JP7774508B2 - Compounds and antimalarials - Google Patents

Description

The present invention relates to compounds and antimalarial agents.

Malaria is an infectious disease caused by infection with protozoa belonging to the genus Plasmodium. It is transmitted by the Anopheles mosquito and causes symptoms such as intermittent fever attacks, anemia, and splenomegaly. In recent years, malaria has become more prevalent due to environmental changes, and it is a global infectious disease with an estimated 200 million to 300 million cases and more than 600,000 deaths per year.

Malaria parasites that infect humans include Plasmodium falciparum (P. falciparum), found throughout the tropical regions of Africa, Asia, and Latin America; Plasmodium vivax (P. vivax), found in tropical and temperate regions around the world; Plasmodium malariae (P. malariae), found worldwide; and Plasmodium ovale (P. ovale), found primarily in tropical West Africa. Among these, infection with Plasmodium falciparum produces the most severe symptoms, easily progressing to severe malaria within one to two weeks of onset, accompanied by encephalopathy, nephropathy, hemolytic anemia, pulmonary edema, cardiac damage, and severe enteritis, leading to multiple organ failure and death within a short period of time.

Typical drugs currently used to treat malaria include chloroquine, primaquine, pyrimethamine, artemisinin, and mefloquine. However, many of these drugs are highly toxic, and with the emergence of drug-resistant parasites, the spread of drug-resistant malaria has become a problem for chemotherapy. The only drug effective against drug-resistant malaria is quinine, but it has an extremely high risk of causing renal failure, making it a high-risk treatment even given current medical standards. Given this situation, there is a growing desire for the development of new non-alkaloid drugs that have high antimalarial activity, low toxicity, and high safety.

In addition, non-alkaloid compounds with antimalarial activity are known to include the natural organic compound artemisinin and cyclic peroxide derivatives such as N-89 (see, for example, Patent Document 1) and N-251.

Japanese Patent Application Laid-Open No. 2000-229965

Artemisinin is currently widely used as a treatment for resistant malaria, but its use alone does not completely cure malaria. Meanwhile, the recently developed N-89 and N-251 have been reported to be capable of completely curing malaria, but they are not yet available as treatments and are somewhat cytotoxic. Furthermore, artemisinin has the drawback of requiring a multi-step process for chemical synthesis, and because N-89 and N-251 use hydrogen peroxide in the manufacturing process, there is a risk of accidents due to intermediates or hydrogen peroxide.

The present invention was made in consideration of the above circumstances, and provides a compound that has reduced cytotoxicity, excellent antimalarial activity, and can be synthesized simply and safely, as well as an antimalarial agent using said compound.

As a result of extensive research to achieve the above-mentioned objective, the inventors discovered that cyclic peroxide derivatives containing fluorine atoms with specific structures have extremely excellent antimalarial activity while suppressing cytotoxicity, leading to the completion of the present invention.

That is, the present invention includes the following aspects.
(1) A compound represented by the following general formula (I):

(In general formula (I), ^R1 and ^R2 each independently represent a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl group, alkoxy group, aryl group, carboxy group, or amino group.)

(2) The compound according to (1), wherein in the general formula (I), R ¹ and R ² each independently represent a hydrogen atom, a fluorine atom, or a substituted or unsubstituted alkyl group.
(3) An antimalarial agent containing the compound according to (1) or (2) as an active ingredient.

The compound of the above aspect can provide a compound that has reduced cytotoxicity, excellent antimalarial activity, and can be synthesized simply and safely. The antimalarial agent of the above aspect contains the compound, has reduced cytotoxicity, and excellent antimalarial activity.

The compound according to one embodiment of the present invention (hereinafter referred to as "this embodiment") will be described in detail below.

≪Compound≫
The compound of this embodiment (hereinafter, sometimes referred to as "compound (I)") is represented by the following general formula (I).

(In general formula (I), ^R1 and ^R2 each independently represent a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl group, alkoxy group, aryl group, carboxy group, or amino group.)

Compound (I) is a fluorine atom-containing cyclic peroxide derivative that possesses a peroxide structure (O-O structure) and two fluorine atoms bonded to an alicyclic structure, giving it extremely excellent antimalarial activity. In other words, compound (I) is useful as a preventive and therapeutic agent for infections caused by malaria parasites.

Examples of malaria parasites to which Compound (I) can be applied include Plasmodium falciparum (P. falciparum), which is distributed throughout the tropical regions of Africa, Asia, and Latin America; Plasmodium vivax (P. vivax), which is distributed in tropical and temperate regions around the world; Plasmodium malariae (P. malariae), which is distributed worldwide; and Plasmodium ovale (P. ovale), which is distributed mainly in tropical West Africa. Among these, Compound (I) is preferably applied to Plasmodium falciparum (P. falciparum).

Furthermore, as shown in the examples below, compound (I) has reduced cytotoxicity.

Furthermore, as described below, compound (I) can be synthesized simply and safely by utilizing a photochemical reaction that uses oxygen or air during the process of introducing a peroxide structure (O-O structure) during the reaction process.

Next, the structure of compound (I) is described in detail below.

< ^R1 and ^R2 >
In general formula (I), R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl group, alkoxy group, aryl group, carboxy group, or amino group.

R ¹ and R ² may be the same or different, but are preferably the same for ease of synthesis.

[Halogen atom]
Examples of the halogen atom in ^R1 and ^R2 include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. Among these, a fluorine atom is preferred.

[Alkyl group]
The alkyl group for ^R1 and ^R2 has from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8 carbon atoms, even more preferably from 1 to 6 carbon atoms, still more preferably from 1 to 4 carbon atoms, still more preferably from 1 to 3 carbon atoms, and particularly preferably from 1 to 2 carbon atoms. The alkyl group may be linear, branched, or cyclic.

Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, cyclopropyl, butyl, isobutyl, and pentyl groups. Of these, methyl and ethyl groups are preferred.

Examples of substituents on the alkyl group include, but are not limited to, halogen atoms, alkoxy groups, and aryl groups. Examples of halogen atoms include those described above, and examples of alkoxy groups and aryl groups include those described below. Among these, for example, halogen atoms or alkoxy groups are preferred as substituents on the alkyl group, and fluorine atoms or alkoxy groups are more preferred.

Examples of alkyl groups substituted with fluorine atoms include, but are not limited to, fluoromethyl groups, difluoromethyl groups, and trifluoromethyl groups.

Examples of alkyl groups substituted with alkoxy groups include, but are not limited to, methoxymethyl groups and ethoxymethyl groups.

[Alkoxy group]
The alkoxy group for ^R1 and ^R2 has from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8 carbon atoms, even more preferably from 1 to 6 carbon atoms, still more preferably from 1 to 4 carbon atoms, still more preferably from 1 to 3 carbon atoms, and particularly preferably from 1 to 2 carbon atoms. The alkoxy group may be linear, branched, or cyclic.

Examples of such alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, iso-propoxy, sec-butoxy, and tert-butoxy groups. Among these, methoxy and ethoxy groups are preferred.

Examples of substituents on the alkoxy group include, but are not limited to, halogen atoms and aryl groups. Examples of halogen atoms include those described above, and examples of aryl groups include those described below. Of these, halogen atoms are preferred as substituents on the alkoxy group, and fluorine atoms are more preferred.

Examples of alkoxy groups substituted with fluorine atoms include, but are not limited to, fluoromethoxy groups, difluoromethoxy groups, and trifluoromethoxy groups.

[Aryl group]
The aryl group in R ¹ and R ² has 6 to 12 carbon atoms, preferably 6 to 10 carbon atoms, and more preferably 6 to 8 carbon atoms.
Such aryl groups include, but are not limited to, phenyl groups and the like.

Examples of substituents on the aryl group include, but are not limited to, halogen atoms and alkyl groups. Examples of halogen atoms and alkyl groups include those described above.

Examples of aryl groups substituted with halogen atoms include, but are not limited to, o-, m-, or p-halogen-substituted phenyl groups such as 4-fluorophenyl and 4-chlorophenyl groups.

Examples of aryl groups substituted with alkyl groups include, but are not limited to, o-, m-, or p-alkyl-substituted phenyl groups such as 2-methylphenyl, 3-methylphenyl, and 4-methylphenyl.

