JP4478437B2 - Method for producing methylene norcamphor - Google Patents

Description

  The present invention relates to a method for producing methylene norcamphor, which is useful as an agrochemical intermediate or the like, that is, 3-methylenebicyclo [2.2.1] -2-heptanone, in high yield, using norcamphor as a starting material.

  Methylene norcamphor is a known compound useful as a raw material for producing 3-acetyl-cyclopentanecarboxylic acid ester, which is an agrochemical intermediate shown in, for example, Japanese Patent Application Laid-Open No. 10-265441. It has been known. For example, the methylene represented by the formula (B) is treated by a two-step reaction in which the norcamphor represented by the formula (A) is treated with an iminium salt (Mannich base) composed of piperidine, formaldehyde and hydrochloric acid and then pyrolyzed. A method for producing norcamphor is known (Non-patent Document 1: Org. Syn. (1973) Vol. 53, 1844, p. 166).

  However, this method requires a two-step operation for the reaction, and the second-stage pyrolysis requires a high temperature of 250 to 260 ° C., which is not an industrially advantageous method. Moreover, the yield is as low as about 18 to 30% calculated from norcamphor, which is problematic in practice.

  Similarly, a method is disclosed in which norcamphor is used as a starting material, treated with piperidine hydrochloride and formaldehyde, ether is added, and 3-piperidinomethyl-2-norbornanone hydrochloride is precipitated as a solid, followed by thermal decomposition ( Non-Patent Document 2: Krieger, H. et al., Suomen Kemistilehti, 39B (1), 8-14 (1966)). However, this method is also a two-step reaction, and the operation is complicated, and the yield is 42%, and it is difficult to say that this method is suitable for industrial production.

  As another method, a method is known in which paraformaldehyde and N-methylanilinium trifluoroacetate are heated in α-tetralone in tetrahydrofuran to introduce a methylene group into a carbon atom adjacent to the ketone (non-patent document). 3: Freeman, Jeremiah P., Organic Synthesis Collective Volume 7, 322-334). The reaction yield of this method is as high as 86 to 91%, and the reaction conditions are moderate. However, trifluoroacetic acid is disadvantageous for industrial use because it is inferior in handleability, and norcamphor is not suitable for this reaction. There is a statement that it is not applicable.

As indicated above, hydrochloric acid is generally used in conventional methods using Mannich bases. On the other hand, JP-A-10-265415 (Patent Document 1) discloses a method for producing methylene norcamphor in which norcamphor is reacted with formaldehyde in the presence of a secondary amine and a carboxylic acid. In this method, the reaction proceeds under relatively mild conditions where the preferred reaction temperature is 130 ° C. or lower, and methylene norcamphor is obtained without requiring isolation of an intermediate. However, the yield is only about 76% calculated from norcamphor. Moreover, in order to obtain this yield, it is necessary to add a large amount of sulfuric acid, which is a strong acid, after the reaction is completed. The yield without adding sulfuric acid is at most about 65%.
Thus, an efficient method for producing methylene norcamphor is not yet known.

  JP-A-10-265415 lists various solvents including an organic solvent mixed solution in addition to an aqueous solvent as a reaction solvent, but only examples of the aqueous solvent are specifically disclosed. . Moreover, after completion | finish of reaction, although solvent extraction is carried out and the product is isolate | separated, the special conditions are not shown about a solvent extraction process.

JP-A-10-265415 Org. Syn. (1973) Vol. 53, 1844, p.166 Krieger, H. et al., Suomen Kemistilehti, 39B (1), 8-14 (1966) Freeman, Jeremiah P., Organic Synthesis Collective Volume 7, 322-334

  Accordingly, an object of the present invention is to provide an industrially advantageous method for producing methylene norcamphor.

  As a result of intensive studies to achieve the above object, the present inventors have found that the higher the temperature of the reaction between norcamphor and formalin in the presence of an organic acid and a secondary amine, the more advantageous the formation of methylene norcamphor. Focusing on the reaction, the inventors have found that excellent results can be obtained by appropriately extracting methylene norcamphor produced from a high-temperature reaction solution, thereby completing the present invention.

