JP2009167161A - Method for producing carboxylic acid having norbornane skeleton and ester thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently producing an exo form or an endo form of a carboxylic acid corresponding to the exo form from a compound having a skeleton of a 7-oxa-2-norbornanecarboxylic acid ester which is a mixture of the exo form and the endo form with high selectivity. <P>SOLUTION: The compound (a 7-oxa-2-norbornanecarboxylic acid ester, a 7-oxa-5-norbornene-2-carboxylic acid ester, etc.) is hydrolyzed in the presence of a basic catalyst in an amount of 0.1-1.5 mol equivalents based on 1 mol of the exo form at -20 to 50°C hydrolytic temperature. In the method, the carboxylic acid corresponding to the exo form or the endo form can be obtained with high selectivity of ≥80 mol% based on the whole carboxylic acid. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention efficiently and selectively produces an exo-form (or endo-form) of a carboxylic acid corresponding to this compound and an endo-form of the compound from a compound having a 7-oxa-2-norbornanecarboxylic acid ester skeleton. Regarding the method.

  Carboxylic acids having an oxanorbornane skeleton such as 7-oxanorbornanecarboxylic acid and 7-oxanorbornenecarboxylic acid are used as electronic materials and pharmaceutical intermediates.

  And since the carboxylic acid having such an oxanorbornane skeleton has different physical properties and physiological activities in the endo isomer and the exo isomer, respectively, a technique for selectively obtaining either isomer, for example, There is a demand for a technique for selectively producing one of them, a technique for separating either one from an isomer mixture, and the like.

  In general, a column purification method is widely known as a method for separating isomers with high selectivity, but such a column purification method is not suitable for carrying out on an industrial scale. Therefore, there is an urgent need to develop a method for selectively producing an endo or exo form of a carboxylic acid having an oxanorbornane skeleton using an industrially simple method.

  In addition, in norbornene carboxylic acids having a structure similar to the carboxylic acid having an oxanorbornane skeleton, a method for selectively producing an exo form thereof is being developed. For example, Japanese Patent Laid-Open No. 2006-160712 (Patent Document 1) discloses 5-norbornene-2-carboxylic acid, which is 5-norbornene-2-carboxylic acid and contains 30 mol% or more of an exo isomer of this carboxylic acid. It is disclosed. Further, this document also discloses a 5-norbornene-2-carboxylic acid ester which is a 5-norbornene-2-carboxylic acid ester containing 30 mol% or more of an exo isomer of this carboxylate ester as a similar compound. ing.

  According to this document, a carboxylic acid containing an exo form as described above preferentially hydrolyzes an ester of an exo form from a mixture of the exo form and endo form of the carboxylic acid (hydrolysis under basic conditions). It is described that it can be produced by a method such as decomposition. In addition, in this document, as a reason that hydrolysis can be performed preferentially by such a method, the steric hindrance around the carboxyl group is smaller in the exo isomer than in the endo isomer, and the ester is decomposed into a carboxylic acid. It is described that the exo form is faster than the endo form, and the exo form can be produced preferentially. However, with this method, it is difficult to sufficiently increase the exo-formation rate (for example, 90% or more).

On the other hand, in this document, as another method for producing a carboxylic acid containing an exo isomer as described above, the isomer of the carboxylic acid is isomerized into an exo isomer in the presence of a base (such as a metal alkoxide) A method for preferentially decomposing exo-forms is also illustrated. However, in this method, as is clear from Example 1, the reactivity of the isomerization reaction is not sufficiently high, and it is difficult to produce a carboxylic acid containing a sufficient amount of exo isomers.
JP 2006-160712 A (claims, paragraph numbers [0035], [0039], [0040], [0042], [0064], Example 1 and Example 3)

  Accordingly, an object of the present invention is to provide compounds having a 7-oxa-2-norbornanecarboxylic acid ester skeleton (such as 7-oxa-2-norbornanecarboxylic acid ester and 7-oxa-5-norbornene-2-carboxylic acid ester). The object is to provide a method for efficiently producing an exo form (or endo form) of a corresponding carboxylic acid and an endo form of the compound.

  Another object of the present invention is to easily produce an exo-form (or endo-form) of a carboxylic acid corresponding to a compound having a 7-oxa-2-norbornanecarboxylic acid ester skeleton and an endo-form of the compound with high selectivity. It is to provide a method that can.

  Still another object of the present invention is to provide an exo-form (or endo-form) of a carboxylic acid corresponding to a compound having a 7-oxa-2-norbornanecarboxylic acid ester skeleton even under mild conditions, and An object of the present invention is to provide an industrially advantageous method capable of producing an end body.

  In order to achieve the above-mentioned object, the present inventor has intensively studied a method for highly selectively obtaining an exo form of 7-oxa-2-norbornanecarboxylic acids, and as a result, isomers of exo form and endo form (stereoisomers). A compound having a 7-oxa-2-norbornanecarboxylic acid ester skeleton (7-oxa-2-norbornanecarboxylic acid ester, 7-oxa-5-norbornene-2-carboxylic acid ester, etc.) that is a mixture is a similar compound. It shows specificity that is significantly different from that of certain 5-norbornene-2-carboxylic acid esters, and the hydrolysis process under the specified catalytic amount and temperature conditions allows the exo form to be hydrolyzed with very high selectivity. The headline and the present invention were completed.

  That is, the production method of the present invention is carried out from a compound (A) having a 7-oxa-2-norbornanecarboxylic acid ester skeleton, which is a mixture of an exo isomer (A1) and an endo isomer (A2), in the presence of a basic catalyst. The exo isomer (A1) is selectively hydrolyzed to produce a carboxylic acid corresponding to the exo isomer (A1) (or a carboxylic acid containing a high proportion of carboxylic acid corresponding to the exo isomer (A1)). A method (selective production method), wherein the proportion of the basic catalyst is 0.1 to 1.5 molar equivalents relative to 1 mol of the exo isomer (A1), and the hydrolysis temperature is -20 ° C. It is a manufacturing method of carboxylic acid which is -50 degreeC. Specifically, the production method of the present invention selectively hydrolyzes the exo form (A1), and separates the reaction product (reaction product, hydrolyzate, carboxylic acid component) from the reaction mixture after hydrolysis ( Alternatively, the carboxylic acid corresponding to the exo isomer (A1) is selectively produced by collecting the carboxylic acid.

  Moreover, in this invention, the said end body (A2) can also be selectively obtained from the reaction product after the hydrolysis obtained by the said method. Therefore, in the present invention, the compound (A) having a 7-oxa-2-norbornanecarboxylic acid ester skeleton, which is a mixture of the exo isomer (A1) and the endo isomer (A2), in the presence of a basic catalyst, A method for selectively producing the endo-form (A2) by selectively hydrolyzing the exo-form (A1) and separating an unreacted product of the compound (A) from the reaction mixture after hydrolysis. In which the proportion of the basic catalyst is 0.1 to 1.5 molar equivalents relative to 1 mole of the exo isomer (A1), and the hydrolysis temperature is −20 ° C. to 50 ° C. A method is also included.

  Examples of the compound (A) include 7-oxa-2-norbornanecarboxylic acid esters (for example, 7-oxa-2-norbornanecarboxylic acid alkyl ester) and 7-oxa-5-norbornene-2-carboxylic acid esters. A compound selected from (for example, 7-oxa-5-norbornene-2-carboxylic acid alkyl ester) may be used.

  The basic catalyst may be at least one selected from metal hydroxides (such as alkali metal hydroxides and alkaline earth metal hydroxides) and metal alkoxides (such as alkali metal alkoxides). Moreover, the ratio of the said basic catalyst may be 0.5-1.4 molar equivalent with respect to 1 mol of exo isomers (A1). The hydrolysis temperature may be about −25 ° C. to 35 ° C. In particular, the hydrolysis temperature may be a relatively low temperature of about −25 ° C. to 15 ° C. When hydrolysis is performed in such a temperature range, selective hydrolyzability can be further enhanced.

  In the method of the present invention, the carboxylic acid corresponding to the exo form (A1) can be obtained with very high selectivity. In detail, the carboxylic acid produced | generated from the reaction mixture (or reaction product) after the said hydrolysis can be isolate | separated, and the carboxylic acid corresponding to an exo body (A1) can be selectively obtained from this carboxylic acid. For example, the method for selectively producing a carboxylic acid corresponding to the exo form (A1) is based on the total (or total amount) of the carboxylic acid (or carboxylic acid corresponding to the compound (A)) generated by hydrolysis. It may be a method for producing a carboxylic acid in which the ratio of the carboxylic acid corresponding to the exo form (A1) is 80 mol% or more.

