JPH11158112A - Production of intermediate for synthesis of dibenzosuberyl-and dibenzosuberenyl-based compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain simply a phenethylbenzoic acid and carboxystilbene its precursor and in a large amount by the condensation of a carboxybenzaldehyde with a phenylacetic acid. SOLUTION: The 2-carboxystilbene shown by formula III is obtained by the condensation of a 2-carboxybenzoaldehyde shown by formula I (R1 -R4 are each H, an alkyl, or an alkoxy) with a phenylacetic acid shown by formula II (R5 -R8 are the same as R1 -R4 ) at a molar ratio of 1:1 in the presence of 1-3 equivalent(s), preferably 1.5-2 equivalents or so, per the phenylacetic acid, of an appropriate base (e.g. sodium acetate) by heating/fusing at 180-200 deg.C, preferably 190-195 deg.C or so, for 7-8 h.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 2-carboxystilbenes and 2-phenethylbenzoic acids useful as intermediates for the synthesis of dibenzosuberyl and dibenzosuberenyl compounds. Dibenzosuberyl and dibenzosuberenyl compounds can be used in peptide chemistry studies,
In the field of peptide drug production, it is used as a linker for solid phase peptide synthesis.

[0002]

2. Description of the Related Art In the study of peptides, the chemical synthesis of peptides is very important. This is because many peptide amides have important physiological activities (such as neurotransmitter hormone and gastrointestinal hormone), and it is generally difficult to produce peptides by genetic engineering.

In recent years, the mainstream of chemical synthesis of peptides has been solid phase synthesis using a fluorenylmethyloxycarbonyl (Fmoc) group as a protecting group for the N-α amino group of amino acids. In order to perform solid phase synthesis of a peptide using a peptide synthesizer, it is necessary that specific cleavage be performed between a resin (solid phase resin) and a peptide chain to be extended,
A suitable linker resin is used for this.

Various linker resins for solid phase peptide synthesis have been reported. Examples of such a linker resin include, for example, JP-A-6-145126, M.
Noda et al., J. Org. Chem., 59, 7968 (1994) describes dibenzosuberyl and dibenzosuberenyl compounds.

[0005] However, there has been no report on a production method suitable for simple and large-scale synthesis of 2-phenethylbenzoic acids, which are important synthetic intermediates of dibenzosuberyl and dibenzosuberenyl compounds. That is, JP-A-6-145126, J. Org. Chem., 59, 7968.
According to (1994), as shown in the following chemical reaction equation, phthalic anhydride is melt-reacted with orthomethoxyphenylacetic acid in the presence of a catalytic amount of sodium acetate to obtain methoxybenzylidenephthalide (10). This methoxybenzylidenephthalide (10) was reacted in the presence of Raney nickel at a hydrogen pressure of 4 kg / cm ² at 50 ° C. for 30 hours to perform catalytic reduction cleavage to give 2- (3′-methoxyphenethyl) benzoic acid (1).
1) was obtained (yield 64%). Although this chemical reaction has a relatively high yield, it requires an autoclave for catalytic reduction and requires a long-time reduction reaction, which is unsuitable for industrial mass production.

[0006]

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Further, as shown in the following chemical reaction formula, R.
Ramage et al., Tetrahedron Letters, 34, 6599-6602
According to (1993), methyl-2-methylbenzoate (12)
With N-bromosuccinimide (NBS) in carbon tetrachloride
(13), which is further reacted with triphenyl phosphorus (P (Ph) ₃ ) to form a phosphonium salt (14).
Use Wittig reagent. This (14) is condensed with meta-anisaldehyde in dioxane using DBU (15), and further hydrolyzed to obtain a 2-carboxystilbene compound (16). And a 2-carboxystilbene compound (1
6) was catalytically reduced using H ₂ / Pd—C to obtain 2- (3′-methoxyphenethyl) benzoic acid (11). According to this synthesis route, each reaction has a high yield, but the synthesis step is long and requires a long time for production, and as a result, 2-phenethylbenzoic acid (11) cannot be produced at low cost.

[0008]

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[0009]

Accordingly, an object of the present invention is to provide 2-phenethylbenzoic acids which are important synthetic intermediates of dibenzosuberyl and dibenzosuberenyl compounds, and 2-carboxystilbenes which are precursors thereof. To provide a production method suitable for simple and large-scale synthesis of

[0010]

The present inventors have found that 2-carboxystilbenes can be obtained by a condensation reaction between 2-carboxybenzaldehydes and phenylacetic acids, and have completed the present invention.