That is, the present invention
[1] In a method for producing methylene norcamphor in which an aqueous solvent is reacted in the presence of a secondary amine and an organic acid by heating formaldehyde and norcamphor to a temperature of 60 ° C. or higher, before or during the reaction. A method for producing methylene norcamphor, comprising adding an extraction solvent for methylene norcamphor.
[2] In a method for producing methylene norcamphor in which an aqueous formaldehyde solution and norcamphor are reacted by heating to a temperature of 60 ° C. or higher in the presence of a secondary amine and an organic acid, A method for producing methylene norcamphor, which comprises adding an extraction solvent.
[3] In a method for producing methylene norcamphor in which an aqueous solvent is reacted in the presence of a secondary amine and an organic acid by heating formaldehyde and norcamphor to a temperature of 60 ° C. or higher. A method for producing methylene norcamphor, comprising adding an extraction solvent and heating to a temperature of 60 ° C or higher.
[4] In a method for producing methylene norcamphor in which a formaldehyde aqueous solution and norcamphor are reacted by heating to a temperature of 60 ° C. or higher in the presence of a secondary amine and an organic acid, an extraction solvent for methylenenorcamphor is added after the heating reaction. And heating to a temperature of 60 ° C. or higher, a method for producing methylene norcamphor.
[5] The production method according to any one of 1 to 4, wherein the heating in the presence of the extraction solvent is performed at a temperature of 80 to 105 ° C.
[6] The production method according to any one of 1 to 4, wherein the extraction solvent is an organic solvent.
[7] As an organic solvent, an organic solvent insoluble in water selected from an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, a chlorine solvent, an ether solvent, an ester solvent, or a mixture thereof The manufacturing method of said 6 used.
[8] The production method according to 7 above, wherein the organic solvent has a boiling point not lower than the heating temperature.
[9] The production method according to any one of 1 to 4, wherein acetic acid is used as the organic acid.
[10] Any of the above 1 to 4 using the formula NHR ¹ R ² (wherein R ¹ and R ² may be the same or different and each represents an alkyl group having 1 to 4 carbon atoms) as the secondary amine. The manufacturing method of crab.
[11] The production method according to 10 above, wherein the secondary amine is diethylamine.
[12] An organic acid is used in an amount of 1.5 to 2.5 equivalents of norcamphor, a secondary amine is used in an amount of 0.5 to 1.5 equivalents of norcamphor, and a formaldehyde aqueous solution having a formaldehyde concentration of 25 to 40% is used as formaldehyde. The production method according to any one of 1 to 4 above, wherein 1 to 2 equivalents of camphor are reacted.

The method of the present invention is simplified as compared with the conventional method, and can be performed under mild conditions. Moreover, it differs from the method described in JP-A-10-265415 having the same basic reaction in that a strong acid such as sulfuric acid is not used, so that the burden of wastewater treatment is reduced and the yield is remarkably improved.
That is, as explained in detail in the section of the background art, in order to obtain the target methylene norcamphor from the reaction solution, a method of thermal decomposition at a high temperature exceeding 200 ° C., or a large amount of organic compound more than 5 times equivalent to norcamphor. A conventional method using an acid or further adding a strong acid such as sulfuric acid after the reaction cannot provide a satisfactory yield, but according to the present invention, surprisingly, in the presence of a heterogeneous extraction solvent phase. Methylene norcamphor is obtained almost quantitatively by heating at a temperature comparable to the reaction temperature of 60 ° C. or higher, desirably 80 ° C. or higher and 105 ° C. or lower. In particular, when acetic acid is used as the organic acid, methylene norcamphor is obtained almost quantitatively even when acetic acid is used in an amount of about 1.5 to 2.5 equivalents relative to norcamphor.

Hereinafter, the method of the present invention will be described in detail.
In the method of the present invention, (1) formaldehyde and norcamphor are heated and reacted at a temperature of 60 ° C. or higher in the presence of a secondary amine and an organic acid in an aqueous solvent, or (2) a secondary amine and an organic acid. In a method for producing methylene norcamphor, in which a formaldehyde aqueous solution (formalin) and norcamphor are reacted at a temperature of 60 ° C. or higher in the presence of water, an extraction solvent for methylene norcamphor is added or heated before or during the reaction. After the reaction, a methylene norcamphor extraction solvent is added and heated to a temperature of 60 ° C. or higher.
When formaldehyde and norcamphor are reacted in the presence of an organic acid and a secondary amine, the product, methylene norcamphor, is an intermediate (an adduct in which an organic acid salt of Mannich base is covalently bonded to the position adjacent to the oxy group). ) And the following equation.

