JP6350910B2 - Method for producing azidoamine derivative - Google Patents

Description

  The present invention relates to a method for producing an azidoamine derivative useful as an intermediate for pharmaceuticals and the like.

  Azidoamine derivatives are important as intermediates for pharmaceuticals and the like, and various production methods have been developed so far. As an example, in the case of 4-azidobutylamine, a method is known in which 1,4-dibromobutane as a raw material is diazide and then subjected to a reduction reaction (Non-Patent Documents 1 and 2). In these methods, after completion of the reduction reaction, methylene chloride is used as a solvent, the target hydrochloride is freed, liquid separation extraction is performed, and then concentration is performed. However, when methylene chloride is used, (i) the target product deteriorates with time, (ii) the solution heats up abnormally during concentration, its starting temperature is as low as about 82 ° C., and there is a problem with safety, (Iii) Methylene chloride has carcinogenicity and is unfavorable for the human body.

“Tetrahedron Letters”, vol. 42, 2001, pages 2709-2711 “Polymer”, vol. 47, 2006, pages 742-750

  An object of the present invention is to provide a method for producing an azidoamine derivative that overcomes problems such as deterioration over time and safety and can be mass-produced on an industrial scale.

式中、Ｒ１〜Ｒ４は各々同一でも異なってもよく、水素原子、アルキル基、アリール基、又はヘテロ環残基を表す。該アルキル基、該アリール基、又は該ヘテロ環残基は更に置換基を有していても良い。ｎは１〜１１の整数を表す。ｎが２以上である場合、複数のＲ３およびＲ４は各々同一でも異なっても良い。
＜２＞
前記芳香族系溶媒がトルエンである＜１＞に記載のアジドアミン誘導体の製造方法。
なお、本発明は上記＜１＞及び＜２＞に関するものであるが、以下その他の事項についても参考のため記載した。 As a result of intensive studies to achieve the above-mentioned object, the present inventors have used an aromatic solvent or an ether solvent at the time of post-treatment, thereby suppressing the deterioration of the object over time, and the heat generation starting temperature during concentration is higher. The present invention was completed. That is, the present invention is achieved by the following.
<1>
A step of obtaining an azidoamine derivative represented by the following general formula (II):
The obtained azidoamine derivative represented by the following general formula (II) is extracted using at least one aromatic solvent selected from toluene, xylene, styrene, benzene, phenol, ethylbenzene, diethylbenzene, isopropylbenzene and diphenylmethane. The process of
A process for producing an azidoamine derivative comprising:

In the formula, R1 to R4 may be the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, or a heterocyclic residue. The alkyl group, the aryl group, or the heterocyclic residue may further have a substituent. n represents an integer of 1 to 11. When n is 2 or more, the plurality of R3 and R4 may be the same or different.
<2>
The method for producing an azidoamine derivative according to <1>, wherein the aromatic solvent is toluene.
Although the present invention relates to the above <1> and <2>, other matters are also described below for reference.

[1]
A step of obtaining an azidoamine derivative represented by the following general formula (II):
A step of extracting the obtained azidoamine derivative represented by the following general formula (II) using an aromatic solvent or an ether solvent,
A process for producing an azidoamine derivative comprising:

In the formula, R1 to R4 may be the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, or a heterocyclic residue. The alkyl group, the aryl group, or the heterocyclic residue may further have a substituent.
n represents an integer of 1 to 11. When n is 2 or more, the plurality of R3 and R4 may be the same or different.
[2]
The method for producing an azidoamine derivative according to [1], wherein the aromatic solvent is toluene.
[3]
The method for producing an azidoamine derivative according to [1], wherein the ether solvent is diisopropyl ether or tert-butyl methyl ether.

  According to the production method of the present invention, an azidoamine derivative that is important as an intermediate for pharmaceuticals, agricultural chemicals, photosensitive materials, electronic materials and the like can be easily produced on an industrial scale.

FIG. 1 is a graph showing the results of Example 2 and Comparative Examples 1-2.

