Method For Producing Oxabicyclooctane Compound

FP17-0071-00IN-UBE TITLE METHOD FOR PRODUCING OXABICYCLOOCTANE COMPOUND 5 TECHNICAL FIELD

[0001] The present invention relates to a method for producing an oxabicyclooctane compound. BACKGROUND 10 [0002] Oxabicyclooctane compounds are, for example, compounds useful as raw materials of medicines, functional materials, and the like. Specifically, (lS,4S,5S)-4-iodo-6-oxabicyclo[3,2,l]octan-7-one represented by the following formula (6) is known to be a raw material of compounds useful as medicines for 15 preventing or treating thrombotic diseases (for example, see Patent Literature 1 and Patent Literature 2). [0003]

[0004] As methods for producing this (lS,4S,5S)-4-iodo-6- 20 oxabicyclo[3,2,l]octan-7-one, for example, production methods in which 3-cycIohexene-l-carboxylic acid is reacted with iodine, potassium iodide, and sodium hydrogen carbonate are known (for example, see Patent Literatures 1 and 2 and Non Patent Literatures 1 1

FP17-0071-OOIN-UBE and 2). [00051

[0006] 5 [Patent Literature 1] WO 2010/231663 [Patent Literature 2] WO 2003/016302 [0007] [NonpatentLiterature 1] Tetrahedron Lett., 32, 1991,1613-1616. [Non Patent Literature 2] Tetrahedron Asymmetry 15,2004, 2057-2060. 10 SUMMARY

[0008] hi the above Patent Literatures 1 and 2 and Non Patent Literatures 1 and 2, (lS,4S,5S)-4-iodo-6-oxabicyclo[3,2,l]octan-7-one is obtained by reacting (S)-3-cyclohexene-l-carboxylic acid with iodine, 15 potassium iodide, and sodium hydrogen carbonate, but iodine atoms in an amount of a total of 4 to 7 times the molar amount of (S)-3-cyclohexene-1-carboxylic acid are added, and none of the production methods are economically preferred production methods. In addition, since an excessive amount of iodine is added, there is also the problem 20 of a waste liquid of iodine being produced in a large amount. Therefore, a production method in which an oxabicyclooctane compound is synthesized in an industrially preferred yield without excessively using iodine is required. In addition, when (1S,4S,5S)~4-iodo-6-oxabicyclo[3,2,l]octan-7-one is used as a raw material of a ?

FP17-0071-OOIN-UBE medicine, it is important to decrease the amounts of isomers and other compounds produced as by-products.

[0009] From the above, it is an object of the present invention to provide a method for producing an oxabicyclooctane compound by an 5 industrially preferred method without using excessive iodine.

[0010] The present invention relates to the following matters:

[0011] 1. A method for producing an oxabicyclooctane compound, comprising: mixing 3-cyclohexene-l-carboxylic acid represented by the following formula (1), iodic acid and/or a salt thereof represented by the 10 following formula (2), an iodide represented by the following formula (3), and an acid (excluding the 3-cyclohexene-l-carboxylic acid) to obtain a mixed liquid; and producing an oxabicyclooctane compound represented by the following formula (4) in the obtained mixed liquid, wherein the iodic acid may also serve as the acid: 15 A^Os (2) wherein A represents a hydrogen atom or an alkali metal, A21 (3) wherein A" represents an alkali metal. 20

[0012] 2. The method according to the 1, wherein the 3-cyclohexene-1-carboxylic acid is (S)-3-cyclohexene-l-carboxylic acid represented by the following formula (5), and 3

FP17-0071-OOTN-UBE the oxabicyclooctane compound obtained is (lS,4S,5S)-4-iodo-6-oxabicyclo[3,2,l]octan-7-one represented by the following formula (6). 5 [0013] 3. The method according to the 1 or 2, wherein the acid comprises at least one selected from the group consisting of hydrochloric acid and acetic acid.

[0014] 4. The method according to any one of the 1 to 3, wherein the 3-cyclohexene-l-carboxylic acid, the iodic acid and/or salt thereof;, 10 the iodide, and the acid are mixed at a temperature of 5°C to 70°C.

[0015] 5. The method according to any one of the 1 to 4, wherein the 3-cyclohexene-l-carboxylic acid, the iodic acid and/or salt thereof, the iodide, and the acid are mixed at a temperature of 10°C to 50°C.

[0016] 6. The method according to any one of the 1 to 5, wherein a 15 sum of amounts of substance of the iodic acid and salt thereof and the iodide is 0.9 mol to 1.4 mol per mol of the 3-cyclohexene-l-carboxylic acid.

[0017] 7. The method according to any one of the 1 to 6, wherein a sum of amounts of substance of the iodic acid and salt thereof and the 20 iodide is 1.0 mol to 1.2 mol per mol of the 3-cyclohexene-l-carboxylic acid.

[0018] 8. The method according to any one of the 1 to 7, wherein a sum of amounts of substance of the iodic acid and salt thereof is 0.4 mol 4

FP17-0071-OOIN-UBE to 0.8 mol per mol of the iodide.

[0019] 9. The method according to any one of the 1 to 8, wherein obtaining the mixed liquid comprises: mixing the 3-cyclohexene-l-carboxylic acid, the iodic acid and/or 5 salt thereof, and the iodide to obtain a mixture; and adding the acid to the mixture to obtain the mixed liquid.

[0020] 10. The method for producing an oxabicyclooctane compound according to any one of the 1 to 8, wherein obtaining the mixed liquid comprises mixing the iodic acid and/or salt thereof and the 10 iodide to obtain a first mixture; adding the 3-cyclohexene-l-carboxylic acid to the first mixture to obtain a second mixture; and adding the acid to the second mixture to obtain the mixed liquid.