[Carboxy group]
Examples of the substituent on the carboxy group include, but are not limited to, alkoxy groups, etc. Examples of the alkoxy group include those mentioned above.

Examples of carboxy groups substituted with alkoxy groups include, but are not limited to, carbomethoxy groups and carboethoxy groups.

[Amino group]
The substituted amino group may be linear, branched, or cyclic in which the substituents are bonded to each other to form a ring structure.

Substituents on the amino group include, but are not limited to, alkyl groups.

Examples of chain amino groups substituted with alkyl groups include, but are not limited to, dimethylamino groups and diethylamino groups.

Examples of cyclic amino groups include, but are not limited to, piperidyl groups and pyrrolidyl groups.

[Preferred R ¹ and R ² ]
Among these, it is preferable that ^R1 and ^R2 each independently represent a hydrogen atom, a fluorine atom, a methyl group, or an ethyl group, and it is more preferable that ^R1 and ^R2 are the same and represent a hydrogen atom, a fluorine atom, a methyl group, or an ethyl group.

Specific examples of preferred compound (I) include compounds represented by the following formulas (I-1) to (I-4) (hereinafter, sometimes referred to as "compound (I-1)"). Note that these compounds are merely examples of preferred compound (I), and preferred compound (I) is not limited to these. In the following formulas, "Me" represents a methyl group, and "Et" represents an ethyl group.

<Method for producing compound (I)>
Compound (I) can be produced, for example, by the method shown in the following chemical reaction formula. The production method for compound (I) will be explained in detail below, dividing it into steps (i) to (iii) shown in the following chemical reaction formula. In the following chemical reaction formula, ^R1 and ^R2 are the same as ^R1 and ^R2 described above. In addition, the compounds represented by general formulas (Ia) to (Ic) may be referred to as compounds (Ia) to (Ic), respectively.

[Step (i)]
In step (i), compound (Ia) is reacted with difluoromethylenephosphonium ylide generated in situ to obtain compound (Ib).
Compound (Ia) is a known diketone compound.
Compound (Ib) is a difluoromethylene ketone compound.

In the reaction in step (i), compound (Ia), sodium chloroacetate in an amount 2 to 6 times (preferably 4 times) the molar amount relative to compound (Ia), tri(n-butyl)phosphine in an amount 2 to 6 times (preferably 4 times) the molar amount relative to compound (Ia), and dry dimethylformamide (solvent) are thoroughly mixed and heated at 100°C to 130°C (preferably 110°C to 120°C) for 5 to 60 minutes (preferably about 15 minutes), and then heated at 120°C to 135°C (preferably about 130°C) for 10 to 60 minutes (preferably about 30 minutes).

Difluorocarbene generated by thermal decomposition of sodium chloroacetate at 100°C or higher and 130°C or lower (preferably 110°C or higher and 120°C or lower) reacts with tri(n-butyl)phosphine to produce difluoromethylenephosphonium ylide, which then reacts with compound (Ia) to produce compound (Ib).

The resulting compound (Ib) can be easily isolated and purified from the reaction mixture by conventional separation techniques, such as column chromatography.

[Step (ii)]
In step (ii), compound (Ib) obtained in step (i) is reacted with a methylene phosphonium ylide in a dry solvent to obtain compound (Ic).
Compound (Ic) is a diene compound.

The solvent used in step (ii) includes tetrahydrofuran, ether, etc., and preferably tetrahydrofuran.
When a Wittig reagent is used for the methylenation of compound (Ib), it is preferable to prepare a methylphosphonium ylide from a methylphosphonium salt in a molar amount of 2.0 to 3.0 times (preferably 2.2 times) the amount of compound (Ib) and potassium tert-butoxide in a molar amount of 1.5 to 2.5 times (preferably 2.0 times) the amount of compound (Ib), and react the methylphosphonium ylide with compound (Ib) at room temperature (about 25±5°C) for 30 minutes to 5 hours (preferably 2 hours).

The resulting compound (Ic) can be easily isolated and purified from the reaction mixture by conventional separation methods, such as column chromatography.

[Step (iii)]
In step (iii), compound (I) is obtained by photoreacting compound (Ic) obtained in step (ii) with a photosensitizer and a co-sensitizer in a suitable solvent in the presence of oxygen.

Solvents used in step (iii) include, for example, dichloromethane and acetonitrile, with acetonitrile being preferred.

Examples of photosensitizers that can be used include 9,10-dicyanoanthracene, 2,4,6-triarylpyrylium tetrafluoroborate, and 2,4,6-triarylpyrylium perchlorate, with 2,4,6-triphenylpyrylium tetrafluoroborate being preferred.

Aromatic hydrocarbons such as naphthalene, durene, and biphenyl, which have stable and long-lived radical cations, can be used as auxiliary sensitizers, with biphenyl being preferred.

The irradiation light preferably has a long wavelength of 350 nm or more and 400 nm or less, which is absorbed only by the photosensitizer. A xenon lamp or sunlight may be used as long as it can irradiate light with a wavelength of 350 nm or more and 400 nm or more. A Lionet light irradiation device (350 nm wavelength lamp (maximum wavelength): 2 W x 15 lamps = 30 W) may also be used.

In the reaction in step (iii), it is preferable to use a photosensitizer (preferably 2,4,6-triphenylpyrylium tetrafluoroborate) in an amount of 0.05 to 0.3 times (preferably 0.1 to 0.2 times) molar amount relative to compound (Ic), and a co-sensitizer (preferably biphenyl) in an amount of 1.5 to 5.0 times (preferably 3.0 times) molar amount relative to compound (Ic).
The reaction temperature is preferably 20° C. or higher and 25° C. or lower, and the reaction time is preferably 5 minutes or higher and 30 minutes or lower.

The resulting compound (I) can be easily isolated and purified from the reaction mixture by conventional separation methods, such as column chromatography.

As described above, compound (I) can be synthesized simply and safely by utilizing a photochemical reaction that uses oxygen or air during the process of introducing the peroxide structure (O-O structure) in step (iii).

<Antimalarial drugs>
The antimalarial agent of this embodiment contains the above-mentioned compound (I) as an active ingredient.

The antimalarial agent of this embodiment contains compound (I) above, thereby reducing cytotoxicity and exhibiting excellent antimalarial activity.

In this specification, "containing as an active ingredient" means containing an amount of compound (I) effective to exert antimalarial activity while suppressing cytotoxicity.

When the antimalarial agent of this embodiment is used to prevent or treat infections caused by malaria parasites, it can be administered orally, by subcutaneous injection, intravenous injection, topical administration, or the like.

Formulations typically include oral preparations such as powders, tablets, fine granules, pills, capsules, and granules, which are prepared as pharmaceutical compositions by mixing with pharmaceutically acceptable carriers, excipients, and other additives; and parenteral preparations such as eye drops, injections, and suppositories.

Subjects to which the compound may be administered include, but are not limited to, humans, monkeys, dogs, cows, horses, sheep, pigs, rabbits, mice, rats, guinea pigs, hamsters, and cells thereof. Among these, mammals or mammalian cells are preferred, and humans or human cells are particularly preferred.

The dosage of the antimalarial agent of this embodiment varies depending on the type of compound (I), the symptoms of the subject, the administration site, the administration method, etc. Those skilled in the art will be able to select an appropriate dosage.

The antimalarial agent of this embodiment may be administered in a single dose or multiple doses. When administered multiple times, the agent may be administered, for example, every 2 to 12 hours, daily, or once every 2 days, 5 days, 1 week, 1.5 weeks, several weeks, 1 month, or several months.

Other Embodiments
In one embodiment, the present invention provides a method for preventing or treating an infection caused by a malaria parasite, comprising administering an effective amount of compound (I) to a patient or animal in need of treatment. Examples of compound (I) include those described above. Examples of malaria parasites include those described above.

In one embodiment, the present invention provides compound (I) for the prevention or treatment of infection caused by malaria parasites. Examples of compound (I) include those similar to those described above. Examples of malaria parasites include those similar to those described above.

In one embodiment, the present invention provides use of compound (I) for producing an antimalarial agent or a pharmaceutical composition for preventing or treating infections caused by malaria parasites. Examples of compound (I) include those similar to those described above. Examples of malaria parasites include those similar to those described above.

