Oxabicyclo [2.1. 1] hexane derivative and synthesis method thereof

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses an oxabicyclo [2.1. 1] hexane derivative, the structural formula of the oxabicyclo [2.1. 1] hexane derivative is # imgabs0 #, and R is selected from a methoxy group, an ethyoxyl group, a trifluoroethyoxyl group and a phenyl group. Ar is selected from the group consisting of phenyl, 4-fluorophenyl, 4-chlorphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethylphenyl, 4-trifluoromethylphenyl, 3-bromophenyl, 2-bromophenyl, 3, 4-difluorophenyl, 2-naphthyl, and 2-thienyl, and a pharmaceutically acceptable salt thereof. The oxabicyclo [2.1. 1] hexane derivative disclosed by the invention has a relatively wide substrate range and can be used as an isostere of m-substituted benzene. Therefore, the derivative has certain application value in the fields of medicinal chemistry and organic synthesis. The oxabicyclo [2.1. 1] hexane derivative disclosed by the invention is high in synthesis yield, mild in synthesis reaction condition and safe, simple and convenient to operate.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to an oxabicyclo[2.1.1]hexane derivative and a synthesis method thereof. Background Art

[0002] With the rapid development of medicinal chemistry, discovering new benzene ring replacement skeletons to assist in the development of new drugs and breaking through the patent restrictions of existing APIs have become urgent problems to be solved in the current field of new drug research and development. As a bioelectronic isostere of meta-disubstituted benzene, the bicyclo[2.1.1]hexane derivative skeleton has received great attention in the fields of synthetic chemistry and medicinal chemistry in recent years. Replacing the middle disubstituted benzene ring of the drug molecule with a (hetero)bicyclo[2.1.1]hexane derivative skeleton through an isostere replacement strategy can not only improve the solubility, lipophilicity and metabolic stability of the drug molecule, but also help to improve the pharmacokinetic properties of the drug molecule. Therefore, the development of new strategies for the construction of heterobicyclo[2.1.1]hexane derivative skeletons has great application prospects.

[0003] Oxabicyclo[2.1.1]hexane is a biological isostere of a class of meta-disubstituted benzenes. Currently, various strategies have been reported for constructing the oxabicyclo[2.1.1]hexane skeleton. For example, photocatalytic single electron transfer [2σ+2π] cyclization (ACS Catal. 2024, 14, 13987-13998), photocatalytic energy transfer [2σ+2π] (J. Am. Chem. Soc. 2022, 144, 20207-20213), Lewis acid-catalyzed [2σ+2π] cyclization, etc. (Angew. Chem. Int. Ed. 2023, 62, e202305043). Although the above methods have a wide range of substrates, the general yield is low, which greatly restricts its scope of application. In 2024, Weiwei Zi et al. reported a case of palladium-catalyzed strain-release ring-opening [2σ+2π] cyclization of vinyl bicyclo[1.1.0]butane with aldehydes or ketones for the synthesis of oxabicyclo[2.1.1]hexane derivatives (Weiwei Zi et al, Palladium-catalysed [2σ+2π]cycloaddition reactions of bicyclo[1.1.0]butaneswith aldehydes, nature synthesis). However, the scope of application of this method to ketone compounds is extremely limited, with only 4 cases reported.

[0004] In view of the shortcomings and limitations of the above methods, developing an efficient synthesis method for oxabicyclo[2.1.1]hexane derivatives with high yield and good substrate adaptability is of great significance in the fields of synthetic chemistry and drug development. Summary of the invention

[0005] In view of the above shortcomings, the present invention provides an oxabicyclo[2.1.1]hexane derivative and a synthesis method thereof. The oxabicyclo[2.1.1]hexane derivative can be used in the field of synthetic chemistry technology, has mild synthesis reaction conditions, high synthesis yield, and good substrate adaptability. The specific technical scheme is as follows:

[0006] An oxabicyclo[2.1.1]hexane derivative, wherein the structural formula of the oxabicyclo[2.1.1]hexane derivative is:

[0007]

[0008] wherein R is selected from methoxy, ethoxy, trifluoroethoxy and phenyl, and Ar is selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethylphenyl, 4-trifluoromethylphenyl, 3-bromophenyl, 2-bromophenyl, 3,4-difluorophenyl, 2-naphthyl and 2-thienyl.

[0009] A method for synthesizing the above-mentioned oxabicyclo[2.1.1]hexane derivative comprises the following steps:

[0010] (1) mixing vinyl bicyclo[1.1.0]butane and methyl arylpropynyl ketone in an organic solvent, adding a metal catalyst / ligand system, stirring for reaction, extracting after the reaction is completed, and collecting an organic phase;

[0011] (2) drying the organic phase obtained in step (1), concentrating under reduced pressure, and separating by silica gel column chromatography to obtain an oxabicyclo[2.1.1]hexane derivative;

[0012] The synthetic route of the oxabicyclo[2.1.1]hexane derivative is as follows:

[0013]

[0014] Preferably, in the above-mentioned method for synthesizing oxabicyclo[2.1.1]hexane derivatives, the reaction temperature is 15 to 30° C. and the reaction time is 10 to 15 hours.

