CN115215814A - Synthetic method of isoxazolidine compounds - Google Patents

Synthetic method of isoxazolidine compounds Download PDF

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CN115215814A
CN115215814A CN202211086127.0A CN202211086127A CN115215814A CN 115215814 A CN115215814 A CN 115215814A CN 202211086127 A CN202211086127 A CN 202211086127A CN 115215814 A CN115215814 A CN 115215814A
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compound
alkyl
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isoxazolidine
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朱曼
刘丙贤
张亚南
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Henan Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/70—[b]- or [c]-condensed containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • 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
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Abstract

The invention discloses a synthesis method of isoxazolidine compounds, belonging to the technical field of organic synthesis. Reacting nitrone compound 1 and ethylene carbonate 2 under the action of rhodium catalyst, silver salt and additive to obtain isoxazolidine compound 3. The invention has the advantages of simple and easy preparation of the initial raw materials, wide application range of the substrate, simple operation and the like, and the obtained isoxazolidine skeleton belongs to the most common skeleton in natural products and has potential pharmaceutical activity.

Description

Synthetic method of isoxazolidine compounds
Technical Field
The invention belongs to the field of metal catalysis carbon-hydrogen bond activation, and particularly relates to a synthesis method and application of isoxazolidine compounds.
Background
The isoxazolidine backbone belongs to the most common unit in natural products. Molecules containing unique isoxazolidine scaffolds have been widely discovered and studied for their biological properties, and their structures have long been of interest to organic and medicinal chemists.
Isoxazolidine backbone compounds are very important active compounds, widely present in natural products, such as Pyridinodamin A-D, (-) -FlueggineA, dactylicapnosine, etc. The medicine is widely used for treating poliomyelitis, rheumatic low back pain, neurasthenia and hemiplegia, and researches prove that the antitumor activity of the compound can be enhanced through structural modification and modification.
Therefore, research and development of an efficient synthesis method of isoxazolidine compounds and modification and reconstruction of the structures of the isoxazolidine compounds have an important effect on screening of drug lead compounds.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide isoxazolidine compounds, and a synthesis method and application thereof. Nitrone compounds and ethylene carbonate are used as initial raw materials and react in the presence of a rhodium catalyst and an additive to obtain isoxazolidine compounds.
The isoxazolidine compound 3 has the following structural general formula;
Figure BDA0003835151820000011
wherein: r is 1 Is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, nitro, amino, C1-C4 alkoxycarbonyl, halogen or forms a naphthyl group with phenyl; r is 2 Is C1-C4 alkyl or benzyl.
The invention also provides a synthesis method of the isoxazolidine compound 3, which comprises the following steps: under the action of a rhodium catalyst, a silver salt and an additive, an oxime ether compound 1 and vinyl ethylene carbonate 2 react to obtain an isoxazole compound 3; the reaction equation is expressed as:
Figure BDA0003835151820000021
wherein: r 1 Is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, nitro, amino, C1-C4 alkoxycarbonyl, halogen or forms a naphthyl group with phenyl; r 2 Is C1-C4 alkyl or benzyl.
Further, in the above technical scheme, the rhodium catalyst is [ Cp ] * RhCl 2 ] 2 。
Further, in the above technical solution, the silver salt is selected from AgSbF 6 。
Further, in the above technical solution, the additive is selected from Ag 2 CO 3 、Cu(OAc) 2 、AgOAc、Na 2 CO 3 Or NaOAc.
Further, in the above technical scheme, the reaction is carried out in an organic solvent, wherein the organic solvent is chlorobenzene, toluene, dichloromethane, dichloroethane, or trifluoroethanol; the reaction temperature is 40-80 ℃.
Further, in the above technical scheme, the molar ratio of the compound 1, the compound 2 and the rhodium catalyst is 1 to 1.5.
Further, in the above technical scheme, the reaction is preferably carried out under the protection of an inert gas.
Further, in the above technical scheme, the oxime ether compound 1 is replaced by
Figure BDA0003835151820000022
The product is
Figure BDA0003835151820000023
The ethylene carbonate 2 is replaced by
Figure BDA0003835151820000031
The product is
Figure BDA0003835151820000032
Replacing the ethylene-2-ethylene carbonate with
Figure BDA0003835151820000033
The product is
Figure BDA0003835151820000034
The ethylene carbonate 2 is replaced by
Figure BDA0003835151820000035
The product is
Figure BDA0003835151820000036
Wherein: r 1 And R 2 The substituents are as described in the above synthetic methods.
