JP2004244417A - Methods for producing 5-formyl-2-methoxybenzoic acid and its ester and intermediate for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing 5-formyl-2-methoxybenzoic acid which is a raw material for an N-benzyldioxothiazolidylbenzamide derivative useful for treating diabetes and hyperlipemia, highly safe and useful for industrially obtaining the 5-formyl-2-methoxybenzoic acid with high purity at a low cost in a large amount, and to provide a method for producing 5-formyl-2-methoxybenzoate esters. <P>SOLUTION: The method for producing the 5-formyl-2-methoxybenzoic acid comprises reacting 5-chloromethyl-2-methoxybenzoic acid with hexamethylenetetramine to obtain 1-[(3-carboxy-4-methoxy)-phenylmethyl]hexamethylenetetraminium chloride and then hydrolyzing the obtained chloride. The method for producing the 5-formyl-2-methoxybenzoate ester comprises esterifying the 5-formyl-2-methoxybenzoic acid according to an ordinary procedure. Thus, the 5-formyl-2-methoxybenzoic acid is industrially advantageously produced with the high purity, and further the 5-formyl-2-methoxybenzoate esters are produced with high purities. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

  The present invention provides a process for industrially and safely obtaining 5-formyl-2-methoxybenzoic acid and its esters useful as a raw material for the production of pharmaceuticals, and a novel 1-chloride, which is an intermediate thereof. [(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium.

  General formula (5)

［式中、Ｒ^１，Ｒ^２は同一又は異なって、水素、炭素数１〜４の低級アルキル基、炭素数１〜３の低級アルコキシ基、炭素数１〜３の低級ハロアルキル基、炭素数１〜３の低級ハロアルコキシ基、ハロゲン原子、水酸基、ニトロ基、炭素数１〜３の低級アルキル基で置換されていても良いアミノ基、及びヘテロ環を、あるいはＲ^１とＲ^２が結合しメチレンジオキシ基を、Ｒ^３は炭素数１〜３の低級アルコキシ基、水酸基、ハロゲン原子を、点線は実線との組み合わせで二重結合又は単結合］
で表されるＮ−ベンジルジオキソチアゾリジニルメチルベンズアミド誘導体は優れた血糖低下及び脂質低下作用を有する化合物として公知である（特許文献１及び非特許文献１）。このようなＮ−ベンジルジオキソチアゾリジニルメチルベンズアミド誘導体の製造には出発原料の一つに５−ホルミル−２−メトキシ安息香酸エステル類が用いられている。

[Wherein, R ¹ and R ² are the same or different and are hydrogen, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 3 carbon atoms, a lower haloalkyl group having 1 to 3 carbon atoms, 1 carbon atom; A lower haloalkoxy group, a halogen atom, a hydroxyl group, a nitro group, an amino group which may be substituted with a lower alkyl group having 1 to 3 carbon atoms, and a heterocycle, or a methylene group wherein R ¹ and R ² are bonded to each other. A dioxy group, R ³ is a lower alkoxy group having 1 to ³ carbon atoms, a hydroxyl group, a halogen atom, and a dotted line is a double bond or a single bond in combination with a solid line]
The N-benzyldioxothiazolidinylmethylbenzamide derivative represented by is known as a compound having an excellent blood glucose lowering and lipid lowering action (Patent Document 1 and Non-Patent Document 1). For the production of such N-benzyldioxothiazolidinylmethylbenzamide derivatives, 5-formyl-2-methoxybenzoic acid esters are used as one of the starting materials.

  Further, 5-formyl-2-methoxybenzoic acid is used as a raw material for producing a substituted phenylpropionic acid derivative as a peroxisome proliferator-activated receptor (PPAR) α agonist (Patent Document 2).

  It is known that such a raw material compound 5-formyl-2-methoxybenzoic acid and ester can be obtained, for example, by the following method.

  1) A method of reacting 2-methoxybenzoic acid with hexamethylenetetramine in trifluoroacetic acid (hereinafter abbreviated as "TFA"), followed by hydrolysis to C-formylation (for example, see Patent Document 3) .

  2) A method for producing 5-formylsalicylic acid or an ester thereof by halomethylating salicylic acid or an ester thereof and then reacting it with hexamethylenetetramine to obtain a hexamethylenetetraminium chloride derivative, and hydrolyzing the derivative (for example, Patent Document 1) 4).