[0015] Preferably, in the above-mentioned method for synthesizing oxabicyclo[2.1.1]hexane derivatives, the organic solvent is dichloromethane, acetone, toluene, chloroform, 1,2-dichloroethane or acetonitrile. .

[0016] Preferably, in the above-mentioned method for synthesizing oxabicyclo[2.1.1]hexane derivatives, the organic solvent is 1,2-dichloroethane.

[0017] Preferably, in the above-mentioned method for synthesizing oxabicyclo[2.1.1]hexane derivatives, the palladium salt is Pd(OAc)2 or Pd2(dba)3.

[0018] Preferably, in the above-mentioned method for synthesizing oxabicyclo[2.1.1]hexane derivatives, the phosphine ligand is DPEphos, Xantphos or dppf.

[0019] Preferably, in the above-mentioned method for synthesizing oxabicyclo[2.1.1]hexane derivatives, the palladium salt is Pd(OAc)2, and the phosphine ligand is DPEphos.

[0020] Preferably, in the above-mentioned synthesis method of oxabicyclo[2.1.1]hexane derivatives, the molar ratio of the vinylbicyclo[1.1.0]butane to methyl arylpropargyl ketone is 1.5-2.0:1, the molar amount of the palladium salt is 5-10% of the molar amount of the methyl arylpropargyl ketone, and the molar amount of the phosphine ligand is 10-12% of the molar amount of the methyl arylpropargyl ketone.

[0021] Preferably, in the above-mentioned method for synthesizing oxabicyclo[2.1.1]hexane derivatives, the extraction is extraction with ethyl acetate; the eluent in the silica gel column chromatography is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 19:1 to 9:1.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. The oxabicyclo[2.1.1]hexane derivative of the present invention has high yield, mild reaction conditions and wide substrate applicability, can be used as a bioisostere of meta-disubstituted benzene, and has certain application value in the fields of medicinal chemistry and organic synthesis.

[0024] 2. The method for synthesizing oxabicyclo[2.1.1]hexane derivatives of the present invention realizes the [2σ+2π] cycloaddition reaction of vinylbicyclo[1.1.0]butane and methyl arylpropynyl ketone through a metal catalyst / ligand system, has a short synthesis route, mild synthesis reaction conditions, and high synthesis yield, and can be applied to the synthesis of oxabicyclo[2.1.1]hexane derivatives with different substitutions. DETAILED DESCRIPTION

[0025] The specific embodiments of the present invention are described in detail below, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments. Unless otherwise defined, all professional terms used hereinafter have the same meaning as those generally understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the protection scope of the present invention. Unless otherwise specifically stated, various raw materials, reagents, instruments and equipment used in the present invention, etc. can be purchased from the market or can be prepared by existing methods.

[0026] The vinyl bicyclo[1.1.0]butane used in the following examples and comparative examples was prepared according to the literature (Ma, X.; Pinto, W.; Pham, LN; Sloman, DL; Han, Y., Synthetic Studies of 2,2-Difluorobicyclo[1.1.1]pentanes(BCP-F2):The Scope and Limitation of Useful Building Blocks for Medicinal Chemists. Eur. J. Org. Chem. 2020, 2020, (29), 4581-4605).

[0027] Example 1

[0028] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0029]

[0030] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0031]

[0032] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment specifically comprises the following steps:

[0033] (1) Vinyl bicyclo[1.1.0]butane 1a (0.2 mmol, 2.0 equivalents) and methyl arylpropynyl ketone 2a (0.1 mmol, 1.0 equivalents) were added to a reaction flask, dissolved with 1,2-dichloroethane (1.0 mL), Pd(OAc)2 (0.01 mmol) and DPEphos (0.012 mmol) were added respectively, and argon gas was filled to protect the reaction. The reactants were stirred at room temperature for 12 hours; the mixture was diluted with brine (2.0 mL), extracted with ethyl acetate (2.0 mL×2), and the organic phase was collected;

[0034] (2) The organic phase was dried, concentrated under reduced pressure, and purified and separated using silica gel chromatography (petroleum ether: ethyl acetate 9:1) to obtain the oxabicyclo[2.1.1]hexane derivative 3a with a yield of 79% (0.079 mmol).

[0035] The nuclear magnetic resonance data of the oxabicyclo[2.1.1]hexane derivative 3a in this example are:

[0036] 1H NMR (400MHz, CDCl3) δ7.42–7.40(m,2H),7.24(d,J=7.2Hz,2H),6.03(dd,J=17.6,10.8Hz,1H),5.35–5.24(m,2H),4.24–4.14(m, 2H),3.77(s,3H),2.62(dd,J=10.4,8.0Hz,1H),2.24(dd,J=8.4,3.6Hz,2H),2.11(dd,J=10.4,8.8Hz,1H),1.23(t,J=7.2Hz,3H).

[0037] 13 C NMR (100MHz, CDCl3) δ167.6,167.1,131.1,127.8,127.2,121.1,118.0,86.7,85.8,84.2,77.1,60.1,56.1,52.2,46.9,42.9,13.2.

[0038] HRMS (TOF-ESI + )m / z:calcd for C 20 H 20 O5Na[M+Na] + 363.1203 found 363.1211.

