JPH0583526B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a novel separation agent, particularly to a separating agent for chromatography for optically resolving racemic compounds. [Prior art] Conventionally, optically active acrylamide polymers have been used as separating agents mainly composed of optically active polymers [G. Blaschke, Angew. Chem. Int. Ed. Engl. 19 , 13
(1980)] or optically active polymethacrylate esters [H. Yuki, Y. Ckamoto, I. Okamoto, J.
Am.Chem.Soc., 101 , 6356 (1980)] or derivatives of naturally occurring polysaccharides such as cellulose are known. [Problems to be solved by the invention] The conventionally used separating agents using optically active polymers are particularly useful when optically resolving racemic compounds, but they cannot necessarily resolve all racemic compounds. , the objects are limited. Therefore, the development of new separation agents that can separate a wider range of racemic compounds is awaited. [Means for Solving the Problems] The present inventors have intensively studied the problems of the conventional art and have arrived at the present invention. That is, the present invention provides an optical compound obtained by polymerizing an optically active anti-head-to-head coumarin dimer represented by the following general formula () or () and a primary or secondary diamine having 2 to 15 carbon atoms. This invention relates to a separating agent containing activated polyamide as a main component.

[ka] or

[Chemical formula] Next, the configuration of the present invention will be explained. (Optically active polyamide) The optically active polyamide of the present invention has the following general formula (a).
Or it has a repeating unit represented by (b). Note that n is a number indicating the degree of polymerization. (a)

[ka] (b)

embedded image Here, A is a residue obtained by removing one active hydrogen from two amino groups of a primary or secondary diamine having 2 to 15 carbon atoms. Such diamines may be saturated or unsaturated. It may also be a mixture of two or more types of diamines, and may be modified with a trivalent or higher valent amine if necessary. An example of the group represented by A below is shown below. −HN(CH ₂ ) ₂ −NH−, −HN−(CH ₂ ) ₆ −NH−,

【formula】

【formula】

[ka]

[ka]

[ka]

[ka]

[ka]

[ka]

[ka]

[ka]

[ka]

[ka]

[Chemical formula] The optically active polyamide of the present invention has the above general formula ()
Alternatively, it can be easily obtained by reacting the (+) or (-) anti-head-to-head coumarin dimer represented by () with the corresponding diamine. Usually no special catalyst is required. A preferred method is to react equimolar amounts of both in an aprotic polar solvent. Preferred examples of the aprotic polar solvent include dimethylacetamide, dioxane, methylpyrrolidone, dimethylsulfoxide, and hexamethylphosphoric triamide. The optically active polyamide used in the separating agent of the present invention usually has a reduced viscosity of 0.2 to 0.8 (0.3 g/in dimethylacetamide).
dl, 30℃). The method for obtaining the optically active dimer used in the optically active polyamide of the present invention is to diamide a diamide obtained from a racemic anti-head-to-head coumarin dimer (hereinafter referred to as (±) dimer) and an optically active amine. It is characterized by separation into stereomers, deamination followed by ring closure, and the process is shown by the formula below.

〔Example〕

Synthesis examples and examples of the separating agent of the present invention are shown below together with comparative examples, but the present invention is not limited to these examples. Facilitation (k') = [(retention time of enantiomer) - dead time)] / dead time separation coefficient (α) = volume ratio of enantiomer that is more strongly adsorbed /
Capacitive resolution of the more weakly adsorbed enantiomer (Rs) = 2 × (distance between the peaks of the more strongly adsorbed enantiomer and the weaker adsorbed enantiomer)/bandwidth of both peaks The synthesis method of the filler used in this example and an example of optical separation using the same are as follows. Synthesis Example 1 58.46 g of (±) dimer was dissolved in 850 ml of dioxane, and 48.47 g of (-)-1-phenylethylamine was added dropwise over 30 minutes while stirring at room temperature. 12
After stirring for an hour, the precipitate was filtered off. The precipitate was washed with dioxane and then dried under vacuum at 60°C to obtain 42.29 g of crystals. The product was diamide (A) from the (+) dimer, and the yield was 39.5%. After concentrating the filtrate, add 1500ml of acetone and methanol.
After adding 150 ml and heating to dissolve, the mixture was left at 5°C for 12 hours. After drying the precipitated crystals, 35.54 g of (-) dimer diamide (B) was obtained. Yield 33.3%. Table 1 shows the properties of these A and B diamides.

[Table] Synthesis Example 2 5346.5 mg of (-) dimer diamide was added to a mixture of 100 ml of 99% ethanol and 50 ml of concentrated hydrochloric acid and refluxed. After 20 hours, refluxing was completed, and after concentration and removal of ethanol, 200 ml of water was added, and the mixture was extracted with ethyl acetate (150 ml x 3). After removing ethyl acetate, 150 ml of acetic acid was added and the mixture was refluxed. After refluxing for 20 hours, acetic acid was removed. The obtained substance was developed on a silica gel column (Wakogel C-200 4φ x 15cm) with 500ml of benzene, followed by 500ml of benzene-ethyl acetate (90:10).
2451.9 mg (83.9%) of (-) dimer crude crystals were obtained. This was recrystallized with ethyl acetate-hexane (1:3) to obtain 1.92 g (65.7%) of (-) dimer. Synthesis Example 3 The (+) dimer diamide was treated in the same manner as in Synthesis Example 2 to obtain the (+) dimer in a yield of 63.4%. Table 2 shows the properties of these (+) and (-) dimers. For reference, the properties of the (±) dimer are also shown.

