JPH04112860A - N-(substituted benzoyl)-n-(3-chlorophenyl)-beta-alanine and salt thereof - Google Patents

Abstract

NEW MATERIAL:An N-(substituted benzoyl)-N-(3-chlorophenyl)-beta-alanine expressed by the formula [X and Y are 1-4C lower alkyl, methoxycarbonyl, dimethylamino, phenyl, cyano, nitro, trifluoromethyl or halogen; m and n are 0-2 (both are not simultaneously 0); Z is H, alkali metal, alkaline earth metal, ammonium or organic cation] and salts thereof. EXAMPLE:N-(2-Methylbenzoyl)-N-(3-chlorophenyl)-beta-alanine. USE:An intermediate for producing 1-(substituted benzoyl)-7chloro-2,3-dihydro-4(1 H)-quinoline derivatives having diuretic, hypotensive, antiedemic and ascitic removing action. PREPARATION:3-(3-Chloroanilino)propionic acid is reacted with a desired substituted benzoyl halide in the presence of a base to afford the compound expressed by the formula.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to the following general formula (I) (wherein X and Y each represent a different substituent, and a linear or branched lower alkyl group,
A methoxycarbonyl group, a dimethylamino group, a phenyl group, a cyan group, a nitro group, a trifluoromethyl group, or a halogen, and n or m is not 0 at the same time, but each is a number from 0 to 2, and 2 is a hydrogen atom. , alkali metals, alkaline earth metals, ammonium, or group, phenyl group, cyano group, nitro group, trifluoromethyl group, or halogen, and n
Or m is not 0 at the same time, but is a number of O to 2, and 2 is a hydrogen atom, an alkali metal, an alkaline earth metal,
Ammonium or an organic cation. This invention relates to a novel N-(substituted benzoyl)-N-(3-chlorophenyl)-β-alanine derivative represented by:

These derivatives have 1-(
(substituted benzoyl)-7-chloro-2,3-dihydro-4
It is extremely useful as a new intermediate in the synthesis of (LH)-quinolinone derivatives.

[Prior Art] Conventionally, N-(substituted benzoyl) proposed by the present inventors
Examples of compounds similar to -N-(3-chlorophenyl)-β-alanine include 2-methyl-N-(3-chlorophenyl)-N-(2-cyanoethyl)benzamide, which is found in JP-A-56-161361. Nitriles such as Bull, Chim, Farm, 1
20 (19811 and Dutch patent NL-6717
N-(3-chlorophenyl) found in Report No. 715 -
Ester bodies such as N-benzoyl-〇-alanine ethyl ester are known.

In addition, the compound of the present invention can be used in industrial applications such as 1-(substituted benzoyl)-7-chloro-23-dihydro-4(L
Regarding the synthesis of H)-quinolinone derivatives, 3-
(3-chloroanilino)propionic acid was cyclized using highly concentrated oleum, and the resulting 7-chloro-2,
A method is known in which 3-dihydro-4(IH)-quinolinone is reacted with various substituted benzoyl halides and further converted into a derivative having the desired physiologically active action (Japanese Patent Laid-Open Publication No. 239270/1983).

[Problems to be Solved by the Invention] However, the above-mentioned 7-tri-4-2,3-dihydro-4
In order to industrially produce (LH)-quinolinone using the method described in Japanese Patent Publication No. 1-55270, it is necessary to use large amounts of fuming sulfuric acid, which is highly dangerous and also poses problems in terms of wastewater treatment. This is extremely problematic from an industrial standpoint. 7-chloro-2,3-dihydro-4(IH)-
Other methods for synthesizing quinolinone include a method using HF/BFx as a cyclization condensation agent as described in Japanese Patent Publication No. 2-22750, and Japanese Patent Application Laid-open Nos. 60-87266 and 60-87267. A method has been proposed in which phosgene is first reacted, the N-position is protected, and then cyclized, as in
/ Because it uses BF and phosgene, it is not suitable for industrial use.

