JPS62198636A - Novel azulene derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A diformylalkylazulene derivative of formula I (R1, R2, R3, R4 and R5 are H or alkyl provided that at least one of them is alkyl). EXAMPLE:1,3-Diformyl-5-methylazulene. USE:Useful as a production raw material for an azulene derivative useful as a drug such as antiulcer agent or carcinostatic agent. Also useful as an intermediate for polymethylene dye which is a sensitizer of an organic photoconductor for electrophotography. Since the compound is a diformyl derivative, substituent compounds (or groups) can be introduced to both formyl groups to enable the synthesis of various useful substances. PREPARATION:The compound of formula I can be produced e.g. by reacting an alkylazulene of formula II with phosphorus oxychloride and dimethyl formamide in the presence of a solvent at <=100 deg.C and alkalizing the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel azulene derivatives useful as raw materials for the production of pharmaceuticals and as intermediates for the production of sensitizers for electrophotographic organic photoconductors, etc. 1 substituted with a formyl group at the 3rd position
, 3-diformyl azulene derivatives.

The formylation of azulens by the Vilsmeier method was already attempted in 1957 ((W, Trei
bs, A.

)1iebsch und 11. Neupert, J.
, The Naturvissenschaft (Naturvisssenschaft)
), Volume 44, Page 352 (1957).

K, Hafner and C, Bernhard,
Angevante, Chew-e
69, p. 533 (1957)], the 1st or 3rd position of the azulene skeleton is formylated.

As an application of this, it is also known that azulene-based polyenaldehydes can be obtained by working with 1-(N-methylanilino)-1-propen-3-al or its vinylogue Zinka aldehyde ( C, Jutz, Angewante, Hemi (Angew,
Chew, ) Vol. 70, p. 270 (1958)).

W. Treibs et al.
The monoformyl form of azulene was obtained by applying the s-meier reaction, but the diformyl form is only the parent azulene and 2,4-dimethyl-7-isoguaiazulene (Ss-guaiazulene or isoguaiazulene),
Regarding alkyl azulene (e.g., 4°7-dimethylazulene, 4,8-dimethylazulene, 2,4.8-)-dimethylazulene, etc.), the diformyl form was not obtained, and 4°7-dimethyl The monoformyl form of azulene has only 1-position substitution, and isomer (3-formyl-4,7-
reported that dimethyl azulene) was not formed (W, Treibs, J, Neupart).
und J, Hiebsch.

Hemische Berichte (Chem, Ber,...) No. 92
Vol., p. 141 (1959)).

Furthermore, Hafner et al. also carried out formylation of 4,6,8-trimethylazulene, but they only obtained a monoformyl compound and did not report that they obtained a diformyl compound (K, Hafnar and C. , Barn
-hard eAnn, t., Vol. 625, p. 108 (1959)).

As mentioned above, in the conventionally known method, a diformyl compound can be obtained from parent azulene and 2,4-dimethyl-7-isoguaiazulene (Se-guaiazulene), but only in the 7-membered ring of parent azulene. There is no example of obtaining a diformyl form of azulene substituted with an alkyl group, and in particular, there is no example of obtaining a 1,3-diformylalkyl azulene in which the 1- and 3-positions are formylated, making it a novel compound.

These diformylalkylazulenes are useful substances as raw materials for producing pharmaceuticals and intermediates for producing sensitizers for electrophotographic organic photoconductors.

In the conventional formylation method, the present inventors have found that monoformylation is not greatly influenced by the position or type of alkyl group, and the reaction proceeds quantitatively in most cases. 1
, 3-diformyl form, and as a result of intensive research in order to obtain the diformyl form, we found that alkyl azulene was treated with phosphorus oxychloride and dimethylformamide or N-
The present invention was achieved by discovering that a novel 1,3-diformylated alkyl azulene can be obtained by reacting it with methylformanilide under specific reaction conditions.

That is, the present invention provides (1) a diformylalkylazulene derivative represented by the following general formula (1) (wherein R,, R,, R,, R4 and R9 are H or an alkyl group. However, R1, R,, R,, It, and R
At least one of 6 is an alkyl group. ) (2) An alkyl azulene represented by the following general formula (II) (in the formula, R1, R,, +(,, R4 and R6 are H or an alkyl group. However, R1, R2, R,, at least one of R and R6 is an alkyl group) in the presence of a solvent.

Alternatively, a diformyl alkyl represented by the following general formula (1), which is made to react with phosphorus oxychloride and dimethylformamide or N-methylformanilide at a temperature of 100°C or lower in the absence of the reaction product to make the reactant alkaline. A method for producing an azulene derivative.