The following examples provide a more specific explanation of the fluorine atom-containing cyclic peroxide derivatives of the present invention. Note that the present invention is not limited to the following examples, and various modifications are possible.

<Production of Compound (I)>
[Production Example 1]
(Production of Compound (I-1))
Compound (I-1) was synthesized according to the following reaction scheme.

1. Step (i): Synthesis of 6,6-difluoro-1,5-di(p-methylphenyl)hex-5-en-1-one (compound (Ib-1)) 2.80 g (10.0 mmol) of 1,5-di(p-methylphenyl)penta-1,5-dione (compound (Ia-1)), 6.29 g (40.0 mmol) of sodium chlorodifluoroacetate, and 8.52 g (40.0 mmol) of tri(n-butyl)phosphine were dissolved in ultra-dehydrated dimethylformamide (10 mL), and the atmosphere in the reaction system was replaced with nitrogen, followed by heating and stirring in an oil bath. The temperature of the oil bath was raised to 130°C within 10 minutes. At around 70°C, both compound (Ia-1) and sodium chlorodifluoroacetate completely dissolved. At around 100°C, sodium chlorodifluoroacetate decomposed to produce difluorocarbene, which reacted with tri(n-butyl)phosphine to form difluoromethylenephosphonium ylide. By maintaining the oil bath temperature at 130°C for 30 minutes, this difluoromethylenephosphonium ylide reacted with compound (Ia-1) to produce compound (Ib-1). Compound (Ib-1) was isolated and purified from the reaction mixture by column chromatography. Specifically, after completion of the reaction, the mixture was cooled to room temperature, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, followed by water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off and the obtained crude product was separated by silica gel column chromatography (elution solvent: dichloromethane-n-hexane, 1:2) to obtain 1.46 g (yield 47% by mass) of compound (Ib-1) as a yellow oil.

The physical properties of compound (Ib-1) are shown below.
Colorless oil, C ₂₀ H ₂₀ F _2O , [MW314.37].
IR(KBr, cm-1):3088 ,3032 ,2954, 2926, 2900, 2871, 1684(C=O), 1608, 1573, 1515, 1453, 1409, 1378, 1362, 1328, 1314, 1303, 1274, 1180, 1120, 1106, 1077, 1036, 1019, 979, 938, 913, 870, 844, 821, 805, 728, 688, 655, 636.
¹ H NMR(400 MHz, CDCl ₃ ) δ: 1.81 (quintet, 2H, J = 7.6 Hz), 2.34 (s, 3H), 2.40 (s, 3H), 2.49 (tt, 2H, J _HH(t) = 7.6 Hz, J _HF(t) = 2.4 Hz), 2.92 (t, 2H, J = 7.6 Hz), 7.13-7.18 (m, 2H), 7.19-7.26 (m, 4H), 7.76-7.82 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ: 21.06 (qurtet, 1C), 21.55 (qurtet, 1C), 22.35 (t, 1C),
27.01 (t, 1C), 37.34 (t, 1C), 91.72 (s, 1C, J _CF(dd) = 19.8 Hz, 14.5 Hz), 128.03 (d, 2C, J _CF(t) = 3.0 Hz), 128.06 (d, 2C), 129.18 (d, 4C), 130.26 (s, 1C), 134.43 (s, 1C), 137.03 (s, 1C), 143.66 (s, 1C), 153.63 (s, 1C, J _CF(t) = 286.1 Hz), 199.28 (s, 1C, C=O).

2. Step (ii): Synthesis of 1,1-difluoro-2,6-di(p-methylphenyl)hepta-1,6-diene (compound (Ic-1)) 16.20 g (44.0 mmol) of methyltriphenylphosphonium bromide and 5.28 g (85% by mass, 40.0 mmol) of potassium tert-butoxide were dissolved in 70 mL of dry tetrahydrofuran, and the mixture was allowed to react at room temperature for 10 minutes under a nitrogen atmosphere to prepare a phosphonium ylide.

To this solution was added a tetrahydrofuran solution (30 mL) of 6.29 g (20.0 mmol) of 6,6-difluoro-1,5-di(p-methylphenyl)hex-5-en-1-one (compound (Ib-1)) and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was separated using silica gel column chromatography (elution solvent: hexane) to obtain 3.23 g (yield 52% by mass) of compound (Ic-1) as a colorless oil.

The physical properties of compound (Ic-1) are shown below.
Colorless oil, C ₂₁ H ₂₂ F ₂ , [MW312.40].
IR(KBr, cm-1): 3085, 3027, 2925, 2867, 1626, 1567, 1514, 1447, 1407, 1379, 1306, 1232, 1188, 1166, 1121, 1107, 1056, 1039, 1020, 939, 894, 822, 795, 734.
¹ H NMR(400 MHz, CDCl ₃ ) δ: 1.51 (quintet, 2H, J = 7.6 Hz), 2.33 (s, 6H), 2.39 (tt, 2H, J _HH(t) = 7.6 Hz, J _HF(t) = 2.4 Hz), 2.47 (t, 2H, J = 7.6 Hz), 4.96 (d, 1H, J = 1.2 Hz), 5.22 (d, 1H, J = 1.2 Hz), 7.06-7.15 (m, 6H), 7.20-7.25 (m, 2H).
¹³ C NMR(100 MHz, CDCl ₃ ) δ: 21.05 (q, 1C), 21.09 (q, 1C), 26.16 (t, 1C),27.07 (t, 1C), 34.57 (t, 1C), 91.89 (s, 1C, J _CF(dd) = 19.0 Hz, 16.0 Hz), 111.79 (t, 1C), 125.95 (d, 2C), 128.03 (d, 2C, J _CF(t) = 3.1 Hz),128.92 (d, 2C), 129.08 (d, 2C), 130.54 (s, 1C), 136.84 (s, 1C), 137.02 (s, 1C), 138.11 (s, 1C), 147.66 (s, 1C), 153.52 (s, 1C, J _CF(t) = 286.9 Hz).

3. Step (iii): Synthesis of 8,8-difluoro-1,5-di(p-methylphenyl)-6,7-dioxabicyclo[3.2.2]nonane (Compound (I-1)) 62.5 mg (0.2 mmol) of Compound (Ic-1) synthesized in Step (ii) above, 7.9 mg (0.02 mmol) of triphenylpyrylium tetrafluoroborate, and 92.5 mg (0.60 mmol) of biphenyl were placed in a Pyrex (registered trademark) test tube (length 20 cm, diameter 30 mm) and dissolved in dry acetonitrile (20 mL). This solution was degassed in an ultrasonic cleaner for 5 minutes and then aerated with oxygen (or air) for 10 minutes. The test tube was fixed to a Lionnet light irradiation device (350 nm lamp (maximum wavelength): 2 W × 15 = 30 W), and the solution was aerated with oxygen and stirred while being irradiated with light (wavelength 350 nm) for 8 minutes. After completion of the reaction, 4.6 mg (0.04 mmol) of 1,4-dioxabicyclo[2.2.2]octane was added, the solvent was distilled off, and the resulting crude product was separated by silica gel thin layer chromatography (developing solvent: dichloromethane:n-hexane, 1:2 (volume ratio)) to isolate 16.1 mg (yield 23% by mass) of compound (I-1).

