JPS58105946A - Preparation of aminobutanol ester derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as a gastroenteric function controlling agent, in high yield and purity, by reacting 2-dimethyl-amino-2-phenylbutanol with 3,4,5-trimethoxybenzoic acid lower alkyl ester in the presence of an alkali metal. CONSTITUTION:2- Dimethylamino- 2-phenylbutanol.3, 4, 5-trimethoxybenzoic acid ester can be prepared by reacting 2-dimethylamino-2-phenylbutanol (A) with 3,4,5- trimethoxybenzoic acid lower alkyl ester (B) in the presence of an alkali metal (e.g. Na, K, etc.). The amount of the alkali metal is about 0.005-0.2mol/mol of (A). The present process has various industrial advantages, i.e. the amount of the catalyst can be reduced to about 1/100-1/10 of the conventional method, the catalyst has excellent stability and handleability, the lower alkyl ester of (B) can be recovered in high yield and reused as a raw material, and the objective compound can be separated directly as high purity crystal from the aqueous layer.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new method for producing 2-dimethylamino-2-phenylbutanol/3,4.5-)rimethoxybenzoic acid ester.

2-dimethylamino-2-phenylbutanol 3,4
．． 5-) Rimethoxybenzoic acid ester (I).

In particular, the maleate salt is a useful pharmaceutical compound as a mlI agent for gastrointestinal function.

Conventionally, as a method for synthesizing this compound CD, for example, (1)
A method of reacting 2-dimethylamino-2-phenylbutanol [I) with the acid halide of 3.4.5-trimethoxybenzoic acid [1'] in the presence of a deoxidizing agent such as triethylamine (Japanese Patent Publication No. 55-16416 No.) and (2) Compound [
■] and the methyl ester of compound [I] are reacted in the presence of a large amount of sodium methylate. French Patent No. 1344455, #l German Patent No. 112151?1
No. 6) are known. However, these methods have a number of drawbacks. That is, in the method (1), the acid halide of the compound CI [], which is a raw material, is an unstable compound and is easily decomposed by moisture, and there are disadvantages such as the need for a large amount of deoxidation. be. Further, in the method (2), sodium methylate is required at a molar ratio of about 1 or more, and furthermore, this methylate is unstable and causes a decrease in the purity of the target compound [I].

Both of these methods were not satisfactory as methods for producing the desired compound CI), as they had drawbacks such as a low yield of the desired compound CI).

As a result of extensive research, the present inventors have surprisingly found that if the compound [...] and the lower alkyl ester of compound (1) are reacted in the presence of a small amount of alkali metal, a highly pure compound CI) can be obtained.
It was found that it was possible to cleave with high yield.

According to the present invention based on such knowledge, the target compound CI)
can be obtained by reacting compound CM) with the lower amyl kylnisol of compound I] in a suitable solvent in the presence of a small amount of an alkali metal F. Compound (N,
) Examples of lower alkyl esters include methyl ester and ethyl ester.

Propyl esters, isopropyl esters, phthyl esters, isobutyl esters, etc. can be advantageously used. Examples of alkali metals are:

For example, sodium, potassium, lithium, etc. are mentioned, and the amount used is 0.005 to 0 for compound LIIJ.
．． A molar ratio of 2, preferably 0.01 to 0.1 mol is sufficient. In addition, there are no particular restrictions on the reaction solvent as long as it is an inert solvent (for example, benzene, toluene,
Since it is preferable to use xylene etc. to accelerate the reaction, it is preferable to use a solvent having a boiling point higher than the boiling point of the alkanol.
As mentioned above, in order to further promote the reaction, it is convenient to continue the addition while distilling off the lower alkanol by-produced during the reaction together with the reaction solvent.

