JP4078328B2 - Method for producing 2-oxindole derivatives - Google Patents

Description

The present invention relates to a method for producing a 2-oxindole derivative, and more particularly to a method for producing a high-purity compound by crystallization from an alkaline solution during crystal extraction of the compound.

2-Oxindole derivatives are used as intermediates for various pharmaceuticals, agricultural chemicals and dyes.

の合成中間体として知られている。
For example, adibendan having 2-oxindole skeleton as a cardiotonic agent for congestive heart disease

It is known as a synthetic intermediate.

  Tyrosine kinase inhibitors useful for the regulation of various epidermal growth have also been produced from 2-oxindole derivatives.

（式中、Ｒはアルキル、アルコキシ、アリール、フェノキシ、ハロゲン、または水素を表す。）
で示される方法｛J.Chem.Edu.70,332(1993) D.S.Soriano ｝により合成できることはすでに公知である。
当該方法によれば、イサチンが脱水メタノール中でヒドラジン水和物と反応して反応混合物の中で懸濁状のヒドラゾン体を形成する。この中間体は反応混合物
から分離され、再結等で生成される。この中間体を、脱水エタノール中で強塩基、例えばナトリウムエトキシドの存在下、Wolff-Kischnar還元をする事により２−オキシインドール誘導体に変換される。
こうして得られた２−オキシインドール誘導体は、一般的に反応液を濃縮後に酸性水中で晶析させる事により粗結晶を得、更に各種溶媒中で再結処理を施して得られる。
例えばＵＳ ４７３０００４では、反応液を濃縮後に酸性水で割り出した結晶をエーテルで洗浄後、ＥｔＯＨで再結精製して２−オキシインドール誘導体を得ている。
ＵＳ ４１６００３２では、同じく反応液を濃縮後に酸性水中で晶析させ、得られた結晶をクロロホルム／エーテルで再結晶精製して目的物を得ている。
J.Chem.Edu.70,332(1993) ＵＳ ４７３０００４ ＵＳ ４１６００３２ The 2-oxindole derivative has the following reaction formula:

(In the formula, R represents alkyl, alkoxy, aryl, phenoxy, halogen, or hydrogen.)
It is already known that it can be synthesized by the method {J. Chem. Edu. 70, 332 (1993) DSSoriano}.
According to this method, isatin reacts with hydrazine hydrate in dehydrated methanol to form a suspended hydrazone in the reaction mixture. This intermediate is separated from the reaction mixture and produced by recrystallization or the like. This intermediate is converted to a 2-oxindole derivative by Wolff-Kischnar reduction in dehydrated ethanol in the presence of a strong base such as sodium ethoxide.
The 2-oxindole derivative thus obtained is generally obtained by concentrating the reaction solution and then crystallizing it in acidic water to obtain a crude crystal, followed by recrystallization in various solvents.
For example, in US 4730004, a crystal obtained by concentrating a reaction solution and then indexed with acidic water is washed with ether and then recrystallized and purified with EtOH to obtain a 2-oxindole derivative.
In US 4160032, the reaction solution is similarly concentrated and crystallized in acidic water, and the obtained crystals are purified by recrystallization with chloroform / ether to obtain the desired product.
J. Chem. Edu. 70,332 (1993) US 4730004 US 4160032

In the above reaction, various by-products are generated for the reason that dimerization of raw materials, intermediates, and products easily occurs. Since polar and nonpolar compounds coexist, the purification method becomes extremely complicated by the usual method, which causes a reduction in the purification yield. According to the method described in the above patent, these by-product compounds cannot be removed to obtain a 2-oxindole derivative having sufficient purity. Furthermore, coloring or the like is also generated due to oxidation or the like, and since this coloring is brought into the crystal of the 2-oxindole derivative, a decoloring operation is necessary, and there are many problems such as a complicated extraction operation, which is a disadvantage in industrial production. ing.

As a result of diligent research to solve these disadvantages of the prior art, the present inventors have found a method for obtaining a highly purified final product with a high yield by a very simple operation, and have led to the present invention. It was.