The invention also provides the transformation application of the isoxazole compound 3, which is used for synthesizing various compounds with potential biological activity.
A: at PPh 3 /I 2 Or PPh 3 /CCl 4 In the presence of the catalyst, iodo-or chloro-isoxazole compounds 5 or compounds 6 are obtained; compound 7 is obtained in the presence of mCPBA;
b: sequentially protected by p-TsCl and NaN 3 Substitution to give compound 10; p-TsCl protection and Zn/AcOH reductive ring opening in sequence, et 3 N/DMAP dehydrates and cyclizes to give 11.
The reaction equation is expressed as follows:
Figure BDA0003835151820000037
wherein: r is 1 Is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, nitro, amino, C1-C4 alkoxycarbonyl, halogen or forms a naphthyl group with phenyl; r 2 Is C1-C4 alkyl or benzyl.
Advantageous effects of the invention
1. The method has the advantages of simple and easy preparation of the initial raw material, mild reaction conditions, short reaction steps, excellent regioselectivity and stereoselectivity, simple post-treatment and wide substrate application range.
2. The product can be diversely converted into more potential bioactive molecules, thereby realizing the later functional synthesis of some important natural products and drug molecules.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
Optimization experiment of reaction conditions
Figure BDA0003835151820000041
Figure BDA0003835151820000042
Figure BDA0003835151820000051
a Reaction conditions:1a(0.1mmol),2a(0.15mmol),[Cp*RhCl 2 ] 2 (4mol％),AgSbF 6 (16mol％),additive(1.0equiv),solvent(1.0mL),60℃,12h,underAr. b [CymeneRuCl 2 ] 2 instead of[Cp*RhCl 2 ] 2 . c withoutAgSbF 6 . d without[Cp*RhCl 2 ] 2 . e Ag 2 CO 3 (0.5eq). f Ag 2 CO 3 (0.5eq),1a:2a＝1:1. g Ag 2 CO 3 (0.5eq),1a:2a＝1:1.2. h Ag 2 CO 3 (0.5eq),80℃, i Ag 2 CO 3 (0.5eq),air.
Example 2
Figure BDA0003835151820000052
Under argon atmosphere, compound 1a (0.1mmol, 18mg) and [ Cp ] were sequentially added to a 25mL pressure-resistant tube * RhCl 2 ] 2 (0.004mmol,5.5mg)、AgSbF 6 (0.016mmol,6.6mg)、Ag 2 CO 3 (0.05mmol, 14mg), the reaction tube was sealed, 2a (0.15mmol, 18mg) and chlorobenzene (1 mL) were added to the mixture under an argon atmosphere, and the reaction tube was placed in a metal bath at 60 ℃ for 12 hours. After the reaction was complete, the solvent was spin dried. Product 3 was isolated by silica gel column chromatography with PE: EA =4, 1, as a white solid (20.0 mg,81%, m.p.81-84 ℃); 1 H NMR(600MHz,CDCl 3 )δ7.37–7.29(m,1H),7.24–7.18(m,2H),7.18–7.13(m,1H),4.95(d,J＝8.0Hz,1H),4.42(m,,1H),3.57(dd,J＝11.6,3.6Hz,1H),4.44–4.39(m,1H),3.39(dd,J＝11.4,7.2Hz,1H),3.06(dd,J＝16.6,2.4Hz,1H),2.98(dd,J＝16.6,8.4Hz,1H),1.95(s,1H),1.28(s,9H). 13 C NMR(101MHz,CDCl 3 )δ143.0,142.2,128.1,127.2,125.2,124.0,82.0,77.4,70.1,62.4,59.7,49.2,31.9,26.9.HRMS(ESI):m/z calcd.for[C 15 H 21 NNaO 2 ,M+Na] + :270.1465；found:270.1457.
example 3 Condition optimization experiment
Figure BDA0003835151820000061
Figure BDA0003835151820000062
Figure BDA0003835151820000071
a Reaction conditions:4(0.1mmol),2(0.15mmol),[Cp*RhCl 2 ] 2 (4mol％),AgSbF 6 (16mol％),additive(0.05mmol),solvent(1.0mL),12h,underAr, b Isolated yields. c NaOAc(0.1mmol).