  Of these conventional methods, the method 1) is unsuitable for mass production due to the use of an expensive and extremely strong organic acid such as TFA, and the method 2) is a method in which a formyl group sensitive to oxidation is retained. It was necessary to methylate the 2-position hydroxyl group of 5-formylsalicylic acid or its ester, and none of these methods was industrially advantageous.

Therefore, the present inventors have made various studies to develop an industrial production method of 5-formyl-2-methoxybenzoic acid esters, and as a result, have found that 1-[(3-alkoxycarbonyl-4-methoxy) phenylmethyl chloride is used. ] An advantageous production method using hexamethylenetetraminium as a production intermediate was found and disclosed (Patent Document 5). Thereafter, the manufacturing method was improved and improved in order to further improve safety, operability and quality.
JP-A-9-48771 WO00 / 75103 pamphlet Japanese Patent No. 2852659 JP-A-48-19539 WO01 / 66549 pamphlet Bioorg. Med. Chem. Lett. , 1999, 9, p. 533.

  The present invention relates to an N-benzyldioxothiazolidinylmethylbenzamide derivative represented by the above general formula (5) and a peroxisome proliferator-activated receptor (PPAR) α which are useful for the treatment of diabetes and hyperlipidemia. In producing a substituted phenylpropionic acid derivative as an agonist, it is intended to provide a method for producing 5-formyl-2-methoxybenzoic acid and its esters, which are raw materials for producing the derivative, in a safe, excellent in operability and with high purity. It is the purpose.

  The inventors of the present invention have conducted repeated studies to obtain 5-formyl-2-methoxybenzoic acid and esters thereof in a safe and industrially high purity, and as a result, have found that 1-[(3-carboxy-4-methoxy) chloride is obtained. The inventors have found that the above problem can be solved by using [phenylmethyl] hexamethylenetetraminium as a production intermediate, and have completed the present invention.

  That is, the present invention is based on the following (I) to (IV).

  (I) Chemical formula (1)

で表される５−クロロメチル−２−メトキシ安息香酸にヘキサメチレンテトラミンを反応させて得られる化学式（２）

Chemical formula (2) obtained by reacting hexamethylenetetramine with 5-chloromethyl-2-methoxybenzoic acid represented by the following formula:

で表される塩化１−［（３−カルボキシ−４−メトキシ）フェニルメチル］ヘキサメチレンテトラミニウムを加水分解することを特徴とする化学式（３）

1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride represented by the following formula:

で表される５−ホルミル−２−メトキシ安息香酸の製造方法。

A method for producing 5-formyl-2-methoxybenzoic acid represented by the formula:

  (II) Chemical formula (1)

で表される５−クロロメチル−２−メトキシ安息香酸にヘキサメチレンテトラミンを反応させて得られる化学式（２）

Chemical formula (2) obtained by reacting hexamethylenetetramine with 5-chloromethyl-2-methoxybenzoic acid represented by the following formula:

で表される塩化１−［（３−カルボキシ−４−メトキシ）フェニルメチル］ヘキサメチレンテトラミニウムを加水分解後、エステル化することを特徴とする一般式（４）

1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride represented by the formula: being esterified after hydrolysis.

（式中、Ｒは低級アルキル基を示す）で表される５−ホルミル−２−メトキシ安息香酸エステルの製造方法。

(Wherein, R represents a lower alkyl group). A method for producing 5-formyl-2-methoxybenzoate.

  (III) Chemical formula (1)

で表される化合物にへキサメチレンテトラミンを酢酸水溶液中で反応させることを特徴とする化学式（３）

Wherein hexamethylenetetramine is reacted with a compound represented by the formula in an aqueous acetic acid solution:

で表される５−ホルミル−２−メトキシ安息香酸の製造方法。

A method for producing 5-formyl-2-methoxybenzoic acid represented by the formula:

  (IV) Chemical formula (2)

で表される塩化１−［（３−カルボキシ−４−メトキシ）フェニルメチル］ヘキサメチレンテトラミニウムであることを特徴とする５−ホルミル−２−メトキシ安息香酸及びそのエステルの製造中間体、を提供するものである。

1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride represented by the formula: 5-formyl-2-methoxybenzoic acid and its production intermediate Is what you do.

  That is, the present invention reacts 5-chloromethyl-2-methoxybenzoic acid (chemical formula (1)) obtained by a known method with hexamethylenetetraoamine to form 1-[(3-carboxy-4-methoxy) chloride. [Phenylmethyl] hexamethylenetetraminium (Chemical formula (2)), and then hydrolyzed to produce 5-formyl-2-methoxybenzoic acid (Chemical formula (3)) with high purity and advantage industrially. By esterification by a usual method, it is possible to industrially produce high-purity 5-formyl-2-methoxybenzoate (general formula (4)). Further, the present invention provides a novel compound 1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride (chemical formula (2)) as a production intermediate therefor.

