JPS5948467A - Preparation of homopiperazine derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound, in high yield, by the ester-exchange of N,N'-bis(3-hydroxypropyl)homopiperazine with a 3,4,5-trimethoxybenzoic acid ester under basic condition while removing the produced lower alcohol. CONSTITUTION:The homopiperazine derivative of formula III {e.g. N,N'-bis[3- (3',4',5'-trimethoxybenzoyloxy)propyl]homopiperazine} is prepared by the ester- exchange reaction of the N,N'-bis(3-hydroxypropyl)-homopiperazine of formula I with the 3,4,5-trimethoxybenzoic acid ester of formula II (R is lower alkyl) in the presence of a base (e.g. sodium ethoxide) while absorbing and removing the by-produced lower alcohol from the system with a molecular sieve. USE:A drug having coronary vessel dilating activity.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides N,N'-bis[3-(5',4',5'
-) Rimethoxybenzoyloxy)-propyl] Homohyherazine production method. Compound C is useful as a medicament that exhibits a coronary artery dilating action.

Conventionally, N,N'-bisC3-(3',4',5'
-Trimethoxybenzoyloxy)propyl]homopiperazine can be produced by 'IfF'; 44
- The method described in Publication No. 23334, that is, N, N'-
Bis(3-hydroxypropyl)homobirazine vC1
5,/l, 5-tritoxybenzoic acid halogen F total reaction or N,N'-bis-(6-balogenprobyl) homobi is reacted with 3.4.5-)rimethoxybenzoic acid metal salt on radin. There are known ways to do this.

However, since the former method uses an acidic substance, there are problems in handling and corrosion of the reaction tank, and there are also industrial disadvantages such as low yield.

As a result of careful consideration by the present inventors in order to solve these drawbacks of the conventional method, we found that 'R;f+s i
N,N'-bis(3-hydroxypropyl)pomobi is 3, which is represented by the general formula (m) (wherein R represents a lower alkyl group)
It has been found that the target compound can be obtained in high yield by performing the transesterification reaction in the presence of a base while adsorbing and removing the lower alcohol that forms 4.5-trimethoxybenzoate with a molecular sieve. The method of the present invention is shown in the following chemical formula.

(R=lower alkyl group) According to flT3 of the present invention, the N,N'-bis(3-hydroxypropyl) homopylene represented by the above formula (II) has a 10- to 20-fold volume J equivalent to radin. 3,4.5 = )° represented by the above formula (III) in benzene
Rimethoxybenzoic acid ester and metal lower alkoxide are allowed to react, and the lower alcohol produced during the reaction is removed using a molecular sieve. /,5/-trimethoxybenzoyloxy)propyl]homobi obtains radin in high yield.

In this case, the 4.5-)rimethoxybenzoic acid ester used is 2.0 to 22 times the mole of the compound represented by formula (11) relative to E7. stomach. Bitten sodium methoxide is U, 1-0.5
Molex cola sieves are suitable for use in the compound represented by the above formula (II), and depending on the structure of the ester moiety, 3A, 4A, 5A or 13X can be It is preferable to use at a temperature of 1 to 20 times.The reaction temperature is preferably from room temperature to the rlB point temperature of the solvent used, and the optimum is 80' to 120°C.The reaction time is 10 to 120 degrees Celsius.
20 hours is better than 11.

Next, the present invention will be explained with reference to Examples.

Example I N,1.1'-bis(3-(3',4',
5'-trimethoxybenzoyloxy)propyl] N,N'-bis(6
-Hydroxypropyl) homobi is Radin, 2.30P (
10,0 mmol) of 3.4.5-) Rimethoxo rest k#? Methyl ester and 0.101i'(1,8
5 mmol] of Sodium F”r Penguin 15
10. The mixture was heated for 10 hours while the methanol produced was adsorbed and removed using a molecular sieve 4A. After the reaction was completed, the reaction solution was diluted twice with 20 g of water and once with 2 g of saturated brine, dried over magnesium KR acid (1 g L), and concentrated under reduced pressure to give 2.8 g of crude product. It was purified using a silica gel column chroma I column (developing solution: 11'ben7ane/methanol (10/2)) to give 2.20 ml (364 mmol). N, N'-bis [3-(3', 4
',5'-trimethoxybenzoyloxy)-propyl]homobi was used to obtain radin.

(s, 18H), 4.35 (t, 4H), Z25 (day,
4H).

ffi −1 1Rν: 2955.1720, 1600, 13
45.1235, 8X 1140.765° Example 2 N, N'-BisC3-('3', 4',
'-Trimethoxybenzoyloxy)propyl] Homobi is N,N'-bis(5-
Hydroxypropyl) Homobi is Radin, 2.5 oil (
10.0 mmol) of 3.4.5-trimethoxybenzoic acid methyl nisder and 0.12f! (1.43 mmol) of potassium ethoxide was dissolved in 15 m/ml of toluene, and the solution was heated and flowed for 12 hours while methanol generated was adsorbed and removed using io, or molecular sieve 4A. After the reaction was completed, the reaction solution was washed twice with 2°m of total water and once with 20 ml of saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product of 2.73P. This was subjected to silica gel column chromatography [Developing solvent:
Benzene/methanol (10/2))
2.23 g (669 mmol) of N,N'-bis[6
-(3',4',5'-trimethoxybenzoyloxy)propyl]homobirazine (↑).

Patent applicant: Nisshin Seifun Co., Ltd. Same day Gastroenterology Co., Ltd.

Claims (1)

[Scope of Claims] N,N'-bis(6-hydroxypropyl)homopiperazine represented by the formula and 3,4 represented by the general formula (wherein R represents a lower alkyl group)
．． 5- A method for producing a homobi-radine derivative represented by the formula, which comprises reacting a trimetoxybenzoate ester in the presence of a molecular sieve and a base.