KR800001357B1 - Process for the preparation of n-(2-substitute-ethyl-1)-3-benzoyl propion amide - Google Patents

Abstract

Title compds. [I, R = H, halogen, lower alky1; X = O, S,: N-R1 (R1 = lower alky1) , useful as cholesterol-lowering agent, were prepd. by reacting II with mixed acid anhydride of benzoy1 propionic acid and chloroethy1 carbonate. Thus, 17.8 g 3-benzoy1 propionic acid, 10.1 g triethy1 amine and 10.85 g chloroethy1 carbonate dissolved in chloroform were stirred with 15.0 g 2-(N-methy1 anilino)ethy1 amine to give 25 g N-[2-(N-ethy1 aniline)ethy1 -3-benzoy1 propion amide.

Description

Method for preparing N- (2-substituted-ethyl-1) -3-benzoyl propionamide

The present invention relates to a process for the preparation of the novel N- (2-substituted-ethyl-1) -3-benzoyl propionamide represented by the following general formula (I).

R¹(여기서 R¹은 저급 알킬기임)를 나타낸다.]Wherein R represents a hydrogen atom, a halogen or a lower alkyl group, and X represents an oxygen atom, a sulfur atom or

R ¹ , where R ¹ is a lower alkyl group.]

N- (2-substituted ethyl-1) -3-benzoyl propionamide (I) obtained by the present invention is a very effective medical substance having cholesterol lowering action. Details thereof will be described later.

Compound (I) of the present invention can be produced, for example, by the following method. In other words, general formula (II)

(Wherein R and X have the same meaning as described above)

The compound represented by the general formula (I) is obtained by reacting the compound represented by the mixture with an acid anhydride produced from benzoyl propionic acid and ethyl chlorocarbon.

The adjustment of β-substituted-ethylamine (II) of the raw materials used in the above method is as follows. That is, in the case of β-phenoxyethylamine, a good yield is obtained by heating a commercially available β-bromoethyl-phenyl ether with phthalimide in the presence of potassium carbonate, and in the case of β-phenylthioethyl amine, 4 Obtained quantitatively by reacting ethylene imine with thiophenol in carbon chloride. In the case of β-N-methylanilino ethyl amine, it is obtained by reacting N-methyl aniline with a bromate of β-bromoethylamine in ethanol.

)과 클로로포름 중에서 반응시킴으로써 일반식(I)로 표시되는 목적 화합물로 유도할 수 있다.The β-substituted ethylamine obtained in this way is a mixed acid anhydride produced from benzoyl propionic acid and ethyl chlorocarbonate (

) And the chloroform to be reacted with the target compound represented by the general formula (I).

The general route of this reaction is shown below.

(Wherein R and X have the same meaning as described above)

Next, the melting points of the compounds of the present invention are shown.

These novel derivatives are extremely effective medical substances having a cholesterol lowering action, and the methods and results of their pharmacological tests are shown below.

A) Serum Cholesterol Lowering Action

Using 300 mg / kg of Triton WR-1339 into the tail vein using Wistar male rats (180-220 g in weight, 5-10 in group 1), 18 hours later, blood was collected and zac Colorimetric quantification was performed by the Zak-Henly variant. The sample was suspended in physiological saline containing 0.2% agar, and 100 mg / kg was administered simultaneously with Triton intraperitoneally.

B) inhibition of free fatty acid release from fat cells

Rat fat cells adjusted by the method of Rod bell were 30 minutes in a sample 10 ⁻⁴ M, Norepinephrine 4 × 10 ⁻⁶ M, and KRB (Krebs bicarbonate buffer) containing albumin 3%. Free fatty acids released by incubation were colorimetrically quantified by the method of Itaya (Ui).

An example is shown below. The numbers in the examples correspond to the compound numbers, and the melting points are in the list and are omitted below.

Example 1

N- [2- (N-ethylaniline) ethyl] -3-benzoylpropion amide

10.85 g of ethyl chlorate dissolved in 15 ml of chloroform in 17.8 g (0.1 mole) of 3-benzoylpropionic acid and 10.1 g (0.1 mole) of triethylamine, and dissolved in 30 ml of chloroform over 1 hour under cooling, angular stripping. (0.1 mol) of solution is added. Furthermore, the reaction solution is stirred for 3 hours. Subsequently, a solution obtained by dissolving 0.1 mol (15.0 g) of 2- (N-methyl anilino) ethylamine in 50 ml of chloroform is added dropwise while stirring, and further, the reaction mixture is stirred for 17 hours. The reaction mixture is then washed with water, the chloroform layer is dried over magnesium sulfate and concentrated under reduced pressure to give an oily residue. A small amount of ether / hexane is added to its oil to crystallize and recrystallized from ethyl acetate / hexane (2/1) to obtain 25 g of the desired product.

