JPH04356473A - New production method of benzylpiperazine derivative - Google Patents

Abstract

PURPOSE:To obtain the title compound by one process in high yield on an industrial scale by reacting specific two kinds of readily handleable compounds on the market as starting raw materials in the presence of a metal hydrogen complex compound, etc. CONSTITUTION:A compound (e.g. piperazine) shown by formula I ((n) is 0-5) is made to react with a compound (e.g. benzaldehyde) shown by formula II (R<1> to R<5> are methoxy or H) in the presence of a metal hydrogen complex compound (preferably sodium boron hydride) or a borane-based reducing agent (e.g. diborane) usually at room temperature to give the objective compound shown by formula III.

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to a new method for producing polymethoxybenzylpiperazine derivatives useful as coronary circulation improving agents or platelet aggregation inhibitors.

0002

[Prior art and its problems] Chemical 4

0003

[C4]

The polymethoxybenzylpiperazine derivative represented by the formula (wherein R represents a methoxy group or a hydrogen atom, and n represents an integer of 0 to 5) and its salts are used as coronary circulation improving agents, platelet aggregation inhibitors, etc. It is a compound that is useful as
No. 60-155171, JP-A-63
-297327, etc.). When using the polymethoxybenzylpiperazine derivative or its salt as a drug for the treatment, mitigation, or prevention of thrombosis such as cerebral thrombosis, myocardial infarction, or coronary artery thrombosis, or diseases such as intravascular coagulation syndrome (DIC), generally Since it is necessary to administer the drug over a long period of time, there has recently become a need for an industrial manufacturing method for producing it in large quantities to meet the demand. As a method for producing polymethoxybenzylpiperazine derivatives in which n is 2 to 5 in Chemical Formula 4, for example, the method described in JP-A-60-155171 is known. The outline of the manufacturing route is shown in Formula 1.

[0005]

[Formula 1]

[0006] That is, the production method described in the publication is a method for producing a compound C or a compound synthesized in two to one steps from a commercially available compound A or a compound B (in the formula, R represents a methoxy group or a hydrogen atom). D (wherein R is the same as above, and X represents a halogen atom) is used as a starting material, and in 1 to 2 steps, the desired compound, compound E (wherein m is an integer of 2 to 5, R is the same as above). All of the manufacturing methods described here require a large number of steps, three from commercially available compounds, resulting in high manufacturing costs, and the use of halides such as Compound C and Compound D, which are highly irritating to the skin. There were several obstacles to corporateization and industrialization, including problems with workability, especially in production.

Furthermore, in chemical formula 4, n=0, R=OCH3
As a method for producing polymethoxybenzylpiperazine derivatives, 2,3,4-trimethoxybenzaldehyde and piperazine (or a piperazine derivative whose 1-position is protected with a protecting group that can be easily deprotected) are reacted in the presence of formic acid ( JP-A-48-32889, French Patent No. 1,
302,958) and a method of reduction with hydrogen in the presence of a Raney nickel catalyst (British Patent No. 929,252).
specification, French Patent No. 1,302,958 specification, etc.)
However, all of them have low yields (20 to 45%) and cannot be adopted as production methods on an industrial scale.

[0008]Therefore, there is a current need for a production method that can produce the desired polymethoxybenzylpiperazine derivatives and the like in a high yield with a small number of steps using commercially available and easily handled compounds as raw materials.

[0009]

OBJECTS OF THE INVENTION The present invention was made in view of the above-mentioned circumstances, and provides a method for producing polymethoxybenzylpiperazine derivatives, etc. in a single step with high yield using commercially available and easily handled compounds as starting materials. The purpose is to provide.

0010

[Structure of the invention] The present invention is based on chemical formula 1

[0011]

[Chemical formula 1]

(wherein n represents an integer of 0 to 5) and the compound represented by the formula 2

[0013]

[Case 2]

A compound represented by the formula (wherein R1 to R5 each independently represents a methoxy group or a hydrogen atom),
Chemical formula 3 characterized in that the reaction is carried out in the presence of a metal hydrogen complex compound or a borane reducing agent.