[0039] Example 2

[0040] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0041]

[0042] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0043]

[0044] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment is the same as that of Example 1, except that 4-fluoroarylpropargyl ketone methyl ester 2b (0.1 mmol, 1.0 equivalent) is used in step (1) to replace arylpropargyl ketone methyl ester 2a to obtain 4-fluorooxabicyclo[2.1.1]hexane derivative 3b with a yield of 78% (0.078 mmol).

[0045] The nuclear magnetic resonance data of the oxabicyclo[2.1.1]hexane derivative 3b in this example are:

[0046] 1H NMR (400MHz, CDCl3) δ7.42–7.37(m,2H),6.96–6.91(m,2H),6.02(dd,J=17.6,10.8Hz,1H),5.35–5.24(m,2H),4.23–4.14(m,2H ),3.77(s,3H),2.60(dd,J=10.0,8.0Hz,1H),2.24(dd,J=8.4,3.2Hz,2H),2.10(dd,J=11.6,10.4Hz,1H),1.23(t,J=7.2Hz,3H).

[0047] 13 C NMR (100MHz, CDCl3) δ167.5,167.0,163.1,160.6,132.9(d,J c-f =8.3Hz),131.0,118.1,117.1(d,J c-f =3.4Hz),114.7,114.4,85.8(d,J c-f =17.3Hz),83.9,77.0,60.1,56.1,52.2,46.9,42.8,13.2.

[0048] 19 F NMR(376MHz, CDCl3)δ-109.9(s).

[0049] HRMS (TOF-ESI + )m / z:calcd for C 20 H 19 FO5Na[M+Na] + 381.1109 found 381.1115.

[0050] Example 3

[0051] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0052]

[0053] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0054]

[0055] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment is the same as that of Example 1, except that in step (1), 4-chloroarylpropargyl ketone methyl ester 2c (0.1 mmol, 1.0 equivalent) is used to replace arylpropargyl ketone methyl ester 2a to obtain 4-chlorooxabicyclo[2.1.1]hexane derivative 3c with a yield of 68% (0.068 mmol).

[0056] The nuclear magnetic resonance data of the oxabicyclo[2.1.1]hexane derivative 3c in this example are:

[0057] 1 H NMR (400MHz, CDCl3) δ7.34(d,J=8.4Hz,2H),7.23–7.19(m,2H),6.02(dd,J=17.6,11.2Hz,1H),5.35–5.25(m,2H),4.23–4.14(m, 2H),3.77(s,3H),2.59(dd,J=10.0,8.0Hz,1H),2.25(dd,J=8.4,2.8Hz,2H),2.11(dd,J=10.4,8.8Hz,1H),1.23(t,J=7.2Hz,3H).

[0058] 13 C NMR (100MHz, CDCl3) δ167.4,167.0,134.0,132.2,131.0,129.0,128.3,128.2,127.6,119.7 ,119.5,118.2,96.9,85.9,85.6,85.2,77.0,60.1,56.1,52.3,52.2,46.9,42.9,28.7,13.2.

[0059] HRMS (TOF-ESI + )m / z:calcd for C 20 H 19 ClO5Na[M+Na] + 397.0813 found 397.0823.

[0060] Example 4

[0061] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0062]

[0063] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0064]

[0065] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment is the same as that of Example 1, except that: in step (1), 4-methyl arylpropargyl ketone methyl ester 2d (0.1 mmol, 1.0 equivalent) is used to replace arylpropargyl ketone methyl ester 2a to obtain 4-methyl oxabicyclo[2.1.1]hexane derivative 3d with a yield of 76% (0.076 mmol).

[0066] The 3d NMR data of the oxabicyclo[2.1.1]hexane derivative of this example are:

[0067] 1 H NMR(400MHz, CDCl3)δ7.30(d,J=8.4Hz,2H),7.04(d,J=7.6Hz,2H),6.02(dd,J=17.2,10.8Hz,1H),5.34–5.23(m,2H),4.24–4.13(m,2H), 3.76(s,3H),2.62(dd,J=9.6,8.0Hz,1H),2.27(s,3H),2.23(dd,J=8.8,5.2Hz,2H),2.09(dd,J=10.4,9.2Hz,1H),1.22(t,J=7.2Hz,3H).

[0068] 13 C NMR (100MHz, CDCl3) δ167.7,167.1,138.0,131.2,130.8,127.9,118.0,86.9,85.7,83.5,77.1,60.1,56.1,52.2,46.9,42.8,20.5,13.2.

[0069] HRMS (TOF-ESI + )m / z:calcd for C 21 H 22 O5Na[M+Na] + 377.1359 found 377.1369.

[0070] Example 5

[0071] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0072]

[0073] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0074]

[0075] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment is the same as that of Example 1, except that: in step (1), 4-methoxy arylpropargyl ketone methyl ester 2e (0.1 mmol, 1.0 equivalent) is used to replace arylpropargyl ketone methyl ester 2a to obtain 4-methoxy oxabicyclo[2.1.1]hexane derivative 3e with a yield of 76% (0.076 mmol).

