KR930005058B1 - The manufacturing method of (s)-1,2-alkanediol with optical activity - Google Patents

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Description

Method for preparing (S) -1,2-alkanediol having optical activity

The present invention relates to a method for preparing (S) -1,2-alkanediol having optical activity, and more particularly, to provide the target compound in high yield with excellent economic efficiency, stability and simplicity. It relates to a method for producing (S) -1,2-alkanediol having optical activity represented by

(Wherein R represents a saturated or unsaturated hydrocarbon group having C ₂ to C ₄ )

The (S) -1,2-alkanediol compound having optical activity provided by the method according to the present invention is very usefully used as an optically active intermediate capable of easily steric adjustment in pharmaceutical synthesis and the like.

Conventionally, in order to obtain a compound represented by formula (I), which is thus usefully used as an optically active intermediate, a series of stereo-adjusted compounds at 2-position, such as D-isopropylidene glycerol, are used as starting materials. A method of obtaining a target compound through an organometallic reaction is known, which is represented by the following equation:

(Wherein R represents the meaning as defined above and R ₁ represents an alkyl group or a cyclic hydrocarbon group.)

However, in such a method, the reaction must be performed under anhydrous conditions, which makes the manufacturing process difficult and cumbersome, and the reagent used is chemically unstable, which may cause an explosion, and furthermore, the target compound finally obtained through a three-step reaction. Yield of about 20% is also very low.

In addition, in the above method, since the compound represented by the general formula (II) used as the starting material is expensive, there is a problem that the method is not economically efficient.

Therefore, the inventors of the present invention have steadily explored and tried to improve the problems of the manufacturing method as described above, and came to complete the present invention.

That is, the present invention has been made to solve the problems of the prior art as described above, the object of the present invention is about 1/100 of the cost compared to the compound represented by the general formula (II) used as a starting material in the prior art By selecting this inexpensive and economical starting material and reacting under mild reaction conditions, the 2-position represented by the general formula (I) with excellent economical efficiency, stability and simple manufacturing process to obtain a desired target compound in high yield. To provide a method for preparing (S) -1,2-alkanediol having (-) optical activity at.

In order to achieve the above object, the present invention is to react D-mannitol represented by the following general formula (III) in a suitable ketone compound, under an acid catalyst to alkoxy in 1-, 2-, 5- and 6-positions. Obtain the first intermediate represented by the following general formula (IV) in which the group is protected, and oxidize it with lead tetraacetate [Pb (OA _C ) ₄ ] in a suitable organic solvent to give the following general formula (V) in an unstable state. A second intermediate was obtained, which was then purified without further purification using a wittig reagent at a temperature of 0 to -20 ° C to obtain a compound represented by the following general formula (VI) to obtain hydrogen and Pd / C. (S) -1,2-alkane having optical activity represented by the following general formula (I), which is obtained by reacting with an alcohol / acid mixed solution having an acid to alcohol ratio of 10 to 40% in the presence of a catalyst. Method for preparing diol It provides:

(Wherein R ₁ and R represent the meaning as defined above.)

In particular, in the present invention, it is preferable to use acetone or cyclohexanone as the ketone compound.

In the present invention, it is preferable to use a Lewis acid catalyst as the acid catalyst.

In the present invention, it is preferable to use any one compound selected from hydrochloric acid, sulfuric acid and acetic acid as the acid component in the alcohol / acid mixed solution.

Hereinafter, the present invention will be described in more detail.

That is, in the present invention, first, the compound represented by the general formula (III), which is inexpensive, is used as a starting material to obtain a compound represented by the general formula (IV), which is then dissolved in an organic solvent and using lead tetraacetate. By oxidation, the compound represented by general formula (V) in an unstable state is obtained.

At this time, the compound represented by the general formula (V) is unstable and easily decomposed, so it should be filtered at a low temperature within a short time.

In the compound represented by the general formula (V) thus obtained, since the carbon atom at the 3-position has a strong electrophilicity under the influence of the hydrogen atom in the carbon at the 1- and 2-positions, it is generally used in the art. Reaction with the used Wittich reagent at low temperature readily yields a reaction intermediate represented by the general formula (VI), which is expressed as follows:

(Wherein R and R ₁ have the same meaning as defined above)

Such a reaction is preferably carried out at a low temperature of about 0 to 20 ℃.

When the reaction temperature is raised to room temperature, the unstable compound of general formula (IV) is decomposed, so that the yield is lowered, and a large amount of impurities are generated.

