JP4338478B2 - Solid phase carrier and solid phase synthesis of liquid crystal compound using it - Google Patents

Description

  The present invention belongs to the technical field of solid phase synthesis, and particularly relates to a solid phase carrier suitable for use in solid phase synthesis of an imine compound and synthesis of an imine type liquid crystal compound using the solid phase carrier.

  As is well known, liquid crystals are widely used in devices such as displays, but there is still room for improvement, and it is necessary to prepare many types of liquid crystals for practical use, and the development of new materials is always desired. Yes.

  In general, liquid crystal molecules have a highly anisotropic rod-like structure, and they must have a rigid core consisting of a linking group and an aromatic ring, a flexible carbon chain, and a terminal substituent that helps the orientation of the molecule. It is said that. When developing a new liquid crystal compound (liquid crystal compound), usually a method of selecting the core first and changing the side chain length little by little is employed. However, there are an infinite number of materials that can be considered, and enormous amounts of time and effort are required to synthesize these compounds one by one and investigate the function of each compound to select the target liquid crystal material.

On the other hand, the combinatorial synthesis method has been known and widely used in the field of drug discovery, and this method uses a combination of several structural elements to efficiently construct a large and diverse compound library in a short time. It is a technique to do. Despite the fact that such methods are already known, there are surprisingly few applications in the field of organic synthesis, particularly in liquid crystal, and examples are found in the following documents.
Org. Biomol. Chem., 1, 1609-1624 (2003) Spec. Chem., 22, 27-28 (2002) Proceedings of the 81st Chemical Society of Japan, 1169 (2002)

  Combinatorial synthesis includes a solid phase synthesis method and a liquid phase synthesis method, but the solid phase synthesis method is more widely used. This is because, in the solid phase synthesis method, the target compound is covalently supported on the solid phase, so that the excess reaction reagent can be removed with a simple operation of washing, and the synthesis route is determined. This is because it has advantages such as being able to quickly synthesize many kinds of compounds and easily applying to automatic synthesis.

  In the combinatorial synthesis method using a solid phase method, a substrate is supported on a solid phase carrier for synthesis, and finally the product is cut out from the solid phase carrier to synthesize a compound. Therefore, in order to carry the substrate on the solid phase carrier without decomposing it and to cut it out from the solid phase carrier, the solid phase carrier including a linker connecting the substrate and the solid phase carrier plays a very important role. However, as described above, there are very few examples of combinatorial synthesis of liquid crystal compounds, and therefore, there are almost no specific examples of solid phase carriers devised for preparing a liquid crystal library composed of a group of compounds having a specific structure. Not issued.

  An object of the present invention is to provide a novel solid phase carrier suitable for use in the preparation of a liquid crystal library and a solid phase synthesis method using the same.

  While the present inventor conducted research on solid phase synthesis of liquid crystals, when a solid phase resin (polymer) to which aminophenylalkanoic acid was bonded was used, a substrate having an imine structure on the solid phase could be easily detached. The present invention has been derived by finding out that it is possible.

  Thus, the present invention provides a solid phase carrier for imine compound synthesis, characterized in that a linker comprising an aminophenylalkanoic acid represented by the following formula (I) is bonded to a support polymer via its carboxyl group. Is to provide.

In the formula (I), n represents an integer of 3 to 8.
Furthermore, according to the present invention, as a preferred example for use in the above solid phase carrier, a method of synthesizing an imine type liquid crystal compound represented by the following formula (II), comprising the following steps (i) to (iii) ) Is provided.

In formula (II), R ¹ represents OC _x H _{2X + 1} (x represents an integer of 8 to 12), SC _y H _{2y + 1} (y represents an integer of 8 to 12), or O (CH ₂ CH ₂ O ) _z C ₂ H ₅ (z represents an integer of 1 to 3), and R ² represents C _n H _{2n + 1} (n represents an integer of 4 to 10).
(I) The solid phase carrier and terephthalaldehyde acid represented by the following formula (A) are mixed to perform a dehydration condensation reaction between the amino group of the solid phase carrier and the aldehyde group of terephthalaldehyde acid. Forming an imine bound to a solid support.