  As described above, the Mannich base salt adduct did not decompose or give methylene norcamphor only in a low yield in the conventional method using hydrochloric acid as an acid unless high temperature was applied. On the other hand, in the above reaction (Japanese Patent Laid-Open No. 10-265415), the equilibrium is biased toward the product even at a relatively low temperature, and in Japanese Patent Laid-Open No. 10-265415, a strong acid is added to the reaction system. It is considered that the yield of methylene norcamphor of formula (B) was improved by capturing the weak acid (carboxylic acid) salt of the amine on the rightmost side of the above formula.

  On the other hand, the present invention is the result of extraction at a predetermined temperature or higher in the presence of an extraction solvent for methylene norcamphor in a high temperature equilibrium reaction system that includes an intermediate and methylene norcamphor and is biased toward the methylene norcamphor side. Is transferred to the extraction solvent, so that the reverse reaction is prevented and the equilibrium is inclined to the product side to obtain a high yield.

  Accordingly, the reaction conditions of the present invention in which formaldehyde and norcamphor are reacted in the presence of an organic acid and a secondary amine are the same as in the method of JP-A-10-265415. Moreover, the solvent immiscible with the reaction solution may be added at any stage before, during or after the reaction of formaldehyde and norcamphor.

  The raw material norcamphor is commercially available, for example, but can be easily produced by a known method (Journal of Organic Chemistry, 45, p. 2030 (1980), US Pat. No. 3,338972, etc.).

  Examples of the organic acid used in the present invention include formic acid, acetic acid, propionic acid, trifluoroacetic acid, methoxyacetic acid, oxalic acid, succinic acid, maleic acid, and fumaric acid. Of these, acetic acid is most preferred. The amount of the organic acid used is 1 to 3 equivalents relative to norcamphor. When acetic acid is used, 1.5 to 2.5 equivalents are used. When there is too little organic acid, reaction efficiency will fall. Even if the organic acid is used in a large excess, the yield does not change.

The secondary amine used in the present invention is a secondary amine represented by the formula NHR ¹ R ² (wherein R ¹ and R ² may be the same or different and each represents an alkyl group having 1 to 4 carbon atoms). In addition, for example, piperidine, pyrrolidine, morpholine, N-methylpiperazine, diethanolamine, N-methylethanolamine and the like can be used. These can be used alone or in combination of two or more. Examples of the secondary amine represented by the formula NHR ¹ R ² include dimethylamine, diethylamine, dipropylamine, dibutylamine, and methylpropylamine. Of these, dimethylamine, diethylamine, dipropylamine, and pyrrolidine are preferred, and diethylamine is most preferred, based on the yield of the product, the amount of by-products, the amount of undecomposed intermediates, and the amount of unreacted raw materials.
The amount of secondary amine used is preferably 0.5 to 2 equivalents relative to norcamphor. When there are too few secondary amines, reaction efficiency will fall. Even if the secondary amine is used in a large excess, the efficiency does not change. When acetic acid is used as the organic acid, 0.5 to 1.5 equivalents are used. An aqueous solution appropriately diluted with water may be used.

  Formaldehyde can be used as an aqueous formaldehyde solution, formaldehyde gas, paraformaldehyde (formaldehyde polymer), trioxane (formaldehyde trimer), etc., but a formalin aqueous solution is most preferable. As the formalin aqueous solution, a commercially available 30 to 40% aqueous solution may be used as it is, or an aqueous solution appropriately diluted with water may be used. The amount of formaldehyde used is preferably 1 to 3 equivalents as a formaldehyde content with respect to norcamphor. In particular, it is desirable to use 1 to 2 equivalents. If the amount of formaldehyde is too small, the reaction yield decreases. Even if formaldehyde is used in a large excess, the yield does not change.

  The reaction between formaldehyde and norcamphor may be carried out in the absence of a solvent or in an organic solvent, but is preferably carried out in an aqueous solvent using an organic acid and formaldehyde as an aqueous solution as described above.

  The reaction is preferably 60 ° C. or higher, preferably 70 to 110 ° C., particularly preferably 80 to 105 ° C. If the temperature is low, the reaction rate decreases. On the other hand, if it is too high, the amount of by-products such as polymer increases, which is not preferable.

  The extraction solvent for methylene norcamphor is a solvent that is substantially immiscible with the reaction solution, that is, forms a phase that is distinguished from the reaction solution under the reaction conditions, and has a higher distribution coefficient of methylene norcamphor than the reaction solvent. Therefore, when an aqueous solvent is used as the reaction solvent, various organic solvents can be used.