[式中Ｒ１は、水素原子、アルキル基、アルコキシ基、アルケニル基、アルキニル基、アリール基、アミノ基、アリールオキシ基、アミド基、ウレイド基、アリルオキシ基、アシル基（ここで用いられるアシル基とは、カルボン酸のカルボキシル基から−ＯＨを除いて誘導される基だけでなく、硫酸、硝酸、燐酸のような無機酸もしくはカルバミン酸、炭酸、スルホン酸、ホスホン酸のような有機酸から−ＯＨを除いて誘導された基も含む、広義の酸から−ＯＨを除いて誘導された基の意味である。）、カルバモイル基、チオール基、アルキルあるいはアリールチオ基、アルキルあるいはアリールスルファモイル基、スルホンアミド基、アルキルあるいはアリールオキシスルホニルアミノ基、アルキルあるいはアリールオキシカルボニルアミノ基、Ｃ３―Ｃ６シクロアルキル基、アラルキル基、Ｏ原子又はＳ原子あるいはＮ原子を少なくとも１個含む５員もしくは６員複素芳香環、Ｏ原子又はＳ原子あるいはＮ原子を少なくとも１個含む５員もしくは６員複素飽和環を表す。
式中Ｒ２、Ｒ３、Ｒ４、Ｒ５はそれぞれ同一または異なって、水素原子、ハロゲン、アミノ基、トリフルオロメチル基、アルキル基、アルコキシ基、アルケニル基、アルキニル基、アリール基、アミノ基、アリールオキシ基、アミド基、ウレイド基、アシル基（ここで用いられるアシル基とは、カルボン酸のカルボキシル基から−ＯＨを除いて誘導される基だけでなく、硫酸、硝酸、燐酸のような無機酸もしくはカルバミン酸、炭酸、スルホン酸、ホスホン酸のような有機酸から−ＯＨを除いて誘導された基も含む、広義の酸から−ＯＨを除いて誘導された基の意味である。）、ヒドロキシ基、カルバモイル基、チオール基、アルキルあるいはアリールチオ基、アルキルあるいはアリールスルファモイル基、スルホンアミド基、アルキルあるいはアリールオキシスルホニルアミノ基、アルキルあるいはアリールオキシカルボニルアミノ基、Ｃ３―Ｃ６シクロアルキル基、アラルキル基、Ｏ原子又はＳ原子あるいはＮ原子を少なくとも１個含む５員もしくは６員複素芳香環、Ｏ原子又はＳ原子あるいはＮ原子を少なくとも１個含む５員もしくは６員複素飽和環を表す。また、Ｒ２とＲ３もしくはＲ３とＲ４もしくはＲ４とＲ５は互いに結合して環を形成してもよい。]で表されるイサチン誘導体を還元することにより得られる下記一般式（２）

[式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５は前記と同義である。]で表される２−オキシインドール誘導体の反応液のｐＨを７．５〜１３に調整し、生成した２−オキシインドール誘導体を晶析させて取り出すことを特徴とする２−オキシインドール誘導体の製造方法を提供するものである。 The following general formula (1)

[Wherein R1 represents a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, an amino group, an aryloxy group, an amide group, a ureido group, an allyloxy group, an acyl group (the acyl group used herein) Is not only a group derived by removing -OH from the carboxyl group of the carboxylic acid, but also -OH from inorganic acids such as sulfuric acid, nitric acid, phosphoric acid or organic acids such as carbamic acid, carbonic acid, sulfonic acid, phosphonic acid. Meaning a group derived by removing -OH from an acid in a broad sense, including a group derived by removing), carbamoyl group, thiol group, alkyl or arylthio group, alkyl or arylsulfamoyl group, sulfone Amido group, alkyl or aryloxysulfonylamino group, alkyl or aryloxycarbonylamino Group, C3-C6 cycloalkyl group, aralkyl group, 5-membered or 6-membered heteroaromatic ring containing at least one O atom or S atom or N atom, 5-membered containing at least one O atom, S atom or N atom or Represents a 6-membered hetero saturated ring.
In the formula, R2, R3, R4 and R5 are the same or different and each represents a hydrogen atom, halogen, amino group, trifluoromethyl group, alkyl group, alkoxy group, alkenyl group, alkynyl group, aryl group, amino group, aryloxy group , an amido group, a ureido group, the acyl group to be used in the a sill group (wherein, not only the group derived by removing the -OH from the carboxyl group of a carboxylic acid, sulfuric acid, nitric acid, or inorganic acids such as phosphoric acid It means a group derived by removing -OH from an acid in a broad sense, including groups derived from organic acids such as carbamic acid, carbonic acid, sulfonic acid, and phosphonic acid by removing -OH. , Carbamoyl group, thiol group, alkyl or arylthio group, alkyl or arylsulfamoyl group, sulfonamido group, alkyl Is an aryloxysulfonylamino group, alkyl or aryloxycarbonylamino group, C3-C6 cycloalkyl group, aralkyl group, 5- or 6-membered heteroaromatic ring containing at least one O atom, S atom or N atom, O atom or A 5-membered or 6-membered heterosaturated ring containing at least one S atom or N atom is represented. R2 and R3, R3 and R4, or R4 and R5 may be bonded to each other to form a ring. The following general formula (2) obtained by reducing the isatin derivative represented by

