JP3256208B2 - Method for producing 2-oxindole - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a process for producing a 2-oxindole compound, particularly, in the presence of a weak base as catalyst.
Reaction of isatin with hydrazine hydrate in polar solvents
The present invention relates to a method for producing a 2-oxindole compound.

[0002]

2. Description of the Related Art Oxindoles represented by the following formula (I):

Embedded image Adibendan (adibendan, as per formula 2) containing an oxindole moiety as a substance associated with a particular type of drug, such as a cardiotonic for congestive heart disease,

Embedded image It is known as an intermediate at the time of production. Tyrosine kinase inhibitors useful for regulating various epidermal growth
inhibitors) are also made from 2-oxindole compounds. Equation 3

Embedded image Is optionally substituted or unsubstituted, wherein R is alkyl, alkoxy, aryl, phenoxy, halogen, or hydrogen. The 2-oxindole compound has the following reaction formula

Embedded image (D.S.Soriano, J. Chem. Edu., 1993, 7
0, 332) is already known. According to the method, isatin (Formula 4) reacts with hydrazine hydrate in dehydrated methanol to form a suspended intermediate in the reaction mixture. This intermediate is further separated from the reaction mixture and purified by a crystallization method. The purified intermediate is dried, and the dehydrated ethanol is subjected to Wolf-Kishner reduction at a higher temperature in the presence of a strong base, for example, sodium ethoxide, to obtain a 2-oxindole compound. The yield of 2-oxindole compound obtained by the above method reaches up to 69%.

[0003]

The above-mentioned method is complicated because preparation of the 2-oxindole compound requires steps such as separation, purification, and drying. In addition, when sodium ethoxide reacts with water, the catalyst loses its catalytic activity. Therefore, in the above method, expensive dehydrated ethanol must be used as a solvent in the reaction mixture. In addition,
Since sodium ethoxide is usually obtained by reacting very active and dangerous sodium with dehydrated ethanol, the above method using large amounts of sodium ethoxide has safety problems. In addition, the following reaction formula

Embedded image There is a method for producing a 2-oxindole compound represented by (Cre
stini and Saladino, Synth.Commun. 1994, 24, 283
Five). According to this, isatin is first dissolved in pure hydrazine, and then reacted with pure hydrazine under post-heating to obtain a 2-oxindole compound. The yield of 2-oxindole compounds obtained in this way reaches up to 76%.

Exposure of pure hydrazine to high temperatures or reaction with oxidizing agents can cause a severe explosion, so the use of pure hydrazine must be very careful and the above method is therefore also impractical. .

In order to cause the reaction, any of the above methods
Requires a high temperature of about 200 ° C. Such a high temperature consumes a large amount of energy, and when a strong base is used as a catalyst, a reactor made of a special anticorrosive material is required.

[0006]

In order to solve the above-mentioned drawbacks of the prior art, the present inventors provide a method for producing a 2-oxindole compound which does not require any of a strong base or pure hydrazine.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION According to the process for producing a 2-oxindole compound of the present invention, a 2-oxindole compound is obtained by reacting isatin with hydrazine hydrate in a polar solvent in the presence of a weak base as a catalyst. .

According to the invention, very good results are obtained by using weak bases instead of the strong bases used as catalysts in the prior art processes. Thus, according to the present invention, careful selection of a weak base and a polar solvent for the reaction mixture results in higher yields than the prior art methods described above.

The polar solvent applied to the method of the present invention is water,
Ethanol, 1-propanol, 2-propanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-butanol, 2-butanol, 1-methyl-2-pyrrolidinone (1-me
thyl-2-pyrrolidinone), N, N'-dimethylformamide, N, N'-dimethylacetamide, dimethylsulfoxide, and mixtures thereof. Among them, N, N'-dimethylformamide is preferred. preferable.

The weak base acts as a catalyst in the reaction of isatin with hydrazine hydrate and can be selected from the group comprising alkali carbonates, alkali acetates, and mixtures thereof, with sodium acetate being more preferred.

The crude product of the 2-oxindole compound obtained by the method of the present invention is further subjected to the following steps: (a) dissolving the crude product of the 2-oxindole compound in a solvent to form a solution;
A step of (b) decolorizing the solution by adding activated carbon and (c) crystallizing the solution while removing the activated carbon from the solution to form a precipitate of a 2-oxindole compound can also be added.

