Fluorinated olefin compounds for anti-myocardial fibrosis, their synthesis methods and applications

Abstract

The present invention discloses a fluorinated olefin compound for anti-myocardial fibrosis, its synthesis method and application, belonging to the technical field of pharmaceutical synthesis. The synthesis method comprises the following steps: adding 0.2 mmol, 2 eq of compound 1a, 0.1 mmol, 1 eq of gem-difluoroolefin derivative 2a, 0.3 mmol, 3 eq of acid-binding agent CS 2 CO 3 , and 0.01 mol of photosensitizer 4CzIPN into a 10 mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24 h. After the reaction is complete, perform column chromatography, and separate with petroleum ether: ethyl acetate = 50:1 to obtain the fluorinated olefin compound. The present invention applies visible light to the synthesis of fluorinated unsaturated olefins, making this synthesis route have the characteristics of high efficiency, environmental friendliness, mild reaction conditions, and simple and easy operation of reaction equipment. Moreover, the fluorinated unsaturated olefin obtained by the present invention has the effect of anti-myocardial fibrosis.

Description

Technical Field

[0001] The present invention relates to a fluorinated olefin compound for anti-myocardial fibrosis, its synthesis method and application, belonging to the technical field of pharmaceutical synthesis. Background Art

[0002] Fluorinated unsaturated olefins are a type of fluorocarbon chemical, and their molecules contain fluorine atoms and double bond structures. Such compounds usually have high chemical stability and special chemical properties, and are widely used in organic synthesis and industry.

[0003] Fluorinated olefins are a class of organic compounds with carbon-hydrogen bonds and carbon-fluorine bonds. In the molecular structure of fluorinated unsaturated olefins, there is usually an olefin structure, that is, a double bond, and at the same time, there are fluorine atom substitutions. Fluorinated unsaturated olefins have both unsaturation and the characteristics of fluorine atoms, so they have unique characteristics in chemical properties.

[0004] Among the existing synthesis methods of fluorinated unsaturated olefins, there is a method of using solvent regulation to catalyze the controllable synthesis of monofluoroolefins and gem-difluoroolefins with rhodium. There are also methods of constructing through carbonyl olefination, such as the Julia Kocienski reaction, the Homer-Wadsworth-Emmons reaction, and the Wittig reaction. However, the existing methods all have harsh reaction conditions and require multiple steps to prepare fluorinated unsaturated olefins. And although the existing fluorinated unsaturated olefins play an important role in the fields of organic synthesis, medicine, agrochemicals, and materials, there is no application of fluorinated unsaturated olefins in the treatment of anti-myocardial fibrosis. Summary of the Invention

[0005] Aiming at the above problems, the purpose of the present invention is to provide a fluorinated olefin compound for anti-myocardial fibrosis.

[0006] At the same time, the present invention provides a synthesis method of a fluorinated olefin compound for anti-myocardial fibrosis. The synthesis method has mild conditions, and it only takes 24 hours under light (40W blue light), and the target fluorinated unsaturated olefin can be obtained through a one-step reaction.

[0007] At the same time, the present invention provides an application of a fluorinated olefin compound for anti-myocardial fibrosis.

[0008] To solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0009] The fluorinated olefin compound for anti-myocardial fibrosis includes the molecular formula:

[0010]

[0011] Among them, in formula (I), R is -H;

[0012] including -Ad, any one of;

[0013] is substituted with -Me at the para position, -Cl, -Br, -Ph, H 3 CO-, I, H 3 CS-

[0014]

[0015] Specifically, the present invention includes the following fluoroolefin compounds 1-17:

[0016]

[0017] A method for synthesizing a fluoroolefin compound for anti-myocardial fibrosis, comprising the following steps:

[0018] Compound 1a (0.2 mmol, 2 eq), gem-difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid-binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) are added to a 10 mL sealed tube at one time. Under nitrogen protection, irradiated with light for 24 h. After the reaction is complete, column chromatography is carried out, and separated with petroleum ether: ethyl acetate = 50:1 to obtain the fluoroolefin compound;

[0019]

[0020] Preferably, the light irradiation is irradiation with a 40 W blue lamp.

[0021] Use of the fluoroolefin compound for anti-myocardial fibrosis of the present invention in the preparation of anti-myocardial fibrosis drugs.

[0022] An anti-myocardial fibrosis drug, comprising the fluoroolefin compound of the present invention.

[0023] Preferably, the anti-myocardial fibrosis drug further comprises a pharmaceutically acceptable excipient.

[0024] Preferably, the excipient includes any one or more of a solvent, a propellant, a solubilizer, a cosolvent, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, a stabilizer, a glidant, a flavoring agent, a preservative, a suspending agent, a coating material, an aromatic agent, an anti-adhesive, a chelating agent, a penetration enhancer, a pH regulator, a buffer, a plasticizer, a surfactant, a foaming agent, a defoaming agent, a thickening agent, an inclusion agent, a moisturizer, an absorbent, a diluent, a flocculant, an anti-flocculant, a filter aid, a release retardant.

[0025] The preparation of the anti-myocardial fibrosis drug containing the present invention, the preparation includes powder, tablets, granules, capsules, injections or oral liquids.

[0026] Compared with the prior art, the present invention has the following advantages:

[0027] The synthesis method of the present invention has mild conditions, and it can be achieved under illumination (40W blue light) for 24h. The target fluorinated unsaturated olefin can be obtained through a one-step reaction. Moreover, the fluorinated unsaturated olefin obtained by the present invention has the effect of anti-myocardial fibrosis.