The method for selectively producing a carboxylic acid corresponding to the exo form (A1) is typically as follows. (1) The basic catalyst is a metal hydroxide (in particular, an alkali metal hydroxide or an alkaline earth metal water). Oxides and the like) and metal alkoxides (especially alkali metal alkoxides and the like), and (2) the compound (A) is a 7-oxa-2-norbornanecarboxylic acid C _1-4 alkyl ester and 7 -Oxa-5-norbornene-2-carboxylic acid is a compound selected from _C1-4 alkyl ester, and the ratio of (3) basic catalyst is 0.8-1 with respect to 1 mol of exo isomer (A1). .2 molar equivalent, (4) hydrolysis temperature is −25 to 35 ° C. (for example, 23 ° C. to 33 ° C.), and (5) exo isomer with respect to the entire carboxylic acid corresponding to compound (A). ( The proportion of the carboxylic acid corresponding to 1) may be a method of producing a carboxylic acid is 85 mol% or more.

  In the method of the present invention, as described above, the exo form (A1) can be hydrolyzed with high selectivity. In the present invention, by utilizing such highly selective hydrolysis of the exo-form (A1), the endo-form (A2) is similarly high in proportion from the unreacted substance remaining without being hydrolyzed. Can be obtained with high selectivity. For example, in the method for selectively producing the endo-form (A2), the ratio of the endo-form (A2) may be 80 mol% or more based on the total unreacted product of the compound (A).

The method for selectively producing the endo-form (A2) typically includes (1) at least a basic catalyst selected from an alkali metal hydroxide, an alkaline earth metal hydroxide, and an alkali metal alkoxide. And (2) the compound (A) is selected from 7-oxa-2-norbornanecarboxylic acid C _1-4 alkyl ester and 7-oxa-5-norbornene-2-carboxylic acid C _1-4 alkyl ester (3) The proportion of the basic catalyst is 0.8 to 1.2 molar equivalents relative to 1 mol of the exo isomer (A1), and (4) the hydrolysis temperature is -23 ° C to 33 ° C. (5) The production method in which the proportion of the endo-form (A2) is 80 mol% or more based on the entire unreacted product of the compound (A) may be used.

  Furthermore, in this invention, the carboxylic acid which contains the carboxylic acid corresponding to this exo body (A2) in a high ratio can be obtained using the said exo body (A1) obtained by the said method. Therefore, in the present invention, an unreacted product of the compound (A) obtained by the above-described method (method for producing the above-mentioned endo-form (A2)) is further hydrolyzed to obtain a carboxyl corresponding to the above-mentioned endo-form (A2) A method for producing an acid (a method for producing selectively) is also included. In such a method, the proportion of the carboxylic acid corresponding to the endo-form (A2) is as high as described above, for example, 80 mol% or more based on the total (or total amount) of the carboxylic acid generated by hydrolysis. May be.

  In this specification, “carboxylic acid corresponding to the compound (A) having a 7-oxa-2-norbornanecarboxylic acid ester skeleton” means a compound in which the ester group of the compound (A) is substituted with a carboxyl group. means. For example, “a carboxylic acid corresponding to an exo form of 7-oxa-2-norbornanecarboxylic acid ester” means “an exo form of 7-oxa-2-norbornane carboxylic acid”, and “7-oxa-2-nor-2-anecarboxylic acid ester”. The “carboxylic acid corresponding to the endo form of norbornane carboxylic acid ester” means “the endo form of 7-oxa-2-norbornane carboxylic acid”. Further, in this specification, “class” such as a compound name includes a case of “having no substituent” and a case of “having a substituent”, and “may have a substituent”. May mean. For example, “7-oxa-2-norbornane carboxylic acid esters” means 7-oxa-2-norbornane carboxylic acid esters which may have a substituent. Further, in the present specification, the carboxylic acid as a product is used not only as a carboxylic acid having a free carboxyl group but also in a meaning including a salt with a basic catalyst (for example, an alkali metal salt of a carboxylic acid). There is a case.

  In the method of the present invention, a reaction having a 7-oxa-2-norbornanecarboxylic acid ester skeleton (7-oxa-2-norbornanecarboxylic acid ester, 7-oxa-5-norbornene is performed by performing a reaction under specific conditions. -2-carboxylic acid ester and the like, and an exo-form (or endo-form) of the carboxylic acid and an endo-form of the compound can be efficiently produced. In particular, in such a method of the present invention, an exo-form (or endo-form) of a carboxylic acid corresponding to a compound having a 7-oxa-2-norbornanecarboxylic acid ester skeleton and an endo-form of the compound are highly selective. It can be easily manufactured. Then, such a method of the present invention includes an exo-form (or endo-form) of a carboxylic acid corresponding to a compound having a 7-oxa-2-norbornanecarboxylic acid ester skeleton, even under mild conditions, This is an industrially advantageous method because it can produce an endo of a compound.

  In the method of the present invention, the compound (A) having a 7-oxa-2-norbornanecarboxylic acid ester skeleton is hydrolyzed (hydrolysis treatment) in the presence of a basic catalyst under specific conditions. The carboxylic acid corresponding to) is produced. In such a method, the compound (A) is a mixture (isomer mixture) of an exo isomer (A1) and an endo isomer (A2). In the method of the present invention, the exo isomer (A1) is selectively selected. Since it is hydrolyzed, a carboxylic acid corresponding to the exo form (A1) (sometimes referred to as carboxylic acid (B1)) is obtained with very high selectivity. That is, the carboxylic acid (or reaction product or carboxylic acid component) separated (recovered) from the hydrolyzed reaction mixture contains the carboxylic acid (B1) at a very high ratio.

  In the present invention, the endo-form (A2) (and also a carboxylic acid corresponding to the endo-form (A2)) is produced by utilizing such selective hydrolysis of the exo-form (A1). Also included is a method, that is, a method of selectively producing the endo-form (A2) by separating an unreacted product of the compound (A) from the reaction mixture after hydrolysis. That is, the unreacted product of the compound (A) after the hydrolysis contains the endo-form (A2) at a very high ratio, and the unreacted product is separated (recovered) from the reaction mixture. Thus, the end body (A2) can be produced with high selectivity.

  The reason why it is obtained with such high selectivity is that the hydrolyzability of the exo form (A1) is higher than the hydrolyzability of the endo form, but such selective hydrolysis of the exo form. Although it is somewhat observed even with a similar compound such as 5-norbornene-2-carboxylic acid ester, it is not a remarkably high selectivity as seen in the present invention.

  Such a compound having a 7-oxa-2-norbornanecarboxylic acid ester skeleton is different from 5-norbornane-2-carboxylic acid ester under normal hydrolysis conditions and exhibits selective hydrolyzability of an exo form. However, in the present invention, it has been found that the exo form can be hydrolyzed with very high selectivity by performing a hydrolysis treatment under a very specific condition of a specific catalyst amount and a specific temperature condition. Below, the method of this invention is explained in full detail.

  The compound (A) has a 7-oxa-2-norbornanecarboxylic acid ester skeleton (the following formula (1)).

(In the formula, R represents an ester-forming group.)
The ester-forming group (or protecting group for carboxyl group) R is not particularly limited as long as it is a group capable of generating a carboxyl group by hydrolysis. For example, a hydrocarbon group {for example, an alkyl group (for example, a methyl group, C _1-12 alkyl group such as ethyl group, isopropyl group, 2-cyclohexyl-2-propyl group, butyl group, s-butyl group, t-butyl group, preferably C _1-8 alkyl group, more preferably C _{1 -6} alkyl groups, especially C _1-4 alkyl groups), cycloalkyl groups (for example, C _3-10 cycloalkyl groups such as cyclohexyl group, 1-methylcyclohexyl group, preferably C _5-8 cycloalkyl groups), bridges Cyclic hydrocarbon group [e.g., decalinyl group (2-methyl-2-decalinyl group, etc.), adamantyl group (2-methyl-2-adamanti) Group, etc.), bi- or tricycloalkyl group such as norbornyl group (such as 2-methyl-2-norbornyl group), an aryl group (e.g., phenyl group, _{C 6-10} aryl group such as 2,4-dinitrophenyl group ), An aralkyl group (for example, a C _6-10 aryl-C _1-4 alkyl group such as a benzyl group, a 2,6-dichlorobenzyl group, a 2-nitrobenzyl group, a triphenylmethyl group)}, a heterocyclic group { For example, an oxacycloalkyl group [eg, an oxa C _5-8 cycloalkyl group such as a tetrahydrofuranyl group (such as 3-methyltetrahydrofuran-3-yl group)], a lactone ring group [eg, a γ-butyrolactone ring group (4- Methyltetrahydro-2-furanon-4-yl group), δ-valerolactone ring group (4-methyltetrahydro-2-pyrone) 4 etc. yl group), etc.], etc.}, a carbamoyl group, N- substituted carbamoyl group [e.g., N- alkylcarbamoyl group (e.g., N- methylcarbamoyl, _{N-C 1-6} alkyl such as N- ethylcarbamoyl group -Carbamoyl group, preferably N-C _1-4 alkyl-carbamoyl group), N-arylcarbamoyl group (eg C _6-10 arylcarbamoyl group such as phenylcarbamoyl group), etc.], phosphinothioyl group [eg dialkylphosphino Ji oil group (e.g., di-C _1-4 alkyl phosphino Ji oil groups such as dimethyl phosphino Chi oil group), diarylphosphino Ji oil group (e.g., di-C ₆ such as diphenylphosphinothioyl group _-10 arylphosphinothioyl group) and the like.