That is, the method for producing 2-carboxystilbenes of the present invention is represented by the following general formula (1):

[0012]

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(In the formula (1), R _{1 to} R ₄ each independently represent a hydrogen atom, an alkyl group or an alkoxy group.) And a 2-carboxybenzaldehyde represented by the following formula (2) :

[0014]

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(In the general formula (2), R _{5 to} R ₈ each independently represent a hydrogen atom, an alkyl group or an alkoxy group.) (3):

[0016]

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(In the general formula (3), R _{1 to} R ₈ have the same meanings as in the general formulas (1) and (2),
Each independently represents a hydrogen atom, an alkyl group or an alkoxy group. This is a method for obtaining 2-carboxystilbenes represented by the following formula:

In this production method, from the viewpoint that 2-carboxystilbenes are intermediates for the synthesis of dibenzosuberyl and dibenzosuberenyl compounds used as solid-phase peptide amide linkers, general formula (1) R _{1 to} R ₈ in to (3) each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or 1 to 4 carbon atoms.
It is preferably an alkoxy group of 4.

Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group and a tert-butyl group.
Examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group,
Examples include an n-butoxy group, a sec-butoxy group, and a tert-butoxy group.

In the condensation reaction between the 2-carboxybenzaldehydes of the general formula (1) and the phenylacetic acids of the general formula (2), decarboxylation is carried out by heating and melting both of them in the presence of a suitable base. Progress with it.

2-carboxybenzaldehydes (1)
The molar ratio of phenylacetic acid and phenylacetic acid (2) is usually 1:
1, but can be appropriately changed according to the reactivity, handleability in post-treatment, and the like.

The base to be used is not particularly restricted but includes, for example, inorganic bases such as hydroxides, acetates, carbonates and hydrogen carbonates of alkali metals and alkaline earth metals. Specifically, sodium acetate, potassium acetate,
Sodium carbonate, potassium carbonate, sodium bicarbonate,
Examples include potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, magnesium carbonate and the like. Of these, sodium acetate is preferred because it has good reactivity and is inexpensive.

The amount of the base to be used is not particularly limited, either.
It is about 1 to 3 equivalents, preferably about 1.5 to 2 equivalents. It suffices if anions of phenylacetic acids are generated.

The condensation reaction temperature is usually about 180-200 ° C, preferably about 190-195 ° C. The condensation reaction time is usually about 7 to 8 hours, but the progress and end point of the reaction can be confirmed by trapping and quantifying the carbon dioxide gas generated by the reaction with an aqueous Ba (OH) ₃ solution or the like.

The reaction can be carried out in a suitable organic solvent. Examples of such a solvent include dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone, hexamethylphosphoramide (HMPA), and the like.

After the completion of the reaction, the product (3) is taken out.
It can be performed by a conventional method. For example, after cooling the reaction solution, it is dissolved in water and an organic solvent such as ethyl acetate, the aqueous layer is made acidic with hydrochloric acid or the like, extracted with ethyl acetate, and the product is extracted from the organic layer. The product (3) is usually obtained as a mixture of a cis form and a trans form.

The method for producing 2-phenethylbenzoic acids of the present invention is represented by the following general formula (1):

[0028]

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(In the formula (1), R _{1 to} R ₄ each independently represent a hydrogen atom, an alkyl group or an alkoxy group.) And a 2-carboxybenzaldehyde represented by the following formula (2) :

[0030]

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(In the general formula (2), R _{5 to} R ₈ each independently represent a hydrogen atom, an alkyl group or an alkoxy group.) (3):

[0032]

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(In the general formula (3), R _{1 to} R ₈ have the same meaning as in the general formulas (1) and (2),
Each independently represents a hydrogen atom, an alkyl group or an alkoxy group. To obtain 2-carboxystilbenes, and reducing the 2-carboxystilbenes,
The following general formula (4):

[0034]

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(In the general formula (4), R _{1 to} R ₈ have the same meaning as in the general formula (3), and each independently represents a hydrogen atom, an alkyl group or an alkoxy group.) This is a method for obtaining 2-phenethylbenzoic acids.

That is, in the method for producing 2-phenethylbenzoic acids, the step of obtaining 2-carboxystilbenes is the same as the above-described method for producing 2-carboxystilbenes.