[0028] The present invention applies visible light to the synthesis of fluorinated unsaturated olefins, making this synthesis route efficient, environmentally friendly, with mild reaction conditions, and the reaction equipment is simple and easy to operate. Detailed implementation manners

[0029] The present invention will be further described in detail below in conjunction with specific embodiments. The following embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0030] Example 1

[0031] The synthesis method of the fluorinated olefin compound with anti-myocardial fibrosis includes the following steps:

[0032] Add compound 1a (0.2 mmol, 2 eq), gem-difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid-binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) into a 10 mL sealed tube at one time. Under nitrogen protection, irradiate for 24h. After the reaction is complete, carry out column chromatography, separate with petroleum ether: ethyl acetate = 50:1, collect the eluate, spin dry, and obtain a colorless transparent liquid to obtain the fluorinated olefin compound 1;

[0033]

[0034] The structural formula of the fluorinated olefin compound 1 is:

[0035] The spectral data for the structural identification of the fluorinated olefin compound 1 are as follows:

[0036] (Z)-4-(1-fluoro-2-(p-tolyl)vinyl)tetrahydro-2H-pyran(1)

[0037] 1 H NMR(500MHz,CDCl 3): δ 7.370 (d, J = 10 Hz, 2H), 7.126 (d, J = 10.0 Hz, 2H), 5.43 (d, J = 51.0 Hz, 1H), 4.046 (dd, J = 14.5 Hz, 4.5 Hz, 2H), 3.451 (td, J = 14.5 Hz, 2.0 Hz, 2H), 2.550 - 2.438 (m, 1H), 2.330 (s, 3H), 1.842 - 1.669 (m, 4H).

[0038] 19 F NMR (471 MHz, CDCl 3 ): -107.988 (s, 1F).

[0039] 13 C NMR (126 MHz, CDCl 3 ): 162.618 (d, J = 330.624 Hz), 136.776 (d, J = 2.772 Hz), 130.770 (d, J = 2.646 Hz), 129.278, 128.469 (d, J = 9.198 Hz), 104.340 (d, J = 11.088 Hz), 67.655, 38.865 (d, J = 32.760 Hz), 29.915 (d, J = 3.024 Hz), 21.338.

[0040] Example 2

[0041] Synthesis method of a fluorinated olefin compound for anti - myocardial fibrosis, comprising the following steps:

[0042] Compound 1a (0.2 mmol, 2 eq), gem - difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid - binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) are added to a 10 mL sealed tube at one time. Under nitrogen protection, it is irradiated with light for 24 h. After the reaction is complete, it is chromatographed, separated with petroleum ether: ethyl acetate = 50:1, the eluate is collected, and the solvent is evaporated to dryness to obtain a colorless transparent liquid, and the fluorinated olefin compound 2 is obtained;

[0043]

[0044] The spectral data for the structural identification of fluorinated olefin compound 2 are as follows:

[0045] (Z)-1-(2 - cyclohexyl - 2 - fluorovinyl)-4 - methylbenzene (2)

[0046] 11H NMR (500 MHz, CDCl 3 ): δ 7.365 (d, J = 10 Hz, 2H), 7.115 (d, J = 10.0 Hz, 2H), 5.398 (d, J = 51.5 Hz, 1H), 2.326 (s, 3H), 2.275 - 2.167 (m, 1H), 1.961 - 1.939 (m, 2H), 1.823 - 1.693 (m, 2H), 1.377 - 1.236 (m, 6H).

[0047] 19 19F NMR (471 MHz, CDCl 3 ): -106.257 (s, 1F).

[0048] 13 13C NMR (126 MHz, CDCl 3 ): 164.731 (d, J = 334.278 Hz), 136.343 (d, J = 2.898 Hz), 131.299 (d, J = 2.520 Hz), 129.202, 128.379 (d, J = 9.072 Hz), 103.488 (d, J = 11.340 Hz), 41.667 (d, J = 30.996 Hz), 30.222 (d, J = 2.646 Hz), 26.064, 21.316.

[0049] Example 3

[0050] Synthesis method of a fluorinated olefin compound with anti - myocardial fibrosis, comprising the following steps:

[0051] Add compound 1a (0.2 mmol, 2 eq), gem - difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid - binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) into a 10 - mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24 h. After the reaction is complete, perform column chromatography, separate with petroleum ether: ethyl acetate = 50:1, collect the eluate, rotary evaporate to obtain a colorless transparent liquid, and obtain the fluorinated olefin compound 3;

[0052]

[0053] The structural formula of the fluorinated olefin compound 3 is:

[0054] The spectral data for the structural identification of the fluorinated olefin compound 3 are as follows:

[0055] (3R,5R)-1-((Z)-2-(4-(tert-butyl)phenyl)-1-fluorovinyl)adamantane(3)

[0056] 1 H NMR(500MHz,CDCl 3 ):7.461 - 7.444(m,2H),7.366 - 7.345(m,2H),5.423(d,J 1 =42.0Hz,1H),2.079(s,3H),1.875 - 1.870(m,7H),1.796 - 1.723(m,7H),1.337(s,9H).

[0057] 19 F NMR(471MHz,CDCl 3 ): - 115.057(s,1F).

[0058] 13 C NMR(126MHz,CDCl 3 ):167.916(d,J=268.128Hz),149.577,131.481,128.324(d,J=7.308Hz),125.398,102.086(d,J=9.828Hz),39.439,36.811,34.611,31.425,28.144.

