JPH1129502A - Separation of compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for separating a specific compound from a mixture containing compounds having different solubility to a solvent. SOLUTION: In a method for separating a specific compound from a mixture containing compounds having different solubility to a solvent, e.g. a mixture of a compound having fulgid structure and a by-product generating its producing process, the mixture is dispersed in the solvents, e.g. toluene, acetonitrile or ethyl acetate, and heated at 40-80 deg.C in which the compound having high solubility is completely dissolved and the compound having low solubility is partially not dissolved and remained, then cooled to grow the crystal of the compound having low solubility, and further heated at a temperature of 40-80 deg.C in which a crystal of the compound having low solubility is not dissolved, then the crystal is separated from the solution dissolving the compound having high solubility.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for separating a specific compound from a mixture containing compounds having different solubilities in a solvent.

[0002]

2. Description of the Related Art Conventionally, a method for separating a specific compound from a mixture containing compounds having different solubilities in a solvent is to add a solvent to the mixture, heat the mixture, dissolve most of the mixture, and filter out insolubles. Thereafter, a method of precipitating the compound by gradually cooling the filtrate was common. However, when the filtrate was gradually cooled, a compound having a high solubility and a compound having a low solubility were almost simultaneously precipitated, and it was difficult to selectively precipitate only one compound.
For this reason, there was a problem that the target product could not be obtained with high purity.

[0003] Further, the crystals precipitated by slow cooling of the filtrate are separated, dissolved in another solvent, the solution is heated to redissolve the crystals, and further cooled slowly to recrystallize. The purity of the target product can be improved. But,
When such recrystallization is performed, there has been a problem that the recovery rate of the target substance is reduced.

[0004]

It has been desired to develop a new technique to compensate for the above-mentioned disadvantages of the prior art. That is, there has been a demand for a method for separating a target compound with high purity and high recovery rate by a simple operation.

[0005]

Means for Solving the Problems The inventors of the present invention have made intensive studies to solve the above problems, and as a result, heated a suspension of a mixture containing compounds having different solubility in a solvent, and then cooled the suspension. By doing so, a fine crystal of a compound having a low solubility is grown to make it difficult to dissolve even by subsequent heating, and this is removed by hot filtration, a method of separation is found, and the present invention has been completed. .

That is, the present invention relates to a method for separating a specific compound from a mixture containing compounds having different solubilities in a solvent, the method comprising dispersing the mixture in a solvent and dissolving all compounds having a high solubility but compounds having a low solubility. Is heated to a temperature at which it remains without being partially dissolved, and then cooled to grow crystals of the compound with low solubility, and further heated to a temperature at which the crystals of the compound with low solubility do not dissolve, and then dissolved. A method for separating a compound, comprising separating the crystal from a solution in which a compound having a large value is dissolved.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail.

In the present invention, a mixture containing two or more kinds of compounds having different solubility in a solvent can be employed without any limitation.

A mixture which can be particularly preferably used is a mixture comprising a compound having a fulgide structure represented by the following general formula (1) and a by-product produced in the production process.

[0010]

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(However,

[0012]

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Is a divalent aromatic hydrocarbon group or a divalent unsaturated heterocyclic group which may have a substituent,
R ¹ is an alkyl group, a cycloalkyl group, an aryl group or a monovalent heterocyclic group,

[0014]

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[0015] is a norbornylidene group or adamantylidene group, X is an oxygen atom, a group> ^{N-R 2} _{group> N-A 1 -B 1 -} (A 2) i - (B 2) j -
R ³ , a group> NA ₃ -A ₄ , or a group> NA ₃ -R ⁴ , wherein R ² is a hydrogen atom, an alkyl group or an aryl group, R ³ is an alkyl group, A naphthyl group or a naphthylalkyl group, R ⁴ is a halogen atom, a cyano group or a nitro group, and A ₁ , A ₂ and A ₃ are the same or different and are an alkylene group, an alkylidene group, a cycloalkylene group or an alkylcycloalkane-diyl; A ₄ is a naphthyl group; B ₁ and B ₂ are
Same or different And i and j each independently represent 0 or 1, but when i is 0, j is 0. ) In the above general formula (1)

[0016]

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As the divalent aromatic hydrocarbon group represented by the formula (1), there can be mentioned a divalent group derived from one benzene ring or two to three condensed rings thereof. As the saturated heterocyclic group, a 5- to 7-membered ring containing one or two oxygen atoms, nitrogen atoms or sulfur atoms as ring-constituting atoms, or a divalent ring derived from a condensed ring thereof with a benzene ring Groups. Specific examples of the divalent aromatic hydrocarbon group include a group having 6 to 14 carbon atoms derived from a benzene ring, a naphthalene ring, a phenanthrene ring, an anthracene ring, and the like. Specific examples of the saturated heterocyclic group include groups having 4 to 9 carbon atoms derived from a furan ring, a benzofuran ring, a pyridine ring, a quinoline ring, an isoquinoline ring, a pyrrole ring, a thiophene ring, a benzothiophene ring, and the like. Can be.

