JP2018058809A - Method for producing oxabicyclooctane compound - Google Patents

Abstract

Provided is a method for producing an oxabicyclooctane compound by an industrially suitable method without using excess iodine. 3-Cyclohexene-1-carboxylic acid, iodic acid of formula (2) and / or salt thereof, iodide of formula (3), and acid (excluding 3-cyclohexene-1-carboxylic acid) A method for producing an oxabicyclooctane compound, comprising mixing to obtain a mixed solution and generating an oxabicyclooctane compound of the formula (4) in the obtained mixed solution. (A1 is H or alkali metal.) (A2 is alkali metal.) [Selection] None

Description

  The present invention relates to a method for producing an oxabicyclooctane compound.

  An oxabicyclooctane compound is a compound useful as a raw material for, for example, pharmaceuticals and functional materials. Specifically, (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3,2,1] octane-7-one represented by the following formula (6) is used for the prevention or treatment of thrombotic diseases. It is known that it is a raw material of a compound useful as a medicine (see, for example, Patent Document 1 and Patent Document 2).

  As a method for producing this (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3,2,1] octane-7-one, for example, 3-cyclohexene-1-carboxylic acid is iodine, iodinated. Production methods for reacting with potassium and sodium hydrogen carbonate are known (see, for example, Patent Documents 1 and 2 and Non-Patent Documents 1 and 2).

International Publication No. 2010/131663 International Publication No. 2003/016302

Tetrahedron Lett. 32, 1991, 1613-1616. Tetrahedron Asymmetry 15, 2004, 2057-2060.

  In Patent Documents 1 and 2 and Non-Patent Documents 1 and 2, (S) -3-cyclohexene-1-carboxylic acid is reacted with iodine, potassium iodide, and sodium bicarbonate (1S, 4S, 5S). ) -4-iodo-6-oxabicyclo [3,2,1] octane-7-one, but a total of 4 to 7 moles to (S) -3-cyclohexene-1-carboxylic acid An amount of iodine atom was added, and none of the production methods was economically suitable. Moreover, since an excessive amount of iodine is added, there is also a problem that a large amount of iodine waste liquid is generated. Therefore, there is a demand for a production method for synthesizing an oxabicyclooctane compound in an industrially suitable yield without excessively using iodine. In addition, when (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3,2,1] octane-7-one is used as a raw material for pharmaceuticals, the amount of by-products of isomers and other compounds is reduced. It is important to.

  As described above, an object of the present invention is to provide a method for producing an oxabicyclooctane compound by an industrially suitable method without using excess iodine.

  The present invention relates to the following matters.

（式中、Ａ^１は水素原子又はアルカリ金属を示す。）

（式中、Ａ^２はアルカリ金属を示す。）

1. 3-cyclohexene-1-carboxylic acid represented by the 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 (the 3- The iodic acid is obtained by mixing (excluding cyclohexene-1-carboxylic acid) to obtain a mixed solution and generating an oxabicyclooctane compound represented by the following formula (4) in the obtained mixed solution. The manufacturing method of the oxabicyclooctane compound which may serve as the said acid.

(In the formula, A ¹ represents a hydrogen atom or an alkali metal.)

(In the formula, A ² represents an alkali metal.)

2. The 3-cyclohexene-1-carboxylic acid is (S) -3-cyclohexene-1-carboxylic acid represented by the following formula (5):
The obtained oxabicyclooctane compound is (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3,2,1] octane-7-one represented by the following formula (6): 2. The production method according to 1.

  3. 3. The production method according to 1 or 2, wherein the acid includes at least one selected from the group consisting of hydrochloric acid and acetic acid.

  4). The production according to any one of 1 to 3, 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 5 to 70 ° C. Method.

  5. The production method according to any one of 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 to 50 ° C. .

  6). Any of 1 to 5 above, wherein the total amount of the iodic acid and its salt and the iodide is 0.9 to 1.4 mol per 1 mol of the 3-cyclohexene-1-carboxylic acid. The manufacturing method as described in any one.

  7). Any of 1 to 6 above, wherein the total amount of the iodic acid and its salt and the iodide is 1.0 to 1.2 mol per 1 mol of the 3-cyclohexene-1-carboxylic acid. The manufacturing method as described in any one.

  8). The manufacturing method as described in any one of said 1-7 whose sum of the substance amount of the said iodic acid and its salt is 0.4-0.8 mol with respect to 1 mol of said iodides.

9. Obtaining the liquid mixture,
Mixing the 3-cyclohexene-1-carboxylic acid, the iodic acid and / or salt thereof, and the iodide to obtain a mixture;
The manufacturing method according to any one of 1 to 8, comprising: adding the acid to the mixture to obtain the mixed solution.