[0059] Example 4

[0060] Synthesis method of a fluorinated olefin compound for anti - myocardial fibrosis, comprising the following steps:

[0061] Add compound 1a(0.2mmol, 2eq), gem - difluoroolefin derivative 2a(0.1mmol, 1eq), acid - binding agent CS 2 CO 3 (0.3mmol, 3eq) and photosensitizer 4CzIPN(0.01mol) into a 10 - mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24h. After the reaction is complete, perform column chromatography, separate with petroleum ether: ethyl acetate = 50:1, collect the eluate, evaporate to dryness to obtain a colorless transparent liquid, and obtain the fluorinated olefin compound 4;

[0062]

[0063] The structural formula of the fluorinated olefin compound 4 is:

[0064] The spectral data for the structural identification of the fluorinated olefin compound 4 are as follows:

[0065] (Z)-1-(tert-butyl)-4-(2-fluoro-3,3-dimethylbut-1-en-1-yl)benzene(4)

[0066] 1 H NMR(500MHz,CDCl 3 ): 7.438 (dt, J 1 = 8.5Hz, J 2 = 2.0Hz, 2H), 7.347 (dt, J 1 = 8.5Hz, J 2 = 2.0Hz, 2H), 5.514 (d, J 1 = 41Hz, 1H), 1.321 (s, 9H), 1.221 (s, 9H).

[0067] 19 F NMR(471MHz,CDCl 3 ): -110.380 (s, 1F).

[0068] 13 C NMR(126MHz,CDCl 3 ): 165.154 (d, J = 271.404Hz), 136.424, 134.984, 126.820 (t, J = 8.82Hz), 102.728 (d, J = 8.19Hz), 67.464, 38.861 (d, J = 25.452Hz), 29.638.

[0069] Example 5

[0070] Synthesis method of a fluorinated olefin compound for anti-myocardial fibrosis, comprising the following steps:

[0071] Add compound 1a (0.2 mmol, 2 eq), gem-difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid-binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) into a 10 mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24 h. After the reaction is complete, perform column chromatography, separate with petroleum ether: ethyl acetate = 50:1, collect the eluate, spin-dry to obtain a colorless transparent liquid, and obtain the fluorinated olefin compound 5;

[0072]

[0073] The structural formula of the fluorinated olefin compound 5 is:

[0074] The spectral data for the structural identification of the fluoroolefin compound 5 are as follows:

[0075] tert-butyl

[0076] (Z)-4-(2-(4-chlorophenyl)-1-fluorovinyl)piperidine-1-carboxylate(5)

[0077] 1 H NMR(500MHz,CDCl 3 ):δ7.384(d,J=11.0Hz,2H),7.266(d,J=11.0Hz,2H),5.515(d,J=50.0Hz,1H),4.193(s,2H),2.776-2.719(m,2H),2.437-2.325(m,1H),1.896-1.864(m,2H),1.576-1.503(m,2H),1.462(s,9H).

[0078] 19 F NMR(471MHz,CDCl 3 ):-105.417(s,1F).

[0079] 13 C NMR(126MHz,CDCl 3 ):163.620(d,J=335.412Hz),154.837,132.576(d,J=4.284Hz),132.081(d,J=2.772Hz),129.808(d,J=9.45Hz),128.710,103.720(d,J=10.710Hz),79.802,39.943(d,J=31.878Hz),31.574,30.328,29.096,28.584.

[0080] Example 6

[0081] A method for synthesizing a fluoroolefin compound with anti-myocardial fibrosis, comprising the following steps:

[0082] Mix compound 1a(0.2mmol,2eq),gem-difluoroolefin derivative 2a(0.1mmol,1eq),acid-binding agent CS 2 CO 3(0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) were added to a 10 mL sealed tube at one time. Under nitrogen protection, it was irradiated with light for 24 h. After the reaction was complete, it was purified by column chromatography with petroleum ether:ethyl acetate = 50:1. The eluent was collected, concentrated by rotary evaporation to obtain a colorless transparent liquid, and the fluorinated olefin compound 6 was obtained;

[0083]

[0084] The structural formula of the fluorinated olefin compound 6 is:

[0085] The spectral data for the structural identification of the fluorinated olefin compound 6 are as follows:

[0086] tert-butyl

[0087] (Z)-4-(2-(4-bromophenyl)-1-fluorovinyl)piperidine-1-carboxylate (6)

[0088] 1 H NMR (500 MHz, CDCl 3 ): δ 7.425 (d, J = 10.5 Hz, 2H), 7.325 (d, J = 10.5 Hz, 2H), 5.405 (d, J = 50.0 Hz, 1H), 4.194 (s, 2H), 2.779 - 2.721 (m, 2H), 2.427 - 2.333 (m, 1H), 1.883 (d, J = 16 Hz, 2H), 1.579 - 1.507 (m, 2H), 1.467 (s, 9H).

[0089] 19 F NMR (471 MHz, CDCl 3 ): -105.012 (s, 1F).

[0090] 13 C NMR (126 MHz, CDCl 3 ): 163.747 (d, J = 268.758 Hz), 154.827, 132.525, 131.662, 130.119 (d, J = 7.686 Hz), 120.703, 103.774 (d, J = 8.442 Hz), 79.796, 43.642, 39.965 (d, J = 25.578 Hz), 29.075, 28.581.

