CN117567386A - Synthesis method of 5, 5-dimethyl-4, 5-dihydro-isoxazole - Google Patents
Synthesis method of 5, 5-dimethyl-4, 5-dihydro-isoxazole Download PDFInfo
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- DIYSFZUJSGOINT-UHFFFAOYSA-N 5,5-dimethyl-4h-1,2-oxazole Chemical compound CC1(C)CC=NO1 DIYSFZUJSGOINT-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000001308 synthesis method Methods 0.000 title abstract description 9
- 229940125904 compound 1 Drugs 0.000 claims abstract description 25
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229940125782 compound 2 Drugs 0.000 claims abstract description 22
- CEBKHWWANWSNTI-UHFFFAOYSA-N 2-methylbut-3-yn-2-ol Chemical compound CC(C)(O)C#C CEBKHWWANWSNTI-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229940126214 compound 3 Drugs 0.000 claims abstract description 21
- RRUDCFGSUDOHDG-UHFFFAOYSA-N acetohydroxamic acid Chemical compound CC(O)=NO RRUDCFGSUDOHDG-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960001171 acetohydroxamic acid Drugs 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 72
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 7
- 230000002051 biphasic effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 64
- 238000001514 detection method Methods 0.000 description 16
- SEPQTYODOKLVSB-UHFFFAOYSA-N 3-methylbut-2-enal Chemical compound CC(C)=CC=O SEPQTYODOKLVSB-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- ACWQBUSCFPJUPN-UHFFFAOYSA-N Tiglaldehyde Natural products CC=C(C)C=O ACWQBUSCFPJUPN-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- CASLETQIYIQFTQ-UHFFFAOYSA-N 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfonyl]-5,5-dimethyl-4h-1,2-oxazole Chemical compound CN1N=C(C(F)(F)F)C(CS(=O)(=O)C=2CC(C)(C)ON=2)=C1OC(F)F CASLETQIYIQFTQ-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000002363 herbicidal effect Effects 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- GOCUAJYOYBLQRH-UHFFFAOYSA-N 2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid Chemical compound C1=CC(OC(C)C(O)=O)=CC=C1OC1=NC=C(C(F)(F)F)C=C1Cl GOCUAJYOYBLQRH-UHFFFAOYSA-N 0.000 description 1
- VEEFADFWCHSFIU-UHFFFAOYSA-N 3-methylbut-3-enal Chemical compound CC(=C)CC=O VEEFADFWCHSFIU-UHFFFAOYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical class C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- -1 5, 5-disubstituted-4, 5-dihydroisoxazole Chemical class 0.000 description 1
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- PXAJQJMDEXJWFB-UHFFFAOYSA-N acetone oxime Chemical compound CC(C)=NO PXAJQJMDEXJWFB-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940043350 citral Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- WTEVQBCEXWBHNA-JXMROGBWSA-N geranial Chemical compound CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to the field of compound synthesis, and particularly relates to a synthesis method of 5, 5-dimethyl-4, 5-dihydro isoxazole. According to the invention, 2-methyl-3-butyn-2-ol is used as a starting material, and reacts with p-toluenesulfonyl chloride under an alkaline condition to generate a compound 1, the obtained compound 1 continuously reacts with acetohydroxamic acid under the alkaline condition to generate a compound 2, the compound 2 generates a compound 3 under an acidic condition, and the compound 3 generates a target product 5, 5-dimethyl-4, 5-dihydro isoxazole under a high temperature condition. The invention provides a novel synthesis method of 5, 5-dimethyl-4, 5-dihydro-isoxazole, which is simple to operate, uses fewer solvents, generates fewer three wastes and has higher economic value and environmental protection value.
Description
Technical Field
The invention belongs to the field of compound synthesis, and particularly relates to a synthesis method of 5, 5-dimethyl-4, 5-dihydro isoxazole.
Background
5, 5-disubstituted-4, 5-dihydroisoxazole is an important intermediate for medicines, agricultural chemicals and the like, and of these, pyroxasulfone (Pyroxasulfone) is widely known as a herbicide having excellent herbicidal activity. And 3-halogenated 5, 5-dimethyl-4, 5-dihydro-isoxazole compounds are important intermediates for preparing haloxyfop herbicides. .