(Ii) The imine produced in the step (i) is reacted with an alcohol represented by the following formula (B), an alcohol containing a thiol or an ether bond, and dehydration condensation with the carboxyl group of the imine The process of making a reaction occur.

In formula (B), R ¹ represents the same as described above in relation to formula (II).
(Iii) and the product of step (ii) and an aniline derivative represented by the following formula (C) are mixed to perform an imine exchange reaction, whereby the compound of formula (II) is converted into a solid phase carrier The process of cutting out from.

In formula (C), R ² represents the same as described above in relation to formula (II).
The present invention further provides, as another aspect, a library of imine-type liquid crystal compounds characterized in that it is composed of each compound represented by the above formula (II).

  As will be apparent from the following description, if the solid phase carrier of the present invention is used, the substrate can be desorbed under mild conditions without using an acid or a base, and a functional group capable of being linked to a linker is attached to the substrate. Not needed on the side.

  Depending on the structure of the amino group-containing compound (for example, aniline derivative) used for various reactions with the functional group (for example, carboxyl group) contained in the imine compound generated by linking to the solid support and the imine exchange reaction. Many and various imine compounds, for example, imine type liquid crystal compounds can be obtained as a library by combinatorial solid phase synthesis.

  In the following, an embodiment of the present invention will be described along the steps of the preparation of the solid phase carrier of the present invention shown in FIG. In the chemical structural formula shown in FIG. 1, carbon atoms and hydrogen atoms are omitted in accordance with a conventional expression. In addition, aminophenylalkanoic acid is shown as aminophenylbutanoic acid for convenience.

Preparation of solid phase carrier The solid phase carrier of the present invention can be obtained by binding an aminophenylalkanoic acid defined by the aforementioned formula (I) to a support polymer (resin) as a linker. That is, by using a support polymer having a functional group such as an amino group or a hydroxyl group on the surface and performing a condensation reaction between the amino group or the hydroxyl group and the carboxyl group of aminophenylalkanoic acid, The polymer and aminophenylalkanoic acid are combined. In FIG. 1, a support polymer (P) having an amino group is schematically shown. As shown as (I ′) in the figure, aminophenylalkanoic acid is reacted with the support polymer in a form in which the amino group is protected with an amino protecting group represented by Boc group (t-butoxycarbonyl group).

  The polymer used as the support polymer in the solid phase carrier of the present invention is not particularly limited, but is generally a polystyrene resin or a copolymer thereof, a polyacrylamide resin or a copolymer thereof, or a polymethacrylic resin. An amide resin or a copolymer thereof is preferably used.

  Since the amino group present on the surface of these resins is generally commercially available in a protected state as a trifluoroacetate salt, in use, after deprotection using triethylamine or the like, the aminophenyl as described above is used. Subject to reaction with alkanoic acid. In addition, examples of the functional group on the surface of the resin include hydroxyl groups such as hydroxymethyl group and benzyl alcohol group, which are also subjected to reaction with aminophenylalkanoic acid.

  As described above, a solid phase carrier in which the amino group-protected body (I ′) of aminophenylalkanoic acid is bound to the support polymer (P) is obtained (shown as (S ′) in FIG. 1). . As is well known, the solid phase carrier (S ′) is treated with a strong acid such as trifluoroacetic acid (TFA) to remove a protecting group typified by the Boc group. A desired solid support (shown as (S) in FIG. 1) can be prepared in which an acid linker is attached to a support polymer.

Synthesis of imine type liquid crystal compound By using the solid phase carrier of the present invention prepared as described above, solid phase combinatorial synthesis of the imine type liquid crystal compound represented by the above-mentioned formula (II) becomes possible.
For this purpose, first, as shown in FIG. 1, a dehydration condensation reaction is performed between the amino group of the solid phase carrier (S) and the aldehyde group of terephthalaldehyde acid (A) to bind to the solid phase carrier. Formed imine (III) [step (i)]. In this step, it is only necessary to mix the solid phase carrier (S) and terephthalaldehyde acid (A) at room temperature.