[0076] The nuclear magnetic resonance data of the oxabicyclo[2.1.1]hexane derivative 3e in this example are:

[0077] 1 H NMR (400MHz, CDCl3) δ7.36–7.33(m,2H),6.76(d,J=8.8Hz,2H),6.03(dd,J=17.6,11.2Hz,1H),5.34–5.23(m,2H),4.24–4.13(m, 2H),3.75(d,J=12.0Hz,6H),2.62(dd,J=10.0,8.0Hz,1H),2.23(dd,J=8.4,5.2Hz,2H),2.13–2.06(m,1H),1.23(t,J=7.2Hz,3H).

[0078] 13 C NMR (100MHz, CDCl3) δ167.7,167.2,159.0,132.5,131.2,118.0,113.1,112.8,86.8,85.7,82.8,77.2,60.1,56.0,54.3,52.1,46.9,42.9,13.2.

[0079] HRMS (TOF-ESI + )m / z:calcd for C 21 H 22 O6Na[M+Na] + 393.1309 found 393.1318.

[0080] Example 6

[0081] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0082]

[0083] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0084]

[0085] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment is the same as that of Example 1, except that in step (1), 4-ethyl arylpropargyl ketone methyl ester 2f (0.1 mmol, 1.0 equivalent) is used to replace arylpropargyl ketone methyl ester 2a to obtain 4-ethyl oxabicyclo[2.1.1]hexane derivative 3f with a yield of 71% (0.071 mmol).

[0086] The 3f NMR data of the oxabicyclo[2.1.1]hexane derivative of this example are:

[0087] 1 H NMR (400MHz, CDCl3) δ7.33(d,J=8.0Hz,2H),7.07(d,J=8.4Hz,2H),6.03(dd,J =17.2,10.8Hz,1H),5.35–5.24(m,2H),4.24–4.14(m,2H),3.76(s,3H),2.63( dd,J=14.4,6.8Hz,1H),2.57(dd,J=15.2,7.6Hz,2H),2.23(dd,J=8.4,5.6Hz, 2H), 2.10 (dd, J=9.2, 7.6Hz, 1H), 1.24 (d, J=7.2Hz, 3H), 1.15 (t, J=7.2Hz, 3H).

[0088] 13 C NMR (100MHz, CDCl3) δ167.7,167.1,144.3,131.2,130.9,127.9,127.3,126.8,118.2,118. 0,86.9,85.7,83.5,77.1,60.1,56.1,52.2,46.9,42.9,28.7,28.0,27.8,14.3,14.1,13.2.

[0089] HRMS (TOF-ESI + )m / z:calcd for C 22 H 24 O5Na[M+Na] + 391.1516 found 391.1525.

[0090] Example 7

[0091] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0092]

[0093] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0094]

[0095] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment is the same as that of Example 1, except that: in step (1), 2 g (0.1 mmol, 1.0 equivalent) of 4-trifluoromethyl arylpropargyl ketone methyl ester is used to replace arylpropargyl ketone methyl ester 2a to obtain 3 g of 4-trifluoromethyl oxabicyclo[2.1.1]hexane derivative with a yield of 45% (0.045 mmol).

[0096] The nuclear magnetic resonance data of the oxabicyclo[2.1.1]hexane derivative 3g in this example are:

[0097] 1 H NMR(400MHz, CDCl3)δ7.58(d,J=1.2Hz,3H),6.10(dd,J=17.6,10.8Hz,1H),5.43–5.33(m,2H),4.31–4.22(m,2H),3. 85(s,3H),2.66(dd,J=10.0,8.2Hz,1H),2.33(d,J=8.0Hz,2H),2.20(dd,J=10.0,8.8Hz,1H),1.30(t,J=7.2Hz,3H).

[0098] 13 C NMR (100MHz, CDCl3) δ167.3,166.9,131.2,130.9,124.2(d,J c-f =3.7Hz),118.3,86.6,86.0,85.2,60.2,56.2,52.3,46.9,42.9,28.7,13.2.

[0099] 19 F NMR(376MHz, CDCl3)δ-62.9(s).

[0100] HRMS (TOF-ESI + )m / z:calcd for C 21 H 19 F3O5Na[M+Na] + 431.1077 found 431.1085.

[0101] Example 8

[0102] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0103]

[0104] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0105]

[0106] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment is the same as that of Example 1, except that: in step (1), 3-bromoarylpropargyl ketone methyl ester 2h (0.1 mmol, 1.0 equivalent) is used to replace arylpropargyl ketone methyl ester 2a to obtain 3-bromooxabicyclo[2.1.1]hexane derivative 3h with a yield of 68% (0.068 mmol).

[0107] The 3h NMR data of the oxabicyclo[2.1.1]hexane derivative of this example are:

[0108] 1 H NMR(400MHz, CDCl3)δ7.56(s,1H),7.40(d,J=8.0Hz,1H),7.35–7.33(m,1H),7.11(t,J=8.0Hz,1H),6.02(dd,J=17.6,10.8Hz,1H),5.35–5 .25(m,2H),4.24–4.15(m,2H),3.78(s,3H),2.59(dd,J=10.0,8.4Hz,1H),2.25(d,J=7.6Hz,2H),2.14–2.10(m,1H),1.23(t,J=7.2Hz,3H).

[0109] 13 C NMR (100MHz, CDCl3) δ167.4,167.0,135.6,133.7,131.1,130.9,129.8,129.5,128.7,125.4, 123.0,121.0,118.2,97.1,86.0,85.5,85.0,76.9,60.2,56.2,52.3,46.9,42.8,28.7,13.2.

