JPS5846515B2 - Method for producing indole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing indole derivatives, and more specifically, a novel method for producing 1-(indol-4-yloxy)-3-(isopropylamino)-2-propatol, which is useful as a pharmaceutical. It is related to.

Conventionally, the method for producing 1-(indol-4-yloxy)-3-(isopropylamino)-2-propatol is
A method in which an alkali metal salt of 4-hydroxyindole is reacted with epichlorohydrin and isopropylamine sequentially, or a reaction product of epichlorohydrin and N-benzylisopropylamine is reacted with an alkali metal salt of 4-hydroxyindole, and then the benzyl group is hydrogenated. There are known methods for dividing the molecule.

However, these all use 4-hydroxyindole as the starting material.

By the way, Journal of Chemical Society (
J, C, 5) p. 1608 (1948), or as seen in French Patent No. 1.540484, etc.
The synthesis yield of hydroxyindole cannot be said to be at an industrially satisfactory level, and not only are there problems in obtaining raw materials in terms of quantity and cost, but also the production of 4-hydroxyindole, which has been obtained with great effort, is difficult to obtain. Even when they are used as raw materials, the above-mentioned production methods all require extremely long reaction times, which poses many problems as industrial production methods for isohead compounds.

In view of the above, the present inventors have conducted intensive research to avoid the use of 4-hydroxyindole as a starting material and selectively use a more reactive compound to produce the above compound industrially. , starting from 4-methoxy-N-benzylindoline, which is known per se and is available at low cost,
We were able to establish an industrially extremely useful new method for producing the above compound using a new compound, none of which has been described in the literature, as an intermediate.

That is, according to the present invention, the known compound general formula (I
) (In the formula, R is a lower alkyl group and Bz is a benzyl group) N-benzyl-4-alkoxyindoline represented by (can be easily synthesized with high yield by intramolecular ring closure of ethylamine, etc.)
The above-mentioned indoline derivative was treated with hydrohalic acid to obtain a new compound N-hair/)-4-hydroxyindoline hydrohalide represented by formula (II) (wherein X is halogen).

The hydrohalide is reacted with an alkali hydroxide and a 2,3-epoxyprobyl derivative represented by the formula (wherein X' is a chlorine or bromine atom or a tosyl group) to form a novel compound represented by the formula (IT). The compound 4-(2,3-epoxypropoxy)-N-penzylindoline is obtained, and the indoline derivative is added to an amine represented by the general formula (V) (wherein R1 is an isopropyl group and R2 is a hydrogen atom or a benzyl group). 1-(indol-4-yloxy)-3 represented by formula (Vl) is obtained by hydrogenolytic elimination of the benzyl group and conversion of the indoline ring to an indole ring by dehydrogenation in any order.
A novel method for preparing indole derivatives to obtain -(isopropylamine)-2-propatur is provided.

According to a particularly preferred embodiment of the present invention, in which the benzyl group is first eliminated and then the indoline ring is dehydrogenated to the indole ring, the process of the present invention can be expressed by the following reaction formula.

(In the formula, R is a lower alkyl group, Bz is a benzyl group, X is a halogen atom, and X' is a chlorine, bromine, or tosyl group.) ) is heated under reflux with hydrohalic acid to produce 4-hydroxy-N-benzylindoline hydrohalide salt (n).

Although it is sufficient for this reaction to simply mix the two and heat to reflux, the reaction can be made to proceed more favorably by adding acetic acid.

As the hydrohalic acid, hydrobromic acid, hydroiodic acid, etc. can be used, but it is convenient to use 48% hydrobromic acid.

The hydrohalide salt of 4-hydroxy-N-benzylindoline is obtained as a stable crystalline product, and is easily converted into free 4-hydroxy-
However, by using excess alkali hydroxide in the subsequent reaction with the 2,3-epoxypropyl derivative, the salt can be converted to free 4-hydroxy-N-benzylindoline, and further the alkali metal salt thereof. It is preferable to use the hydrohalide salt as it is in the next step because it can be converted into the following form.

The second step in the method of the present invention is the 4-
Hydroxy-N-benzylindoline or its salt (
If) is reacted with 2,3-epoxypropyl derivative (III) together with alkali hydroxide to form 4-(2,3-epoxypropoxy)-N-benzylindoline compound (I
This is the process of obtaining V).

The alkali hydroxide used here is preferably sodium hydroxide or potassium hydroxide, and the 2゜3-epoxypropyl derivative (III) is 2,3-epoxypropyl chloride or 2,3-epoxypropyl bromide. , p-toluenesulfonyl-2,3-epoxypropane.

