CN116396279A - Gamma-butenolide derivative and preparation method and application thereof - Google Patents
Gamma-butenolide derivative and preparation method and application thereof Download PDFInfo
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- CN116396279A CN116396279A CN202310314290.6A CN202310314290A CN116396279A CN 116396279 A CN116396279 A CN 116396279A CN 202310314290 A CN202310314290 A CN 202310314290A CN 116396279 A CN116396279 A CN 116396279A
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- butenolide
- phenyl
- butenolide derivative
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- GOUILHYTHSOMQJ-UHFFFAOYSA-N gamma-butenolide Natural products CCC1OC(=O)C=C1 GOUILHYTHSOMQJ-UHFFFAOYSA-N 0.000 title claims abstract description 79
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- 239000002994 raw material Substances 0.000 claims abstract description 8
- -1 cyano, benzyloxycarbonyl Chemical group 0.000 claims description 54
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 28
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- 229940125904 compound 1 Drugs 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims description 9
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
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- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a gamma-butenolide derivative, and a preparation method and application thereof. The invention provides a gamma-butenolide derivative, which has a structure shown in a general formula (I), can be prepared by one-step reaction, has the effect of inhibiting the activity of a calcium ion channel, is expected to be applied to treating neuropathic pain, and has potential application value in the field of neuroscience. In addition, the preparation method takes the compounds which are available in the market or are easy to synthesize as raw materials, and the reaction process has the characteristics of simple operation, mild condition, few steps, high reaction speed, low cost, less generated waste, high atom economy and the like, and is suitable for large-scale popularization and application.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a gamma-butenolide derivative, and a preparation method and application thereof.
Background
Gamma-butenolide structures are widely found in natural products and pharmaceutically active molecules, with more than 10% of the natural compound molecules containing gamma-butenolide structures. Meanwhile, a plurality of complex natural products can be synthesized through the gamma-butenolide derivative, and the gamma-butenolide derivative is widely applied to a plurality of fields such as materials, agriculture, biology, medicine and the like. Based on the advantages of the gamma-butenolide structure, the development of a high-efficiency synthesis method of the compound becomes a research hot spot of synthetic chemistry.
The traditional synthesis method of gamma-butenolide derivatives mainly focuses on modification of gamma-butenolide rings, and utilizes ester groups and alkenyl groups of the gamma-butenolide rings as nucleophilic or electrophilic reagents to react, so that a series of gamma-substituted derivatives are obtained, and the method has the defects of difficult synthesis, harsh conditions and limited structure of the obtained derivatives. Another efficient synthesis method of gamma-butenolide derivatives is to construct a gamma-butenolide skeleton through one-step reaction, but the research of the method is relatively less. Therefore, the development of the efficient and rapid synthesis method of the gamma-butenolide derivatives has important significance.
In recent years, hu Wenhao teaches that the subject group has rapidly developed by utilizing the technology of capturing carboxyl ylide by imine through Mannich reaction, but still has certain limitations, mainly represented by low activity of carboxyl ylide, and difficult control of enolization process, so that capturing is difficult; in addition, the ylide metal carbene source formed is mostly an α -carbonyl carbene formed from α -carbonyl diazos, such that the structure of the product is limited. Therefore, on the basis of the research, if a method for rapidly and efficiently synthesizing the gamma-butenolide derivatives by using a non-diazonium carbene source can be developed, the method has important significance for promoting the synthesis of the gamma-butenolide derivatives.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a method for efficiently synthesizing gamma-butenolide derivatives, and the prepared gamma-butenolide derivatives have certain enantioselectivity and can be used as calcium channel blockers for preparing medicaments for treating neuropathic pain; in addition, the preparation method has the advantages of few steps, quick reaction, low-cost and easily-obtained raw materials, simple and safe operation.
In order to achieve the above purpose, the present invention is realized by the following technical scheme:
the first aspect of the invention provides a gamma-butenolide derivative, which has a structure shown in a general formula (I):
in the formula (I), R is 1 Selected from hydrogen atoms and aralkyl groups; r is R 2 Selected from electron withdrawing groups; ar (Ar) 1 Selected from aryl or substituted aryl; ar (Ar) 2 Selected from aryl or substituted aryl; the substituted aryl is selected from alkyl, alkoxy, nitro or halogen substituted aryl.
Preferably, said R 1 Selected from the group consisting of a hydrogen atom, a benzyl group; r is R 2 Selected from cyano, benzyloxycarbonyl; ar (Ar) 1 Selected from aryl, methyl substituted aryl, nitro substituted aryl, methoxy substituted aryl or halo substituted aryl; ar (Ar) 2 Selected from aryl, methyl substituted aryl, methoxy substituted aryl or halo substituted aryl.
More preferably, said R 1 Selected from the group consisting of a hydrogen atom, a benzyl group; r is R 2 Selected from cyano, benzyloxycarbonyl; ar (Ar) 1 Selected from phenyl, fluorophenyl, chlorophenyl, bromophenyl, methyl or methoxy substituted phenyl; ar (Ar) 2 Selected from phenyl, chlorophenyl, bromophenyl, methyl-substituted phenyl, methoxy or trifluoromethyl-substituted aryl.
More preferably, the R 1 Selected from the group consisting of a hydrogen atom, a benzyl group; r is R 2 Selected from cyano, benzyloxycarbonyl; ar (Ar) 1 Selected from phenyl, 3-bromophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 3,4, 5-triA methoxyphenyl group; ar (Ar) 2 Selected from phenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-nitrophenyl, 6-chlorophenyl, 6-bromophenyl, 7-chlorophenyl.
More preferably, the gamma-butenolide derivative is selected from at least one of compounds 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n, 3o, 3p, 3q, 3 r:
the second aspect of the invention also provides a preparation method of the gamma-butenolide derivative according to the first aspect, which specifically comprises the following steps: the preparation method of the gamma-butenolide derivative comprises the following steps: according to the following chemical reaction formula, compound 1 and compound 2 are taken as raw materials, cuBr is taken as a catalyst, compound 1, compound 2 and CuBr are firstly mixed and dissolved in an organic solvent to prepare a solution, and then the solution is heated to 80 ℃ to react for 1-5 min, so that a target product shown in a general formula (I) can be prepared;
r in the formula 1 、R 2 、Ar 1 、Ar 2 The general formula (I) is the same as that of the formula (I).
The gamma-butenolide derivative can be prepared by one-step reaction, and the reaction takes a commercially available or easily synthesized compound as a raw material, and has the characteristics of simple operation, mild condition, few steps, high reaction speed, low cost, less generated waste, high atom economy, high yield and the like, and is easy to popularize and apply.