The synthesis method reported at present mainly comprises the following steps:
(1) Synlett2008, no.6,827-830 and chem.eur.j.2010, vol.16, 11325-11339 disclose methods of making 4, 5-dihydroisoxazole derivatives using ketoxime. Since ketone is produced as a by-product, this method causes a decrease in atom utilization rate, and is not industrially preferred because of poor productivity and operability, a large burden on the environment, and uneconomical.
(2) The preparation method disclosed by W02011063842 is to prepare 5, 5-dimethyl-4, 5-dihydro-isoxazole by ring closure of 3-methyl-2-butenal and acetoxime in the presence of an acid-base catalyst; TW201945347A discloses a method for preparing 5, 5-dimethyl-4, 5-dihydro-isoxazole compounds from aqueous solutions of 3-methyl-2-butenal and hydroxylamine in the presence of an acid-base catalyst. 3-methyl-2-butenal is a raw material for preparing citral, which is prepared by high-temperature isomerization of 3-methyl-3-butenal catalyst, so that the cost of the above preparation method is also high.
Disclosure of Invention
Aiming at the problems of expensive raw materials, complex reaction steps, more three wastes and the like in the prior art, the invention provides a novel method for synthesizing 5, 5-dimethyl-4, 5-dihydro-isoxazole, which is simple to operate, uses fewer solvents, generates fewer three wastes and has higher economic value and environmental protection value.
The structural formula of the 5, 5-dimethyl-4, 5-dihydro-isoxazole synthesized by the invention is as follows:
。
the technical scheme adopted by the invention for achieving the purpose is as follows:
the invention provides a synthesis method of 5, 5-dimethyl-4, 5-dihydro isoxazole, which comprises the following steps:
(A) Under alkaline conditions, reacting 2-methyl-3-butyn-2-ol with p-toluenesulfonyl chloride to generate a compound 1;
(B) Under alkaline conditions, the compound 1 reacts with acetohydroxamic acid to generate a compound 2;
(C) Compound 2 under acidic conditions to form compound 3;
(D) The compound 3 generates a target product 5, 5-dimethyl-4, 5-dihydro-isoxazole under the high temperature condition;
further, in the step (A), the molar ratio of the 2-methyl-3-butyn-2-ol to the p-toluenesulfonyl chloride is 1: 1.02-1.5, wherein the temperature of the reaction is-5-50 ℃.
Further, according to the synthesis method of claim 2, in the step (a), the alkaline condition is achieved by adding a base; the alkali includes, but is not limited to, organic and inorganic bases, preferably, triethylamine, sodium hydroxide, potassium hydroxide; the molar ratio of the 2-methyl-3-butyn-2-ol to the alkali is 1:2.1 to 3.6.
Further, in the step (a), the reaction is performed in a two-phase solvent, wherein the solvent is water and an organic solvent; the mass ratio of water to solvent is 1:2 to 10; the organic solvents include, but are not limited to: toluene, xylene, n-heptane, n-octane, and the like.
Further, in the step (B), the molar ratio of the compound 1 to the acetohydroxamic acid is 1:1.02 to 1.5; the reaction temperature is-5-50 ℃.
Further, in step (C), the acidic condition is achieved by adding an acid; the acids include, but are not limited to, hydrochloric acid, sulfuric acid, acetic acid, formic acid, or phosphoric acid.
Further, in step (C), the pH of the reaction is in the range of 0 to 6, preferably 3 to 4; the reaction temperature is-5-50 ℃.
Further, in the step (D), the reaction solvent is an organic solvent after the liquid separation in the step (C); the reaction temperature is from 90 to 150℃and preferably the reflux temperature of the solvent used.
Compared with the prior art, the invention has the beneficial effects that: compared with the prior art, the synthesis method provided by the invention only needs one-pot operation, is simple to operate, uses fewer types of solvents, generates fewer three wastes, and has higher economic value and environmental protection value.
Detailed Description
The invention is further illustrated below with reference to specific examples. The following description is merely exemplary in nature and is in no way intended to limit the scope of the present disclosure. Other embodiments, which are not creatively obtained by the person skilled in the art without departing from the inventive concept, are also within the protection scope.