[Wherein R 1, R 2, R 3, R 4, R 5 have the same meanings as described above. The pH of the reaction solution of the 2-oxindole derivative represented by the formula is adjusted to 7.5 to 13, and the produced 2-oxindole derivative is crystallized and taken out. A method is provided.

According to the method of the present invention, a high-purity 2-oxindole derivative, which is difficult to produce by a general method, can be produced with high yield and high purity by a simple operation. It is useful as an industrial production method of 2-oxindole derivatives that are important raw materials for pharmaceuticals and the like, and can greatly reduce the production cost.

The production method of the present invention will be described in detail.
In the present invention, the isatin derivative is first converted into a 2-oxindole derivative by a known method. The isatin derivative which is a raw material used in the production method of the present invention is a compound represented by the general formula (1). (In the formula, R1, R2, R3, R4 and R5 have the same meanings as described above.)
Although the manufacturing method of a raw material isatin derivative is not specifically limited, For example, the isatin derivative obtained by making an isonitrosoacetanilide derivative from substituted aniline and then ring-closing reaction can be used.

In general, an isatin derivative is reacted with hydrazine hydrate in a suitable solvent to form a hydrazone derivative. This intermediate is used as is in the next step or separated from the reaction mixture and then subjected to Wolff-Kischnar reduction in the presence of a strong base, such as sodium ethoxide, in an appropriate solvent to give the 2-oxindole derivative. Convert.

The 2-oxindole derivative represented by the general formula (2) thus obtained is taken out as a crystal. The important point of the present invention is that the pH in the system during crystallization is kept alkaline. Since the reaction is carried out using a strong alkali, it is strongly alkaline with a pH> 13 at the end of the reaction. Generally, the crystals are taken out by concentration of the reaction solution, crystallization with acidic water, and filtration. However, in this operation, various impurities by-produced during the reaction are brought in, and the extracted crystal must be purified again by recrystallization or the like.
However, the impurities produced as a by-product have properties similar to those of the target 2-oxindole derivative, so that a purification effect is not seen, resulting in wasting a lot of cost and labor.

On the other hand, crystallization is possible even with the reaction solution as it is, but since the 2-oxindole derivative forms a salt with an alkali metal , in an aqueous crystallization system, the loss to the filtrate increases and the yield decreases. It will be connected. When crystallization is performed in a system for taking out as a salt, the 2-oxindole derivative must be crystallized by neutralizing the salt again, which is complicated as an operation and a purification effect cannot be obtained.

In the present invention, acid is added during crystallization to adjust the pH between 13 and 7.5 for crystallization. Thereby, the target crystal can be obtained without reducing the yield and introducing almost no impurities.

The acid used here is selected from mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, and organic acids such as acetic acid and p-toluenesulfonic acid, and hydrochloric acid is particularly advantageous from an industrial point of view.

The amount of acid used is not constant depending on the amount of alkali used in the reduction reaction, but is usually 1 equivalent or less, preferably 0.85 to 0.95 equivalent to the alkali used.