Next, as shown in FIG. 1, the solid phase-supported imine (III) produced in the step (i) is reacted with the compound represented by the above-described formula (B) to obtain the carboxyl of the imine (III). A dehydration condensation reaction is carried out with the group [step (ii)]. Here, the compound R ¹ H of the formula (B) is an alcohol (when R ¹ is OC _x H _{2x + 1} ), a thiol (when R ¹ is SC _y H _{2y + 1} ), or an alcohol containing an ether bond (R ¹ is O (CH ₂ CH ₂ O) _z C ₂ H ₅ ), and by reaction with the carboxyl group of imine (III), ester (—CO · OC _× H _{2x + 1} ) and thioester (—CO · SC, respectively). _x H _{2x +} 1), or Echirupori will form a (oxyethylene) ester _{(-CO · O (CH 2 CH} 2 O) z C 2 H 5). This step (ii) increases the diversity of the finally obtained imine compound.

  In the solid phase synthesis, it is necessary to finally cut out the product from the solid phase support. In the synthesis method of the present invention using the solid phase carrier (S) described above, the inventor has obtained the product (IV) of the above step (ii) and the aniline derivative represented by the above formula (C). It has been found that the target compound (II) is excised from the solid phase carrier by mixing and imine exchange reaction [step (iii)]. That is, when an excess amount of the aniline derivative (C) is added to the imine (IV), the added aniline derivative is replaced with a component of the imine, and a new imine is generated and cut out from the solid support. This exchange reaction proceeds only by mixing (IV) and (C) and heating from room temperature to about 50 ° C.

  As understood from the above, in the solid phase synthesis of the present invention, the substrate can be desorbed from the solid phase carrier under mild conditions without using acid or base as in the conventional general solid phase synthesis method. It is possible, and it is not necessary for the substrate to have a functional group for linking with the linker.

The above description along FIG. 1 shows a preferred example of solid-phase combinatorial synthesis of an imine compound of formula (II) exhibiting liquid crystallinity, but solid-phase synthesis of the present invention using aminophenylalkanoic acid as a linker. The present invention is not limited to the above case, and can be applied to the synthesis of other liquid crystal compounds, and not only liquid crystal compounds but also general imine compounds. For example, the aromatic ring of the aniline derivative may have various substituents such as an alkyl group and a halogen group in addition to the alkoxy group represented by the formula (C). Obtainable.
Hereinafter, examples will be described in order to specifically show the features and embodiments of the present invention, but the present invention is not limited thereto.

Preparation of solid phase carrier A solid phase carrier having 4-aminophenylbutanoic acid as a linker was prepared according to the scheme shown in FIG.
Lanthanum AMM resin (aminomethylpolystyrene resin) (trifluoroacetate, PS-D series manufactured by Mimotopes, Australia, 38 μmol / 1) 405 (15.4 mmol) in 5% triethylamine (DMF, dichloromethane 1: 1 mixture) It was immersed in 500 mL of the solution and shaken (10 minutes × 2). Thereafter, it was washed with a mixed solution of DMF and dichloromethane 1: 1 (10 minutes × 2), and finally washed with dichloromethane (10 minutes × 2) to obtain (P).
To 405 (P), 8.32 g (61.6 mmol, 4 equiv.) Of HOBt (1-hydroxybenzotriazole), 17.18 g (61.6 mmol, 4 equiv.) Of 4-aminophenylbutanoic acid with Boc-modified amino group, DMF
88 mL and 44 mL of dichloromethane were added and shaken for 10 minutes. Finally, a solution of 19.3 mL of 1,3-diisopropylcarbodiimide (15.6 g, 123 mmol, 8 equiv.) In 88 mL of dichloromethane was added, and the mixture was further shaken for 15 hours. After removing the reaction solution by decantation, the resin was washed with DMF (3 minutes × 3) and dichloromethane (3 minutes × 3) to obtain (S ′).
300 mL of 15% trifluoroacetic acid (dichloromethane solution) was added to the Boc solid phase support (S ′) and shaken (3 hours × 2). After removing the solution by decantation, the resin was washed with DMF (3 minutes × 3) and further immersed in a 5% triethylamine (DMF, dichloromethane 1: 1 mixture) solution and shaken (10 minutes × 2). . Then, it was washed with a mixed solution of DMF and dichloromethane 1: 1 (10 minutes × 2), and finally washed with dichloromethane (10 minutes × 2) to obtain 405 solid phase carriers (S).