10. Obtaining the mixed solution comprises mixing the iodic acid and / or salt thereof and the iodide to obtain a first mixture;
Adding the 3-cyclohexene-1-carboxylic acid to the first mixture to obtain a second mixture;
The manufacturing method of the oxabicyclooctane compound as described in any one of said 1-8 including adding the said acid to a said 2nd mixture and obtaining the said liquid mixture.

  ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of a highly purified oxabicyclooctane compound with an industrially suitable yield can be provided by an industrially suitable method, without using excess iodine.

  The materials exemplified in this specification can be used singly or in combination of two or more unless otherwise specified. The numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively. In the numerical ranges described stepwise in the present specification, the upper limit value or lower limit value of a numerical range of a certain step may be replaced with the upper limit value or lower limit value of the numerical range of another step. Further, in the numerical ranges described in this specification, the upper limit value or the lower limit value of the numerical range may be replaced with the values shown in the examples.

  Hereinafter, a preferred embodiment of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

  The production method of the oxabicyclooctane compound of the present embodiment includes a 3-cyclohexene-1-carboxylic acid represented by the formula (1), an iodic acid represented by the formula (2) and / or a salt thereof, and the formula (3). ) And an acid (excluding the 3-cyclohexene-1-carboxylic acid) to obtain a mixed solution, and in the resulting mixed solution, oxabicyclooctane represented by the formula (4) Producing a compound. For example, the 3-cyclohexene-1-carboxylic acid represented by the formula (1), the iodic acid and / or salt thereof represented by the formula (2), and the iodide represented by the formula (3) are mixed. Furthermore, the oxabicyclooctane compound shown by said Formula (4) is obtained by making it contact with an acid (except the said 3-cyclohexene-1-carboxylic acid). In the production method of the present embodiment, for example, according to the following reaction formula, 3-cyclohexene-1-carboxylic acid reacts with iodic acid and / or its salt, iodide and acid.

（式中、Ａ^１、及びＡ^２は前記と同義である。）

(In the formula, A ¹ and A ² are as defined above.)

  In this embodiment, the iodic acid may also serve as the acid. That is, when the iodic acid is used, an acid other than iodic acid may not be used depending on the amount of iodic acid used.

(3-Cyclohexene-1-carboxylic acid)
3-Cyclohexene-1-carboxylic acid used in the present embodiment is represented by the following formula (1).

  This compound can be synthesized, for example, from 4,4-dimethyl-2-oxotetrahydrofuran-3-yl acrylate as described in Non-Patent Document 1. This compound can also be synthesized from a methylbenzylamine salt of 3-cyclohexene-1-carboxylic acid as described in Patent Document 1. This compound can also be obtained as a commercial product.

  3-Cyclohexene-1-carboxylic acid is an optically active substance, and is represented by (R) -3-cyclohexene-1-carboxylic acid (hereinafter sometimes referred to as “R-form”) and the following formula (5). (S) -3-cyclohexene-1-carboxylic acid (hereinafter also referred to as “S-isomer”) shown. 3-Cyclohexene-1-carboxylic acid may be a mixture of R-form and S-form. As 3-cyclohexene-1-carboxylic acid, (S) -3-cyclohexene-1-carboxylic acid is preferable from the viewpoint of improving the pharmacological activity of the compound after derivatization. When (S) -3-cyclohexene-1-carboxylic acid is used, (R) -3-cyclohexene-1-carboxylic acid may be contained in (S) -3-cyclohexene-1-carboxylic acid. However, from the viewpoint of improving the pharmacological activity of the compound after derivatization, the enantiomeric excess is preferably 99% ee or more.

  In this embodiment, a salt of 3-cyclohexene-1-carboxylic acid (carboxylate) may be used, and the carboxylate is brought into contact with an acid described later to obtain 3-cyclohexene-1-carboxylic acid. You may use for the manufacturing method of a form. As the carboxylate, for example, alkali metal carboxylate, alkaline earth metal carboxylate, ammonium carboxylate and the like can be used.

(Iodic acid and its salts)
Iodic acid and its salt used in the present embodiment are represented by the following formula (2).

In the formula (2), A ¹ represents a hydrogen atom or an alkali metal. Examples of the alkali metal include lithium, sodium, potassium, cesium, and francium. A ¹ is preferably sodium, potassium or cesium, more preferably sodium or potassium, and still more preferably potassium. By using such iodic acid and / or a salt thereof, an oxabicyclooctane compound can be obtained at an industrially more suitable reaction rate and yield. In the present embodiment, a plurality of types of iodic acid and / or a salt thereof, in which A ¹ in formula (2) is different, may be used, but it is preferable to use a single type of iodic acid and / or a salt thereof. In addition, iodic acid and / or a salt thereof may be used as it is, or may be used by dissolving or suspending in an organic solvent such as water or alcohol or a mixed solvent thereof.