[0015]

[Chemical formula 3]

This invention provides a method for producing a benzylpiperazine derivative represented by the formula (wherein R1 to R5 and n are the same as above).

That is, as a result of extensive research in order to achieve the above object, the present inventors have developed a commercially available chemical compound 2 that is easy to handle.
The compound represented by (hereinafter abbreviated as compound (2))
is used as a starting material, and this and the compound shown by chemical formula 1 (
Hereinafter, it will be abbreviated as compound (1). ) and a specific reducing agent,
That is, the present invention was completed by discovering that the compound (3) can be obtained in a good yield in one step by reacting in the presence of a metal hydrogen complex compound or a borane reducing agent.

Specific examples of compound (2), which is a raw material compound of the present invention, include benzaldehyde, o-methoxybenzaldehyde, m-methoxybenzaldehyde,
p-methoxybenzaldehyde, 2,3-dimethoxybenzaldehyde, 2,4-dimethoxybenzaldehyde, 2,5-dimethoxybenzaldehyde, 3,4-dimethoxybenzaldehyde, 3,5-dimethoxybenzaldehyde, 2,3,4-trimethoxybenzaldehyde, 2,4,6-trimethoxybenzaldehyde, 3,4
, 5-trimethoxybenzaldehyde, etc., but are not limited thereto. That is, in the reaction of the present invention, there are no restrictions on the number and position of methoxy groups, so compound (2) may be appropriately selected depending on the target compound.

Specific examples of compound (1), which is another raw material compound used in the present invention, include piperazine, hydroxyethylpiperazine, 2-(2-hydroxyethoxy)ethylpiperazine, 2-[2-(2- -hydroxyethoxy)ethoxy]ethylpiperazine and the like. In Chemical Formula 1, the piperazine derivative in which n is 2 to 5 can be easily obtained by a normal N-alkylation reaction in which piperazine and the corresponding polyethylene chlorohydrin are reacted in a suitable solvent in the presence of an acid deoxidizing agent. , it is sufficient to use what is obtained in this way.

[0020] Examples of metal hydrogen complex compounds used as specific reducing agents in the present invention include sodium borohydride, lithium aluminum hydride, lithium borohydride, and sodium bis(2-methoxyethoxy)aluminum hydride. , sodium cyanoborohydride, and the like. Among these, sodium borohydride is particularly preferred since it is relatively inexpensive and has low toxicity. However, since sodium cyanoborohydride is highly toxic, some practical problems remain.

[0021] Examples of the borane reducing agent used in the present invention include diborane, dimethylamine borane,
Typical examples include pyridine borane. The reaction according to the present invention, that is, the reaction in which a carbonyl compound and amines are condensed in the presence of a reducing agent, is generally known as a reductive alkylation reaction, but since this reaction is reversible, the reaction is performed in the opposite direction. It is considered advantageous to generate iminium salts to suppress this. Therefore, this reaction is usually carried out under acidic conditions, and is usually carried out in the presence of an acid such as formic acid.

However, when the specific reducing agent according to the present invention is used, the reaction proceeds extremely efficiently regardless of the liquid nature of the reaction solution, and the desired benzylpiperazine derivative can be obtained in high yield. This was extremely surprising considering the above reaction theory.

[0023] In the production method of the present invention, the amounts of compound (1) and compound (2) used may be equimolar or slightly larger than one of them. If you increase one or the other,
From the standpoint of post-treatment, etc., it is usually preferable to have a large amount of compound (2), but this is not particularly restrictive.

The amount of the reducing agent used in the present invention is as follows:
) may be used in an amount of usually 1 to 20 times equivalent, preferably 2 to 8 times equivalent.