Preferably, the reaction mole ratio of the compound 1 to the compound 2 to the CuBr is 1.2-1.5:1-1.2:0.08-0.1. In the reaction process, when the dosage of the compound 1 and the compound 2 is too large and exceeds the range, side reactions are increased, byproducts are increased, the atom economy is not met, and the yield of a final target product is influenced; when the ratio of the amount of the reaction raw materials is within the above range, the amount of by-products is minimized, and the yield of the final target product is higher, which accords with the atomic economy.
More preferably, the molar ratio of compound 1, compound 2 to CuBr is 1.2:1.0:0.1.
Preferably, the organic solvent is used in an amount of 10 mL-15 mL/mmol based on the amount of compound 2. More preferably, the amount of organic solvent is 10mL/mmol based on the amount of compound 2.
Preferably, the reaction temperature is 78-82 ℃ and the reaction time is 1-5 min. More preferably, the reaction temperature is 80℃and the reaction time is observed by a change in the color of the solution (from red to pale yellow), usually 1 to 5 minutes.
Preferably, the organic solvent includes, but is not limited to, ethyl acetate.
The third aspect of the invention also provides the application of the gamma-butenolide derivative in preparing a calcium channel blocker.
The fourth aspect of the invention also provides the application of the gamma-butenolide derivative in preparing a medicament for treating neuropathic pain.
The gamma-butenolide derivative provided by the invention has the effect of inhibiting the activity of a calcium ion channel, can be used as a calcium ion channel blocker for preparing a medicament for treating neuropathic pain, and has potential application value in the field of neuroscience.
Preferably, in the aspect of preparing the calcium channel blocker or the neuropathic pain medicine, the gamma-butenolide derivative is selected from at least one of compounds 3a, 3c, 3d, 3f, 3g, 3h, 3i, 3n, 3o, 3q and 3 r:
in a fifth aspect, the present invention also provides a calcium channel blocker or a medicament for treating neuropathic pain, wherein the calcium channel blocker or the medicament comprises the gamma-butenolide derivative according to the first aspect as a main active ingredient.
Preferably, the calcium channel blocker or the medicament further comprises a pharmaceutically acceptable carrier and/or excipient, and is prepared into clinically acceptable dosage forms. The dosage forms refer to injection, tablet, capsule and the like which are commonly used in clinic. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if some drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
More preferably, the excipient refers to diluents, binders, lubricants, disintegrants, co-solvents, stabilizers and other pharmaceutical substrates useful in the pharmaceutical arts. The carrier is a functional pharmaceutical adjuvant acceptable in the pharmaceutical field and comprises a surfactant, a suspending agent, an emulsifying agent and a plurality of novel pharmaceutical polymer materials, such as cyclodextrin, chitosan, polylactic acid, polyglycolic acid-polylactic acid copolymer, hyaluronic acid and the like.
Compared with the prior art, the invention has the beneficial effects that:
the invention discloses a preparation method of gamma-butenolide derivatives, which can be prepared by one-step reaction, and the prepared gamma-butenolide derivatives have the effect of inhibiting the activity of calcium ion channels, are expected to be applied to the treatment of neuropathic pain, and have potential application values in the field of neuroscience. Meanwhile, the preparation method takes the compounds which are available in the market or are easy to synthesize as raw materials, and the reaction process has the characteristics of simple operation, mild condition, few steps, high reaction speed, low cost, less generated waste, high atom economy and the like, and is suitable for large-scale popularization and application.
Drawings
FIG. 1 is a bar graph of gamma-butenolide derivatives inhibiting calcium channel activity.
Detailed Description
The following describes the invention in more detail. The description of these embodiments is provided to assist understanding of the present invention, but is not intended to limit the present invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
The experimental methods in the following examples, unless otherwise specified, are conventional, and the experimental materials used in the following examples, unless otherwise specified, are commercially available.
EXAMPLE 1 gamma-butenolide derivatives and process for preparing the same
The gamma-butenolide derivative has a structure shown in a general formula (I):
the synthesis reaction formula of the gamma-butenolide derivative is as follows:
the preparation method of the gamma-butenolide derivative comprises the following steps: according to the chemical reaction formula, compound 1 and compound 2 are taken as raw materials, cuBr is taken as a catalyst (the reaction mole ratio of compound 1 to compound 2 to CuBr is 1.2:1.0:0.1; the dosage of the organic solvent is 10mL/mmol based on the dosage of compound 2), compound 1, compound 2 and CuBr are firstly mixed in the organic solvent (ethyl acetate) to prepare a solution, and then the solution is heated to 80 ℃ to react for 1-5 min, so that the target product shown in the general formula (I) can be prepared.
Formula (I) and reaction formulaIn the formula, R is 1 Selected from hydrogen atoms and aralkyl groups; r is R 2 Selected from electron withdrawing groups; ar (Ar) 1 Selected from aryl or substituted aryl; ar (Ar) 2 Selected from aryl or substituted aryl; the substituted aryl is selected from alkyl, alkoxy, nitro or halogen substituted aryl.
Preferably, said R 1 Selected from the group consisting of a hydrogen atom, a benzyl group; r is R 2 Selected from cyano, benzyloxycarbonyl; ar (Ar) 1 Selected from aryl, methyl substituted aryl, nitro substituted aryl, methoxy substituted aryl or halo substituted aryl; ar (Ar) 2 Selected from aryl, methyl substituted aryl, methoxy substituted aryl or halo substituted aryl.
More preferably, said R 1 Selected from the group consisting of a hydrogen atom, a benzyl group; r is R 2 Selected from cyano, benzyloxycarbonyl; ar (Ar) 1 Selected from phenyl, fluorophenyl, chlorophenyl, bromophenyl, methyl or methoxy substituted phenyl; ar (Ar) 2 Selected from phenyl, chlorophenyl, bromophenyl, methyl-substituted phenyl, methoxy or trifluoromethyl-substituted aryl.
More preferably, said R 1 Selected from the group consisting of a hydrogen atom, a benzyl group; r is R 2 Selected from cyano, benzyloxycarbonyl; ar (Ar) 1 Selected from phenyl, 3-bromophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 3,4, 5-trimethoxyphenyl; ar (Ar) 2 Selected from phenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-nitrophenyl, 6-chlorophenyl, 6-bromophenyl, 7-chlorophenyl.