  In this embodiment, only iodic acid may be used, only iodate may be used, and iodic acid and its salt may be mixed and used. In this embodiment, as described later, since it is preferable to add an acid separately from iodic acid, it is preferable to use only iodate.

(Iodide)
The iodinated product used in the present embodiment is represented by the following formula (3).

In formula (3), A ² represents an alkali metal. Examples of the alkali metal include lithium, sodium, potassium, cesium, and francium. A ² is preferably sodium, potassium or cesium, more preferably sodium or potassium, and still more preferably potassium. By using such an iodide or a salt thereof, an oxabicyclooctane compound can be obtained at an industrially more suitable reaction rate and yield. In the present embodiment, a plurality of types of iodides having different A ² in the formula (3) may be used, but a single type of iodide is preferable. The iodide may be used as it is, or may be used by dissolving or suspending in an organic solvent such as water or alcohol or a mixed solvent thereof.

(Amount of the iodic acid and its salt and the iodide used)
Iodic acid and its salts need to be used in combination with iodide. From the viewpoint of efficiently producing an oxabicyclooctane compound while reducing the amount of iodine discarded, the sum of the amounts of the iodic acid and its salt and the iodide is 1 mol of the 3-cyclohexene-1-carboxylic acid. Is preferably 0.9 mol to 2.0 mol, more preferably 0.9 mol to 1.4 mol, still more preferably 0.9 mol to 1.2 mol, and even more. Preferably it is 1.0 mol-1.2 mol, Most preferably, it is 1.0 mol-1.1 mol. When the sum of the substance amounts of the iodic acid and its salt and the iodide is not less than the above lower limit, the reaction is likely to proceed sufficiently, and if it is not more than the above upper limit, the side reaction proceeds, inorganic residues, etc. Therefore, the purity of the product is not easily lowered.

  From the viewpoint of efficiently producing an oxabicyclooctane compound, the sum of the substance amounts of iodic acid and its salt is preferably 0.4 mol to 0.8 mol, more preferably, with respect to 1 mol of the iodide. Is 0.4 mol to 0.6 mol. By setting it as such a range, progress of a side reaction can be suppressed, maintaining an industrially suitable reaction rate, and an oxabicyclooctane compound can be manufactured with a higher yield.

  From the above, in this embodiment, the sum of the substance amounts of the iodic acid and its salt and the iodide is 0.9 to 1.4 mol with respect to 1 mol of the 3-cyclohexene-1-carboxylic acid. And the sum of the substance amounts of the iodic acid and its salt is preferably 0.4 to 0.8 mol per 1 mol of the iodide, and the iodic acid and its salt and the substance of the iodide. The sum of the amounts is 1.0 to 1.2 mol per 1 mol of the 3-cyclohexene-1-carboxylic acid, and the sum of the substance amounts of the iodic acid and its salt is 1 mol of the iodide. It is more preferable that it is 0.4-0.6 mol.

(acid)
In this embodiment, as the acid (excluding the carboxylic acid represented by the formula (1)), an inorganic acid, an organic acid, and an aqueous solution thereof can be used. Examples of the inorganic acid include hydrogen halides such as hydrogen chloride and hydrogen bromide; halogen oxo acids such as periodic acid; sulfuric acids such as sulfuric acid and fluorosulfonic acid; phosphoric acids such as phosphoric acid and hexafluorophosphoric acid; Examples thereof include 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 hexafluoroantimonic acid. Examples of the organic acid include sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and trifluoromethanesulfonic acid; carboxylic acids such as acetic acid, formic acid, citric acid, and benzoic acid (shown in the above formula (1)) Except for carboxylic acids)); phenols such as cresol and catechol. Although part or all of the acid here may be iodic acid of the above formula (2), it is preferable not to use iodic acid as the acid in order to reduce the iodine used. The acid used in this embodiment is preferably hydrochloric acid, sulfuric acid, nitric acid, or acetic acid, more preferably hydrochloric acid or acetic acid, and more preferably acetic acid. In addition, you may use these acids individually or in mixture of 2 or more types. By using these acids, the amount of by-products of isomers and other compounds can be reduced. Such an effect is particularly remarkable when acetic acid is used.