Subsequently, the compound represented by the general formula (VI) obtained as described above was hydrogen-reduced at the same time using an alcohol / acid mixed solution having an acid-to-alcohol ratio of 10 to 40% in the presence of hydrogen and a Pd / C catalyst. By removing the protecting group, the target compound represented by the general formula (I) can be easily obtained, which is represented by the following reaction scheme:

Meanwhile, in the ketone compound usable in the present invention, R ₁ may be an alkyl group or a cyclic hydrocarbon group. In particular, R ₁ is preferably an alkyl group having _{1 to 5} carbon atoms, more preferably a propyl group, an isopropyl group, an n-butyl group, an iso-butyl group, a tert-butyl group, a pendyl group, or the like, or a cyclic hydrocarbon group. , Preferably a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.

Further, as the Lewis acid catalyst usable in the present invention include ZnCl _2, AlCl _3, BF ₃ and the like.

That is, in the method according to the present invention, it is possible to obtain (S)-, 2-alkanediol having optical activity stably at low temperature through a three step reaction in high yield.

Next, a preferred embodiment of the present invention is described.

However, these examples are provided only to illustrate the present invention in more detail, the scope of the present invention is not limited only to these examples. In addition, all% used below means weight%.

Example 1

90 g of zinc chloride, 400 ml of acetone, and 100 g of D-mannitol (I) were added to the reactor and stirred at room temperature for 4 to 6 hours. The resulting reaction solution was filtered to remove the unreacted product, followed by 180 g of potassium carbonate (50% aqueous solution). Was added to filtrate and remove the zinc compound, and the filtrate thus obtained was concentrated to 100 ml under reduced pressure, and then solidified by addition of 1000 ml of petroleum ether, which was then filtered and dried in vacuo at a temperature of 80 ° C. in general formula (IV). 84 g (yield: 58% of theory) of 1,2,5,6- diisopropylidene-D-mannitol (melting point: 126-127 degreeC) represented by the following were obtained.

35.0 g of 1,2,5,6-diisopropylidene-D-mannitol dissolved in 600 ml of tetrahydrofuran at a temperature of 0 ° C. was added thereto, and 82.8 g of lead tetraacetate was added thereto, followed by stirring for 2 hours. After raising the temperature to room temperature and further stirring for 1.5 hours, 37 g of potassium carbonate was added to the reaction solution to stop the reaction, and the mixture was filtered through diatomaceous earth (Preparation of Liquid A: At this time, the general formula (V) (R) -2,3-isopropylidene glyceraldehyde is unstable and easily decomposed, so it should be filtered at a low temperature for a short time).

Meanwhile, 213 g of n-butyltriphenylphosphonium bromide was added to a reactor different from the above at 0 ° C., 200 ml of tetrahydrofuran was added and dispersed, and then 334 ml of n-butyllithium (1.6 mol hexane solution) was further added. Bihitic reagent was prepared.

The obtained Wittihi reagent was added to the A solution obtained above, stirred for 1 hour while maintaining the temperature at 0 ° C, pure water was added to the reaction solution obtained, and extracted three times with 1000 ml of diethyl ether, After drying over sulfuric acid-magnesium, concentrated under reduced pressure, the resulting concentrate was distilled under reduced pressure under a pressure of 5 Torr at a temperature of 72 to 76 ° C. to obtain pure 37.7 g (yield: 83% of theory). (S) -1,2-isopropylidene-3-heptene-diol was obtained:

NMR (CDCl ₃ , ppm): δ = 5.5 (m, 2H, -CH = CH-)

IR (neat, cm ^-1 ): υ _-O- = 1060

Meanwhile, 600 g of a mixed solution of 20 g of (S) -1,2-isopropylidene-3-heptene-diol, 4.0 g of 5% Pd / C and 25% acetic acid / anhydrous alcohol obtained as described above was added to the reactor, After stirring under hydrogen atmosphere at a temperature of 30 ° C. for about 4 hours, the reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and distilled under reduced pressure under a pressure of 5 Torr at a temperature of 90 to 95 ° C. to obtain the desired compound. 13.2 g (yield: 85% of theory) of (S) -1,2-heptanediol having optical activity represented by formula (I) were obtained:

NMR (CDCl ₃ , ppm): δ = 2.9 (S, 2H, -OH),

3.5 (m, 2H, -O-CH ₂ -CO-),

3.7 (m, 1H, -O-C-CH-O-)

IR (knit, cm ^-1 ): υ _OH = 3345

: -20 ± 2 (c = 2 in ethanol)

Example 2

Preparation of 1,2,5,6-diisopropylidene-D-mannitol of Example 1, except that 570 ml of cyclohexanone was added instead of acetone as a ketone compound and vacuum dried at a temperature of 70 ° C. Substantially the same as the method, pure 75 g (yield: 40% of theory) of 1,2,5,6-dicyclohexylidene-D-mannitol (melting point: 105-107) represented by the general formula (IV). C) was obtained.