Of these groups R, a group capable of easily generating (or leaving) a carboxyl group by hydrolysis treatment, for example, an alkyl group (for example, a C _1-6 alkyl group) and the like are preferable. A lower alkyl group such as a group (eg, a C _1-4 alkyl group, preferably a C _1-2 alkyl group) is preferable.

  In addition, as long as the compound (A) has a 7-oxa-2-norbornanecarboxylic acid ester skeleton, it may have an unsaturated bond or a substituent. Examples of the unsaturated bond (double bond) include appropriate sites of the 7-oxanorbornenecarboxylic acid ester skeleton, for example, the 2-position and 5-position. The compound (A) having a typical unsaturated bond includes a compound having a 7-oxa-5-norbornene-2-carboxylic acid ester skeleton (the following formula (2)).

(Wherein R is the same as above)
The substituent is usually a substituent (non-reactive) that is not a reactive group for a basic catalyst (for example, a carboxyl group, an acid anhydride group, a sulfo group, a phosphoric acid group, or an acid group containing these groups). Group), for example, a hydrocarbon group {for example, an aliphatic hydrocarbon group [an alkyl group (for example, a C _1-20 alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, preferably a C _1-10 alkyl group)] ), Saturated aliphatic hydrocarbon groups (eg, C _1-20 saturated aliphatic hydrocarbon groups) such as cycloalkyl groups (eg, cyclopentyl group, cyclohexyl group); alkenyl groups (eg, C ₂₋ such as vinyl group) ₂₀ alkenyl group, etc.) an unsaturated aliphatic hydrocarbon group such as (e.g., C _1-20 unsaturated aliphatic hydrocarbon group), etc.], aryl group (e.g., phenyl, tolyl, xylyl , _{C 6-18} aryl group such as a naphthyl group, preferably a _{C 6-10} aryl group), an aromatic such as an aralkyl group (a benzyl group and _{C 6-10} aryl _{-C 1-4} alkyl group such as a phenethyl group) Hydrocarbon group etc.}, ether group [or substituted hydroxyl group, for example, alkoxy group (for example, C _1-20 alkoxy group such as methoxy group, ethoxy group, preferably C _1-10 alkoxy group, etc.), cycloalkoxy group ( C _5-10 cycloalkyloxy group such as cyclohexyloxy group), aryloxy group (C _6-10 aryloxy group such as phenoxy group), aralkyloxy group (for example, C _6-10 aryl such as benzyloxy group) -C _1-4 alkyl group)], a thioether group [or substituted mercapto group, for example, Al _{(C 1-20} alkylthio group such as methylthio group, preferably a _{C 1-20} alkylthio group, more preferably _{C 1-10,} such as an alkylthio group) thio group, etc.], acyl group (formyl groups, _C such as acetyl group _{1 20} acyl group, preferably C _1-10 acyl group), alkoxycarbonyl group (C _1-4 alkoxycarbonyl group such as methoxycarbonyl group), halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom etc.) Nitro group, nitrile group (cyano group), amino group, substituted amino group (dialkylamino group etc.), amide group (or amide-containing group such as carbamoyl group), hydroxyl group (or hydroxyl group-containing group), etc. It is done.

Typical substituents include hydrocarbon groups (eg, C _1-20 aliphatic hydrocarbon groups, C _6-18 aromatic hydrocarbon groups), nitrile groups, amino groups, amide groups, halogen atoms, acyl groups ( Formyl group), hydroxyl group and the like. The hydrocarbon group may have a substituent (for example, a substituent other than the hydrocarbon group among the above-exemplified substituents).

  The compound (A) may have these substituents alone or in combination of two or more. The number of substituents substituted on the compound (A) may be, for example, 1 to 3, preferably about 1 to 2. In addition, although the substituted position of a substituent is not specifically limited, Usually, 3rd-position, 5th-position, and / or 6-position of 7-oxa norbornene carboxylic acid skeleton may be sufficient.

  Further, the substituent includes an ester group similar to the ester group (—COOR) substituted at the 2-position of the compound (A). That is, the compound (A) may have another ester group (carboxylic acid ester group) in addition to the 2-position ester group (—COOR). The number of such other ester groups is, for example, about 1 to 3, preferably about 1 to 2. The other ester group may be the same group as the ester group substituted at the 2-position, or may be an ester group different in the type of R. Usually, the other ester group is often the same as the ester group at the 2-position. In addition, the substitution position of such an ester group may usually be the 3rd, 5th and / or 6th position of the 7-oxanorbornenecarboxylic acid skeleton.

  In the present specification, when the compound (A) has a plurality of ester groups as described above, the “endo-form” means that the ester group at the 2-position is “endo-form” unless otherwise specified. Is meant to be a compound. For example, when the 2-position ester group is an endo form and the 5-position ester group is an exo form (exo adduct), it is referred to as an endo form of the compound (A). When the ester group at the 2-position is an endo form (endo addition), the ester group at the 3-position is usually also an endo form (endo addition), and the ester group at the 2-position is an exo form (exo addition). In some cases, the ester group at the 3-position is usually also an exo form (exo addition).

  Specific compounds (A) include 7-oxa-2-norbornanecarboxylic acid esters, 7-oxa-5-norbornene-2-carboxylic acid esters, and the like.

Examples of 7-oxa-2-norbornanecarboxylic acid esters (or 7-oxa-bicyclo [2.2.1] heptane-2-carboxylic acid esters) include, for example, 7-oxa-2-norbornanecarboxylic acid ester { For example, 7-oxa-2-norbornanecarboxylic acid alkyl ester [for example, methyl 7-oxa-2-norbornanecarboxylate, ethyl 7-oxa-2-norbornanecarboxylate, t-butyl 7-oxa-2-norbornanecarboxylate 7-oxa-2-norbornanecarboxylic acid C _1-10 alkyl ester, preferably 7-oxa-2-norbornanecarboxylic acid C _1-6 alkyl ester, more preferably 7-oxa-2-norbornanecarboxylic acid C _{1 -4} alkyl ester] the expression, such as (1), R is water carbonized A compound which is a group}, 7-oxa-2-norbornanecarboxylic acid ester having a substituent {for example, alkyl-7-oxa-2-norbornanecarboxylic acid alkyl ester [for example, 5-methyl-7-oxa-2- Methyl norbornanecarboxylate, methyl 5-ethyl-7-oxa-2-norbornanecarboxylate, methyl 5-butyl-7-oxa-2-norbornanecarboxylate, methyl 5-hexyl-7-oxa-2-norbornanecarboxylate, C _1-20 alkyl-7-oxa-2-norbornanecarboxylic acid C _1-10 such as ethyl 5-methyl-7-oxa-2-norbornanecarboxylate, methyl 2-methyl-7-oxa-2-norbornanecarboxylate alkyl esters, preferably _{C 1-10} alkyl-7-oxa-2 Noruboruna Carboxylic acid _{C 1-6} alkyl ester, more preferably such _{C 1-8} alkyl-7-oxa-2-norbornane carboxylic acid _{C 1-4} alkyl esters, cycloalkyl-7-oxa-2-norbornane carboxylic acid alkyl ester [For example, C _5-10 cycloalkyl-7-oxa-2-norbornanecarboxylic acid C _1-10 alkyl ester such as methyl 5-cyclohexyl-7-oxa-2-norbornanecarboxylate], aryl-7-oxa- 2-norbornanecarboxylic acid alkyl ester [for example, C _6-10 aryl-7-oxa-2-norbornanecarboxylic acid C _1-10 alkyl ester such as methyl 5-phenyl-7-oxa-2-norbornanecarboxylic acid] and the like 7-oxa-2-nor having a hydrocarbon group of Renan such as carboxylic acid ester} and the like.