[0021] According to the present invention, a method for producing 15 a high purity oxabicyclooctane compound in an industrially preferred yield by an industrially preferred method without using excessive iodine can be provided. DETAILED DESCRIPTION 20 [0022] For a material illustrated herein, one can be used singly or two or more can be used in combination unless otherwise noted. A numerical value range represented by using "to" represents a range including the numerical values described before and after "to" as the minimum value and tire maximum value respectively. For numerical 25 value ranges described in stages herein, the upper limit value or lower limit value of a numerical value range in a stage may be replaced by the 5

FP17-0071-001N-UBE upper limit value or lower limit value of a numerical value range in another stage. For a numerical value range described herein, the upper limit value or lower limit value of the numerical value range may be replaced by a value shown in Examples. 5 [0023] One preferred embodiment of the present invention will be described below in detail. However, the present invention is not limited to the following embodiment.

[0024] A method for producing an oxabicyclooctane compound in this embodiment comprises mixing 3-cyclohexene-l-carboxylic acid 10 represented by the above formula (1), iodic acid and/or a salt thereof represented by the above formula (2), an iodide represented by the above formula (3), and an acid (excluding the above 3-cyclohexene-l-carboxylic acid) to obtain a mixed liquid; and producing an oxabicyclooctane compound represented by the above formula (4) in the 15 obtained mixed liquid. For example, the 3-cyclohexene-l-carboxylic acid represented by the above fomiula (1), the iodic acid and/or salt thereof represented by the above formula (2), and the iodide represented by the above formula (3) are mixed and further mixed with an acid (excluding the above 3-cyclohexene-l-carboxylic acid) to obtain the 20 oxabicyclooctane compound represented by the above formula (4). In the production method in this embodiment, for example, 3-cyclohexene-l-carboxylic acid reacts with iodic acid and/or a salt thereof, an iodide, and an acid according to the following reaction formula: [0025] 6

FP17-0071-OOIN-UBE 1 '■y wherein A and A have the same meanings as the above.

[0026] In this embodiment, the above iodic acid may also serve as the above acid. In other words, when the above iodic acid is used, an 5 acid other than iodic acid may not be used according to the amount of iodic acid used. [0027] (3-Cyclohexene-l-carboxylic Acid) The 3-cyclohexene-l-carboxylic acid used in this embodiment is represented by the following formula (1): 10 [0028] a COOH (i.

[0029] This compound can be synthesized, for example, from 4,4-dimethyl~2-oxotetrahydrofuran-3-yl acrylate, as described in the above Non Patent Literature 1. This compound can also be synthesized from 15 the methylbenzylamine salt of 3-cyclohexene-l-carboxylic acid, as described in the above Patent Literature 1. This compound is also available as a commercial product.

[0030] 3-Cyclohexene-l-carboxylic acid is an optically active substance and encompasses (R)-3 -cyclohexene-1 -carboxylic acid 20 (hereinafter sometimes referred to as an "R form") and (S)-3-cydohexene-1-carboxylic acid represented by the following formula (5) (hereinafter sometimes referred to as an "S form"). The 3-cyclohexene-1-carboxylic acid may be a mixture of the R form and the

FP17-0071-OOIN-UBE S form. As the 3-cyclohexene-l-carboxylic acid, (S)-3-cyclohexene-1-carboxylic acid is preferred from the viewpoint of improvement in the pharmacological activity of the compound after derivatization. When (S)-3-cyclohexene-1 -carboxylic acid is used, (R)-3-cyclohexene-1 - 5 carboxylic acid may be included in the (S)-3-cyclohexene-1- carboxylic acid, but it is preferred that the enantiomeric excess be 99% ee or more from the viewpoint of improvement in the pharmacological activity of the compound after derivatization. [0031] 10

[0032] In this embodiment, a salt of 3-cyclohexene-l-carboxylic acid (carboxylate) may be used, and may be used in the production method in this embodiment after the carboxylate is mixed with an acid described later to form 3-cyclohexene-l-carboxylic acid. As the 15 carboxylate, for example, an alkali metal carboxylate, an alkaline earth metal carboxylate, and an ammonium carboxylate can be used.

[0033] (Iodic Acid and Salt Thereof) The iodic acid and salt thereof used in this embodiment is represented by the following formula (2); 20 [0034] A1103 (2)

[0035] wherein A1 represents a hydrogen atom or an alkali metal. Examples of the alkali metal include lithium, sodium, potassium, cesium, and francium. A1 is preferably sodium, potassium, or cesium, 25 more preferably sodium or potassium, and further preferably potassium. 8

FP17-0071-OOIN-UBE By using such iodic acid and/or a salt thereof, the oxabicyclooctane compound can be obtained with an industrially more preferred reaction rate and yield. In this embodiment, a plurality of iodic acids and/or salts thereof in which A1 in the above formula (2) is different may be 5 used, but it is preferred to use one iodic acid and/or salt thereof. In addition, the iodic acid and/or salt thereof may be used as they are, or may be dissolved or suspended in water, an organic solvent such as an alcohol, or a mixed solvent thereof and used.