[0091] Example 7

[0092] A method for synthesizing a fluorinated olefin compound with anti-myocardial fibrosis, comprising the following steps:

[0093] Compound 1a (0.2 mmol, 2 eq), gem-difluoroalkene derivative 2a (0.1 mmol, 1 eq), acid scavenger CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) were added to a 10 mL sealed tube at once. Under nitrogen protection, it was irradiated with light for 24 h. After the reaction was complete, it was purified by column chromatography with petroleum ether:ethyl acetate = 50:1 for separation. The eluent was collected, evaporated to dryness, and a colorless transparent liquid was obtained to obtain the fluoroalkene compound 7;

[0094]

[0095] The structural formula of the fluoroalkene compound 7 is as follows:

[0096] The spectral data for the structural identification of the fluoroalkene compound 7 are as follows:

[0097] tert-butyl(Z)-4-(1-fluoro-2-(p-tolyl)vinyl)piperidine-1-carboxylate(7)

[0098] 1 1H NMR (500 MHz, CDCl 3 ): δ 7.359 (d, J = 10.0 Hz, 2H), 7.123 (d, J = 10.0 Hz, 2H), 5.367 (d, J = 51.0 Hz, 1H), 4.191 (s, 2H), 2.786 - 2.726 (m, 2H),

[0099] 2.428 - 2.329 (m, 4H), 1.904 - 1.874 (m, 2H), 1.555 - 1.515 (m, 2H), 1.470 (s, 9H).

[0100] 19 19F NMR (471 MHz, CDCl 3 ): -107.397 (s, 1F).

[0101] 13 13C NMR (126 MHz, CDCl 3): 162.586 (d, J = 266.49 Hz), 154.872, 136.788, 130.732, 129.274, 128.467 (d, J = 7.182 Hz), 104.491 (d, J = 8.694 Hz), 79.728, 43.681, 39.933 (d, J = 25.956 Hz), 29.205, 28.597, 21.333。

[0102] Example 8

[0103] Synthesis method of a fluoroolefin compound for anti-myocardial fibrosis, comprising the following steps:

[0104] Add compound 1a (0.2 mmol, 2 eq), gem-difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid-binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) into a 10 mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24 h. After the reaction is complete, perform column chromatography, separate with petroleum ether:ethyl acetate = 50:1, collect the eluate, evaporate to dryness, obtain a white solid, and obtain fluoroolefin compound 8;

[0105]

[0106] The structural formula of fluoroolefin compound 8 is:

[0107] The spectral data for the structural identification of fluoroolefin compound 8 are as follows:

[0108] tert-butyl

[0109] (Z)-4-(2-([1,1'-biphenyl]-4-yl)-1-fluorovinyl)piperidine-1-carboxylate (8)

[0110] 1 H NMR (500 MHz, CDCl 3 ): δ 7.613 - 7.534 (m, 6H), 7.457 - 7.419 (m, 2H), 7.359 - 7.322 (m, 1H), 5.512 (d, J = 50.0 Hz, 1H), 4.219 (s, 2H), 2.804 - 2.746 (m, 2H), 2.478 - 2.368 (m, 1H), 1.934 - 1.903 (m, 2H), 1.589 - 1.548 (m, 2H), 1.484 (s, 9H).

[0111] 19 F NMR (471 MHz, CDCl 3 ): -105.780 (s, 1F).

[0112] 13 C NMR (126 MHz, CDCl 3 ): 163.383 (d, J = 267.876 Hz), 154.855, 140.832, 139.691, 132.681, 128.972 (d, J = 7.812 Hz), 128.910, 127.405, 127.219, 127.059, 104.335 (d, J = 8.442 Hz), 79.755, 43.643, 40.005 (d, J = 25.704 Hz), 29.173, 28.590.

[0113] Example 9

[0114] Synthesis method of a fluorinated olefin compound for anti - myocardial fibrosis, comprising the following steps:

[0115] Add compound 1a (0.2 mmol, 2 eq), gem - difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid - binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) into a 10 mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24 h. After the reaction is complete, perform column chromatography, separate with petroleum ether: ethyl acetate = 50:1, collect the eluate, evaporate to dryness to obtain a colorless transparent liquid, and obtain fluorinated olefin compound 9;

[0116]

[0117] The structural formula of fluorinated olefin compound 9 is:

[0118] The spectral data for the structural identification of fluorinated olefin compound 9 are as follows:

[0119] tert - butyl

[0120] (Z)-4-(1 - fluoro - 2-(4 - methoxyphenyl)vinyl)piperidine - 1 - carboxylate (9)

[0121] 1 H NMR (500 MHz, CDCl 3 ): 7.228 (t, J 1 = 10.0 Hz, J 2= 20 Hz, 1H), 7.056 - 7.023 (m, 2H), 6.778 (dd, J 1 = 10.5 Hz, J 2 = 3.5 Hz, 1H), 5.442 (d, J = 50.0 Hz, 1H), 4.199 (s, 2H), 3.807 (s, 3H), 2.785 - 2.724 (m, 2H), 2.446 - 2.325 (m, 1H), 1.910 - 1.878 (m, 2H), 1.562 - 1.520 (m, 2H), 1.469 (s, 9H).

[0122] 19 F NMR (471 MHz, CDCl 3 ): -84.614 (d, J = 45.216 Hz, 1F), -86.423 (d, J =

[0123] 45.687 Hz, 1F).