Examples of 7-oxa-5-norbornene-2-carboxylic acid esters (or 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid esters) include the 7-oxa-2 -Compounds corresponding to norbornanecarboxylic esters, for example 7-oxa-5-norbornene-2-carboxylic acid esters {for example 7-oxa-5-norbornene-2-carboxylic acid alkyl esters [for example 7-oxa- 7-oxa-5-norbornene-2 such as methyl 5-norbornene-2-carboxylate, ethyl 7-oxa-5-norbornene-2-carboxylate, t-butyl 7-oxa-5-norbornene-2-carboxylate - carboxylic acid _{C 1-10} alkyl ester, preferably 7-oxa-5-norbornene-2-carboxylic acid _{C 1-6} alkyl Ester, such as more preferably 7-oxa-5-norbornene-2-carboxylic acid _{C 1-4} alkyl ester] above expressions such (2) The compound wherein R is a hydrocarbon group in}, 7-oxa having substituent -5-norbornene-2-carboxylic acid ester {for example, alkyl-7-oxa-5-norbornene-2-carboxylic acid alkyl ester [for example, methyl 2-methyl-7-oxa-5-norbornene-2-carboxylate] C _1-20 alkyl-7-oxa-5-norbornene-2-carboxylic acid C _1-10 alkyl ester, preferably C _1-10 alkyl-7-oxa-5-norbornene-2-carboxylic acid C _1-6 alkyl esters, more preferably _{C 1-8} alkyl-7-oxa-5-norbornene-2-carboxylic acid _{C 1-4} Al Such as 7-oxa-5-norbornene-2-carboxylic acid ester having a hydrocarbon group such as etc.] glycol ester}, and the like.

Representative compounds (A) include 7-oxa-2-norbornanecarboxylic acid ester [for example, 7-oxa-2-norbornanecarboxylic acid alkyl ester (7-oxa-2-norbornanecarboxylic acid C _1-2 alkyl ester). Etc.], 7-oxa-5-norbornene-2-carboxylic acid ester [for example, 7-oxa-5-norbornene-2-carboxylic acid alkyl ester (for example, 7-oxa-5-norbornene-2-carboxylic acid) C _1-2 alkyl ester) and the like.

  As described above, compound (A) is a mixture (isomer mixture) of exo isomer (A1) and endo isomer (A2). In such an isomer mixture of the compound (A), the ratio of the exo isomer (A1) is, for example, about 5 to 70 mol%, preferably about 10 to 65 mol%, more preferably about 20 to 60 mol%. Also good. In the method of the present invention, even if the ratio of the exo form (A1) contained in the isomer mixture is small, the corresponding exo form of the carboxylic acid can be produced with high selectivity.

  In addition, as the compound (A), a commercially available product may be used, or a compound synthesized by a known or conventional method may be used.

The basic catalyst used in the method of the present invention is only required to act as a hydrolysis catalyst for the compound (A) (the ester group of the compound (A)). For example, a metal hydroxide [for example, an alkali metal hydroxide (for example, , Sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (eg, calcium hydroxide), etc.], metal alkoxides [eg, alkali metal alkoxides (eg, sodium methoxide, potassium methoxide, sodium ethoxy) Alkali metal _C1-4 alkoxides, etc.), alkali metal phenoxides, corresponding alkaline earth metal alkoxides, etc.], metal hydrides [alkali metal hydrides (eg, sodium hydride, etc.)], metal carbonates Salts [eg, alkali metal carbonates such as sodium carbonate ), Alkaline earth metal carbonates (for example, calcium carbonate, etc.)], hydrogen carbonate metal salts (for example, alkali metal hydrogen carbonate salts (for example, sodium bicarbonate), etc.), strong alkaline ion exchange resins, etc. It is done. These basic catalysts may be used alone or in combination of two or more.

  Preferred basic catalysts include metal-containing base catalysts such as metal hydroxides and metal alkoxides. Of these, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, and alkali metal alkoxides such as sodium methoxide are preferable from the viewpoint of economy. Such a catalyst is excellent as a highly selective exo-form hydrolysis catalyst in the present invention, is inexpensive, and is extremely advantageous economically.

  The reason why selective hydrolyzability can be improved by using a metal-containing catalyst is not clear, but the metal of the metal-containing base catalyst is an oxygen atom (oxa group) located at the 7-position of the compound (A) and an exo-form. It is considered that selective hydrolysis is further promoted by a steric factor that the bidentate coordination to the oxygen atom (carbonyl oxygen) of the ester group is easy. Such a steric factor is not found in the similar compound such as 5-norbornene-2-carboxylic acid ester, and such a difference, together with the reaction under specific conditions, It is presumed that this is a factor that can realize selective hydrolysis of a very high exo form. In addition, even if the 5-norbornane-2-carboxylic acid ester is hydrolyzed under the specific conditions in the present invention, no remarkable specificity is observed in the selectivity of exo-hydrolysis.

  From the viewpoint of selectively hydrolyzing the exo isomer (A1), the proportion of the basic catalyst is usually 1 mol (or exo isomer) of the exo isomer (A1) (or the ester group of the exo isomer (A1)). A1) ester group) can be selected from a range of 0.1 to 1.5 molar equivalents, for example 0.5 to 1.4 molar equivalents, preferably 0.6 to 1.3 molar equivalents, Preferably, it may be 0.7 to 1.2 molar equivalents (for example, 0.8 to 1.2 molar equivalents), particularly 1.1 molar equivalents or less (for example, 0.75 to 1.05 molar equivalents). . In addition, the said ratio may be a ratio with respect to 1 mol of the total amount of ester groups, when the said compound (A) is a compound which has ester groups other than 2-position. By using the basic catalyst in the above proportion, the exo form (A1) can be hydrolyzed with very high selectivity under the specific temperature conditions described later. If the proportion of the basic catalyst is too large (for example, a proportion exceeding 1.5 molar equivalents relative to the exo isomer (A1) mol), the hydrolysis of the endo isomer (A2) also proceeds, and endo in the carboxylic acid produced This is not preferable because the body content increases (that is, the reaction selectivity decreases).

  The method of mixing (adding) the basic catalyst to the reaction system is not particularly limited, and various addition methods such as batch addition, continuous addition, and sequential addition can be applied. However, as the reaction scale increases, the temperature increases due to heat generation. When control becomes difficult, continuous addition or sequential addition may be preferable.

Hydrolysis (hydrolysis treatment) can be usually performed in the presence of a solvent in addition to the basic catalyst. Such a solvent may usually be composed of at least a protic solvent for hydrolysis. The protic solvent is not particularly limited, and water, alcohols [for example, alkanol (for example, C _1-6 alkanol such as methanol, ethanol, 1-propanol, 2-propanol, preferably C _1-4 alkanol), Monools such as cycloalkanol (such as cyclopentanol and cyclohexanol), aralkyl alcohol (such as benzyl alcohol and phenethyl alcohol); polyols such as alkanediol (such as C _2-6 alkanediol such as ethylene glycol) and glycerin] Hydroxyl group-containing solvents such as These protic solvents may be used alone or in combination of two or more.

  Of these protic solvents, water and alkanol are preferred. Of these, water and methanol are preferable from the viewpoint of economy.

  As long as the solvent is composed of at least a protic solvent as described above, the solvent may be composed of only a protic solvent, or may be composed of a protic solvent and an aprotic solvent. Although it does not specifically limit as an aprotic solvent, Usually, a solvent miscible with a protic solvent, for example, ketones (acetone etc.), ethers (cyclic ethers, such as dioxane and tetrahydrofuran), etc. are mentioned.

  The solvent (such as a protic solvent) may be mixed in the reaction system as a solution of the basic catalyst, may be mixed in the reaction system separately from the basic catalyst, and these are combined and mixed in the reaction system. May be. The mixing method is the same as in the case of the basic catalyst.

  The amount of the protic solvent used in the hydrolysis is, for example, 0.1 to 30 parts by weight, preferably 0.2 to 10 parts by weight, and more preferably 0.5 parts by weight with respect to 1 part by weight of the compound (A). About 5 parts by weight may be used.

