CN109516962A - Novel method for synthesizing 2, 6-difluorophenyl-1- (4, 5-dihydroisoxazole) -3-ethyl ketone - Google Patents
Novel method for synthesizing 2, 6-difluorophenyl-1- (4, 5-dihydroisoxazole) -3-ethyl ketone Download PDFInfo
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- CN109516962A CN109516962A CN201811523612.3A CN201811523612A CN109516962A CN 109516962 A CN109516962 A CN 109516962A CN 201811523612 A CN201811523612 A CN 201811523612A CN 109516962 A CN109516962 A CN 109516962A
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- C07—ORGANIC CHEMISTRY
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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Abstract
The invention discloses a new method for synthesizing 2, 6-difluorophenyl-1- (4, 5-dihydroisoxazole) -3-ethyl ketone. The synthetic route avoids the step of synthesizing the intermediate 1, 3-difluoro-2-styrene, overcomes the defects that the intermediate is easy to volatilize and difficult to store and the synthetic operation has high danger because sodium hydride is needed in the synthetic process in the prior art, so that the synthetic process is more suitable for large-scale production; the synthesis route has high yield, and the final target 2, 6-difluorophenyl-1- (4, 5-dihydroisoxazole) -3-ethyl ketone is purified in a recrystallization mode, so that the purity of the product is up to 98%; and the raw materials used in the synthetic route are all commercial production raw materials, and are cheap and easy to obtain.
Description
Technical field
The present invention relates to organic synthesis and technical field of medicine synthesis, a kind of specially synthesis 2,6- difluorophenyl -1- (4,
5- dihydro-isoxazole) -3- ethyl ketone new method.
Background technique
2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone is a kind of important medicine intermediate, is: fluorine
The key intermediate of thiazole pyrrole ethyl ketone, fluorine thiazole pyrrole ethyl ketone be E.I.Du Pont Company research and development first piperidyl thiazole it is different he oxazolines kill
Microbial inoculum has both protection and therapeutic activity.Its target site is novel, exists to late blight, downy mildew, root rot, stem rot, epidemic disease etc.
Interior oomycetes diseases show brilliant preventive effect.Fluorine thiazole pyrrole ethyl ketone is to potato, grape, vegetables and other Featured crops
Upper oomycetes diseases have brilliant preventive effect, such as cucumber downy mildew, muskmelon downy mildew, downy mildew of garpe, Chinese cabbage downy mildew, tomato evening
Epidemic disease, the late blight of potato, capsicum epidemic disease etc..
The synthetic route of 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone is both needed to first prepare centre at present
The fluoro- 2- styrene of body 1,3- bis-2,6- difluorophenyl-is further prepared by the fluoro- 2- styrene of 1,3- bis- again
1- (4,5- dihydro-isoxazole) -3- ethyl ketone.
Application publication number: CN105541830A, a kind of patent name: the hair of Fungicidal compounds, preparation method and applications
Bright patent discloses the synthetic route of 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone, and reaction equation is such as
Under:
But said synthesis route has the following deficiencies:
1, due to intermediate 1, the fluoro- 2- styrene of 3- bis- is volatile, so the intermediate is caused not save steadily in the long term,
It when needing to use the intermediate during organic synthesis, can only voluntarily be synthesized, and be dosed into down in time in post synthesis
In the reaction of one step.
2, intermediate 1 is being prepared, is needing to use sodium hydride during the fluoro- 2- styrene of 3- bis-, and the chemistry of sodium hydride
Activity is very high, is easy to cause burning and explosion under heated or moist environment, this results in operational danger in synthesis process
Greatly.
3, in addition, the starting material cost used of said synthesis route is relatively high high, such as 2,6- difluorobenzaldehyde.
The above problem, which results in the synthetic route, cannot achieve large-scale production, therefore we need to design a new conjunction
Problems of the prior art are overcome at route.
Summary of the invention
The purpose of the present invention is to provide a kind of synthesis 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketones
New method, to solve the problems mentioned in the above background technology.