The physical properties of compound (I-1) are shown below.
Colorless prisms (recrystallization solvent: n-hexane), melting point: 115-116°C, C ₂₁ H ₂₂ F ₂ O ₂ , [MW 344.40].
IR(KBr, cm ^-1 ): 3062, 3027, 2979, 2957, 2946, 2926, 2860, 1511, 1467, 1451, 1432, 1415, 1354, 1333, 1315, 1244, 1191, 1170, 1150, 1107, 1092, 1065, 1029, 1020, 996, 948, 888, 844, 806, 790, 762, 716, 653, 578, 568, 553, 537, 519, 499.
¹ H NMR (400 MHz, CDCl ₃ )δ: 1.90-2.00 (m, 1H), 2.02-2.19 (m, 1H), 2.20-2.38 (m, 3H), 2.339 (s, 3H), 2.343 (s, 3H), 2.49-2.58 (m, 1H), 2.79-2.98 (m, 2H), 7.15-7.21 (m, 4H), 7.28-7.33 (m, 2H),7.42-7.47 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ )δ: 19.67 (t, 1C, J _CF(d) = 4.6 Hz), 20.99 (q, 1C), 21.06 (q, 1C), 37.11 (t, 1C, J _CF(d) = 5.3 Hz), 39.04 (t, 1C), 43.79 (t, 1C, J _CF(dd) = 28.8 Hz, 23.5 Hz), 83.13 (s, 1C, J _CF(dd) = 5.3 Hz, 4.6 Hz), 86.03 (s, 1C, J _CF(dd) = 26.6Hz, 24.3 Hz), 118.90 (s, 1C, J _CF(t) = 251.2 Hz), 124.23 (d, 2C), 126.00 (d, 2C), 128.76 (d, 2C), 129.23 (d, 2C), 134.70 (s, 1C, J _CF(d) = 3.0 Hz), 137.63 (s, 1C), 137.80 (s, 1C), 141.31 (s, 1C).
Anal.calcd for C ₂₁ H ₂₂ F ₂ O ₂ : C, 73.24%; H, 6.44%. Found: C, 73.40%; H, 6.46%.
MS (ASAP) m/z 345 ([M+H] ⁺ ).

[Production Example 2]
(Production of Compound (I-2))
Compound (I-2) was synthesized according to the following reaction scheme.

1. Step (i): Synthesis of 6,6-difluoro-1,5-di(p-ethylphenyl)hex-5-en-1-one (compound (Ib-2)) 3.08 g (10.0 mmol) of 1,5-di(p-ethylphenyl)penta-1,5-dione (compound (Ia-2)), 6.29 g (40.0 mmol) of sodium chlorodifluoroacetate, and 8.52 g (40.0 mmol) of tri(n-butyl)phosphine were dissolved in ultra-dehydrated dimethylformamide (10 mL), and the atmosphere in the reaction system was replaced with nitrogen, followed by heating and stirring in an oil bath. The temperature of the oil bath was raised to 130°C within 10 minutes. At around 70°C, both compound (Ia-2) and sodium chlorodifluoroacetate completely dissolved. At around 100°C, sodium chlorodifluoroacetate decomposed to produce difluorocarbene, which reacted with tri(n-butyl)phosphine to form difluoromethylenephosphonium ylide. By maintaining the oil bath temperature at 130°C for 30 minutes, this difluoromethylenephosphonium ylide reacted with compound (Ia-2) to produce compound (Ib-2). Compound (Ib-2) was isolated and purified from the reaction mixture by column chromatography. Specifically, after the reaction was completed, the mixture was cooled to room temperature, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, followed by water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off and the obtained crude product was separated by silica gel column chromatography (elution solvent: dichloromethane-n-hexane, 1:2 (volume ratio)) to obtain 1.83 g (yield 53% by mass) of compound (Ib-2) as a yellow oil.

The physical properties of compound (Ib-2) are shown below.
Yellow oil, C ₂₂ H ₂₄ F ₂ O, [MW342.42].
IR(KBr, cm-1): 3086, 3030, 2966, 2933, 2896, 2873, 1684(C=O), 1607, 1570, 1515, 1458, 1413, 1365, 1308, 1263, 1231, 1181, 1155, 1109, 1061, 1019, 998, 983, 939, 924, 834, 784.
¹ H NMR(400 MHz, CDCl ₃ ) δ: 1.24 (t, 3H, J = 7.6 Hz), 1.25 (t, 3H, J = 7.6 Hz), 1.82 (quintet, 2H, J = 7.6 Hz), 2.50 (tt, 2H, J _HH(t) = 7.6 Hz, J _HF(t) = 2.4 Hz), 2.64 (qurtet, 2H, J = 7.6 Hz), 2.70 (qurtet, 2H, J = 7.6 Hz), 2.93 (t, 2H, J = 7.6 Hz), 7.16-7.21 (m, 2H), 7.22-7.28 (m, 4H), 7.79-7.84 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ: 15.15 (qurtet, 1C), 15.36 (qurtet, 1C), 22.39 (t, 1C), 27.03 (t, 1C), 28.47 (t, 1C), 28.89 (t, 1C), 37.40 (t, 1C), 91.76 (s, 1C, J _CF(dd) = 19.0 Hz, 15.2Hz), 127.97 (d, 2C), 128.00 (d, 2C), 128.09 (d, 2C, J _CF(t) = 3.0 Hz), 128.18 (d, 2C), 130.50 (s, 1C), 134.66 (s, 1C), 143.34 (s, 1C), 149.85 (s, 1C), 153.67 (s, 1C, J _CF(t) = 287.6 Hz), 199.34 (s, 1C, C=O).

2. Step (ii): Synthesis of 1,1-difluoro-2,6-di(p-ethylphenyl)hepta-1,6-diene (compound (Ic-2)) 16.20 g (44.0 mmol) of methyltriphenylphosphonium bromide and 5.28 g (85% by mass, 40.0 mmol) of potassium tert-butoxide were dissolved in 70 mL of dry tetrahydrofuran, and the mixture was allowed to react at room temperature for 10 minutes under a nitrogen atmosphere to prepare a phosphonium ylide.

To this solution was added a tetrahydrofuran solution (30 mL) of 6.85 g (20.0 mmol) of 6,6-difluoro-1,5-di(p-ethylphenyl)hex-5-en-1-one (compound (Ib-2)) and the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was separated using silica gel column chromatography (elution solvent: hexane) to obtain 3.49 g (yield 51% by mass) of compound (Ic-2) as a colorless oil.

The physical properties of compound (Ic-2) are shown below.
Colorless oil, C ₂₃ H ₂₆ F ₂ , [MW 340.45].
IR(KBr, cm-1): 3083, 3049, 3026, 2965, 2932, 2871, 1625, 1562, 1514, 1459, 1411, 1375, 1308, 1232, 1188, 1166, 1110, 1061, 1019, 966, 941, 893, 836, 783.
¹ H NMR(400 MHz, CDCl ₃ ) δ: 1.23 (quintet, 3H, J = 7.6 Hz), 1.24 (quintet, 3H, J = 7.6 Hz), 1.53 (quintet, 2H, J = 7.6 Hz), 2.41 (tt, 2H, J _HH(t) = 7.6 Hz, J _HF(t) = 2.4 Hz), 2.48 (t, 2H, J = 7.6 Hz), 2.63 (qurtet, 4H, J = 7.6 Hz), 4.97 (d, 1H, J = 1.2 Hz), 5.23 (d, 1H, J = 1.2 Hz), 7.09-7.19 (m, 6H), 7.23-7.29 (m, 2H)
¹³ C NMR (100 MHz, CDCl ₃ ) δ: 15.37 (qurtet, 1C), 15.47 (qurtet, 1C), 26.19 (t, 1C), 27.06 (t, 1C), 28.47 (t, 2C), 34.57 (t, 1C), 91.91 (s, 1C, J _CF(dd) = 19.0 Hz, 15.2 Hz), 111.81 (t, 1C), 126.00 (d, 2C), 127.72 (d, 2C), 127.85 (d, 2C),128.07 (d, 2C, J _CF(t) = 3.1 Hz), 130.74 (s, 1C), 138.32 (s, 1C), 143.14 (s, 1C), 143.40 (s, 1C), 147.67 (s, 1C), 153.55 (s, 1C, J _CF(t) = 287.6 Hz).

3. Step (iii): Synthesis of 8,8-difluoro-1,5-di(p-ethylphenyl)-6,7-dioxabicyclo[3.2.2]nonane (Compound (I-2)) 68.0 mg (0.2 mmol) of Compound (Ic-2) synthesized in Step (ii) above, 7.9 mg (0.02 mmol) of triphenylpyrylium tetrafluoroborate, and 92.5 mg (0.60 mmol) of biphenyl were placed in a Pyrex (registered trademark) test tube (length 20 cm, diameter 30 mm) and dissolved in dry dichloromethane (20 mL). This solution was degassed in an ultrasonic cleaner for 5 minutes and then aerated with oxygen for 10 minutes. The test tube was fixed to a Lionnet light irradiation device (350 nm wavelength lamp (maximum wavelength): 2 W × 15 lamps = 30 W), and the solution was aerated with oxygen and irradiated with light (350 nm wavelength) for 8 minutes while stirring. After completion of the reaction, 4.6 mg (0.04 mmol) of 1,4-dioxabicyclo[2.2.2]octane was added, the solvent was distilled off, and the resulting crude product was separated by silica gel thin layer chromatography (developing solvent: dichloromethane:n-hexane, 1:2 (volume ratio)) to isolate 18.4 mg (yield 25% by mass) of compound (I-2).

