JPH02279671A - Production of 1,4-dimethylcarbazole derivative - Google Patents

Abstract

PURPOSE:To obtain 1,4-dimethylcarbazole derivative in extremely high yield by reacting an indole derivative with 2,5-hexanedione by using an acid addition salt of ion exchange resin containing pyridyl group as a catalyst. CONSTITUTION:An indole derivative shown by formula II (R1 and R2 are H, lower alkoxy or OH which may be replaced) is reacted with 2,5-hexanedione shown by formula III in the presence of an acid addition salt of ion exchange resin containing pyridyl group to give a 1,4-dimethylcarbazole derivative (e.g. 6-methoxy-1,4-dimethylcarbazole) shown by formula 1. For example, p- toluenesulfonate of pyridine type ion exchange resin is used as the catalyst. The method has an extremely high yield and simple post-treatment. The recovered catalyst can be economically reused. The compound is useful as an intermediate for ellipticine having antitumor action.

Description

Detailed Description of the Invention - [Field of Industrial Application] The present invention is directed to the use of 1,4-dimethylcarbazole derivatives, more specifically, as intermediates for the synthesis of eribticin derivatives having anti-1liIi tumor activity. The general formula (1
) (In the formula, R1 and 11 represent a hydrogen atom, a lower dimethyloxy group, or an optionally protected hydroxyl group.)

[Conventional technology and issues]

Many ellipdicine derivatives having a pyridocarbazole skeleton (Japanese Unexamined Patent Publication No. 61-377!19) have antitumor activity; for example, 2N-methyl-9-hydroxyeributinium acetate is effective against breast cancer. Yes [mouth ull, Cancer (Paris) 6
8. 437-441 (1981)], eributicin and 9-methoxyellipticin were used in experimental animals + rt
Mouse leukemia L-1210 and Sarco 718
0 (Sarcoma180, solid) [J, Mad, lem.

18, 755-760 (1975)].

Thus, ellipticine derivatives include, for example, Au5t,
J, Che[I+, 20.2715~2'? 27 (1
907);J.

Che+n, Soc, Perkin 1,1698~
1704 (1977); Tetrahedron Le
ft,, 1261~1264 (1!17B);
As described in European Patent Specification No. 9445, etc., it is derived from a 1,4-dimethylcarbazole derivative. For this reason, 1. 4-dimethylcarbasol derivatives are useful compounds as synthetic intermediates for eribdicine derivatives.

Conventionally, as a method for producing 1,4-dimethylcarbazole derivatives, an indole derivative and 2,5-hexanedione are mixed in a solvent such as ethanol or dioxane with hydrochloric acid gas, p-1 luenesulfonic acid, or boron difluoride ether. A method of reacting using a strong acid such as a complex as a catalyst is known.

However, since such conventional methods use strong acids as they are, a large amount of tar etc. is generated, and J. Chem.
Sac, 1962.3482 1. /1-dimethylcarbazole in 36% yield, and
J, Chew, 20.2715 (19G?) contains 38% 6-medoxy 1,4-dimethylcarbazole
The yield was extremely low. However, the indole derivative used as a raw material is not commercially available as an industrial reagent and is expensive.
The low yield of the above steps has been a bottleneck in the production of ellipticine derivatives since many steps are required.

[Means to solve the problem]

Under such circumstances, Honzagi 1 conducted intensive research to solve the above problems, and as a result, using an acid addition salt of an ion exchange resin having a pyridyl group as a catalyst, the indole derivative and 2.5 -1,4-dimethylcarbazole derivative (1,4-dimethylcarbazole derivative (
It was discovered that 1) could be obtained, and the present invention was completed.

The method of the present invention is carried out by the following reaction formula.

(In the formula, R and lζ are the same as above) That is,
The present invention provides 1.4-.-
This is a method for producing dimethylcarbazole derivative (1).

The acid addition salt of the ion exchange resin having a pyridyl group of the catalyst used in the present invention has a structure in the molecule represented by the following formula (IV) (wherein X represents an anionic acid 11). , and those with structural units. Such a resin is, for example, KBK-316 from Koei Kagaku QKosha.
It is commercially available as. Also, x.

As the acid anidine represented by 1! , strong inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and hydrogen tetrafluoroboric acid; residual presence of methanesulfonic acid, benzenesuflephone R1p-) luenesulfonic acid, nitrobenzenesulfonic acid, etc.! The anion of the a acid is preferred. These catalysts contain 0.5-4. (It is preferable to use j times the molar amount.