Although the reaction can be suitably carried out in any inert solvent, the reaction can be carried out particularly suitably using polar solvents such as alcohol, water, and other polar solvents, and polar solvents such as dimethylformamide and dimethyl sulfoxide.

Compound (IV) thus obtained is then reacted with isopropylamine or N-benzylisopropylamine to give 4-(3-isopropylamino-2-hydroxypropoxy)-N-benzylindoline (■) or 4
-(3-N-Benzylisopropylamino-2-hydroxypropoxy)-N-benzylindoline (VI[D
It will be done.

The reaction is particularly preferably carried out in a reaction solvent such as methyl cellosolve or ethyl cellosolve.

The reaction is completed in a very short time (1 to 2 hours) by simply heating the reaction mixture to reflux.

Isolation of compound (■) or (■) is not necessary, and the subsequent debenzylation and dehydrogenation treatment from the indoline ring to the indole ring are immediately carried out.

Debenzylation can be carried out using e.g. alcohol, methyl cellosolve,
In a solvent such as ethyl cellosolve, in the presence of a hydrogenation catalyst,
The conversion from an indoline ring to an indole ring is carried out by a hydrogenolysis method known per se, in which heating and stirring are carried out while passing hydrogen, and the conversion from an indoline ring to an indole ring is carried out using methyl cellosolve, ethyl cellosolve,
The dehydrogenation is carried out by heating under reflux in a solvent that does not participate in the reaction, such as dioxane or tetrahydrofuran, in the presence of a dehydrogenation catalyst, which is also known per se.

These debenzylation and dehydrogenation from an alicyclic compound to an aromatic ring compound are carried out on the compound (V[) or (VII[)) in any order as mentioned above.
-(indol-4-yloxy)-3-(isopropylamino)-2-propatol (VD) can be obtained, and since debenzylation and dehydrogenation are reaction means known per se, solvents, catalysts, etc. , reaction conditions, etc. can be selected as appropriate.

However, in a particularly preferred embodiment of the present invention described above, a solvent common to both alcohol, methyl cellosolve, or ethyl cellosolve, and a catalyst common to both, such as palladium carbon or Raney nickel, are selectively used, and hydrogen decomposition is carried out while passing hydrogen. A method of successively carrying out debenzylation and dehydrogenation in the same system by carrying out debenzylation and then cutting off the supply of hydrogen and carrying out dehydrogenation by heating and stirring, or vice versa. will be adopted.

In the case of compound (■), if dehydrogenation is first performed using a palladium carbon or Raney nickel catalyst without supplying hydrogen, debenzylation will proceed simultaneously and the target compound (VL) will be obtained, but This is because compound (V[) has only one benzyl group, so hydrogen obtained by dehydrogenation can be used for debenzylation.

However, in order to ensure debenzylation and dehydrogenation of the ring, first debenzylate compound (■) or (Vll[) as shown in the reaction scheme above, and then dehydrogenate. It is more preferable to tighten it.

Thus, in the present invention, 4-alkoxy-N-benzylindoline, which can be easily synthesized, is used as a starting material,
All of the intermediates (n) to (■) are produced via new compounds that have not been described in the literature, but the reactions proceed in a short time and in high yields, producing 1-(indole- 4-yloxy)-3-(isopropylamine)-2
- A method for producing propatool (Vl) industrially and advantageously is provided.

The present invention will be explained below with reference to Examples.

Example 1 a) Preparation of N-benzyl-4-hydroxyindoline.

3.14 g of N-benzyl-4-methoxyindoline, 2 ml of acetic acid, 48% hydrobromic acid 3077I71! The mixture was heated under reflux for 4 hours and then cooled to yield 3.18 g of the hydrobromide salt of the present compound.

Yield 79.9% Nuclear magnetic resonance spectrum (in deuterated chloroform) δ3.13 (4H) δ4.25 (2H) δ
6.20(2H) b) Preparation of 4-(2,3-epoxypropoxy)-N-benzylindoline Epichlorohydrin 1.
6g of N-benzyl-4-hydroxyindoline hydrobromide and 51n of dimethylformamide were added thereto.
1 and 0.5 g of potassium hydroxide were added dropwise.

After reacting at room temperature for 4 hours, the mixture was extracted with ethyl ether, and the ethyl ether layer was concentrated under reduced pressure to obtain 0.67 g of the present compound.