Example 4
Figure BDA0003835151820000072
Under the condition of argon, a 25mL pressure-resistant pipe is filled with the mixtureTo this mixture were added compounds 4a (0.1mmol, 18mg) and [ Cp ] in this order * RhCl 2 ] 2 (0.004mmol,5.5mg)、AgSbF 6 (0.016mmol, 6.6mg) and 4A molecular sieve (60 mg), the reaction tube was sealed, compound 2a (0.15mmol, 18mg) and trifluoroethanol (1 mL) were added to the mixture under argon, and the reaction tube was placed in a metal bath at 80 ℃ for reaction for 12 hours. And (4) completely spin-drying the solvent after the reaction. Isolation by silica gel column chromatography with DCM: methanol =20 gave product 4aa, a white solid (18.5mg, 76%, m.p.124-126 ℃); 1 H NMR(400MHz,CDCl 3 )δ7.26–7.15(m,4H),5.31(s,1H),4.12(d,J＝8.4Hz,1H),3.92(d,J＝12.4Hz,1H),3.83(dd,J＝12.4,8.8Hz,1H),3.74–3.69(m,1H),3.55–3.48(m,1H),3.15(dd,J＝16.0,8.8Hz,1H),3.10–3.01(m,2H),2.91(dd,J＝16.4,4.0Hz,1H),2.88–2.78(m,1H),2.69(ddd,J＝16.0,8.4,2.0Hz,1H). 13 C NMR(151MHz,CDCl 3 )δ165.1,142.3,139.9,129.1,127.4,125.6,124.8,74.9,64.4,62.6,52.7,48.1,36.3,36.2.HRMS(ESI):m/z calcd.For[C 14 H 16 N 2 O 2 ,M+H] + 267.1104,found:267.1100.
example 5 Condition optimization experiment
Figure BDA0003835151820000081
Figure BDA0003835151820000082
a Reaction conditions:1a(0.1mmol),2c(0.1mmol),[Cp*RhCl 2 ] 2 (4mol％),AgSbF 6 (16mol％),Ag 2 CO 3 (0.05mmol),solvent(1.0mL),80℃,12h,underAr. b Isolated yields. c Ag 2 CO 3 (0.05mmol),NaOAc(0.05mmol), d AgOAc(0.05mmol),KHCO 3 (0.05mmol).
Example 6
Figure BDA0003835151820000083
Under argon atmosphere, compound 1a (0.1mmol, 18mg), compound 2c (0.1mmol, 33mg) and [ Cp ] were sequentially added to a 25mL pressure-resistant tube * RhCl 2 ] 2 (0.004mmol,5.5mg)、AgSbF 6 (0.016mmol,6.6mg)、Ag 2 CO 3 The reaction tubes (14mg, 0.05mmol) and NaOAc (5mg, 0.05mmol) were sealed, chlorobenzene (1 mL) was added to the mixture under argon, and the reaction tubes were placed in a metal bath at 80 ℃ for 24 hours. And (5) completely spin-drying the solvent after the reaction. Isolation by PE: EA =6: silica gel column chromatography gave the product 3ac as a yellow liquid (28.2mg, 61%); 1 H NMR(400MHz,CDCl 3 )δ8.19(s,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝8.8Hz,2H),7.32–7.28(m,1H),7.26–7.20(m,3H),7.10–7.06(m,1H),7.04–6.99(m,2H),6.96(d,J＝8.0Hz,2H),4.75(d,J＝8.4Hz,1H),3.94(d,J＝10.0Hz,1H),3.04(dd,J＝17.2,8.0Hz,1H),2.89(dd,J＝16.8,7.6Hz,1H),2.43–2.37(m,1H),2.24(s,3H),1.27(s,9H). 13 CNMR(101MHz,CDCl 3 )δ143.4,140.4,137.1,137.0,129.4,129.3,128.0,127.7,127.6,127.3,126.9,126.4,125.9,125.3,124.3,121.7,81.7,69.0,58.6,49.2,32.3,26.4,21.5.HRMS(ESI):m/z calcd.For[C 27 H 31 N 2 O 2 S,M+H] + 463.2050,found:463.2050.