  In this embodiment, when using acids other than iodic acid, the usage-amount of the acid to be used is 0.3 mol-5.0 with respect to 1.0 mol of 3-cyclohexene-1-carboxylic acid, for example. Moles, preferably 0.4 moles to 2.0 moles, more preferably 0.5 moles to 2.0 moles, still more preferably 0.8 moles to 1.5 moles, and even more. Preferably it is 1.0 mol-1.2 mol, Most preferably, it is 1.0 mol-1.1 mol. By setting it as such a range, an oxabicyclooctane compound can be obtained with a higher yield, maintaining an industrially suitable reaction rate. When iodic acid is used also as the acid, it is preferable to use iodic acid within the range described in (Amount of iodic acid and its salt and iodide used).

(Oxabicyclooctane compound)
The oxabicyclooctane compound obtained by this embodiment is represented by the following formula (4).

  The compound represented by the formula (4) has three asymmetric carbons. Since the compound represented by the formula (4) has a bicyclo structure, it includes four stereoisomers. The three-dimensional structure of the compound represented by the formula (4) depends on the structure of the 3-cyclohexene-1-carboxylic acid compound used as a raw material. For example, when (S) -3-cyclohexene-1-carboxylic acid compound is used, a compound represented by the following formula (6) is obtained. When (R) -3-cyclohexene-1-carboxylic acid compound is used, a compound represented by the following formula (7) is obtained.

  The compound represented by the formula (4) is preferably a compound represented by the formula (6) from the viewpoint of availability of the compound and improvement of the pharmacological activity of the compound after derivatization. Therefore, as a preferable oxabicyclooctane compound, since it is a compound useful as a raw material for pharmaceuticals, functional materials and the like, (1S, 4S, 5S) -4-iodo-6-oxabicyclo represented by the formula (6) is used. [3,2,1] octane-7-one. In (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3,2,1] octane-7-one, (1R, 4R, 5R) -4-iodo-6-oxabicyclo [3 , 2,1] octane-7-one may be contained, but from the viewpoint of improving the pharmacological activity of the compound after derivatization, the enantiomeric excess is preferably 99% ee or more.

(Manufacturing method of this embodiment)
In the production method of the present embodiment, 3-cyclohexene-1-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 resulting mixed solution. Specifically, for example, an oxabicyclooctane compound is produced by the following method.
A. Mixing the 3-cyclohexene-1-carboxylic acid, the iodic acid and / or salt thereof, and the iodide to obtain a mixture; adding the acid to the mixture to obtain the mixture; Including methods.
B. Mixing the iodic acid and / or salt thereof and the iodide to obtain a first mixture, and adding the 3-cyclohexene-1-carboxylic acid to the first mixture to form a second mixture And obtaining the mixed solution by adding the acid to the second mixture.
C. Mixing the iodic acid and / or salt thereof, the iodide, and an acid to obtain a mixture; and adding the 3-cyclohexene-1-carboxylic acid to the mixture to obtain the mixture. Including methods.

  From the viewpoint of efficiently producing an oxabicyclooctane compound while reducing the amount of iodine discarded, Method A or Method B is preferred, and Method B is more preferred.

(solvent)
In the production method of this embodiment, a solvent may be used, and a solvent may not be used. That is, in this embodiment, the reaction of 3-cyclohexene-1-carboxylic acid with iodic acid and / or its salt, iodide, and acid can be performed in the absence of a solvent or in the presence of a solvent. In this embodiment, it is preferable to use a solvent (react in the presence of a solvent).