The present invention will be described in more detail below.
The present invention provides a step of obtaining an azidoamine derivative represented by the following general formula (II), and the obtained azidoamine derivative represented by the following general formula (II) is extracted using an aromatic solvent or an ether solvent. A process for producing an azidoamine derivative.
The method for obtaining the azidoamine derivative represented by the following general formula (II) is not particularly limited, and a known method can be used, but preferably the diazide derivative represented by the following general formula (I) is reduced. And a method for preparing an azidoamine derivative represented by the following general formula (II).
Moreover, it is preferable to perform concentration after the step of extracting the obtained azidoamine derivative represented by the following general formula (II) using an aromatic solvent or an ether solvent. The concentration method is not particularly limited, and a known method can be used. For example, vacuum distillation is preferable.
The diazide derivative represented by the following general formula (I), which can be used in the present invention, can be prepared by diaziding a commercially available dihalogenoalkane compound by a known method (for example, experimental Chemistry Course (4th edition) Volume 20, Chapter 8, Maruzen, etc.).

In the formula, R1 to R4 may be the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, or a heterocyclic residue, and the alkyl group, the aryl group, or the heterocyclic residue is further substituted. You may have.
n represents an integer of 1 to 11. When n is 2 or more, the plurality of R3 and R4 may be the same or different.

In the formula, R1 to R4 may be the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, or a heterocyclic residue, and the alkyl group, the aryl group, or the heterocyclic residue is further substituted. You may have.
n represents an integer of 1 to 11. When n is 2 or more, the plurality of R3 and R4 may be the same or different.

In the general formulas (I) and (II), the alkyl group represented by R1 to R4 may be linear, branched, or cyclic. For example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Examples thereof include linear, branched or cyclic alkyl groups having 1 to 12 carbon atoms such as nonyl, decyl, undecyl, dodecyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
Examples of the aryl group represented by R1 to R4 include 6 to 10-membered monocyclic or bicyclic aryl groups such as phenyl and naphthyl.
Examples of the heterocyclic residue represented by R1 to R4 include nitrogen such as imidazolyl, oxazolyl, triazolyl, thiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazyl, furyl, thienyl, benzothiazolyl, benzoxazolyl, and quinolyl. Examples thereof include a 5- to 10-membered monocyclic or bicyclic heterocyclic residue containing at least one atom, oxygen atom or sulfur atom.
R1 to R4 are preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and a phenyl group, more preferably a hydrogen atom and an alkyl group having 1 to 4 carbon atoms, and particularly preferably a hydrogen atom.
The alkyl group, the aryl group, or the heterocyclic residue may further have a substituent. The further substituent is not particularly limited as long as it does not cause a side reaction, and examples thereof include an alkyl group, an aryl group, and a heterocyclic residue.
n represents an integer of 1 to 11. Preferably it is an integer of 1-7, More preferably, it is an integer of 2-5, Most preferably, it is 3.

The reduction method of a diazide derivative can also be performed by a well-known method (For example, Experimental Chemistry Course (4th edition) Volume 20, Chapter 6, Maruzen publication etc.).
Specific examples include catalytic reduction using platinum, Raney nickel, palladium-carbon (Pd-C), ruthenium, Lindlar catalyst, and the like; reduction using triphenylphosphine, diborane, sulfide, sodium borohydride and the like. The reduction method can be arbitrarily selected, but is preferably a reduction reaction using triphenylphosphine.
When triphenylphosphine is used, the amount used is usually 0.9 to 3.0 mol, preferably 1.0 to 2.5 mol, and more preferably 1.1 to 2.0 mol with respect to 1 mol of the diazide derivative.

The reduction reaction with triphenylphosphine is preferably performed in a two-layer system of an organic solvent and an acid aqueous solution. The organic solvent to be used is not particularly limited as long as it dissolves the substrate, is insoluble in water, and inhibits the reaction. Specifically, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, tridecane, 2-methyldodecane, 4-ethylundecane, tetradecane, pentadecane, 3,3-dimethyltridecane, hexadecane, heptadecane, 2- Aliphatic solvents such as methyl-4-ethyltetradecane; aromatic solvents such as toluene, xylene, styrene, benzene, phenol, ethylbenzene, diethylbenzene, isopropylbenzene, diphenylmethane; diisopropyl ether, tert-butyl methyl ether, diethyl ether Ether solvents such as methylcyclopentyl ether; ethylene glycol diacetate, ethylene glycol distearate, ethylene glycol diacrylate, diethylene glycol di Glycol solvents such as cetate and diethylene glycol diacrylate; 1,4-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, 9,10-dihydroanthracene, 9,10-dihydrophenanthrene, 4,5,9,10 -Hydrogenated aromatic solvents such as tetrahydropyrene, 1,2,3,6,7,8-hexahydropyrene, dodecahydrotriphenylene and the like.
Among these, aromatic solvents and ether solvents are preferable, and toluene, diisopropyl ether, and tert-butyl methyl ether are more preferable.
The amount of the solvent to be used varies depending on the substrate, but is usually 4 to 10 ml, preferably 5 to 8 ml with respect to 1 g of the diazide derivative.