In order to further illustrate the preparation method of the gamma-butenolide derivatives, the following specific description will be given by taking the compounds 3a-3r as examples:
(1) Preparation of Compound 3a
the preparation process comprises the following steps:
(1) 2- (2-oxetan-3-ylidene) malononitrile (0.1 mmol), 2-cyclopropene-1-carboxylic acid (0.12 mmol), cuprous bromide (0.01 mmol) were dissolved in 1.0mL ethyl acetate;
(2) Heating the obtained solution in an oil bath pot to 80 ℃ for reaction for 3min, and when obvious color change (from red to light yellow) of the solution is observed, indicating that the reaction is completed;
(3) After the reaction was completed, the obtained crude product was purified by column chromatography (petroleum ether: ethyl acetate=100:2 as eluent) to obtain a pure product, the isolated yield of the product was 87%, and the dr value of the compound was 67:33. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,DMSO)δ11.40(s,1H),7.90(s,1H),7.65(s,2H),7.46(s,1H),7.35(dd,J＝36.2,14.1Hz,4H),7.14–6.97(m,2H),6.23(s,1H),5.75(s,1H)； 1 HNMR minor (500MHz,DMSO)δ11.33(s,1H),8.03(s,1H),7.86(d,J＝5.4Hz,2H),7.46(s,1H),7.35(dd,J＝36.2,14.1Hz,4H),7.14–6.96(m,2H),6.01(s,1H),5.82(s,1H)； 13 CNMR mix (126MHz,DMSO)δ172.65,172.18,170.53,169.99,145.07,144.50,143.19,142.66,133.15,133.06,131.78,131.59,130.27,130.11,129.22,129.05,128.97,127.45,127.28,125.41,124.96,123.17,123.01,122.41,111.94,111.61,111.50,80.00,79.51,54.17,53.75,40.46,40.29,40.12,39.96,39.79,39.62,39.46,27.80,27.16；HRMS(ESI)calcd for[C 21 H 13 N 3 O 3 Na] + ＝[M+Na] + ＝378.0849,found 378.0844。
(2) Preparation of Compound 3b
Compound 3b is R 1 Is a hydrogen atom, R 2 Is cyano, ar 1 Is phenyl, ar 2 The structure of the compound 3b is shown as a formula (3 b) as a gamma-butenolide derivative of 5-fluorophenyl:
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substituting 2- (2-oxetan-3-ylidene) malononitrile of step (1) with 2- (5-fluoro-2-oxetan-3-ylidene) malononitrile, i.e. Ar of Compound 3a 2 The phenyl group was converted to the 5-fluorophenyl group of compound 3b, which gave compound 3b in 88% isolated yield having a dr value of 67:33. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,DMSO)δ11.47(s,1H),7.97(d,J＝1.4Hz,1H),7.74–7.66(m,2H),7.51–7.37(m,3H),7.34–7.16(m,2H),7.10–7.00(m,1H),6.31(s,1H),5.79(s,1H)； 1 H NMR minor (500MHz,DMSO)δ11.39(s,1H),8.06(s,1H),7.88(d,J＝6.2Hz,2H),7.51–7.37(m,3H),7.34–7.16(m,2H),7.09–7.00(m,1H),6.06(s,1H),5.88(s,1H)； 13 C NMR mix (126MHz,DMSO)δ172.55,172.04,170.46,169.94,159.17,159.09,157.27,157.19,144.93,144.44,139.57,139.10,133.18,130.32,130.21,129.23,129.11,128.88,127.45,127.29,123.92,123.85,123.77,118.51,118.35,118.16,113.50,113.30,112.94,112.76,112.74,112.70,111.72,111.62,111.32,111.14,79.72,79.28,54.56,54.05,27.46,27.02；HRMS(ESI)calcd for[C 21 H 12 N 3 O 3 FNa] + ＝[M+Na] + ＝396.0755,found 396.0754。
(3) Preparation of Compound 3c
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substituting 2- (2-oxetan-3-ylidene) malononitrile of step (1) with 2- (5-chloro-2-oxetan-3-ylidene) malononitrile, i.e. Ar of Compound 3a 2 Conversion of phenyl into 5-chlorophenyl of Compound 3c, the product can be preparedThe isolated yield was 89% and the dr value of this compound was 67:33. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,DMSO)δ11.55(s,1H),7.98(s,1H),7.69(d,J＝3.3Hz,2H),7.49(dt,J＝12.5,7.5Hz,2H),7.43–7.36(m,3H),7.02(d,J＝8.3Hz,1H),6.31(s,1H),5.79(s,1H)； 1 H NMR minor (500MHz,DMSO)δ11.48(s,1H),8.05(s,1H),7.86(dd,J＝7.6,1.7Hz,2H),7.49(dt,J＝12.5,7.5Hz,2H),7.43–7.36(m,3H),7.06(d,J＝8.0Hz,1H),6.04(s,1H),5.89(s,1H)； 13 C NMR mix (101MHz,DMSO)δ172.32,171.82,170.41,169.95,144.92,144.49,142.20,141.72,133.22,131.77,131.57,130.31,130.22,129.21,129.13,128.90,127.47,127.29,126.98,125.71,125.17,124.33,113.05,111.71,111.30,111.15,79.67,79.25,54.40,53.86,27.46,26.99；HRMS(ESI)calcd for[C 21 H 12 N 3 O 3 ClNa] + ＝[M+Na] + ＝412.0459,found412.0459。
(4) Preparation of Compound 3d
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substituting 2- (2-oxetan-3-ylidene) malononitrile of step (1) with 2- (5-bromo-2-oxetan-3-ylidene) malononitrile, i.e. Ar of Compound 3a 2 The phenyl group was converted to the 5-bromophenyl group of compound 3d, which was prepared in 85% isolated yield as compound 3d having a dr value of 68:32. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,DMSO)δ11.50(s,1H),7.90(s,1H),7.62(s,2H),7.44(s,2H),7.39(s,1H),7.31(s,2H),6.89(d,J＝7.1Hz,1H),6.25(s,1H),5.71(s,1H)； 1 HNMR minor (500MHz,DMSO)δ11.43(s,1H),8.00(s,1H),7.79(d,J＝4.5Hz,2H),7.55(s,2H),7.39(s,1H),7.31(s,2H),6.93(s,1H),6.01(s,1H),5.81(s,1H)； 13 C NMR mix (126MHz,DMSO)δ172.28,171.74,170.42,169.98,144.93,144.52,142.59,142.09,134.51,134.36,133.24,130.30,130.21,129.20,129.13,128.91,128.48,127.92,127.48,127.28,124.68,114.55,113.47,111.72,111.31,79.68,79.32,54.36,53.81,27.47,26.97；HRMS(ESI)calcd for[C 21 H 12 N 3 O 3 BrNa] + ＝[M+Na] + ＝455.9954,found455.9952。