example 7
Figure BDA0003835151820000091
Under argon atmosphere, compound 1a (0.1mmol, 18mg) and [ Cp ] were sequentially added to a 25mL pressure-resistant tube * RhCl 2 ] 2 (0.004mmol,5.5mg)、AgSbF 6 (0.016mmol,6.6mg)、Ag 2 CO 3 (0.05mmol, 14mg), the reaction tube was sealed, compound 2b (0.15mmol, 19mg) and dichloroethane (1 mL) were added to the mixture under the protection of argon, and the reaction tube was placed in a metal bath at 60 ℃ for 20 hours. And after the reaction is completed, spin-drying the solvent. The product 3ab, a yellow oil (8.0 mg, 31%) was isolated by silica gel column chromatography with PE: EA = 2; 1 H NMR(400MHz,CDCl 3 )δ7.23(dt,J＝8.0,4.0Hz,1H),7.15–7.07(m,3H),4.80(d,J＝8.0Hz,1H),4.39(ddd,J＝10.0,7.2,3.2Hz,1H),3.66(ddd,J＝16.4,9.2,4.8Hz,2H),3.40(ddd,J＝15.6,7.6,4.0Hz,1H),3.03(dd,J＝16.2,4.4Hz,1H),2.88(dd,J＝16.4,8.4Hz,1H),1.69–1.62(m,1H),1.56–1.46(m,1H),1.19(s,9H). 13 C NMR(151MHz,CDCl 3 )δ143.4,142.5,127.9,127.0,125.3,124.2,80.9,69.4,61.6,59.6,51.7,33.4,32.0,27.0.HRMS(ESI):m/z calcd.For[C 16 H 23 NNaO 2 ,M+Na] + 284.1621,found:284.1611.
example 8
Figure BDA0003835151820000101
Under argon atmosphere, compound 1a (0.1mmol, 18mg) and [ Cp ] were sequentially added to a 25mL pressure-resistant tube * RhCl 2 ] 2 (0.004mmol,5.5mg)、AgSbF 6 (0.016mmol,6.6mg)、Ag 2 CO 3 (0.05mmol, 14mg), the reaction tube was sealed, compound 2d (0.3mmol, 35mg) and chlorobenzene (1 mL) were added to the mixture under argon, and the reaction tube was placed in a 50 ℃ metal bath for 12 hours. And (5) completely spin-drying the solvent after the reaction. The product, 3ad, was isolated by silica gel column chromatography over PE: EA =4 to give a yellow oily liquid (15.0 mg, 69%); 1 H NMR(400MHz,CDCl 3 )δ7.32–7.23(m,1H),7.19–7.07(m,3H),4.71(d,J＝8.0Hz,1H),4.20(t,J＝7.6Hz,1H),3.32(t,J＝8.0Hz,1H),3.28–3.17(m,1H),3.05(dd,J＝16.4,7.2Hz,1H),2.76(d,J＝16.4Hz,1H),1.18(s,9H). 13 C NMR(101MHz,CDCl 3 )δ143.8,140.9,127.9,127.4,125.8,125.0,73.7,68.9,58.9,47.2,34.6,26.7.HRMS(ESI):m/z calcd.For[C 14 H 20 NO,M+H] + 281.1539,found:281.1539
example 9
According to the reaction conditions of example 2, different compounds 1 and 2a were used, and the reaction results were as follows:
Figure BDA0003835151820000111
example 10
Compound 1 having a natural drug backbone was reacted with compound 2a according to the reaction conditions of example 2, and the reaction results were as follows:
Figure BDA0003835151820000121
EXAMPLE 11 Synthesis of Compound 5a
Figure BDA0003835151820000122
Under the condition of argon, sequentially adding a compound 3aa (0.2mmol, 50mg), triphenylphosphine (0.6 mmol, 157mg) and imidazole (0.6 mmol, 40mg) into a 25mL pressure-resistant tube, adding 10mL toluene under the protection of argon, sealing the reaction tube, placing the reaction tube in a metal bath at 110 ℃ for reacting for 6 hours, and after the reaction is completed, spin-drying the solvent. Compound 5a was isolated by silica gel column chromatography (PE: EA = 10) as a white solid, melting point: 79 to 83 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.25–7.18(m,1H),7.18–7.03(m,3H),4.85(d,J＝7.6Hz,1H),4.58(dd,J＝14.0,7.2Hz,1H),3.49(ddd,J＝15.6,7.6,4.4Hz,1H),3.10(dd,J＝16.8,4.4Hz,1H),3.05(dd,J＝10.0,6.0Hz,1H),2.95(dd,J＝16.8,8.4Hz,1H),2.85(dd,J＝10.0,8.0Hz,1H),1.19(s,9H). 13 C NMR(101MHz,CDCl 3 )δ144.0,142.6,128.7,127.8,125.9,124.8,83.1,70.5,60.5,52.0,32.1,27.5,3.0.HRMS(ESI):m/z calcd.for[C 15 H 20 NINaO,M+Na] + :358.0662；found:358.0670.