The method of the present invention involves the use of 6 ml of alcohol in a solvent that does not participate in the reaction, such as methanol, ethanol, turmix, isopropyl alcohol toluene, dioxane, acetonitrile, diglyme, etc.
It is carried out by reacting for 20-100 hours at a temperature of 0-150°C.

After the reaction, the resin catalyst is filtered from the reaction mixture, and the solvent is distilled off from the filtrate to obtain the 1,4-dimethylcarbazole derivative (
Since the crude crystals of 1) are obtained, there is no need for complicated post-treatments such as extraction and water washing, which are required in conventional methods that use strong acids as they are as catalysts. In addition, the recovered catalyst can be reused as is for the next reaction.

〔Effect of the invention〕

As mentioned above, the present invention has various advantages such as extremely high yield, easy post-treatment, and economical since the recovered catalyst can be reused in the next reaction.

〔Example〕

Next, an example will be given and explained.

Example 1 Pyridine type ion exchange resin [Koei Kaban Yosei, Niguchi X-
316] p-toluenesulfonate (equivalent to 6.8 meq.) was mixed with 500 mg of 5-methoxyindole (3,
4 mmol), 215-hexanedione 542 mg
(4.8 mmol) was added to a mixture of 2.5 mm of ethanol and heated under reflux for 72 hours. The resin was separated while hot and washed with ethanol. The filtration and washing liquids were combined and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (solvent: dichloromethane) to obtain fi'i'M L, 6-meth, xy-1,4-dimethylcarbaso'- Obtained 612 mg of
80% yield based on indole).

Melting point 136.5-137.0°C Examples 2-5 6-Medoxy 1. 4-dimethylcarbazole was obtained.

Table 1 Table 2 Examples 6 to 11 The results are shown in Table 2 in the same manner except that the acid salts in Table 2 were used in place of the p-toluenesulfonate of the ion exchange resin in Example 1. A yield of 6-medoxy 1,4-dimethylcarbasol was obtained.

Below are blank spaces Example 12 5.0 g (42.7 mmol) of indole, 6-8 g (59.6 mmol) of bovine sandione and 0X-316 p-) luenesulfonate (4
2.8 mmol equivalent) in 25 mN ethanol,
The mixture was heated under reflux for 20 hours. The resin was filtered off while hot and washed with ethanol. 1. The filtrate and washing liquid were combined and the solvent was distilled off under reduced pressure (4. The residue was purified by silica gel chromatography (solvent dichloroform) 1. 6.7g of 1,4-dimethylcarbazole was obtained (yield 80% based on indole).
%).

Melting point 9765-98.0°C Example 13 4-methoxyindole 545 mg (3,7 mmol), 2,5-hexanedione f, 1 g (9,6 mmol)
mole) and Kl! X-316.p-) Luxunsulfonate (equivalent to 3.7 milliequivalents) was added to ethanol 10 and heated under reflux for 38 hours. The same treatment as in Example 12 was carried out to obtain 56211 Ig of 5-methoxy-1,4-dimethylcarbazole (yield 67% based on 4-methoxyindole).

Melting point 135.0°C Example 14 4-benzyloxindole 5, Og (22.4 mmol), 2.5-hexanedione 3.6 g < 31.6 mmol) and K[! X-316-p -) Luxunsulfonate (equivalent to 22,4 meq.
rnl and heated under reflux for 5 hours under 3B. Example 1
Treated in the same manner as in 2 to obtain 5 benzyl t =) - C 1.4
-4.1 g of dimethylcarbazole < 4-
Yield 01% based on benzyloxindole).

Melting point 129.5°C Example 15 5.6-Simethoxyindole 1. (] to (5, fi mmol), 2 + 5-hekidzinjin t1.!l
(7,9 mmol) and UX-31ti・l)
l-ru, T-sulfonate (5.7 milliliters [d tag 1
The mixture was added to 1 liter of ethanol and heated under reflux for 35.5 hours.

f3,7-cymethoxy 1 was treated in the same manner as in Example 12.
4-dimethylcarbazole (1,78%, 5.6-
Yield 49% based on dimethoxyindole).

Melting point IBL, 9℃ that's all

Claims (1)

[Claims] 1. General formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R_1 and R_2 represent a hydrogen atom, a lower alkoxy group, or an optionally protected hydroxyl group) General formula (I) characterized by reacting an indole derivative represented by ) with 2,5-hexanedione in the presence of an acid addition salt of an ion exchange resin having a pyridyl group. A method for producing a 1,4-dimethylcarbazole derivative represented by ▼ (wherein R_1 and R_2 are the same as above).