The solvent used in the step of purifying the crude product of the 2-oxindole compound is dichloromethane, hexane, 1,2-dichloroethane, toluene, ethyl acetate, 2-propanol, isopropyl ether, ethanol,
Any of water and a mixture thereof may be used.
Dichloroethane is preferred. The amount of activated carbon added is 3-10wt% based on the weight of crude 2-oxindole compound
And 5 wt% is more preferable.

In practice, the preparation of the 2-oxindole compounds according to the process of the invention is preferably carried out at a reaction temperature of 60 to 250 ° C., in particular, at 100 ° C., the molar ratio of the weak base sodium acetate to isatin is 0.03: 1 to 0.3: 1 is more preferable. In addition, isatin has a molar concentration in a polar solvent
0.2-3.5M is preferred.

[0014]

Hereinafter, the present invention will be described based on Examples and Comparative Examples.
The surprisingly good results of the present invention are explained in more detail.

Example 1 In a flask, 166 g (1.1 mol) of isatin was dissolved in 650 ml of N, N'-dimethylformamide, and 70 ml of hydrazine hydrate (1.1 mol) having a concentration of 80% and N, N'-dimethylformamide 1 were dissolved.
80 ml was uniformly mixed, and this was added little by little to the flask. Then, 8.3 g (0.1 mol) of sodium acetate was added to the flask, and the reaction mixture was heated to 100 ° C. for 8 hours in order to react isatin with hydrazine hydrate. After the reaction was completed, the polar solvent was removed by distillation, and 500 ml of water was added to the remaining mixture. The mixture is then
The mixture was extracted twice with 00 ml and further dried to obtain a crude product of 2-oxindole, a yellowish solid. The yield of 2-oxindole thus obtained is 95% and the purity is 97%
Met.

The above crude product of 2-oxindole is dissolved in 420 ml of dichloroethane in a heated state, and 7.1 g of activated carbon (about 5 wt% based on the weight of the crude product of 2-oxindole) is added for decolorization. did. When the activated carbon was removed by a filtration device, a colorless solution was obtained. The solution was then allowed to cool and a precipitate of 2-oxindole was obtained by crystallization. Subsequently, the crystallized 2-oxindole is separated from the solution and dried, 128 g of powdered solid 2-oxindole
was gotten. The yield of 2-oxindole is 85%,
Purity was 99.5%.

Examples 2 to 4 As polar solvents, 1-methyl-2-pyrrolidinone and
N, N'-dimethylacetamide or dimethylsulfoxide was used, and the others were the same as in Example 1.
Constructed ~ 4. Yields 59%, 72% or 6 respectively
1%.

Example 5 As a weak base, sodium carbonate was used, and the molar ratio of isatin: hydrazine hydrate: sodium carbonate was 1:
Same as Example 1 except that 1: 0.04. The yield was 61%.

Example 6 Potassium carbonate was used as a weak base, and isatin:
Hydrazine hydrate: potassium carbonate molar ratio is 1: 1: 0.03
Same as Example 1 except that The yield was 52%.

Example 7 Isatin had a molarity of 3.4 M in N, N'-dimethylformamide, and sodium carbonate was used as a weak base.
All conditions were the same as in Example 1 except that the molar ratio of isatin: hydrazine hydrate: sodium carbonate was 1: 1: 0.09. The yield was 68%.

Example 8 Isatin had a molarity of 3.4 M in N, N'-dimethylformamide, potassium carbonate was used as a weak base, and the molar ratio of isatin: hydrazine hydrate: sodium carbonate was 1: Except that 1: 1: 7, the conditions were the same as in Example 1. A 65% yield was obtained.

COMPARATIVE EXAMPLE 1 A strong base, ie lithium hydroxide, was used instead of a weak base, except that the molar ratio of isatin: hydrazine hydrate: lithium hydroxide was 1: 1: 0.2. Was the same as in Example 1. The yield was 64%.

COMPARATIVE EXAMPLE 2 A strong base, ie, sodium hydroxide, was used in place of the weak base, and the procedure was carried out except that the molar ratio of isatin: hydrazine hydrate: sodium hydroxide was 1: 1: 0.1. Same as Example 1. The yield was 66%.

Comparative Example 3 A strong base, ie potassium hydroxide, was used in place of the weak base, and the procedure was carried out except that the molar ratio of isatin: hydrazine hydrate: potassium hydroxide was 1: 1: 0.08. Same as Example 1. As a result, the yield was 63%.

Comparative Example 4 Isatin had a molarity of 3.4 M, a strong base, ie, lithium hydroxide was used in place of the weak base, and the molar ratio of isatin: hydrazine hydrate: lithium carbonate was 1: 1: 0.4. Other than that, the same as Example 1. 52% for yield
was gotten.

