JP2001199963A - Method for producing quinolylpropenal - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing 3-[2-cyclopropyl-4-fluorophenyl)-3- quinolyl]prop-2-enal in high yield from a quinolylacrylonitrile derivative by a simple means. SOLUTION: This method comprises the following process: 3-[2- cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-ene nitrite is reduced by Raney nickel in the presence of formic acid and water at 0.25-1 vol. time based on the formic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a quinolylpropenal derivative from a quinolylacrylonitrile derivative. The quinolylpropenal derivative obtained by the production method of the present invention is, for example, a compound useful as a synthetic intermediate of a cholesterol-lowering agent (HMG-CoA reductase inhibitor).

[0002]

2. Description of the Related Art Conventionally, as a method for producing a quinolylpropenal derivative, quinoline acrylate is reduced with diisobutylaluminum hydride to obtain quinolylpropanol, which is then converted to oxalyl chloride and dimethyl sulfoxide or manganese dioxide. A two-step production method is known, which comprises oxidizing to quinolyl propenal using a compound (J. Med. Chem., 34 , 367 (19).
91)). As a method for producing a propenal compound by selectively reducing only a cyano group to a formyl group while maintaining a double bond of an acrylonitrile compound, a method using diisobutylaluminum hydride as a reducing agent is known. (Heterocycles, 29 , 691 (1989)). However, any of these methods requires the use of diisobutylaluminum hydride or manganese dioxide, which requires complicated handling and post-treatment, and is disadvantageous as an industrial production method.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems and to obtain a quinolylpropenal derivative from a quinolylacrylonitrile derivative in a high yield by a simple method. Another object of the present invention is to provide a method for producing a quinolylpropenal derivative which is more advantageous.

[0004]

SUMMARY OF THE INVENTION The object of the present invention is to provide the following equation (1).

[0005]

Embedded image

The quinolyl acrylonitrile derivative {3- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] prop-2-ennitrite} represented by the formula Formula (2) characterized in that it is reduced with Raney nickel in the presence of 25 to 1 volume of water.

[0007]

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The problem is solved by a method for producing a quinolylpropenal derivative {3- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] prop-2-enal} represented by the formula:

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The quinolylacrylonitrile derivative of the formula (1), which is a starting material for the production process of the present invention, is a novel compound, but is a known 2-cyclopropyl-4- (4-
(Fluorophenyl) quinoline-3-carbaldehyde (JP-A-1-279866, EP-A-304066, U.S. Pat. No. 5,011,930) includes diethyl cyanomethyl phosphonate, preferably sodium hydroxide. It can be produced by reacting with a suitable base in the presence of a solvent such as an aromatic hydrocarbon.

The Raney nickel used in the reduction reaction used in the production method of the present invention is an alloy containing nickel and aluminum as main components, and has a nickel content of preferably 10 to 90% by weight, more preferably 40% by weight. ~ 80
% By weight. Normally, expanded Raney nickel is used, but pretreated Raney nickel or stabilized Raney nickel can be used by various methods. Further, Raney nickel containing metals such as cobalt, iron, lead, chromium, titanium, molybdenum, vanadium, manganese, tin, and tungsten can also be used.

[0011] The amount of Raney nickel used in the reduction reaction of the production method of the present invention is preferably 0.1% in terms of nickel atom, based on the quinolylacrylonitrile derivative as the raw material.
It is 30 to 2 times by weight, more preferably 0.30 to 1.2 times by weight.

The reduction reaction using Raney nickel in the production method of the present invention is carried out in the presence of formic acid and water in an amount of 0.25 to 1 times the volume of formic acid. According to the study of the present inventor, by using water in this range, the desired quinolylpropenal derivative of the formula (2) can be obtained in high yield.
It was also confirmed that the reaction can be obtained under a reaction condition that can be easily controlled.

The amount of formic acid used is preferably 0.25 to 50 times the weight of the raw material quinolylacrylonitrile,
More preferably, it is 1 to 40 times by weight.

In carrying out the reduction reaction in the present invention, a solvent other than formic acid or water may be present. The solvent that can be used is not particularly limited as long as it does not inhibit the reaction. For example, amides such as N, N-dimethylformamide; methanol, ethanol,
Alcohols such as isopropyl alcohol and t-butyl alcohol; ketones such as acetone and methyl ethyl ketone; aliphatic hydrocarbons such as pentane and cyclohexane;
And aromatic hydrocarbons such as toluene and xylene.