In the hydrolysis, the reaction temperature (hydrolysis temperature) can be selected from the range of 50 ° C. or less (eg, about −20 ° C. to 50 ° C.), for example, −15 ° C. to 40 ° C., preferably −10 ° C. to 30 ° C. More preferably, it may be about 0 to 25 ° C., and may usually be about 0 ° C. to room temperature (for example, 20 ° C.). In particular, in the hydrolysis, the reaction temperature (hydrolysis temperature) is −30 ° C. to 50 ° C., preferably −27 ° C. to 40 ° C. (eg, −25 ° C. to 35 ° C.), more preferably −23 ° C. to 33 ° C. (For example, about −22 ° C. to 32 ° C.) or about 20 ° C. or less (for example, −25 ° C. to 15 ° C., preferably −22 ° C. to 12 ° C., more preferably −20 ° C. to 10 ° C.) The temperature may be relatively low.
In the present invention, in addition to the specific amount of the basic catalyst, by setting the reaction temperature within the specific range as described above, the exo form (A1) can be efficiently hydrolyzed with high selectivity. Since the temperature range as described above can be adjusted without excessive heating or cooling, highly selective hydrolysis can be performed under mild conditions in the present invention. In addition, when reaction temperature is too high (for example, temperature exceeding 50 degreeC), hydrolysis of an end body (A2) will also advance easily and it is unpreferable. On the other hand, if the reaction temperature is too low, the reaction rate (hydrolysis rate) decreases, which is not preferable from the viewpoint of economy. In particular, when the solvent is water, the reaction system becomes a sherbet and the reaction is extremely difficult to proceed.

  In addition, you may perform a hydrolysis under the pressure under normal pressure, pressurization, or pressure reduction. The atmosphere of the reaction system is not particularly limited, and may be an oxidizing atmosphere such as an air atmosphere or a non-oxidizing atmosphere such as a nitrogen atmosphere or a rare gas atmosphere (such as an argon atmosphere).

  Moreover, you may perform a hydrolysis reaction by any methods, such as a batch type, a semibatch type, and a continuous type.

  The reaction product after hydrolysis can be separated and purified by separation means such as filtration, concentration, distillation, extraction, crystallization, recrystallization, column chromatography, etc., or a separation means combining these.

  As described above, a carboxylic acid (B) (or a carboxylic acid generated by hydrolysis) corresponding to the compound (A) is obtained, and such carboxylic acid (B) includes the exo isomer (A1). A large amount of carboxylic acid (B1) corresponding to is contained. That is, by separating or recovering an unreacted product (an unreacted product of the compound (A)) from the reaction product (or reaction mixture) after the hydrolysis, a carboxylic acid corresponding to the exo isomer (A1) ( A carboxylic acid rich in B1) is obtained. Specifically, the carboxylic acid separated from the reaction mixture after hydrolysis contains a large amount of carboxylic acid (B1). The unreacted material contains a large amount of the end body (A1).

  Examples of the carboxylic acid (B) include carboxylic acids corresponding to the compound (A), such as 7-oxa-2-norbornane carboxylic acids and 7-oxa-5-norbornene-2-carboxylic acids.

Examples of 7-oxa-2-norbornanecarboxylic acids (or 7-oxa-bicyclo [2.2.1] heptane-2-carboxylic acids) include 7-oxa-2-norbornanecarboxylic acid and 7 having a substituent. -Oxa-2-norbornanecarboxylic acid {eg alkyl-7-oxa-2-norbornanecarboxylic acid [eg 5-methyl-7-oxa-2-norbornanecarboxylic acid, 2-methyl-7-oxa-2-norbornane C _1-20 alkyl-7-oxa-2-norbornane carboxylic acid such as carboxylic acid, preferably C _1-10 alkyl-7-oxa-2-norbornane carboxylic acid, more preferably C _1-8 alkyl-7-oxa 7-oxa-2-norbornanecarboxylic acid having a hydrocarbon group such as 2-norbornanecarboxylic acid] Etc.} and the like.

Examples of 7-oxa-5-norbornene-2-carboxylic acids (or 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acids) include, for example, 7-oxa-5-norbornene- 2-carboxylic acid, substituted 7-oxa-5-norbornene-2-carboxylic acid {for example, alkyl-7-oxa-5-norbornene-2-carboxylic acid [for example, 2-methyl-7-oxa-5 -C _1-20 alkyl-7-oxa-5-norbornene-2-carboxylic acid such as norbornene-2-carboxylic acid, preferably C _1-10 alkyl-7-oxa-5-norbornene-2-carboxylic acid, preferably a hydrocarbon group such as _C, such as _1-8 alkyl-7-oxa-5-norbornene-2-carboxylate] 7-oxa-5-norbornene-2- Such as carboxylic acid}, and the like.

  As described above, such a carboxylic acid (B) contains an exo isomer (B1) at a very high ratio. For example, in the carboxylic acid (B) (or the carboxylic acid generated by hydrolysis), the proportion of the carboxylic acid [the exo isomer (B1) of the carboxylic acid (B)] corresponding to the exo isomer (A1) is the carboxylic acid ( B) 75 mol% or more (for example, 78 to 100 mol%), preferably 80 mol% or more (for example, 83 to 99.9 mol%), more preferably, based on the whole (or carboxylic acid generated by hydrolysis) May be 85 mol% or more (for example, 88 to 99.8 mol%), particularly 90 mol% or more (for example, 92 to 99.5 mol%). In particular, in the present invention, when the hydrolysis temperature is set to a relatively low temperature as described above (for example, about −25 ° C. to 15 ° C.), the exo-form (A1) of the carboxylic acid (B) is supported. The proportion of carboxylic acid to be used is 93 mol% or more (for example, 94 to 100 mol%), preferably 95 mol% or more (for example, 95 to 100 mol%), more preferably, based on the entire carboxylic acid (B). A very high ratio of 96 mol% or more (for example, 96 to 100 mol%) is also possible.

  In the method of the present invention, the carboxylic acid may be obtained in the form of a salt of a carboxylic acid and a basic catalyst (for example, an alkali metal salt of carboxylic acid). Such a salt can be easily converted into a carboxylic acid by subjecting it to a neutralization treatment. Neutralization treatment includes acids having higher acidity than carboxylic acids (for example, hydrohalic acids such as hydrogen chloride (or hydrochloric acid), inorganic acids such as sulfuric acid and nitric acid; haloalkane carboxylic acids such as sulfonic acids and trifluoroacetic acid, etc. The organic acid) can be used by a conventional method.

  As described above, in the method of the present invention, the carboxylic acid (B1) corresponding to the exo form (A2) can be obtained. By using this carboxylic acid (B1), the carboxylic acid (B1) Derivatives thereof (for example, the exo form (A2) and the like) can also be obtained. For example, the exo isomer (A2) (or an isomer mixture containing a large amount of exo isomer (A2)) can be produced by esterifying the carboxylic acid (B1) (or carboxylic acid generated by hydrolysis). As the esterification method, a conventional method can be used by using a compound corresponding to the ester group (for example, alcohols such as alkanol).

  In the method of the present invention, the carboxylic acid as the hydrolysis product contains an exo form with high selectivity, but the unreacted product (ie, ester) of the compound (A) includes As many end bodies are included. For this reason, an endo-body can also be obtained highly selectively using such an unreacted substance.

That is, in the present invention, the unreacted product separated from the hydrolyzed reaction mixture (that is, a part of the compound (A) containing a large amount of the end product (A2)) to the end product (A2) (further described later). You may selectively manufacture carboxylic acid (B2)) corresponding to an end body (A2).
Below, the method to manufacture an end body (A2) is explained in full detail.

  The endo form can be produced (selectively produced) by separating the unreacted product of the compound (A) from the reaction mixture after hydrolysis. Separation of unreacted substances from the reaction mixture may be carried out directly from the reaction mixture, or may be carried out after separating the carboxylic acid produced from the reaction mixture (separated by the above-mentioned method or the like). Usually, the unreacted product can be obtained directly or indirectly by separating (recovering) the unreacted product or removing (separating) the carboxylic acid from the reaction mixture. The unreacted product may be separated in the form of the unreacted product itself, or may be separated in the form of a mixture (for example, a liquid mixture) containing a solvent or the like in addition to the unreacted product.

  The method for separating unreacted substances from such a reaction mixture is not particularly limited, and for example, extraction, crystallization, distillation, recrystallization, reprecipitation, chromatography (column chromatography, etc.), etc. can be used. Among these, preferable separation methods include extraction, crystallization, column chromatography and the like. These separation methods may be used alone or in combination of two or more.