To achieve the above object, the invention provides the following technical scheme: a kind of synthesis 2,6- difluorophenyl -1- (4,5- bis-
Hydrogen isoxazole) -3- ethyl ketone new method, which includes the following steps,
Step 1, by compound 1 and Ethyl formate prepare compound 2, reaction equation is as follows:
Step 2, by 7 prepare compound 3 of compound 2 and compound, reaction equation is as follows:
Step 3, by chemicals 3 and triethylene diamine cyclization prepare compound 4, reaction equation is as follows:
Step 4 prepares final product 2 by compound 4,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone,
Its reaction equation is as follows:
Preferably, in the step 2, compound 7 passes through such as following reactional equation by compound 6 and triethyl orthoformate
Formula is prepared:
Preferably, in the step (2), the molar ratio of compound 2 and chemical combination 7 is 1:(1-1.2).
Preferably, the specific synthetic method of the step (2) are as follows: compound 2 and compound 7 are added in reaction flask, so
Methanol and 20% sodium hydrate aqueous solution are added afterwards, is stirred 2-5 hours at 25-35 DEG C；TLC shows fully reacting, by system
Water and ethyl acetate is added after being concentrated into no methanol, liquid separation is stood after being sufficiently stirred, water phase is extracted with ethyl acetate 1-3 times, has
Anhydrous sodium sulfate drying is concentrated to get compound 3 after machine mutually merges.
Preferably, the specific synthetic method of the step (1) are as follows: tetrahydrofuran and diisopropylamine, nitrogen are added in reaction flask
System temperature is down to -40 DEG C under gas shielded；N-BuLi hexane solution is added dropwise into reaction system, drips and finishes insulated and stirred
0.5h；Dry ice ethanol bath is cooled to -70 DEG C of dropwise addition compounds 1, drips Bi Baowen 1h；- 70 DEG C of temperature control, dropwise addition Ethyl formate (78g,
1.05mol), above compound 1 and the molar ratio of Ethyl formate are risen again after dripping complete insulated and stirred 1h for 1:(1.2-1.5) to 20-
30 DEG C reaction 1-3 hours, after fully reacting purifying obtain compound 2.
Preferably, the specific synthetic method of the step (3) are as follows: ethyl alcohol and compound 3 are added into reaction flask, then
The molar ratio of addition hydroxylamine hydrochloride and triethylene diamine, above compound 3 and triethylene diamine is 1:(2-4)；Reaction system exists
It is stirred at room temperature 2-5 hours；System is concentrated into after no fraction after fully reacting, water is added, filter cake is added to second by agitation and filtration
It is dissolved in acetoacetic ester, anhydrous sodium sulfate drying is concentrated to give compound 4.
Preferably, the specific synthetic method of the step (4) are as follows: compound 4 is added into reaction flask, salt is then added
Aqueous acid and acetone are stirred at room temperature 2-5 hours；Ethyl acetate and water is added after fully reacting into system, after being sufficiently stirred
Liquid separation is stood, water phase is extracted with ethyl acetate 1-3 times, merges organic phase, organic phase is washed 1 time with saturated common salt, by organic phase
Dry, petroleum ether and ethyl acetate (PE:EA=5:1), 10-15 DEG C recrystallizes to obtain 2,6- difluorophenyl -1- (the different evil of 4,5- dihydros
Azoles) -3- ethyl ketone.
Preferably, the specific synthetic method of the compound 7 are as follows: compound 6, triethyl orthoformate are added into reaction flask
And p-methyl benzenesulfonic acid, the molar ratio of compound 6 and triethyl orthoformate are 1:(1.2-1.5), stirring 8-12 is small at 20-30 DEG C
When, reaction system distills to obtain compound 7 after fully reacting.
Compared with prior art, the beneficial effects of the present invention are:
(1) compared with the prior art, the step of this synthetic route avoids synthetic intermediate 1, bis- fluoro- 2- styrene of 3-,
It is volatile not easy to maintain to overcome prior art intermediate, and due to synthesis process needs to use sodium hydride and synthetic operation is endangered
Dangerous big defect, so that the synthesis technology be made to be more suitable for large-scale production.
(2) yield is higher, and final goal 2, and 6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone passes through weight
The mode of crystallization is purified, and product purity is up to 98%.