In view of these problems, industrial production of 1-(substituted benzoyl)-7-chloro-2,3-dihydro-4(IH) quinolinone derivatives is proposed in JP-A No. 63-239270. For this purpose, separate intermediates and production methods were desperately needed.

[Means for Solving the Problems] As a result of intensive studies to solve the above-mentioned problems, the present inventors discovered that N-(substituted benzoyl)-N- is novel in itself.
(3-chlorophenyl)β-alanine and its salts were discovered, and 1-(substituted benzoyl)-7- was proposed in Japanese Patent Publication No. 63-239270 using these derivatives in an industrially very advantageous method. It has been found that chloro-2°3-dihydro-4(IH)-quinolinone derivatives can be prepared.

That is, the present invention provides diuretic, antihypertensive, antiedema and 1-(substituted benzoyl)-7-chloro-2,3-dihydro-4 (LH), which has ascites removal effect
-It has made it possible to produce quinolinone derivatives by an industrially extremely advantageous method.

-F]9 The synthesis of the compound of formula (I) uses 3-(3-chloroanilino)propionic acid, which is a known compound per se, as a starting material, and an organic or inorganic base and a polar or non-polar base that does not participate in the reaction. This can be achieved by reacting with a desired substituted benzoyl halide in the presence of a solvent.

Examples of organic bases used at this time include aliphatic and aromatic tertiary amines such as triethylamine, tri-n-butylamine, N,N-dimethylaniline, and pyridine; examples of inorganic bases include alkali metals, Mention may be made of alkaline earth metal hydroxides, carbonates and bicarbonates.

The solvent used is not particularly limited as long as it does not participate in the reaction, but examples include non-polar solvents such as toluene, monochlorobenzene, dichloromethane, polar solvents such as tetrahydrofuran, 4-dioxane, acetonitrile, and water. It is also possible to adopt a heterogeneous system of a nonpolar solvent and water or a homogeneous system such as a water-soluble solvent and water.

The amount of substituted benzoyl halides used is based on the 3-
(3-chloroanilino)propionic acid, 0.7 to 1.3 times the molar ratio near the theoretical amount, preferably 09 to 1
．． Similarly, the amount of organic or inorganic base used is a 1.0 to 1.5 times molar ratio of the theoretical amount to a slight excess of 3-(3-chloroanilino)propionic acid as the raw material. , preferably 1.0 to 1.1 times the molar ratio.

The amount of the solvent to be used is 1 to 30 times, preferably 3 to 15 times, the weight of the raw acid.

The reaction temperature is carried out in the range of -10 to 50°C, preferably 0 to 30°C, and usually the substituted benzoyl halides are mixed with 3-[3-chloroanilino)propionic acid in order to maintain an appropriate temperature. It is desirable to drop a solvent dilution of the base.

The compound of the present invention represented by general formula (I) can be in the form of a salt with any base. Specific salt forms include 5, for example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, salts with organic bases such as ammonium salts, benzylamine salts, and diethylamine salts, and arginine salts. Examples include salts and salts with amino acids such as lysine salts.

N-(substituted benzoyl)-N- thus obtained
(3-chlorophenyl)-β-alanine is purified by recrystallization, column chromatography, etc., if necessary, to produce 1-(substituted benzoyl), which has diuretic, hypotensive, etc.
It can be easily converted into a -7-di4-2,3-dihydro-4(LH)-quinolinone derivative by the following method.

That is, the synthesized N-(substituted benzoyl)N-(3-chlorophenyl)-β-alanine and its salts are converted into N-substituted benzoyl by using reagents such as thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, or phosgene if necessary. )-N-(3-
(chlorophenyl)-β-alanyl chloride, and further, this acid chloride derivative is subjected to an intramolecular Friedel-Crach reaction in the presence of a Lewis acid catalyst such as anhydrous aluminum chloride, ferric chloride, or antimony pentachloride. Easily cyclized, 1-(substituted benzoyl)-7-chloro-2
, 3-dihydro-4(IH)-quinolinone.