  In a typical method, an unreacted product can be obtained by separating and purifying a reaction mixture (usually a reaction mixture) produced by hydrolysis by the above method (extraction, crystallization, chromatography, etc.). . In the extraction, the extraction solvent is not particularly limited as long as it can dissolve unreacted substances and does not dissolve carboxylic acid (including salts of carboxylic acid and basic catalyst). Conventional solvents [for example, organic solvents] (Acetic acid esters such as methyl acetate and ethyl acetate)] can be used. Since the salt of a carboxylic acid and a basic catalyst is often water-soluble, a solvent that is not miscible with water may be particularly suitably used as the organic solvent. In crystallization, the crystallization solvent may be a good solvent for carboxylic acid and a poor solvent for unreacted substances, and can be appropriately selected according to the type of solvent in the reaction mixture.

  In addition, when an unreacted substance is obtained in the form of a mixed solution containing a solvent, the solvent may be further removed by concentration or the like, if necessary.

  The end body (A2) can be obtained as described above. In addition, the ratio of the endo isomer (A2) obtained from the unreacted product is the same as the ratio of the carboxylic acid (B1) corresponding to the exo isomer as the hydrolysis product, which is very high. For example, the ratio of the endo form (A2) is 75 mol% or more (for example, 78 to 100 mol%), preferably 80 mol% or more (for example, 83 to 83 mol%) with respect to the entire unreacted product of the compound (A). 99.9 mol%), more preferably 85 mol% or more (for example, 88 to 99.8 mol%), particularly 90 mol% or more (for example, 92 to 99.5 mol%). In the same manner as described above, when the hydrolysis temperature is set to a relatively low temperature as described above (for example, about −25 ° C. to 15 ° C.), the proportion of the endo form (A2) is changed to the compound (A2). ) Based on the total unreacted product of 93 mol% (for example, 94 to 100 mol%), preferably 95 mol% or more (for example, 95 to 100 mol%), more preferably 96 mol% or more (for example, It is also possible to use a very high ratio (96-100 mol%).

  The unreacted product of the compound (A) obtained as described above contains the endo isomer (A2) at a high ratio as described above, and the end product (A2) is used at a high ratio by using such an unreacted product. A carboxylic acid (carboxylic acid (B2)) corresponding to the body (A2) can be obtained. That is, the carboxylic acid (B) endo-form (or carboxylic acid corresponding to the endo-form (A2)) can be easily obtained by hydrolyzing the unreacted product. Therefore, in the present invention, the unreacted product of the compound (A) obtained by the above method (the method for producing the end product (A2)) is further hydrolyzed (hydrolysis treatment) to obtain the end product (A2). And a method of producing a carboxylic acid corresponding to (a method of selectively producing).

  As the hydrolysis treatment of the unreacted product, not only the same method as described above but also a conventional method can be used. That is, even if it does not depend on the above specific conditions, carboxylic acid (B2) (or carboxylic acid containing a high ratio of carboxylic acid (B2)) can be selectively obtained by conventional hydrolysis treatment. . As described above, the carboxylic acid may be obtained in the form of a salt such as a salt of a carboxylic acid and a basic catalyst (for example, an alkali metal salt of carboxylic acid). Such a salt can be easily converted into a carboxylic acid by subjecting it to a neutralization treatment. For example, the unreacted product is hydrolyzed in the presence of a basic catalyst and, if necessary, neutralized (e.g., neutralized using an acid having a higher acidity than the carboxylic acid) to give a carboxylic acid. An acid (B2) (or a carboxylic acid containing a large amount of carboxylic acid (B2)) may be obtained.

  The proportion of the carboxylic acid (B2)) corresponding to the endo product (A2) obtained from the unreacted product is the same as the proportion of the carboxylic acid (B2) as the hydrolysis product. For example, the ratio of the carboxylic acid (B2) corresponding to the endo form (A2) is 75 mol% or more (for example, 78 to 100%) with respect to the entire carboxylic acid generated by hydrolysis of the unreacted product of the compound (A). Mol%), preferably 80 mol% or more (for example, 83 to 99.9 mol%), more preferably 85 mol% or more (for example 88 to 99.8 mol%), particularly 90 mol% or more (for example, 92 ˜99.5 mol%). Similarly to the above, when the hydrolysis temperature is set to a relatively low temperature as described above (for example, about −25 ° C. to 15 ° C.), the carboxylic acid (B2) corresponding to the end form (A2) is used. Is 93 mol% or more (for example, 94 to 100 mol%), preferably 95 mol% or more (for example, 95 to 95 mol%) based on the entire carboxylic acid produced by hydrolysis of the unreacted product of compound (A). 100 mol%), more preferably 96 mol% or more (for example, 96 to 100 mol%), and a very high ratio is also possible.

  In the present invention, the carboxylic acid (B1), the endo-form (A2) or the carboxylic acid (B2) can be selectively produced, but by combining these production methods, at least two of these components can be selectively obtained. May be. For example, in the method of the present invention, the exo isomer (A1) is selectively hydrolyzed from the compound (A) in the presence of a basic catalyst, and the reaction product is separated from the hydrolyzed reaction mixture. To produce the carboxylic acid corresponding to the exo form (A1), and to separate the unreacted compound (A) from the reaction mixture after hydrolysis, thereby producing the end form (A2). Also good. In addition, the exo isomer (A1) is selectively hydrolyzed from the compound (A) in the presence of a basic catalyst, and the reaction product is separated from the hydrolyzed reaction mixture, whereby the exo isomer ( A carboxylic acid corresponding to A1) is produced, an unreacted product of the compound (A) is separated from the reaction mixture after hydrolysis, an unreacted product of the obtained compound (A) is hydrolyzed, and the endo A carboxylic acid corresponding to the body (A2) may be produced.

  The method of the present invention corresponds to a compound having a 7-oxa-2-norbornanecarboxylic acid ester skeleton (7-oxa-2-norbornanecarboxylic acid ester, 7-oxa-5-norbornene-2-carboxylic acid ester, etc.). The exo form (or endo form) of the carboxylic acid and the endo form of the compound can be efficiently produced with high selectivity, despite a simple process. In addition, the method of the present invention can be applied with mild reaction conditions, and an inexpensive basic catalyst can be used.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

(Synthesis Example 1) 7-Oxa-bicyclo [2.2.1] hepta-5-ene-2-carboxylic acid methyl ester (endo: exo = 50: 50) synthesis method 3 L four-necked flask substituted with nitrogen Were added 900 g of methylene chloride, 88.1 g of aluminum chloride and 570 g of methyl acrylate, and cooled to 10 ° C. While confirming that the reaction temperature was 15 ° C. or lower, 1200 g of furan was continuously added over 1 hour. After adding furan and aging at 15 ° C. for 1 hour, 300 g of 10% hydrochloric acid was added dropwise while maintaining the temperature at 20 ° C. or lower. Thereafter, the solution was separated, the lower layer was extracted, and concentrated at 10 mmHg and 30 ° C. or lower. The concentrated liquid was analyzed by gas chromatography and ¹ H-NMR. As a result, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester (endo: exo = 50 : 50) was produced in an amount of 510 g (yield 50%).

Synthesis Example 2 Synthesis Method of 7-Oxa-bicyclo [2.2.1] heptane-2-carboxylic acid methyl ester (endo: exo = 50: 50) 200 g of methanol was added to a nitrogen-substituted 3 L four-necked flask. 50 g of 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Synthesis Example 1 (endo: exo = 50: 50), palladium catalyst [Pd / C ( 2 g of Pd content: 5% by weight wetted in water] was added, frozen with liquid nitrogen, and degassed with a vacuum pump. Thereafter, the reaction system was replaced with hydrogen. The reactor was returned to room temperature and stirred for 3 hours, and then the palladium catalyst was filtered and concentrated while maintaining 10 torr (mmHg) at 30 ° C. or lower. After concentration, the reaction solution was analyzed by gas chromatography and ¹ H-NMR. As a result, it was found that 7-oxa-bicyclo [2.2.1] heptane-2-carboxylic acid methyl ester (endo: exo = 50: 50) was 50. 0.1 g (yield 99%) was produced.