(wherein R1, R, , R, , R4 and R5 are the same as above).

The alkyl group serving as a substituent is an alkyl group having one or more carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, and the like.

The compound of the present invention is 1,3-diformyl-4゜6.8-
trialkyl azulene, 1,3-diformyl-4-alkyl azulene, 1,3-diformyl-5-alkyl azulene, 1,3-diformyl-6-alkyl azulene, 1
,3-diformyl-4,5-dialkylazulene, 1,
3-diformyl-4,6-dialkyl azulene, 1,3
-diformyl-4,7-dialkylazulene, 1.3-
Diformyl-4,8-dialkyl azulene etc. 1 For example, 1,3-diformyl-4,6,8-trimethyl azulene, 1,3-diformyl-4゜6.8-1-ethyl azulene, 1,3 -diformyl-4,6,8-tri-t-butylazulene, 1°3-diformyl-4,6,8
- trioctyl azulene, 1,3-diformyl-5-methyl azulene, 1,3-diformyl-5-dityl azulene, 1゜3-diformyl-5-t-butyl azulene, 1
, 3-diformyl-5-octyl azulene, 1,3-diformyl-6-methyl azulene, 1,3-diformyl-
6-nityl azulene, 1,3-diformyl-6-propyl azulene, 1,3-diformyl-6-t-butyl azulene, 1,3-diformyl-6-pentyl azulene, 1
, 3-diformyl-6-hexyl azulene, 1,3-diformyl-6-hebutyl azulene, 1,3-diformyl-6-octyl azulene, 1,3-diformyl-4-methyl azulene, 1,3-diformyl -4-dityl azulene, 1,3-diformyl-4-t-butyl azulene, 1
, 3-diformyl-4-octyl azulene, 1,3-diformyl-4,5-dimethyl azulene, 1,3-diformyl-4,5-diethyl azulene, 1,3-diformyl-4,5-di-t- Butyl azulene, 1,3-diformyl-4,5-dioctyl azulene, 1,3-diformyl-4゜6-diethyl azulene, 1,3-diformyl-4
゜6-diethyl azulene, 1,3-diformyl-4゜6
-di-t-butylazulene, 1,3-diformyl-4,
6-dioctyl azulene, 1,3-diformyl-4,7
-diethyl azulene, 1,3-diformyl-4,7-diethyl azulene, 1,3-diformyl-4,7-di-t
-butyl azulene, 1°3-diformyl-4,7-dioctyl azulene, 1,3-diformyl-4,8-dimethyl azulene, 1,3-diformyl-4,8-diethyl azulene, 1,3-diformyl-4 , 8-di-t-butyl azulene, 1,3-diformyl-4,8-dioctyl azulene, and the like.

The novel 1,3-diformylalkylazulene of the present invention is
For example, it is manufactured as follows.

The corresponding alkyl azulene in the presence or absence of a solvent, phosphorus oxychloride and dimethylformamide, N-
React with methylformanilide or formylpiperidine. Although the reaction temperature can be 100°C or higher, the reaction is usually performed at 100°C or lower. Although the reaction temperature can be set to 0°C, it is preferably 0°C or higher since dimethylformamide or N-methylformanilide is also used as a solvent.

The solvent used in the reaction is usually dimethylformamide or N-methylformanilide, which also serves as a reaction reagent and is also used as a solvent. Examples of other solvents include orthodichlorobenzene and methylene chloride.

The amount of phosphorus oxychloride is 2 molar equivalents or more relative to the alkyl azulene, and in some cases, 3 molar equivalents or more is preferable.

The reactants are then made alkaline and the desired products 1,
3-diformylalkylazulene is obtained.

As the alkaline reagent, ordinary alkaline reagents may be used. For example, alkali metal hydroxides, alkaline earth metal hydroxides,
Alkaline salts of organic acids, soda carbonate, etc. are used.

The alkyl azulene, which is a raw material compound for the compound of the present invention, can be synthesized by the following synthesis method, for example, by adding 2,4
- Heat with dinitrochlorobenzene to 80-90℃
), after cooling, a mixture of dialkylamine and the same alkylpyridine as above is added and reacted at room temperature (5 to 40°C). The reaction solution is ice-cooled, cyclopentadiene and sodium methylate are added, heated (40 to 45°C), allowed to react, and then, after recovering the solvent, the same alkylpyridine as above is added, or ethanol and pyridine are added. In addition,
It can be obtained by heating and reacting (K
, Hafner and H, Kaiser Ann, Vol. 618, p. 151 (1958)
).