[0124] 13 C NMR (126 MHz, CDCl 3 ): 163.351 (d, J = 268.254), 159.731, 154.869, 134.897, 129.48, 121.237 (d, J = 6.93 Hz), 113.919 (d, J = 8.064 Hz), 112.894, 104.644 (d, J = 8.19 Hz), 79.769, 55.343, 39.992 (d, J = 25.704 Hz), 29.141, 28.597.

[0125] Example 10

[0126] Synthesis method of a fluorinated olefin compound with anti - myocardial fibrosis, comprising the following steps:

[0127] Add compound 1a (0.2 mmol, 2 eq), gem - difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid - binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) into a 10 mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24 h. After the reaction is complete, perform column chromatography, separate with petroleum ether: ethyl acetate = 50:1, collect the eluate, spin - dry to obtain a colorless transparent liquid, and obtain fluorinated olefin compound 10;

[0128]

[0129] The structural formula of fluorinated olefin compound 10 is:

[0130] The spectral data for the structural identification of the fluoroolefin compound 10 are as follows:

[0131] (Z)-4-(1-fluoro-2-(4-isopropylphenyl)vinyl)tetrahydro-2H-pyran(10)

[0132] 1 H NMR(500MHz,CDCl 3 ): 7.421(d, J = 10.5Hz, 2H), 7.193(d, J = 10.5Hz, 2H), 5.450(d, J 1 = 51.0Hz, 1H), 4.052(dd, J 1 = 14.50Hz, J 2 = 10.5Hz, 2H), 3.456(td,

[0133] J 1 = 14.50Hz, J 2 = 2.5Hz, 2H) 2.946 - 2.843(m, 1H), 2.556 - 2.446(m, 1H), 1.326(d, J = 8.5Hz, 6H).

[0134] 19 F NMR(471MHz,CDCl 3 ): -107.977(s, 1F).

[0135] 13 C NMR(126MHz,CDCl 3 ): 162.676(d, J = 266.616Hz), 147.798, 131.170, 128.544(d, J = 7.182Hz), 126.634, 104.309(d, J = 98.82Hz), 67.630, 38.845(d, J = 26.208Hz), 33.976, 29.916, 24.055.

[0136] Example 11

[0137] A method for synthesizing a fluoroolefin compound with anti-myocardial fibrosis, comprising the following steps:

[0138] Mix compound 1a(0.2mmol, 2eq), gem-difluoroolefin derivative 2a(0.1mmol, 1eq), and an acid-binding agent CS 2 CO 3(0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) were added to a 10 mL sealed tube at one time. Under nitrogen protection, it was irradiated with light for 24 h. After the reaction was complete, it was subjected to column chromatography, and separated with petroleum ether:ethyl acetate = 50:1. The eluate was collected, evaporated to dryness, and a colorless transparent liquid was obtained to obtain fluorinated olefin compound 11;

[0139]

[0140] The structural formula of fluorinated olefin compound 11 is:

[0141] The spectral data for the structural identification of fluorinated olefin compound 11 are as follows:

[0142] (Z)-4-(2-(3,5-dimethylphenyl)-1-fluorovinyl)tetrahydro-2H-pyran (11)

[0143] 1 H NMR (500 MHz, CDCl 3 ): 7.112 (s, 2H), 6.870 (s, 1H), 5.404 (d, J 1 = 51.0 Hz, 1H), 4.763 (s, 1H), 4.048 (dd, J 1 = 14.0 Hz, J 2 = 10.0 Hz, 2H), 3.454 (td, J 1 = 14.50 Hz, J 2 = 2.5 Hz, 2H), 2.547 - 2.436 (m, 1H), 2.304 (s, 6H), 1.842 - 1.668 (m, 4H).

[0144] 19 F NMR (471 MHz, CDCl 3 ): -107.105 (s, 1F).

[0145] 13 C NMR (126 MHz, CDCl 3 ): 162.873 (d, J = 267.12 Hz), 137.988, 133.415, 128.754, 126.403 (d, J = 6.93 Hz), 104.555 (d, J = 8.316 Hz), 67.627, 38.877 (d, J = 26.082 Hz), 29.882, 21.453.

[0146] Example 12

[0147] Synthesis method of a fluorinated olefin compound for anti-myocardial fibrosis, comprising the following steps:

[0148] Add compound 1a (0.2 mmol, 2 eq), gem-difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid-binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) into a 10 mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24 h. After the reaction is complete, perform column chromatography, separate with petroleum ether:ethyl acetate = 50:1, collect the eluate, evaporate to dryness to obtain a colorless transparent liquid, and obtain fluorinated olefin compound 12;

[0149]

[0150] Spectral data for the structural identification of fluorinated olefin compound 12 is as follows:

[0151] (Z)-4-(2-(3,5-dichlorophenyl)-1-fluorovinyl)tetrahydro-2H-pyran (12)

[0152] 1 H NMR (500 MHz, CDCl 3 ): 7.356 - 7.351 (m, 2H), 7.207 - 7.198 (m, 1H), 5.372 (d, J 1 = 48.5 Hz, 1H), 4.051 (dd, J 1 = 10.0 Hz, J 2 = 4.0 Hz, 2H), 3.447 (td, J 1 = 14.50 Hz, J 2 = 2.5 Hz, 2H), 2.564 - 2.453 (m, 1H), 1.832 - 1.796 (m, 2H), 1.754 - 1.651 (m, 2H).

[0153] 19 F NMR (471 MHz, CDCl 3 ): -102.333 (s, 1F).