(Example 1) Reprecipitation method In a 300 mL four-necked flask purged with nitrogen, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Synthesis Example 1 was obtained. (End body: exo body = 50: 50) 30 g (0.21 mol) and 15 g of methanol were added and cooled to 10 ° C. Then, 20.3 g (sodium methoxide: 0.105 mol) of a methanol solution containing sodium methoxide (NaOCH ₃ ) in a proportion of 28% by weight was dropped in 30 minutes and aged for 1 hour. Thereafter, the mixture was concentrated using an evaporator at 30 ° C. and 10 torr until no distillate was discharged. When the concentrated solution was dropped into 100 g of stirred ethyl acetate at room temperature, a white powder was deposited. Filtration was performed after the dropwise addition, and the filtrate was concentrated at 30 ° C. and 10 torr using an evaporator to obtain 15.2 g of a yellow transparent liquid. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester was obtained in a yield of 50%. It was obtained, and it was endo-form: exo-form = 95: 5 (molar ratio, others are the same). Moreover, when the filtrate after drying was analyzed by liquid chromatography, sodium 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylate was obtained in a yield of 48%. Body: exo body = 5: 95. Then, 100 mL of 5N hydrochloric acid was added little by little to the obtained filtrate, and when filtration was performed, endo-form: exo-form = 5: 95 and 7-oxa-bicyclo [2.2.1] hepta-5 -En-2-carboxylic acid was obtained quantitatively.

(Example 2) Extraction Into a nitrogen-substituted 300 mL four-necked flask, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Synthesis Example 1 (endo) Body: Exo body = 50: 50) 30 g (0.21 mol) and 15 g of methanol were added and cooled to 10 ° C. And 30 weight% NaOH aqueous solution 14.0g (NaOH: 0.105mol) was dripped in 30 minutes, and it age | cure | ripened for 1 hour. Thereafter, ethyl acetate was added to the reaction solution and stirred for 10 minutes, and then transferred to a separatory funnel and separated. When the organic layer was concentrated at 30 ° C. and 10 torr using an evaporator, 15.1 g of a yellow transparent liquid was obtained. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester was obtained in a yield of 49%. End-form: exo-form = 90: 10. The aqueous layer was concentrated, dried, and analyzed by liquid chromatography. As a result, sodium 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylate was obtained in a yield of 49%. End body: exo body = 10: 90.

(Example 3)
30 g of 7-oxa-bicyclo [2.2.1] heptane-2-carboxylic acid methyl ester obtained in Synthesis Example 2 (endo form: exo form = 50: 50) was added to a nitrogen-substituted 300 ml four-necked flask. (0.21 mol) and 15 g of methanol were added and cooled to 10 ° C. And 30 weight% NaOH aqueous solution 14.0g (NaOH: 0.105mol) was dripped in 30 minutes, and it age | cure | ripened for 1 hour. Thereafter, ethyl acetate was added to the reaction solution and stirred for 10 minutes, and then transferred to a separatory funnel and separated. When the organic layer was concentrated at 30 ° C. and 10 torr using an evaporator, 15.1 g of a yellow transparent liquid was obtained. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, 7-oxa-bicyclo [2.2.1] heptane-2-carboxylic acid methyl ester was obtained in a yield of 49%. Exo form = 91: 9. Further, when the aqueous layer was concentrated, dried, and analyzed by liquid chromatography, sodium 7-oxa-bicyclo [2.2.1] heptane-2-carboxylate was obtained in a yield of 50%. Exo form = 9: 91.

Example 4
To a 300 mL four-necked flask substituted with nitrogen, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Synthesis Example 1 (endo isomer: exo isomer = 50) : 50) 30 g (0.21 mol) and methanol 15 g were added and cooled to 10 ° C. And 30 weight% NaOH aqueous solution 11.2g (NaOH: 0.084mol) was dripped in 30 minutes, and it age | cure | ripened for 1 hour. Thereafter, ethyl acetate was added to the reaction solution and stirred for 10 minutes, and then transferred to a separatory funnel and separated. When the organic layer was concentrated at 30 ° C. and 10 torr using an evaporator, 15.1 g of a yellow transparent liquid was obtained. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester was obtained in a yield of 59%. End-form: exo-form = 78: 22. The aqueous layer was concentrated, dried, and analyzed by liquid chromatography. As a result, sodium 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylate was obtained in a yield of 40%. End body: exo body = 10: 90.

(Comparative Example 1)
To a 300 mL four-necked flask substituted with nitrogen, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Synthesis Example 1 (endo isomer: exo isomer = 50) : 50) 30 g (0.21 mol) and methanol 15 g were added and heated to 60 ° C. And 30 weight% NaOH aqueous solution 14.0g (NaOH: 0.105mol) was dripped in 30 minutes, and it age | cure | ripened for 1 hour. Thereafter, ethyl acetate was added to the reaction solution and stirred for 10 minutes, and then transferred to a separatory funnel and separated. When the organic layer was concentrated at 30 ° C. and 10 torr using an evaporator, 15.1 g of a yellow transparent liquid was obtained. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester was obtained in a yield of 49%. End-form: exo-form = 55: 45. The aqueous layer was concentrated, dried, and analyzed by liquid chromatography. As a result, sodium 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylate was obtained in a yield of 49%. End-form: exo-form = 45: 55.

(Example 5)
To a 300 mL four-necked flask substituted with nitrogen, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Synthesis Example 1 (endo isomer: exo isomer = 50) : 50) 30 g (0.21 mol) and methanol 15 g were added and cooled to 10 ° C. Then, 16.8 g of 30 wt% NaOH aqueous solution (NaOH: 0.126 mol) was added dropwise in 30 minutes and aged for 1 hour. Thereafter, ethyl acetate was added to the reaction solution and stirred for 10 minutes, and then transferred to a separatory funnel and separated. When the organic layer was concentrated at 30 ° C. and 10 torr using an evaporator, 15.1 g of a yellow transparent liquid was obtained. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester was obtained in a yield of 39%. , Endo-form: exo-form = 99: 1. The aqueous layer was concentrated, dried, and analyzed by liquid chromatography. Sodium 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylate was obtained in a yield of 60%. End-form: exo-form = 18: 82.

(Comparative Example 2)
To a 300 mL four-necked flask substituted with nitrogen, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Synthesis Example 1 (endo isomer: exo isomer = 50) : 50) 30 g (0.23 mol) and methanol 15 g were added and cooled to 10 ° C. And 30 weight% NaOH aqueous solution 28.0g (NaOH: 0.21mol) was dripped in 30 minutes, and it age | cure | ripened for 1 hour. Thereafter, ethyl acetate was added to the reaction solution and stirred for 10 minutes, and then transferred to a separatory funnel and separated. When the organic layer was concentrated at 30 ° C. and 10 torr using an evaporator, 15.1 g of a yellow transparent liquid was obtained. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester was hardly obtained. The aqueous layer was concentrated, dried, and analyzed by liquid chromatography. Sodium 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylate was obtained in a yield of 99%. End-form: exo-form = 50: 50.

(Comparative Example 3) (Norbornene)
30 g (0.21 mol) of norbornane-5-ene-2-carboxylic acid methyl ester (endo isomer: exo isomer = 50: 50) synthesized in the same manner as in Synthesis Example 1 in a nitrogen-substituted 300 mL four-necked flask Then, 15 g of methanol was added and cooled to 10 ° C. And 30 weight% NaOH aqueous solution 14.0g (NaOH: 0.105mol) was dripped in 30 minutes, and it age | cure | ripened for 1 hour. Thereafter, ethyl acetate was added to the reaction solution and stirred for 10 minutes, and then transferred to a separatory funnel and separated. When the organic layer was concentrated at 30 ° C. and 10 torr using an evaporator, 15.1 g of a yellow transparent liquid was obtained. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, norbornane-5-ene-2-carboxylic acid methyl ester was obtained in a yield of 49%, and endo isomer: exo isomer = 74: 26. It was. Further, when the aqueous layer was concentrated, dried and analyzed by liquid chromatography, sodium norbornane-5-ene-2-carboxylate was obtained in a yield of 49%, and the endo form: exo form = 26: 74. It was.

(Example 6)
To a 300 mL four-necked flask substituted with nitrogen, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Synthesis Example 1 (endo isomer: exo isomer = 50) : 50) 30 g (0.21 mol) and methanol 15 g were added and cooled to 0 ° C. Then, 20.3 g (NaOCH ₃ : 0.105 mol) of a methanol solution containing sodium methoxide (NaOCH ₃ ) at a ratio of 28% by weight was added dropwise at 0 ° C. over 30 minutes, and aged for 1 hour. Thereafter, the mixture was concentrated using an evaporator at 30 ° C. and 10 torr until no distillate was discharged. When the concentrated solution was dropped into 100 g of stirred ethyl acetate at room temperature, a white powder was deposited. Filtration was performed after the dropwise addition, and the filtrate was concentrated at 30 ° C. and 10 torr using an evaporator to obtain 15.2 g of a yellow transparent liquid. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester was obtained in a yield of 50%. , Endo-form: exo-form = 96: 4. Moreover, when the filtrate was dried and analyzed by liquid chromatography, sodium 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylate was obtained in a yield of 48%. End isomer: exo isomer = 4: 96.