(5) Preparation of Compound 3e
Compound 3e is R 1 Is a hydrogen atom, R 2 Is cyano, ar 1 Is phenyl, ar 2 The structure of the compound 3e is shown as a formula (3 e) as a gamma-butenolide derivative of 5-methylphenyl:
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substituting 2- (2-oxetan-3-ylidene) malononitrile of step (1) with 2- (5-methyl-2-oxetan-3-ylidene) malononitrile, i.e. Ar of Compound 3a 2 The phenyl group was converted to the 5-methylphenyl group of compound 3e, which was prepared to give compound 3e in 88% isolated yield with a dr value of 70:30. Mass spectrum information of the compound is as follows:
1 H NMR major (400MHz,DMSO)δ11.19(s,1H),7.93(s,1H),7.86–7.82(m,2H),7.49–7.44(m,3H),7.24(d,J＝6.8Hz,2H),6.92(d,J＝8.2Hz,1H),5.92(s,1H),5.80(s,1H),2.25(s,3H)； 1 H NMR minor (400MHz,DMSO)δ11.26(s,1H),7.89(s,1H),7.69–7.64(m,2H),7.39–7.35(m,3H),7.13(d,J＝5.9Hz,2H),6.87(d,J＝8.4Hz,1H),6.16(s,1H),5.72(s,1H),2.20(s,3H)； 13 C NMR mix (126MHz,DMSO)δ172.50,172.12,170.56,170.08,145.15,144.58,140.67,140.51,140.22,140.06,133.20,133.03,132.12,132.05,131.99,131.79,130.23,130.10,129.19,129.08,127.46,127.27,125.92,125.47,122.58,111.97,111.61,111.42,111.22,79.98,79.51,54.28,53.79,27.79,27.27,21.20,21.15.HRMS(ESI)calcd for[C 22 H 15 N 3 O 3 Na] + ＝[M+Na] + ＝392.1006,found 392.1006。
(6) Preparation of Compound 3f
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substituting 2- (2-oxetan-3-ylidene) malononitrile of step (1) with 2- (5-methoxy-2-oxetan-3-ylidene) malononitrile, i.e. Ar of Compound 3a 2 The phenyl group was converted to the 5-methoxyphenyl group of compound 3f, which was prepared in 86% isolated yield as a compound 3f having a dr value of 67:33. Mass spectrum information of the compound is as follows:
1 H NMR max (500MHz,DMSO)δ11.23(s,1H),7.90(d,J＝1.2Hz,1H),7.68(d,J＝3.5Hz,2H),7.41–7.35(m,3H),7.08–6.87(m,3H),6.27(s,1H),5.75(s,1H),3.65(s,3H)； 1 HNMR min (500MHz,DMSO)δ11.15(s,1H),8.04(s,1H),7.88(d,J＝6.5Hz,2H),7.47(q,J＝5.7Hz,3H),7.08–6.87(m,3H),6.01(s,1H),5.84(s,1H),3.65(s,3H)； 13 C NMR mix (126MHz,DMSO)δ172.49,171.95,170.63,170.01,155.53,155.35,145.09,144.56,136.27,135.70,133.14,133.06,130.28,130.14,129.22,129.09,128.98,127.42,127.27,123.53,116.18,112.49,112.10,112.01,111.93,111.87,111.55,79.91,79.48,55.97,55.89,54.50,54.04,27.70,27.18；HRMS(ESI)calcd for[C 22 H 15 N 3 O 4 Na] + ＝[M+Na] + ＝408.0955,found 408.0956。
(7) Preparation of Compound 3g
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substituting 2- (2-oxetan-3-ylidene) malononitrile of step (1) with 2- (5-nitro-2-oxetan-3-ylidene) malononitrile, i.e. Ar of Compound 3a 2 Conversion of phenyl to 3g of 5-nitrophenyl gives 3g of compound with a yield of 84% isolated, and a dr value of 67:33. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,DMSO)δ12.16(s,1H),8.33(s,2H),8.08(s,1H),7.70(s,2H),7.48(d,J＝6.7Hz,1H),7.39(s,1H),7.25(d,J＝8.9Hz,1H),6.53(s,1H),5.90(s,1H)； 1 HNMR minor (500MHz,DMSO)δ12.16(s,1H),8.51–8.38(m,2H),8.16(s,1H),7.87(d,J＝6.5Hz,2H),7.48(d,J＝6.7Hz,1H),7.39(s,2H),7.25(d,J＝8.9Hz,1H),6.27(s,1H),6.00(s,1H)； 13 C NMR mix (126MHz,DMSO)δ173.14,172.54,170.24,169.90,149.53,149.05,144.70,142.91,133.35,130.33,130.24,129.18,129.11,128.82,128.68,127.50,127.30,123.34,121.70,120.96,111.92,111.52,111.12,79.57,79.16,54.08,53.65,27.28,26.71；HRMS(ESI)calcd for[C 21 H 12 N 4 O 5 Na] + ＝[M+Na] + ＝378.0849,found 378.0844。
(8) Preparation of Compound 3h
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substituting 2- (2-oxetan-3-ylidene) malononitrile of step (1) with 2- (6-chloro-2-oxetan-3-ylidene) malononitrile, i.e. Ar of Compound 3a 2 The phenyl group was converted to the 6-chlorophenyl group of compound 3h, which was prepared in 92% isolated yield with a dr value of 67:33. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,DMSO)δ11.62(s,1H),7.97(d,J＝1.7Hz,1H),7.72(dd,J＝6.6,2.9Hz,2H),7.50–7.32(m,4H),7.17(dd,J＝8.1,1.8Hz,1H),7.05(d,J＝1.7Hz,1H),6.30(s,1H),5.79(d,J＝1.5Hz,1H)； 1 H NMR minor (500MHz,DMSO)δ11.54(s,1H),8.08(s,1H),7.89(dd,J＝7.6,1.8Hz,2H),7.50–7.32(m,4H),7.26–7.22(m,1H),7.09(d,J＝1.3Hz,1H),6.06(s,1H),5.86(s,1H)； 13 C NMR mix (126MHz,DMSO)δ172.62,172.16,170.39,169.95,144.90,144.70,144.41,144.23,136.26,136.04,133.21,133.12,130.31,130.21,129.20,129.10,128.90,127.48,127.32,126.93,126.53,123.11,122.98,121.31,121.28,111.77,111.69,111.41,111.21,79.81,79.31,53.90,53.50,27.68,27.08；HRMS(ESI)calcd for[C 21 H 12 N 3 O 3 ClNa] + ＝[M+Na] + ＝412.0459,found 412.0456。
(9) Preparation of Compound 3i