[0154] 13 C NMR (126 MHz, CDCl 3): 162.794 (d, J = 266.49 Hz), 150.046, 130.807, 128.286 (d, J = 7.308 Hz), 125.507, 104.217 (d, J = 8.946 Hz), 67.647, 38.863 (d, J = 26.334 Hz), 34.672, 31.406, 29.924 (d, J = 1.26 Hz).

[0155] Example 13

[0156] A method for synthesizing a fluoroolefin compound with anti-myocardial fibrosis, comprising the following steps:

[0157] Add compound 1a (0.2 mmol, 2 eq), gem-difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid-binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) into a 10 mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24 h. After the reaction is complete, perform column chromatography, separate with petroleum ether: ethyl acetate = 50:1, collect the eluate, evaporate to dryness, and obtain a pale yellow transparent liquid to obtain fluoroolefin compound 13;

[0158]

[0159] The structural formula of fluoroolefin compound 13 is:

[0160] The spectral data for the structural identification of fluoroolefin compound 13 are as follows:

[0161] (Z)-4-(1-fluoro-2-(4-iodophenyl)vinyl)tetrahydro-2H-pyran (13)

[0162] 1 H NMR (500 MHz, CDCl 3 ): 7.633 (dt, J 1 = 10.5 Hz, J 2 = 5.0 Hz, 2H), 7.210 (d, J 1 = 10.5 Hz, J 2 = 3.0 Hz, 2H), 5.393 (d, J = 50.0 Hz, 1H), 4.047 (dd, J 1 = 10.0 Hz, J 2 = 4.5 Hz, 2H), 3.447 (td, J 1 = 14.50 Hz, J 2=2.5Hz, 2H), 2.547 - 2.437 (m, 1H), 1.840 - 1.803 (m, 2H), 1.763 - 1.660 (m, 2H).

[0163] 19 F NMR (471 MHz, CDCl 3 ): -105.054 (s, 1F).

[0164] 13 C NMR (126 MHz, CDCl 3 ): 163.959 (d, J = 269.01 Hz), 137.634, 133.133, 130.342 (d, J = 7.56 Hz), 103.711 (d, J = 8.442 Hz), 92.179, 67.550, 38.908 (d, J = 25.956 Hz), 29.745.

[0165] Example 14

[0166] Synthesis method of a fluorinated olefin compound with anti - myocardial fibrosis, comprising the following steps:

[0167] Add compound 1a (0.2 mmol, 2 eq), gem - difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid - binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) into a 10 mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24 h. After the reaction is complete, perform column chromatography, separate with petroleum ether: ethyl acetate = 50:1, collect the eluate, evaporate to dryness to obtain a colorless transparent liquid, and obtain fluorinated olefin compound 14;

[0168]

[0169] The structural formula of fluorinated olefin compound 14 is:

[0170] The spectral data for the structural identification of fluorinated olefin compound 14 are as follows:

[0171] (Z)-6-(2 - fluoro - 3,3 - dimethylbut - 1 - en - 1 - yl)-2,3 - dihydrobenzo[b][1,4]dioxine (14)

[0172] 1 H NMR (500 MHz, CDCl 3): 7.071 (d, J = 2.5 Hz, 2H), 6.690 - 6.934 (m, 1H), 6.799 (d, J = 10.5 Hz, 2H), 5.405 (d, J = 50.5 Hz, 1H), 4.248 (s, 4H), 1.999 (s, 9H).

[0173] 19 F NMR (471 MHz, CDCl 3 ): -111.348 (s, 1F).

[0174] 13 C NMR (126 MHz, CDCl 3 ): 167.198 (d, J = 268.506 Hz), 143.363, 142.437, 127.811, 122.062 (d, J = 7.056 Hz), 117.323 (d, J = 8.442 Hz), 117.136, 101.722 (d, J = 9.702 Hz), 64.533 (d, J = 15.372 Hz), 35.513 (d, J = 23.94 Hz), 27.6 (d, J = 1.764 Hz).

[0175] Example 15

[0176] Synthesis method of a fluorinated olefin compound for anti - myocardial fibrosis, comprising the following steps:

[0177] Add compound 1a (0.2 mmol, 2 eq), gem - difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid - binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) into a 10 mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24 h. After the reaction is complete, perform column chromatography, separate with petroleum ether: ethyl acetate = 50:1, collect the eluate, rotary evaporate to obtain a pale yellow transparent liquid, and obtain fluorinated olefin compound 15;

[0178]

[0179] The structural formula of fluorinated olefin compound 15 is:

[0180] The spectral data for the structural identification of fluorinated olefin compound 15 are as follows:

[0181] (Z)-4-(1 - fluoro - 2-(4-(methylthio)phenyl)vinyl)tetrahydro - 2H - pyran (15)

[0182] 1 H NMR (500 MHz, CDCl 3 ): 7.401 (d, J = 10.5 Hz, 2H), 7.203 (d, J = 10.5 Hz, 2H), 5.416 (d, J = 50.0 Hz, 1H), 4.047 (dd, J 1 = 14.5 Hz, J 2 = 4.0 Hz, 2H), 3.449 (td, J 1 = 14.5 Hz, J 2 = 2.5 Hz, 2H), 2.551 - 2.441 (m, 4H), 1.842 - 1.806 (m, 2H), 1.768 - 1.665 (m, 2H).