EXAMPLE 12 Synthesis of Compound 6a
Figure BDA0003835151820000131
Under the condition of argon, 3aa (0.1mmol, 25mg) and triphenylphosphine (0.3mmol, 80mg) are sequentially added into a 25mL pressure-resistant tube, 2mL carbon tetrachloride is added under the protection of argon, the reaction tube is sealed, the reaction tube is placed in a metal bath at 90 ℃ for reaction overnight, and after the reaction is completed, the reaction tube is placed in a metal bath for reactionAnd spin-drying the solvent. Compound 6a was isolated by silica gel column chromatography (PE: EA = 8) as a yellow solid, melting point: 53-57 ℃. 1 H NMR(600MHz,)δ7.27–7.22(m,1H),7.16–7.13(m,2H),7.11(dd,J＝8.4,4.8Hz,1H),4.86(d,J＝7.7Hz,1H),4.48–4.44(m,1H),3.52–4.47(m,3.0Hz,1H),3.36(dd,J＝11.4,5.4Hz,1H),3.19(dd,J＝10.8,7.8Hz,1H),3.14(dd,J＝16.8,3.0Hz,1H).,2.97(dd,J＝16.8,8.4Hz,1H),1.19(s,9H). 13 C NMR(101MHz,CDCl 3 )δ143.3,141.8,128.1,127.3,125.4,124.1,80.4,69.5,59.5,51.2,50.4,31.6,26.9.HRMS(ESI):m/z calcd.for[C 15 H 21 ClNO,M+H] + :266.1306；found:266.1311.
EXAMPLE 13 Synthesis of Compound 7a
Figure BDA0003835151820000141
Under argon, compound 3aa (0.2mmol, 50mg) and 2mL of diethyl ether were added sequentially to a 25mL pressure resistant tube, m-chloroperoxybenzoic acid (0.8mmol, 138mg) was slowly added under argon protection to the tube in an ice-water bath, the tube was sealed, the tube was placed in an ice-water bath for reaction for 2h, and 2mL of 10% sodium bicarbonate and 2mL of 10% sodium thiosulfate solution were added thereto and vigorously stirred for 20 minutes. The mixture was extracted with DCM (5 mL) and the organic phase was washed with saturated sodium carbonate solution and then brine, na 2 SO 4 Dry, filter and concentrate the crude product in vacuo directly to the reaction.
The crude product was dissolved in THF (2 mL) in a 25mL round bottom flask and 2N hydrochloric acid solution (exothermic reaction) was added slowly dropwise in an ice-water bath. The solution was stirred in an ice bath for 30 minutes, then neutralized with saturated sodium carbonate solution and extracted with DCM. The organic phase was washed with water and brine, na 2 SO 4 Dried, filtered and concentrated in vacuo, and isolated by silica gel column chromatography (DCM: methanol = 20) to give compound 7a as a white solid (22mg, 54%). Melting point: 102-104 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.67(d,J＝7.7Hz,1H),7.59–7.48(m,1H),7.41(d,J＝7.6Hz,1H),7.29(t,J＝7.6Hz,1H),4.24(dt,J＝7.2,4.0Hz,1H),3.72(dd,J＝11.2,3.6Hz,1H),3.65(dd,J＝11.2,7.2Hz,1H)3.24–3.06(m,2H),2.81–2.73(m,1H),2.35(s,1H),1.65(s,1H). 13 C NMR(101MHz,CDCl 3 )δ207.5,154.6,136.7,135.1,127.4,126.6,123.9,71.6,65.3,50.2,27.8.HRMS(ESI):m/z calcd.for[C 15 H 23 NNaO 2 ,M+Na] + :215.0679；found:215.0679.