[Table] Synthesis example 4 (-) anti-head-head coumarin dimer 0.2552g
(0.9 mmol) and an equimolar amount of p-phenylenediamine were dissolved in 1.7 ml of dimethylacetamide,
It was left at 80°C for 24 hours. After the reaction was completed, the product was dropped into methanol to obtain a polymer (yield: 87%). The reduced viscosity of the obtained polymer (0.3 g/dl in dimethylacetamide, 30°C) was 0.36, and [α] _D
= -89.4, [α] ₄₃₅ = -260.0° (0.5 g/100 ml in dimethylacetamide). Synthesis Example 5 Using hexamethylene diamine as the diamine, 0.8 mmol was reacted in 1.6 ml of dimethylacetamide in the same manner as in Synthesis Example 4. The yield and properties are shown in Table 3. Synthesis example 6 N,N'-dimethylhexamethylenediamine
A similar reaction was carried out using 2.9 mmol in 3.5 ml of dimethylacetamide. The yield and properties are shown in Table 3. Synthesis Example 7 Using 2.1 mmol of m-xylylenediamine, 4.3
ml of dimethylacetamide. The yield and properties are shown in Table 3. Synthesis Example 8 Using 1 mmol of 4,4'-diaminodiphenyl ether, the reaction was carried out in the same manner in 2.0 ml of dimethylacetamide. The yield and properties are shown in Table 3. Synthesis Example 9 Using 1 mmol of piperazine, the reaction was carried out in the same manner in 2.1 ml of dimethylacetamide. The yield and properties are shown in Table 3.

[Table] Example of manufacturing adsorbent 1 Porous silica gel, for example, average particle size is 10 μm
manufactured by Merck & Co., Ltd. with an average pore diameter of 1000 Å.
After drying LiChrospher SI 1000 (5.48 g), toluene (30 ml), triethylamine (4 ml), and diphenyldichlorosilane (4 ml) are added thereto. The mixture is refluxed for 24 hours. The reaction mixture is poured into methanol (300 ml), the insoluble matter is collected by filtration, thoroughly washed with methanol, and then dried. Yield 5.50g. Adsorbent Production Example 2 4.43g of silica gel treated as above was added with polyamide (reduced viscosity
0.36, specific rotation in DMAc [α] _D −89.4° (c0.50))
After adding 1.00 g of DMF solution (9 ml), DMF is distilled off. Wash the residue thoroughly with methanol (filler A). Adsorbent Production Example 3 0.51 g of polyamide (reduced viscosity 0.68, specific optical rotation [α] _D −59.0° (c0.49) in DMAc) synthesized by the method of Synthesis Example 5 was added to 3.00 g of similar silica gel. DPF
After adding the solution (7 ml), the DMF is distilled off. Wash the residue thoroughly with methanol (filler B). Adsorbent Production Example 4 0.42 g of polyamide (reduced viscosity 0.35, specific optical rotation [α] _D −100.2° (c0.50) in DMAc) synthesized by the method of Synthesis Example 6 was added to 3.00 g of the same silica gel. DMF
After adding the solution (7 ml), the DMF is distilled off. Wash the residue thoroughly with methanol (filler C). Adsorbent manufacturing agent 5 Add 1.00 g of polyamide (reduced viscosity 0.51, specific optical rotation in DMAc [α _D +30.6° (c0.50)) synthesized by the method of Synthesis Example 9 to 4.68 g of similar silica gel. After adding DMF solution (9 ml), DMF is distilled off. The residue is thoroughly washed with methanol (filler D). Separation Examples 1 to 8 Fillers A to D produced by the above method were packed into a liquid chromatography column, and optical resolution of various racemates was performed. JASCO Corporation's detector
Using UVIDEC 100V (product name), the liquid pump is
Trirotar V (trade name) was used. The columns are made of stainless steel, have an inner diameter of 0.45 cm, and a length of 25 cm. Each column is filled with each filler using a high-pressure slurry method.
~D. The dead volume of the column is
It was 2.5 to 2.6 ml. As the solvent, a mixture of hexane/isopropanol = 9/1 was used at a flow rate of 0.5 ml/min. At a flow rate of 0.5 ml/min, the number of theoretical plates in benzene was 2200 for column A, 2600 for column B, 2800 for column C, and 2100 for column D. The racemic bodies tested and their resolution results are shown in Table 4 below.
As shown. In addition, Production Example 1 was prepared using the polymers of Synthesis Examples 7 and 8.
As a result of producing an adsorbent in the same manner as above, the same separation effect as above was obtained.

【table】

Claims (1)

[Scope of Claims] 1. An optically active anti-head-to-head coumarin dimer represented by the following general formula () or () and having 2 to 15 carbon atoms.
A separating agent whose main component is an optically active polyamide obtained by polymerizing a first or second diamine. [C] or [C]