JPS6038353A - Production of epsilon-guanidino-eta-caproic acid rho-ethoxycarbonylphenyl ester - Google Patents

Abstract

PURPOSE:To produce the titled compound in high purity, by carrying out the reaction of epsilon-guanidinocaproic acid with p-hydroxybenzoic acid ethyl ester via a mixed acid anhydride using a dihydroquinoline derivative. CONSTITUTION:The objective compound is produced by reacting epsilon-quanidinocaproic acid or its salt with p-hydroxybenzoic acid ethyl ester. The reaction is carried out by reacting epsilon-guanidinocaproic acid or its salt first with the dihydroquinoline derivative of formula II (R1 is lower alkyl; R2 is lower alkyl or ethoxycarbonylphenyl), and then reacting the resultant mixed acid anhydride of formula III (R is lower alkyl) with p-hydroxybenzoic acid ethyl ester in a solvent such as dimethylformamide at room temperature or under cooling. USE:Remedy for pancreatitis.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing ε-guanidino-n-caproic acid p-ethoxycarbonylphenyl ester. This compound is a substance used in the treatment of pancreatitis disease.

The present invention relates to a novel method for producing the compound. That is, and-guanidinocaproic acid or its salt and p
This is a method in which a dihydroquinoline derivative is used in the reaction with -hydroxybenzoic acid ethyl ester.

Here, the salt form of 9-guanidinocaproic acid is used. Examples of dihydroquinoline derivatives include compounds represented by the formula [wherein R1 represents a lower alkyl group and R2 represents a lower alkyl group or an ethoxycarbonylphenyl group]. Here, in 1, the lower alkyl group refers to a C0-4 alkyl group.

Examples of solvents used in the reaction include dimethylformamide, dimethylsulfoxide, ethylpyrrolidone, dimethylacetamide, aqueous acetonitrile, aqueous tetrahydrofuran, and aqueous dioxane, and the reaction is carried out at room temperature to low temperature.

In a preferred embodiment of the present invention, ε-guanidino-
Either a method of adding a dihydroquinoline derivative into a mixture of caproic acid or its salt and p-hydroxybenzoic acid ethyl ester, or a method of adding ε- into a dihydroquinoline derivative.
A method of adding a mixture of guanidino-n=caproic acid or its salt and p-hydroxybenzoic acid ethyl ester is mentioned.

In the present invention, the reaction mechanism is considered to proceed via a mixed acid anhydride, as shown below.

Group H, rJ>-State C taste C0Q4Q)-cODcΔd5
-IN [In the formula, R1 and R2 are the same as above. M represents an acid. ] In the present invention, E-guanidino-n-cuff.

Ronic acid is best used in the form of its hydrochloride, and the obtained ε-
guanidino-n-caproic acid p-ethoxycarbonylphenyl ester hydrochloride c) sodium bicarbonate in water;
Induced to carbonate by sodium carbonate, potassium carbonate, etc. Then, a highly pure carbonate of the compound is obtained.

E-guanidino-n-caproic acid p obtained by
-Ethoxycarbonylphenyl ester salt is easily salt-exchanged when reacted with methanesulfonic acid in acetone, and turns into methanesulfonate. The mono-guanidino n-caproic acid p-ethoxycarbonylphenyl ester methanesulfonate thus obtained can be obtained very easily and as a highly pure crystal of the compound when crystallized using methyl isobutyl ketone as a solvent. The use of solvents is extremely advantageous industrially.

The present invention will be further explained in detail with reference to Examples below.

Example 1.