[0183] 19 F NMR (471 MHz, CDCl 3 ): -106.871 (s, 1F).

[0184] 13 C NMR (126 MHz, CDCl 3 ): 163.053 (d, J = 267.372 Hz), 137.040, 130.546, 128.946 (d, J = 7.56 Hz), 126.670, 103.989 (d, J = 8.82 Hz), 67.609, 38.878 (d, J = 26.082 Hz), 29.853, 15.953.

[0185] Example 16

[0186] Synthesis method of a fluorinated olefin compound for anti - myocardial fibrosis, comprising the following steps:

[0187] Add compound 1a (0.2 mmol, 2 eq), gem - difluoroolefin derivative 2a (0.1 mmol, 1 eq), acid - binding agent CS 2 CO 3 (0.3 mmol, 3 eq) and photosensitizer 4CzIPN (0.01 mol) into a 10 mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24 h. After the reaction is complete, perform column chromatography, separate with petroleum ether: ethyl acetate = 50:1, collect the eluate, rotary evaporate to obtain a colorless transparent liquid, and obtain fluorinated olefin compound 16;

[0188]

[0189] The structural formula of fluorinated olefin compound 16 is:

[0190] The spectral data for the structural identification of fluorinated olefin compound 16 are as follows:

[0191] (Z)-1-(2-fluoro-3,3-dimethylbut-1-en-1-yl)-2-methoxybenzene(16)

[0192] 1 H NMR(500MHz,CDCl 3 ): 6.761 - 6.660(m, 2H), 5.951(s, 2H), 5.414(d, J 1 = 50.0Hz, 1H), 3.897(s, 3H), 1.206(s, 9H).

[0193] 19 F NMR(471MHz,CDCl 3 ): -110.466(s, 1F).

[0194] 13 C NMR(126MHz,CDCl 3 ): 167.381(d, J = 269.262Hz), 148.910, 143.459, 134.095(d, J 1 = 2.142Hz), 128.702, 108.138(d, J = 7.308Hz), 102.859(d, J = 9.198Hz), 102.226(d, J = 9.45Hz), 101.466, 56.576, 35.567(d, J = 24.192Hz), 27.575(d, J = 1.764Hz).

[0195] Example 17

[0196] Synthesis method of a fluorinated olefin compound for anti - myocardial fibrosis, comprising the following steps:

[0197] Add compound 1a(0.2mmol, 2eq), gem - difluoroolefin derivative 2a(0.1mmol, 1eq), acid - binding agent CS 2 CO 3 (0.3mmol, 3eq) and photosensitizer 4CzIPN(0.01mol) into a 10mL sealed tube at one time. Under nitrogen protection, irradiate with light for 24h. After the reaction is complete, perform column chromatography, separate with petroleum ether: ethyl acetate = 50:1, collect the eluate, evaporate to dryness to obtain a colorless transparent liquid, and obtain fluorinated olefin compound 17;

[0198]

[0199] The structural formula of fluorinated olefin compound 17 is:

[0200] The spectral data for the structural identification of the fluoroolefin compound 17 are as follows:

[0201] 4-((1Z,3E)-1-fluoro-4-(p-tolyl)buta-1,3-dien-1-yl)tetrahydro-2H-pyran(17)

[0202] 1 H NMR(500MHz,CDCl 3 ): 7.304(d, J = 10.0Hz, 2H), 7.117(d, J = 10.0Hz, 2H), 6.972(dd, J 1 = 20.0Hz, J 2 = 13.5Hz, 1H), 6.459(d, J = 19.5Hz, 1H), 5.404(dd, J 1 = 45.0Hz, J 2 = 13.5Hz, 1H), 4.028(dd, J 1 = 14.0Hz, J 2 = 4.5Hz, 2H), 3.434(td, J 1 = 14.5Hz,

[0203] J 2 = 2.5Hz, 2H), 2.510 - 2.402(m, 1H), 2.332(s, 3H), 1.807 - 1.771(m, 2H), 1.714 - 1.611(m, 2H).

[0204] 19 F NMR(471MHz,CDCl 3 ): -109.412(s, 1F).

[0205] 13 C NMR(126MHz,CDCl 3 ): 163.084(d, J = 265.104Hz), 137.494, 134.722, 130.778(d, J = 3.024Hz), 129.465, 126.355, 119.629(d, J = 5.67Hz), 105.668(d, J = 11.97Hz), 67.575, 38.072(d, J = 25.704Hz), 29.705, 21.374.

[0206] Pharmacological activity

[0207] Materials and methods

[0208] 1. Isolation and culture of CFb (angiotensin II-induced neonatal rat cardiac fibroblasts)

[0209] For Wistar rats aged 1 - 3 days after birth, open the chest aseptically, take the myocardium, wash it with D-Hank's solution, cut it into fragments of 1 mm × 1 mm × 1 mm size, and digest it repeatedly with 0.125% trypsin (in a 37°C water bath, 8 min each time) -1 ) Collect the digestion supernatants each time and centrifuge (1000 r·min -1 , 5 min), discard the supernatant, resuspend the precipitate with IMDM medium containing 10% serum to make a cell suspension, inoculate it into a culture flask, and place it in an incubator at 37°C and 5% CO 2 for culture. Remove endothelial cells and cardiomyocytes by differential adhesion method. The 3rd - 5th passage cells were used in the experiment.