  According to the present invention, since 5-chloromethyl-2-methoxybenzoic acid (chemical formula (1)) is used as a starting material, it is more chemically stable than that obtained when its ester is used as a starting material, and the reaction time is lower. This is advantageous in that it has excellent operability. Then, a novel intermediate 1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride (chemical formula (2)) obtained by reaction with hexamethylenetetramine can be obtained safely and with high purity. Therefore, it is industrially advantageous. In producing 5-formyl-2-methoxybenzoic acid (chemical formula (3)), 1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride (chemical formula (2)) is produced. After the reaction, the resulting compound can be obtained in good yield by decomposition, but can also be produced by heating the starting compound (chemical formula (1)) in an aqueous acetic acid solution in the presence of hexamethylenetetramine, which is industrially advantageous. A method is also provided.

  In producing N-benzyldioxothiazolidylmethylbenzamide derivatives and substituted phenylpropionic acid derivatives as peroxisome proliferator-activated receptor (PPAR) α agonists useful for the treatment of diabetes and hyperlipidemia, A novel 1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride was found as a new production intermediate for producing 5-formyl-2-methoxybenzoic acid and esters as starting materials. Was. By using this, there is provided an industrially advantageous method by which 5-formyl-2-methoxybenzoic acid and its esters can be produced safely, with good operability and with high purity.

  The starting compound 5-chloromethyl-2-methoxybenzoic acid represented by the chemical formula (1) can be prepared by a known method (for example, R. Quellet et al., Bull. Soc. Chem. Fr., 1969, (5), 1698). .) Is easily synthesized.

  1-[(3-Carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride represented by the chemical formula (2) is obtained by dissolving the raw material compound of the chemical formula (1) in an organic solvent if necessary. If methylenetetramine is added to a solution in which the methylenetetramine is dissolved or suspended in an organic solvent with stirring, then heated and stirred and then cooled, crystals can be obtained with a high yield.

  The organic solvent to be used is not particularly limited, but for example, 10-fold to 15-fold amount of 2-propanol can be mentioned.

  The amount of hexamethylenetetramine used in the reaction is preferably 1 to 3 moles relative to the raw material compound of the chemical formula (1).

  The reaction is carried out with stirring between room temperature and the boiling point of the solvent for 2 to 5 hours. After completion of the reaction, the reaction mixture is cooled, and the precipitated crystals are collected by filtration and washed with an organic solvent, to give 1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride of the formula (2) with high purity. can get. At this time, the raw material compound of the chemical formula (1) used for the reaction does not need to be particularly dried.

  The obtained 1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride of the chemical formula (2) can be easily hydrolyzed as it is, without particular drying, to form the 5-formyl- It can be 2-methoxybenzoic acid.

  Although the conditions for the hydrolysis are not particularly limited, for example, 50% of 2 to 3 times the volume of 1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride of the chemical formula (2) is used. (V / v) Heating and stirring may be performed at 90 ° C to 110 ° C using an acetic acid aqueous solution. The hydrolysis reaction is completed in 2 to 3 hours. The reaction solution is cooled to be acidic, and the crystals are collected by filtration, washed with water and dried to obtain 5-formyl-2-methoxybenzoic acid of the above formula (3).

  The 5-formyl-2-methoxybenzoic acid represented by the chemical formula (3) is obtained by reacting the compound of the chemical formula (1) with hexamethylenetetramine in an aqueous acetic acid solution at room temperature to 110 ° C. The production intermediate of the chemical formula (2) can also be obtained without isolation. The amount of hexamethylenetetramine used in the reaction is preferably 2 to 3 times the mole of the compound of the formula (1). The amount of the acetic acid aqueous solution is preferably 3 to 5 times the amount of the compound of the formula (1). In addition, by using an aqueous acetic acid solution of 50% (v / v) as the aqueous acetic acid solution, it is possible to obtain 5-formyl-2-methoxybenzoic acid with high purity only by filtering the crystals by making the reaction solution acidic. It is preferable in terms of operability.

  To produce the 5-formyl-2-methoxybenzoic acid ester represented by the general formula (4), the 5-formyl-2-methoxybenzoic acid (chemical formula (3)) obtained as described above is used. It can be easily obtained by heating in a usual manner, that is, heating under an acid catalyst (for example, acid chloride) in a lower alcohol.