[0110] HRMS (TOF-ESI + )m / z:calcd for C 20 H 19 BrO5Na[M+Na] + 441.0308 found 441.0318.

[0111] Example 9

[0112] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0113]

[0114] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0115]

[0116] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment is the same as that of Example 1, except that: in step (1), 2-bromoarylpropargyl ketone methyl ester 2i (0.1 mmol, 1.0 equivalent) is used to replace arylpropargyl ketone methyl ester 2a to obtain 2-bromooxabicyclo[2.1.1]hexane derivative 3i with a yield of 53% (0.053 mmol).

[0117] The nuclear magnetic resonance data of the oxabicyclo[2.1.1]hexane derivative 3i in this example are:

[0118] 1 H NMR (400MHz, CDCl3) δ7.51–7.43(m,2H),7.19(s,1H),7.15–7.09(m,1H),6.03(dd,J=17.2,10.8Hz,1H),5.36–5.25(m,2H),4.2 3–4.13(m,2H),3.79(s,3H),2.72(dd,J=9.2,8.0Hz,1H),2.26(dd,J=8.6,3.2Hz,2H),2.22–2.17(m,1H),1.31(t,J=7.2Hz,3H).

[0119] 13 C NMR (100MHz, CDCl3) δ167.4,167.0,132.9,131.4,131.1,129.0,125.9,124.9,123.3,118.1,86.0,60.2,56.4,52.2,46.9,43.0,28.7,13.1.

[0120] HRMS (TOF-ESI + )m / z:calcd for C 20 H 19 BrO5Na[M+Na] + 441.0308 found 441.0315.

[0121] Example 10

[0122] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0123]

[0124] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0125]

[0126] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment is the same as that of Example 1, except that: in step (1), 3,4-difluoroarylpropargyl ketone methyl ester 2j (0.1 mmol, 1.0 equivalent) is used to replace arylpropargyl ketone methyl ester 2a to obtain 3,4-difluorooxabicyclo[2.1.1]hexane derivative 3j with a yield of 56% (0.056 mmol).

[0127] The nuclear magnetic resonance data of the oxabicyclo[2.1.1]hexane derivative 3j in this example are:

[0128] 1 H NMR (400MHz, CDCl3) δ7.25–7.20(m,1H),7.18–7.14(m,1H),7.07–7.00(m,1H),6.02(dd,J=17.2,10.8Hz,1H),5.35–5.25(m,2H),4.2 4–4.14(m,2H),3.78(s,3H),2.57(dd,J=10.0,8.0Hz,1H),2.25(d,J=7.6Hz,2H),2.11(dd,J=10.0,8.4Hz,1H),1.24(t,J=7.2Hz,3H).

[0129] 13 C NMR (100MHz, CDCl3) δ167.3,166.9,130.9,127.7,120.1,118.2,116.4,86.0,60.2,56.1,52.3,46.9,42.9,28.7,13.2.

[0130] 19 F NMR (377MHz, CDCl3) δ -128.0 (d, J = 20.5Hz), -134.8 (d, J = 20.5Hz), -135.2 (d, J = 20.4Hz), -137.0 (d, J = 21.2Hz).

[0131] HRMS (TOF-ESI + )m / z:calcd for C 20 H 18 F2O5Na[M+Na] + 399.1015 found 399.1025.

[0132] Embodiment 11

[0133] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0134]

[0135] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0136]

[0137] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment is the same as that of Example 1, except that: in step (1), 2-naphthylarylpropynyl ketone methyl ester 2k (0.1 mmol, 1.0 equivalent) is used to replace arylarylpropynyl ketone methyl ester 2a to obtain the oxabicyclo[2.1.1]hexane derivative 3k with a yield of 62% (0.062 mmol).

[0138] The 3k nuclear magnetic resonance data of the oxabicyclo[2.1.1]hexane derivative of this example are:

[0139] 1 H NMR(400MHz, CDCl3)δ7.95(s,1H),7.75–7.68(m,3H),7.45–7.40(m,3H),6.04(dd,J=17.6,10.8Hz,1H),5.36–5.25(m,2H),4.28–4 .14(m,2H),3.79(s,3H),2.67(dd,J=10.4,7.6Hz,1H),2.27(d,J=8.0Hz,2H),2.12(dd,J=15.8,7.0Hz,1H),1.24(t,J=7.2Hz,3H).

[0140] 13 C NMR (100MHz, CDCl3) δ167.6,167.1,132.0,131.8,131.2,131.1,127.4,126.9,126.8,126. 7,125.9,125.6,118.3,118.1,87.1,85.8,84.4,77.2,60.1,56.2,52.2,47.0,42.9,13.2.

[0141] HRMS (TOF-ESI + )m / z:calcd for C 24 H 22 O5Na[M+Na] + 413.1359 found 413.1370.

