JP3210683B2 - Isomer separation method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 1,3-dioxolan or
The present invention relates to a method for separating stereoisomers of a 1,3-dioxane derivative, and the method for separating isomers of the present invention can be used in the field of fine chemistry mainly for pharmaceuticals.

[0002]

[Problems to be solved by the prior art and the invention] 1,3 −
Dioxolane and 1,3-dioxane derivatives are 1,2
As protected compounds of-and 1,3-diols, they are industrially important as intermediates of various fine chemicals, mainly pharmaceuticals. However, in general chemical synthesis, the mixture is often a mixture of isomers, and in particular, the optical isomer is a 1: 1 mixture, that is, a so-called racemate. Needless to say, it is desirable to use it as a pure product for most purposes, but there is no good method for separating these. For example, the following general formula (1)

[0003]

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[0004] The optically active 2,2-dimethyl-1,
3-Dioxolan-4-methanol is highly useful as an intermediate for pharmaceuticals composed of various optically active substances such as β-blockers. This racemate can be derived from glycerin at low cost, but since there is no good resolving method, the optically active compound is subjected to multi-step chemical treatment from mannose or biological resolution from racemate (JP-A-63-94986). ) Etc. However, these methods have problems such as high cost due to the multi-stage production process, only one of the optical isomers being obtained, and insufficient optical purity. As can be seen from this example, a method for efficiently resolving stereoisomers, including optical isomers, of 1,3-dioxolane and 1,3-dioxane derivatives has been required.

[0005]

Means for Solving the Problems The present inventor has considered the importance of separating the stereoisomers of 1,3-dioxolane and 1,3-dioxane derivatives, and has conducted intensive studies.
The present inventors have found that the separation of the stereoisomers can be effectively achieved by utilizing the formation of a clathrate compound with ans-1,2-disubstituted cyclic compound, and have reached the present invention.

That is, the present invention relates to 1,3-dioxolan or 1,1-dioxolan.
A mixture of stereoisomers of the 3-dioxane derivative is represented by the formula
It is intended to provide an isomer separation method characterized in that separation is carried out using a trans-1,2-disubstituted cyclic compound having a spiro structure represented by (a) .

[0007]

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In the present invention, 1,3-dioxolan or 1,3
-Dioxane derivatives are represented by the following formula (I) or (I
I)

[0009]

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And a stereoisomer having one or more substituents at least at the 4-position or higher. The number of substituents at the 4- or higher position,
There is no particular limitation on the type. The 2-position carbon may have any structure, but the following structure is generally used.

[0011]

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On the other hand, the substituent at the 4- or higher-position may have any number of bonds, for example, alkyl groups (substituents, which may have an unsaturated bond) which are highly important. Is -CH ₂ OR ³ , -CH ₂ NHR ³ (R ³ is H
, An alkyl group, an aryl group, an acyl group, a phosphonyl group, a phosphoryl group or a sulfonyl group, which may have a substituent or an unsaturated bond. Aryl group (which may have a substituent) An acyl group, a carboxyl group, an alkoxycarbonyl group and the like are important. Among them, compounds with high industrial utility are
2,2-Dimethyl-1,3-dioxolane-4-methanol and those obtained by substituting an alcoholic proton of the methanol residue with an aromatic group. Intermediate for synthesizing pharmaceuticals of

The trans- having a spiro structure referred to in the present invention.
1,2 - disubstituted cyclic compound is represented by the formula (a)
1,3-dioxolane or a compound to be separated
It forms a clathrate compound with a 1,3-dioxane derivative .

When the object to be separated is an optical isomer,
Needless to say, the trans-1,2-disubstituted cyclic compound must be optically active. The optically active compound may be obtained by any method, but deriving from tartaric acid is an excellent method in terms of its easiness and availability of raw materials .