Furthermore, this quinolinone derivative is disclosed in JP-A No. 63-239270.
1-(substituted benzoyl)-7-chloro-2,3-dihydro-4(LH)-quinolinone-4-oxime derivative, which exhibits diuretic, antihypertensive effects, etc., by the method described in the above publication. It is something that can be transformed.

In the present invention, the substituted benzoyl moiety is
The 1-position acyl group of the compound described in JP-A No. 39270 or JP-A-1-121269 may also be used, and the resulting compound may be the acyl group at the 1-position of the compound described in JP-A-63-239270 or JP-A-1-1212.
It can be applied to the synthesis of the compounds described in No. 69.

[Effects of the Invention] When the compound of the present invention is used, there is no need to use highly dangerous reagents such as fuming sulfuric acid and phosgene, which are found in known techniques.
2,3-dihydro-4(LH)-quinolinone derivative,
It is extremely useful because it can be produced industrially safely and without causing problems such as wastewater treatment.

The compound of the present invention is a compound of 1-(substituted benzoyl)-7-chloro-2,3- which has diuretic, antihypertensive, anti-edema and ascites removal activity, which is disclosed in JP-A No. 63-239270.
Since it has many applications in the synthesis of dihydro-4(IH)-quinolinone derivatives, it is extremely useful as a new intermediate in the synthesis of said derivatives.

[Example] Examples illustrating the present invention are shown below.

Example I 6 g of N-2-methylbenzoyl-N-(3-chlorophenyl)-β-alanine 3-(3-chloroanilino)propionic acid are dissolved in 40 mQ of dichloromethane and triethylamine 3. 03g was added.

Subsequently, 4.4 g of o-toluic acid chloride was added dropwise over about 30 minutes at the same temperature, and then the reaction solution was returned to room temperature and stirred for 2 hours. Add the finished solution to 230 mI of 1N-HCl.
After stirring and washing, the dichloromethane layer was separated. The same layer was further washed with water and separated, then dried over anhydrous magnesium sulfate, and dichloromethane was distilled off under reduced pressure. The distilled residue gradually crystallized by standing at room temperature. After dispersing and washing the precipitated crystals with a small amount of ether, filtration and drying were carried out to obtain 6.7 g of the desired white crystals of N-(2-methylbenzoyl)-N-(3-chlorophenyl)-β-alanine. rate 7
4%) was obtained.

m, p,: 110.5-112.5°C m/z:
317 (molecular ion beak) 'H-NMR (CDC1,), δ (ppm)2
, 34 (s, 3H1, 2,73 (t, 21 (1.

4, 20 ft, 2H), 7.05-7.30
(m, 8H)”C-NMR (CDC1,), δ
(ppm): 19.3. 32.3. ．． 45.5
゜125.2. 125.9. 127.4°12
7.5. 127.6. 129.1°129.9
．． 130.3. 134.4°134.7.
135.4. 142.9171.3. 176.
1°I R (KBr), cm-': 1735, 1615. 1590. 15B0
゜1480, 1415. 1250. 123
Example 2 6 g of 3-(3-chloroanilino)propionic acid was added to IN
-N a OH30 + nI2 with stirring, 5 to 10
2.4-dichlorobenzoyl chloride at a temperature of 5 °C
．． 97 g of 60 m 12 tetrahydrofuran solution
It dripped over time. After completion of the dropwise addition, tetrahydrofuran was distilled off under reduced pressure, and the remaining residue was adjusted to pH approximately 1 with 2N-HCβ. About 60 mg of dichloromethane was added, the precipitated oil was extracted and separated, and then washed with water.
After drying over anhydrous magnesium sulfate, dichloromethane was distilled off under reduced pressure.