In the examples described below, all materials were commercially available unless otherwise specified.
In the following examples, the concentrations are mass percent concentrations unless otherwise specified.
In the examples below, yield = actual mass of product x purity/theoretical mass of product.
Example 1
50g of water and 100g of toluene are taken and put into a reaction bottle, 8.58g (0.1 mol) of 2-methyl-3-butyn-2-ol and 25.55g (0.25 mol) of triethylamine are added, 21.18g (0.11 mol) of p-toluenesulfonyl chloride is added dropwise after the temperature is reduced to 0 ℃, after 2h of reaction, the 2-methyl-3-butyn-2-ol is detected by HPLC and less than 0.5% (HPLC area%), and the purity of the compound 1 is more than 99% (HPLC area%).
After the reaction, 8.34g (0.11 mol) of acetohydroxamic acid is continuously added dropwise, the reaction is carried out at 0 ℃ for 2.5 hours, and then the HPLC detection of the compound 1 is less than 0.5% (HPLC area%) and the purity of the compound 2 is more than 97% (HPLC area%). After the reaction of the compound 1 is finished, 36 percent hydrochloric acid is dripped, the pH value of the reaction system is maintained to be 3, the temperature is raised to 25 ℃ for continuous reaction for 2 hours, the HPLC detection of the compound 2 is less than 0.5 percent (HPLC area percent), and the purity of the compound 3 is more than 98 percent (HPLC area percent). After the reaction of the compound 2 is finished, liquid separation treatment is carried out, the temperature of the obtained toluene layer is raised to 110 ℃ for reflux reaction for 4 hours, and the HPLC detection of the compound 3 is less than 0.5 percent (HPLC area%). After the reaction of the compound 3 is finished, desolventizing is carried out, and 9.16g of 5, 5-dimethyl-4, 5-dihydro-isoxazole oily matter is obtained after desolventizing, the purity is 96.7%, and the total yield is 89.4%.
Example 2
50g of water and 150g of dimethylbenzene are taken into a reaction bottle, 8.58g (0.1 mol) of 2-methyl-3-butyn-2-ol and 13.33g (0.32 mol) of sodium hydroxide are added, 26.96g (0.14 mol) of p-toluenesulfonyl chloride is added dropwise after the temperature is reduced to minus 5 ℃, the temperature is raised to 25 ℃ after the dropwise addition is finished, after 0.5 hour of reaction, the 2-methyl-3-butyn-2-ol is detected by HPLC and is less than 0.5% (HPLC area%), and the purity of the compound 1 is more than 99% (HPLC area%).
After the reaction, 9.86g (0.13 mol) of acetohydroxamic acid is continuously added dropwise, the HPLC detection of the compound 1 is less than 0.5% (HPLC area%) after the reaction is carried out for 1h at 25 ℃, and the purity of the compound 2 is more than 98% (HPLC area%). After the reaction of the compound 1 is finished, sulfuric acid is added dropwise, the pH value of the reaction system is maintained to be 3.5, the reaction is continued for 2 hours, the HPLC detection of the compound 2 is less than 0.5% (HPLC area%), and the purity of the compound 3 is more than 98% (HPLC area%). After the reaction of the compound 2 is finished, the obtained xylene layer is heated to 140 ℃ for reflux reaction for 2 hours, and the HPLC detection of the compound 3 is less than 0.5 percent (HPLC area%). After the reaction of the compound 3 is finished, desolventizing is carried out, and 9.22g of 5, 5-dimethyl-4, 5-dihydro-isoxazole oily matter is obtained after desolventizing, the purity is 97.5%, and the total yield is 90.7%.
Example 3
40g of water and 160g of n-heptane are taken into a reaction flask, 8.58g (0.1 mol) of 2-methyl-3-butyn-2-ol and 18.70g (0.30 mol) of potassium hydroxide are added, 23.11g (0.12 mol) of p-toluenesulfonyl chloride is added dropwise after the temperature is reduced to 10 ℃, the temperature is raised to 35 ℃ after the dropwise addition, after 0.5 hour of reaction, the 2-methyl-3-butyn-2-ol is detected by HPLC and is less than 0.5% (HPLC area%), and the purity of the compound 1 is more than 99% (HPLC area%).