(3) raw material that this synthetic route is used is to commercially produce raw material, cheap and easy to get.
Detailed description of the invention
Fig. 1 is compound 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone1H-NMR spectrum.
Specific embodiment
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other
Embodiment shall fall within the protection scope of the present invention.
The synthetic route that the present invention prepares 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone is for example following anti-
It answers shown in equation:
Scheme 1:
Scheme 2:
Embodiment 1: laboratory synthesis
Step 1: the preparation of compound 2
Experimental implementation: be added into the 3L reaction flask of dried and clean tetrahydrofuran (1L) and diisopropylamine (135g,
1.3mol), system temperature is down to -40 DEG C under nitrogen protection.N-BuLi hexane solution is added dropwise into reaction system
(456mL, 2.5mol/L) drips and finishes insulated and stirred 0.5h.Dry ice ethanol bath be cooled to -70 DEG C of dropwise addition compounds 1 (100g,
0.88mol), Bi Baowen 1h is dripped.It -70 DEG C of temperature control, is added dropwise Ethyl formate (78g, 1.05mol), drips and be back to after finishing insulated and stirred 1h
20-30 degree reacts 1h.
Post-processing: TLC (PE:EA=10:1, raw material Rf:0.9, product Rf:0.4) shows raw material without residue.To system
Middle addition water (1.5L) and methyl tertiary butyl ether(MTBE) (500mL), stand liquid separation, water phase methyl tertiary butyl ether(MTBE) after being sufficiently stirred
(500mL) is extracted 2 times, and merge organic phase washed once with saturated salt solution, and the dry compound 2 that is concentrated to give of organic phase is reddish oil
Shape object (110g), yield 88%.
Compound 21H-NMR (CDCl3) δ: 6.95 (2H, t, J=12Hz), 7.53 (1H, tt), 10.31 (1H, s).
Step 2: the preparation of compound 7
Experimental implementation: compound 6 (50g, 0.58mol) is added into the 500mL there-necked flask of dried and clean, primitive nail triethylenetetraminehexaacetic acid
Ester (94g, 0.64mol) and p-methyl benzenesulfonic acid (5g, 0.03mol), 20-30 DEG C is stirred overnight.
Post-processing: it is pale yellow oily liquid that reaction system water pump distillation (100 degree of bottom temperature, 50 degree of top temperature), which obtains compound 7,
(60g, purity:90%), yield 65%.
Compound 71H-NMR (CDCl3) δ: 1.14 (6H, t, J=4Hz), 1.31 (3H, s), 2.16 (3H, s), 3.41
(4H,m)。
Step 3: the preparation of compound 3
Experimental implementation: compound 2 (50g, 0.35mol) and compound 7 are added into the 3L reaction flask of dried and clean
Methanol (500mL) and 20% sodium hydrate aqueous solution (500mL) is then added in (56.3g, 0.35mol).30 degree of stirrings of reaction
2h。
Post-processing: TLC (PE:EA=10:1, raw material Rf:0.4, product Rf:0.8) shows raw material without residue.By system
Water (500mL) and ethyl acetate (300mL) is added after being concentrated into no methanol, liquid separation, water phase acetic acid second are stood after being sufficiently stirred
Ester (200mL) extracts 1 time, after organic phase merges anhydrous sodium sulfate it is dry be concentrated to give compound 3 be light yellow oil (46g,
Purity:95%), yield 46%.
Compound 31H-NMR (CDCl3) δ: 1.18 (6H, t, J=4Hz), 1.4 (3H, s), 3.47 (4H, m), 6.85
(2H, t, J=8Hz), 7.22 (1H, m), 7.48 (1H, d, J=16Hz), 7.76 (1H, d, J=16Hz).
Step 4: the preparation of compound 4
Experimental implementation: be added into the 500mL there-necked flask of dried and clean ethyl alcohol (200mL) and compound 3 (20g,
0.07mol), hydroxylamine hydrochloride (31g, 0.14mol) and triethylene diamine (46g, 0.21mol) is then added.Reaction system is in room
Temperature stirring 2h.