  The solvent used is not particularly limited as long as it does not inhibit the reaction. As the solvent, for example, water and various organic solvents can be used. Examples of the organic solvent include alcohols such as methanol, ethanol, propanol, ethylene glycol, isobutanol, 2-butanol, 2-ethyl-1-butanol, n-octanol, benzyl alcohol, and terpineol; acetone, methyl ethyl ketone, methyl Ketones such as isobutyl ketone, cyclopentanone, cyclohexanone, acetophenone, and isophorone: methyl acetate, ethyl acetate, butyl acetate, methyl benzoate, butyl benzoate, methyl salicylate, ethyl malonate, 2-ethoxyethane acetate, and acetic acid Esters such as 2-methoxy-1-methylethyl; N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylformamide, N-methylpyrrolidone, N-ethylpyrrolidone, Amides such as hexamethylphosphoric triamide; ureas such as 1,3-dimethyl-2-imidazolidinone and 1,3-dimethylimidazolidine-2,4-dione; dimethyl sulfoxide and diethyl sulfoxide Sulfoxides; sulfones such as sulfolane; nitriles such as acetonitrile, propionitrile, butyronitrile, and benzonitrile; lactones such as γ-butyrolactone; diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, tert- Butyl methyl ether, anisole, phenetole, 1,2-dimethoxybenzene, 1,3-dimethoxybenzene, 1,4-dimethoxybenzene, 1,2-methylanisole, 1,3-methylanisole, 1,4-methyl Ethers such as luanisole, 1,2-methylenedioxybenzene, 2,3-dihydrobenzofuran, phthalane, 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; benzene, toluene, xylene, mesitylene, pseudocumene, hemimelitene, durene, isodurene, planitene, ethylbenzene, cumene, tert-butylbenzene, cyclohexylbenzene, triisopropylbenzene, phenylacetylene, indane , Methylindane, indene, tetralin, naphthalene, 1-methylnaphthalene, 2-methylnaphthalene, phenyloctane, and di Aromatic hydrocarbons such as phenylmethane; phenol, 1,2-cresol, 1,3-cresol, 1,4-cresol, 1,2-methoxyphenol, 1,3-methoxyphenol, and 1,4-methoxyphenol Phenols 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-1,3-dimethylbenzene, 2-chlorotoluene, 2-chloro-1,4-dimethylbenzene, 4-chloro-1,2 -Dimethylbenzene, 2,5-dichlorotoluene, m-chlorotoluene, 1-chloro-2,3-dimethylbenze , 4- (trifluoromethoxy) anisole, and trifluoromethoxybenzene, etc .; aliphatic hydrocarbons such as hexane, heptane, octane, cyclohexane, and limonene; dichloromethane, chloroform, carbon tetrachloride Halogenated aliphatic hydrocarbons such as 1,2-dichloroethane, 1,3-dichloropropane, and 1,2-dibromoethane; 2,6-dimethylpyridine, 2,6-ditert-butylpyridine, etc. Examples thereof include pyridines. The solvent used in this embodiment is preferably water, alcohols, or nitriles, and more preferably water. In addition, you may use these solvents individually or in mixture of 2 or more types.

  When using the said solvent, the usage-amount is suitably adjusted with the homogeneity, stirring property, etc. of a reaction liquid. The amount of the solvent used is, for example, preferably 0.1 to 1000 g, more preferably 0.3 to 500 g, and still more preferably 0.5 to 200 g with respect to 1 g of 3-cyclohexene-1-carboxylic acid. And more preferably 0.5 to 100 g.

(temperature)
The reaction temperature of the present embodiment is not particularly limited when producing an oxabicyclooctane compound. The reaction temperature is preferably 5 ° C. to 100 ° C., more preferably 10 ° C. to 80 ° C., and further preferably 10 ° C. to 60 ° C., from the viewpoint of avoiding complicated operation surfaces such as cooling and temperature rise. is there. From the viewpoint of suppressing side reactions and obtaining (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3,2,1] octane-7-one at an industrially suitable reaction rate. The temperature is preferably 5 ° C to 70 ° C, more preferably 10 ° C to 50 ° C, still more preferably 15 ° C to 40 ° C, and even more preferably 15 ° C to 30 ° C. As the reaction temperature increases, diastereomers of (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3,2,1] octane-7-one, other oxabicyclo compounds (hereinafter referred to as “analogs”) The amount of by-products such as “compounds”) may increase. Therefore, in order to obtain a product useful as a pharmaceutical intermediate, it is necessary to control the reaction temperature within the above range. In particular, diastereomers have similar chemical and physical properties to (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3,2,1] octane-7-one and are removed. Therefore, it is necessary to reduce the amount of diastereomers produced. In addition, reaction temperature means the temperature (for example, temperature of reaction solution) of the reaction system at the time of mixing 3-cyclohexene-1-carboxylic acid, iodic acid and / or its salt, iodide, and an acid. When reacting 3-cyclohexene-1-carboxylic acid in multiple stages as in the above-described method A and method B, the reaction temperatures (temperatures at the time of mixing) in each stage may be the same or different. Good.

(Pressure, gas)
The reaction pressure (pressure during mixing) in the production method of the present embodiment is not particularly limited. Moreover, the reaction environment (environment during mixing) is not particularly limited. The reaction (mixing) may be performed, for example, in air, in an inert gas (for example, nitrogen, argon, helium), or in a mixed gas thereof. The reaction (mixing) is preferably performed in an inert gas.

(Reduction operation)
In the present embodiment, unreacted iodic acid represented by the formula (2) and / or a salt thereof may remain in the reaction system (for example, a solution after the reaction), but sodium sulfite, sodium bisulfite, or By using a reducing agent such as sodium thiosulfate (for example, mixed in the solution after the reaction), iodic acid and / or a salt thereof can be deactivated. The amount of the reducing agent to be used is preferably 1.0-fold mol to 6.0-fold mol with respect to the total of iodic acid and its salt remaining in the solution after completion of the reaction. The inactivation of iodic acid and / or a salt thereof can be confirmed by potassium iodide starch paper or the like.