Elemental Analysis Value (%)

Calculated Value: C: 73.52 H: 7.14 N: 9.03

Found: C: 73.15 H: 7.28 N: 8.95

Example 2

N- [2- (N-methyl-P-chloroanilino) ethyl] -3-benzoylpropionamide

In the same manner as in Example 1, 10.85 g (0.1 mol) of ethyl chloro carbonate, 17.82 g (0.1 mol) of 3-benzoylpropionic acid, 10.1 g (0.1 mol) of triethyl amine, and 2- (N-methyl-P-chloro 18.2 g (0.1 mol) of anilino) -ethylamines are reacted in chloroform to obtain the desired product. Quantity 27g.

Elemental Analysis Value (%)

Calculated Value C: 66.17 H: 6.13 N: 8.13

Found C: 66.17 H: 6.04 N: 8.10

Example 3

N- [3- (N-methyl-P-bromoanilino) ethyl] -benzoylpropionamide

In the same manner as in Example 1, 7.6 g (0.07 mol) of ethyl chloro carbonate, 12.5 g (0.07 mol) of 3-benzoylpropionic acid, 7.3 g (0.07 mol) of triethylamine, and 2-N-methyl-P-bromo 16.0 g (0.07 mol) of anilino-ethylamine are reacted in chloroform to afford the title compound. Quantity 20g.

Elemental Analysis Value (%)

Calculated C: 58.52 H: 5.44 N: 7.20

Found C: 58.73 H: 5.53 N: 7.10

Example 4

N- [2- (phenylthio) ethyl] -benzoylpropion amide

The reaction is carried out in the same manner as in the case of N-methyl, but the reaction time is remarkably high in the case of sulfur, which is characterized by a short reaction time.

In the same manner as in Example 1, ethyl chlorate, triethylamine and 3-benzoylpropionic acid were reacted on a scale of 0.1 mol, and a solution of 15.3 g (0.1 mol) of 2- (phenylthio) ethylamine was added thereto. Add. Quantity 29g. Recrystallize from benzene.

Elemental Analysis Value (%)

Calculated C: 68.98 H: 6.11 N: 4.47

Found C: 68.70 H: 6.26 N: 4.17

Example 5

N- [2- (P-tolylthio) ethyl] -3-benzoyl-propionamide

By the same operation as in Example 4, a target product having a crude amount of 33 g was obtained on a scale of 0.1 mol. This is recrystallized from benzene.

Elemental Analysis Value (%)

Calculated C: 69.69 H: 6.47 N: 4.28

Found C: 69.58 H: 6.42 N: 4.15

Example 6

N- [2- (P-chloryl thio) ethyl] -3-benzoyl propionamide

The reaction is carried out in the same manner as in the case of N-methyl body, but in the case of sulfur body, the reactivity is remarkably high, so the reaction time is short.

In the same manner as in Example 1, ethyl chlorocarbonate, triethylamine and 3-benzoylpropionic acid were reacted on a scale of 0.1 mol, and a 18.8 g (0.1 mol) of chloroform solution of 2- (P-chlorophenylthio) ethylamine was added. When added, crystals are precipitated directly. This is filtered, the chloroform layer is washed with water, dried and the chloroform is distilled off under reduced pressure to obtain crystals in the residue. Firstly, the target product with 34g of fresh water is obtained in combination with the crystals. This is recrystallized from benzene-ethyl acetate.

Elemental Analysis Value (%)

Calculated C: 62.15 H: 5.21 N: 4.03

Found C: 62.11 H: 5.23 N: 3.74

Example 7

N- [2- (P-chlorophenoxy) ethyl] -3-benzoylpropionamide

As in the case of the sulfur body, the reactivity was higher than that of the N-CH ₃ body, and the post-treatment method was also performed in the same manner as in the case of the sulfur body. An objective of 20 g of fresh water is obtained on a scale of 0.06 moles.

Elemental Analysis Value (%)

Calculated C: 65.16 H: 5.47 N: 4.22

Found C: 65.00 H: 5.43 N: 4.16

Claims (1)

N- (2-substituted ethyl-1) -3- of general formula (I) characterized by reacting a compound of general formula (I) with benzoyl propionic acid and a mixed acid anhydride produced with ethyl chloro Method for preparing benzoyl propionamide.

Wherein R is a hydrogen atom, a halogen or a lower alkyl group X is an oxygen atom, a sulfur atom or

R ¹ , where R ¹ is a lower alkyl group.