JP3289338B2 - Norcamphor manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing norcamphor useful as an intermediate for pharmaceuticals and the like.

[0002]

2. Description of the Related Art As a method for obtaining norcamphor by oxidizing norbornanol with hypochlorite, an aqueous solution of sodium hypochlorite or potassium hypochlorite in dichloromethane or ethyl acetate in the presence of tetrabutylammonium hydrogen sulfate is used. A method of oxidizing norbornanol with an aqueous solution (Tetrahedron Lett., 20, 1641 (1976) and Isr. J. Chem., 26, 229 (1985)) is known.

[0003]

However, in the above-mentioned method, there is a problem that the yield is low and the purity of the norcamphor product is low due to a side reaction, which is not necessarily industrially satisfactory. Did not. An object of the present invention is to provide a method for producing norcamphor which solves such a problem.

[0004]

That is, the present invention relates to a method for preparing norbornanol and hypochlorite in a hydrocarbon solvent,
It is intended to provide a process for producing norcamphor characterized by reacting in the presence of water, a quaternary ammonium salt and an acid.

[0005] The raw material norbornanol used in the present invention may be either an exo form or an endo form, or a mixture thereof. Moreover, those optically active substances may be used.

[0006] Examples of the hypochlorite used in the present invention include sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, etc. Among them, sodium hypochlorite is particularly preferable. Is preferred. Examples of the form of use of these hypochlorites include solids, aqueous solutions, and the like.However, anhydrous sodium hypochlorite and potassium hypochlorite are unstable. Is preferably used in an aqueous solution. These are used in an amount of 1 to 10 equivalents to the raw material norbornanol,
Preferably it is in the range of 1.1 to 3 equivalents.

As the quaternary ammonium salt, for example,
Tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride,
Examples thereof include benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, N-octylpyridinium chloride, and N-laurylpyridinium chloride. Of these, tetrabutylammonium bromide is particularly preferred. These quaternary ammoniums are used in an amount of 0.01 to 2 equivalents, preferably 0.05 to 1 equivalent, based on the raw material norbornanol.
The range of equivalents. When these quaternary ammonium salts are not used, it takes a long time to eliminate norbornanol as a raw material, and the yield of the desired norcamphor is low, which is not preferable.

[0008] Specific examples of the acid used in the present invention include sulfuric acid and hydrochloric acid. The amount of these used is in the range of 0.5 to 10 equivalents, preferably 1 to 5 equivalents to norbornanol as a raw material.

The hydrocarbon used as a solvent includes:
For example, an aromatic hydrocarbon such as benzene, toluene, xylene and the like, and an aliphatic hydrocarbon such as hexane, heptane and cyclohexane, alone or in a mixture, are exemplified, and the use amount thereof is not particularly limited.

[0010] The amount of water used is sufficient as long as it can dissolve the hypochlorite used in the reaction, but the upper limit is not particularly limited. When hypochlorite is used as an aqueous solution, it is not necessary to use additional water, but in some cases, additional water may be added.

[0011] The reaction temperature is usually in the range of 0 to 100 ° C, preferably 0 to 50 ° C. The reaction time varies depending on the type of hypochlorite or quaternary ammonium salt, and is not particularly limited. The reaction is terminated when the raw material norbornanol disappears.

After completion of the reaction, unreacted hypochlorite is decomposed with a reducing agent such as sodium thiosulfate, and then subjected to ordinary post-treatment operations, for example, extraction, liquid separation, and concentration. The desired norcamphor can be obtained. This product has a sufficiently high purity without performing any refining operation. However, in some cases, it can be further purified by an operation such as sublimation or steam distillation.

[0013]

Industrial Applicability According to the present invention, norcamphor useful as an intermediate for a drug or the like can be industrially advantageously produced with high purity. This compound is, for example, J. Med. Che
m., 31, 1847 (1988) can be suitably used as an intermediate of the thromboxane A2 receptor antagonist.

[0014]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto.

Example 1 In a four-necked flask equipped with a stirrer, thermometer, dropping funnel and condenser, (±) -exo-norbornanol 11.2 g and tetrabutylammonium bromide 3.2 were added.
g, and after adding and dissolving 300 ml of toluene,
120 g of 25% aqueous sulfuric acid was added. 20 to 2
At 5 ° C., 80.6 g of a 12% aqueous solution of sodium hypochlorite was added dropwise over 3 hours. After completion of the addition, the mixture was stirred at the same temperature for 5 hours.

After completion of the reaction, sodium thiosulfate was added to the reaction mixture until the yellow color of sodium hypochlorite disappeared, and the mixture was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order. It was concentrated to obtain 10.7 g of (±) -norcamphor having a purity of 99.2%.

This was purified by sublimation to obtain 8.3 g of (±) -norcamphor having a purity of 100%.

Example 2 In a four-necked flask equipped with a stirrer, thermometer, dropping funnel and condenser, (±) -exo-norbornanol 11.2 g and tetrabutylammonium bromide 3.2 were added.
g, 300 ml of hexane was added and dissolved,
100 g of 35% hydrochloric acid was added. 20 to 2
At 5 ° C., 80.6 g of a 12% aqueous solution of sodium hypochlorite was added dropwise over 3 hours. After completion of the addition, the mixture was stirred at the same temperature for 3 hours.