Post-processing: TLC (PE:EA=5:1, raw material Rf:0.8, product Rf:0.4) shows raw material without residue.System is dense
Water 200ml is added after being reduced to no fraction, filter cake is added to dissolution, anhydrous sulphur in ethyl acetate (120ml) by stirring 0.5h filtering
The dry compound 4 that is concentrated to give of sour sodium is white solid (15.6g, purity:90%), yield 74%.
Compound 41H-NMR (CDCl3) δ: 1.16 (6H, t, J=4Hz), 1.4 (3H, s), 2.32 (1H, m), 2.77
(1H, m), 3.54 (4H, m), 6.6 (1H, m), 6.79 (2H, t, J=8Hz), 7.18 (1H, m).
Step 5: the preparation of 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone
Experimental implementation: compound 4 (15.6g, 0.07mol) is added into the 500mL there-necked flask of dried and clean, is then added
Aqueous hydrochloric acid solution (75mL, 2mol/L) and acetone (156mL), are stirred at room temperature 2h.
Post-processing: TLC shows raw material without residue.Ethyl acetate (100mL) and water (50mL) are added into system, sufficiently stirs
Liquid separation is stood after mixing, water phase is extracted 1 time with ethyl acetate (100mL), merges organic phase.Organic phase is washed 1 time with saturated common salt,
Organic phase is dry, and petroleum ether, ethyl acetate (PE:EA=5:1) 50ml, 10-15 degree recrystallizes to obtain 2,6- difluorophenyl -1-
(4,5- dihydro-isoxazole) -3- ethyl ketone is light red solid (8g, purity:98%), yield 68%.
Referring to Figure 1,2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone1H-NMR(CDCl3)δ:
2.07 (3H, m), 2.98 (1H, m), 3.26 (1H, m), 5.69 (1H, m) 6.95 (2H, t, J=8Hz), 7.36 (1H, m).
Compared with the prior art, the step of this synthetic route avoids synthetic intermediate 1, bis- fluoro- 2- styrene of 3-, overcomes
Prior art intermediate is not volatile easy to maintain, and since synthesis process needs to use sodium hydride and synthetic operation risk
Big defect, so that the synthesis technology be made to be more suitable for large-scale production；This synthetic route yield is higher, and final goal 2,6- bis-
Fluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone is purified by way of recrystallization, and product purity is up to 98%；
And the raw material that this synthetic route is used is to commercially produce raw material, cheap and easy to get.
Claims (8)
1. a kind of new method for synthesizing 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone, it is characterised in that: should
Synthetic method includes the following steps,
Step (1), by compound 1 and Ethyl formate prepare compound 2, reaction equation is as follows:
Step (2), by 7 prepare compound 3 of compound 2 and compound, reaction equation is as follows:
Step (3), by chemicals 3 and triethylene diamine cyclization prepare compound 4, reaction equation is as follows:
Step (4) prepares final product 2 by compound 4,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone,
Reaction equation is as follows:
2. the new side of synthesis 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone according to claim 1
Method, it is characterised in that: in the step (2), compound 7 passes through such as following reactional equation by compound 6 and triethyl orthoformate
Formula is prepared:
3. the new side of synthesis 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone according to claim 1
Method, it is characterised in that: in the step (2), the molar ratio of compound 2 and chemical combination 7 is 1:(1-1.2).
4. the new side of synthesis 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone according to claim 3
Method, it is characterised in that: the specific synthetic method of the step (2) are as follows: compound 2 and compound 7 are added in reaction flask, so
Methanol and 20% sodium hydrate aqueous solution are added afterwards, is stirred 2-5 hours at 25-35 DEG C；TLC shows fully reacting, by system
Water and ethyl acetate is added after being concentrated into no methanol, liquid separation is stood after being sufficiently stirred, water phase is extracted with ethyl acetate 1-3 times, has
Anhydrous sodium sulfate drying is concentrated to get compound 3 after machine mutually merges.