After the reaction is completed, if necessary, after removing the remaining alkali metal from the reaction mixture, the target compound [■] is extracted from the reaction solution with hydrochloric acid, and an alkali is added to the hydrochloric acid extracted layer to neutralize it.
The target compound LIJ can be isolated and obtained by extraction with an organic solvent, but if a small amount of acetic acid is added to the Jl acid extraction layer prior to the neutralization operation during the subsequent II & treatment, neutralization can be achieved. As the process progresses, the highly pure target compound [1] is directly precipitated as crystals from the aqueous layer, which simplifies the operation.

This is extremely advantageous in terms of saving solvent. On the other hand, lower af-arekyl ester of compound [1), which is an unreacted raw material, can be recovered at a high rate from the mother liquor (reaction liquid) extracted with hydrochloric acid, and can be reused as a raw material as it is.

Note that the starting material compound (I) of the present invention has two types of optical isomers based on one asymmetric carbon atom.

The method of the present invention uses any of these optically active substances,
Furthermore, the corresponding target compound [I] can be similarly produced using an optically inactive racemate.

As explained in detail below (9) According to the method of the present invention, compared to the known method, (1) the amount of catalyst is about 1/100 to 1/10
(2) The stability of these catalysts,
Rated 2 for ease of handling. In addition, (3) it is possible to recover the unreacted lower alkoxyl ester of compound (It) as a raw material at a high rate, and it can be reused as a raw material as it is.Furthermore, (4) the target compound [−■
The method of the present invention is an excellent industrial production method, as it has many advantages, such as the ability to obtain high-purity crystals directly from the aqueous layer in a high yield.

Example] 2-dimethylamino-2-7enylbutanol 13.2
F and 3,4.5-)rimethoxybenzoic acid methyl ester (23.2 F C1,5 molar ratio) to toluene 305
In addition to w41, refluxing toluene 30- is distilled off under heating. Next, 65"f of entertainment sodium was added, and 120" of toluene was distilled off under heating for about 30 minutes), followed by 65 q of metallic sodium IA (total 0.084 molar ratio).
was added, and toluene 4s- was distilled off under heating (about 1 hour and 30 minutes). The remaining metallic sodium is removed in a refrigerator, and the desired product is extracted from the toluene layer by dilution with 2% salt. After adding a small amount of acetic acid to the extracted layer, a 20% aqueous solution of sodium hydroxide is added dropwise. By filtering the precipitated crystals and drying them, ・crude 2-dimethylamino-2-phenylbutanol・
Parent 4. I-trimethoxybenzoic acid ester 24, is obtained. Yield: 91.1 This product was recrystallized from n-hexane to yield ■17.
Gives crystal 22.1f at 9-80°C. Recover astringent methyl ester 8.6F.

Example 2 2-dimethylamino-2-7enylbutanol S”?(
From 0,11el ratio) and )””n10OrI11
The reaction and treatment were carried out in the same manner as in Example 1 (however, the heating time was 3.
time, toluene distillation amount: 22 d), 6.62 d of crude 2-dimethylamino-2-7enylbutanol/3.4.5-trimethoxybenzoic acid ester was obtained. Yield 65.8m Example 3 2-dimethylamino-2-phenylbutanol 3.3Q
), 3,4.5-) Rimethoxybenzoic acid methyl ester 5.8 Q (1,5 molar ratio), metal sodium h1
6ri (Q, 042 molar ratio) and Silene 66 ready-to-boil.
The reaction and treatment were carried out in the same manner as in Example 1 (however, 42# was used for toluene distillation 1), and the crude '! 12-dimethylamino-2-phenylbutanol/3,4.5-)rimethobenzoic acid ester 5.8:11 is obtained. Yield: 88.1%

Claims (1)

[Claims] (1) 2-dimethylamino-2-phenylbutanol and 3.4.5-) lower alkyl rimethoxybenzoic acid ester are reacted in the presence of an alkali metal. Butanol 3
, 4.5-) Process for producing rimethoxybenzoryo ester. +2) The manufacturing method according to claim 1, wherein the low a alkyl ester is a methyl ester. (3; The manufacturing method according to Claim 11 ε, wherein the alkali metal is sodium.