Example 14
Synthesis of Compound 10
Figure BDA0003835151820000151
To a 25mL round bottom flask, under argon, were added compound 3aa (0.3mmol, 75mg), tsCl (0.45mmol, 1.5eq), DMAP (0.06mmol, 0.2equiv), and DCM (6 mL) in that order. Et was added to the flask in an ice-water bath 3 N (0.9mmol, 3.0eq). The reaction was stirred at room temperature overnight. After complete consumption of the starting material, it was concentrated in vacuo and isolated by column chromatography on silica gel (PE: EA = 6) to give compound 9a as a yellow solid (112mg, 92%) with a melting point of 78-81 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.65(d,J＝8.3Hz,2H),7.23(d,J＝8.0Hz,2H),7.20–7.15(m,1H),7.13–7.05(m,2H),7.01–6.89(m,1H),4.78(d,J＝7.6Hz,1H),4.42(dt,J＝7.8,6.2Hz,1H),3.77(d,J＝6.2Hz,2H),3.43–3.39(m,1H),3.01–2.78(m,2H),2.36(s,3H),1.12(s,9H). 13 C NMR(101MHz,CDCl 3 )δ144.9,143.1,141.5,132.7,129.8,128.1,127.9,127.3,125.3,124.1,78.8,69.6,68.9,59.7,50.1,31.5,26.8,21.6.HRMS(ESI):m/z calcd.for[C 22 H 28 NO 4 S,M+H] + :402.1734；found:402.1727.
The compound 9a (80mg, 0.2mmol, naN) 3 (52mg, 0.8mmol, 4eq) and DMF (2 mL) were added to a 10mL Schlenk tube, and the reaction was stirred overnight at 70 ℃. After complete consumption of the starting material, concentrated in vacuo and isolated by silica gel column chromatography (Hex/EA/DCM = 10): 79 to 83 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.28–7.22(m,1H),7.17–7.12(m,2H),7.10(dd,J＝8.0,4.0Hz,1H),4.82(d,J＝8.0Hz,1H),4.41–4.37(m,1H),3.45–3.41(m,1H),3.18(dd,J＝12.8,7.6Hz,1H),3.04–2.88(m,3H),1.20(s,9H). 13 C NMR(101MHz,CDCl 3 )δ143.3,141.8,128.2,127.3,125.3,124.1,82.1,69.8,59.8,50.5,42.4,31.5,26.9.HRMS(ESI):m/z calcd.for[C 15 H 20 NNaO,M+Na] + :295.1529；found:295.1520.
EXAMPLE 15 Synthesis of Compound 11a
Figure BDA0003835151820000161
Compound 3ta (0.2 mmol), p-TsCl (0.3 mmol, 1.5eq), and DMAP (0.04mmol, 0.2eq) were charged into a 25mL round-bottomed flask, and DCM (5 mL) was added under nitrogen. The reaction flask was placed in an ice-water bath, to which Et was added 3 N (0.6mmol, 3.0eq), and stirred at room temperature overnight. After the raw materials are completely consumed, the raw materials are concentrated in vacuum and separated by silica gel column chromatography to obtain a crude product.
Under argon, add the crude (0.2 mmol), zn (2.0 mmol, 130mg), THF (1.0 mL), acOH (2.0 mL) and H 2 O (1.0 mL), the reaction was stirred at 80 ℃ overnight. The mixture was filtered through a pad of celite, eluting with ethyl acetate, concentrated and purified by silica gel column chromatography (DCM: methanol = 10) to give the product as a white solid.