(Neutralization operation)
In this embodiment, since an acid is used, a neutralization operation for neutralizing the reaction system may be performed before purification. Examples of the basic compound used in the neutralization operation include alkali metal or alkaline earth metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, Calcium hydroxide, strontium hydroxide, etc.), alkali metal or alkaline earth metal carbonate (lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, etc.), alkali metal or Alkali earth metal alkoxides, alkali metal or alkaline earth metal carboxylates, alkali metal or alkaline earth metal phosphates, basic ion exchange resins, zeolites with base points, and the like. As the basic compound, an alkali metal or alkaline earth metal hydroxide or carbonate is preferably used, and a carbonate is more preferably used. These basic compounds may be used alone or in combination.

  The usage-amount of a basic compound may be 0.1 mol or more on a simple substance basis with respect to 1 mol of used acids, for example. The amount of the basic compound used when the basic compound is dissolved in water is appropriately adjusted in consideration of the capacity of the reaction apparatus and the like.

(Purification operation)
In this embodiment, you may refine | purify the crude product containing the oxabicyclooctane compound produced | generated in the liquid mixture. The crude product containing the oxabicyclooctane compound can be isolated and purified by a general method such as filtration, extraction, distillation, sublimation, recrystallization, column chromatography and the like. From the viewpoint of obtaining a high-purity oxabicyclooctane compound with higher yield, purification by recrystallization and / or extraction is preferable, and purification by recrystallization is more preferable. When a 3-cyclohexene-1-carboxylic acid compound having a specific steric structure is used as a raw material, an oxabicyclooctane compound having a high enantiomeric excess can be obtained.

  Recrystallization (recrystallization operation) can be performed by a generally known method. For example, a method of recrystallization by sublimation, a method of recrystallization by concentrating a solution of an oxabicyclooctane compound under reduced pressure, a method of recrystallization by dropping a solvent having low solubility in a solution of an oxabicyclooctane compound, A method of recrystallization by leaving it to stand at room temperature (20 ° C.) for a long time, a method of recrystallization by adding a seed crystal to a saturated solution of an oxabicyclooctane compound, and the like are known. The recrystallization method is appropriately set according to solubility, crystal structure, and the like. Since the oxabicyclooctane compound is soluble in various solvents, the oxabicyclooctane compound can be crystallized while appropriately adjusting the solvent used. The same applies to the method of obtaining crystals of (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3,2,1] octan-7-one.

  In the recrystallization operation, water and various organic solvents can be used as the solvent. Examples of the organic solvent include alcohols such as methanol, ethanol, propanol, and isobutanol; ketones such as acetone, methyl ethyl ketone, cyclohexanone, and acetophenone: methyl acetate, ethyl acetate, methyl benzoate, and 2-methoxy-acetate Esters such as 1-methylethyl; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and N, N-diethylformamide; 1,3-dimethyl-2-imidazolidinone, and 1, Ureas such as 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; -Buchi Lactones such as lactones; ethers such as diethyl ether, tetrahydrofuran, dioxane, tert-butyl methyl ether, anisole, phenetole, 1,2-dimethoxybenzene, and 2,3-dihydrobenzofuran; dimethyl carbonate, and 1,2- Carbonates such as butylene glycol carbonate; thioethers such as thioanisole and ethylphenyl sulfide; aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene and naphthalene; phenols such as phenol and 1,2-cresol Halogenated aromatic hydrocarbons such as chlorobenzene, 1,2-dichlorobenzene, 1-chloronaphthalene, and 4- (trifluoromethoxy) anisole; hexane, heptane, octane, cyclohexane, and Aliphatic hydrocarbons such as limonene; halogenated aliphatic hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dibromoethane; 2,6-dimethylpyridine, and 2,6-ditert- Examples thereof include pyridines such as butylpyridine.

  In this recrystallization operation, the solvent used in other purification operations may be used as it is, or the above-mentioned solvent may be newly added to perform the recrystallization operation.

  After the recrystallization operation, the oxabicyclooctane compound can be obtained as a crystal by filtration, and the high-purity oxabicyclooctane compound can be obtained by washing the crystal with a solvent having low solubility of the oxabicyclooctane compound. Can do.

  In the extraction (extraction operation), impurities are removed by dissolving in the aqueous layer, the organic layer in which the oxabicyclooctane compound is dissolved is taken out, and the obtained organic solvent is concentrated under reduced pressure. Thereby, the solid of an oxabicyclooctane compound can be obtained.