In the case where another solvent as described above is used in the reduction reaction, it is preferably used in an amount of not more than 60 times by weight, more preferably not more than 10 times by weight, based on the starting quinolylacrylonitrile derivative. Can be These solvents may be used alone or in combination of two or more.

The reduction reaction of the present invention is preferably carried out by bringing formic acid and water into contact with a quinolyl acrylonitrile derivative in the presence of Raney nickel in a liquid phase. For example, Raney nickel, quinolyl acrylonitrile are prepared in an inert gas atmosphere. Derivatives, formic acid, and water are mixed, and the mixture is heated and stirred, for example, under normal pressure or under pressure. The reaction temperature at that time is preferably 20 to 110 ° C,
More preferably, it is 30 to 80 ° C.

If necessary, the reactivity may be adjusted by adding an inorganic base, an organic base, a platinum salt, etc. to the system (Teruo Kubo, Shinichiro Komatsu, Raney Catalyst (Kawaken Fine Chemicals) Published by Co., Ltd.), 123-14
On page 7).

The final product, the quinolylpropenal derivative of the formula (2), is filtered and extracted after completion of the reaction, and separated and separated by a general method such as distillation, recrystallization, column chromatography and the like. Purified.

[0019]

EXAMPLES Next, the present invention will be described specifically with reference to examples, but the scope of the present invention is not limited to these examples.

Reference Example 1 Synthesis of 3- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] prop-2-ennitrite Internal volume equipped with a stirrer, thermometer and dropping funnel 100m
L in a glass flask under a nitrogen atmosphere under a atmosphere of 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-.
4.98 g (17.1 mmol) of carboxaldehyde, 3.10 mL (18.8 mmol) of 98% pure diethylcyanomethylphosphonate, 0.15 mL (0.33 mL) of tricaprylmethylammonium chloride (Aliquat 336: manufactured by Aldrich) Mmol) and toluene 3
5 mL was added, and the solution temperature was maintained at 25 to 35 ° C.
A 10.1 g (50.5 mmol) weight% aqueous sodium hydroxide solution was slowly added dropwise over 50 minutes, and the mixture was reacted at the same temperature for 3 hours. Thereafter, 0.14 mL (0.85 mmol) of 98% pure diethylcyanomethylphosphonate was added and reacted at the same temperature for 66 hours. After completion of the reaction, 5 mL of water was added, and the mixture was stirred for 30 minutes. 50 mL of toluene was added to the obtained reaction solution, the organic layer was separated, washed with 10 mL of a 10% by weight aqueous sodium hydroxide solution, and 10 mL of saturated saline was added. Then, 1 mol / L hydrochloric acid 5.6
After neutralization by adding mL, the organic layer was taken out and transferred to a 200-mL glass flask equipped with a stirrer. Then, 1.60 g of anhydrous sodium sulfate was added and stirred at room temperature for 1 hour. Further, activated carbon 0.14 g (powder type: manufactured by Wako Pure Chemical Industries, Ltd.) and silica gel (Wakogel C-200: manufactured by Wako Pure Chemical Industries, Ltd.) After adding 0.62 g and stirring at room temperature for 1.75 hours, the mixture was filtered through Celite,
Celite was washed with 50 mL of toluene. The obtained reaction solution was concentrated under reduced pressure to precipitate crystals. The crystals were dissolved by heating, and then 30 mL of hexane was added and the mixture was heated under reflux for 30 minutes. Thereafter, the solution was cooled to 5 ° C. and stirred for 2 hours. Crystals were precipitated. The crystals were filtered, washed with 30 mL of hexane, and dried under reduced pressure.
After drying at 5 ° C., 4.81 g of 3- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] prop-2-ennitrite was obtained as white crystals (yield 90%). .