The acid used as the aqueous solution is not particularly limited as long as it forms an addition salt, but is preferably an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, and more preferably hydrochloric acid or sulfuric acid.
The amount of the acid used is usually 0.9 to 2.7 molar equivalents, preferably 1.0 to 2.5 molar equivalents, more preferably 1.2 to 2.0 molar equivalents, relative to the diazide derivative.
In this reaction, an appropriate amount of water is added to the system in addition to the above acid. The amount of water to be added is 0.1 to 1.5 ml, preferably 0.2 to 1.2 ml, more preferably 0.3 to 1.0 ml with respect to 1 ml of the organic solvent used.
The reaction temperature is usually in the range of 0 to 20 ° C, preferably 5 to 10 ° C. These reactions are usually completed within 24 hours, and in many cases, disappearance of raw materials is confirmed in 8 to 20 hours.

After completion of the reduction reaction, the obtained target product is preferably subjected to separation extraction and then concentration post-treatment. The solvent used in this step is the above-described aromatic solvent or ether solvent.
Examples of the aromatic solvent include toluene, xylene, styrene, benzene, phenol, ethylbenzene, diethylbenzene, isopropylbenzene, diphenylmethane and the like, and toluene is particularly preferable.
Examples of the ether solvent include diisopropyl ether, tert-butyl methyl ether, diethyl ether, methyl cyclopentyl ether, and the like, and diisopropyl ether or tert-butyl methyl ether is particularly preferable.
The solvent used in the reduction reaction and the post-treatment solvent may be the same or different, but the same solvent is preferably used in terms of operability and cost.
The number of times of liquid separation is usually 2 to 7 times, preferably 2 to 5 times. The amount of the solvent used in one liquid separation is 1 to 10 ml, preferably 2 to 5 ml per 1 g of the azidoamine derivative.

  The separated organic layers are preferably combined and concentrated under reduced pressure. The degree of vacuum during concentration is usually 1.0 to 20 pKa, preferably 3.0 to 7.0 pKa. Moreover, the temperature in the case of concentration is 0-60 degreeC normally, Preferably it is 5-40 degreeC.

EXAMPLES Next, although an Example is given and this invention is demonstrated concretely, this invention is not limited to these.
The reaction tracking and yield of the target product were analyzed by H ¹ -NMR (measuring solvent: DMSO), and the presence or absence of impurities was analyzed by high-performance liquid chromatography (HPLC), and the content was analyzed by the ratio of peak areas.
The HPLC measurement conditions were as follows: column: ODS-80TS, eluent: methanol / water (V / V = 7/3), buffer: 0.1% acetic acid, detector: RI, flow rate: 1.0 ml / min, column Temperature: carried out at 40 ° C.
In addition, Example 3, 6 and 7 shall be read as Reference Example 3, 6 and 7, respectively.

Example 1 Synthesis of 4-azidobutylamine
An aqueous solution in which 150.0 g (694.7 mmol) of 1,4-dibromobutane was dissolved in 150 ml of dimethylformamide, and 150.0 g (2.31 mol) of sodium azide was dissolved in 450 ml of water was added dropwise thereto. Stir at 85 ° C. for 8 hours. After completion of the reaction, the internal temperature was cooled to 30 ° C., 375 ml of water and 300 ml of toluene were added, and the mixture was stirred for 5 minutes and then separated. The aqueous layer was extracted again with 300 ml of toluene, and the two obtained toluene layers were combined and washed with 343.7 g of a 20% aqueous sodium chloride solution to obtain a toluene solution of 1,4-diazidobutane.