  The solvent used for the extraction operation is the same as the solvent used for the recrystallization operation.

  By the above recrystallization operation and extraction operation, a higher purity oxabicyclooctane compound can be obtained. The purification operation is appropriately changed according to the physical properties such as the boiling point and solubility of the oxabicyclooctane compound to be produced. The recrystallization operation and the extraction operation are represented by the formula (6) among oxabicyclooctane compounds. It is particularly preferably applied when purifying the indicated compounds.

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

Example 1
(Synthesis of (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one)

[First step]
In a container having a capacity of 500 mL equipped with a reflux condenser, a dropping funnel, a thermometer and a stirrer, 270 mL of water, 28.2 g (0.13 mol) of potassium iodate, and 43.8 g (0.26 mol) of potassium iodide ) Was added and mixed, then 45.0 g (0.36 mol,> 99% ee) of (S) -3-cyclohexene-1-carboxylic acid was added with stirring, and the mixture was stirred at room temperature (20 ° C.) for 2 hours. The reaction was allowed for 5 hours.

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

[Third step]
After completion of the reaction in the second step, 56.2 g (0.089 mol) of a 20 mass% aqueous sodium sulfite solution was added to the obtained reaction solution, and the mixture was stirred at room temperature (20 ° C.). Thereafter, the precipitated crystals were filtered. The obtained crystals were washed twice with 90 mL of water and then dried to give (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one as ocher crystals. 85.3 g (0.34 mol) were obtained (yield; 95%,> 99% ee, content 98.2%). No brown granular material (brown particles) was found in the obtained crystals. The presence or absence of brown grains was confirmed visually.

  The obtained (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one was analyzed by high performance liquid chromatography (HPLC). , 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octan-7-one peak area% value is estimated to be 99.27 area%, including diastereomers. The sum of the area% values of the peaks corresponding to the related compounds was 0.73 area%.

(Example 2)
(Synthesis of (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one)
[First step]
In a container with a volume of 100 mL equipped with a reflux condenser, a dropping funnel, a thermometer and a stirrer, water 30 mL, acetonitrile 3.9 g, potassium iodate 3.4 g (15.8 mmol), and potassium iodide 5.3 g (31.7 mmol) was added and mixed, then 5.0 g (39.6 mmol,> 99% ee) of (S) -3-cyclohexene-1-carboxylic acid was added with stirring and room temperature ( (20 ° C.) for 2.5 hours.

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

[Third step]
After completion of the reaction in the second step, 6.3 g (9.9 mmol) of a 20 mass% aqueous sodium sulfite solution was added to the obtained reaction solution, and the mixture was stirred at room temperature (20 ° C.). Thereafter, the precipitated crystals were filtered. The obtained crystals were washed twice with 10 mL of water and then dried to give (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one as ocher crystals. 9.3 g (36.7 mmol) were obtained (yield; 93%,> 99% ee, content 97.3%). No brown granular material (brown particles) was found in the obtained crystals.

  The obtained (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one was analyzed by high performance liquid chromatography (HPLC). , 4S, 5S) -4-Iodo-6-oxabicyclo [3.2.1] octan-7-one peak area% value is estimated to be 99.09 area%, including diastereomers. The sum of the area% values of the peaks corresponding to the related compounds was 0.10 area%.

(Example 3)
(Synthesis of (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one)
[First step]
In a 500 mL container equipped with a reflux condenser, a dropping funnel, a thermometer and a stirrer, 270 mL of water, 28.2 g (0.13 mol) of potassium iodate, and 43.8 g (0.26 mol) of potassium iodide ) Was added and mixed, then 45.0 g (0.36 mol,> 99% ee) of (S) -3-cyclohexene-1-carboxylic acid was added with stirring, and the mixture was stirred at room temperature (20 ° C.) for 2 hours. The reaction was allowed for 5 hours.

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

[Third step]
After completion of the reaction in the second step, 96.8 g (0.054 mol) of a 7% by mass aqueous sodium sulfite solution was added to the obtained reaction solution, and the mixture was stirred at room temperature (20 ° C.). Thereafter, the precipitated crystals were filtered. The obtained crystals were washed with 180 mL of water and then dried to give (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one 86. 0 g (0.34 mol) was obtained (yield; 96%,> 99% ee, content 99.4%). No brown granular material (brown particles) was found in the obtained crystals.

  The obtained (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one was analyzed by high performance liquid chromatography. As a result, (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octan-7-one has a peak area% value of 99.69 area%, which is an analogous compound estimated to contain diastereomers. The sum of the corresponding peak area% values was 0.31 area%.

