JPS6296486A - Separation of benzaldehyde derivative - Google Patents

Abstract

PURPOSE:To industrially and advantageously separate an isomer, by subjecting an isomeric mixture of methoxymethylenedioxybenzaldehyde to liquid chromatography using a synthetic adsorbent as a separating agent in a solution of a lower alcohol, etc. CONSTITUTION:A mixture of 2-methoxy-3,4-methylenedioxybenzaldehyde expressed by formula I with 4-methoxy-2,3-methylenedioxybenzaldehyde expressed by formula II which are mutually isomers is separated. In the process, a synthetic adsorbent, preferably having porous crosslinked polystyrene as a main structure and pore physical properties of 100-1,500m<2>/g surface area and 0.1-2.0ml/g pore volume is used as a separating agent and the above- mentioned mixture in a lower alcohol or mixed solution thereof with water is subjected to liquid chromatography. A 1-3C alcohol is preferred for the lower alcohol.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for separating benzaldehyde derivatives. More specifically, the present invention relates to a method for separating isomers contained in two-methoxy-3,l-methylenedioxybenzaldehyde, which is a compound useful as an intermediate raw material for the production of medical products, agricultural chemicals, etc.

[Conventional technology]

Cometoxie 3. As a known synthesis method for l-methylene dioxybenzaldehyde, l-methoxyco, 3-
There is a method using Vilsmei@r formylation reaction of methylenedioxybenzene.

(For example, Chem, Ber, , /0ko, 2
1,63,191,9;J,Chem,Soc,,P
erkln I, /9t'l, 709;Tst
rahedron, QO, Jj, 2q, /9g<<Refer to the year) [Problem to be solved by the invention] However, in this method, cometoxy, 7.4'
- An isomer of methylenedioxybenzaldehyde, dermethoxyco, 3-methylenedioxybenzaldehyde, is produced, e.g., J, Chem, Soc,
According to Perkin Trans 1,19g17,709, isomers are produced at a ratio of 1-2 to the target product. Therefore, it is necessary to efficiently separate both compounds that have similar physical properties. For example, Cher+hBu,
/ 0ko, Yu44. ? (/Delta) and Tetrah
edron.

For lIo, ss:tq(tqglI), there is a method of isolating the target product by repeating recrystallization with absolute ethanol, and +L Chum, Soc, Perkin
Trans+I,')09(19r4') has
A method of chromatographic separation using silica gel has been reported. However, these methods are not necessarily efficient methods, and the development of an industrially advantageous separation method has been desired.

[Means for solving problems]

The present inventors conducted intensive studies on a method for separating isomer mixtures containing two-methoxy-3, coumethylenedioxybenzaldehyde and dermethoxyyl, 3-methylenedioxybenzaldehyde. By subjecting the isomer mixture solution to liquid column chromatography under the conditions of
We have discovered that isomer mixtures can be separated efficiently, and have arrived at the present invention.

That is, the essence of the present invention is that the following structural formulas m and (2)
The present invention relates to a method for separating benzaldehyde derivatives, which comprises subjecting a mixture of benzaldehyde m44 represented by: to liquid column chromatography in a mixed solution of water.

The present invention will be described in detail below. I will clarify.

The synthetic adsorbents used in the present invention include crosslinked polymers obtained by polymerizing, copolymerizing, or condensation polymerization of various organic polymerizable monomers, or crosslinked polymers obtained by polymerizing or copolymerizing various polymerizable monomers. Examples include crosslinked polymers obtained by performing a crosslinking reaction after condensation polymerization, or those obtained by chemically modifying these crosslinked polymers.

Of course, the chromatographic separation ability of a synthetic adsorbent is also greatly influenced by the surface area and pore volume of the synthetic adsorbent, preferably /o om2/g-/! r
o om27g-1 More preferably, ? o om+/
It has a surface area of y--/ s o o, ;, il, and o, 1 ml/f-co, oml/'? , more preferably 0.3 ml / f ~ / 4 ml, / ji'
It is desirable to have a pore volume of

On the other hand, the basic unit structure of the synthetic adsorbent also affects the isomer maintenance capacity and separation ability, but for the purpose of the present invention, an aromatic copolymer mainly composed of styrene and divinylbenzene is used. Preferably, the base structure is a combination.

Examples of such synthetic adsorption agents include Diaion HP-10. ．． 20. Yu/, 3θ.

IIo and ToriO (Tamatsuki Kasei Kogyo (stock system, registered trademark);
Examples include Sepa beads, 5P-206, :107, gOθ and qoo (manufactured by Mitsubishi Chemical Corporation, trademark Noborito); Amberlite XAD-, 2 and + (manufactured by Rohm and Haas, trademark).

When carrying out chromatography using such a synthetic adsorbent, the method of the present invention operates in a lower alcohol or a mixed solution of lower alcohol and water from the viewpoint of separability and solubility of the isomer mixture.

Examples of the lower alcohol 17 include methanol, ethanol, n-propanol, benzlovanol, etc., and methanol is preferably used.

