JP2000086625A - Production of n-substituted-3-pyrroline compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an N-substituted-3-pyrroline compound in good selectivity by a simple method. SOLUTION: This method for producing an N-substituted-3-pyrroline compound of general formula I (R1 is a 1-6C alkyl or alkenyl group, phenyl which may be substituted, or an alkyl group or alkenyl group having an aromatic substituent) comprises a process for reacting cis-2-butene-1,4-diol with a halogen- supplying source in the presence of a base and a process for cyclizing the reaction product with a primary amine of general formula II : R1-NH2.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing pyrrolines. Another object of the present invention is to provide an industrially excellent method for obtaining pyrrolines efficiently by a simple method. As is well known, pyrrolines are useful compounds that can be used as synthetic intermediates for pharmaceuticals, agricultural chemicals and the like.

[0002]

2. Description of the Related Art As a method for obtaining a target N-substituted-3-pyrroline compound by cyclizing a derivative thereof with an amine using cis-2-butene-1,4-diol as a starting material, for example, , Cis-1,4-dichloro-2-butene as an intermediate (US Pat. No. 3,691,198), and cis-2-butene-1,4-diol dimesylate as an intermediate (Synthetic Communications 20, 227, (1990)), 1, 2, 4-
A compound using a butanetriol derivative as a cyclization precursor (US Pat. No. 5,703,244 and JP-A-5-58995) is known.

[0003]

However, cis-1, 4
-Dichloro-2-butene is a carcinogen and it is difficult to synthesize it at low cost;
Butene-1,4-diol dimesylate is a compound which is unstable in the air and has the property of decomposing and corroding metals, and a 1,2,4-butanetriol derivative as a cyclization precursor Has many disadvantages, such as the necessity of going through many reaction steps, and conventional techniques are hardly industrially useful.

[0004]

The present inventors have conducted intensive studies to solve these problems, and as a result, they have found that an N-substituted-3-pyrroline compound can be efficiently produced by a simple method. The invention has been reached. That is, the present invention provides an N-substituted-3-pyrroline compound represented by the general formula (1)

Embedded image (R ¹ represents an alkyl or alkenyl group having 1 to 6 carbon atoms, an optionally substituted phenyl group, or an alkyl or alkenyl group having an aromatic substituent.) Bottom, cis-2-
Reacting the butene-1,4-diol and a halide source (first step), and further the general formula (2) primary amine R ¹ -NH ₂ · · · (2) represented by (R ¹ is (Representing an alkyl or alkenyl group having 1 to 6 carbon atoms, an optionally substituted phenyl group, or an alkyl or alkenyl group having an aromatic substituent)) (a second step). Thus, an N-substituted-3-pyrroline compound is produced.

As is well known, cis-2-butene-1,4-
Diols are inexpensive and readily available compounds. Using this as a starting material, it is possible to obtain a target N-substituted-3-pyrroline compound with good selectivity without going through complicated processing steps.
It can be said that the significance in the field of medical and agricultural chemicals is great.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the base used in the first step can be arbitrarily selected as long as it does not react with a substrate, but a tertiary organic amine is particularly preferred. Specific examples include triethylamine, tripropylamine,
Tributylamine, tribenzylamine, N, N'-dimethylaniline, N, N'-dimethyltoluidine, pyridine, 1,4-dimethylaminopyridine and the like are preferable, and triethylamine is preferable. The amount used is preferably 2.0 to 3.0 mol, more preferably 2.0 to 2.2 mol, per 1 mol of 2-butene-1,4-diol. In this range, the reaction can be carried out efficiently and economically.