[0036] In this embodiment, only iodic acid may be used, only an 10 iodate may be used, or iodic acid and a salt thereof may be mixed and used. In this embodiment, as described later, it is preferred to add an acid apart from iodic acid, and therefore it is preferred to use only an iodate. [0037] (Iodide) 15 The iodide used in this embodiment is represented by the following formula (3):

[0038] A21 (3)

[0039] wherein A2 represents an alkali metal. Examples of the 20 alkali metal include lithium, sodium, potassium, cesium, or franciuni. A is preferably sodium, potassium, or cesium, more preferably sodium or potassium, and further preferably potassium. By using such an iodide, the oxabicyclooctane compound can be obtained with an industrially more preferred reaction rate and yield. In this embodiment, 25 a plurality of iodides in which A2 in the above formula (3) is different may be used, but one iodide is preferred. In addition, the iodide may 9

FP17-0071-001N-UBE be used as it is, or may be dissolved or suspended in water, an organic solvent such as an alcohol, or a mixed solvent thereof and used.

[0040] (Amounts of Above Iodic Acid and Salt Thereof and Above Iodide Used) 5 It is necessary to use the iodic acid and salt thereof in combination with the iodide. The sum of the amounts of substance of the above Iodic acid and salt thereof and the above iodide is preferably 0.9 mol to 2.0 mol, more preferably 0.9 mol to 1.4 mol, further preferably 0.9 mol to 1.2 mol, still more preferably 1.0 mol to 1.2 mol, and particularly 10 preferably 1.0 mol to 1.1 mol per mol of the above 3-cycIohexene-l-carboxylic acid from the viewpoint of efficiently producing the oxabicyclooctane compound while decreasing the amount of iodine discarded. When the sum of the amounts of substance of the above iodic acid and salt thereof and the above iodide is equal to or more than 15 the above lower limit value, the reaction is likely to proceed sufficiently, and when the sum of the amounts of substance of the above iodic acid and salt thereof and the above iodide is equal to or less than the above upper limit value, a decrease in the purity of the product due to the progress of side reactions, the residue of inorganic matter, and the like is 20 less likely to occur.

[0041] The sum of the amounts of substance of the above iodic acid and salt thereof is preferably 0.4 mol to 0.8 mol, more preferably 0.4 mol to 0.6 mol, per mol of the above iodide from the viewpoint of efficiently producing the oxabicyclooctane compound. By setting the 25 sum of the amounts of substance of the above iodic acid and salt thereof in such a range, it is possible to suppress the progress of side reactions 10

FP17-0071-00IN-UBE and produce the oxabicyciooctane compound in a higher yield while maintaining an industrially preferred reaction rate.

[0042] From the above, in this embodiment, it is preferred that the sum of the amounts of substance of the above iodic acid and salt thereof 5 and the above iodide be 0.9 mol to 1.4 mol per mol of the above 3-cyclohexene-1 -carboxylic acid, and that the sum of the amounts of substance of the above iodic acid and salt thereof be 0.4 mol to 0.8 mol per mol of the above iodide, and it is more preferred that the sum of the amounts of substance of the above iodic acid and salt thereof and the 10 above iodide be 1.0 mol to 1.2 mol per mol of the above 3-cyclohexene- 1-carboxylic acid, and that the sum of the amounts of substance of the above iodic acid and salt thereof be 0.4 mol to 0.6 mol per mol of the above iodide. [0043] (Acid) 15 In this embodiment, as the acid (excluding the carboxylic acid represented by the above formula (1)), inorganic acids, organic acids, and aqueous solutions thereof can be used. Examples of the inorganic acids include hydrogen halides such as hydrogen chloride and hydrogen bromide; halogen oxoacids such as periodic acid; sulfuric acids such as 20 sulfuric acid and fluorosulfonic acid; phosphoric acids such as phosphoric acid and hexafluorophosphoric acid; boric acids such as boric acid and tetrafluoroboric acid; nitric acids such as nitric acid; chromic acids such as chromic acid; and antimonic acids such as hexaiTuoroantimonic acid. Examples of the organic acids include 25 sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, beiizenesulfonic acid, and trifluoromethanesulfonic acid; carboxylic 11

FP17-O071-00IN-UBE acids (excluding the carboxylic acid represented by the above formula (1)) such as acetic acid, formic acid, citric acid, and benzoic acid; and phenols such as cresol and catechol. Some or all of the acid here may be the iodic acid of the above-described formula (2), but in order to 5 decrease iodine used, it is preferred not to use iodic acid as the above acid. The acid used in this embodiment is preferably hydrochloric acid, sulfuric acid, nitric acid, or acetic acid, further preferably hydrochloric acid or acetic acid, and more preferably acetic acid. These acids may be used singly, or two or more of these acids may be mixed and used. 10 By using these acids, the amounts of isomers and other compounds produced as by-products can be decreased. Such an effect is particularly significant when acetic acid is used.

[0044] In this embodiment, when an acid other than iodic acid is used, the amount of the acid used is, for example, 0.3 mol to 5.0 mol, 15 preferably 0.4 mol to 2.0 mol, more preferably 0.5 mol to 2.0 mol, further preferably 0.8 mol to 1.5 mol, still more preferably 1.0 mol to 1.2 mol, and particularly preferably 1.0 mol to 1.1 mol per mol of 3-cyclohexene-1-carboxylic acid. By setting the amount of the acid used in such a range, the oxabicyclooctane compound can be obtained in a 20 higher yield while an industrially preferred reaction rate is maintained. When iodic acid is also used as the above acid, it is prefeired to use iodic acid in the range described in (Amounts of Above Iodic Acid and Salt Thereof and Above Iodide Used). [0045] (Oxabicyclooctane Compound) 25 The oxabicyclooctane compound obtained by this embodiment is represented by the following formula (4): 12

FP17-0071-OOIN-UBE

[0046]