The compounds of the present invention are useful as raw materials for the production of azulene derivatives useful as pharmaceuticals, such as antiulcer agents or anticancer agents, and as intermediates for polymethylene dyes, sensitizers for electrophotographic organic photoconductors, and the like. Since it is a diformyl compound, it is possible to introduce a substituent compound (or group) into both formyl groups, which enables the synthesis of various useful substances.

Task-1 The compound of the present invention is a novel compound, and is useful as a raw material for the production of pharmaceuticals and an intermediate for the production of sensitizers for electrophotographic organic photoconductors.

Tips ■ The present invention will be explained in more detail with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.

T! LfLL Synthesis of 6-tart-butyl azulene 2.0 g (0.9 mmol) of 2,4-dinitrochlorobenzene and 4-tert-butylpyridine (commercial product 99
%) Heat 25 ml at 80-90°C for 4 hours. After cooling, 1.5 g of diethylamine (20,0
mmol) of 4-tart-butylpyridine (10 ml
) Add the solution.

React at 30-35°C for 12 hours. Cool the reaction solution on ice,
0.7 g (10.6 mmol) of cyclopentadiene,
Sodium methylate [storium 0.3g (13,
0 mmol) and methanol loml)]
and react at 40 to 45°C for 4 hours. Next, the solvent was collected until the internal temperature reached 105 to 110°C, and then 10 ml of 4-tart-butylpyridine was added.
React for 4 days at 0-115°C.

Next, the solvent was collected under reduced pressure, the residue was extracted with hexane, and after washing with dilute hydrochloric acid and water, the hexane was collected and recrystallized from ethanol to obtain 1.2 g of 6-tart-butyl azulene (1.2 g m, p). , 97-98°C. Yield 67
% Reference Example 26-Synthesis of n-octylazulene (1) 4-
Synthesis of n-octylpyridine lithium metal 7ao,0
mol) was dispersed in 400 ml of ether, 78.5 g (0.5 mol) of brombentene was added dropwise, and the temperature was gradually raised.
Reflux to unreact and completely dissolve the lithium. This solution was slowly added dropwise to a solution of γ-picoline, 4[i, 6 g (0.5 mol), in ether (50 ml) at 15 to 20°C.

Then 89.5 g (0.5 mol) of n-heptyl bromide is added dropwise. After reacting for 1 hour, add 100 ml of water. Next, 120 ml of hydrochloric acid was added to separate the aqueous layer, made alkaline with 50% Na0+1, and the liberated oil was extracted with ether. After washing with water, the solvent was recovered to obtain an oil. Vacuum distillation port, P, 1
48 g of 4-n-octylpyridine of 11 g of 45-150°/4 mm are obtained. Yield 54% picrote
: m, p, 88@(literature value, P, 9110.1
mm11g, picrate m, p, 88.5
"nD" 1.4858) (2) Synthesis of 6-n-octyl azulene 40 g of 2,4-dinitrochlorobenzene
Dissolved in 80g of ethanol, 4-octylpyridine 4
6. was added, refluxed for 2 hours, and after cooling, 50 g of pyridine was added. Add a solution of diethylamine 32 in pyridine (50 g) and react at 40°C for 5 hours.

The reaction solution was cooled with water, 14 g of cyclopentadiene was added dropwise, and then sodium methylate (prepared from 4 g of sodium and 50 ml of methanol) was added and reacted at 40 to 45° C. for 3 hours. The solvent is recovered, 200 ml of pyridine is newly added, and the mixture is stirred at 116° C. for 2 hours. Collect pyridine, extract the residue with hexane, wash with dilute hydrochloric acid and water, and collect hexane.
Silica gel column treatment and recrystallization (ethanol) to obtain the desired 6-n-octyl azulene8. Get Og. yield,
Theoretical yield 13.9% from dinitrochlorobenzene, 4-
Apparent yield 17.4% from octylpyridine.

The synthesis of these starting compounds is usually carried out by [Method J described in the literature,
P, Wibout and J, W, Hey, Recuei.
ldes Travaux Chimiques de
s Pays-Bas.

(Reel, Trav, Chim) Volume 72, No. 5
13 (1953), the raw material compound 4-n-octylpyridine was used as the solvent, but in the water droplet, inexpensive ethanol and pyridine were used as the solvents.