  The organic solvent is not particularly limited as long as it is a solvent that dissolves methylene norcamphor, has a boiling point equal to or higher than the reaction temperature, does not mix with water, and is stable under reaction conditions. For example, aliphatic hydrocarbon solvents such as hexane and cyclohexane, aromatic hydrocarbon solvents such as benzene, toluene, xylene, chlorobenzene and o-dichlorobenzene, chlorine solvents such as dichloroethane, ethers such as diisopropyl ether and dibutyl ether And solvent solvents and ester solvents such as ethyl acetate, propyl acetate, and butyl acetate. In particular, an organic solvent having a boiling point of 110 ° C. or higher is preferable because of easy temperature control. Examples of such solvents include toluene (boiling point: 110.6 ° C.), xylene (boiling point: about 139 ° C.), chlorobenzene (monochlorobenzene 132.0 ° C.). These organic solvents may be used alone or in a mixture. Moreover, as described above, it may be added after completion of the reaction, or a part or all of it may be coexisted during the reaction as long as it does not affect the formation of methylene norcamphor.

In the first method of the present invention, in the method for producing methylene norcamphor in which formaldehyde and norcamphor are reacted by heating in the presence of a secondary amine and an organic acid, the extraction of methylenenorcamphor is performed before or during the heating reaction. A solvent is added and heated to a temperature of 60 ° C., preferably 80-105 ° C. after the addition.
In the second method of the present invention, in the method for producing methylene norcamphor in which formaldehyde and norcamphor are heated and reacted in the presence of a secondary amine and an organic acid, the reaction temperature is 60 ° C., preferably 80 to 105 ° C. After the heating reaction, an extraction solvent is added and further heated to a temperature of 60 ° C, preferably 80 to 105 ° C.
When the heating temperature is lower than 60 ° C., the reaction efficiency is lowered. On the other hand, when the temperature exceeds 105 ° C., byproducts such as a polymer are increased.
During the heating, the reaction solution and the extraction solvent may be separated into layers, but preferably the same operation as a normal extraction operation such as mixing, stirring and shaking of the reaction system is performed. The heating time is preferably 5 hours or less, more preferably 0.5 hours or more and 3 hours or less. If the time is too short, the reaction and extraction will not proceed sufficiently and the yield will decrease. In the present invention, if the heterogeneous liquid phase is sufficiently mixed (that is, if the interface between the two phases is sufficiently large), the heating time is short and there is no problem, and an excessively long reaction time decreases the production efficiency. .

  As shown in the results of Examples described later, when the extraction solvent is separated by stirring at a temperature of 80 to 105 ° C. as a heterogeneous liquid phase, methylene norcamphor is obtained almost quantitatively in the extraction solvent. Further, a solution containing the product methylene norcamphor as it is or as a moderately concentrated solution is, for example, a raw material for producing 3-acetyl-cyclopentanecarboxylic acid ester which is an agrochemical intermediate shown in JP-A-10-265441 Have sufficient quality to use as. Of course, methylene norcamphor may be isolated and purified by distillation or the like, and it may be desirable from the viewpoint of transportation and storage.

  EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to the following Example.

Example 1:
425 g (3.853 mol) of norcamphor and 460 g (7.660 mol) of acetic acid were introduced into a reactor having a capacity of 3 L equipped with a stirring blade and a cooling pipe, and 280 g (3. 828 mol) of diethylamine was slowly added. Next, 460 g (5.673 mol) of a 37% strength formalin aqueous solution was added at 95 ° C. to 100 ° C. over 3 hours. After completion of the reaction, 1 L of toluene was added while maintaining the reaction solution at 90 ° C, and the mixture was kept at 88 ° C to 95 ° C and stirred for 2 hours. The organic layer was separated by cooling to 30 ° C. or lower, and the aqueous layer was further extracted twice with 500 ml of toluene, and combined with the organic layer. As a result of gas chromatography analysis, 450 g (3.680 mol) of methylene norcamphor was contained in the organic layer. The yield was 95.5%.

Example 2:
The reaction and the extraction treatment operation of the present invention were performed in the same manner as in Example 1 except that xylene was used as the extraction solvent. As a result of analysis by gas chromatography, the yield of methylene norcamphor was 95.1%.