[0047] The compound represented by the above formula (4) has three asymmetric carbons. The compound represented by the above 5 formula (4) has a bicyclo structure and therefore encompasses four stereoisomers. The stereostructure of the compound represented by the above formula (4) depends on the structure of the 3-cyclohexene-l-carboxylic acid compound used as a raw material. For example, when a (S)~3~cyclohexene~l-carboxylic acid compound is used, a compound 10 represented by the following formula (6) is obtained. When a (R)-3-cyclohexene-1-carboxylic acid compound is used, a compound represented by the following formula (7) is obtained. [0048]

[0050] As the compound represented by the above formula (4), the compound represented by the formula (6) is preferred from the viewpoint of the easy availability of the compound and improvement in 20 the pharmacological activity of the compound after dcrivatization. 13

FP17-0071-00IN-UBE Therefore, examples of preferred oxabicyclooctane compounds include (lS,4S,5S)-4-iodo-6~oxabicyclo[3,2,l]octan-7-one represented by the formula (6) because it is a compound useful as a raw material of medicines, functional materials, and the like. (!R,4R,5R)-4-iodo-6- 5 oxabicyclo[3,2,l]octan~7-one may be included in (lS,4S,5S)-4-iodo-6-oxabicyclo[3,2,l]octan~7-one, but it is preferred that the enantiomeric excess be 99% ee or more from the viewpoint of improvement in the pharmacological activity of the compound after derivatization. [0051 ] (Production Method in This Embodiment) 10 In the production method in this embodiment, 3-cyclohexene-l-carboxylic acid is mixed with iodic acid and/or a salt thereof, an iodide, and an acid, and an oxabicyclooctane compound is produced in the obtained mixed liquid. Specifically, the oxabicyclooctane compound is produced, for example, by the following methods: 15 A. A method comprising mixing the above 3-cyclohexene-l-carboxylic acid, the above iodic acid and/or salt thereof, and the above iodide to obtain a mixture; and adding the above acid to the above mixture to obtain the above mixed liquid. B. A method comprising mixing the above iodic acid and/or salt thereof 20 and the above iodide to obtain a first mixture; adding the above 3-cyclohexene-1-carboxylic acid to the above first mixture to obtain a second mixture; and adding the above acid to the above second mixture to obtain the above mixed liquid. C. A method comprising mixing the above iodic acid and/or salt thereof, 25 the above iodide, and an acid to obtain a mixture; and adding the above 3-cyclohexene-l-carboxylic acid Lo the above mixture to obtain the 14

FP17-0071-OOIN-UBE above mixed liquid.

[0052] From the viewpoint of efficiently producing the oxabicyclooctane compound while decreasing the amount of iodine discarded, the production method in this embodiment is preferably the 5 method A or the method B, more preferably the method B.

[0053] (Solvent) In the production method in this embodiment, a solvent may be used, or a solvent may not be used. In other words, in this embodiment, the reaction of 3~cyclohexene-I-carboxylic acid with iodic 10 acid and/or a salt thereof, an iodide, and an acid can be performed in the absence of a solvent or in the presence of a solvent. In this embodiment, it is preferred to use a solvent (perform the reaction in the presence of a solvent).

[0054] The solvent used is not particularly limited as long as it 15 does not inhibit the reaction. As the solvent, for example, water and various organic solvents can be used. Examples of the organic solvents include alcohols such as methanol, ethanol, propanol, ethylene glycol, isobutanol, 2-butanol, 2-ethyl-l-butanol, n-octanol, benzyl alcohol, and terpineol; ketones such as acetone, methyl ethyl ketone, 20 methyl isobutyl ketone, cyclopentanone, cyclohexanone, acetophenone, and isophorone; esters such as methyl acetate, ethyl acetate, butyl acetate, methyl benzoatc, butyl benzoate, methyl salicylate, ethyl malonate, 2-ethoxyethyl acetate, and 2-mcthoxy-l-methylethyl acetate; amides such as N,N-dimethylforrnamide, N,N-dimethylacetamide, N,N- 25 diethylformamide, N-methylpyrrolidone, N-ethylpyrrolidone, and hexamethylphosphoric tri amide; ureas such as l,3-dimethyl-2- 15

FP17-O071-00IN-UBE imidazolidinone and l,3-dimethylimidazolidine-2,4-dione; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile, propionitrile, butyronitrile, and benzonitrile; lactones such as y-butyrolactone; ethers such as diethyl 5 ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydroiuran, dioxane, tert-butyl methyl ether, anisole, phenetole, 1,2-dimethoxybenzene, 1,3-dimcthoxybenzene, 1,4-dimethoxybenzene, 1,2-methylanisole, 1,3-methylanisole, 1,4-methylanisole, 1,2-methylenedioxybenzene, 2,3-dihydrobenzofuran, phthalan, 10 octyloxybenzene, diphenyl ether, and ethyl cellosolve; carbonates such as dimethyl carbonate and 1,2-butylene glycol carbonate; thioethers such as thioanisole and ethyl phenyl sulfide; aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, pseudocumene, hemimellitene, durene, isodurene, prehnitene, ethylbenzene, cumene, 15 tert-butylbenzene, cyclohexylbenzenc, triisopropylbenzene, phenylacetylene, indan, methylindan, indene, tetralin, naphthalene, 1-methylnaphthalene, 2-methylnaphthalene, phenyloctane, and diphenylmethane; phenols such as phenol, 1,2-cresol, 1,3-cresol, 1,4-cresol, 1,2-methoxyphenol, 1,3-methoxyphenol, and 1,4- 20 methoxyphenol; halogenated aromatic hydrocarbons such as chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,4-trichlorobenzene, bromobenzene, 1,2-dibromobenzene, 1,3-dibromobenzene, 1,4-dichlorotoluene, 1-chloronaphthalene, 2,4-dichlorotoluene, 2-chloro-l ,3-dimethylbenzene, 2-chlorotoluene, 2- 25 chloro-l,4-dimethylbenzene, 4-chloro-l,2-dimethylbenzene, 2,5-dichlorotoluerie, m-ehlorotoluene, l-chloro-2,3-dimethylbenzene, 4- 16