[0142] Example 12

[0143] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0144]

[0145] The synthesis route of the oxabicyclo[2.1.1]hexane derivative of this embodiment is:

[0146]

[0147] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this embodiment is the same as that of Example 1, except that: in step (1), 2-thiophene propynyl ketone methyl ester 21 (0.1 mmol, 1.0 equivalent) is used to replace aryl propynyl ketone methyl ester 2a to obtain oxabicyclo[2.1.1]hexane derivative 31 with a yield of 41% (0.041 mmol). The nuclear magnetic resonance data of the oxabicyclo[2.1.1]hexane derivative 31 of this embodiment are:

[0148] 1 H NMR (400MHz, CDCl3) δ7.22–7.19(m,2H),6.90(dd,J=4.8,4.0Hz,1H),6.02(dd,J=17.4,10.8Hz,1H),5.35–5.25(m,2H),4.24– 4.14(m,2H),3.77(s,3H),2.59(dd,J=10.4,8.4Hz,1H),2.25(dd,J=8.4,4.8Hz,2H),2.13–2.08(m,1H),1.25(t,J=7.2Hz,3H).

[0149] 13 C NMR (100MHz, CDCl3) δ167.4,167.0,132.1,131.0,126.9,125.9,118.1,87.9,85.9,80.1,77.2,60.2,56.2,52.3,46.9,42.8,28.7,13.1.

[0150] HRMS (TOF-ESI + )m / z:calcd for C 18 H 18 O5SNa[M+Na] + 369.0767 found 369.0775.

[0151] Examples 13 to 16 and Comparative Examples 1 to 10

[0152] The synthetic routes of Examples 13 to 16 and Comparative Examples 1 to 10 are:

[0153]

[0154] The difference between Examples 13 to 21 and Comparative Examples 1 to 5 and Example 1 is that the catalyst and the ligand are different or the organic solvent is different. The specific information of the catalyst, the ligand and the organic solvent is shown in Table 1. The yield of the obtained oxabicyclo[2.1.1]hexane derivative is shown in Table 1. It can be seen from Table 1 that the catalyst, the ligand and the organic solvent will affect the progress of the synthesis reaction and the yield of the oxabicyclo[2.1.1]hexane derivative.

[0155] Table 1 Catalysts, ligands, organic solvents and yield data of Examples 13 to 21 and Comparative Examples 1 to 5

[0156] Serial number [Pd] LA solvent yield(%) Example 1 <![CDATA[Pd(OAc)2]]> DPEphos <![CDATA[CH2ClCH2Cl]]> 79 Embodiment 13 <![CDATA[Pd(dba)2]]> DPEphos <![CDATA[CH2Cl2]]> 31 Embodiment 14 <![CDATA[Pd2(dba)3]]> DPEphos <![CDATA[CH2Cl2]]> 33 Embodiment 15 <![CDATA[Pd(OAc)2]]> Xantphos <![CDATA[CH2Cl2]]> 53 Example 16 <![CDATA[Pd(OAc)2]]> dppf <![CDATA[CH2Cl2]]> 45 Embodiment 17 <![CDATA[Pd(OAc)2]]> DPEphos MeCN 75 Embodiment 18 <![CDATA[Pd(OAc)2]]> DPEphos <![CDATA[CH2Cl2]]> 73 Embodiment 19 <![CDATA[Pd(OAc)2]]> DPEphos <![CDATA[CHCl3]]> 61 Embodiment 20 <![CDATA[Pd(OAc)2]]> DPEphos Toluene 46 Embodiment 21 <![CDATA[Pd(OAc)2]]> DPEphos Acetone 70 Comparative Example 1 <![CDATA[PdCl2]]> DPEphos <![CDATA[CH2Cl2]]> nd Comparative Example 2 <![CDATA[Pd(OAc)2]]> <![CDATA[pph3]]> <![CDATA[CH2Cl2]]> trace Comparative Example 3 <![CDATA[Pd(OAc)2]]> DPPE <![CDATA[CH2Cl2]]> 7 Comparative Example 4 <![CDATA[Pd(OAc)2]]> DPEphos THF 21 Comparative Example 5 <![CDATA[Pd(OAc)2]]> DPEphos MeOH nd

[0157] Application Example 1

[0158] An oxirane oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0159]

[0160] The synthetic route of the oxirane oxabicyclo[2.1.1]hexane derivative of this application example is:

[0161]

[0162] The synthesis method of the oxirane oxabicyclo[2.1.1]hexane derivative of this application example specifically comprises the following steps:

[0163] (1) Add oxabicyclo[2.1.1]hexane derivative 3a (0.1 mmol, 1.0 equivalent) and m-chloroperbenzoic acid (0.2 mmol, 2 equivalents) into a reaction flask, dissolve with dichloromethane (1.0 mL), and stir the reactants at room temperature for 12 hours; dilute the mixture with brine (2.0 mL), and extract with ethyl acetate (2.0 mL×2), and collect the organic phase;

[0164] (2) The organic phase was dried, concentrated under reduced pressure, and purified and separated using silica gel chromatography (petroleum ether: ethyl acetate 9:1) to obtain the oxirane oxabicyclo[2.1.1]hexane derivative 4 with a yield of 52% (0.052 mmol).

[0165] The nuclear magnetic resonance data of the oxirane oxabicyclo[2.1.1]hexane derivative 4 of this example are:

[0166] 1H NMR (400MHz, CDCl3) δ7.49–7.46(m,2H),7.36–7.29(m,3H),4.30–4.20(m,2H),3.84(d,J=2.8Hz,3H),3.30(dd,J=6.4,3.6Hz, 1H),2.88–2.86(m,1H),2.73–2.68(m,1H),2.66–2.48(m,1H),2.26(d,J=8.0Hz,1H),2.18–1.98(m,2H),1.29(t,J=7.2Hz,3H).