The physical properties of compound (I-2) are shown below.
Colorless needle crystals (recrystallization solvent: n-hexane), melting point: 94-95°C, C ₂₃ H ₂₆ F ₂ O ₂ , [MW 372.45].
IR(KBr, cm ^-1 ): 3091, 3028, 2963, 2929, 2871, 1512, 1455, 1429, 1413, 1354, 1333, 1293, 1261, 1190, 1170, 1151, 1105, 1094, 1065, 1028, 995, 948, 888, 836, 820, 795, 784, 754, 656, 627.
¹ H NMR (400 MHz, CDCl ₃ )δ: 1.23 (t, 3H, J = 7.6 Hz), 1.24 (t, 3H, J = 7.6 Hz), 1.90-2.01 (m, 1H), 2.04-2.20 (m, 1H), 2.21-2.39 (m, 3H), 2.50-2.59 (m, 1H), 2.64 (qurtet, 2H, J = 7.6 Hz), 2.65 (qurtet, 2H, J = 7.6 Hz), 2.80-3.00 (m, 2H), 7.18-7.24 (m, 4H), 7.31-7.36 (m, 2H), 7.44-7.50 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ )δ: 15.26 (q, 1C), 15.42 (q, 1C), 19.68 (t, 1C, J _CF(d) = 4.5 Hz), 28.41 (t, 2C), 37.12 (t, 1C, J _CF(d) = 4.6 Hz), 39.05 (t, 1C), 43.79 (t, 1C, J _CF(dd) = 28.8 Hz, 22.8 Hz), 83.14 (s, 1C, J _CF(t) = 4.5 Hz), 86.04 (s, 1C, J _CF(dd) = 26.5 Hz, 24.2 Hz)，118.94 (s, 1C, J _CF(t) = 251.9 Hz), 124.31 (d, 2C), 126.06 (d, 2C), 127.53 (d, 2C), 128.03 (d, 2C), 134.91 (s, 1C, J _CF(d) = 3.8 Hz), 141.52 (s, 1C), 143.95 (s, 1C), 144.01 (s, 1C).
Anal.calcd for C ₂₃ H ₂₆ F ₂ O ₂ : C, 74.17%; H, 7.04%. Found: C, 74.01%; H, 7.02%.
MS (ASAP) m/z 373 ([M+H] ⁺ ).

[Production Example 3]
(Production of Compound (I-3))
Compound (I-3) was synthesized according to the following reaction scheme.

1. Step (i): Synthesis of 6,6-difluoro-1,5-diphenylhex-5-en-1-one (Compound (Ib-3)) 2.53 g (10.0 mmol) of 1,5-diphenylpenta-1,5-dione (Compound (Ia-3)), 6.29 g (40.0 mmol) of sodium chlorodifluoroacetate, and 8.52 g (40.0 mmol) of tri(n-butyl)phosphine were dissolved in ultra-dehydrated dimethylformamide (10 mL). The atmosphere in the reaction system was replaced with nitrogen, and the mixture was heated and stirred in an oil bath. The temperature of the oil bath was raised to 130°C within 10 minutes. At around 70°C, both Compound (Ia-3) and sodium chlorodifluoroacetate were completely dissolved. At around 100°C, sodium chlorodifluoroacetate decomposed to produce difluorocarbene, which reacted with tri(n-butyl)phosphine to form difluoromethylenephosphonium ylide. The oil bath temperature was maintained at 130°C for 30 minutes, whereby this difluoromethylenephosphonium ylide reacted with compound (Ia-3) to produce compound (Ib-3). Compound (Ib-3) was isolated and purified from the reaction mixture by column chromatography. Specifically, after completion of the reaction, the mixture was cooled to room temperature, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, followed by water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was separated by silica gel column chromatography (elution solvent: dichloromethane-n-hexane, 1:2 (volume ratio)) to obtain 1.52 g (yield 53% by mass) of compound (Ib-3) as a yellow oil.

The physical properties of compound (Ib-3) are shown below.
Yellow oil, C ₁₈ H ₁₆ F ₂ O, [286.32].
IR(KBr, cm-1): 3087, 3060, 3028, 2957, 2939, 2873, 1684(C=O), 1598, 1579, 1544, 1497, 1447, 1411, 1373, 1348, 1304, 1281, 1266, 1231, 1203, 1180, 1154, 1118, 1072, 1030, 1002, 988, 940, 924, 916, 859, 844, 795, 763, 720, 690,
660, 645.
¹ H NMR(400 MHz, CDCl ₃ ) δ: 1.84 (quintet, 2H, J = 7.6 Hz), 2.53 (tt, 2H, J _HH(t) = 7.6 Hz, J _HF(t) = 2.4 Hz), 2.96 (t, 2H, J = 7.6 Hz), 7.24-7.29 (m, 1H), 7.30-7.39 (m, 4H), 7.40-7.47 (m, 2H), 7.50-7.58 (m, 1H), 7.86-7.92 (m, 2H).
¹³ C NMR(100 MHz, CDCl ₃ ) δ: 22.27 (t, 1C, J _CF(t) = 2.3 Hz), 27.01 (t, 1C), 37.46 (t, 1C), 91.93 (s, 1C, J _CF(t) = 17.5 Hz), 127.32 (d, 1C), 127.93 (d, 2C), 128.19 (d, 2C, J _CF(t) = 3.1 Hz), 128.49 (d, 2C), 128.53 (d, 2C), 132.94 (d, 1C), 133.31 (s, 1C, J _CF(d) = 1.5 Hz), 136.88 (s, 1C), 153.74 (s, 1C, J _CF(t) = 287.6 Hz), 199.58 (s, 1C, C=O).

2. Step (ii): Synthesis of 1,1-difluoro-2,6-diphenylhepta-1,6-diene (compound (Ic-3)) 16.20 g (44.0 mmol) of methyltriphenylphosphonium bromide and 5.28 g (85% by mass, 40.0 mmol) of potassium tert-butoxide were dissolved in 70 mL of dry tetrahydrofuran, and the mixture was allowed to react at room temperature for 10 minutes under a nitrogen atmosphere to prepare a phosphonium ylide.

To this solution was added a tetrahydrofuran solution (30 mL) of 5.73 g (20.0 mmol) of 6,6-difluoro-1,5-diphenylhex-5-en-1-one (compound (Ib-3)) and the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was separated using silica gel column chromatography (elution solvent: hexane) to obtain 4.83 g (yield 85% by mass) of compound (Ic-3) as a colorless oil.

The physical properties of compound (Ic-3) are shown below.
Colorless oil, C ₁₉ H ₁₈ F ₂ , [MW 284.34].
IR(KBr, cm-1) : 3083,3058, 3027, 2935, 2867, 1627, 1601, 1575, 1496, 1445, 1386, 1343, 1306, 1232, 1167, 1122, 1074, 1056, 1029, 1002, 943, 897, 841, 778, 762, 697.
¹ H NMR(400 MHz, CDCl ₃ ) δ: 1.53 (quintet, 2H, J = 7.6 Hz), 2.42 (tt, 2H, J _HH = 7.6 Hz, J _HF = 2.4 Hz), 2.50 (t, 2H, J = 7.6 Hz), 5.01 (d, 1H, J = 1.2 Hz), 5.25 (d, 1H, J = 1.2 Hz), 7.21-7.35 (m, 10H).
¹³ C NMR(100 MHz, CDCl ₃ ) δ: 26.11 (t, 1C), 27.04 (t, 1C), 34.57 (t, 1C), 92.09 (s, 1C, J _CF(dd) = 20.0 Hz, 14.0 Hz), 112.62 (t, 1C), 126.08 (d, 2C), 127.16 (d, 1C), 127.33 (d, 1C), 128.18 (d, 2C, J _CF(t) = 3.0 Hz), 128.25 (d, 2C), 128.38 (d, 2C), 133.55 (s, 1C, J _CF(d) = 2.3 Hz), 141.02 (s, 1C), 147.86 (s, 1C), 153.61 (s, 1C, J _CF(dd) = 288.4 Hz, 285.3 Hz).

