodium hydrogen or sodium alkoxide.
3. according to the method for claim 1, it is characterised in that described reaction temperature is 0 ~ 30 DEG C.
4. according to the method for claim 1, it is characterised in that alcohol or ether solvent include methanol, ethanol, tetrahydrofuran.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610616248.XA CN107673967A (en) | 2016-08-01 | 2016-08-01 | A kind of preparation method of α fluoro propionyl acetic acid esters |
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| CN201610616248.XA CN107673967A (en) | 2016-08-01 | 2016-08-01 | A kind of preparation method of α fluoro propionyl acetic acid esters |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101965328A (en) * | 2007-12-26 | 2011-02-02 | 基因里克斯(英国)有限公司 | Process to pregabalin |
| CN102060784A (en) * | 2009-11-13 | 2011-05-18 | 南通法茵克医药化工有限公司 | Method for synthesizing 6-ethyl-5-fluoro-4-hydroxy pyrimidine and intermediate thereof |
-
2016
- 2016-08-01 CN CN201610616248.XA patent/CN107673967A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101965328A (en) * | 2007-12-26 | 2011-02-02 | 基因里克斯(英国)有限公司 | Process to pregabalin |
| CN102060784A (en) * | 2009-11-13 | 2011-05-18 | 南通法茵克医药化工有限公司 | Method for synthesizing 6-ethyl-5-fluoro-4-hydroxy pyrimidine and intermediate thereof |
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Application publication date: 20180209 |