CN115073390B - 4, 5-Dihydro-isoxazole derivative and preparation method and application thereof - Google Patents
4, 5-Dihydro-isoxazole derivative and preparation method and application thereof Download PDFInfo
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- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical class C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 239000002253 acid Substances 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- RRUDCFGSUDOHDG-UHFFFAOYSA-N acetohydroxamic acid Chemical compound CC(O)=NO RRUDCFGSUDOHDG-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000036632 reaction speed Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- -1 but not limited to Chemical group 0.000 description 17
- 125000003118 aryl group Chemical group 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 125000003107 substituted aryl group Chemical group 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 125000000547 substituted alkyl group Chemical group 0.000 description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006019 1-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a 4, 5-dihydro-isoxazole derivative and a corresponding preparation method thereof, wherein the preparation method comprises the following steps: reacting acetohydroxylamine with a compound having a structure shown in formula (I) under the catalysis of acid to obtain the 4, 5-dihydroisoxazole derivative. The preparation method of the 4, 5-dihydro-isoxazole derivative provided by the invention adopts low-cost acetylhydroxylamine as a raw material, and the raw material cost is low; the reaction condition is mild, high-temperature and high-pressure conditions are not needed, the equipment requirement is low, the reaction speed is high, and the purity and the yield of the prepared product are high; the whole reaction process is simple, has strong rough tolerance and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to a 4, 5-dihydro-isoxazole derivative and a corresponding preparation method and application thereof, belonging to the technical field of chemical medicines.
Background
Many active natural products contain isoxazoline or an unsaturated analogue oxazoline thereof, and compounds containing dihydro-isoxazoline structural units often have various pharmaceutical activities such as anti-inflammatory, antifungal, antibacterial and the like, and are compounds with great practical value. In the existing process for preparing the dihydro-isoxazoline compound, the preparation is often carried out under the conditions of high temperature and high pressure, and the problems of high preparation cost and low yield exist.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a 4, 5-dihydro-isoxazole derivative. The invention also aims to provide a preparation method of the 4, 5-dihydroisoxazole derivative, which has the advantages of simple preparation process, mild reaction conditions, high reaction speed and low cost. Furthermore, it is an object of the present invention to provide the use of said 4, 5-dihydroisoxazole derivatives.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a4, 5-dihydroisoxazole derivative having the structural formula:
Wherein: r 1、R2 are each independently, identically or differently selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, aryl or substituted aryl.
According to some preferred embodiments of the invention, the derivative has the structure shown below:
Another object of the present invention is to provide a process for producing a 4, 5-dihydroisoxazole derivative as described above, which comprises the steps of: reacting acetohydroxylamine with a compound having a structure shown in formula (I) under the catalysis of acid to obtain the 4, 5-dihydroisoxazole derivative; the reaction process is shown as the following formula:
Wherein: r1 and R2 are each independently, identically or differently selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, aryl or substituted aryl.
According to one embodiment, the preparation steps of the 4, 5-dihydroisoxazole derivative comprise: under the catalysis of acid, the acetylhydroxylamine and the compound with the structure shown in the formula (I) are subjected to condensation reaction.
Further, the preparation method of the 4, 5-dihydroisoxazole derivative comprises the following steps: under the catalysis of acid, the acetylhydroxylamine and the compound with the structure shown in the formula (I) are subjected to condensation reaction at 0-80 ℃.
Preferably, it is: the acid is at least one of trifluoroacetic acid, trifluoro sulfonic acid, benzoic acid, acetic acid, hydrochloric acid, sulfuric acid and phosphoric acid.
It is further preferred that: the reaction mole ratio of the acetohydroxylamine to the acid to the compound with the structure shown in the formula (I) is 1: (0.01-0.05): (0.9-1).
The 4, 5-dihydro-isoxazoline derivative disclosed by the invention can be applied to the fields of fine chemical engineering, pesticides and medicines.