3. Step (iii): Synthesis of 8,8-difluoro-1,5-diphenyl-6,7-dioxabicyclo[3.2.2]nonane (Compound (I-3)) 56.9 mg (0.2 mmol) of Compound (Ic-3) synthesized in Step (ii), 7.9 mg (0.02 mmol) of triphenylpyrylium tetrafluoroborate, and 92.5 mg (0.60 mmol) of biphenyl were placed in a Pyrex (registered trademark) test tube (length 20 cm, diameter 30 mm) and dissolved in dry acetonitrile (20 mL). This solution was degassed in an ultrasonic cleaner for 5 minutes and then aerated with oxygen for 10 minutes. The test tube was fixed to a Lionnet light irradiation device (350 nm wavelength lamp (maximum wavelength): 2 W × 15 lamps = 30 W), and the solution was irradiated with light (350 nm wavelength) for 15 minutes while aerating and stirring oxygen. After completion of the reaction, 4.6 mg (0.04 mmol) of 1,4-dioxabicyclo[2.2.2]octane was added, the solvent was evaporated, and the resulting crude product was separated by silica gel thin layer chromatography (developing solvent: dichloromethane:n-hexane, 1:2 (volume ratio)) to isolate 10.7 mg (yield 17% by mass) of compound (I-3).

The physical properties of compound (I-3) are shown below.
Colorless prism-like crystals (recrystallization solvent: n-hexane), melting point: 89-90°C, C ₁₉ H ₁₈ F ₂ O ₂ , [MW 316.34].
IR(KBr, cm ^-1 ): 3068, 3037, 2993, 2951, 2919, 2882, 2840, 1493, 1468, 1447, 1436, 1392, 1360, 1329, 1294, 1259, 121 3, 1184, 1149, 1106, 1075, 1059, 1035, 997, 974, 944, 927, 896, 846, 822, 800, 757, 699, 659, 631, 595.
¹ H NMR (400 MHz, CDCl ₃ )δ: 1.92-2.02 (m, 1H), 2.05-2.23 (m, 1H), 2.23-2.40 (m, 3H), 2.52-2.60 (m, 1H), 2.84-3.01 (m, 2H), 7.25-7.45 (m, 8H), 7.54-7.60 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ )δ: 19.64 (t, 1C, J _CF(d) = 4.6 Hz), 37.15 (t, 1C, J _CF(d) = 4.6 Hz), 39.05 (t, 1C), 43.84 (t, 1C, J _CF(dd) = 28.8 Hz, 23.5 Hz), 83.20 (s, 1C, J _CF(dd) = 5.3 Hz, 4.4 Hz), 86.13 (s, 1C, J _CF(dd) = 26.5Hz, 24.3 Hz), 118.87 (s, 1C, J _CF(t) = 251.9 Hz), 124.25 (d, 2C), 126.04 (d, 2C), 127.87 (d, 1C), 128.06 (d, 3C), 128.60 (d, 2C), 137.64 (s, 1C, J _CF(dd) = 3.8 Hz, 1.5 Hz), 144.23 (s, 1C).
Anal.calcd for C ₁₉ H ₁₈ F ₂ O ₂ : C, 72.14%; H, 5.74%. Found: C, 72.21%; H, 5.63%.
MS (ASAP) m/z 317 ([M+H] ⁺ ).

[Production Example 4]
(Production of Compound (I-4))
Compound (I-4) was synthesized according to the following reaction scheme.

1. Step (i): Synthesis of 6,6-difluoro-1,5-di(p-fluorophenyl)hex-5-en-1-one (compound (Ib-4)) 2.88 g (10.0 mmol) of 1,5-di(p-fluorophenyl)penta-1,5-dione (compound (Ia-4)), 6.29 g (40.0 mmol) of sodium chlorodifluoroacetate, and 8.52 g (40.0 mmol) of tri(n-butyl)phosphine were dissolved in ultra-dehydrated dimethylformamide (10 mL), and the atmosphere in the reaction system was replaced with nitrogen, followed by heating and stirring in an oil bath. The temperature of the oil bath was raised to 130°C within 10 minutes. At around 70°C, both compound (Ia-4) and sodium chlorodifluoroacetate completely dissolved. At around 100°C, sodium chlorodifluoroacetate decomposed to produce difluorocarbene, which reacted with tri(n-butyl)phosphine to form difluoromethylenephosphonium ylide. By maintaining the oil bath temperature at 130°C for 30 minutes, this difluoromethylenephosphonium ylide reacted with compound (Ia-4) to produce compound (Ib-4). Compound (Ib-4) was isolated and purified from the reaction mixture by column chromatography. Specifically, after completion of the reaction, the mixture was cooled to room temperature, and 150 mL of water was added. The mixture was then extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, followed by water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off and the obtained crude product was separated by silica gel column chromatography (elution solvent: dichloromethane-n-hexane, 1:2 (volume ratio)) to obtain 1.58 g (yield 49% by mass) of compound (Ib-4) as a yellow oil.

The physical properties of compound (Ib-4) are shown below.
Yellow oil, C ₁₈ H ₁₄ F ₄ O, [322.30].
IR(KBr, cm-1): 3074, 2961, 2936, 2873, 1686(C=O), 1599, 1458, 1409, 1367, 1299, 1201, 1157, 1119, 1096, 1036, 1014, 1001, 984, 939, 926, 837, 791, 740, 685, 657, 597.
¹ H NMR(400 MHz, CDCl ₃ ) δ: 1.81 (quintet, 2H, J = 7.6 Hz), 2.49 (tt, 2H, J _HH(t) = 7.6 Hz, J _HF(t) = 2.4 Hz), 2.93 (t, 2H, J = 7.6 Hz), 7.02-7.15 (m, 4H), 7.27-7.34 (m, 2H), 7.88-7.96 (m, 2H).
¹³ C NMR(100 MHz, CDCl ₃ ) δ: 22.11 (t, 1C), 27.09 (t, 1C), 37.27 (t, 1C), 91.14 (s, 1C, J _CF(dd) = 19.8 Hz, 16.0Hz), 115.51 (d, 2C, J _CF(d) = 21.2 Hz), 115.65 (d, 2C, J _CF(d) = 22.0 Hz), 129.15 (s, 1C, J _CF(t) = 3.0 Hz), 129.89 (d, 2C, J _CF(dt) = 8.4 Hz, 3.0 Hz), 130.53 (d, 2C, J _CF(d) = 9.2 Hz), 133.29 (s, 1C, J _CF(d) = 3.1 Hz), 153.71 (s, 1C, J _CF(t) = 286.9 Hz), 161.90 (s, 1C, J _CF(d) = 245.9 Hz), 165.70 (s, 1C, J _CF(d) = 253.4 Hz), 197.80 (s, 1C, C=O).

2. Step (ii): Synthesis of 1,1-difluoro-2,6-di(p-fluorophenyl)hepta-1,6-diene (compound (Ic-4)) 16.20 g (44.0 mmol) of methyltriphenylphosphonium bromide and 5.28 g (85% by mass, 40.0 mmol) of potassium tert-butoxide were dissolved in 70 mL of dry tetrahydrofuran, and the mixture was allowed to react at room temperature for 10 minutes under a nitrogen atmosphere to prepare a phosphonium ylide.

To this solution was added a tetrahydrofuran solution (30 mL) of 6.45 g (20.0 mmol) of 6,6-difluoro-1,5-di(p-fluorophenyl)hex-5-en-1-one (compound (Ib-4)) and the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was separated using silica gel column chromatography (elution solvent: hexane) to obtain 5.15 g (yield 81% by mass) of compound (Ic-4) as a colorless oil.