  In the general formula (4), the lower alkyl group is a methyl group, an ethyl group or a propyl group, and is preferably a methyl group.

  The 5-formyl-2-methoxybenzoic acid and its ester obtained by the present invention are useful for treating N-benzyldioxothiazolidinyl which is useful for the treatment of diabetes and hyperlipidemia by the following known methods. A methylbenzamide derivative can be obtained.

  Next, the present invention will be specifically described with reference examples and examples, but the present invention is not limited by these examples.

<Reference example> 5-Chloromethyl-2-methoxybenzoic acid After dissolving 25.0 g of paraformaldehyde in 274 mL of concentrated hydrochloric acid, 76.1 g of 2-methoxybenzoic acid was added, and hydrogen chloride was stirred at 30 to 35 ° C for 6 hours for 6 hours. Gas was blown. After completion of the reaction, the mixture was stirred overnight at 19 to 20 ° C under water cooling, 457 mL of water was added to the reaction solution at 19 to 26 ° C, and the mixture was stirred at 21 to 22 ° C for 30 minutes. The precipitated crystals were collected by filtration and washed with 91 mL of water.

  The title compound was obtained with a wet yield of 115.9 g (100% yield, used wet in the next step).

Example 1 1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride A solution obtained by suspending 21.0 g (1.50 mol) of hexamethylenetetramine in 63.1 mL of 2-propanol was used. The mixture was heated to 5 ° C., and a solution prepared by dissolving 23.1 g (wet) of 5-chloromethyl-2-methoxybenzoic acid (equivalent to 0.100 mol) in 201 mL of 2-propanol at room temperature was added at 59 to 62 ° C. for 39 minutes. . After the introduction, the mixture was stirred at 62 to 64 ° C for 1 hour, and further refluxed for 1 hour. After cooling, the precipitated crystals were collected by filtration at 61 ° C and washed with 40 mL of 2-propanol. The title compound was obtained with a wet weight of 31.8 g.

The wet crystals were blown and dried overnight at 40 ° C. for instrumental analysis to obtain 28.3 g (83.0%) of 1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 3.87 (3H, s), 4.08 (2H, s), 4.41 to 5.07 (12H, m), 7.26 (1H, d, J = 8.8 Hz), 7.62 (1H, dd, J = 2.4, 8.8 Hz), 7.76 (1H, d, J = 2.4 Hz).
MS (FAB +): m / e 305 [M-Cl] ⁺ .
_{HR-MS (m / e)} : Calculated _{C 15 H 21 N 4 O 3} : 305.1614
Obtained: 305.1613.

<Example 2> 5-formyl-2-methoxybenzoic acid 15.2 g of 1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride synthesized in the same manner as in Example 1 (wet) (0 Was added to 90 mL of 50% acetic acid, and the mixture was heated to 98 ° C. while distilling off the solvent, and then stirred at 98 to 99 ° C. for 2 hours. After 90 mL of water was added to the reaction solution, 6 mol / L hydrochloric acid was added to adjust the pH to 1.7, and the mixture was stirred at 18 to 25 ° C for 30 minutes, and then the precipitated crystals were collected by filtration. After washing with 40 mL of water and drying at 40 ° C. overnight, 10.4 g of 5-formyl-2-methoxybenzoic acid (57.8% based on 2-methoxybenzoic acid) was obtained.
Elemental analysis: As C ₉ H ₈ O ₄ Calculated values: C 60.00%, H 4.48%
Obtained: C 59.81%, H 4.44%.
MS (EI +): m / e 180 [M] ⁺ .
HR-MS (m / e): Calculated for C ₉ H ₈ O ₄ : 180.0423
Obtained: 180.0439.
mp. 174-175 ° C.