The reaction according to the present invention is usually carried out in a solvent, and the solvent used here must be one that can dissolve the raw materials and that does not adversely affect the reducing power of the reducing agent used. For example, when using a reducing agent that is used in an alcoholic solvent such as sodium borohydride, use an alcoholic solvent such as methanol, ethanol, propanol, or a mixture of these and water. A solvent is preferably used, and when a reducing agent used in a non-aqueous solvent such as lithium aluminum hydride or diborane is used, an ether solvent such as ether or tetrahydrofuran is preferably used. In addition, since dimethylamine borane, pyridine borane, etc. need to be freed, the process is carried out in an acidic solvent such as acetic acid, or an acid is required when used in a neutral solvent.

[0026] The reaction is usually carried out at room temperature, and there is no need for particular heating. Furthermore, since it is an exothermic reaction, it is optional to cool it as necessary. The reaction usually ends when the reducing agent is added, but it is optional to continue stirring for a predetermined time as necessary after the reducing agent is added. The generated compound (3) can be obtained, for example, by extracting by a normal extraction operation and then concentrating under reduced pressure. Further, the salts of compound (3) can be easily obtained by adding an acid such as hydrochloric acid or sulfuric acid to the reaction solution or the above-mentioned extract. If necessary, these may be optionally purified by a method such as recrystallization.

According to the method of the present invention, the target compound (3) can be obtained from the commercially available raw material compound (2) in one step and in an extremely high yield.
) can be synthesized. Furthermore, among the specific reducing agents according to the present invention, sodium borohydride is particularly inexpensive and has low toxicity, so its use is particularly advantageous when producing compound (3) on an industrial scale. Examples are shown below, but the present invention is not limited to these Examples in any way.

[0028]

【Example】

Example 1. Synthesis of N-2-(2-hydroxyethoxy)ethyl-N'-2,3,4-trimethoxybenzylpiperazine and its hydrochloride 2-(2-hydroxyethoxy)ethylpiperazine 8
．． 7 g and 9.8 g of 2,3,4-trimethoxybenzaldehyde were dissolved in 50 ml of methanol, and 1.9 g of sodium borohydride was added little by little while stirring at room temperature. After the addition, the mixture was stirred until the foaming subsided, and then the solvent was distilled off under reduced pressure. The residue was dissolved by adding 20 ml of ethyl acetate and 60 ml of 10% aqueous hydrochloric acid solution, and the resulting aqueous layer was separated. Add 10% sodium hydroxide aqueous solution to the aqueous layer and p
After adjusting to H≈10, extraction was performed with 50 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give N-2-(2-hydroxyethoxy)ethyl-N'-2,3,4-trimethoxybenzylpiperazine 13 Obtained .7 g as an oil. Dissolve this in 50ml of acetone and add 6.9ml of concentrated hydrochloric acid.
The precipitated crystals were collected by filtration and recrystallized from methanol to give white needle-like N-2-(2-hydroxyethoxy).
16.0 g of ethyl-N'-2,3,4-trimethoxybenzylpiperazine hydrochloride was obtained. Yield 75%. m. p.
The 214°C (decomposition), IR and NMR data were consistent with those of the standard product (described in JP-A-60-155171).

Example 2. Synthesis Example 1 of N-2-(2-hydroxyethoxy)ethyl-N'-3,4-dimethoxybenzylpiperazine hydrochloride. In the same manner as above, N-2-(2-hydroxyethoxy)ethyl-N'-3,4-dimethoxy was prepared from 8.7 g of 2-(2-hydroxyethoxy)ethylpiperazine and 8.3 g of 3,4-dimethoxybenzaldehyde. 14.1 g (yield 71%) of benzylpiperazine hydrochloride was obtained. m. p. The 205°C (decomposition), IR and NMR data were consistent with those of the standard product (described in JP-A-60-155171).