In addition, the mixing ratio of the lower alcohol-water mixed solution also affects the separation of the isomer mixture by the synthetic adsorbent, and the synthetic adsorbent compound +1) (2-methoxy-3
, 'I-methylenedioxybenzaldehyde) and compound +2) (4'-methoxy-2,3-methylenedioxybenzaldehyde) was found to vary greatly depending on the alcohol-water mixing ratio. It was.

As shown in Figure 2, the selectivity K(2) of compound (2) in the bath solution decreases as the alcohol concentration increases. Then K(2)
becomes smaller than i and o (compound (2) is more easily adsorbed), and the selectivity is reversed.

In the method of the present invention, in order to efficiently separate isomers, it is preferable to select the alcohol concentration so that K(1) is greater than or equal to / or less than 9. K(2)
When is very close to 80, the difference in selectivity of the adsorbent for compound (1) and compound (2) is too small to separate the isomers sufficiently.

However, if K(2) is 0 or more, even if the alcohol concentration is too low, the solubility of the isomer mixture will be low, which is disadvantageous in terms of operation.

Therefore, for example, when methanol is used as alcohol, the methanol concentration is 30 to 70 vol.
0 vol% or more is suitable.

There are no particular restrictions on the mode of liquid column chromatography carried out according to the method of the present invention, but usually the separating agent is packed in a column with a packing layer of 30 to 30 Q crn.
A solution of the isomer mixture is passed through the column, which is packed so that the column is about 400 mm thick.

The liquid flow rate is 0.0, the volume velocity is 0. ／ ”= ／
0. OL/1 resin is suitable.

6 degrees of isomer mixture is 1 to 30ψ/1 (within solubility range)
As mentioned above, lower alcohol, strained water, or a lower alcohol-water mixture is used as a solution once a month.

When the isomer mixture solution continues to flow into the column according to the method of the present invention, in the range where the alcohol concentration of the solution becomes (1) or K(2)≧〇, the compound (2) is initially
only leaks out, and later the compound (]) begins to leak out.

Therefore, by collecting the outflow fraction of the cloth before a certain amount of compound (1) begins to flow out, only compound (2) can be separated.
Compound (2) with a reduced content of Compound (1) can be obtained.

In addition, in order to separate only compound (1) or to obtain compound (1) with a reduced content of compound (2), after injecting a predetermined amount of the solution containing the above-mentioned isomer mixture into the column, 3θ~? of a lower alcohol, preferably methanol, without isomer mixture as eluent. Ovo1
% aqueous solution, and the isomer mixture is eluted from the column by elution chromatography on a synthetic adsorbent.

In this way, compound (2) first flows out into the column effluent, then (E compound (1) flows out with a delay, and -0
- Because the a degree peak positions of the efflux of both components are different, the compound (
By collecting the effluent fraction after the effluent concentration of 2) has decreased below a certain value, it is possible to obtain compound (1) with a reduced content of compound (2).
) or only compound (1) can be separated.

At this time, when the effluent concentration of compound (2) has decreased to a certain value, if the eluent is switched to a bath liquid with a higher alcohol concentration than the initial 'D degree, such as pure alcohol, it will remain in the column. Since compound (1), which is present in the sample, is easily eluted, compound v/Jfl) can be recovered at a high concentration.

In addition, in the range where the alcohol temperature of the solution is K(2)≦〇, compound (1) starts to flow out first, and compound (2) flows out later; By collecting the effluent fraction before it begins to flow out for a certain period of time, only compound (1) can be separated, and compound (2) with a reduced content of compound (2) after straining can be obtained.

〔Example〕

Hereinafter, the present invention will be explained in more detail according to Reference Examples and Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.

Reference Example 1 Synthetic adsorbent Diaion HP s / (Mitsubishi Kasei Corporation ■, registered trademark), synthetic adsorbent Sepabead 5p2oq (Mitsubishi Chemical Corporation ■, registered trademark), and silica gel Wakogel C-/θ0 (manufactured by Wako Tsumugi Pharmaceutical ■, (registered trademark) were weighed out in water volume (smt), respectively, and nimethoxy-3, I
I-methylenedioxybenzaldehyde (compound (1)
), and eumethoxyco, 3-methylenedioxybenzaldehyde (compound (2)) /:l at a concentration of 0 C/l.
The mixture was added to a weighed Erlenmeyer flask and shaken for 2 hours using a CoSC constant temperature shaker. After shaking, the adsorbent was separated into a furnace, the concentrations of compound (1) and compound (2) in the supernatant were measured, and the concentrations of compound (1) and compound (2) for each adsorbent were determined.
The sum g1 of the adsorption periods was calculated.

The results are shown in Figure 1.

Reference examples: Synthetic adsorbent DIAION HP, 2/(Mitsubishi Chemical Corporation, registered trade name, λ) and synthetic adsorbent Sepabead SP Yu0
7 (Mitsubishi Chemical Industries (Scoop, 1r registered trademark)) was weighed in water, and the compound (1) was weighed at o, qyg-/l.
, a solution lθθ of a concentrated I group of methanol or ethanol and water containing compound (2) at a concentration of 0727−/l.
ml was added to the Erlenmeyer flask and shaken for an extended period of time in a constant temperature shaker at 1.25C.