Compound 3i is R 1 Is a hydrogen atom, R 2 Is cyano, ar 1 Is phenyl, ar 2 The structure of the compound 3i is shown as a formula (3 i) which is a gamma-butenolide derivative of 6-bromophenyl:
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substituting 2- (2-oxetan-3-ylidene) malononitrile of step (1) with 2- (6-bromo-2-oxetan-3-ylidene) malononitrile, i.e. Ar of Compound 3a 2 Conversion of phenyl into 6-bromophenyl of Compound 3i, can be preparedThe product isolation yield was 88% to compound 3i, which had a dr value of 67:33. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,DMSO)δ11.64(s,1H),7.96(s,1H),7.71(s,2H),7.46(s,1H),7.44–7.26(m,4H),7.18(m,1H),6.29(s,1H),5.78(s,1H)； 1 H NMR minor (500MHz,DMSO)δ11.55(s,1H),8.16(s,1H),7.89(d,J＝5.9Hz,2H),7.46(s,1H),7.44–7.25(m,4H),7.22(m,1H),6.26(s,1H),5.84(s,1H)； 13 C NMR(126MHz,DMSO)δ172.56,172.00,170.37,169.96,144.89,144.84,144.55,144.36,133.11,130.29,130.21,129.20,129.10,128.90,127.49,127.33,126.79,125.99,125.80,124.71,124.46,121.77,121.66,114.45,111.77,111.69,111.41,111.21,79.76,79.30,53.96,53.58,27.61,26.97；HRMS(ESI)calcd for[C 21 H 12 N 3 O 3 BrNa] + ＝[M+Na] + ＝455.9954,found 455.9956。
(10) Preparation of Compound 3j
Compound 3j is R 1 Is a hydrogen atom, R 2 Is cyano, ar 1 Is phenyl, ar 2 The structure of the compound 3j is shown as a formula (3 j) as a gamma-butenolide derivative of 7-chlorophenyl:
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substituting 2- (2-oxetan-3-ylidene) malononitrile of step (1) with 2- (7-chloro-2-oxetan-3-ylidene) malononitrile, i.e. Ar of Compound 3a 2 The phenyl group was converted to the 7-chlorophenyl group of compound 3j, which was prepared in 90% isolated yield with a dr value of 67:33. Mass spectrum information of the compound is as follows:
1 H NMR major (400MHz,CDCl 3 )δ8.47(s,1H),7.84–7.77(m,1H),7.65–7.58(m,1H),7.47–7.35(m,3H),7.31(d,J＝7.9Hz,1H),7.25(d,J＝1.7Hz,1H),7.10(t,J＝8.0Hz,1H),5.72(d,J＝1.6Hz,1H),4.70(s,1H)； 1 H NMR minor (400MHz,CDCl 3 )δ8.25(s,1H),7.69(d,J＝7.6Hz,1H),7.65–7.58(m,1H),7.53(d,J＝8.2Hz,1H),7.47–7.35(m,3H),7.28(s,1H),7.19(d,J＝1.8Hz,1H),5.54(d,J＝1.7Hz,1H),4.85(s,1H)； 13 C NMR mix (126MHz,DMSO)δ172.63,172.15,170.40,169.95,144.87,144.40,141.05,140.56,133.25,133.15,131.89,131.71,130.32,130.20,129.21,129.09,128.90,127.50,127.36,124.59,124.43,124.27,124.18,124.10,123.65,115.69,111.72,111.63,111.38,111.20,79.85,79.38,54.76,54.40,27.78,27.19；HRMS(ESI)calcd for[C 21 H 12 N 3 O 3 ClNa] + ＝[M+Na] + ＝412.0459,found 412.0456。
(11) Preparation of Compound 3k
Compound 3k is R 1 Is a hydrogen atom, R 2 Is carbobenzoxy group Ar 1 Is phenyl, ar 2 The gamma-butenolide derivative is phenyl, and the structure of the compound 3k is shown as a formula (3 k):
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substitution of 2- (2-oxetan-3-ylidene) malononitrile in step (1) to benzyl-2-cyano-2- (2-oxetan-3-ylidene) ethyl ester, i.e. R of Compound 3a 2 The cyano group is converted into the benzyloxycarbonyl group of the compound 3k, which is prepared in a yield of 88% isolated from the compound 3k having a dr value of 63:31:6. Mass spectrum information of the compound is as follows:
1 H NMR major (400MHz,CDCl 3 )δ8.68(s,1H),7.61(d,J＝2.0Hz,1H),7.49(dd,J＝7.9,1.7Hz,2H),7.33–7.28(m,5H),7.25(d,J＝1.7Hz,1H),7.23–7.19(m,1H),7.17–7.09(m,2H),6.80(dd,J＝14.2,7.9Hz,2H),5.71(d,J＝1.7Hz,1H),5.18–4.90(m,2H),4.61(s,1H)； 1 H NMR middle (400MHz,CDCl 3 )δ8.37(s,1H),7.63(d,J＝1.5Hz,1H),7.53–7.47(m,1H),7.43(d,J＝1.8Hz,1H),7.33–7.28(m,5H),7.26(s,1H),7.23(s,1H),7.17–7.09(m,2H),6.89(t,J＝7.7Hz,2H),5.70(d,J＝1.8Hz,1H),5.18–4.90(m,2H),4.57(s,1H)； 1 HNMR minor (400MHz,CDCl 3 )δ8.35(s,1H),7.73(d,J＝1.8Hz,1H),7.54–7.42(m,2H),7.33–7.28(m,5H),7.25(dd,J＝5.0,2.5Hz,1H),7.23–7.19(m,1H),7.17–7.09(m,2H),7.07–6.76(m,2H),5.57(d,J＝1.8Hz,1H),5.18–4.90(m,2H),4.79(s,1H)； 13 C NMR mix (101MHz,CDCl 3 )δ173.67,173.33,170.08,170.03,162.69,162.50,141.70,140.91,140.65,135.04,134.79,133.85,133.68,130.67,130.61,129.90,128.89,128.83,128.71,128.68,128.64,128.56,128.51,128.44,128.39,127.18,127.06,124.45,123.91,123.75,123.44,122.57,113.53,112.62,111.00,110.96,80.33,79.98,69.10,55.06,54.30,41.46,41.43；HRMS(ESI)calcd for[C 28 H 20 N 2 O 5 Na] + ＝[M+Na] + ＝487.1264,found487.1262。
(12) Preparation of Compound 3l
Compound 3l is R 1 Is benzyl, R 2 Is cyano, ar 1 Is phenyl, ar 2 The gamma-butenolide derivative is phenyl, and the structure of the compound 3l is shown as a formula (3 l):