<Example 3> 5-Formyl-2-methoxybenzoic acid 35.0 g (0.250 mol) of hexamethylenetetramine was dissolved in 84 mL of 50% acetic acid, and 21.8 g (wet) of 5-chloromethyl-2-methoxybenzoic acid was dissolved. (Equivalent to 0.100 mol) was charged at 22 to 26 ° C. After the introduction, the mixture was stirred at 22 to 27 ° C for 1 hour, and further refluxed for 1 hour. After completion of the reaction, 84 mL of water and 42 mL of concentrated hydrochloric acid were added, and the mixture was stirred at 20 to 25 ° C for 30 minutes. The precipitated crystals were collected by filtration, washed with 20 mL of water, and dried by blowing air at 40 ° C. overnight to obtain 11.3 g (62.8% of 2-methoxybenzoic acid) of 5-formyl-2-methoxybenzoic acid.
mp. 172-175 ° C

<Example 4> 1-[(3-Carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride First step: Dissolve 50.1 g of 5-chloromethyl-2-methoxybenzoic acid paraformaldehyde in 548 mL of concentrated hydrochloric acid. Thereafter, 152.2 g (1.00 mol) of 2-methoxybenzoic acid was charged, and hydrogen chloride gas was blown in at 30 to 35 ° C for 6 hours with stirring. After completion of the reaction, 913 mL of water was added to the reaction solution at 20 to 26 ° C, and the mixture was stirred at 22 to 24 ° C for 30 minutes. The precipitated crystals were collected by filtration and washed with 183 mL of water.

  The title compound was obtained with a wet yield of 230.2 g (100% yield was used as is in the next step).

Second step: 1-[(3-Carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride 230.0 g (wet) (equivalent to 1.00 mol) of 5-chloromethyl-2-methoxybenzoic acid in 2-propanol The solution dissolved in 2006 mL was added to a solution of 210.3 g of hexamethylenetetramine suspended in 631 mL of 2-propanol at 20 to 24 ° C, and the mixture was refluxed at 20 to 28 ° C for 1 hour and further refluxed for 1 hour. After cooling and stirring at 23 to 30 ° C. for 1 hour, the precipitated crystals were collected by filtration and washed with 401 mL of 2-propanol.

  The title compound was obtained with a wet yield of 504.0 g (100% yield was used as is in the next step).

Third step: 5-Formyl-2-methoxybenzoic acid 13.8% of 1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride (equivalent to 1.00 mol) is added to 900 mL of 50% acetic acid. After evaporating the solvent to 98 ° C. while distilling off the solvent, the mixture was stirred at 98 ° C. for 2 hours. 900 mL of water was added, the pH was adjusted to 2 with 6 mol / L hydrochloric acid, and the mixture was stirred at 22 to 25 ° C for 30 minutes. The precipitated crystals were collected by filtration, washed with 400 mL of water, and dried by blowing at 40 ° C. overnight.

  The title compound was obtained in a yield of 104.5 g (58.0%).

  mp. 173-175 ° C.

Fourth step: Methyl 5-formyl-2-methoxybenzoate 104.1 g of 5-formyl-2-methoxybenzoic acid was suspended in 520 mL of methanol, and 90.7 g of acetyl chloride was added dropwise at 24 to 35 ° C. Stirred at 36 ° C. for 5 hours. After 780 mL of water was added dropwise to the reaction solution at 28 to 31 ° C, the pH was adjusted to 7 with a 2 mol / L aqueous sodium hydroxide solution, and the mixture was stirred at 24 to 25 ° C for 30 minutes. The precipitated crystals were collected by filtration, washed with 780 mL of water, and dried by blowing air at 40 ° C. overnight.

  The title compound was obtained in a yield of 99.2 g (88.4%).

  mp. 86-87 ° C.

  INDUSTRIAL APPLICABILITY The present invention is capable of industrially and safely producing 5-formyl-2-methoxybenzoic acid and its esters useful as a raw material for producing pharmaceuticals.

Claims (4)

Chemical formula (1)

Chemical formula (2) obtained by reacting hexamethylenetetramine with 5-chloromethyl-2-methoxybenzoic acid represented by the following formula:

1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride represented by the following formula:

A method for producing 5-formyl-2-methoxybenzoic acid represented by the formula: Chemical formula (1)

Chemical formula (2) obtained by reacting hexamethylenetetramine with 5-chloromethyl-2-methoxybenzoic acid represented by the following formula:

1-[(3-carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride represented by the formula: being esterified after hydrolysis.

(Wherein, R represents a lower alkyl group). A method for producing 5-formyl-2-methoxybenzoate. Chemical formula (1)

Chemical formula (3) characterized by reacting hexamethylenetetramine with 5-chloromethyl-2-methoxybenzoic acid represented by the following formula in an aqueous acetic acid solution.

A method for producing 5-formyl-2-methoxybenzoic acid represented by the formula: Chemical formula (2)

1-[(3-Carboxy-4-methoxy) phenylmethyl] hexamethylenetetraminium chloride represented by the formula: 5-formyl-2-methoxybenzoic acid and an intermediate thereof for producing an ester thereof.