Example 3. Synthesis Example 1 of N-2-[2-(2-hydroxyethoxy)ethoxy]ethyl-N'-2,3,4-trimethoxybenzylpiperazine hydrochloride. In the same manner as above, 10.9 g of 2-[2-(2-hydroxyethoxy)ethoxy]ethylpiperazine
and 2,3,4-trimethoxybenzaldehyde 9.
16.0 g (yield 68%) of N-2-[2-(2-hydroxyethoxy)ethoxy]ethyl-N'-2,3,4-trimethoxybenzylpiperazine hydrochloride was obtained from 8 g. m. p. The 186°C (decomposition), IR and NMR data were consistent with those of the standard product (described in JP-A-60-155171).

Example 4. Synthesis Example 1 of N-2-[2-(2-hydroxyethoxy)ethoxy]ethyl-N'-3,4-dimethoxybenzylpiperazine hydrochloride. In the same manner as above, 10.9 g of 2-[2-(2-hydroxyethoxy)ethoxy]ethylpiperazine
and 15.4 g (yield 70%) of N-2-[2-(2-hydroxyethoxy)ethoxy]ethyl-N'-3,4-dimethoxybenzylpiperazine hydrochloride from 8.3 g of 3,4-dimethoxybenzaldehyde. Obtained. m. p. 1
The 95°C (decomposition), IR and NMR data were consistent with those of the standard product (described in JP-A-60-155171).

Example 5. N-2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl-N'
Synthesis Example 1 of -2,3,4-trimethoxybenzylpiperazine hydrochloride. N-2-[2- [2-(2-
hydroxyethoxy)ethoxy]ethoxy]ethyl-N
16.7 g (yield: 65%) of '-2,3,4-trimethoxybenzylpiperazine hydrochloride was obtained. m. p. 139℃
(decomposition), IR and NMR data are from the standard (Unexamined Japanese Patent Publication No. 1983
-155171)).

Example 6. N-2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl-N'
Synthesis Example 1 of -3,4-dimethoxybenzylpiperazine hydrochloride. 2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethylpiperazine
13.1g and 3,4-dimethoxybenzaldehyde
From 8.3 g N-2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl-N'-3,4-
13.9 g (yield 63%) of dimethoxybenzylpiperazine hydrochloride was obtained. m. p. The 155°C (decomposition), IR and NMR data were consistent with those of the standard product (described in JP-A-60-155171).

Example 7. N-2-[2-[2-[2-(
Synthesis of 2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl-N'-2,3,4-trimethoxybenzylpiperazine hydrochloride Example 1. In the same way as 2
-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethylpiperazine 15.
3g and 2,3,4-trimethoxybenzaldehyde
From 8.7 g, 13.7 g of N-2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl-N'-2,3,4-trimethoxybenzylpiperazine hydrochloride ( A yield of 62% was obtained. m. p. 11
The IR and NMR data at 9°C (decomposition) were consistent with those of the standard product (described in JP-A-60-155171).

Example 8. N-2-[2-[2-[2-(
Synthesis of 2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl-N'-3,4-dimethoxybenzylpiperazine hydrochloride Example 1. In the same way as 2-[2
-[2-[2-(2-hydroxyethoxy)ethoxy]
15.3 g of ethoxy]ethoxy]ethylpiperazine and 8.3 g of 3,4-dimethoxybenzaldehyde to N
-2-[2-[2-[2-(2-hydroxyethoxy)
Ethoxy]ethoxy]ethoxy]ethyl-N'-3,4
-Dimethoxybenzylpiperazine hydrochloride 16.1 g (yield 60%) was obtained. m. p. The 155°C (decomposition), IR and NMR data were consistent with those of the standard product (described in JP-A-60-155171).