[0167] 13 C NMR (100MHz, CDCl3) δ167.2,166.7,131.0,128.0,127.2,120.8,87.2,85.4,85. 3,83.6,77.2,60.2,55.9,52.3,47.6,44.6,44.0,43.8,40.8,39.8,28.7,13.1.

[0168] HRMS (TOF-ESI + )m / z:calcd for C 20 H 20 O6Na[M+Na] + 379.1152 found 379.1161.

[0169] Application Example 2

[0170] An alkyl oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0171]

[0172] The synthetic route of the alkyl oxabicyclo[2.1.1]hexane derivative of this application example is:

[0173]

[0174] The synthesis method of the alkyl oxabicyclo[2.1.1]hexane derivative of this application example specifically comprises the following steps:

[0175] (1) The oxabicyclo[2.1.1]hexane derivative 3a (0.1 mmol, 1.0 equivalent) and palladium carbon (10% supported on activated carbon 17.4 mg, containing 55% water) were added to ethyl acetate (1.0 mL), the mixture was degassed three times to place it in a H2 atmosphere, and refluxed at 50°C for 12 h. The mixture was diluted with brine (2.0 mL) and extracted with ethyl acetate (2.0 mL×2), and the organic phase was collected;

[0176] (2) The organic phase was dried, concentrated under reduced pressure, and purified and separated using silica gel chromatography (petroleum ether: ethyl acetate 9:1) to obtain the alkyl oxabicyclo[2.1.1]hexane derivative 5 with a yield of 88% (0.088 mmol).

[0177] The nuclear magnetic resonance data of the alkyl oxabicyclo[2.1.1]hexane derivative 5 of this example are:

[0178] 1 H NMR (400MHz, CDCl3) δ7.22–7.18(m,2H),7.13–7.08(m,2H),4.18–4.08(m,2H),3.65(s,3H),2.89–2.81(m,1H),2.52–2.43 (m,2H),2.09–1.95(m,2H),1.89(dd,J=16.8,8.4Hz,2H),1.77–1.70(m,3H),1.20(t,J=7.2Hz,3H),0.90(t,J=7.6Hz,3H).

[0179] 13 C NMR (100MHz, CDCl3) δ172.1,168.6,140.6,127.3,124.9,86.8,84.5,59.7,54.2,51.1,43.4,41.3,36.0,29.2,23.1,13.2,8.1.

[0180] HRMS (TOF-ESI + )m / z:calcd for C 20 H 26 O5Na[M+Na] + 369.1672 found 369.1679.

[0181] Application Example 3

[0182] An aldehyde oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0183]

[0184] The synthetic route of the aldehyde oxabicyclo[2.1.1]hexane derivative of this application example is:

[0185]

[0186] The method for synthesizing the aldehyde oxabicyclo[2.1.1]hexane derivative of this application example specifically comprises the following steps:

[0187] (1) Add oxabicyclo[2.1.1]hexane derivative 3a (0.1 mmol, 1.0 equivalent), ruthenium trichloride (0.01 mmol, 10 mol%) and sodium periodate (0.2 mmol, 2 equivalent) into a reaction flask, dissolve with acetonitrile: water = 6:1 (1.4 mL), stir the reactants at room temperature for 2 hours; dilute the mixture with brine (2.0 mL), extract with ethyl acetate (2.0 mL×2), and collect the organic phase;

[0188] (2) The organic phase was dried, concentrated under reduced pressure, and purified and separated using silica gel chromatography (petroleum ether: ethyl acetate 9:1) to obtain the aldehyde oxabicyclo[2.1.1]hexane derivative 6 with a yield of 40% (0.040 mmol).

[0189] The nuclear magnetic resonance data of the aldehyde oxabicyclo[2.1.1]hexane derivative 6 in this example are:

[0190] 1 H NMR (400MHz, CDCl3) δ7.46–7.37(m,2H),7.27–7.19(m,3H),4.26–4.12(m,2H),3.77(s,3H),3.70(dd,J=11 .4,4.0Hz,1H),2.54(dd,J=18.0,8.8Hz,1H),2.29–2.21(m,2H),2.05–2.00(m,1H),1.23(t,J=7.2Hz,3H).

[0191] 13 C NMR (100MHz, CDCl3) δ167.5,167.4,166.8,131.0,128.0,127.3,120.8,87 .5,87.3,83.4,77.0,68.6,62.2,60.2,56.5,52.3,44.3,40.1,28.7,13.2.

[0192] HRMS (TOF-ESI + )m / z:calcd for C 19 H 18 O6Na[M+Na] + 365.0996 found 365.1005.