After completion of the reaction, sodium thiosulfate was added to the reaction mixture until the yellow color of sodium hypochlorite disappeared, and the mixture was separated. The aqueous layer was extracted with 100 ml of toluene and separated, and the obtained toluene layer was combined with the organic layer, washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution in that order, and further concentrated to a purity of 98.9%. (±) -Norcamphor 10.2g
I got

Example 3 In a four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, 11.2 g of (1S, 2S, 4R) -norbornanol (98% ee in optical purity) and tetrabutylammonium bromide 3 were added. .2 g and toluene 3
After adding and dissolving 00 ml, 120 g of 25% sulfuric acid aqueous solution was added. To this mixture, 80.6 g of a 12% aqueous sodium hypochlorite solution was added dropwise at 20 to 25 ° C. over 3 hours, and after completion of the addition, the mixture was stirred at the same temperature for 5 hours.

After completion of the reaction, sodium thiosulfate was added to the reaction mixture until the yellow color of sodium hypochlorite disappeared, and the mixture was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order. Concentrate to 99.3% purity (1S, 4
10.8 g of R) -norcamphor (98% optical purity) was obtained.

Example 4 The reaction and reaction were carried out in the same manner as in Example 3 except that (±) -endo-norbornanol was used in place of (1S, 2S, 4R) -norbornanol used as a raw material in Example 3. After the treatment, 10.7 g of (±) -norcamphor having a purity of 99.1% was obtained.

Examples 5 to 8 Instead of (1S, 2S, 4R) -norbornanol used as a raw material in Example 3, (±) -exo-norbornanol was used and tetrabromide used as a quaternary ammonium salt was used. The reaction and post-treatment were carried out in the same manner as in Example 3 except that various quaternary ammonium salts shown in Table 1 were used instead of butylammonium to obtain (±) -norcamphor. Table 1 shows the results.

[0024]

[Table 1]

Comparative Example 1 In a four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, 11.2 g of (±) -exo-norbornanol was charged, and 300 ml of toluene was added.
After dissolution, 120 g of 25% aqueous sulfuric acid was added. To this mixture, 80.6 g of a 12% aqueous solution of sodium hypochlorite was added dropwise at 20 to 25 ° C over 3 hours, and after the addition was completed, the mixture was stirred at the same temperature for 35 hours. After completion of the reaction, sodium thiosulfate was added to the reaction mixture until the yellow color of sodium hypochlorite disappeared, and the mixture was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and further concentrated. 47.3% purity (±)
-10.1 g of norcamphor was obtained.

Comparative Example 2 In a four-necked flask equipped with a stirrer, thermometer, dropping funnel and condenser, (±) -exo-norbornanol 11.2 g and tetrabutylammonium bromide 3.2 were added.
g, 300 ml of ethyl acetate was added and dissolved, and 120 g of 25% aqueous sulfuric acid was added. 20 to this mixture
80.6% aqueous solution of sodium hypochlorite at ~ 25 ° C
g was added dropwise over 3 hours, and after completion of the addition, the mixture was stirred at the same temperature for 7 hours. After completion of the reaction, sodium thiosulfate was added to the reaction mixture until the yellow color of sodium hypochlorite disappeared, and the mixture was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and further concentrated. 10.0 g of (±) -norcamphor having a purity of 78.7% was obtained.

Comparative Example 3 In a four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, 11.2 g of (±) -exo-norbornanol and 3.2 g of tetrabutylammonium bromide were added.
g, 300 ml of dichloromethane was added and dissolved, and then 120 g of 25% aqueous sulfuric acid was added. 2 in this mixture
80. 12% aqueous sodium hypochlorite solution at 0-25 ° C
6 g was added dropwise over 3 hours, and after completion of the addition, the mixture was stirred at the same temperature for 5 hours. After completion of the reaction, sodium thiosulfate was added to the reaction mixture until the yellow color of sodium hypochlorite disappeared, and the mixture was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and further concentrated. 9.9 g of (±) -norcamphor having a purity of 83.6% was obtained.

──────────────────────────────────────────────────続 き Continuation of front page (72) Inventor Masayoshi Minami 2-10-1, Tsukahara, Takatsuki-shi, Osaka Sumitomo Chemical Co., Ltd. (56) References JP-A-61-225148 (JP, A) JP-A Sho 62-228037 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 45/30 C07C 49/433 C07C 49/437 B01J 31/02 102 C07B 61/00 300

Claims (4)

(57) [Claims] 1. A process for producing norcamphor, comprising reacting norbornanol and hypochlorite in a hydrocarbon solvent in the presence of water, a quaternary ammonium salt and an acid. 2. The method according to claim 1, wherein the hypochlorite is sodium hypochlorite. 3. The method according to claim 1, wherein the quaternary ammonium salt is tetrabutylammonium bromide. 4. The method according to claim 1, wherein the acid is sulfuric acid or hydrochloric acid.