5. the new side of synthesis 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone according to claim 1
Method, it is characterised in that: the specific synthetic method of the step (1) are as follows: tetrahydrofuran and diisopropylamine, nitrogen are added in reaction flask
System temperature is down to -40 DEG C under gas shielded；N-BuLi hexane solution is added dropwise into reaction system, drips and finishes insulated and stirred
0.5h；Dry ice ethanol bath is cooled to -70 DEG C of dropwise addition compounds 1, drips Bi Baowen 1h；- 70 DEG C of temperature control, dropwise addition Ethyl formate (78g,
1.05mol), above compound 1 and the molar ratio of Ethyl formate are risen again after dripping complete insulated and stirred 1h for 1:(1.2-1.5) to 20-
30 DEG C reaction 1-3 hours, after fully reacting purifying obtain compound 2.
6. the new side of synthesis 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone according to claim 1
Method, it is characterised in that: the specific synthetic method of the step (3) are as follows: ethyl alcohol and compound 3 are added into reaction flask, then plus
Enter hydroxylamine hydrochloride and triethylene diamine, the molar ratio of above compound 3 and triethylene diamine is 1:(2-4)；Reaction system is in room
Temperature stirring 2-5 hours；System is concentrated into after no fraction after fully reacting, water is added, filter cake is added to acetic acid by agitation and filtration
It is dissolved in ethyl ester, anhydrous sodium sulfate drying is concentrated to give compound 4.
7. the new side of synthesis 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone according to claim 1
Method, it is characterised in that: the specific synthetic method of the step (4) are as follows: compound 4 is added into reaction flask, hydrochloric acid is then added
Aqueous solution and acetone are stirred at room temperature 2-5 hours；Ethyl acetate and water is added after fully reacting into system, is sufficiently stirred rear quiet
Liquid separation is set, water phase is extracted with ethyl acetate 1-3 times, merges organic phase, and organic phase is washed 1 time with saturated common salt, will be organic relevant
Dry, petroleum ether and ethyl acetate (PE:EA=5:1), 10-15 DEG C recrystallizes to obtain 2,6- difluorophenyl -1- (the different evil of 4,5- dihydros
Azoles) -3- ethyl ketone.
8. the new side of synthesis 2,6- difluorophenyl -1- (4,5- dihydro-isoxazole) -3- ethyl ketone according to claim 2
Method, it is characterised in that: the specific synthetic method of the compound 7 are as follows: compound 6, triethyl orthoformate are added into reaction flask
And p-methyl benzenesulfonic acid, the molar ratio of compound 6 and triethyl orthoformate are 1:(1.2-1.5), stirring 8-12 is small at 20-30 DEG C
When, reaction system distills to obtain compound 7 after fully reacting.
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| CN201811523612.3A CN109516962A (en) | 2018-12-13 | 2018-12-13 | Novel method for synthesizing 2, 6-difluorophenyl-1- (4, 5-dihydroisoxazole) -3-ethyl ketone |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009094445A2 (en) * | 2008-01-25 | 2009-07-30 | E. I. Du Pont De Nemours And Company | Fungicidal hetercyclic compounds |
| CN102227423A (en) * | 2008-12-02 | 2011-10-26 | 纳幕尔杜邦公司 | Fungicidal heterocyclic compounds |
| CN102791133A (en) * | 2010-01-07 | 2012-11-21 | 纳幕尔杜邦公司 | Fungicidal heterocyclic compounds |
| CN105541830A (en) * | 2015-12-14 | 2016-05-04 | 北京迪尔乐农业高新技术研发中心 | Sterilization compound and preparation method and application thereof |
-
2018
- 2018-12-13 CN CN201811523612.3A patent/CN109516962A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009094445A2 (en) * | 2008-01-25 | 2009-07-30 | E. I. Du Pont De Nemours And Company | Fungicidal hetercyclic compounds |
| CN101970432A (en) * | 2008-01-25 | 2011-02-09 | 杜邦公司 | Fungicidal hetercyclic compounds |
| CN102227423A (en) * | 2008-12-02 | 2011-10-26 | 纳幕尔杜邦公司 | Fungicidal heterocyclic compounds |
| CN102791133A (en) * | 2010-01-07 | 2012-11-21 | 纳幕尔杜邦公司 | Fungicidal heterocyclic compounds |
| CN105541830A (en) * | 2015-12-14 | 2016-05-04 | 北京迪尔乐农业高新技术研发中心 | Sterilization compound and preparation method and application thereof |
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