After shaking, the non-absorbing agent was filtered, and the residual dust of compound (1) and compound (2) in the supernatant liquid was separated and quantified by liquid chromatography, and the compounds of each adsorbent under various conditions H- were determined. The selectivity for (1) and (2) was determined by the following formula.

Residual concentration of compound (1) in solution The results are shown in Figure 2.

In addition, in the figure, person is Sepabeads SP, 207 in methanol solution, B is Sepabeads SP Co07 in ethanol solution,
C shows the results for Diaion HP2/ in methanol solution.

Example 1 Synthetic adsorbent Sepabeads sp, zOy (Mitsubishi Chemical Corporation ■,
(registered trademark) was weighed in a volume of 75 cm in water and packed into a glass column with an inner diameter of Qm and a height of 1 OOOfl.

1. Compound (1) was added to this column. ! ;3'if/l,
5 of methanol containing compound (2), 11.9 f/
Inject 0 vol water attack solution tsomt (cot7 as one resin), and further add 73 jr methanol solution of j' Ovolφ.
Omt was injected. After that, 7000 methanol solution of special grade reagent was injected. At this time, the injection speed was all 15
0 mt/hr, and the temperature was 21 to -gC.

Compounds in the effluent from the column during the above operation (
1) and compound (2) against the stock solution (C/C
o) is shown in Figure 3. Compound (2) is about 2! ;t/ starts to be eluted from one resin, and compound (1) starts to be eluted from about s-s t
/t-ml fat started to be eluted.

Ko S-! r 5 t/ - By taking the effluent fraction of the resin, g of compound (2) that does not contain compound (1) is obtained.
It was possible to recover with a yield of 6%. Furthermore, by collecting a fraction of the effluent from the got7't-resin, it was possible to separate and recover compound (1) substantially free of compound (2) at a yield of 7 g%.

Example: Synthetic adsorbent Sepabeads 5 paoq (Mitsubishi Chemical Industries, Ltd.,
Weigh the volume of Registration 11 in water, and the inner diameter is 15 Ill.
II+, height/000 nun glass column was packed.

Compound (1) was added to a column containing 8 gg5I-/l and compound (2) was added to a column containing 0.1. ．． 95v of methanol operating 3f/
ol water bath solution was injected at a flow rate of /00 ml/hr.

As a result of analyzing compound (1) and compound (2) in the column effluent, compound (1) started leaking from the iqomt of the column effluent, while compound (2) started leaking from the iqomt of the column effluent. It started leaking from the moment I got there.

790-/2 of column effluent! ; By collecting the Oml fraction, it was possible to separate and recover 87Li- (yield: ?O%) of compound (1) that did not contain compound (2).

〔Effect of the invention〕

By the method of the present invention, mutually isomer components of niemethoxy-3, coumethylenedioxybenzaldehyde and comethoxy, 3-methylenedioxypenzaldehyde, which are useful compounds as intermediates for medicines, agricultural chemicals, etc., can be separated. , can be achieved industrially with great efficiency.

Furthermore, the above isomers can be separated by recrystallization using a lower alcohol solvent, etc., but if the present invention is applied in combination with the recrystallization method as a method for recovering useful substances from the crystallization mother liquor, the yield, The industrial value is extremely large in terms of cost etc.

[Brief explanation of drawings]

FIG. 1 is a diagram showing the relationship between methanol concentration and adsorption 1t of compounds (1) and (2), which was not obtained in Reference Example 1. FIG. 2 is a diagram showing changes in selectivity K(2) depending on alcohol concentration, obtained in Reference Example 2. (A) Sepapes SP, 2θ7 (methanol solution),
(B) Kesepa beads 5 pxoq (ethanol bath solution), (
C) is the result for Diaion HP, 2t (methanol solution). FIG. 3 is a diagram showing the brightness of bath products from the column effluent in Example tK. Applicant: Mitsubishi Kasei Corporation Daikonjin 3F Buried Officer - 7 others Figure 1 Methanol concentration (vol, ",") Star 2 Figure A/Immediate concentration (volX)

Claims (3)

[Claims] (1) The following structural formulas (1) and (2): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (1) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (2) One of the mixtures of benzaldehyde derivatives shown in In the separation method, a synthetic adsorbent is used as a separating agent, and the mixture is treated with lower alcohol or lower alcohol-
A method for separating benzaldehyde derivatives, which comprises performing liquid column chromatography treatment in a mixed solution of water. (2) As a synthetic adsorbent, the main structure is porous crosslinked polystyrene or its derivative, and the surface area is 100 to 15
The method according to claim 1, characterized in that a synthetic adsorbent having pore physical properties of 0.00 m^2/g and a pore volume of 0.1 to 2.0 ml/g is used. (3) The method according to claim 1, characterized in that methanol, ethanol, n-propanol or isopropanol is used as the lower alcohol.