Into the reactor, 82.8 g of lead tetraacetate and 35.0 g of 1,2,5,6-dicyclohexylidene-D-mannitol (IV) obtained above dissolved in 600 ml of tetrahydrofuran at a temperature of 0 ° C. were added, and for 2 hours. After stirring, the temperature was raised to room temperature again and stirred for 1.5 hours. Then, 37 g of potassium carbonate was added to the reaction solution to stop the reaction, followed by filtration through diatomaceous earth (preparation of A solution).

Meanwhile, 213 g of n-butyltriphenylphosphonium bromide and 200 ml of tetrahydrofuran were added and dispersed in another reactor at a temperature of 0 ° C., followed by addition of 334 ml of n-butyllithium (1.6 mol hexane solution) to obtain a Vichy reagent. Prepared.

The Vitich reagent thus obtained was added to the solution (A) obtained above, stirred while maintaining the temperature at −15 ° C. for 1 hour, pure water was added to the reaction solution obtained, and extracted three times with 1000 ml of diethyl ether. The mixture was dried over sulfuric acid-magnesium, concentrated under reduced pressure, and the concentrated solution was distilled under reduced pressure at a pressure of 5 Torr at a temperature of 72 to 76 ° C. to give pure (S) -1,2-cyclohex represented by the general formula (VI). 40.1 g (yield: 85% of theory) of silidene-3-heptene-diol were obtained.

A mixed solution of 20 g of (S) -1,2-cyclohexylidene-3-heptene-diol, 4.0 g of 5% Pd / C and 35% sulfuric acid / anhydrous alcohol represented by the above general formula (VI) in the reactor After adding 600 ml and stirring under hydrogen atmosphere for 4 hours at a temperature of 30 ° C., the reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and distilled under reduced pressure under a pressure of 5 Torr at a temperature of 90 to 95 ° C. (S) -1,2-heptanediol (yield: 87% of theory) which is represented by General formula (I) which is a target compound to obtain was obtained.

Comparative Example 1

The Vitis reagent was added to the liquid (A) and reacted while maintaining the temperature at 10 ° C, concentrated under reduced pressure, and then distilled under reduced pressure at a temperature of 72 to 76 ° C. By the method, (S) -1,2-heptanediol (I) (yield: 39.2% of theory) was obtained.

Comparative Example 2

The Vitis reagent was added to the solution (A) and reacted while maintaining the temperature at -30 ° C, except that a mixed solution of 50% sulfuric acid / anhydrous alcohol was used instead of the mixed solution of 25% acetic acid / anhydrous alcohol. Treatment was carried out in substantially the same manner as in Example 1 to obtain (S) -1,2-heptanediol (I) (yield: 39% of theory).

As described above, in the method according to the present invention, D-mannitol is a starting material which is about 1/100 inexpensive compared to the compound represented by the general formula (II) used as a starting material in a conventional manufacturing method. It is possible to obtain a high yield of (S) -1,2-alkanediol having (-) optical activity at 2-position, which is a desired compound stably at low temperature through a series of three-step reactions. Able to know.

Claims (4)

D-mannitol represented by the following general formula (III) is reacted under an acid catalyst in a ketone compound to be represented by the following general formula (IV) in which the alkoxy group at the 1-, 2-, 5- and 6-positions is protected An intermediate was obtained, which was oxidized with lead tetraacetate [Pb (OA _C ) ₄ ] in an organic solvent to obtain a second intermediate represented by the following general formula (V) in an unstable state, which was then purified without purification. The reaction was carried out at a temperature of 0 to 20 ° C. to obtain a compound represented by the following general formula (VI), and an alcohol / acid having an acid to alcohol ratio of 10 to 40% in the presence of hydrogen and a Pd / C catalyst. Method for producing (S) -1,2-alkanediol having optical activity represented by the following general formula (I), which is obtained by reacting with a mixed solution: (Wherein R represents a saturated or unsaturated hydrocarbon group having C ₂ to C ₄ , and R ₁ represents an alkyl group or a cyclic hydrocarbon group.) The method for producing (S) -1,2-alkanediol having optical activity represented by general formula (I) according to claim 1, wherein the ketone compound is acetone or cyclohexanone. The method for producing (S) -1,2-alkanediol having optical activity represented by general formula (I) according to claim 1, wherein the acid catalyst is a Lewis acid catalyst. (S) -1 having optical activity represented by general formula (I) according to claim 1, wherein the acid in the alcohol / acid mixed solution is any one compound selected from hydrochloric acid, sulfuric acid and acetic acid. Method for the preparation of 2-alkanediol.