The invention has the beneficial effects that: the preparation method of the 4, 5-dihydro-isoxazole derivative adopts low-cost acetylhydroxylamine as a raw material, and has low raw material cost; the reaction condition is mild, high-temperature and high-pressure conditions are not needed, the equipment requirement is low, the reaction speed is high, and the purity and the yield of the prepared product are high; the whole reaction process is simple, has strong rough tolerance and is suitable for large-scale industrial production.
Detailed Description
The 4, 5-dihydroisoxazole derivative is prepared by adopting the following reaction mechanism:
Specifically, the preparation method of the 4, 5-dihydroisoxazole derivative comprises the following steps: under the catalysis of acid, reacting acetohydroxylamine with a compound with a structure shown in a formula (I) at 0-80 ℃, preferably 20-35 ℃ for 4-10 hours, and then decompressing and rectifying and recovering fractions to obtain the 4, 5-dihydroisoxazole derivative with the structure shown in a formula (II).
Wherein R 1、R2 are each independently, identically or differently selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, aryl or substituted aryl. As will be appreciated by those skilled in the art, 4, 5-dihydroisoxazole derivatives are those obtained by the corresponding substitution of the groups at the R1 and R2 positions of 4, 5-dihydroisoxazole.
Specifically, in the present invention, the above-mentioned C1-C6 alkyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl and the like; further preferred are straight or branched alkyl groups having 1 to 4 carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, and the like.
The above substituted alkyl group, substituted aryl group is understood to be alkyl groups having substituent groups and aryl groups having substituent groups, and these substituent groups include, but are not limited to, halogen atoms, nitro groups, cyano groups, hydroxyl groups, amine groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 alkoxy groups, phenyl groups, phenoxy groups, and the like; for example, the substituted aryl may be a halogenated aryl or a heteroaryl, and the substituted alkyl may be a halogenated alkyl or a heteroalkyl.
Specifically, the C1-C6 haloalkyl group refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms substituted with 1 to 13 halogen atoms which may be the same or different, wherein the halogen atoms may be fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, or the like. Taking halogen atoms as an example of fluorine atoms, in the present invention, C1-C6 haloalkyl includes, but is not limited to: fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2, 3-pentafluoropropyl 2, 2-trifluoro-1-trifluoromethyl ethyl, heptafluoropropyl, 1, 2-tetrafluoro-1-trifluoromethyl ethyl, 4-fluorobutyl 4-chlorobutyl, 4-bromobutyl, 2,3, 4-heptafluorobutyl, 5-fluoropentyl, 6-fluorohexyl and the like. The halogen alkyl of C1-C6 with other halogen atoms is obtained by replacing the corresponding halogen atoms with fluorine atoms, and the details are not repeated here. The C1-C6 haloalkyl group is further preferably a straight-chain or branched alkyl group having 1 to 4 carbon atoms substituted with 1 to 9 halogen atoms which may be the same or different, and the halogen atoms may be fluorine atoms, chlorine atoms, bromine atoms, iodine atoms or the like. Taking halogen atoms as fluorine atoms for example, C1-C4 haloalkyl groups include, but are not limited to: fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2, 3-pentafluoropropyl 2, 2-trifluoro-1-trifluoromethyl ethyl, heptafluoropropyl, 1, 2-tetrafluoro-1-trifluoromethyl ethyl 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2,3, 4-heptafluorobutyl, and the like. The halogen alkyl of C1-C4 with other halogen atoms is obtained by replacing the corresponding halogen atoms with fluorine atoms, and the details are not repeated here.
Furthermore, C3-C6 cycloalkyl refers to cycloalkyl groups having 3-6 carbon atoms, including but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; C2-C6 alkenyl refers to straight or branched chain alkenyl groups having 2 to 6 carbon atoms including, but not limited to: ethenyl, 1-propenyl, isopropenyl, 2-propenyl, 1-butenyl, 1-methyl-1-propenyl, 2-butenyl, 1, 3-butadienyl, 1-pentenyl, 1-hexenyl and the like; C2-C6 alkynyl refers to straight or branched chain alkynyl groups having 2 to 6 carbon atoms including, but not limited to: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 2-butynyl, 1-pentynyl, 1-hexynyl and the like; C1-C6 alkoxy refers to (C1-C6) alkyl-O- (herein, (C1-C6) alkyl is as defined previously), including but not limited to: methoxy, ethoxy, propoxy, isopropoxy, butoxy, secondary butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and the like.