In the present invention, the halogen source used in the first step may be a sulfonyl halide represented by the general formula (3): R ² —SO ₂ Z (3) (where R ² is 1 to 6 carbon atoms) Represents an aliphatic hydrocarbon group, an aromatic hydrocarbon group which may be substituted, or a hydrocarbon group substituted with an aromatic hydrocarbon group, and Z represents a halogen atom. Examples of the halogen atom Z of the sulfonyl halide include a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom is preferable. As the substituent R ² , a methyl group, an ethyl group, an n-propyl group, an iso
-Propyl group, n-butyl group, iso-butyl group, t-
Butyl, cyclohexyl, vinyl, allyl, methallyl, homoallyl, trifluoromethyl, and other linear, branched, and cyclic saturated or unsaturated aliphatic hydrocarbon groups, or phenyl and chlorophenyl groups , Dichlorophenyl, trichlorophenyl, fluorophenyl, difluorophenyl, trifluorophenyl, bromophenyl, dibromophenyl, tribromophenyl, nitrophenyl, dinitrophenyl, trinitrophenyl, cyanophenyl , Dicyanophenyl group, tricyanophenyl group, tolyl group, dimethylphenyl group, trimethylphenyl group, trifluoromethylphenyl group, unsubstituted or substituted aromatic hydrocarbon groups such as naphthyl group, or benzyl group,
Phenylethyl group, phenethyl group, naphthylmethyl group,
Examples thereof include a hydrocarbon group substituted with an aromatic hydrocarbon group such as a 1-phenylvinyl group and a 2-phenylvinyl group. Specific examples include methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-toluenesulfonyl chloride, naphthylsulfonyl chloride,
Benzylsulfonyl chloride, methanesulfonyl bromide, trifluoromethanesulfonyl bromide, benzenesulfonyl bromide, p-chlorobenzenesulfonyl bromide, p-bromobenzenesulfonyl bromide, p-
Toluenesulfonibromide, naphthylsulfonylbromide, benzylsulfonylbromide, methanesulfonyliodide, trifluoromethanesulfonyliodide, benzenesulfonyliodide, p-chlorobenzenesulfonyliodide, p-bromobenzenesulfonyliodide,
p-toluenesulfonyiodide, naphthylsulfonyliodide, benzylsulfonyliodide and the like. Preferred are methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride, and particularly preferred is methanesulfonyl chloride. Also,
The amount used is preferably 2.0 to 3.0 mol per mol of 2-butene-1,4-diol, and is preferably 2.0 to 2.2 mol.
Mole is more preferred. In this range, the reaction can be carried out efficiently and economically. In particular, when the first step and the second step are continuously performed, in the second step, a side reaction occurs between the excess sulfonyl halide remaining at the end of the first step and the primary amine to be charged, so that 2.0 mols as much as possible. It is preferably close to

In the present invention, the substituent R ¹ of the primary amine used in the second step is methyl, ethyl, n
-Propyl group, iso-propyl group, n-butyl group, i
Of a linear, branched, or cyclic saturated or unsaturated aliphatic hydrocarbon group such as a so-butyl group, a t-butyl group, a cyclohexyl group, a vinyl group, an allyl group, a methallyl group, a homoallyl group, and a trifluoromethyl group Or a phenyl group,
Chlorophenyl, dichlorophenyl, trichlorophenyl, fluorophenyl, difluorophenyl, trifluorophenyl, bromophenyl, dibromophenyl, tribromophenyl, nitrophenyl, dinitrophenyl, trinitrophenyl, cyanophenyl Unsubstituted or substituted aromatic hydrocarbon groups such as phenyl group, dicyanophenyl group, tricyanophenyl group, tolyl group, dimethylphenyl group, trimethylphenyl group, trifluoromethylphenyl group, naphthyl group, or benzyl group , Phenylethyl group, phenethyl group, naphthylmethyl group, 1-phenylvinyl group, 2-
A hydrocarbon group substituted with an aromatic hydrocarbon group such as a phenylvinyl group is exemplified. Specific examples include ethylamine, n-propylamine, isopropylamine,
Examples thereof include n-butylamine, isobutylamine, t-butylamine, allylamine, homoallylamine, benzylamine, aniline, chloroaniline, bromoaniline, and toluidine. The amount used is 1 to 8 with respect to 1 mol of cis-2-butene-1,4-diol.
It is preferably used in moles, more preferably 3 to 5 moles.
In this range, the reaction can be carried out efficiently and economically.

Regarding the solvent used in the present invention, any solvent may be used in the first step as long as it can dissolve cis-2-butene-1,4-diol. Examples include chloroform, dichloromethane, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, diethyl ether, ethyl acetate, methyl propionate, acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like. , Methyl ethyl ketone and methyl isobutyl ketone. The amount used may be an arbitrary amount according to the slurry concentration of the salt generated during the reaction, and may be solvent-free as long as there is no problem. In the second step, a water-soluble solvent such as methanol, ethanol and acetone, a hydrocarbon solvent such as hexane, cyclohexane, benzene, toluene and xylene, chloroform, dichloromethane, carbon tetrachloride, 1,1-dichloroethane, and 1,2- In addition to halogen solvents such as dichloroethane, etc., diethyl ether, ethyl acetate, methyl propionate and the like can be mentioned, and various solvents can be used. In particular, when the first step and the second step are performed continuously, the same solvent can be used in the two steps.
The amount used may be any amount according to the slurry concentration of the salt generated during the reaction, and may be solvent-free.