Example 9. Synthesis of N-2-(2-hydroxyethoxy)ethyl-N'-2,3,4-trimethoxybenzylpiperazine and its hydrochloride 2-(2-hydroxyethoxy)ethylpiperazine 8
．． 7g and 9.8g of 2,3,4-trimethoxybenzaldehyde were dissolved in 50ml of tetrahydrofuran,
While cooling with ice and stirring, 1.9 g of lithium aluminum hydride was added little by little. After the addition, the mixture was returned to room temperature and reacted with stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was prepared in Example 1. 15.0 g (yield: 70%) of N-2-(2-hydroxyethoxy)ethyl-N'-2,3,4-trimethoxybenzylpiperazine hydrochloride was obtained. m
．． p. 214°C (decomposition), IR and NMR data are as in Example 1. It was consistent with that obtained in .

Example 10. Synthesis of N-2-(2-hydroxyethoxy)ethyl-N'-2,3,4-trimethoxybenzylpiperazine and its hydrochloride 2-(2-hydroxyethoxy)ethylpiperazine 8
．． 7 g and 9.8 g of 2,3,4-trimethoxybenzaldehyde were dissolved in 50 ml of acetic acid, and 3.5 g of dimethylamine borane was gradually added thereto while stirring under ice cooling. After the reaction solution was returned to room temperature and reacted for 1 hour, 10% aqueous sodium hydroxide solution was added to adjust the pH to approximately 10, and the mixture was extracted with 50 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give N-2-(2-hydroxyethoxy)ethyl-N'-
2,3,4-Trimethoxybenzylpiperazine was obtained as an oil. Dissolve this in 50ml of acetone and add 6.9g of concentrated hydrochloric acid.
The crystals precipitated by the addition of 14. 5 g (68% yield) was obtained. m. p.
214°C (decomposition), IR and NMR data are from Example 1.
．． It was consistent with that obtained in .

Comparative Example 1. Synthesis of N-2-(2-hydroxyethoxy)ethyl-N'-2,3,4-trimethoxybenzylpiperazine and its hydrochloride 2-(2-hydroxyethoxy)ethylpiperazine 8
．． 7 g and 9.8 g of 2,3,4-trimethoxybenzaldehyde were dissolved in 50 ml of formic acid, and the reaction solution was refluxed for 10 hours. At this time, the reaction solution was colored black. After the reaction, the temperature was returned to room temperature, and Example 10. When processed according to
2-hydroxyethoxy)ethyl-N'-2,3,4-
7.3 g (yield 34%) of trimethoxybenzylpiperazine hydrochloride was obtained. m. p. 214°C (decomposition), IR and NMR data are as in Example 1. It was consistent with that obtained in .

[0039]

[Effects of the Invention] As described above, the present invention provides a new and extremely useful method for producing polymethoxybenzylpiperazine, which is useful as various pharmaceuticals. The objective benzylpiperazine derivative can be obtained from the raw material compound in one step and in high yield, and especially when sodium borohydride is used as the specific reducing agent according to the present invention, the reducing agent is Because it is inexpensive and has low toxicity, it is extremely advantageous for producing polymethoxybenzylpiperazine derivatives and the like on an industrial scale, and is therefore a great invention that contributes to this industry.

Claims (3)

[Claims] Claim 1: A compound represented by the formula 1 [Chemical 1] (wherein n represents an integer of 0 to 5) and a compound represented by the formula 2 [Chemical 2] (wherein R1 to R5 each independently represent methoxy (representing a group or a hydrogen atom) in the presence of a metal hydrogen complex compound or a borane-based reducing agent. is the same as above.) A method for producing a benzylpiperazine derivative. 2. The metal hydride complex according to claim 1, wherein the metal hydride complex is sodium borohydride, lithium aluminum hydride, lithium borohydride, sodium bis(2-methoxyethoxy)aluminum hydride or sodium cyanoborohydride. Method for producing benzylpiperazine derivatives. 3. The method for producing a benzylpiperazine derivative according to claim 1, wherein the borane reducing agent is diborane, dimethylamine borane or pyridine borane.