The physical properties of compound (Ic-4) are shown below.
Colorless oil, C ₁₉ H ₁₆ F ₄ , [320.32].
IR(KBr, cm-1): 3084, 3050, 2936, 2868, 1628, 1604, 1510, 1457, 1406, 1312, 1299, 1237, 1161, 1121, 1094, 1056, 1014, 944, 899, 838, 815, 740.
¹ H NMR(400 MHz, CDCl ₃ ) δ: 1.49 (quintet, 2H, J = 7.6 Hz), 2.39 (tt, 2H, J _HH(t) = 7.6 Hz, J _HF(t) = 2.4 Hz), 2.46 (t, 2H, J = 7.6 Hz), 5.00 (d, 1H, J = 1.2 Hz), 5.20 (d, 1H, J = 1.2 Hz), 6.93-7.04 (m, 6H), 7.25-7.31 (m, 2H).
¹³ C NMR(100 MHz, CDCl ₃ ) δ: 25.88 (t, 1C), 27.04 (t, 1C), 34.62 (t, 1C), 91.25 (s, 1C, J _CF(dd) = 21.3 Hz, 14.4 Hz), 112.69 (t, 1C), 115.07 (d, 2C, J _{CF (d)} = 21.2 Hz), 115.35 (d, 2C, J _{CF (d)} = 21.2 Hz), 127.64 (d, 2C, J _CF(d) = 8.4 Hz),129.36 (s, 1C), 129.82 (d, 2C, J _CF(dt) = 7.6 Hz, 3.0 Hz), 136.97 (s 1C, J _CF(d) = 3.0 Hz), 146.73 (s, 1C), 153.37 (s, 1C, J _CF(t) = 286.9 Hz), 161.82 (s, 1C, J _CF(d) = 245.9 Hz), 162.26 (s, 1C, J _CF(d) = 245.1 Hz).

3. Step (iii): Synthesis of 8,8-difluoro-1,5-di(p-fluorophenyl)-6,7-dioxabicyclo[3.2.2]nonane (Compound (I-4)) 64.1 mg (0.2 mmol) of Compound (Ic-4) synthesized in Step (ii), 7.9 mg (0.02 mmol) of triphenylpyrylium tetrafluoroborate, and 92.5 mg (0.60 mmol) of biphenyl were placed in a Pyrex (registered trademark) test tube (length 20 cm, diameter 30 mm) and dissolved in dry acetonitrile (20 mL). This solution was degassed in an ultrasonic cleaner for 5 minutes and then aerated with oxygen for 10 minutes. The test tube was fixed to a Lionnet light irradiation device (350 nm wavelength lamp (maximum wavelength): 2 W × 15 lamps = 30 W), and the solution was aerated with oxygen and irradiated with light (350 nm wavelength) for 10 minutes while stirring. After completion of the reaction, 4.6 mg (0.04 mmol) of 1,4-dioxabicyclo[2.2.2]octane was added, the solvent was evaporated, and the resulting crude product was separated by silica gel thin layer chromatography (developing solvent: dichloromethane:n-hexane, 2:3 (volume ratio)) to isolate 6.6 mg (yield 17% by mass) of compound (I-4).

The physical properties of compound (I-4) are shown below.
Colorless prism-like crystals, melting point: 116-117°C (recrystallization solvent: n-hexane), C ₁₉ H ₁₆ F ₄ O ₂ , [352.32].
IR(KBr, cm ^-1 ): 3078, 3041, 2958, 2934, 2890, 1601, 1556, 1508, 1430, 1409, 1355, 1329, 1308, 1292, 1263, 1229 , 1166, 1098, 1089, 1065, 1027, 1016, 999, 952, 897, 836, 810, 792, 768, 699, 662, 623, 600, 573.
¹ H NMR (400 MHz, CDCl ₃ )δ: 1.94-2.03 (m, 1H), 2.05-2.19 (m, 1H), 2.20-2.39 (m, 3H), 2.48-2.56 (m, 1H), 2.84-2.95 (m, 2H), 7.03-7.10 (m, 4H), 7.37-7.43 (m, 2H), 7.49-7.56 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ )δ: 19.532 (t, 1C, J _CF(d) = 4.5 Hz), 39.986 (t, 1C, J _CF(d) = 4.5 Hz), 38.981 (t, 1C), 43.727 (t, 1C, J _CF(dd) = 28.8 Hz, 23.5 Hz), 83.018 (s, 1C, J _CF(dd) = 5.3 Hz, 4.5 Hz), 85.894 (s, 1C, J _CF(dd) = 26.5 Hz, 24.3 Hz), 114.996 (d, 2C, J _CF(d) = 21.2 Hz), 115.493 (d, 2C, J _CF(d) = 22.0 Hz), 118.623 (s, 1C, J _CF(t) = 252.0 Hz), 126.224 (d, 2C, J _CF(d) = 8.3 Hz), 128.037 (d, 2C, J _CF(d) = 8.4 Hz), 133.239 (s, 1C), 139.834 (s, 1C), 162.220 (s, 1C, J _CF(d) = 245.8 Hz), 162.478 (s, 1C, J _CF(d) = 245.8 Hz).
Anal.calcd for C ₁₉ H ₁₆ F ₄ O ₂ : C, 64.77%; H, 4.58%. Found: C, 64.90%; H, 4.64%.
MS (ASAP) m/z 353 ([M+H] ⁺ ).

Comparative Production Example 1
(Production of Compound (II-1))
Compound (II-1) was synthesized according to the following reaction scheme.

1. Step (i)': Synthesis of 2,6-di(p-methylphenyl)hepta-1,6-diene (Compound (IIb-1)) 16.20 g (44.0 mmol) of methyltriphenylphosphonium bromide and 5.28 g (85% by mass, 40.0 mmol) of potassium tert-butoxide were dissolved in 70 mL of dry tetrahydrofuran, and the mixture was allowed to react at room temperature for 10 minutes under a nitrogen atmosphere to prepare a phosphonium ylide.

To this solution was added a tetrahydrofuran solution (30 mL) of 2.80 g (10.0 mmol) of 1,5-di(p-methylphenyl)penta-1,5-dione (compound (IIa-1)), and the mixture was stirred at room temperature for 30 minutes, then heated and refluxed for 3 hours. The mixture was then stirred at room temperature for 15 hours. After the reaction was complete, 150 mL of water was added, and the mixture was extracted three times with 100 mL of ether. The ether layer was washed with aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was separated using silica gel column chromatography (elution solvent: hexane) to obtain 2.72 g (yield 98% by mass) of compound (IIb-1) as a colorless oil.

The physical properties of compound (IIb-1) are shown below.
Colorless oil, C ₂₁ H ₂₄ , [MW 276.42].
IR (KBr) cm ^-1 : 3082, 3048, 3024, 2989, 2941, 2865, 1605, 1566, 1513, 1447.
¹ H-NMR (400 MHz, CDCl ₃ ) δppm: 1.61 (quintet, 2H, J = 7.2 Hz), 2.34 (s, 6H), 2.51 (t, 4H, J = 7.2 Hz), 4.99 (dt, 2H, J = 1.6 Hz, 1.2 Hz), 5.24 (d, 2H, J = 1.6 Hz), 7.07-7.13 (m, 4H), 7.23-7.28 (m, 4H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δppm: 21.07 (q, 2C), 26.64 (t, 1C), 34.770 (t, 2C), 111.63 (t, 2C), 125.95 (d, 4C), 128.91 (d, 4C), 136.96 (s, 2C), 138.21 (s, 2C), 147.98 (s, 2C).

2. Step (ii)': Synthesis of 1,5-di(p-methylphenyl)-6,7-dioxabicyclo[3.2.2]nonane (Compound (II-1)) 55.3 mg (0.2 mmol) of Compound (IIb-1) synthesized in Step (i)', 15.8 mg (0.04 mmol) of triphenylpyrylium tetrafluoroborate, and 92.5 mg (0.60 mmol) of biphenyl were placed in a Pyrex (registered trademark) test tube (length 20 cm, diameter 30 mm) and dissolved in dry acetonitrile (20 mL). The solution was degassed in an ultrasonic cleaner for 5 minutes and then aerated with oxygen for 10 minutes. The test tube was fixed to a Lionnet light irradiation device (350 nm wavelength lamp (maximum wavelength): 2 W × 15 lamps = 30 W), and the solution was irradiated with light (350 nm wavelength) for 8 minutes while aerating and stirring oxygen. After completion of the reaction, 4.6 mg (0.04 mmol) of 1,4-dioxabicyclo[2.2.2]octane was added, the solvent was distilled off, and the resulting crude product was separated by silica gel thin layer chromatography (developing solvent: dichloromethane:n-hexane, 1:1 (volume ratio)) to isolate 45.9 mg (yield 74 mass%) of compound (II-1).