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substitution of 2- (2-oxetan-3-ylidene) malononitrile in step (1) to 2- (1-benzyl-2-oxetan-3-ylidene) ethyl ester, i.e. R of Compound 3a 1 The conversion of the hydrogen atom to the benzyl group of compound 3l gives compound 3l with a product isolation yield of 88% and a dr value of 67:33. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,CDCl 3 )δ7.73(dd,J＝20.6,6.7Hz,1H),7.47–7.32(m,8H),7.29(d,J＝7.1Hz,2H),7.11(d,J＝6.8Hz,1H),7.06(t,J＝6.9Hz,1H),6.95–6.86(m,2H),5.68(s,1H),5.07(d,J＝15.2Hz,1H),4.95(d,J＝15.2Hz,1H),4.75(s,1H)； 1 H NMR minor (500MHz,CDCl 3 )δ7.47–7.32(m,9H),7.29(d,J＝7.1Hz,2H),7.01–6.96(m,2H),6.95–6.86(m,2H),5.58(s,1H),5.07(d,J＝15.2Hz,1H),4.95(d,J＝15.2Hz,1H),4.60(d,J＝15.4Hz,1H)； 13 C NMR mix (126MHz,CDCl 3 )δ170.15,169.77,169.49,169.09,143.09,142.59,140.66,139.77,135.78,135.16,134.58,134.34,132.01,131.68,130.40,130.19,129.21,128.95,128.92,128.71,128.49,128.29,128.12,127.99,127.84,127.45,127.40,126.96,124.72,124.50,124.41,121.12,120.57,110.86,110.70,109.64,109.24,79.34,78.82,54.32,53.76,44.62,28.05,27.72；HRMS(ESI)calcd for[C 28 H 19 N 3 O 3 Na] + ＝[M+Na] + ＝468.1319,found468.1319。
(13) Preparation of Compound 3m
Compound 3m is R 1 Is a hydrogen atom, R 2 Is cyano, ar 1 Is 3-bromophenyl, ar 2 The gamma-butenolide derivative is phenyl, and the structure of the compound 3m is shown as a formula (3 m):
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substitution of 2-cyclopropene-1-carboxylic acid in step (1) to 1- (3-bromophenyl) cycloprop 2-ene-1-carboxylic acid, ar of Compound 3a 1 The phenyl group was converted to the 4-bromophenyl group of compound 3m, which was prepared in 95% isolated yield with a dr value of 68:32. Mass spectrum information of the compound is as follows:
1 HNMR major (500MHz,DMSO)δ11.42(s,1H),8.13(s,1H),7.92(s,1H),7.73(d,J＝7.8Hz,1H),7.58(d,J＝7.9Hz,1H),7.44(t,J＝7.9Hz,1H),7.34(dd,J＝14.1,6.9Hz,2H),7.06(t,J＝7.8Hz,1H),7.01(d,J＝7.7Hz,1H),6.24(s,1H),5.79(s,1H)； 1 H NMR minor (500MHz,DMSO)δ11.35(s,1H),8.20(s,1H),8.11(s,1H),7.91(s,1H),7.66(d,J＝7.9Hz,1H),7.44(t,J＝7.9Hz,1H),7.34(dd,J＝14.1,6.9Hz,2H),7.15(d,J＝7.5Hz,1H),7.06(t,J＝7.8Hz,1H),5.99(s,1H),5.86(s,1H)； 13 C NMR mix (126MHz,DMSO)δ172.55,172.06,170.23,169.72,146.82,146.25,143.17,142.67,132.99,132.85,131.82,131.64,131.51,131.38,131.25,131.16,129.95,129.75,126.40,126.20,125.36,124.96,123.22,123.10,122.53,122.40,122.34,111.89,111.78,111.55,111.32,80.16,79.63,54.08,53.68,27.82,27.23；HRMS(ESI)calcd for[C 21 H 12 N 3 O 3 BrNa] + ＝[M+Na] + ＝455.9954,found455.9959。
(14) Preparation of Compound 3n
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substitution of 2-cyclopropene-1-carboxylic acid in step (1) to 1- (4-chlorophenyl) cycloprop 2-ene-1-carboxylic acid, ar of Compound 3a 1 The phenyl group was converted to the 4-chlorophenyl group of compound 3n, which was prepared in 94% isolated yield with a dr value of 67:33. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,DMSO)δ11.40(s,1H),8.01(s,1H),7.91(d,J＝8.5Hz,1H),7.72(d,J＝8.4Hz,1H),7.55(d,J＝8.5Hz,1H),7.48–7.29(m,3H),7.16–6.97(m,2H),6.23(s,1H),5.76(s,1H)； 1 H NMR minor (500MHz,DMSO)δ11.33(s,1H),8.11(s,1H),7.91(d,J＝8.5Hz,1H),7.72(d,J＝8.4Hz,1H),7.55(d,J＝8.5Hz,1H),7.48–7.29(m,3H),7.16–6.97(m,2H),6.00(s,1H),5.83(s,1H)； 13 C NMR mix (126MHz,DMSO)δ172.60,172.11,170.35,169.84,145.80,145.24,143.17,142.66,135.02,134.89,131.96,131.87,131.60,129.32,129.23,129.18,129.02,128.03,127.80,125.41,124.95,123.17,123.03,122.36,111.91,111.52,80.11,79.62,54.11,53.68,27.80,27.18；HRMS(ESI)calcd for[C 21 H 12 N 3 O 3 ClNa] + ＝[M+Na] + ＝412.0459,found412.0456。
(15) Preparation of Compound 3o
Compound 3o is R 1 Is a hydrogen atom, R 2 Is cyano, ar 1 Is 4-bromophenyl, ar 2 The gamma-butenolide derivative is phenyl, and the structure of the compound 3o is shown as a formula (3 o):
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substitution of 2-cyclopropene-1-carboxylic acid in step (1) to 1- (4-bromophenyl) cycloprop 2-ene-1-carboxylic acid, ar of Compound 3a 1 The phenyl group was converted to the 4-bromophenyl group of compound 3o, which was prepared in 86% isolated yield with a dr value of 67:33. Mass spectrum information of the compound is as follows:
1 H NMR major (400MHz,DMSO)δ11.39(s,1H),8.02(d,J＝1.7Hz,1H),7.64(d,J＝8.6Hz,2H),7.59(d,J＝8.6Hz,2H),7.32(dd,J＝15.2,7.6Hz,2H),7.09–6.95(m,2H),6.22(s,1H),5.75(d,J＝1.6Hz,1H)； 1 H NMR minor (400MHz,DMSO)δ11.33(s,1H),8.11(d,J＝1.6Hz,1H),7.84(d,J＝8.5Hz,2H),7.69(d,J＝8.6Hz,2H),7.40(d,J＝7.3Hz,2H),7.09–6.95(m,2H),5.98(s,1H),5.82(d,J＝1.5Hz,1H)； 13 C NMR mix (126MHz,DMSO)δ172.58,172.10,170.31,169.78,145.90,145.33,143.18,142.65,132.27,132.12,131.94,131.81,131.62,129.46,129.25,128.35,128.14,125.38,124.93,123.82,123.66,123.18,123.05,122.35,111.91,111.79,111.58,111.53,80.12,79.61,54.08,53.68,27.78,27.18；HRMS(ESI)calcd for[C 21 H 12 N 3 O 3 BrNa] + ＝[M+Na] + ＝455.9954,found455.9954。
(15) Preparation of Compound 3p
Compound 3p is R 1 Is a hydrogen atom, R 2 Is cyano, ar 1 Is 4-methylphenyl, ar 2 Is phenyl groupThe structure of the gamma-butenolide derivative, compound 3p is shown as formula (3 p):