In the present method, 2-carboxystilbenes (3) are reduced. This reduction can be performed by catalytic reduction using a Pd-C catalyst or the like. The used amount of the catalyst such as the Pd-C catalyst is about 5 to 10% by weight based on the 2-carboxystilbenes (3). Further, the catalytic reduction can be performed by dissolving 2-carboxystilbenes (3) in, for example, methanol or the like and in the presence of the catalyst in a stream of hydrogen, and does not require high-pressure hydrogen in an autoclave.

After the completion of the reaction, the product (4) is taken out.
It can be performed by a conventional method. For example, the solvent is distilled off, and a crude crystal of the product (4) is taken out. Thereafter, purification is performed if necessary.

According to the method of the present invention, 2-phenethylbenzoic acids, which are intermediates for synthesizing dibenzosuberyl and dibenzosuberenyl compounds, can be obtained using the above-mentioned 2-carboxy compound, which is also available as a commercial product (Aldrich). From the benzaldehydes (1) and the phenylacetic acids (2), a simple 2
It can be obtained by a step synthesis reaction. These two-step synthesis reactions have good yields and are suitable for mass synthesis.

[0040]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. [Example 1] (Synthesis of 2-carboxy-3'-methoxystilbene (16))

[0041]

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2-carboxybenzaldehyde (17)
5.0 g (33.3 mmol) and 5.534 g (33.3 mmol) of m-methoxyphenylacetic acid (18) were heated and stirred at 190 to 195 ° C. for 8 hours in the presence of 5.404 g (66.6 mmol) of sodium acetate. . Carbon dioxide generated by the reaction was quantified by trapping with an aqueous solution of Ba (OH) ₃ , and the end point of the reaction was confirmed.

After cooling the reaction solution to room temperature, 50 ml of water and 50 ml of ethyl acetate were added and dissolved. 10% HC in water layer
The mixture was acidified (pH: about 4.0) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over anhydrous MgSO ₄ , and the solvent was distilled off to obtain a crude product. The crude product was subjected to silica gel column chromatography, purified using ethyl acetate-hexane (1: 3) as a developing solvent, and 6.40 g of 2-carboxy-3′-methoxystilbene (16) (yield: 76.4). %).

NMR ppm (CDCl ₃ ): 3.83
_{(3H, s, OCH 3)} , 6.84 (1H, q, C-
4'H, J = 8.1 Hz, J = 2.7 Hz, J = 0.8
Hz), 7.02 (1H, d, olefin, J = 15.
9 Hz), 7.08 (1H, dd, C-2'H, J =
2.7 Hz, J = 2.4 Hz), 7.16 (1H, d,
C-6′H, J = 7.8 Hz), 7.28 (1H, t,
C-5'H, J = 8.1 Hz), 7.36 (1H, d
t, C-4H, J = 7.6 Hz, J = 1.1 Hz),
7.57 (1H, dt, C-5H, J = 7.8 Hz, J
= 1.6 Hz), 7.74 (1H, d, C-6H, J =
7.6 Hz), 8.06 (1H, d, olefin, J =
15.9 Hz), 8.09 (1H, dd, C-3H, J
= 7.6Hz, J = 1.6Hz)

Elemental analysis: C ₁₆ H ₁₄ O ₃ Theoretical value: C: 75.58, H: 5.55 Analysis value: C: 75.42, H: 5.29

Example 2 (Synthesis of 2- (3′-methoxyphenethyl) benzoic acid (11))

[0047]

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The 2-carboxy-3 ′ obtained in Example 1
1.14 g (4.5 mmol of methoxystilbene (16)
l) was dissolved in 30 ml of methanol, and 5% Pd-C 1
Then, a catalytic reduction reaction was carried out at room temperature for 1 hour in a hydrogen stream. The solvent was distilled off to obtain a crude crystal. The crude crystals were recrystallized from ethyl acetate-hexane to give colorless needle crystals.
-(3'-methoxyphenethyl) benzoic acid (11) 0.9
8 g (yield: 85.0%) was obtained.