The physical properties of compound (II-1) are shown below.
Colorless plate crystals, C ₂₁ H ₂₄ O ₂ , [MW 308.41].
Melting point: 198-199 °C.
IR (KBr) cm-1: 3052, 3022, 2999, 2970, 2918, 2860, 1604, 1513, 1477, 1448.
¹ H-NMR (400 MHz, CDCl ₃ ) δppm: 1.85-1.94 (m, 1H), 1.98-2.11 (m, 1H), 2.14-2.21 (m, 2H), 2.25-2.42 (m, 6H), 2.33 (s, 6H), 7.12-7.17 (m, 4H), 7.30-7.35 (m, 4H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δppm: 21.00 (q, 2C), 21.27 (t, 1C), 29.36 (t, 2C), 40.48 (t, 2C), 82.65 (s, 2C), 124.32 (d, 4C), 128.91 (d, 4C), 136.73 (s, 2C), 143.51 (s, 2C).

[Test Example 1]
(Malaria parasite growth inhibition test)
1. Pre-culturing of malaria parasites Plasmodium falciparum (P. falciparum FCR-3 Strain (ATCC 30932)) was used in this test. The medium used in this test was filter-sterilized RPMI 1640 medium, adjusted to pH 7.4, and supplemented with 10 v/v% human serum. Malaria parasites were cultured at an _O2 concentration of 5 v/v%, _CO2 concentration of 5 v/v%, _N2 concentration of 90 v/v%, and a temperature of 36.5°C. The hematocrit value (volume ratio of red blood cells in the red blood cell suspension) was set to 5 v/v%. The initial infection rate of Plasmodium falciparum at the start of culture was 0.1%. Culture was performed using a 24-well culture plate, the medium was changed daily, and subcultured at an infection rate of 4%. The infection rate was measured by preparing thin smear samples, staining them with Giemsa or Diff-Quick, and then measuring them under a microscope (oil immersion, 1000x magnification), and the malaria parasite infection rate was calculated using the following formula.

"Malaria parasite infection rate (%)" = {(number of infected red blood cells) / (total number of red blood cells)} x 100

2. Infection of Erythrocytes by Malaria Parasites in the Presence of Candidate Compounds. Cultured malaria parasite-infected erythrocytes were collected by centrifugation and washed with serum-containing medium. Uninfected erythrocytes were then added to achieve an initial infection rate of 0.3%. The hematocrit value at this time was 3%. Compound (I-1), one of the candidate compounds used in this study, was dissolved in dimethyl sulfoxide (DMSO), dimethylformamide (DMF), or sterile water to prepare the designated samples. 5 μL to 10 μL of each sample was added to a 24-well culture plate. Samples were prepared in duplicate or triplicate. 10 μL of sterile water, DMF, or DMSO was added per well as a control. Next, 990 μL to 995 μL of a Plasmodium falciparum culture medium prepared in advance was added and gently pipetted to uniformly suspend the samples in the medium. The culture plates were cultured for 72 hours in a CO ₂ -O ₂ -N ₂ (5 v/v%, 5 v/v%, 90 v/v%) incubator. After that, thin smears were prepared for each well, stained, and observed under a microscope to calculate the malaria parasite infection rate for the samples with the candidate compound added and the malaria parasite infection rate for the control. The 50% growth inhibitory concentration (EC ₅₀ ) for malaria parasites was calculated from the calculated malaria parasite infection rate using the following formula. The results are shown in Table 1. In the formula, a represents the initial malaria parasite infection rate, b represents the malaria parasite infection rate when the sample was added, and c represents the malaria parasite infection rate when no sample was added (control).

"Growth rate (%)" = {(b - a) / (c - a)} x 100

[Test Example 2]
(Mouse FM3A cell proliferation inhibition test)
The F28-7 strain, a wild-type strain of mouse mammary carcinoma-derived FM3A cells, was used. The medium was ES medium supplemented with inactivated fetal bovine serum at 2 v/v%, and the cells were cultured at 37°C with a _CO2 concentration of 5 v/v%. Under these conditions, the doubling time of FM3A cells was approximately 12 hours. After preculture, cells in the logarithmic growth phase were diluted with medium to a concentration of 5 x ¹⁰⁴ cells/mL.

The samples used were those prepared in Test Example 1 above. 5 μL to 10 μL of sample solution was added to a 24-well culture plate (when medium and other substances were added, the final concentration was 1 × 10 ⁻⁴ mol/L (M) to 1 × 10 ⁻⁶ mol/L (M)). Samples were prepared in duplicate or triplicate. As controls, 10 μL of sterile water, DMF, or DMSO was added per well. Next, 990 μL to 995 μL of the prepared culture cell suspension was added and gently pipetted to uniformly suspend the cells in the medium. After 48 hours of culture, the number of cells in each well was counted using a cell controller (CC-108, manufactured by Toa Medical Electrics Co., Ltd.), and the proliferation rate was calculated using the following formula: In the formula, A represents the initial cell number, B represents the control cell number after 48 hours, and C represents the cell number 48 hours after sample addition.

"Growth rate (%)" = {(C - A) / (B - A)} x 100

The cell growth inhibitory activity was calculated from the number of cells in the wells to which the sample was added and the number of cells in the control. The cytotoxicity of the sample was evaluated in this way and expressed as the cell growth inhibitory concentration (EC ₅₀ ). The results are shown in Table 1. The EC ₅₀ value in Table 1 refers to the concentration (molar concentration) of the sample at which the growth rate or malaria parasite infection rate in the culture medium of malaria parasites or FM3A cells when no sample was added (control) is taken as 100%, and the growth rate of the control is inhibited by 50% by the addition of the sample.

The antimalarial activity of the sample was evaluated from the ratio of the _EC50 value of the malaria parasite sample to that of the FM3A cells (chemotherapeutic index, see the formula below), and efficacy was measured. For comparative reference, the same test was also performed on compound (II-1), which has the same bicyclic skeletal structure as compound (I-1) but does not have a fluorine atom on the skeleton, and chloroquine, which is used as an antimalarial agent. The results are shown in Table 1.

For comparison, Table 2 also shows literature values for the efficacy measurements of the known antimalarial drugs quinine and artemisinin, as well as the recently developed antimalarial compounds N-89 and N-251.

Reference 1: Takaya Y et al., “Novel antimalarial guaiane-type sesquiterpenoids from Nardostachys chinensis roots.”, Tetrahedron Lett., Vol. 39, pp. 1361-1364, 1998.
Reference 2: Kim HS et al., “Synthesis and antimalarial activity of novel medium-sized 1,2,4,5-tetraoxacycloalkanes.”, J. Med. Chem., Vol. 44, pp. 2357-2361, 2001.
Reference 3: JP 2000-229965 A Reference 4: Yusuke Wataya et al., "Antimalarial Drugs", Pharmacia, Vol. 44, No. 1, pp. 32-36, 2008.

These results demonstrate that the compound of this embodiment has reduced cytotoxicity and excellent inhibitory activity against malaria parasite proliferation.

The compound of this embodiment has reduced cytotoxicity, excellent antimalarial activity, and can be easily and safely synthesized. The antimalarial agent of this embodiment contains the compound, has reduced cytotoxicity, and excellent antimalarial activity.

Claims (3)

A compound represented by the following general formula (I):
(In general formula (I), ^R1 and ^R2 each independently represent a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl group, alkoxy group, aryl group, carboxy group, or amino group.) The compound according to claim 1, wherein in the general formula (I), R ¹ and R ² each independently represent a hydrogen atom, a fluorine atom, or a substituted or unsubstituted alkyl group. An antimalarial agent containing the compound of claim 1 or 2 as an active ingredient.