[0210] 2. Experimental grouping and drug administration

[0211] Control group: IMDM medium with 1% serum;

[0212] Model group: Ang II 10 -7 mol·L -1 ;

[0213] Drug administration group: IMDM medium containing Ang II 10 -7 mol·L -1 and compound 1 - 17 (80 mmol / L -1 ).

[0214] 3. Cell growth and proliferation experiment (MTT method)

[0215] Make a cell suspension of CFb in the logarithmic growth phase, inoculate it into a 96-well plate at a concentration of 1×10 5 ·mL -1 , 200 μL per well. After drug administration (80 mmol / L -1 ), incubate for 24 h. Add 20 μL of MTT solution (5 mg·L -1 ) to each well, continue to culture at 37°C for 4 h to terminate the culture, add 150 μL of DMSO to each well, shake for 10 min, and then measure the optical density (OD) value at a wavelength of 490 nm on an enzyme-linked immunosorbent assay (ELISA) reader.

[0216] Cell proliferation rate = OD value of each experimental group / OD value of the control group × 100%.

[0217] 4. Determination of TGF-β1 protein (ELISA method)

[0218] Make a cell suspension of the 3rd passage CFb, at a concentration of 2.5×10 5 ·mL -1Inoculate at a concentration into 24-well plates, 1 mL per well. After treatment with each factor, aspirate the cell supernatant at 24 h of culture and detect TGF-β strictly according to the kit instructions. 1 Content.

[0219] 5. Determination of type I collagen content (ELISA method)

[0220] Prepare a cell suspension from the 3rd passage of CFb and inoculate it into 24-well plates at a concentration of 2.5×10 5 ·mL -1 Concentration, 1 mL per well. After treatment with each factor, aspirate the cell supernatant at 24 h and detect the content of type I collagen according to the reagent instructions.

[0221] Table 1 Content of type I collagen, TGF-β 1 , cell proliferation rate

[0222]

[0223]

[0224] Results:

[0225] MTT results showed that: under the same culture conditions, the cell proliferation rate in the Ang II model group was significantly higher than that in the control group (P<0.01). After 24 h of culture with drug administration, the cell proliferation rate results are shown in Table 1. Among them, the cell proliferation rates of compound 4 (135.4±15.9), compound 5 (151.2±2.9), compound 8 (154.71±11.84), compound 12 (146.99±2.45) and compound 17 (131.79±8.49) were lower than those in the Ang II model group (160±20.33), but only compound 4, 5, 12, 17 had statistical significance (P<0.05, P<0.01). Therefore, compound 4, 5, 12 and 17 can effectively inhibit the proliferation of CFb cells.

[0226] TGF-β1 protein content detection experiment: The content of TGF-β1 can be significantly increased after 24 h of Ang II treatment, showing a difference compared with the control group (P<0.01). After 24 h of drug administration, compound 4 (994.0±118.6), compound 8 (1023.91±1.76), compound 10 (1002.4±16.6), compound 12 (981.63±2.45) and compound 17 (985.98±5.71) can inhibit the induction of TGF-β1 by Ang II.

[0227] Type I collagen content detection experiment: The content of type I collagen can be significantly increased after 24 h of Ang II treatment, showing a difference compared with the control group (P<0.01). After 24 h of drug administration, compounds 4 (184.81±33.09), 8 (332.52±39.89), 12 (187.53±45.76) and 17 (114.39±36.18) can inhibit the induction of Ang II on type I collagen.

[0228] Based on the above experiments, it is shown that compounds 4, 12, and 17 can effectively inhibit the proliferation of CFb cells and reduce the contents of TGF-β1 and type I collagen, and have a good effect on anti-myocardial fibrosis.

[0229] It should be understood that, in order to streamline the present disclosure and assist in understanding one or more of the various inventive aspects, in the foregoing description of the exemplary embodiments of the present invention, the various features of the present invention are sometimes grouped together into a single embodiment or the description thereof. However, the disclosed method should not be construed as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as reflected by the claims, the inventive aspects lie in less than all of the features of the foregoing disclosed embodiments. Thus, the claims following the detailed description are hereby expressly incorporated into the detailed description, where each claim stands on its own as a separate embodiment of the present invention.

[0230] Although the present invention has been described in terms of a limited number of embodiments, those skilled in the art within the technical field will appreciate that other embodiments can be envisioned within the scope of the invention as thus described. In addition, it should be noted that the language used in this specification has been principally selected for readability and instructional purposes and not for the purpose of explaining or limiting the subject matter of the invention. Accordingly, many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the appended claims. For the scope of the present invention, the disclosure of the present invention is illustrative, not restrictive, and the scope of the present invention is defined by the appended claims.

[0231] The above are only the preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A fluorinated olefin compound for preventing myocardial fibrosis, characterized in that: The following fluorinated olefin compounds:

2. Use of the anti-myocardial fibrosis fluorinated olefin compound according to claim 1 in the preparation of anti-myocardial fibrosis drugs.

3. An anti-myocardial fibrosis drug, characterized in that: Comprising the fluorine-containing olefin compound as claimed in claim 1.

4. The anti-myocardial fibrosis drug according to claim 3, characterized in that: Pharmaceutically acceptable excipients are also included.

5. The anti-myocardial fibrosis drug according to claim 3, characterized in that: Excipients include any one or more of solvents, propellants, solubilizers, co-solvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants, deflocculating agents, filter aids, and release retardants.

6. A preparation comprising the anti-myocardial fibrosis drug according to claim 3, characterized in that: Preparations include powders, tablets, granules, capsules, injections or oral solutions.

Images