These substituents are not particularly restricted but include, for example, halogen atoms such as chlorine, bromine and iodine:
Alkyl groups having 1 to 4 carbon atoms such as methyl group and ethyl group: alkoxy groups having 1 to 4 carbon atoms such as methoxy group and ethoxy group: 6 to 6 carbon atoms such as phenyl group, tolyl group and xylyl group
10 aryl groups: an alkoxyaryl group having 7 to 14 carbon atoms (an aryl group having 6 to 10 carbon atoms substituted by an alkoxy group having 1 to 4 carbon atoms): amino group: nitro group: cyano group, etc. Can be.

In the general formula (1), the alkyl group, cycloalkyl group, aryl group and heterocyclic group represented by R ¹ are the above-mentioned alkyl group having 1 to 4 carbon atoms, 3 to 1 carbon atoms.
A 5- to 7-membered ring containing 1 to 2 cycloalkyl groups, an aryl group having 6 to 10 carbon atoms and an oxygen atom, a nitrogen atom, or a sulfur atom as a ring-constituting atom, or a condensation thereof with a benzene ring A monovalent group derived from a ring can be mentioned.

R ² when the group X is a group containing a nitrogen atom
The alkyl group and the aryl group represented by are the same as R ¹ . The alkylene group represented by A ₁ , A ₂ and A ₃ is preferably a group having 1 to 4 carbon atoms such as a methylene group, an ethylene group, a propylene group, a trimethylene group, a tetramethylene group, and the alkylidene group is ethylidene. Group, a propylidene group, an isopropylidene group or the like having 2 to 4 carbon atoms, a cycloalkylene group is preferably a cyclohexylene group, and an alkylcycloalkane-diyl group is dimethylcyclohexane-diyl. Groups are preferred. Further, the alkyl group represented by R ³ is the same as the above-described R ¹ , and the naphthylalkyl group is preferably a group having 11 to 14 carbon atoms such as a naphthylmethyl group and a naphthylethyl group.

The following compounds can be exemplified as compounds that can be suitably used in the present invention.

1) N-cyanomethyl-6,7-dihydrido-4-methyl-2-phenylspiro (5,6-benzo [b] thiophendicarboximide-7,2'-tricyclo [3.3.1. 1 ^3.7 ] decane) 2) N-cyanomethyl-6,7-dihydrido-2- (p
-Methoxyphenyl) -4-methylspiro (5,6-benzo [b] thiophendicarboximide-7,2'-
Tricyclo [3.3.1.1 ^3.7 ] decane) 3) N-cyanomethyl-6,7-dihydrido-4-methylspiro (5,6-benzo [b] thiophendicarboximide-7,2'-tricyclo [3 3.3.1.
^13.7 ] decane) 4) 6,7-dihydrido-N-methoxycarbonylmethyl-4-methyl-2-phenylspiro (5,6-benzo [b] thiophendicarboximide-7,2'-tricyclo [3. 3.1.1 ^3.7 ] decane) 5) 6,7-dihydrido-4-methyl-2- (p-methylphenyl) -N-nitromethylspiro (5,6-benzo [b] thiophendicarboximide-7 , 2'-tricyclo [3.3.1.1 ^3.7] decane) 6) N-cyanomethyl-6,7-dihydride-4-cyclopropyl-3- methylspiro (5,6-benzo [b]
Thiophene-dicarboximide -7,2'- tricyclo [3.3.1.1 ^3.7] decane) 7) N-cyanomethyl-6,7-dihydride-4-cyclopropyl - spiro (5,6-benzo [b] Thiophenedicarboximide-7,2'-tricyclo [3.3.
1.1 ^3.7 ] decane).

In the production process of the compound having a fulgide structure described above, the by-products produced are described above from the results of mass spectrometry and nuclear magnetic resonance analysis.

[0024]

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It is presumed that the skeleton of the norbornylidene group or the adamantylidene group is partially changed.

In the present invention, the mixture may contain two or more compounds having different solubilities in a solvent. Particularly, the target substance is 90% by weight or more, and the impurity is 10% by weight.
When the target substance is separated from the following mixture, it is preferable because the target substance can be separated with high purity, for example, at 99% by weight or more.