FP17-0071-001N-UBE (trifluoromethoxy)anisole, and tri fluoromethoxybenzene; aliphatic hydrocarbons such as hexane, heptane, octane, cyclohexane, and limonene; halogenated aliphatic hydrocarbons such as dichloromethane, chl oroform, carbon tetrachloride, 1,2-dichloroethane, 1,3- 5 dichloropropane, and 1,2-dibromoethane; and pyridines such as 2,6-dimethylpyridine and 2,6-di-tert-butylpyridine. The solvent used in this embodiment is preferably water, an alcohol, or a nitrile, farther preferably water. These solvents may be used singly, or two or more of these solvents may be mixed and used. 10 [0055] When the above solvent is used, the amount of the solvent used is appropriately adjusted according to the uniformity and stirring properties of the reaction solution, and the like. The amount of the solvent used is, for example, preferably O.lg to 1000 g, more preferably 0.3g to 500 g, further preferably 0.5g to 200 g, and particularly more 15 preferably 0.5g to 100 g per g of 3-eyclohexene-l-carboxylic acid,

[0056] (Temperature) The reaction temperature in this embodiment is not particularly limited when the oxabicyclooctane compound is produced. The reaction temperature is preferably 5°C to 100°C, more preferably 10°C 20 to 80°C, and further preferably 10°C to 60°C from the viewpoint of avoiding complicatedness in terms of operations such as cooling and heating. The reaction temperature is preferably 5°C to 70°C, more preferably 10°C to 50°C, further preferably 15°C to 40°C, and still more preferably 15°C to 30°C from the viewpoint of suppressing side 25 reactions and obtaining (lS,4S,5S)-4-iodo-6-oxabicyclo[3,2,l]octan-7-one at an industrially preferred reaction rate. With an increase in 17

FP17-0071-00IN-UBE reaction temperature, the amounts of produced by-products such as the diastereoisomers of (1 S,4S,5S)-4-iodo-6-oxabicyclo[3,2,l]octan~7-one and other oxabicyclo compounds (hereinafter also referred to as "analogous compounds") may increase. Therefore, in order to obtain a 5 product useful as a medicine intermediate, it is necessary to control the reaction temperature in the above range. Particularly the diastereoisomers are analogous to (lS,4S,5S)-4-iodo-6-oxabicyclo[3,2,l]octan-7-one in chemical properties and physical properties and may be difficult to remove, and therefore it is necessary 10 to decrease the amount of the diastereoisomers produced. The reaction temperature means the temperature of the reaction system (for example, the temperature of the reaction solution) when the 3-cyclohexene-l-carboxylic acid, the iodic acid and/or salt thereof, the iodide, and the acid are mixed. When the 3-cyclohexene-l-carboxylic acid is reacted 15 in multiple stages as in the above-described method A and method B, the reaction temperature in the respective stages (temperature during mixing) may be the same or different. [0057] (Pressure and Gas) The reaction pressure (pressure during mixing) in the production 20 method in this embodiment is not particularly limited. In addition, the reaction environment (environment during mixing) is also not particularly limited. The reaction (mixing) may be performed, for example, in air, in an inert gas (for example, nitrogen, argon, or helium), or in a mixed gas thereof. It is preferred that the reaction (mixing) be 25 performed in an inert gas.

[0058] (Reduction Operation) 18

FP17-0071-OOIN-UBE In this embodiment, the iodic acid and/or salt thereof represented by the above formula (2) and the like that are unreacted may remain in the reaction system (for example, the solution after the reaction), but the iodic acid and/or salt thereof and the like can also be deactivated by 5 using a reducing agent such as sodium sulfite, sodium hydrogen sulfite, or sodium thiosulfate (for example, mixing it into the solution after the reaction). The amount of the reducing agent used is preferably 1.0 to 6.0 times the total molar amount of the iodic acid and salt thereof remaining in the solution after the completion of the reaction. The fact 10 that the iodic acid and/or salt thereof and the like are deactivated can be confirmed by potassium iodide starch paper or the like. [0059] (Neutralization Operation) In this embodiment, acids are used, and therefore the neutralization operation of neutralizing the reaction system may be 15 performed before purification. Examples of the basic compound used in the neutralization operation include hydroxides of alkali metals or alkaline earth metals (lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, and the like), 20 carbonates of alkali metals or alkaline earth metals (lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, and the like), alkoxides of alkali metals or alkaline earth metals, carboxylates of alkali metals or alkaline earth metals, 25 phosphates of alkali metals or alkaline earth metals, basic ion exchange resins, and zeolites having a base point. As the basic compound, 19

FP17-0071-OOIN-UBE preferably hydroxides or carbonates of alkali metals or alkaline earth metals are used, and more preferably carbonates are used. These basic compounds may be used singly, or a plurality of these basic compounds may be mixed and used. 5 [0060] The amount of the basic compound used may be, for example, 0.1 mol or more on a simple substance basis per mol of the acids used. The amount of the basic compound used when the basic compound is dissolved in water and used, is appropriately adjusted considering also the volume of the reaction apparatus, and the like. 10 [0061] (Purification Operation) In this embodiment, the crude product comprising the oxabicyclooctane compound produced in the mixed liquid may be purified. The crude product comprising the oxabicyclooctane compound can be isolated and purified by general methods of, foi¬ ls example, filtration, extraction, distillation, sublimation, recrystallization, and column chromatography. From the viewpoint of being able to obtain a high purity oxabicyclooctane compound in a better yield, it is preferred to perform purification by recrystallization and/or extraction, and it is more preferred to perform purification by recrystallization. 20 When a 3-cyclohexene-l-carboxylic acid compound having a particular stereostructure is used as a raw material, an oxabicyclooctane compound in which the enantiomeric excess is high can be obtained.