The aryl is preferably phenyl, p-trifluoromethylphenyl and p-bromophenyl; the substituted aryl group may be a halogenated aryl group, and the halogenated aryl group is preferably a fluorinated aryl group, a chlorinated aryl group, a brominated aryl group, or an iodinated aryl group.
The acid is at least one of trifluoroacetic acid, trifluoro sulfonic acid, benzoic acid, acetic acid, hydrochloric acid, sulfuric acid and phosphoric acid. The amount of the acid is not particularly limited, and may be, for example: just the amount of the catalyst which can catalyze the reaction of the acetohydroxylamine. As a preferred embodiment, in order to increase the yield and purity of the reaction product, in the present invention, the molar ratio of the acetylhydroxylamine, the acid, and the compound having the structure represented by formula (I) is 1: (0.01-0.05): (0.9-1).
The technical scheme of the present invention will be further described with reference to specific examples, but the present invention is not limited to the following examples. The raw materials used in the present invention are commercially available unless otherwise specified. In addition, in each example, the yield referred to was calculated as: yield = actual mass of product purity/theoretical mass of product.
Example 1
Into the reaction flask was charged 7.5g (i.e., 0.1 mol) of acetohydroxylamine as a reactant,8.4G (formula I, relative molecular weight 84.12, 0.0998 mol), 0.11g of trifluoroacetic acid are reacted at 25℃for 4h with stirring, the reaction is monitored by GC sampling, and the reaction is complete; after the reaction, the mixture was distilled under reduced pressure at 17mbar to 18mbar and the fractions were collected at 44℃to 48℃to give an oily product7.8G. The purity was 98.1% and the yield (calculated as acetohydroxylamine) was 76.4% as determined by HPLC. 1H NMR (400 MHz, CDCl 3): δ1.40 (6 h, s), 2.75 (2 h, d), 7.06 (1 h, br s), mass spectrum data are as follows: ESI (M+H): 100.07.
Example 2
Into the reaction flask was charged 7.5g (i.e., 0.1 mol) of acetohydroxylamine as a reactant,8.4G (formula I, relative molecular weight 84.12, 0.0998 mol), and 0.12g trifluoroacetic acid at 40℃for 4h, and sampling and GC monitoring the reaction, the reaction of formula (I) being complete; after the reaction, the mixture was distilled under reduced pressure at 17mbar to 18mbar and the fractions were collected at 44℃to 48℃to give an oily productThe purity was 98.6% and the yield (calculated as acetohydroxylamine) was 77.2% as determined by HPLC. The nuclear magnetic data and mass spectrum data are the same as in example 1.
Example 3
Into the reaction flask was charged 7.5g (i.e., 0.1 mol) of acetohydroxylamine as a reactant,8.4G (formula I, relative molecular weight 84.12, 0.0998 mol), and 0.12g trifluoroacetic acid at 65℃for 4h, and sampling and GC monitoring the reaction, formula (I) is complete; after the reaction, the mixture was distilled under reduced pressure at 17mbar to 18mbar and the fractions were collected at 44℃to 48℃to give an oily productThe purity was 98.8% and the yield (calculated as acetohydroxylamine) was 77.5% as determined by HPLC. The nuclear magnetic data and mass spectrum data are the same as in example 1.
Example 4
Into the reaction flask was charged 7.5g (i.e., 0.1 mol) of acetohydroxylamine as a reactant,8.4G (formula I, relative molecular weight 84.12, 0.0998 mol) and 0.15g of trifluoromethanesulfonic acid at 25℃for 4h, the reaction is monitored by sampling GC and is completely reacted; after the reaction, the mixture was distilled under reduced pressure at 17mbar to 18mbar and the fractions were collected at 44℃to 48℃to give an oily productThe purity was 98.1% and the yield (calculated as acetohydroxylamine) was 75.2% as determined by HPLC. The nuclear magnetic data and mass spectrum data are the same as in example 1.