The remaining oil was mixed with ethyl acetate/n-hexane/acetic acid = 10/2.
The target N-(2,4-dichlorobenzoyl)-N- was purified by silica gel column chromatography at 0/1.
5.87 g (yield: 55.3%) of white crystals of (3-chlorophenyl)-β-alanine were obtained.

m, p,: 112.5-113.5°C m/z:
371 (molecular ion beak) 'H-NMR (CDC1,), δ (ppm):
2.76 (t, 2H), 4.20ft, 2H).

? , HN3.23 (m, 7H) CNMR (CDCIs), δ (ppm):
32.1. 45.4. 126.1°126.8.
127.8 129.4. 129.5°131.4. 134.1 135.5. 142.1°IR (KBr), cm 1730, 1660°14B0. 1440° 128.2° 134.7° 167.2° 1615° 1590° 1405° 1320° Examples 3 to 19 In the same manner as in Example 1, the compounds shown in the following table were obtained.

General Formula (IA) Reference Example 1 117 g of N-(2-methylbenzoyl)-N-(3-chlorophenyl)-β-alanine was dispersed in 1,2-dichloroethane 30n+J2, and a small amount of DMF was added and cooled on ice. After adding 5.3 g of thionyl chloride, the temperature was gradually raised and stirred at 50°C for about 2 hours.
, 2-dichloroethane and a small excess of thionyl chloride were removed to give pale yellow oi1 N-(2-methylbenzoyl)N-(
3-chlorophenyl)-β-alanyl chloride 12.
7g was obtained.

'H-NMR (CDC1,), δ (ppm)
:2.33(s, 3H1, 3,00ft, 2H).

4.21ft, 2H), 6.97~? , 11 (m, 8
H)”C-NMR(CDCIs), δ(pp
m): 19.4. 32.3. 45.3°125.2. 125.8. 127.2°127.4
．． 127.6. 129.2°13,, O, l.

134.9° 171.1° I R, (liquid film) 1780° 1430° Reference Example 2 130.4° 135.1° 171.8 m 1370° 134.6 142.8° 1580° 1470° Reference Example 1 N-(2-methylbenzoyl)-N synthesized by
-(3-10lophenyl)-β-alanyl chloride
11.1 g of 1,72-dichloroethane 50+nJ2
Anhydrous aluminum chloride dissolved in water and cooled with water 10.13
g was added. The temperature was gradually raised while stirring, and the reaction was carried out at 35 to 40°C for 7 hours. After the reaction, the reaction solution was poured into iced hydrochloric acid water, washed for a while, and then the organic layer was separated. Furthermore, the organic layer was washed with diluted hydrochloric acid, saturated brine, saturated sodium bicarbonate, and saturated brine in this order, dried over anhydrous magnesium sulfate, and then 1,2-dichloroethane was distilled off under reduced pressure. The remaining oil was treated with diisopropyl ether, and the precipitated crystals were filtered, washed and dried to give yellow crystals of 1-(2-methylbenzoyl)-7-chloro-2,3.
-dihydro-4(IH)-quinolinone 7.8 g (yield 788%) was obtained.

m, p,: 106-108°C IR(KBr), cm-': 1695, 1655. 1405. 1380°H-
NMR (CDC13), δ (ppm):
2, 34 fs, 3H], 2.80 (t, 2
)1).

4.16(t, 2H1,7,17~7.36(m, 6H
1,7,96 (d, IH) Patent applicant Hodogaya Chemical Industry Co., Ltd. Mochida Pharmaceutical Co., Ltd. (2 idiots)

Claims (1)

[Claims] The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X and Y each represent a different substituent, and a straight chain or branched lower alkyl group,
A methoxycarbonyl group, a dimethylamino group, a phenyl group, a cyano group, a nitro group, a trifluoromethyl group, or a halogen, n or m is not 0 at the same time, but each is a number from 0 to 2, and Z is a hydrogen atom , an alkali metal, an alkaline earth metal, ammonium, or an organic cation. ) Novel N-(substituted benzoyl)-N-
(3-chlorophenyl)-β-alanine and its salts.