After the reaction, 10.62g (0.14 mol) of acetohydroxamic acid is continuously added dropwise, and the reaction is carried out at 35 ℃ for 1h, wherein the purity of the compound 2 is more than 97 percent (HPLC area%) after the HPLC detection of the compound 1 is less than 0.5 percent (HPLC area%). After the reaction of the compound 1 is finished, acetic acid is added dropwise, the pH value of the reaction system is maintained to be 4, and the reaction is continued for 1h, wherein the HPLC detection of the compound 2 is less than 0.5% (HPLC area%) and the purity of the compound 3 is more than 96% (HPLC area%). After the reaction of the compound 2 is finished, liquid separation treatment is carried out, the obtained n-heptane layer is heated to 98 ℃ for reflux reaction for 8 hours, and the HPLC detection of the compound 3 is less than 0.5 percent (HPLC area%). After the reaction of the compound 3 is completed, desolventizing is carried out, and 9.59g of 5, 5-dimethyl-4, 5-dihydro-isoxazole oily matter is obtained after desolventizing, the purity is 91.2%, and the total yield is 88.2%.
Example 4
150g of water and 500g of toluene are put into a reaction bottle, 34.33g (0.4 mol) of 2-methyl-3-butyn-2-ol and 47.61g (0.84 mol) of potassium hydroxide are added, 78.75g (0.408 mol) of p-toluenesulfonyl chloride is added dropwise after the temperature is reduced to minus 5 ℃, the temperature is raised to 35 ℃ after the dropwise addition, after 0.5 hour of reaction, the 2-methyl-3-butyn-2-ol is detected by HPLC and is less than 0.5% (HPLC area%), and the purity of the compound 1 is more than 99% (HPLC area%).
After the reaction, 30.94g (0.408 mol) of acetohydroxamic acid is continuously added dropwise, the temperature is reduced to 20 ℃ and the temperature is kept for reaction 2, then the HPLC detection of the compound 1 is less than 0.5% (HPLC area%) and the purity of the compound 2 is more than 99% (HPLC area%). And after the reaction of the compound 1 is finished, 36 percent hydrochloric acid is dripped, the pH value of a reaction system is regulated to 1, and the reaction is continued for 1 hour after the dripping of the hydrochloric acid, wherein the HPLC detection of the compound 2 is less than 0.5 percent (HPLC area percent), and the purity of the compound 3 is more than 98 percent (HPLC area percent). After the reaction of the compound 2 is finished, liquid separation treatment is carried out, the temperature of the obtained toluene layer is raised to 110 ℃ for reflux reaction for 4 hours, and the HPLC detection of the compound 3 is less than 0.5 percent (HPLC area%). After the reaction of the compound 3, desolventizing was performed to obtain 36.94g of an oily substance, the purity of which was 97.8%, and the total yield of which was 91.1%.
Example 5
50g of water and 200g of n-octane are taken into a reaction bottle, 8.58g (0.1 mol) of 2-methyl-3-butyn-2-ol and 10.42g (0.25 mol) of sodium hydroxide are added, 21.18g (0.11 mol) of p-toluenesulfonyl chloride is added dropwise at 25 ℃, the temperature is raised to 50 ℃ after the addition, after 0.5 hour of reaction, the 2-methyl-3-butyn-2-ol is detected by HPLC and less than 0.5% (HPLC area%), and the purity of the compound 1 is more than 99% (HPLC area%).
After the reaction, 8.34g (0.11 mol) of acetohydroxamic acid is continuously added dropwise, the reaction is carried out at 50 ℃ for 0.5h, and then the HPLC detection of the compound 1 is less than 0.5% (HPLC area%) and the purity of the compound 2 is more than 96% (HPLC area%). After the reaction of the compound 1 is finished, formic acid is added dropwise, the pH value of the reaction system is maintained to be 2, the reaction is continued for 1h, HPLC detection is carried out on the compound 2, wherein the purity of the compound 3 is more than 98 percent (HPLC area percent), and the compound 2 is less than 0.5 percent (HPLC area percent). After the reaction of the compound 2 is finished, liquid separation treatment is carried out, the obtained n-octane layer is heated to 127 ℃ for reflux reaction for 4 hours, and the HPLC detection of the compound 3 is less than 0.5 percent (HPLC area%). After the reaction of the compound 3 is finished, desolventizing is carried out, and 9.42g of 5, 5-dimethyl-4, 5-dihydro-isoxazole oily matter is obtained after desolventizing, the purity is 93.3%, and the total yield is 88.7%.