Comparative Example 1:
The same reaction as in Example 1 was performed using 425 g (3.853 mol) of norcamphor, and the same reaction as in the example was performed until the end of the reaction. After completion of the reaction, it was cooled to 20 ° C. Thereto was added 1 L of toluene at 20 ° C., and the mixture was stirred for 2 hours. The organic layer was separated, and the aqueous layer was further extracted twice with 500 ml of toluene and combined with the organic layer. As a result of analysis by gas chromatography, the organic layer contained 280 g (2.293 mol) of methylene norcamphor. The yield was 59.5%.

Comparative Example 2:
20 g (0.18 mol) of norcamphor is placed in a 200 ml three-necked reaction vessel equipped with a dropping funnel, a condenser, and a thermometer, dissolved in 3.5 g (0.06 mol) of acetic acid, and heated to 100 ° C. A solution prepared by dissolving 20 g (0.27 mol) of diethylamine and 22.5 g (0.27 mol) of 37% aqueous formalin in 16.5 g (0.27 mol) of acetic acid was added for 1.5 hours. It was dripped over. After completion of dropping, the solution was further stirred at 100 ° C. for 1 hour. After completion of the reaction, 45 g of 30% sulfuric acid aqueous solution was added, 200 g of water was further added, extraction was performed twice with 80 ml of methylene chloride, and the solvent was distilled off to obtain 20.1 g of a crude product (yield: 75. 5%, purity 83.2%).

According to the method of the present invention, methylene norcamphor can be produced from norcamphor on an industrial scale under mild conditions as compared with the conventional method. Further, unlike the method described in JP-A-10-265415, since a strong acid such as sulfuric acid is not used, the burden of wastewater treatment is reduced and the yield is remarkably improved. The obtained methylene norcamphor is useful, for example, as a raw material for producing an agrochemical intermediate (for example, 3-acetyl-cyclopentanecarboxylic acid ester as disclosed in JP-A-10-265441) and is particularly purified. It has sufficient quality even without going through the process.

Claims (6)

In an aqueous solvent, a secondary amine represented by the formula NHR ¹ R ² (wherein R ¹ and R ² may be the same or different and each represents an alkyl group having 1 to 4 carbon atoms), formic acid, acetic acid In the presence of an organic acid selected from propionic acid, trifluoroacetic acid, methoxyacetic acid, oxalic acid, succinic acid, maleic acid, and fumaric acid, formaldehyde and norcamphor are reacted by heating to a temperature of 60 ° C. or higher. In the method for producing methylene norcamphor, hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, dichloroethane, diisopropyl ether, dibutyl ether, ethyl acetate, propyl acetate, butyl acetate, or a mixture thereof is added. Methylene norcampha, characterized by heating to a temperature of 60 ° C or higher -Manufacturing method. Secondary amines represented by the formula NHR ¹ R ² (wherein R ¹ and R ² may be the same or different and each represents an alkyl group having 1 to 4 carbon atoms) and formic acid, acetic acid, propionic acid, tri A methylene norcamphor reaction in which an aqueous formaldehyde solution and norcamphor are heated to a temperature of 60 ° C. or higher in the presence of an organic acid selected from fluoroacetic acid, methoxyacetic acid, oxalic acid, succinic acid, maleic acid, and fumaric acid. In the production method, hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, dichloroethane, diisopropyl ether, dibutyl ether, ethyl acetate, propyl acetate, butyl acetate, or a mixture thereof is added to at least 60 ° C. Method for producing methylene norcamphor characterized by heating to temperature .   The production method according to claim 1 or 2, wherein the heating in the presence of the extraction solvent is performed at a temperature of 80 to 105 ° C.   The production method according to claim 1, wherein acetic acid is used as the organic acid.   The production method according to claim 1 or 2, wherein the secondary amine is diethylamine. An organic acid selected from formic acid, acetic acid, propionic acid, trifluoroacetic acid, methoxyacetic acid, oxalic acid, succinic acid, maleic acid, and fumaric acid is used in an amount of 1.5 to 2.5 equivalents of norcamphor, and the formula NHR ¹ R ² (wherein R ¹ and R ² may be the same or different and each represents an alkyl group having 1 to 4 carbon atoms), 0.5 to 1.5 equivalents of norcamphor are used. The method according to claim 1 or 2, wherein, as formaldehyde, a formalin aqueous solution having a formaldehyde concentration of 25 to 40% is reacted with norcamphor in an amount of 1 to 2 equivalents.