[Examples 4 to 23]
(Synthesis of (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one)
As shown in Table 1 below, the reaction temperature in the first to third steps, the reaction time in the second step, the number of equivalents of potassium iodide, the number of equivalents of potassium iodate, the type of acid, the number of equivalents of acid, and sulfurous acid The experiment was performed in the same manner as in Example 3 except that the equivalent number of sodium was changed. The yield and content of the obtained (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octan-7-one, the content of diastereomers and related compounds, and The presence or absence is as shown in the table below.

(Example 24)
(Synthesis of 4-iodo-6-oxabicyclo [3.2.1] octane-7-one)

[First step]
In a container with an internal volume of 300 mL equipped with a reflux condenser, a dropping funnel, a thermometer and a stirrer, 120 mL of water, 12.6 g (0.06 mol) of potassium iodate, and 19.5 g (0.12 mol) of potassium iodide ) Was added and mixed, then 20.0 g (0.16 mol) of the racemic 3-cyclohexene-1-carboxylic acid was added with stirring, and the mixture was reacted at room temperature (20 ° C.) for 2.5 hours with stirring. .

[Second step]
After completion of the reaction in the first step, 9.5 g (0.36 mol) of acetic acid was added to the obtained reaction solution, mixed, and reacted at room temperature (20 ° C.) for 3 hours with stirring.

[Third step]
After completion of the reaction in the second step, 23.0 g (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.). Thereafter, the precipitated crystals were filtered. The obtained crystals were washed twice with 40 mL of water and then dried to give (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one as ocher crystals. And 38.2 g (0.15 mol) of a mixture of (1R, 4R, 5R) -4-iodo-6-oxabicyclo [3.2.1] octan-7-one (yield; 96%) . From this, even if it is a racemic body of 3-cyclohexene-1-carboxylic acid, reaction advances similarly to the case where (S) -3-cyclohexene-1-carboxylic acid is used, and an oxabicyclooctane compound is obtained. I understood that.

  According to the present invention, an oxabicyclooctane compound can be produced by an industrially suitable method without using excess iodine. In addition, (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3,2,1] octane-7-one, which is a kind of oxabicyclooctane compound, is an important compound as a raw material for producing pharmaceuticals. It is.

Claims (10)

3-cyclohexene-1-carboxylic acid represented by the 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 (the 3- The iodic acid is obtained by mixing (excluding cyclohexene-1-carboxylic acid) to obtain a mixed solution and generating an oxabicyclooctane compound represented by the following formula (4) in the obtained mixed solution. The manufacturing method of the oxabicyclooctane compound which may serve as the said acid.

(In the formula, A ¹ represents a hydrogen atom or an alkali metal.)

(In the formula, A ² represents an alkali metal.)

The 3-cyclohexene-1-carboxylic acid is (S) -3-cyclohexene-1-carboxylic acid represented by the following formula (5):
The oxabicyclooctane compound is (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3,2,1] octane-7-one represented by the following formula (6): The manufacturing method as described.

  The production method according to claim 1 or 2, wherein the acid includes at least one selected from the group consisting of hydrochloric acid and acetic acid.   The 3-cyclohexene-1-carboxylic acid, the iodic acid and / or salt thereof, the iodide, and the acid are mixed at a temperature of 5 to 70 ° C. Production method.   The production 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 to 50 ° C. Method.   The sum of the substance amounts of the iodic acid and its salt and the iodide is 0.9 to 1.4 mol with respect to 1 mol of the 3-cyclohexene-1-carboxylic acid. The manufacturing method as described in any one.   The sum of the substance amounts of the iodic acid and its salt and the iodide is 1.0 to 1.2 mol per 1 mol of the 3-cyclohexene-1-carboxylic acid. The manufacturing method as described in any one.   The manufacturing method as described in any one of Claims 1-7 whose sum of the substance amount of the said iodic acid and its salt is 0.4-0.8 mol with respect to 1 mol of said iodides. Obtaining the liquid mixture,
Mixing the 3-cyclohexene-1-carboxylic acid, the iodic acid and / or salt thereof, and the iodide to obtain a mixture;
The manufacturing method according to claim 1, comprising: adding the acid to the mixture to obtain the mixed solution. Obtaining the liquid mixture,
Mixing the iodic acid and / or salt thereof and the iodide to obtain a first mixture;
Adding the 3-cyclohexene-1-carboxylic acid to the first mixture to obtain a second mixture;
The method for producing an oxabicyclooctane compound according to claim 1, comprising: adding the acid to the second mixture to obtain the mixed solution.