NMR ppm (CDCl ₃ ): 2.92
(2H, t, methylene, J = 7.8 Hz), 2.34
(2H, t, methylene, J = 7.8 Hz), 3.78
_{(3H, s, OCH 3)} , 6.74 (1H, dd, C-
4'H, J = 7.8 Hz, J = 1.2 Hz), 6.78
(1H, t, C-2′H, J = 1.2 Hz), 6.83
(1H, d, C-6'H, J = 7.8 Hz), 7.19
(1H, t, C-5'H, J = 7.8 Hz), 7.25
(1H, dd, C-3H, J = 7.5 Hz, J = 1.2
Hz), 7.32 (1H, dt, C-5H, J = 7.5)
(t) Hz, J = 1.2 (d) Hz), 7.47 (1H, d
t, C-4H, J = 7.5 (t) Hz, J = 1.5 (d) H
z), 8.08 (1H, dd, C-6H, J = 7.5H)
z, J = 1.2 Hz)

Elemental analysis: C ₁₆ H ₁₆ O ₃ Theoretical value: C: 74.98, H: 6.29 Analysis value: C: 74.99, H: 6.46

Reference Example 2- (3 ′) obtained in Example 2
-Methoxyphenethyl) benzoic acid (11) can be cyclized to be converted to a dibenzosuberyl compound (19) by treating with PPA (polyphosphoric acid) as shown in the following scheme. The four-step reaction can lead to a dibenzosuberyl-based linker (23). Further, the dibenzosuberyl-based linker resin (24) can be bound to the resin.

[0052]

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Further, a dibenzosuberyl compound (19)
Can be converted to a dibenzosuberenyl-based compound (25) as shown in the following scheme, and can be converted to a dibenzosuberenyl-based linker resin (26) by the same reaction as described above.

[0054]

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(Description of Abbreviations) PTS: paratoluenesulfonic acid HOBT: N-hydroxybenzotriazole PyBop: benzotriazol-1-yl-oxy-
Tris-pyrrolidino-phosphonium-hexafluorophosphate NMM: N-methylmorpholine TGS: Tentagel-S TEA: Triethylamine

[0056]

According to the production method of the present invention, as described above, two-carboxybenzaldehydes and phenylacetic acids which are available are synthesized by a simple two-step synthesis reaction.
Phenethyl benzoic acids can be obtained. These two
The synthesis reaction of the step has a good yield and is suitable for mass synthesis. Therefore, the production method of the present invention is useful as a simple and inexpensive industrial production method of 2-phenethylbenzoic acids. According to the present invention, 2-phenethylbenzoic acids, which are important synthetic intermediates for dibenzosuberyl and dibenzosuberenyl compounds, are provided at low cost, so that dibenzosuberyl and dibenzosuberenyl compounds can also be obtained at low cost.
As a result, it is considered that the present invention can greatly contribute to the field of peptide chemistry research and peptide drug production.

Claims (3)

[Claims] 1. The following general formula (1): (In the general formula (1), R _{1 to} R ₄ each independently represent a hydrogen atom, an alkyl group or an alkoxy group.) And a 2-carboxybenzaldehyde represented by the following general formula (2): 2] (In the general formula (2), R _{5 to} R ₈ each independently represent a hydrogen atom, an alkyl group or an alkoxy group.) The phenylacetic acid represented by the general formula (3) : (In the general formula (3), R _{1 to} R ₈ have the same meaning as in the general formulas (1) and (2), and each independently represents a hydrogen atom, an alkyl group or an alkoxy group.) To obtain 2-carboxystilbenes represented by
A method for producing 2-carboxystilbenes. 2. The following general formula (1): (In the general formula (1), R _{1 to} R ₄ each independently represent a hydrogen atom, an alkyl group or an alkoxy group.) And a 2-carboxybenzaldehyde represented by the following general formula (2): 5] (In the general formula (2), R _{5 to} R ₈ each independently represent a hydrogen atom, an alkyl group or an alkoxy group.) The phenylacetic acid represented by the general formula (3) : (In the general formula (3), R _{1 to} R ₈ have the same meaning as in the general formulas (1) and (2), and each independently represents a hydrogen atom, an alkyl group or an alkoxy group.) To obtain 2-carboxystilbenes represented by
The 2-carboxystilbenes are reduced to give the following general formula (4): (In the general formula (4), R _{1 to} R ₈ have the same meaning as in the general formula (3), and each independently represents a hydrogen atom, an alkyl group or an alkoxy group.)
A method for producing 2-phenethylbenzoic acids, which obtains phenethylbenzoic acids. 3. The condensation reaction between a 2-carboxybenzaldehyde represented by the general formula (1) and a phenylacetic acid represented by the general formula (2) is performed in the presence of sodium acetate. Or the method of 2.