ε-guanidino-n-caproic hydrochloride 6, 2 9
f was added to 85 ml of N,N-dimethylformamide and dissolved by heating. After cooling to room temperature, 9.97 f of p-hydroxybenzoic acid ethyl ester was added. Then EEDQ
8.16 g was added and reacted at room temperature for 24 hours. Slow evolution of carbon dioxide gas was observed. It was concentrated under reduced pressure, 5Qml of toluene was added to the residue, and extracted with 5Qml of water. The resulting aqueous layer was washed with 59 ml of toluene and 0 ml was added thereto, and an aqueous solution consisting of 5.01 ml of sodium bicarbonate and 50 ml of water was added little by little and reacted for 15 minutes. The precipitated crystals were separated, washed with water, and washed with acetic acid to give ε-guanidine, non-n-caproic acid, p-dicarbonyl chloride, etc.
6.25 h of carbonate-free white crystals were obtained. m, p 83
-86C yield: 54.3% Example 2 6.001 ε-guanidino-n-caprone Hp-engineered toxycarbonylphenyl ester carbonate obtained in Example 1 was suspended in dOml of acetone, and 1.0 ml of methanesulfonic acid was suspended in dOml of acetone. 5
7 Da was added dropwise and reacted for 10 minutes. After separating the insoluble matter and distilling off the acetone under reduced pressure, 725 ml of methyl isobutyl ketone was added to the residue, and after heating and dissolving, it was cooled. 6,36 f/ was obtained. m, p,
Recrystallization from 90-91t:'methyl etheptyl chloride gave ε-guanidino-n-cabrosiic acid p-ethoxycarbonylphenyl ester methanesulfonate 6,289.

m, I), 90-91C Yield 96.4%Example 3゜ε-guanidino-n-caproate 1M 6.299% N
, N-dimethylformamide (35ml) and dissolved by heating. After cooling at room temperature, 5.989 g of p-hydroxybenzoic acid ethyl ester was added. Then lIDQ10.01
g and reacted at room temperature for 24 hours. Slow evolution of carbon dioxide gas was observed. Concentrate under reduced pressure and add 10% of toluene to the residue.
0 ml was added and extracted with 50 ml of water.

The resulting aqueous layer was saturated with sodium chloride, extracted with ethyl acetate, and concentrated under reduced pressure. Add 3Qml of water to the residue, add little by little an aqueous solution consisting of 5.041ml of sodium bicarbonate and 50ml of water, and react for 15 minutes. Separate the precipitated crystals, wash with water, and then with acetone to obtain ε-guanidino-〇-
6.869 white crystals of caproic acid p-ethoxycarbonylphenyl ester carbonate were obtained.

m, p, 88-90? Z' Yield 59.6% Example 4
゜6.00y of monoguanidino-caproic acid p-ethoxycarbonylphenyl ester carbonate obtained in Example 3 was clouded with 30ml of acetone, and 1.57ml of methanesulfonic acid was added.
f was added dropwise and reacted for 10 minutes. Insoluble matter was separated and the acetone was distilled off under reduced pressure, and the resulting crystals were poured into 25 ml of methyl isobutyl ketone! The product was recrystallized with methyl isobutyl ketone and then washed with ether to obtain ε-guanidino-n-caproic acid p-ethoxycarbonylphenyl ester methanesulfonate 6.311.

m, T), 90-91C yield 96.9% In addition, in the examples, EED Ql: N-ethoxyracarbonyl-2
-ethoxy-1,2-dihydroquinoline, IIDQ is N-isobutoxycarbonyl-2-isosoftoxy1
, 2-dihydroquinoline.

Patent Applicant: Teikoku Kagaku Sangyo Co., Ltd., Commissioner of the Patent Office, 1゜ Indication of the case and its relationship with the -Production method of guanidino n-caproic acid p-ethoxycarbonylphenyl ester 3, Person making amendment case Patent applicant address: Osaka City 1-1-18-4 Kitahorie 1-chome, Nishi-ku, Specification subject to amendment

Claims (1)

[Claims] Formula 1 [wherein R represents a lower alkyl group]. ε-guanidino-n-caproic acid p, which is characterized by reacting a mixed acid anhydride represented by the formula or a salt thereof with p-hydroxybenzoic acid ethyl ester to obtain a compound represented by the formula or a salt thereof - A method for producing ethoxycarbonylphenyl ester or a salt thereof. 2. The manufacturing method according to claim 1, wherein the salt is a hydrochloride. 3. When reacting ε-guanidinocaproic acid or its salt with p-hydroxybenzoic acid ethyl ester to obtain and-guanidino n-caproic acid p-ethoxycarbonylphenyl ester or its salt, 1. A method for producing ε-guanidino-n-caproic acid p-ethoxycarbonyl ester or a salt thereof, which comprises using a dihydroquinoline derivative. 4. The manufacturing method according to claim 3, wherein the salt is a hydrochloride.