[0062] The recrystallization (recrystallization operation) can be performed by a generally known method. For example, a method of 25 performing recrystallization by sublimation, a method of perfonning recrystallization by concentrating a solution of the oxabicyclooctane 20

FP17-0071-OOIN-UBF compound under reduced pressure, a method of performing recrystallization by dropping a solvent having low solubility into a solution of the oxabicyclooctane compound, a method of performing recrystallization by standing in a solution at room temperature (20°C) 5 for a long time, and a method of performing recrystallization by adding seed crystals to a saturated solution of the oxabicyclooctane compound are known. The method of recrystallization is appropriately set according to the solubility, the crystal structure, and the like. The oxabicyclooctane compound is soluble in various solvents, and 10 therefore the oxabicyclooctane compound can be crystallized while the solvent used is appropriately adjusted. A method for obtaining crystals of (lS,4S,5S)-4-iodo-6-oxabicyclo[3,2,l]octan-7-one is also similar.

[0063] In the recrystallization operation, water and various organic solvents can be used as the solvent. Examples of the organic solvents 15 include alcohols such as methanol, ethanol, propanol, and isobutanol; ketones such as acetone, methyl ethyl ketone, cyclohexanone, and acetophenone; esters such as methyl acetate, ethyl acetate, methyl benzoate, and 2-methoxy-l-methylethyl acetate; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N,N- 20 diethylformamide; ureas such as l,3-dimethyl-24midazolidinone and l,3-dimethyIimidazolidine-2,4-dione; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile, propionitrile, butyronitrile, and benzonilrile; lactones such as y-butyrolactone; ethers such as diethyl ether, tetrahydrofuran, 25 dioxane, tert-butyl methyl ether, anisole, phenetole, 1,2-dimetboxybenzene, and 2,3-dihydrobenz,ofuran; carbonates such as 21

FP17-0071-OOTN-UBE dimethyl carbonate and 1,2-hutylene glycol carbonate; thioethers such as thioanisole and ethyl phenyl sulfide; aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, and naphthalene; phenols such as phenol and 1,2-cresol; halogenated aromatic hydrocarbons such as 5 chlorobenzene, 1,2-dichlorobenzene, 1 -chloronaphthalene, and 4- (trifluoromethoxy)anisole; aliphatic hydrocarbons such as hexane, heptane, octane, cyclohexane, and limonene; halogenated aliphatic hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dibromoethane; and pyridines such as 2,6- 10 dimethylpyridine and 2,6-di-tert-butylpyridine.

[0064] In this recrystallization operation, a solvent used in another purification operation may be used as it is, or the recrystallization operation may be performed by newly adding the above-described solvent. 15 [0065] After the recrystallization operation, the oxabicyclooctane compound can be obtained as crystals by filtration, and a high purity oxabicyclooctane compound can be obtained by washing the crystals with a solvent in which the solubility of the oxabicyclooctane compound is low, or the like. 20 [0066] In the extraction (extraction operation), the impurities are removed by dissolving them in an aqueous layer, the organic layer in which the oxabicyclooctane compound is dissolved is removed, and the obtained organic solvent is concentrated under reduced pressure. Thus, a solid of the oxabicyclooctane compound can be obtained. 25 [0067] The solvent used in the extraction operation is the same as the solvent used in the above recrystallization operation. 22

FP17-0071-OOIN-UBE

[0068] A higher purity oxabicyclooctane compound can be obtained by the above recrystallization operation and extraction operation. The purification operation is appropriately changed according to the physical properties, such as boiling point and solubility, 5 of the produced oxabicyclooctane compound, and the above recrystallization operation and extraction operation are particularly preferably applied when the compound represented by the above formula (6), among oxabicyclooctane compounds, is purified. 10 EXAMPLES

[0069] Next, the present invention will be specifically described by giving Examples, but the scope of the present invention is not limited to these. 15 [0070] (Example 1) (Synthesis of (IS,4Ss5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one)

[0071]

[0072] [First Step] 20 270 mL of water, 28.2 g (0.13 mol) of potassium iodate, and 43.8 g (0.26 mol) of potassium iodide were added to a container having an internal volume of 500 mL equipped with a reflux condenser, a dropping funnel, a thermometer, and a stirring apparatus, and mixed, and then 45.0 g of (S)-3-cyclohexcnc-l-carboxylic acid (0.36 mol, > 23

FP17-0071-OOIN-UBE 99% ee) was added with stirring, and the mixture was reacted at room temperature (20°C) for 2.5 hours with stirring.

[0073] [Second Step] After the completion of the reaction in the first step, 37.2 g (0.36 5 mol) of 35 mass % hydrochloric acid was added to the obtained reaction solution and mixed, and the mixture was reacted at room temperature (20°C) for 3 hours with stirring.