the preparation process of the compound is different from that of the compound 3a in that: substitution of 2-cyclopropene-1-carboxylic acid in step (1) to 1- (4-methylphenyl) cycloprop 2-ene-1-carboxylic acid, ar of Compound 3a 1 The phenyl group was converted to the 4-methylphenyl group of compound 3p, which was prepared to give compound 3p in a yield of 95% isolated with a dr value of 69:31. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,DMSO)δ11.39(s,1H),7.83(s,1H),7.58(d,J＝8.0Hz,2H),7.40(d,J＝7.2Hz,1H),7.32(t,J＝7.3Hz,2H),7.17(d,J＝7.9Hz,2H),7.04(t,J＝7.4Hz,1H),6.23(s,1H),5.73(s,1H),2.27(s,3H)； 1 H NMR minor (500MHz,DMSO)δ11.32(s,1H),7.98(s,1H),7.77(d,J＝8.0Hz,2H),7.28(d,J＝7.9Hz,2H),7.10(s,1H),7.04(t,J＝7.4Hz,1H),6.99(d,J＝7.8Hz,2H),6.01(s,1H),5.78(s,1H),2.33(s,3H)； 13 C NMR mix (126MHz,DMSO)δ172.71,172.22,170.62,170.09,143.89,143.21,142.67,140.02,139.87,132.99,132.89,131.71,131.53,129.77,129.60,127.32,127.15,126.41,126.18,125.44,124.97,123.14,122.95,122.45,111.96,111.62,111.46,79.95,79.48,54.20,53.77,27.79,27.14,21.39,21.31；HRMS(ESI)calcd for[C 22 H 15 N 3 O 3 Na] + ＝[M+Na] + ＝392.1006,found 392.1008。
(17) Preparation of Compound 3q
Compound 3q is R 1 Is a hydrogen atom, R 2 Is cyano, ar 1 Is 4-trifluoromethyl phenyl, ar 2 The gamma-butenolide derivative is phenyl, and the structure of the compound 3q is shown as a formula (3 q):
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: substituting 2-cyclopropene-1-carboxylic acid in step (1) with 1- (4-trifluoromethylphenyl) cycloprop-2-ene-1-carboxylic acid, i.e., ar of Compound 3a 1 The phenyl group was converted to 4-trifluoromethylphenyl group of compound 3q to give compound 3q in a yield of 95% isolated with a dr value of 67:33. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,DMSO)δ11.43(s,1H),8.27(s,1H),8.09(s,1H),8.01(d,J＝7.8Hz,1H),7.74(t,J＝8.7Hz,1H),7.63(t,J＝7.8Hz,1H),7.45(s,1H),7.34(t,J＝7.6Hz,1H),7.07(t,J＝7.5Hz,1H),7.02(d,J＝7.8Hz,1H),6.26(s,1H),5.82(s,1H)； 1 H NMR minor (500MHz,DMSO)δ11.36(s,1H),8.32(s,1H),8.27(s,1H),8.21(d,J＝7.8Hz,1H),7.83(d,J＝7.7Hz,1H),7.74(t,J＝8.7Hz,1H),7.34(t,J＝7.6Hz,2H),7.14(s,1H),7.07(t,J＝7.5Hz,1H),6.02(s,1H),5.89(s,1H)； 13 C NMR mix (126MHz,DMSO)δ172.56,172.06,170.31,169.82,147.34,146.74,143.17,142.68,131.82,131.80,131.62,131.59,131.42,131.18,130.43,130.30,130.20,130.18,130.06,129.97,129.92,129.81,129.67,129.55,127.66,127.57,126.72,126.62,126.59,125.50,125.40,124.98,123.92,123.89,123.74,123.70,123.33,123.24,123.20,123.08,122.36,111.88,111.54,80.27,79.75,54.08,53.64,27.84,27.26.HRMS(ESI)calcd for[C 22 H 12 N 3 O 3 F 3 Na] + ＝[M+Na] + ＝446.0728,found446.0727。
(18) Preparation of Compound 3r
Compound 3R is R 1 Is a hydrogen atom, R 2 Is cyano, ar 1 Is 3,4, 5-trimethoxyphenyl, ar 2 The gamma-butenolide derivative is phenyl, and the structure of the compound 3r is shown as a formula (3 r):
the preparation process of the compound is the same as that of the compound 3a, and the difference is that: 2-The cyclopropene-1-carboxylic acid is replaced by 1- (3, 4, 5-trimethoxyphenyl) cycloprop-2-ene-1-carboxylic acid, i.e. Ar of compound 3a 1 The phenyl group was converted to 3,4, 5-trimethoxyphenyl group of compound 3r, which was prepared in 86% isolated yield with a dr value of 64:36. Mass spectrum information of the compound is as follows:
1 H NMR major (500MHz,DMSO)δ11.39(s,1H),8.02(s,1H),7.33(d,J＝8.0Hz,2H),7.24(s,1H),7.07(t,J＝29.4Hz,3H),6.24(s,1H),5.73(s,1H),3.73(dd,J＝52.1,31.3Hz,9H)； 1 H NMR minor (500MHz,DMSO)δ11.32(s,1H),8.06(s,1H),7.43(s,2H),7.24(s,1H),7.07(t,J＝29.4Hz,3H),6.00(s,1H),5.81(s,1H),3.73(dd,J＝52.1,31.3Hz,9H)； 13 CNMR mix (126MHz,DMSO)δ172.66,172.20,170.56,170.04,153.42,153.28,144.54,143.84,143.17,142.68,139.39,139.24,132.63,132.51,131.78,131.61,125.44,125.03,124.66,124.42,123.22,123.12,122.39,111.94,111.49,105.03,104.83,79.86,79.34,60.59,60.52,56.50,56.42,54.09,53.62,27.95,27.37.HRMS(ESI)calcd for[C 24 H 19 N 3 O 6 Na] + ＝[M+Na] + ＝468.1166,found468.1169。
EXAMPLE 2 use of gamma-butenolide derivatives in the treatment of neuropathic pain
The embodiment provides that the gamma-butenolide derivative can be used as a calcium channel blocker for preparing medicaments for treating neuropathic pain. In this example, 11 gamma-butenolide derivatives ( compounds 3a, 3d, 3c, 3g, 3f, 3h, 3i, 3q, 3o, 3n, 3 r) were used as examples to search for changes in the concentration of calcium ion influx after acting on cells to activate calcium channels. Proved by researches, the compound (gamma-butenolide derivative) can effectively inhibit the activity of a calcium ion channel, improve the selectivity and the action effect of the calcium ion channel, and has the potential of being used for treating neuropathic pain.
