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

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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
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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
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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
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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
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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]
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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.
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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
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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
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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

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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):
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[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

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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

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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-
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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

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(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

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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)
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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

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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