[0015] For the production of the clathrate compound in the method of the present invention, any method may be used. In the most general method, a compound to be separated and an appropriate amount of the cyclic compound are dissolved in a solvent, and a clathrate compound is precipitated by changing the temperature, evaporating the solvent, or adding a poor solvent.
Alternatively, the mixture itself to be separated can be used as a solvent. Even when both are solid, a clathrate compound may be generated simply by mixing. Further, both components can be crystallized by applying an ultra-high pressure in the absence of a solvent or in the presence of a solvent. In such a case, crystals different from those under normal pressure may be formed. The solid thus obtained shows physical properties (melting point, crystal form, etc.) different from those of the starting material, and if it contains both starting materials, it is understood that a clathrate compound is formed. . Any method of recovering the compound to be separated from the clathrate compound may be used, but the simplest method is to separate only components having a low boiling point into another vessel by distillation under reduced pressure. By such an operation, the content of the specific isomer in the target 1,3-dioxolan or 1,3-dioxane derivative can be increased. In order to further increase the purity, it is a good method to recrystallize at the stage of the clathrate compound, but in some cases, a recrystallization operation can be applied after the recovery. Unnecessary isomers can also be removed by forming a clathrate compound.

The separation by the trans-1,2-disubstituted cyclic compound is not limited to the above-mentioned clathrate compound. For example, the trans-1,2-disubstituted cyclic compound is separated from the column packing material by any method. Various embodiments are possible, such as performing gas or liquid chromatography using this.

[0017]

The method of the present invention comprises the steps of preparing 1,3-dioxolan and 1,3
-The reason why the trans-1,2-disubstituted cyclic compound used in the present invention interacts with a 1,3-dioxolane ring or a 1,3-dioxane ring is not clear why it is suitable for isomer separation of a dioxane derivative. It has a size and polarity that is easy to do,
It is considered that a clathrate compound is easily formed.

[0018]

The trans-1,2-disubstituted cyclic compound used in the method of the present invention can be easily derived from, for example, tartaric acid and can be repeatedly used. Accordingly, the present invention provides industrially useful 1,3-dioxolane and 1,3-dioxolane.
This makes it possible to supply a large amount of a dioxane derivative with high purity.

[0019]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to examples, but it goes without saying that the present invention is not limited to these examples.

Embodiment 1 The following equation (1)

[0021]

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5.5 g of a racemic 2,2-dimethyl-1,3-dioxolan-4-methanol represented by the formula:
A mixture of 10.0 g of the (-)-trans-1,2-disubstituted cyclic compound represented by (a) in 20 ml of toluene and 20 ml of n-hexane was allowed to stand at room temperature for one day to obtain colorless needles. Generated. This was recrystallized twice, and the generated crystal was separated by filtration to obtain 8.5 g of a clathrate compound. [Α] _D −53.05 ゜ (c = 0.352, CHCl ₃ ).

The crystals were charged into a distillation apparatus and heated to 110 ° C. while reducing the pressure with a vacuum pump to obtain 1.04 g of (+)-2,2-dimethyl-1,3-dioxolan-4-methanol. .

[Α] _D is + 11.39 ° (c = 1.03, CH ₃ OH)
And comparison with literature values (J. Am. Chem. Soc., 102 , 6304 (1
980)), corresponding to an optical purity of 100%.

Embodiment 2 The following equation (2)

[0026]

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Spiro [cyclohexane-1,2 'represented by the formula
-Racemic form of [1,3] dioxolane-4'-methanol]
2.0 g and (−)-trans −1,
3.0 g of the 2-disubstituted cyclic compound was dissolved in 10 ml of toluene and 10 ml of n-hexane, and allowed to stand overnight to obtain 2.75 g of a white powder. This was recrystallized to obtain 1.78 g of a purified clathrate compound. This was decomposed at 165 ° C. in the same manner as in Example 1 to obtain 0.2 g of (+)-spiro [cyclohexane-1,2 ′.
-[1,3] dioxolan-4'-methanol was obtained.

[Α] _D is +7.65 ゜ (c = 0.81, CH ₃ OH), and is compared with literature values (RR Schmidtet. Al., J. Carbohyd
r. Res., 3 , 67 (1984)), corresponding to an optical purity of 100%.

────────────────────────────────────────────────── ─── Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 317/00 C07D 319/00 C07B 57/00 340 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A trans-1,2-disubstituted cyclic compound having a spiro structure represented by the formula (a), which is a mixture of stereoisomers of a 1,3-dioxolane or a 1,3-dioxane derivative. An isomer separation method comprising separating using a compound. Embedded image