Synthesis of imine type liquid crystal compound Using the solid phase carrier (S) prepared in Example 1, an imine type liquid crystal compound represented by the formula (II) was synthesized according to the scheme shown in FIG.
<Condensation of solid phase carrier and terephthalaldehyde acid: Step (i)>
A DMF solution (80 mL) of terephthalaldehyde acid (2.54 g, 16.9 mmol, 5.3 equiv.) Was added to 84 solid supports (S) and shaken at room temperature for 24 hours. The reaction solution was removed by decantation and then washed with DMF (30 seconds × 3) and then with dichloromethane (30 seconds × 3) to obtain (III).

<Condensation of alcohol containing alcohol, thiol or ether bond: Step (ii)>
Nonanol Condensation [Synthesis of (IV) (R ¹ = OC ₉ H ₁₉ )]:
28 mL of 3-dimethylaminopyridine 32.5 mg (0.266 mmol, 0.25 equiv.), 1-nonanol 0.74 mL (610 mg, 4.3 mmol, 4 equiv.), 1,3-diisopropylcarbodiimide 5.33 mL (4.4 g, 34 mmol, 32 equiv.) Was dissolved in dichloromethane. This solution was added to a solution containing 28 resins (III) condensed with terephthalaldehyde acid and shaken for 3 hours. The reaction solution was removed by decantation, and then washed with DMF (30 seconds × 3) and then with dichloromethane (30 seconds × 3) to obtain (IV) (R ¹ = OC ₉ H ₁₉ ).
Nonanethiol Condensation [Synthesis of (IV) (R ¹ = SC ₉ H ₁₉ )]:
(IV) (R ¹ = SC ₉ H ₁₉ ) was obtained in the same manner as described above using 0.81 mL (680 mg, 4.3 mmol, 4 equiv.) Of 1-nonanethiol instead of 1-nonanol.
Condensation of diethylene glycol monoethyl ether [synthesis of (IV) (R ¹ ═O (CH ₂ CH ₂ O) ₂ C ₂ H ₅ )]:
(IV) (R ¹ ═O (CH ₂ CH ₂ O) ₂ C ₂ H ₅ is carried out in the same manner as above using 0.58 mL (580 mg, 4.3 mmol, 4 equiv.) Of diethylene glycol monoethyl ether instead of 1-nonanol. )