In the present invention, a mixture containing compounds having different solubilities in a solvent is dispersed in the solvent. Solvents used for dispersion include those having 1 carbon atom such as methanol, ethanol, propanol, isopropanol and butanol.
Alcohols of 4 to: ketones such as methyl ethyl ketone and methyl isobutyl ketone: ethers such as ethylene glycol dimethyl ether: esters such as ethyl acetate and normal propyl acetate: nitriles such as acetonitrile: aromatic hydrocarbons such as toluene. And other known solvents can also be used. These solvents can be used alone or as a mixed solvent of two or more kinds.

When the above-mentioned compound having a fulgide structure and its by-product are used as a mixture, ketones, ethers, esters, nitriles, and aromatic hydrocarbons can be suitably used as a solvent. .

The concentration of the mixture in the solvent is preferably dispersed in the range of 5 to 20% by weight. By heating the suspension dispersed in the solvent, it is necessary to leave all the compounds with high solubility and some of the compounds with low solubility without dissolving them. It is not preferable to completely dissolve even a compound having a low solubility since fine crystals of the compound having a low solubility do not grow as nuclei in the subsequent cooling. The heating temperature depends on the type of the mixture or the solvent to be separated, but when the mixture of the compound having the fulgide structure and the by-product by-produced in the production process is used as the mixture, 40 to 80 ° C. , Preferably 50-70
It is desirable to be in the range of ° C.

After heating to the above temperature range and cooling, fine crystals of a compound having low solubility become nuclei and crystals grow. The cooling rate is preferably slow cooling for the purpose of growing crystal nuclei, and it is usually preferable to cool at a rate of 0.2 to 0.5 ° C / min. Temperature reached by cooling is 20-30 ° C
Is enough. Generally, it is preferable to cool to the attained temperature in 20 to 300 minutes. By this cooling, crystals of the compound having low solubility are grown. At this time, there is no problem even if a compound having high solubility is precipitated. At the cooling temperature, it is preferable that the temperature is normally maintained for about 30 minutes to 10 hours to sufficiently grow the crystal nuclei of the compound having low solubility.

The above-mentioned heating and cooling may be repeated any number of times. It is preferable that the number of repetitions be large, because crystals of the compound having low solubility grow large and the solubility in the solvent becomes low. Normally, it is desirable to repeat 2 to 5 times in consideration of the insolubility of a compound having low solubility in a solvent due to the growth of crystal nuclei and the labor of operation.

After repeatedly heating and cooling the above suspension, the compound with high solubility is dissolved, but the compound is heated to a temperature at which the compound with low solubility in which crystal nuclei have grown has remained and filtered by hot filtration. Compounds with low solubility can be removed. The crystal size of the compound having low solubility at the time of hot filtration is preferably in the range of 0.1 to 500 μm, because the amount of the compound dissolved in the solvent can be reduced.
In particular, the thickness is preferably 10 μm or more in consideration of dissolution prevention by heating and filterability in operation.

When the temperature at the time of hot filtration is too low, a compound having a high solubility is not sufficiently dissolved, so that when a compound having a high solubility is recovered as a target substance, the recovery rate is deteriorated. If the temperature is too high, the low solubility compound in which the crystal nuclei have grown is redissolved. If the high solubility compound is used as the target compound, the purity is reduced due to the incorporation of the low solubility compound. Therefore, the temperature of hot filtration is 40
The range is preferably from 80 to 80 ° C, more preferably from 50 to 70 ° C.

The filter used in the hot filtration is not particularly limited. However, in view of safety during the hot filtration, a closed filter such as a pressure filter, a filter press, and a cartridge filter is preferable.

The filtrate from which low-solubility compounds having crystal nuclei grown thereon are removed by hot filtration is gradually cooled by a known method to precipitate high-solubility compounds, which can be separated by a method such as filtration.

[0036]

According to the present invention, a mixture of a compound having a high solubility in a solvent and a compound having a low solubility is repeatedly heated and cooled to grow fine crystals of the compound having a low solubility in a heated state. However, the target compound can be separated with high purity and high recovery rate by preventing re-dissolution and removing the crystals by hot filtration.

[0037]

EXAMPLES The present invention will now be described in more detail with reference to typical examples, but the present invention is not limited to these examples. The number of repetitions of heating and cooling, hot filtration, particle size distribution, and purity analysis were performed by the following methods.

(1) Number of repetitions: After the suspension dispersed in the solvent was heated, it was gradually cooled, and the process cycle until crystal precipitation was set to one.

(2) Hot filtration: The solution was filtered under pressure with nitrogen (0.1 MPa) using the following pressure filter.