The obtained 3- [2-cyclopropyl-4-
(4-Fluorophenyl) -3-quinolyl] prop-2
-The physical property values of ennitrite are described below. Melting point: 175-176 ° C, EI-MS (m / e): 31
3 (M-1), CI-MS (m / e): 315 (M +
1)

Example 1 Production of 3- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] prop-2-enal 5 mL of internal volume equipped with a stirrer, thermometer and dropping funnel 3- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] prop-2-ennitrite 3 synthesized in Reference Example 1 in a nitrogen atmosphere under a nitrogen atmosphere.
14 mg (1.0 mmol), 2.25 mL formic acid (10
0% formic acid conversion, 60 mmol), water 0.75 mL, and water-containing developed Raney nickel (manufactured by Kawaken Fine Chemical Co., Ltd .: NDHT-90: nickel content 50% by weight)
Product) 620 mg (5.3 mmol as nickel atom)
Was added and reacted at 80 ° C. for 1.5 hours. After the reaction,
After cooling to room temperature and adding 9 mL of water and 9 mL of 1 mol / L hydrochloric acid, the catalyst was filtered through celite. The celite was then washed twice with 1 mL of 2-butanol and twice with 9 mL of toluene.
After washing twice, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to yield a yellow solid having a purity of 97%.
307 mg of 3- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] prop-2-enal in% (area percentage by high performance liquid chromatography)
Was obtained (91% yield).

The physical properties of 3- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] prop-2-enal are described below. CI-MS (m / e); 318 (M + 1) ¹ H-NMR (CDCl ₃ , δ (ppm)): 1.07 to
1.13 (2H, m), 1.40-1.45 (2H,
m), 2.32 to 2.37 (1H, m), 6.43 (1
H, dd, J = 7.8, 16.2 Hz), 7.22-
7.26 (4H, m), 7.35 to 7.38 (2H,
m), 7.55 (1H, d, J = 16.2 Hz), 7.
64 to 7.69 (1H, m), 7.97 (1H, d, J
= 8.4 Hz), 9.51 (1H, d, J = 7.5H)
z)

Example 2 The same operation as in Example 1 was carried out except that the reaction conditions were changed to 65 ° C. for 5 hours to obtain a yield of 8
At 3%, 3- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] prop-2-enal was obtained.

Example 3 The same operation as in Example 2 was carried out except that the used amount of formic acid was changed to 1.8 mL and the used amount of water was changed to 1.2 mL. 3- [2-
Cyclopropyl-4- (4-fluorophenyl) -3-
[Quinolyl] prop-2-enal was obtained.

Example 4 The amount of formic acid used was 2.55 mL
And the same operation as in Example 2 was carried out except that the amount of water used was changed to 0.45 mL.
[2-cyclopropyl-4- (4-fluorophenyl)
-3-quinolyl] prop-2-enal was obtained.

Comparative Example 1 The same operation as in Example 2 was carried out except that the used amount of formic acid was changed to 1.2 mL and the used amount of water was changed to 1.8 mL, to give 3- [2-cyclopropyl. −
4- (4-Fluorophenyl) -3-quinolyl] prop-2-enal was obtained with a yield of 70%.

[0028]

According to the production method of the present invention, the quinolylpropenal derivative of the formula (2) can be produced in a high yield from the quinolylacrylonitrile derivative of the formula (1) by a simple method. Therefore, it is possible to provide an industrially advantageous method for producing quinolyl acrolein.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Shigeei Nishino 5 in 1978 Kogushi, Oji, Ube City, Yamaguchi Prefecture Inside Ube Research Institute, Ltd. (72) Inventor Hideyoshi Shima 5 Ube in 1978, Kogushi, Obe City, Ube City, Yamaguchi Prefecture Inside Ube Research Institute, Kosan Co., Ltd. (72) Inventor Takashi Harada 5 at 1978 Kogushi, Oji, Ube City, Yamaguchi Prefecture Inside Ube Research Laboratories (72) Inventor Naoko Okada 5 Ube, 1978 Kogushi Oaza, Ube City, Yamaguchi Prefecture Ube Industries, Ltd. F-term in the Ube Research Laboratories (reference) 4C031 BA07 BA08 BA09 4H039 CA62 CB30

Claims (3)

[Claims] (1) Formula (1) Wherein the quinolylacrylonitrile derivative represented by the formula is reduced with Raney nickel in the presence of formic acid and 0.25 to 1 times by volume of water with respect to formic acid,
Formula (2) A method for producing a quinolylpropenal derivative represented by the formula: 2. The quinolyl according to claim 1, wherein Raney nickel is used in an amount of 0.30 to 2 times by weight in terms of nickel atom with respect to the quinolyl acrylonitrile derivative of the formula (1). A method for producing a propenal derivative. 3. The quinolylpropenal derivative according to claim 1, wherein formic acid is used in an amount of 0.25 to 50 times by weight based on the quinolylacrylonitrile derivative of the formula (1). Manufacturing method.