1. Synthesis of 3-diformyl-4,6,8-trimethylazulene 4. 1.36 g (8 mmol) of 6.8-trimethyl azulene was dissolved in 32 ml of dimethylformamide.

While cooling with water, 4.0 g (26 mmol) of phosphorus oxychloride is added dropwise, and the mixture is stirred at 18 to 20° C. for 90 minutes to carry out the reaction. The reaction solution was poured into Taden ice water, made alkaline with dilute caustic soda solution, extracted with chloroform, washed with water, and recovered the solvent.
6. Add a formylated product of 8-trimethylazulene. The monoformyl compound is eluted using chloroform on activated alumina chromatography, and then the diformyl compound is eluted with chloroform/acetonitrile 40:1. After recovering the solvent, 0.14 g of diformyl compound was obtained. Yield 7.7% 1.3-diformyl-4,6,8-trimethylazulene m, p, 167-168'λwax (
ethanol) 475nniIR (KBr)
Qc=o 1635011-1HNMR δ(pp+a) Assignment 10.35 1.3-CI(O 8,632-H 7,525,7-H 3,074,8-Mn 2.70 6-H5 W 1,3 -Synthesis of diformyl-5-methylazulene 0.34g (2.4 mmol) of 5-methylazulene was dissolved in dimethylformamide 8 mol, and 1.2 g (7.5 mmol) of phosphorus oxychloride was added under water cooling, and the temperature was gradually raised. 7
React for 45 minutes at 3-75°C. After cooling, it was poured into ice water and made alkaline with dilute caustic soda solution.
Chloroform extraction, water washing, solvent recovery, column chromatography (
0.25 g of 1°3-diformyl-5-methylazulene was obtained by treatment with activated alumina. Yield 53%. The physical properties of the obtained 1,3-diformyl-5-methylazulene are as follows.

m, p, 136~137@λwax
(Ethanol) 490nmIR (KBr)
-v) c=o 1640cm-"'HNMR δ (ppm) N6 genus 10, 22 1 or 3-CIIOlo, 20
3 or 1-ClO 2,784-H 9,658-H 8,502-H 8,036-H 7,737-H 2,825-Me Transverse 1,3-diformyl-6-tart-butyl Synthesis of azulene 0.44 g (2.4 mmol) of 6-tart-butyl azulene was dissolved in 8 ml of dimethylformamide, 1.2 g (7.5 mmol) of phosphorous oxychloride was added under water cooling, and the reaction was carried out in the same manner as in Example 2. After the treatment, 0.11 g of 1,3-diformyl-6-tart-butyl azulene was obtained. Yield 19.2% 1.3-diformyl-6-tart-butyl azulene r
ri, p 127~128'λmax
(Ethanol) 475 stop IRVlc2o 1638 (!II -1J (N
MR δ (ppm) Attribution 10.20 1.3-ClO2,452-H 9,704,8-H 8,055,7-H l,50 t-Bu 1 degree ± 1,3-diformyl-6- Synthesis of octyl azulene 1.0 phosphorus oxychloride in 15 ml of dimethylformamide
g (6,5 mmol) and then 6-octylazulene O,lOg (0,45 mmol) and heated at 60°C.
Let it react for 3 hours. After cooling, post-treatment was carried out in the same manner as in Example 2, and 1,3-diformyl-6-octyl azulene 0.
Obtain 0.6g. Yield 24% m, p, 53°C λmax (ethanol) 475nn+IR (KBr)
Qc=o 1638 (1m-”) The 1,3-diformylalkylazulene of the present invention is a new compound and can be used as a raw material for the production of pharmaceuticals and as an intermediate for the production of sensitizers for electrophotographic organic photoconductors. It is useful as a compound, and the production method allows the reaction to be carried out under mild conditions.

Claims (2)

[Claims] (1) Diformylalkylazulene derivative represented by the following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (I) (In the formula, R_1, R_2, R_3, R_4 and R_5 are H or an alkyl group. .However, R_1, R_2, R_
3, at least one of R_4 and R_5 is an alkyl group. ) (2) Alkyl azulene represented by the following general formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R_1, R_2, R_3, R_4 and R_5 are H or an alkyl group. However, , R_1, R_2, R_
3, at least one of R_4 and R_5 is an alkyl group. ) The following general formula (I) is characterized in that the reaction product is made alkaline by reacting with phosphorus oxychloride and dimethylformamide or N-methylformanilide at a temperature of 100°C or less in the presence or absence of a solvent. A method for producing a diformylalkylazulene derivative represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) (In the formula, R_1, R_2, R_3, R_4 and R_5 are the same as above)