Example 5
Into the reaction flask was charged 7.5g (i.e., 0.1 mol) of acetohydroxylamine as a reactant,8.4G (formula I, relative molecular weight 84.12, 0.0998 mol) and sulfuric acid 0.11g at 25℃for 4h, sampling and GC monitoring the reaction, the reaction being complete; after the reaction, the mixture was distilled under reduced pressure at 17mbar to 18mbar and the fractions were collected at 44℃to 48℃to give an oily productThe purity was 98.1% and the yield (calculated as acetohydroxylamine) was 76.2% as determined by HPLC. The nuclear magnetic data and mass spectrum data are the same as in example 1.
Example 6
The procedure of example 1 is followed except that an equimolar amount of formula (I) is replaced byFor the obtained oily productAnd detecting, wherein nuclear magnetic data of the magnetic resonance detector are as follows: 1H NMR (400 MHz, CDCl 3): delta 7.11 (br s, 1H), 4.71-4.60 (m, 1H), 3.07 (ddd, 1H), 2.57 (ddd, 1H), 1.32 (d, 3H); the purity was 98.7% by HPLC and the yield was 72.6% based on acetylhydroxylamine.
Example 7
The procedure of example 1 is followed except that an equimolar amount of formula (I) is replaced byFor the obtained oily productThe nuclear magnetic data of the product were ：1H NMR(400MHz,CDCl3)：δ7.08(t,1H),4.23(ddd,1H),2.92(ddd,1H),2.69(ddd,1H),1.90–1.83(m,1H),1.79–1.70(m,2H),1.69–1.56(m,2H),1.47(m,1H),1.30–1.09(m,3H),1.08–0.91(m,2H);HPLC, the purity was 98.4%, and the yield was 72.7% based on acetylhydroxylamine.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention. In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Moreover, any combination of the various embodiments of the present invention can be made, as long as it does not depart from the gist of the present invention, which is also regarded as the content of the present invention.
Claims (3)
1. A preparation method of a 4, 5-dihydro-isoxazole derivative,
The derivative has the following structure:
The method is characterized in that: the method comprises the following steps: reacting acetohydroxylamine with a compound having a structure shown in formula (I) under the catalysis of acid to obtain the 4, 5-dihydroisoxazole derivative; the reaction process is shown as the following formula:
wherein, under the catalysis of acid, acetylhydroxylamine and a compound with a structure shown as a formula (I) are subjected to condensation reaction; the reaction mole ratio of the acetohydroxylamine to the acid to the compound with the structure shown in the formula (I) is 1: (0.01-0.05): (0.9-1).
2. The process for producing a4, 5-dihydroisoxazole derivative according to claim 1, characterized in that: under the catalysis of acid, the acetylhydroxylamine and the compound with the structure shown in the formula (I) are subjected to condensation reaction at 0-80 ℃.
3. The process for producing a4, 5-dihydroisoxazole derivative according to claim 1, characterized in that: the acid is at least one of trifluoroacetic acid, trifluoro sulfonic acid, benzoic acid, acetic acid, hydrochloric acid, sulfuric acid and phosphoric acid.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111491926A (en) * | 2017-12-15 | 2020-08-04 | 组合化学工业株式会社 | Novel method for producing 5, 5-disubstituted-4, 5-dihydroisoxazoles |
| CN112004805A (en) * | 2018-04-27 | 2020-11-27 | 组合化学工业株式会社 | Process for producing 5, 5-disubstituted-4, 5-dihydroisoxazoles |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111491926A (en) * | 2017-12-15 | 2020-08-04 | 组合化学工业株式会社 | Novel method for producing 5, 5-disubstituted-4, 5-dihydroisoxazoles |
| CN112004805A (en) * | 2018-04-27 | 2020-11-27 | 组合化学工业株式会社 | Process for producing 5, 5-disubstituted-4, 5-dihydroisoxazoles |
Non-Patent Citations (1)
| Title |
|---|
| Antti Pohjakallio等.Synthesis of 2-Isoxazolines: Enantioselective and Racemic Methods Based on Conjugate Additions of Oximes.Chem. Eur. J..2010,第16卷11325-11339. * |
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