Yield 79.5% Melting point 36-37°C (methanol) c)
Production of 1-(indol-4-yloxy)-3-(isopropylamine)-2-propanol: (a) 2.81 g of 4-(2,3-epoxypropoxy)-N-benzylindoline, N-benzylisopropyl 2.7 g of amine and 10 d of methyl cellosolve were heated under reflux for 2 hours.

Then, it was concentrated under reduced pressure, 40 ml of ethanol and 2 g of 10% palladium on carbon were added, and the mixture was stirred at 50'C in the presence of hydrogen.
The benzyl group was removed.

The hydrogen was then removed and the contents heated to reflux.

After cooling, the catalyst was removed, EE was reduced, and the mixture was concentrated to dryness.

The residue was recrystallized from methanol to give the current compound 1.799
(yield 72%).

Melting point 171-173°C8 (b) 4-(2,3-epoxypropoxy)-N-
Benzyl indoline 2.81g, isopropylamine 6
10 TL of ethyl cellosolve was heated under reflux for 4 hours.

The reaction mixture was then treated in the same manner as in (a) above to obtain the present compound.

Yield: 1.7g. Example 2 1) Preparation of 4-(2-hydroxy-3-(isopropylamino)furopoxy]-N-benzylindoline 4-(2,3-epoxypropoxy)- obtained according to a) and b) of Example 1 N-benzylindoline 2.81F
, ethyl cellosolve 10ml 1. 6g of isopropylamine
The mixture was heated to reflux with stirring for 6 hours.

The reaction mixture was then concentrated to dryness under reduced pressure and extracted with chloroform.

The chloroform layer was concentrated to dryness under reduced pressure and recrystallized from ethyl ether to obtain 2.8 g of the present compound.

Yield 82.3% Melting point 86-87°C Nuclear magnetic resonance spectrum: δCDCl31.00 (3H,
S, C-CH5) δ1.10 (3H, S, C-C
H5) δ2.20 (2H, broad 0H1-NH
) 2) Production of 4-(2-hydroxy-3-(isopropylamino)propoxytuindoline: 4-[
2-hydroxy-3-(isopropylamine)propoxy)-N-benzylindoline 3g, ethanol 45T
2 g of 1% 10% palladium on carbon was stirred at 50° C. in the presence of hydrogen.

After confirming that the benzyl group was eliminated, the catalyst was removed, and the filtrate was concentrated under reduced EE and recrystallized from chloroform to obtain the present compound.

Yield 1.5B (yield 70%) Melting point 92-93°C.

3) Production of 1-(indol-4-yloxy)-3-(isopropylamine)-2-propanol: 4-[2-hydroxy-3-(isopropylamine)propoxy]indoline obtained in 2) 2. Og 100rf
The mixture was heated under reflux for 8 hours with 2.0 g of 10% palladium on carbon in Ll of mesitylene.

The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and recrystallized from ethanol to obtain 1.53 g (yield: 77%) of the title compound.

Melting point 171~IIR, NMR spec It matched that of .

73°c.

Tor is a standard product synthesized separately.

Claims (1)

[Scope of Claims] 1 N-benzyl-4-alkoxyindoline represented by the general formula (I) (wherein R is a lower alkyl group and Bz is a benzyl group) is treated with a hydrohalic acid to form a compound of the general formula (II). ) (in the formula, X is halogen) A step of obtaining a hydrohalide of N-benzyl-4-hydroxyindoline represented by the general formula (III) X' is a chlorine or bromine atom, or a tosyl group) to form a 4-(2,3-epoxypropoxy)-N represented by the general formula (IV).
- a step of obtaining benzylindoline, and the above 4-
(2,3-Epoxypropoxy)-N-benzylindoline is reacted with an amine represented by the general formula (V) (where R1 is an isopropyl group and R2 is a hydrogen atom or a benzyl group), and then the benzyl group is hydrogen decomposed. 1-(indol-4-yluoquine)-3 represented by the formula (VI) can be obtained by performing chemical elimination and conversion of the indoline ring to an indole ring by dehydrogenation in any order.
A method for producing an indole derivative, comprising the step of obtaining -(isopropylamino)-2-propatol. 2 A patent in which hydrogenolytic elimination of a benzyl group and conversion of an indoline ring to an indole ring by dehydrogenation are carried out continuously in the same system by supplying and cutting off hydrogen supply in the presence of a catalyst. The method according to claim 1. 3. The method according to claim 2, wherein the catalyst is a palladium-carbon or nickel catalyst.