For this reason, this example used the primary culture of rat dorsal root ganglion cells, and the calcium imaging technique, using 40mM KCl to activate calcium channels, causing calcium influx, and then compared the change in calcium channel concentration after calcium channel activation when different compounds (gamma-butenolide derivatives) were incubated, thereby exploring the effect of gamma-butenolide derivatives on the calcium channel activity of DRG neurons. The experiment is divided into an experimental group (gamma-butenolide derivatives) and a control group (DMSO), and the inhibition effect of different compounds on the activity of a calcium ion channel is obtained by comparing the calcium ion concentration change of cells of the experimental group and the control group. The specific experimental process is as follows:
the experiment used primary cultured rat dorsal root ganglion cells (Dorsal root ganglion neuron, DRG). The animals used for the experiments were SD rats (male, 4-6 weeks old purchased from Dien Gene technologies Inc., guangzhou), and all animal experiments were conducted under the relevant regulations and guidelines. Rats were first anesthetized with isoflurane, and then the spinal column of the rats was isolated, the spinal canal was cut, and the spinal cord was exposed. About 30-40 dorsal root ganglion cells (DRG) were isolated from the intervertebral foramina by means of a microscope, the just isolated DRG was transferred to 2mL of preheated (37 ℃) DMEM (containing 10% FBS and 1% PS), and after centrifugation to remove impurities, 500. Mu.L of pancreatin was added to the EP tube containing the DRG and the medium, and the medium was gently and slowly blown with a pipette. The EP tube was then transferred to a 37℃incubator for digestion for about 50min. After digestion, the pellet in the EP tube was blown off with a pipette, centrifuged in a centrifuge, and the supernatant was removed, followed by addition of 480. Mu. LDMEM (containing 10% FBS and 1% PS) and mixing to form a cell suspension. The obtained DRG cell suspension was attached to a 12-well plate, and 1mL of DMEM medium was added thereto, and the mixture was placed in a cell incubator (37 ℃ C., 5% CO) 2 ) And (3) culturing for more than 4 hours, and then performing calcium ion imaging.
The calcium ion imaging method comprises the following steps: DRG neurons were incubated for 30min in an external solution containing 3. Mu.M Fura-2AM dye to explore intracellular Ca prior to the experiment 2+ Is a variation of (c). In the experiment, the external solution was continuously infused into the DRG neurons at a flow rate of 0.5mL/min (139mMNaCl,3mM KCl,0.8mM MgCl 2 ,1.8mM CaCl 2 10mM HEPES,5mM glucose,pH 7.4, reagents were purchased from Sigma-Aldrich) to the end of the experiment (about 30 minutes) during which time fluorescence imaging was performed using an inverted microscope (Nikon), with images taken every 5 seconds, at a stable baseline (F) 0 ) After start ofRecord and perfuse 40mM KCl at 14min, 90mM KCl at 23min, and switch back to the external fluid for the rest of the time. Wherein the living neurons are identified with 90mM KCl infused, and the inhibition rate of gamma-butenolide derivatives on the activity of calcium ion channels is calculated with 40mM KCl. After shooting, subtracting shooting background, intracellular Ca 2+ DeltaF for concentration change of (2) 0 /F 1 Ratio calculation of (F) 0 Taking the average value of 1min after perfusion stabilization as a fluorescence baseline value; f (F) 1 For fluorescence peaks generated after infusion of the stimulating compound, Δf 0 ＝F 1 -F 0 ) And neurons 10% above baseline were considered as responsive neurons. The gamma-butenolide derivatives were diluted with DMSO and prepared as a 50mM mixture. Neuronal cells were divided into experimental and control groups, the experimental groups were incubated overnight with 1uL of 50mM compound in medium, while the control group bath was only supplemented with 1uL dmso.
As shown in figure 1, the 11 selected gamma-butenolide derivatives ( compounds 3a, 3d, 3c, 3g, 3f, 3h, 3i, 3q, 3o, 3n and 3 r) have good effect of inhibiting the activity of calcium channels (note: the control group defaults to 0), which suggests that the gamma-butenolide derivatives of the invention are expected to be used as calcium channel blockers for preparing medicaments for treating neuropathic pain, and have important potential application values.
The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, and yet fall within the scope of the invention.
Claims (10)
1. The gamma-butenolide derivative is characterized by having a structure shown in a general formula (I):
in the formula (I), R is 1 Selected from hydrogen atoms and aralkyl groups; r is R 2 Selected from electron withdrawing groups; ar (Ar) 1 Selected from aryl or substituted aryl; ar (Ar) 2 Selected from aryl or substituted aryl; the substituted aryl is selected from alkyl, alkoxy, nitro or halogen substituted aryl.
2. A gamma-butenolide derivative according to claim 1, wherein R 1 Selected from the group consisting of a hydrogen atom, a benzyl group; r is R 2 Selected from cyano, benzyloxycarbonyl; ar (Ar) 1 Selected from phenyl, 3-bromophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 3,4, 5-trimethoxyphenyl; ar (Ar) 2 Selected from phenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-nitrophenyl, 6-chlorophenyl, 6-bromophenyl, 7-chlorophenyl.
3. A gamma-butenolide derivative according to claim 1 or 2, wherein said gamma-butenolide derivative is selected from at least one of the compounds 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n, 3o, 3p, 3q, 3 r:
4. a method for producing a gamma-butenolide derivative according to any one of claims 1 to 3, wherein the method for producing a gamma-butenolide derivative comprises: according to the following chemical reaction formula, compound 1 and compound 2 are taken as raw materials, cuBr is taken as a catalyst, compound 1, compound 2 and CuBr are firstly mixed and dissolved in an organic solvent to prepare a solution, and then the solution is heated to 80 ℃ to react for 1-5 min, so that a target product shown in a general formula (I) can be prepared;
r in the formula 1 、R 2 、Ar 1 、Ar 2 The same claim 1 or claim 2.
5. The method for producing gamma-butenolide derivatives according to claim 4, wherein the molar ratio of the compound 1 to the compound 2 to the CuBr is 1.2 to 1.5:1 to 1.2:0.08 to 0.1.
6. The method for producing gamma-butenolide derivatives according to claim 4, wherein the reaction temperature is 78 to 82℃and the reaction time is 1 to 5 minutes.
7. Use of a gamma-butenolide derivative according to any one of claims 1-3 for the preparation of a calcium channel blocker.
8. Use of a gamma-butenolide derivative according to any one of claims 1-3 in the manufacture of a medicament for the treatment of neuropathic pain.
9. The use according to claim 7 or 8, wherein the gamma-butenolide derivative is selected from at least one of the compounds 3a, 3c, 3d, 3f, 3g, 3h, 3i, 3n, 3o, 3q, 3 r:
10. a calcium channel blocker or a medicament for treating neuropathic pain, characterized in that the calcium channel blocker or the medicament takes the gamma-butenolide derivative according to any one of claims 1-3 as a main active ingredient.
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