  Next, the whole toluene solution of 1,4-diazidobutane is cooled to an internal temperature of 5 to 10 ° C., 107.0 g (1.03 mol) of commercially available hydrochloric acid and 418 ml of water are added, and then triphenylphosphine 199 is added under a nitrogen atmosphere. 0.5 g (76.1 mmol) and 750 ml of toluene were added and reacted (reduction reaction) for 12 hours in a nitrogen atmosphere. The reaction solution was filtered and then separated, and the resulting aqueous layer was washed twice with 300 ml of toluene. Next, this aqueous layer was cooled to an internal temperature of 0 to 5 ° C., an aqueous solution in which 150.0 g (266.6 mmol) of sodium hydroxide was dissolved in 225 ml of water was dropped, and the mixture was stirred for 20 minutes. Extraction and liquid separation were performed by adding 450 ml of toluene, and the obtained organic layer was concentrated under reduced pressure at 6.7 kPa or more and an internal temperature of 35 ° C. or less to obtain 65.8 g of an oily target product. The conversion yield by NMR was 83%.

(Example 2)
The oily target product (vacuum concentrate) obtained in Example 1 was stored at room temperature, and the impurity generation rate was measured.

(Comparative Examples 1-2 Synthesis of 4-azidobutylamine)
The synthesis was performed in the same manner as in Example 1 except that the reaction solvent for the reduction reaction and the extraction solvent after the reduction reaction were changed from toluene to dichloromethane, and storage at room temperature (Comparative Example 1) and refrigerated storage at 5 ° C. or lower (Comparative Example) 2), and the impurity generation rate was measured in the same manner as in Example 1.
The results of Example 2 and Comparative Examples 1 and 2 are shown in FIG.

  From the results shown in FIG. 1, it is clear that toluene has little impurities even after 4 weeks of storage at room temperature, and is effective in suppressing deterioration over time as compared with dichloromethane.

(Example 3)
The synthesis was performed in the same manner as in Example 1 except that the reaction solvent for the reduction reaction and the outlet solvent after the reduction reaction were changed from toluene to tert-butyl methyl ether (abbreviated as MTBE).

(Examples 4-7, Comparative Examples 3-4)
The objects obtained in Examples 1 and 3 and Comparative Example 1 were adjusted to solutions having the concentrations shown in Table 1, and the calorific value and exothermic temperature were measured with a differential scanning calorimeter (DSC).
The DSC measurement conditions were as follows: DSC6200 manufactured by SII Nano Technology, temperature program: 30 to 400 ° C., container: Au plating.
Table 1 shows the results.

MTBE represents tert-butyl methyl ether.
In the case of a normal compound, the higher the concentration as a solution, the higher the risk of explosiveness and heat generation. However, in the case of the azidoamine derivative of the present invention, heat generation starts at a lower temperature when the concentration is lower in the dichloromethane solution. This is presumably because an excess amount of dichloromethane before the start of concentration and an azidoamine derivative reacted to generate impurities.

Since the heat generation start temperature decreases and the heat generation amount increases at a low concentration, it is a very dangerous state in the middle of concentration, and from this, the method of the present invention can avoid the danger. Is clear.
The present invention is a method for producing an azidoamine that exhibits an effect of suppressing deterioration over time and has high safety, and is an extremely practical production method capable of synthesizing a target product without any problem even on an industrial scale.

Claims (2)

A step of obtaining an azidoamine derivative represented by the following general formula (II):
The obtained azidoamine derivative represented by the following general formula (II) is extracted using at least one aromatic solvent selected from toluene, xylene, styrene, benzene, phenol, ethylbenzene, diethylbenzene, isopropylbenzene and diphenylmethane. The process of
A process for producing an azidoamine derivative comprising:

In the formula, R1 to R4 may be the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, or a heterocyclic residue. The alkyl group, the aryl group, or the heterocyclic residue may further have a substituent. n represents an integer of 1 to 11. When n is 2 or more, the plurality of R3 and R4 may be the same or different.   The method for producing an azidoamine derivative according to claim 1, wherein the aromatic solvent is toluene.

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