Comparative example 1
150g of toluene is taken and put into a reaction bottle, 8.58g (0.1 mol) of 2-methyl-3-butyn-2-ol and 13.33g (0.32 mol) of sodium hydroxide are added, 26.96g (0.14 mol) of p-toluenesulfonyl chloride is added dropwise after the temperature is reduced to 5 ℃, the temperature is raised to 25 ℃ after the completion of the dropwise addition, after 6 hours of reaction, the 2-methyl-3-butyn-2-ol is detected by HPLC to be less than 0.5% (HPLC area%), and the purity of the compound 1 is more than 97% (HPLC area%).
After the completion of the reaction, 9.86g (0.13 mol) of acetohydroxamic acid was continuously added dropwise, and after the reaction was carried out at 25℃for 24 hours, the HPLC detection of compound 1 was still > 70% (HPLC area%) and the reaction was stopped.
Comparative example 2
150g of water is taken and put into a reaction bottle, 8.58g (0.1 mol) of 2-methyl-3-butyn-2-ol and 13.33g (0.32 mol) of sodium hydroxide are added, 26.96g (0.14 mol) of p-toluenesulfonyl chloride is added dropwise after the temperature is reduced to 5 ℃, the temperature is raised to 25 ℃ after the dropwise addition, after 24h of reaction, the 2-methyl-3-butyn-2-ol is detected to be more than 30% (HPLC area%) by HPLC, the compound is detected to be 1 < 5% (HPLC area%) by HPLC, and the reaction is stopped.
Claims (9)
1. A method for synthesizing 5, 5-dimethyl-4, 5-dihydro-isoxazole, which is characterized by comprising the following steps:
(A) Under alkaline conditions, reacting 2-methyl-3-butyn-2-ol with p-toluenesulfonyl chloride to generate a compound 1;
；
(B) Under alkaline conditions, the compound 1 reacts with acetohydroxamic acid to generate a compound 2;
；
(C) Compound 2 under acidic conditions to form compound 3;
；
(D) The compound 3 generates a target product 5, 5-dimethyl-4, 5-dihydro-isoxazole under the high temperature condition;
。
2. the synthetic method of claim 1, wherein in step (a), the molar ratio of 2-methyl-3-butyn-2-ol to p-toluenesulfonyl chloride is 1: 1.02-1.5, wherein the reaction temperature is-5-50 ℃.
3. The synthetic method of claim 2 wherein in step (a), the alkaline condition is achieved by addition of a base; such bases include, but are not limited to, organic bases and inorganic bases; preferably, the alkali is triethylamine, sodium hydroxide or potassium hydroxide; the molar ratio of the 2-methyl-3-butyn-2-ol to the alkali is 1:2.1 to 3.6.
4. A synthetic method according to any one of claims 1 to 3, wherein in step (a), the reaction is carried out in a biphasic solvent, the solvent being water and an organic solvent; the mass ratio of water to solvent is 1:2 to 10; the organic solvents include, but are not limited to: toluene, xylene, n-heptane or n-octane.
5. The synthetic method of claim 1 wherein in step (B), the molar ratio of compound 1 to acetohydroxamic acid is 1:1.02 to 1.5.
6. The synthetic method according to claim 1 or 5, wherein in step (B), the temperature of the reaction is-5 to 50 ℃.
7. The synthetic method of claim 1 wherein in step (C), the acidic conditions are achieved by acid addition; the acids include, but are not limited to, hydrochloric acid, sulfuric acid, acetic acid, formic acid, or phosphoric acid.
8. The synthetic method of claim 7 wherein in step (C), the pH of the reaction is between 0 and 6; preferably, the pH value is 3-4; the temperature of the reaction is-5-50 ℃.
9. The method according to claim 1, wherein in the step (D), the solvent for the reaction is an organic solvent after the separation of the step (C); the temperature of the reaction is 90-150 ℃.
Priority Applications (1)
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