(Example 7)
To a 300 mL four-necked flask substituted with nitrogen, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Synthesis Example 1 (endo isomer: exo isomer = 50) : 50) 30 g (0.21 mol) and methanol 15 g were added and kept at 30 ° C. Then, 20.3 g (sodium methoxide: 0.105 mol) of a methanol solution containing sodium methoxide (NaOCH ₃ ) in a proportion of 28% by weight was dropped in 30 minutes and aged for 1 hour. Thereafter, the mixture was concentrated using an evaporator at 30 ° C. and 10 torr until no distillate was discharged. When the concentrated solution was dropped into 100 g of stirred ethyl acetate at room temperature, a white powder was deposited. Filtration was performed after the dropwise addition, and the filtrate was concentrated at 30 ° C. and 10 torr using an evaporator to obtain 15.2 g of a yellow transparent liquid. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester was obtained in a yield of 50%. As a result, endo-form: exo-form = 88: 12. Moreover, when the filtrate after drying was analyzed by liquid chromatography, sodium 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylate was obtained in a yield of 49%. Body: exo body = 12:88.

(Example 8)
To a 300 mL four-necked flask substituted with nitrogen, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Synthesis Example 1 (endo isomer: exo isomer = 50) : 50) 30 g (0.21 mol) and methanol 15 g were added and cooled to −10 ° C. And 30 weight% NaOH aqueous solution 14.0g (NaOH: 0.105mol) was dripped in 30 minutes, and it age | cure | ripened for 1 hour. Thereafter, ethyl acetate was added to the reaction solution and stirred for 10 minutes, and then transferred to a separatory funnel and separated. When the organic layer was concentrated at 30 ° C. and 10 torr using an evaporator, 15.1 g of a yellow transparent liquid was obtained. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester was obtained in a yield of 50%. , Endo-form: exo-form = 97: 3. The aqueous layer was concentrated, dried, and analyzed by liquid chromatography. As a result, sodium 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylate was obtained in a yield of 49%. End-form: exo-form = 3: 97.

Example 9
To a 300 mL four-necked flask substituted with nitrogen, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Synthesis Example 1 (endo isomer: exo isomer = 50) : 50) 30 g (0.21 mol) and methanol 15 g were added and cooled to -20 ° C. And 30 weight% NaOH aqueous solution 14.0g (NaOH: 0.105mol) was dripped in 30 minutes, and it age | cure | ripened for 1 hour. Thereafter, ethyl acetate was added to the reaction solution and stirred for 10 minutes, and then transferred to a separatory funnel and separated. When the organic layer was concentrated at 30 ° C. and 10 torr using an evaporator, 15.1 g of a yellow transparent liquid was obtained. When the obtained liquid was analyzed by liquid chromatography and ¹ H-NMR, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester was obtained in a yield of 50%. , Endo-form: exo-form = 97: 3. The aqueous layer was concentrated, dried, and analyzed by liquid chromatography. As a result, sodium 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylate was obtained in a yield of 49%. End-form: exo-form = 3: 97.

(Example 10)
Into a nitrogen-substituted 300 mL four-necked flask, 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid methyl ester obtained in Example 2 (endo-form: exo-form = 90 : 10) 22 g (0.144 mol) and 11 g of water were added and cooled to 6 ° C. And 30 weight% NaOH aqueous solution 24.9g (0.19mol) was dripped, hold | maintaining near the same temperature, and also age | cure | ripened for about 1 hour. Then, ethyl acetate and water were added and extracted, and the organic layer was removed. Then, 35% hydrochloric acid was added dropwise to the aqueous layer to adjust the pH of the aqueous layer to 1. As a result, a white solid was precipitated, and this precipitate was filtered by Nutsche to obtain 1.6 g of 7-oxa-bicyclo [2.2.1. ] Hepta-5-ene-2-carboxylic acid (endo isomer: exo isomer = 100: 0) was obtained. On the other hand, the filtrate was further extracted with ethyl acetate to remove the aqueous layer, and then the ethyl acetate layer was concentrated and crystallized by adding hexane. Subsequently, filtration, rinsing with hexane and drying were performed, and 14.3 g of 7-oxa-bicyclo [2.2.1] hept-5-ene-2-carboxylic acid (endo isomer: exo isomer = 90: 10) ( 0.14 mol) was obtained with a yield of 97%.

Claims (13)

  In the presence of a basic catalyst, the exo isomer (A1) is selected from the compound (A) having a 7-oxa-2-norbornanecarboxylic acid ester skeleton, which is a mixture of the exo isomer (A1) and the endo isomer (A2). Hydrolyzing to selectively produce a carboxylic acid corresponding to the exo form (A1), wherein the proportion of the basic catalyst is 0.1-1 with respect to 1 mole of the exo form (A1). The manufacturing method of carboxylic acid which is 0.5 molar equivalent and whose hydrolysis temperature is -30 degreeC-50 degreeC.   In the presence of a basic catalyst, the exo isomer (A1) is selected from the compound (A) having a 7-oxa-2-norbornanecarboxylic acid ester skeleton, which is a mixture of the exo isomer (A1) and the endo isomer (A2). Hydrolyzing and separating the unreacted compound (A) from the hydrolyzed reaction mixture to selectively produce the endo (A2), wherein the ratio of the basic catalyst Is 0.1-1.5 molar equivalent with respect to 1 mol of said exo isomers (A1), and a hydrolysis temperature is -30 degreeC-50 degreeC.   The process according to claim 1 or 2, wherein the compound (A) is a compound selected from 7-oxa-2-norbornanecarboxylic acid esters and 7-oxa-5-norbornene-2-carboxylic acid esters.   The compound (A) is a compound selected from 7-oxa-2-norbornanecarboxylic acid alkyl ester and 7-oxa-5-norbornene-2-carboxylic acid alkyl ester. Production method.   The production method according to claim 1, wherein the basic catalyst is at least one selected from a metal hydroxide and a metal alkoxide.   The production method according to any one of claims 1 to 5, wherein the proportion of the basic catalyst is 0.5 to 1.4 molar equivalents relative to 1 mol of the exo isomer (A1).   The method according to any one of claims 1 to 6, wherein the hydrolysis temperature is -25 ° C to 35 ° C.   The production method according to any one of claims 1 to 7, wherein the hydrolysis temperature is -25 ° C to 15 ° C.   The manufacturing method of Claim 1 which selectively manufactures the carboxylic acid whose ratio of the carboxylic acid corresponding to an exo body (A1) is 80 mol% or more with respect to the whole carboxylic acid produced | generated by hydrolysis. (1) The basic catalyst is at least one selected from an alkali metal hydroxide, an alkaline earth metal hydroxide, and an alkali metal alkoxide, and (2) the compound (A) is 7-oxa-2-norbornane A compound selected from a carboxylic acid C _1-4 alkyl ester and a 7-oxa-5-norbornene-2-carboxylic acid C _1-4 alkyl ester, wherein the proportion of the basic catalyst is an exo isomer (A1) It is 0.8-1.2 molar equivalent with respect to 1 mol, (4) Hydrolysis temperature is -23 degreeC-33 degreeC, (5) Exo body with respect to the whole carboxylic acid produced | generated by hydrolysis The manufacturing method of Claim 1 or 9 which selectively manufactures the carboxylic acid whose ratio of the carboxylic acid corresponding to (A1) is 85 mol% or more.   The production method according to claim 2, wherein the proportion of the endo form (A2) is 80 mol% or more based on the entire unreacted product of the compound (A). (1) The basic catalyst is at least one selected from an alkali metal hydroxide, an alkaline earth metal hydroxide, and an alkali metal alkoxide, and (2) the compound (A) is 7-oxa-2-norbornane A compound selected from a carboxylic acid C _1-4 alkyl ester and a 7-oxa-5-norbornene-2-carboxylic acid C _1-4 alkyl ester, wherein the proportion of the basic catalyst is an exo isomer (A1) It is 0.8-1.2 molar equivalent with respect to 1 mol, (4) Hydrolysis temperature is -23 degreeC-33 degreeC, (5) The ratio of an endo-form (A2) is compound (A). The production method according to claim 2 or 11, which is 80 mol% or more based on the entire unreacted product.   A method for selectively producing a carboxylic acid corresponding to the endo form (A2) by further hydrolyzing an unreacted product of the compound (A) obtained by the method according to claim 2.