Under nitrogen, the solid product (0.2 mmol), DMAP (0.1mmol, 0.5eq) were added to a Schlenk tube, followed by DCM (2 mL). The reaction flask was placed in an ice-water bath, to which Et was added 3 N (0.6mmol, 3.0eq). The reaction was stirred at room temperature overnight. After complete consumption of the starting material, concentrated in vacuo and isolated by column chromatography on silica gel (Hex/DCM/methanol = 10. 1 H NMR(400MHz,CDCl 3 )δ7.31–7.21(m,4H),7.21–7.14(m,2H),7.14–7.05(m,3H),4.56(d,J＝8.0Hz,1H),3.95(dd,J＝7.2,4.0Hz,1H),3.89(d,J＝13.2Hz,1H),3.83(d,J＝13.2Hz,1H),3.13(dd,J＝16.8,9.8Hz,1H),2.92(ddd,J＝10.0,7.6,3.6Hz,1H),2.75(dd,J＝16.8,4.2Hz,1H),2.67(dd,J＝9.8,4.4Hz,1H),2.51(dd,J＝10.0,4.0Hz,1H),2.07(s,1H). 13 C NMR(101MHz,CDCl 3 )δ143.3,141.3,139.3,128.8,128.4,127.9,127.0,126.3,125.8,125.0,77.8,70.7,59.1,57.3,50.8,36.3.HRMS(ESI):m/z calcd.for[C 18 H 20 NO,M+H] + :266.1539；found:266.1539.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. The isoxazolidine compound 3 is characterized in that the structure general formula structure is as follows:
Figure FDA0003835151810000011
wherein: r 1 Is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, nitro, amino, C1-C4 alkoxycarbonyl halogen or forms a naphthyl radical with phenyl; r is 2 Is C1-C4 alkyl or benzyl.
2. The method for synthesizing isoxazolidine compounds 3 according to claim 1, which comprises the following steps: under the action of a rhodium catalyst, a silver salt and an additive, an oxime ether compound 1 and ethylene carbonate 2 react to obtain an isoxazole compound 3; the reaction equation is expressed as:
Figure FDA0003835151810000012
wherein: r 1 Is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, nitro, amino, C1-C4 alkoxycarbonyl, halogen or forms a naphthyl group with phenyl; r 2 Is C1-C4 alkyl or benzyl.
3. The method for synthesizing isoxazolidines 3 according to claim 2, wherein: the rhodium catalyst is [ Cp * RhCl 2 ] 2 。
4. The isoxazolidines according to claim 2The synthetic method of the compound 3 is characterized by comprising the following steps: the silver salt is selected from AgSbF 6 。
5. The method for synthesizing isoxazolidines 3 according to claim 2, wherein: the additive is selected from Ag 2 CO 3 、Cu(OAc) 2 、AgOAc、Na 2 CO 3 Or NaOAc.
6. The method for synthesizing isoxazolidines 3 according to claim 2, wherein: the reaction is carried out in an organic solvent, wherein the organic solvent is chlorobenzene, toluene, dichloromethane, dichloroethane or trifluoroethanol; the reaction temperature is 40-80 ℃.
7. The method for synthesizing isoxazolidine compounds according to claim 2, wherein: the molar ratio of the compound 1 to the compound 2 to the rhodium catalyst is 1.
8. The method for synthesizing isoxazolidine compounds according to claim 2, wherein: the reaction is carried out under the protection of inert gas.
9. The method for synthesizing isoxazolidine compounds according to claim 2, wherein: the oxime ether compound 1 is replaced by
Figure FDA0003835151810000021
The product is
Figure FDA0003835151810000022
Replacing the ethylene-2-ethylene carbonate with
Figure FDA0003835151810000023
The product is
Figure FDA0003835151810000024
Replacing the ethylene-2-ethylene carbonate with
Figure FDA0003835151810000025
The product is
Figure FDA0003835151810000026
Replacing the ethylene-2-ethylene carbonate with
Figure FDA0003835151810000027
The product is
Figure FDA0003835151810000028
Wherein: r 1 Is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, nitro, amino, C1-C4 alkoxycarbonyl, halogen or forms a naphthyl radical with phenyl; r 2 Is C1-C4 alkyl or benzyl.
10. A method for synthesizing isoxazole compounds 5,6,7,10 and 11, which is characterized by comprising the following steps: obtaining an isoxazole 3 by a process according to any of claims 2 to 7, followed by contacting the isoxazole 3 at PPh 3 /I 2 Or PPh 3 /CCl 4 In the presence of the catalyst, iodo or chloro isoxazole compound 5 or compound 6 is obtained; compound 7 is obtained in the presence of mCPBA; sequentially protected by p-TsCl and NaN 3 Substitution to give compound 10; p-TsCl protection and Zn/AcOH reductive ring opening in sequence, et 3 N/DMAP is subjected to dehydration cyclization to obtain 11; the reaction equation is expressed as follows:
Figure FDA0003835151810000031
wherein: r is 1 Is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, nitro, amino, C1-C4 alkoxycarbonyl, halogen or forms a naphthyl group with phenyl; r 2 Is C1-C4 alkyl or benzyl.
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