[0074] [Third Step] After the completion of the reaction in the second step, 56.2 g 10 (0.089 mol) of a 20 mass % sodium sulfite aqueous solution was added to the obtained reaction solution, and the mixture was stirred at room temperature (20°C). Then, the precipitated crystals were filtered. The obtained crystals were washed twice with 90 mL of water and then dried to obtain 85.3 g (0.34 mol) of (lS,4S,5S)-4-iodo-6- 15 oxabicyclo[3.2.1]octan-7-one as ocher crystals (yield; 95%, > 99% ee, content 98.2%). No brown granular material (brown grains) was seen in the obtained crystals. The presence or absence of brown grains was visually confirmed.

[0075] When the obtained (lS,4S,5S)-4-iodo-6- 20 oxabicyclo[3.2.1]octan-7-one was analyzed by high performance liquid chromatography (HPLC), the area % value of the peak corresponding to (lS,4S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one was 99.27 area % and the total of the area % values of the peaks corresponding to analogous compounds presumed to comprise diastereoisomers was 0.73 25 area % in the HPLC chart.

[0076] (Example 2) 24

FP17-0071-001N-UBE (Synthesis of (lS,4S,5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one) [First Step] 30 mL of water, 3.9 g of acetonitrile, 3.4 g (15.8 mmol) of potassium iodate, and 5.3 g (31.7 mmol) of potassium iodide were 5 added to a container having an internal volume of 100 mL equipped with a reflux condenser, a dropping funnel, a thermometer, and a stirring apparatus, and mixed, and then 5.0 g of (S)-3-cyclohexene-l-carboxylic acid (39.6 mmol, > 99% ee) was added with stirring, and the mixture was reacted at room temperature (20°C) for 2.5 hours with 10 stirring.

[0077] [Second Step] After the completion of the reaction in the first step, 4.1 g (39.6 mmol) of 35 mass % hydrochloric acid was added to the obtained reaction solution and mixed, and the mixture was reacted at room 15 temperature (20°C) for 3 hours with stirring.

[0078] [Third Step] After the completion of the reaction in the second step, 6.3 g (9.9 mmol) of a 20 mass % sodium sulfite aqueous solution was added to the obtained reaction solution, and the mixture was stkred at room 20 temperature (20°C). Then, the precipitated crystals were filtered. The obtained crystals were washed twice with 10 mL of water and then dried to obtain 9.3 g (36.7 mmol) of (lS,4S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one as ocher crystals (yield; 93%, > 99% ee, content 97.3%). No brown granular material (brown grains) was seen 25 in the obtained crystals.

[0079] When the obtained (lS,4S;5S)-4-iodo-6- 25

FP17-0071-OOIN-UBE oxabicyclo[3.2.1]octan~7-one was analyzed by high performance liquid chromatography (HPLC), the area % value of the peak corresponding to (lS,4S;5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one was 99.09 area % and the total of the area % values of the peaks corresponding to 5 analogous compounds presumed to comprise diastereoisomers was 0.10 area % in the HPLC chart.

[0080] (Example 3) (Synthesis of (lS,4S,5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one)

First Step

10 270 mL of water, 28.2 g (0.13 mol) of potassium iodate, and 43.8 g (0.26 mol) of potassium iodide were added to a container having an internal volume of 500 mL equipped with a reflux condenser, a dropping funnel, a thermometer, and a stirring apparatus, and mixed, and then 45.0 g of (S)-3-cyclohexene-l-carboxylic acid (0.36 mol, > 15 99% cc) was added with stirring, and the mixture was reacted at room temperature (20°C) for 2.5 hours with stirring.

[0081] [Second Step] After the completion of the reaction in the first step, 22.1 g (0.37 mol) of acetic acid was added to the obtained reaction solution and 20 mixed, and the mixture was reacted at room temperature (20°C) for 3 hours with stirring.

[0082] [Third Step] After the completion of the reaction in the second step, 96.8 g (0.054 mol) of a 7 mass % sodium sulfite aqueous solution was added to 25 the obtained reaction solution, and the mixture was stirred at room temperature (20°C). Then, the precipitated crystals were filtered. 26

FP17-0071-OOIN-UBE The obtained crystals were washed with 180 mL of water and then dried to obtain 86.0 g (0.34 mol) of (lS,4Ss5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one as yellowish white crystals (yield; 96%, > 99% ee, content 99.4%). No brown granular material (brown grains) 5 was seen in the obtained crystals.

[0083] When the obtained (lS,4S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one was analyzed by high performance liquid chromatography, the area % value of the peak corresponding to (lS,4S,5S)-4-iodo~6-oxabicyclo[3.2.1]octan-7-one was 99.69 area % 10 and the total of the area % values of the peaks corresponding to analogous compounds presumed to comprise diastereoisomers was 0.31 area % in the HPLC chart. [0084] [Examples 4 to 23] (Synthesis of (lS,4S,5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one) 15 Experiments were performed as in Example 3 except that the reaction temperature in the first step to the third step, the reaction time in the second step, the number of equivalents of potassium iodide, the number of equivalents of potassium iodate, the type of the acid, the number of equivalents of the acid, and the number of equivalents of 20 sodium sulfite were changed as shown in the following Table 1. The yield and content of the obtained (lS,4S,5S)~4-iodo-6-oxabicyclo[3.2.1]octan-7-one, the content of diastereoisomers and analogous compounds, and the presence or absence of brown grains are also as shown in the table below.