<Cutting of imine with alkoxyaniline: step (iii)>
Synthesis of ester (II) (R ¹ = OC ₉ H ₁₉ , R ² = C ₈ H ₁₇ ) with 4-octyloxyaniline:
A solution prepared by dissolving 168.2 mg (0.760 mmol, 5 equiv.) Of 4-octyloxyaniline in DMF was added to 4 resins (IV) (R ¹ = OC ₉ H ₁₉ ) and added at 50 ° C. for 3 hours. Heated. Subsequently, after the solvent was distilled off under reduced pressure, excess aniline was removed through 10 g of silica gel column chromatography (hexane / ethyl acetate 5/1). Finally, 48.3 mg (0.107 mmol, 66% yield) of ester (II) (R ¹ = OC ₉ H ₁₉ , R ² = C ₈ H ₁₇ ) was purified by HPLC (hexane / ethyl acetate 19/1). Obtained as crystals.
Spectral data
¹ H NMR (300 MHz, CDCl ₃ ) δ0.88
(3H, t, J = 6.9 Hz), 0.89 (3H, t, J = 6.7 Hz), 1.23-1.48 (22H, m), 1.79 (4H, m), 3.98
(2H, t, J = 6.6 Hz), 4.34 (2H, t, J = 6.6 Hz), 6.93 (2H, d, J = 9.1 Hz), 7.26 (2H, d, J = 9.1 Hz), 7.95 (2H , d, J = 8.2 Hz), 8.12 (2H, d, J = 8.2 Hz), 8.53 (1H, s). IR (ATR) 1712, 1621
cm ^-1 . MS (CI): m / z 480 ([M + H] ⁺ , 100%). HRMS (CI): calcd for C ₃₁ H ₄₆ NO ₃
([M + H] ⁺ ), 480.3478, found 480.3473.
Cleavage of thioester (II) (R ¹ = SC ₉ H ₁₉ , R ² = C ₆ H ₁₃ ) with 4-hexyloxyaniline (when purified by chromatography):
A solution prepared by dissolving 146.9 mg (0.76 mmol, 5 equiv.) Of 4-hexyloxyaniline in DMF was added to 4 resins (IV) (R ¹ = SC ₉ H ₁₉ ) and added at 50 ° C. for 3 hours. Heated. Subsequently, after the solvent was distilled off under reduced pressure, excess aniline was removed through 10 g of silica gel column chromatography (hexane / ethyl acetate 5/1). Finally, it was purified by HPLC (hexane / ethyl acetate 5/1) to obtain 57.6 mg (0.123 mmol, yield 81%) of thioester (II) (R ¹ = SC ₉ H ₁₉ , R ² = C ₆ H ₁₃ ). Obtained as crystals.
Spectral data
¹ H NMR (300 MHz, CDCl ₃ ) δ0.89
(3H, t, J = 6.0 Hz), 0.92 (3H, t, J = 6.0 Hz), 1.25-1.37 (14H, m), 1.45 (4H, m), 1.69
(2H, quint, J = 7.4 Hz), 1.80 (2H, quint,
J = 6.6 Hz), 3.09 (2H, t, J = 7.4 Hz), 3.98 (2H, t, J = 6.6 Hz), 6.94 (2H, d, J = 8.8
Hz), 7.27 (2H, d, J = 8.8 Hz), 7.95 (2H, d, J = 8.2 Hz), 8.05 (2H, d, J = 8.2 Hz), 8.53
(1H, s). IR (ATR) 1649, 1619 cm ^-1 . MS (CI): m / z 467 ([M] ⁺ ,
100%). HRMS (CI): calcd for C ₂₉ H ₄₁ NO ₂ S
([M] ⁺ ), 467.2858, found 467.2841.
Cutting out thioester (II) (R ¹ = SC ₉ H ₁₉ , R ² = C ₁₀ H ₂₁ ) with 4-decanyloxyoxyaniline (when recrystallized):
A solution prepared by dissolving 189.7 mg (0.76 mmol, 5equiv.) Of 4-decanyloxyoxyaniline in DMF was added to 4 resins (IV) (SR ¹ = SC ₉ H ₁₉ ) at 50 ° C. After heating for 3 hours, the solvent was distilled off under reduced pressure. Recrystallized from DMF, the first and second crystals were combined to give 45.5 mg (0.0869 mmol, 57% yield) of thioester (II) (R ¹ = SC ₉ H ₁₉ , R ² = C ₁₀ H ₂₁ ) Got as. Although it was confirmed that the mother liquor contained (II), it was not purified.
Spectral data
¹ H NMR (300 MHz, CDCl ₃ ) δ0.88 (6H, t, J = 6.3 Hz), 1.22-1.49 (26H, m), 1.69 (2H, quint,
J = 7.4 Hz), 1.80 (2H, quint, J = 6.6 Hz),
3.09 (2H, t, J = 7.4 Hz), 3.98 (2H, t, J = 6.6 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.95 ( 2H, d, J = 8.5 Hz), 8.05 (2H, d, J = 8.5 Hz), 8.53 (1H, s) .IR (ATR) 1647,
1620 cm ^-1 . MS (CI): m / z 523 ([M] ⁺ , 100%). HRMS (CI): calcd for C ₃₃ H ₄₉ NO ₂ S
([M] ⁺ ), 523.3484, found 523.3500.
Cutting out of ester (II) (R ¹ ═O (CH ₂ CH ₂ O) ₂ C ₂ H ₅ , R ² ═C ₆ H ₁₃ ) with 4-octyloxyaniline:
A solution in which 168.2 mg (0.76 mmol, 5 equiv.) Of 4-octyloxyaniline was dissolved in DMF was prepared, and this was converted into four resins (IV) (R ¹ ═O (CH ₂ CH ₂ O) ₂ C ₂ H _5. ) And heated at 50 ° C. for 3 hours. Subsequently, after distilling off the solvent under reduced pressure, excess aniline was purified by 10 g silica gel column chromatography (hexane / ethyl acetate).
Excluded through 1/1). Finally, it was purified by HPLC (hexane / ethyl acetate 2/1) to give 23.8 mg of ester (II) (R ¹ ═O (CH ₂ CH ₂ O) ₂ C ₂ H ₅ , R ¹ ═OC ₈ H ₁₇ ) 0.051 mmol, yield 33%) as crystals.
Spectral data
¹ H NMR (300 MHz, CDCl ₃ ) δ0.89 (3H, t, J = 6.9 Hz), 1.21 (3H, t, J = 7.0
Hz), 1.26-1.40 (8H, m), 1.47 (2H, m), 1.80 (2H, quint,
J = 6.0 Hz), 3.54 (2H, q, J = 7.0 Hz), 3.63 (2H, m), 3.71 (2H, m),
3.87 (2H, t, J = 4.7 Hz), 3.98 (2H, t, J = 6.0 Hz), 4.51 (2H, t, J = 4.7 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.27 ( 2H, d, J = 8.8 Hz), 7.95 (2H, d, J = 8.2 Hz), 8.16 (2H, d, J = 8.2 Hz), 8.54 (1H, s). IR (ATR) 1717,
1621 cm ^-1 . MS (CI): m / z 470 ([M + H] ⁺ , 100%). HRMS (CI): calcd for C ₂₈ H ₄₀ NO ₅
([M + H] ⁺ ), 470.2906, found 470.2892.