Comparative Example 5 Isatin had a molarity of 3.4 M, a strong base was used in place of the weak base, that is, sodium hydroxide.
The molar ratio of hydrazine hydrate: sodium carbonate is 1: 1: 0.
Except for 2, it was the same as Example 1. A 57% yield was obtained.

Comparative Example 6 Isatin had a molar concentration of 3.4 M, a strong base, ie, potassium hydroxide was used in place of the weak base, and the molar ratio of isatin: hydrazine hydrate: potassium carbonate was 1: 1: 0.1. All were the same as Example 1 except that As a result, the yield was 54%.

COMPARATIVE EXAMPLE 7 Ethylene glycol was used as a polar solvent, the molarity of isatin was 0.2 M, and a strong base, that is, potassium hydroxide was used instead of a weak base. Isatin: hydrazine hydrate: mol of potassium carbonate The ratio is 1: 1: 1 and the reaction temperature is 1
Same as Example 1 except maintained at 40 ° C. The yield was 51%.

Comparative Example 8 Ethanol was used as a polar solvent, the molarity of isatin was 0.2 M, a strong base, ie, sodium methoxide was used instead of a weak base, and a molar ratio of isatin: hydrazine hydrate: sodium methoxide Was as in Example 1 except that the reaction temperature was maintained at 1: 3: 1 and the reaction temperature was 80 ° C. The yield was 27%.

As can be seen from the results of the above Examples and Comparative Examples, the present invention was able to improve the yield of 2-oxindole compounds by carefully choosing a weak base and a polar solvent in the reaction mixture. .

──────────────────────────────────────────────────続 き Continued on the front page (58) Investigated field (Int. Cl. ⁷ , DB name) C07D 209/34 CA (STN) REGISTRY (STN)

Claims (13)

(57) [Claims] An alkali carbonate or alkali acetate as a catalyst,
And a reaction between isatin and hydrazine hydrate in a polar solvent in the presence of a weak base selected from the group comprising a mixture thereof and a mixture thereof. (Wherein R is alkyl, alkoxy, aryl, phenoxy, halogen or hydrogen). 2. The method according to claim 1, wherein the polar solvent is water, ethanol, 1-propanol, 2-propanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-butanol,
-Butanol, 1-methyl-2-pyrrolidinone, N, N'-dimethylformamide, N, N'-dimethylacetamide,
2. The method for producing a 2-oxindole compound according to claim 1, wherein the method is selected from the group consisting of dimethyl sulfoxide and a mixture thereof. 3. The method for producing a 2-oxindole compound according to claim 2, wherein the polar solvent is N, N'-dimethylformamide. 4. The method for producing a 2-oxindole compound according to claim 1, wherein said weak base is sodium acetate. 5. The method according to claim 4, wherein the molar ratio of the sodium acetate to the isatin is 0.03: 1 to 0.3: 1.
2. The method for producing a 2-oxindole compound according to the above. 6. The method for producing a 2-oxindole compound according to claim 1, wherein the reaction between isatin and hydrazine hydrate is carried out at a temperature of 60 to 250 ° C. 7. The method according to claim 6, wherein the reaction temperature is 100 ° C.
2. The method for producing a 2-oxindole compound according to the above. 8. The method according to claim 1, wherein the isatin has a molarity of 0.2 to 3.5 M in the polar solvent.
A method for producing an oxindole compound. 9. The method for producing a 2-oxindole compound according to the present invention further comprises: (a) dissolving a crude product of the 2-oxindole compound in a solvent to form a solution; and (b) adding activated carbon to the solution to decolorize the solution. 2. The method for producing a 2-oxindole compound according to claim 1, comprising: (c) crystallizing the solution while removing activated carbon from the solution to form a precipitate of the 2-oxindole compound. 10. The method according to claim 1, wherein the solvent is dichloromethane, hexane,
The method for producing a 2-oxindole compound according to claim 9, which is selected from the group consisting of 1,2-dichloroethane, toluene, ethyl acetate, 2-propanol, isopropyl ether, ethanol, water, and a mixture thereof. . 11. The method for producing a 2-oxindole compound according to claim 10, wherein said solvent is 1,2-dichloroethane. 12. The method for producing a 2-oxindole compound according to claim 9, wherein the activated carbon is added in an amount of 3 to 10% by weight based on the weight of the crude product of the 2-oxindole compound. 13. The method for producing a 2-oxindole compound according to claim 12, wherein the activated carbon is added in an amount of 5 wt% based on the weight of the crude product of the 2-oxindole compound.