FP17-0071-OOIN-UBE * eq represents the number of equivalents of the amount of substance based on (S)-3-cyclohexene-l-carboxylic acid which is a raw material. * Content represents the content of (lS.4S,5S)-4-iodo-6-oxabicyclo[3,2,l]octan-7-one included in the product and is quantified (weight %) by HPLC. 5 * pa% represents an area % value in high performance liquid chromatography (HPLC). 29

FP17-0071-001N-UBE

[0086] (Example 24) (Synthesis of 4-Iodo-6-oxabicyclo[3.2.1]octan-7-one)

[0087] 5 [0088] [First Step] 120 mL of water, 12.6 g (0.06 mol) of potassium iodate, and 19.5 g (0.12 mol) of potassium iodide were added to a container having an internal volume of 300 mL equipped with a reflux condenser, a dropping funnel, a thermometer, and a stirring apparatus, and mixed, 10 and then 20.0 g (0.16 mol) of a racemic body of 3-cyclohexene-l-carboxylic acid was added with stirring, and the mixture was reacted at room temperature (20°C) for 2.5 hours with stirring. [0089] [Second Step] After the completion of the reaction in the first step, 9.5 g (0.36 15 mol) of acetic acid was added to the obtained reaction solution and mixed, and the mixture was reacted, at room temperature (20°C) for 3 hours with stirring. [0090] [Third Step] After the completion of the reaction in the second step, 23.0 g 20 (0.02 mol) of a 13 mass % sodium sulfite aqueous solution was added to the obtained reaction solution, and the mixture was stirred at room temperature (20°C). Then, the precipitated crystals were filtered. The obtained crystals were washed twice with 40 mL of water and then dried to obtain 38.2 g (0.15 mol) of a mixture of (lS,4S,5S)-4-iodo-6- 30

FP17-0071-OOIN-UBE oxabicyclo[3.2.1]octan-7~one and (iR,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one as ocher crystals (yield; 96%). From this, it was found that even with the racemic body of 3-cyclohexene-l-carboxylic acid, the reaction proceeded and an oxabicyclooctane 5 compound was obtained as in the case where (S)-3-cyclohexene-l-carboxylic acid was used.

[0091] According to the present invention, an oxabicyclooctane compound can be produced by an industrially preferred method without using excessive iodine. In addition, (lS,4S;5S)-4-iodo-6- 10 oxabicyclo[3,2,l]octan-7-one, which is one of oxabicyclooctane compounds, is also an important compound as a raw material for producing a medicine. 31

FP17-0071-OOiN-UBE WHAT TS CLAIMED IS: 1. A method for producing an oxabicyclooctane compound, comprising: mixing 3-cyclohexene-l-carboxyiic acid represented by the 5 following formula (1), iodic acid and/or a salt thereof represented by the following formula (2), an iodide represented by the following formula (3), and an acid (excluding the 3-cyclohexene-l-carboxyiic acid) to obtain a mixed liquid; and producing an oxabicyclooctane compound represented by the 10 following formula (4) in the obtained mixed liquid, wherein the iodic acid may also serve as the acid: /\.COOH I T (1) AlI03 (2) wherein A represents a hydrogen atom or an alkali metal, 15 A2I (3) wherein A represents an alkali metal. 2. The method according to claim 1, wherein the 3-cyclohexene-l- 20 carboxyiic acid is (S)-3-cyclohexene-l -carboxyiic acid represented by the following formula (5), and the oxabicyclooctane compound is (lS,4S,5S)-4-iodo-6-oxabicyclo[3,2,i]octan-7-one represented by the following formula (6). 32

FP17-0071-00IN-UBE 3. The method according to claim 1 or 2, wherein the acid comprises 5 at least one selected from the group consisting of hydrochloric acid and acetic acid. 4. The method according to any one of claims 1 to 3, wherein the 3-cyclohexene-1-carboxylic acid, the iodic acid and/or salt thereof, the 10 iodide, and the acid are mixed at a temperature of 5°C to 70°C. 5. The method according to any one of claims 1 to 4, wherein the 3-cyclohexene-1-carboxylic acid, the iodic acid and/or salt thereof, the iodide, and the acid are mixed at a temperature of 10°C to 50°C. 15 6. The method according to any one of claims 1 to 5, wherein a sum of amounts of substance of the iodic acid and salt thereof and the iodide is 0.9 mo I to 1.4 mol per mol of the 3-cyclohexene-l-carboxylic acid. 20 7. The method according to any one of claims 1 to 6, wherein a sum of amounts of substance of the iodic acid and salt thereof and the iodide is 1.0 mol to 1.2 mol per mol of the 3-cyclohexene-l-carboxylic acid. 33

FP17-0071-00IN-UBE 8. The method according to any one of claims 1 to 7, wherein a sum of amounts of substance of the iodic acid and salt thereof is 0.4 mol to 0.8 mol per mol of the iodide. 5 9. The method according to any one of claims 1 to 8, wherein obtaining the mixed liquid comprises: mixing the 3-cyclohexene-l-carhoxyhc acid, the iodic acid and/or salt thereof, and the iodide to obtain a mixture; and adding the acid to the mixture to obtain the mixed liquid. 10 10. The method for producing an oxabicyclooctane compound according to any one of claims 1 to 8, wherein obtaining the mixed liquid comprises: mixing the iodic acid and/or salt thereof and the iodide to obtain a 15 first mixture; adding the 3-cyclohexene-l-carboxylie acid to the first mixture to obtain a second mixture; and adding the acid to the second mixture to obtain the mixed liquid. 20 Dated this 23 day of June 2017 (RRNair) Reg. No.: IN/PA- 121 Of De Penning & De Penning Agent for the Applicants 34