As described above, the 2-oxindole derivative obtained in the present invention can be obtained with a purity of 99.5% or more as measured by HPLC. If it is used normally, recrystallization, column chromatography, distillation after removal. It is not necessary to perform such purification.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1

A 500 ml flask equipped with a stirrer, reflux condenser and thermometer was charged with 100 g (0.61 mol) of 5-fluoroisatin and 300 ml of methanol, and gradually 56.8 g (0.11 mol) of 60% hydrazine aqueous solution was stirred at room temperature. Added to. After completion of the addition, the mixture was heated and refluxed for 13 hours or longer. After completion of the reaction, the mixture was cooled and the precipitated crystals were filtered. After washing with 80 ml of methanol and drying, 103.7 g of 3-hydrazino-5-fluoro-2-oxindole was obtained. Yield 95.0%. Yellow crystals.

Example 2

A 500 ml flask equipped with a stirrer, a reflux condenser and a thermometer was charged with 100.0 g (0.56 mol) of 3-hydrazino-5-fluoro-2-oxindole and 400 ml of methanol and boiled to reflux. A solution prepared by dissolving 44.8 g (1.12 mol) of sodium hydroxide in 225 ml of methanol was gradually added dropwise to this suspension. After completion of the dropwise addition, the boiling reaction was continued for about 3 hours to complete the reaction. After completion of the reaction, 330 ml of MeOH was recovered at normal pressure. After recovery, 250 ml of water was added and dissolved, and 250 ml of 4N hydrochloric acid was gradually added to cause crystallization. After stirring overnight under ice cooling, the crystals were filtered. The pH of the filtrate was 12.3. The filtered crystals were washed with water until the washing solution had a pH of 7, and then dried to obtain 74.3 g of 5-fluoro-2-oxindole. Yield 85.0%. Slight yellowish white acicular crystals. As a result of analyzing the obtained crystals by HPLC, the area percentage of the target compound was 99.8%.

Example 3

5-Chloro-2-oxindole was obtained by the same reaction and post-treatment except that 3-hydrazino-5-fluoroisatin of Example 2 was changed to 3-hydrazino-5-chloroisatin. Yield 87.2%. Fine brownish white acicular crystals. The pH of the filtrate was 12.2.
As a result of analyzing the obtained crystals by HPLC, the area percentage of the target compound was 99.8%.

Comparative Example 1

A 500 ml flask equipped with a stirrer, a reflux condenser and a thermometer was charged with 100.0 g (0.56 mol) of 3-hydrazino-5-fluoro-2-oxindole and 400 ml of methanol and boiled and refluxed. A solution prepared by dissolving 44.8 g (1.12 mol) of sodium hydroxide in 225 ml of methanol was gradually added dropwise to this suspension. After completion of the dropwise addition, the boiling reaction was continued for about 3 hours to complete the reaction. After completion of the reaction, 330 ml of MeOH is recovered at normal pressure. After completion of the recovery, 250 ml of water was added, and further 295 ml of 4N hydrochloric acid was gradually added to cause crystallization. The mixture was stirred overnight under ice-cooling, and the crystals were filtered. The pH of the filtrate was 1.8. The filtered crystals were washed with water until the washing solution had a pH of 7, and then dried to obtain 76.3 g of 5-fluoro-2-oxindole. Yield 87.3%. Fine brownish white acicular crystals.
As a result of analyzing the obtained crystals by HPLC, the area percentage of the target compound was 98.7%.

Claims (3)

The following general formula (1)

Wherein R1 represents a hydrogen atom. Each of R2, R3, R4, R5 of the formula are identical or different and each represents a hydrogen atom or a halogen. The following general formula (2) obtained by reducing the isatin derivative represented by

[Wherein R 1, R 2, R 3, R 4, R 5 have the same meanings as described above. The pH of the reaction solution of the 2-oxindole derivative represented by formula (1) is adjusted to 12.2 to 13, and the produced 2-oxindole derivative is crystallized and taken out. Method. The method for producing a 2-oxindole derivative according to claim 1, wherein R1 is a hydrogen atom, and any of R2, R3, R4, and R5 is a halogen atom . The method for producing a 2-oxindole derivative according to claim 1 or 2, wherein R1, R2, R4, and R5 are hydrogen atoms, and R3 is a fluorine or chloro atom .