KR800000814B1 - Process for preparing morphorinones - Google Patents

Abstract

X=H, halogen, lower alkyl, carboxyl, lower alkoxy, alkoxycarbonyl or carbamoyl;Y=H, halogen, lower alkyl, alkoxy, aralkyloxy, OH, carboxyl, carbonyl or cyano; Z=O or S), useful as anticholesteremics, were prepd. by reaction of epoxides (II; R1=H, lower alkyl) and phenylglycines(III). Thus, 5.3 g N-(m-chlorophenyl) glycine ethylester and 4.6 g p-chlorophenylglycidyl ether were reacted at 180≰C for 24 hr to give 4-(m-chloropheny)-6-(p- ! chlorophenoxymethyl)-2-morphorinone.

Description

Preparation of Morpholinone Derivatives

The present invention relates to a method for producing a novel morpholinone derivative represented by general formula (I).

(In the above meal)

Z represents an oxygen or sulfur atom and X represents a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower alkoxy group, a lower alkoxycarbonyl group or a carbamoyl group. Y represents a hydrogen atom, a halogen atom or a lower alkyl group when Z is a sulfur atom, and a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, an aralkyloxy group or a carboxyl group when Z is an oxygen atom. , Lower alkoxy carbonyl group or cyano group.)

The present inventors have completed the present invention by discovering that the novel compound is effective while trying to search for a compound which has a triglyceride and cholesterol lowering effect in the blood and is useful as an agent for preventing and treating atherosclerosis. That is, this morpholinin derivative represented by general formula (I) has the following general formula

(Y, Z are the same as above)

Epoxides and general formula

(Where X is the same as above and R ₁ represents a hydrogen atom or a lower alkyl group)

The phenylglycine derivatives represented by the formula 3 are directly or at a temperature of 80-180 ° C. in the presence of organic solvents such as benzene, toluene, xylene, N, N-dimethylformamide, dioxane and acetic acid, for example. It is obtained by making it react for 24 hours. This reaction is promoted by acid catalysts, such as hydrochloric acid, sulfuric acid, and acetic acid, for example.

The product in reaction of [II] and [III] was consistent with the product [I] when [VI] was made to react with known compound [V] (Khimicheskie Sredstva Zashchity Rastenii 1970, 256). It is unthinkable that the reaction of [V] and [VI] produces [VII], therefore, in the reaction of [II] and [III], it is concluded that the SN ₂ reaction occurred at the terminal carbon with little steric hindrance. do. In general, it is known that the reaction between phenylglycidyl ethers and anilines occurs at terminal carbons with little steric hindrance. (Chemical Review 59 P737 (1959)).

(Wherein A represents chlorine or cancellation, and X, Y and Z are the same as above).

The morpholinone derivative (I) thus obtained is a completely novel substance and has a significant lipid lowering action. The blood lipid lowering activity is shown in the 1st table | surface.

[Table 1]

Percent reduction in serum lipids after oral administration of 100 mg / kg / day to normal blood lipid content mice (8 week old male mice) for 3.5 days.

Note: The compound name (number) corresponds to that in the second table.

The values shown in Table 1 indicate the change in the concentrations of serum cholesterol and triglycerides after 3.5 days of treatment with each compound at a dose of 100 mg / kg / day. These compounds were administered orally using esophageal mediators twice a day to a group of 10 mice each.

Blood was then collected, usually 4 hours after the last dose, and the cholesterol concentration in serum was measured by an automated analyzer by Lavin and Jack's method, and triglyceride concentration by Casra and Redera's method. In the various examples described in Table 1, the% reduction rate of the treated bacteria is for untreated control bacteria (placebo bacteria), and the value of placebo bacteria is expressed as 100, and as is clear from these results, Compound 2 and Compound 87 Has a stronger triglyceride lowering effect than clofibrate.

Next, although an Example demonstrates this invention in detail, this invention is not limited only to this Example.

Example 1

Preparation of 4- (m-chlorophenyl) -6- (P-chlorophenoxymethyl) -2-morpholinone.

5.3 g (0.025 mol) of N- (m-chlorophenyl) glycine ethyl ester and 4.6 g (0.025 mol) of P-chlorophenyl glycidyl ether were heated at 180 ° C. for 24 hours, cooled, and crystallized from ethanol. Get a decision. The mother liquor was concentrated under reduced pressure, and the residue was refluxed in 10 ml of acetic acid for 6 hours, and then acetic acid was distilled off under reduced pressure, and crystallized in ethanol to obtain 1.5 g of crystals. Both were recrystallized in ethanol-benzene to obtain 5.0 g (yield 57%) of crystals having a melting point of 128-129 ° C.

Elemental Analysis Value: C ₁₇ H ₁₅ ClNO ₃

Hereinafter, a group of compound [I] could be manufactured by the same operation. They are indicated collectively in the second table. In addition, the substance manufactured by the method of Example 1 is represented by compound number 28.

[Table 2]

Claims (1)

The manufacturing method of the morpholinone derivative represented by following General formula [II] characterized by making the epoxide derivative represented by General formula [II], and the phenylglycine derivative represented by General formula [III] react.

Wherein R ₁ represents a hydrogen atom or a lower alkyl group, Z represents an oxygen or sulfur atom, X represents a hydrogen atom, a halogen atom, a lower alkyl group, a carboxyl group, a lower alkoxy group, a lower alkoxycarbonyl group or a carbamo Display the diary. Y represents a hydrogen atom, a halogen atom or a lower alkyl group when Z is a sulfur atom, and a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an aralkyloxy group, a hydroxyl group or a carboxyl group when Z is an oxygen atom. , Lower alkoxy, carbonyl or cyano group.