The transition temperature of the compound synthesized by the method described in Example 2 was measured, and the characteristics as a liquid crystal were evaluated. The transition temperature was measured under a polarizing microscope by placing the sample between two glass plates and placing the sample on a stage with a temperature controller.
The measurement results are summarized in Tables 1 to 3. In the table, Cr represents a crystal, SmC represents a smectic C phase, SmA represents a smectic A phase, SmF represents a smectic F phase, N represents a nematic phase, and Iso represents an isotropic liquid. Each number represents a transition temperature (° C. ).

  Since the characteristics of various functional materials using liquid crystals such as display elements greatly depend on the characteristics of the liquid crystal substance used, it is important to efficiently and quickly synthesize new liquid crystal candidate compounds having excellent characteristics. According to the present invention, a number of imine derivatives that can be novel liquid crystal compounds can be efficiently and rapidly synthesized by solid-phase combinatorial synthesis using a new linker. In addition, since the present invention can be applied to general organic compounds having an imine group even outside the liquid crystal field, application in the field of pharmaceutical development can also be expected.

The steps of preparing the solid phase carrier of the present invention and further synthesizing an imine type liquid crystal compound using the solid phase carrier will be outlined.

Claims (3)

A solid phase carrier for imine compound synthesis, characterized in that a linker comprising an aminophenylalkanoic acid represented by the following general formula (I) is bonded to a support polymer via its carboxyl group.

[In formula (I), n shows the integer of 3-8. ] A method for synthesizing an imine liquid crystal compound represented by the following formula (II) using the solid phase carrier according to claim 1,

[In the formula (II), R ¹ represents OC _x H _{2X + 1} (x represents an integer of 8 to 12), SC _y H _{2y + 1} (y represents an integer of 8 to 12), or O (CH ₂ CH ₂ O) _z C ₂ H ₅ (z represents an integer of 1 to 3), and R ² represents C _n H _{2n + 1} (n represents an integer of 4 to 10). ]
(I) The solid phase carrier and terephthalaldehyde acid represented by the following formula (A) are mixed to perform a dehydration condensation reaction between the amino group of the solid phase carrier and the aldehyde group of terephthalaldehyde acid. Forming an imine bound to a solid support;

(Ii) The imine produced in the step (i) is reacted with an alcohol represented by the following formula (B), an alcohol containing a thiol or an ether bond, and dehydration condensation with the carboxyl group of the imine Conducting the reaction;

[In formula (B), R ¹ represents the same as described above in relation to formula (II). ]
(Iii) and the product of step (ii) and an aniline derivative represented by the following formula (C) are mixed to perform an imine exchange reaction, whereby the compound of formula (II) is converted into the solid phase. Cutting out from the carrier;
A method comprising the steps of:

[In formula (C), R ² represents the same as described above in relation to formula (II). ] A library of imine-type liquid crystal compounds comprising each compound represented by the formula (II) according to claim 2.

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