Pressurized filter: Holder with universal tank KST-
142-UH (manufactured by ADVANTEC) Filter: quantitative filter paper No. 5C (manufactured by ADVANTEC) (3) Particle size distribution meter: The particle size was measured using Mastersizer MS-20 (manufactured by MALVERN).

(4) Purity analysis: Measured using high performance liquid chromatography PU-980, UV-970 (manufactured by JASCO Corporation).

Column: Wakosil 5c18 φ4.6mm × 150mm
(Wako Pure Chemical Industries, Ltd.) Mobile phase: acetonitrile / water = 90/10 (V / V) (Acetonitrile was manufactured by Wako Pure Chemical Industries, Ltd.) Analysis conditions: UV 254 nm sample 0.1 g / 10 chloroform 10 ml Injection volume 1 μl In the following examples, the mixtures shown in the following Table 1 were used. Here, a compound having a fulgide structure (target substance)
Is a compound having a high solubility, and a by-product (impurity) is a compound having a low solubility.

[0043]

[Table 1]

Example 1 No. 1 shown in Table 1 About three kinds of mixtures of 1-3,
The concentration of the mixture dissolved or dispersed in the solvent is 1
Each of them was dispersed in various organic solvents shown in Table 2 so as to be 0% by weight. This was warmed to 65 ° C. At this time, all the compounds with high solubility (target substances) are dissolved,
It was visually confirmed that the compound (impurity) having low solubility did not dissolve and maintained a solid state. Then 0.5 ° C
The temperature was slowly cooled to 20 ° C. at a rate of / min and maintained at 20 ° C. for 1 hour. This heating and cooling operation was repeated the number of times shown in Table 2. Thereafter, the mixture was heated to 60 ° C., hot-filtered at that temperature, and the degree of growth of crystal nuclei due to repetition of heating and cooling was evaluated based on the crystal diameter of the filtrate (compound having low solubility).
The results are shown in Table 2.

[0045]

[Table 2]

[0046]

[Table 3]

Example 2 No. 2 shown in Table 1 About four kinds of mixtures of 4-7,
The concentration of the mixture dissolved or dispersed in the solvent is 1
It was dispersed in toluene so as to be 0% by weight. Then 6
The cooling time from 5 ° C. to 20 ° C. was set to the value shown in Table 3, and the procedure was performed in the same manner as in Example 1 except that heating and cooling were repeated twice. The results are shown in Table 3.

[0048]

[Table 4]

Example 3 No. 3 shown in Table 1 About seven kinds of mixtures of 1-7,
The procedure was performed in the same manner as in Example 1 except that the type and concentration of the solvent were changed as shown in Table 4, and that heating and cooling were repeated three times. Thereafter, the mixture was heated to 60 ° C., and hot-filtered at that temperature. The compositions of the obtained filtrate and filtrate are shown in Table 4. The filtrate was dried under reduced pressure at 50 ° C. for 5 hours and then weighed.
Next, the filtrate was cooled to 20 ° C. at a rate of 2 ° C./min, kept for 2 hours, and the precipitated target product was isolated by filtration. The recovered amount of the target substance was measured at 50 ° C. for 5 hours after drying under reduced pressure. The results are shown in Table 4.

[0050]

[Table 5]

[0051]

[Table 6]

[0052]

[Table 7]

[0053]

[Table 8]

[0054]

[Table 9]

Comparative Example 1 The solvent shown in Table 4 was added to the mixture of No. 4 in Table 1,
Most of the mixture was dissolved by warming to ° C.
After filtering off the insoluble matter, the filtrate was cooled at a rate of 0.5 ° C./min for 20 minutes.
By slowly cooling to ℃, the target product was precipitated as crystals and separated by filtration. Table 4 shows the results.

Comparative Example 2 A solvent shown in Table 4 was added to each crystal of the target product separated by filtration in Comparative Example 1, and all the crystals were dissolved by heating to 75 ° C. The target product was recrystallized by gradually cooling the solution to 20 ° C. at a rate of 0.5 ° C./min, and this was filtered. The results are shown in Table 4.

Claims (1)

[Claims] 1. A method for separating a specific compound from a mixture containing compounds having different solubilities in a solvent, wherein the mixture is dispersed in a solvent, and all compounds having a high solubility are dissolved, but some compounds having a low solubility are partially dissolved. After heating to a temperature such that it remains without dissolving, and then cooling to grow crystals of the compound with low solubility, and further heating to a temperature at which the crystals of the compound with low solubility do not dissolve,
A method for separating a compound, comprising separating the crystal from a solution in which a compound having high solubility is dissolved.