[0193] Application Example 4

[0194] An oxabicyclo[2.1.1]hexane derivative having the structural formula:

[0195]

[0196] The synthetic route of the oxabicyclo[2.1.1]hexane derivative of this application example is:

[0197]

[0198] The synthesis method of the oxabicyclo[2.1.1]hexane derivative of this application example specifically comprises the following steps:

[0199] (1) Add oxabicyclo[2.1.1]hexane derivative 3a (0.1 mmol, 1.0 equivalent) and DIBAL-H (0.8 mL, 0.6 mmol, 6 equivalents) into a reaction flask, dissolve with tetrahydrofuran (1.0 mL), and stir the reactants at -78°C for 2 hours; dilute the mixture with brine (2.0 mL), and extract with ethyl acetate (2.0 mL×2), and collect the organic phase;

[0200] (2) The organic phase was dried, concentrated under reduced pressure, and purified and separated using silica gel chromatography (petroleum ether: ethyl acetate 2:1) to obtain the oxabicyclo[2.1.1]hexane derivative 7 with a yield of 83% (0.083 mmol).

[0201] The nuclear magnetic resonance data of the oxabicyclo[2.1.1]hexane derivative 7 of this example are:

[0202] 1 H NMR (400MHz, CDCl3) δ7.47–7.45(m,2H),7.34–7.27(m,3H),6.05(dd,J=17.2,10.8Hz,1H),5.35–5.24(m,2H),4.14–4.1 0(m,1H),3.86–3.79(m,4H),3.55(s,1H),2.33(dd,J=10.4,7.6Hz,1H),2.05–2.00(m,1H),1.81(dd,J=10.8,8.4Hz,2H).

[0203] 13 C NMR (100MHz, CDCl3) δ132.4,130.9,127.7,127.3,121.1,117.0,87.1,87.0,85.4,78.9,63.8,60.2,55.7,45.3,39.8.

[0204] HRMS (TOF-ESI + )m / z:calcd for C 17 H 18 O3Na[M+Na] + 293.1148 found 293.1157.

[0205] In summary, the synthesis method of the oxabicyclo[2.1.1]hexane derivatives of the present invention has simple synthesis steps and mild reaction conditions, and can be applied to the synthesis of oxabicyclo[2.1.1]hexane derivatives with different substitutions. The synthesized oxabicyclo[2.1.1]hexane derivatives have the potential to serve as new heterocyclic scaffolds in candidate drugs.

[0206] The foregoing description of specific exemplary embodiments of the present invention is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present invention to the precise form disclosed, and it is clear that many changes and variations can be made based on the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present invention and various different selections and changes. The scope of the present invention is intended to be limited by the claims and their equivalents.

Claims

1. An oxabicyclo[2.1.1]hexane derivative, characterized in that The structural formula of the oxabicyclo[2.1.1]hexane derivative is: Wherein, R is methoxy, ethoxy, trifluoroethoxy or phenyl, and Ar is phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethylphenyl, 4-trifluoromethylphenyl, 3-bromophenyl, 2-bromophenyl, 3,4-difluorophenyl, 2-naphthyl or 2-thienyl.

2. A method for synthesizing the oxabicyclo[2.1.1]hexane derivative according to claim 1, characterized in that: The following steps are involved: (1) Vinylbicyclo[1.1.0]butane 1 and methyl arylpropynyl ketone 2 are mixed in an organic solvent, palladium salt and chiral phosphine ligand are added, stirred for reaction, extracted after the reaction is completed, and the organic phase is collected; (2) drying the organic phase obtained in step (1), concentrating under reduced pressure, and separating by silica gel column chromatography to obtain an oxabicyclo[2.1.1]hexane derivative; The synthetic route of the oxabicyclo[2.1.1]hexane derivative is as follows:

3. The method for synthesizing the oxabicyclo[2.1.1]hexane derivative according to claim 2, characterized in that: The reaction temperature is 15-30° C., and the reaction time is 10-15 hours.

4. The method for synthesizing the oxabicyclo[2.1.1]hexane derivative according to claim 2, characterized in that: The organic solvent is dichloromethane, acetone, toluene, chloroform, 1,2-dichloroethane or acetonitrile.

5. The method for synthesizing the oxabicyclo[2.1.1]hexane derivative according to claim 4, characterized in that: The organic solvent is 1,2-dichloroethane.

6. The method for synthesizing the oxabicyclo[2.1.1]hexane derivative according to claim 2, characterized in that: The palladium salt is Pd(OAc)2 or Pd2(dba)3.

7. The method for synthesizing an oxabicyclo[2.1.1]hexane derivative according to claim 2, characterized in that: The phosphine ligand is DPEphos, Xantphos or dppf.

8. The method for synthesizing an oxabicyclo[2.1.1]hexane derivative according to claim 6 or 7, characterized in that: The palladium salt is Pd(OAc)2, and the phosphine ligand is DPEphos.

9. The method for synthesizing an oxabicyclo[2.1.1]hexane derivative according to claim 2, characterized in that: The molar ratio of the vinyl bicyclo[1.1.0]butane to methyl arylpropargyl ketone is 1.5-2.0:1, the molar amount of the palladium salt is 5-10% of the molar amount of the methyl arylpropargyl ketone, and the molar amount of the phosphine ligand is 10-12% of the molar amount of the methyl arylpropargyl ketone.

10. The method for synthesizing an oxabicyclo[2.1.1]hexane derivative according to claim 2, characterized in that: The extraction is performed by using ethyl acetate; the eluents in the silica gel column chromatography are petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 19:1 to 9:1.

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