The reaction temperature in the present invention is preferably 0 ° C. to 15 ° C. when the sulfonyl halide is added dropwise in the first step, and may be cooled in an ice bath or the like. After completion of the dropping, the temperature is preferably from room temperature to 60 ° C. In the second step, the temperature is preferably from room temperature to 100 ° C., depending on the reactivity of the cis-2-butene-1,4-diol derivative and the primary amine to be reacted.

Regarding the treatment operation and the isolation operation of the target substance in the present invention, in the transition from the first step to the second step, this can be performed continuously, and if necessary, such as filtration or extraction, etc. Such a simple method may be used.
The term “continuous” as used herein means that the reaction solution obtained in the first step is transferred to the next second step without any treatment. Therefore, in the case where R ² —SO ₂ Z (3) (where R ² and Z are the same as those described above) is used as the halogen source in the first step, the resulting products are shown below. Even in the case of a mixture of such compounds, the mixture may be cyclized as it is in the second step, and separation of each compound and conversion to a single compound can be omitted.

[0012]

Embedded image (R ² represents an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group which may be substituted, or a hydrocarbon group substituted with an aromatic hydrocarbon group, and Z represents a halogen atom. Similarly, in the processing operation after the completion of the cyclization reaction, which is the second step, a simple method such as filtration or extraction may be used as necessary. Specifically, the primary amine is directly added to the reaction-terminated liquid in the first step, the cyclization reaction in the second step is performed, and then the primary amine is deposited in the first and second steps.
A method of concentrating the salt of the tertiary organic amine and the primary amine after filtering or extracting and removing the salt, or after once filtering or extracting and removing the salt of the tertiary organic amine precipitated at the end of the reaction in the first step, A cyclization reaction is performed in the second step by charging a primary amine, and a salt of the primary amine precipitated at the end of the reaction is concentrated by filtration or extraction and removal,
Either method can be used.

[0013]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto. Note that the manufacturer grades of the reagents used here correspond to the first grade level.

(Example 1) (Preparation of reaction solution in the first step) 35.4 g (0.4 mol) of cis-2-butene-1,4-diol,
83.8 g (0.8 mol) of triethylamine, 416.6 g of ethyl acetate
Was added to a reaction vessel, and 91.8 g (0.8 mol) of methanesulfonyl chloride was dropped in an ice bath (5 ° C to 10 ° C) over 30 minutes.
After completion of the dropwise addition, the temperature was raised to 50 ° C., and the reaction was further performed for 2 hours. After completion of the reaction, the precipitated solid was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain cis-1,4-dichloro-2-butene: cis-4-chloro-2-buten-1-ol methanesulfonylate. : Cis-2-butene-1,4-diol 60.0 g of a cis-2-butene-1,4-diol derivative mixture having a composition ratio of 5: 4: 1 was obtained. Hereinafter, the prepared solution was reacted with various amines.

(Example 2) (Second step: cyclization reaction) 60.0 g of the reaction solution of the first step prepared in Example 1 was dissolved in about 250 g of toluene, and 171.7 g of benzylamine (1.6 mol
l) was added and reacted for 2 hours at room temperature. After completion of the reaction, the precipitated solid was separated by filtration, 42.0 g of 35% hydrochloric acid aqueous solution was added to the filtrate, and unreacted benzylamine was removed by filtration as a hydrochloride, and the obtained filtrate was concentrated under reduced pressure. 57.0 g of N-benzyl-3-pyrroline (89.5% yield)
Obtained.

Example 3 (Second Step: Cyclization Reaction) 117.0 g (1.6 mol) of n-butylamine in an ice bath (5 ° C. to 10 ° C.)
C), and the same treatment as in Example 2 was carried out to obtain 46.1 g (yield 92.0%) of N-butyl-3-pyrroline.

(Example 4) (Second step: cyclization reaction) Aniline was reacted under the conditions of 149.0 g (1.6 mol) and 50 ° C.
By performing the same treatment as in Example 2, 52.2 g (yield 90.0%) of N-phenyl-3-pyrroline was obtained.

(Example 5) (Second step: cyclization reaction) Toluidine (171.7 g, 1.6 mol) was reacted under the condition of 50 ° C, and the same treatment as in Example 2 was carried out to give N-tolyl-3-. 56.8 g (yield 89.2%) of pyrroline were obtained.

Example 6 (Continuous Reaction of First Step and Second Step) 35.4 g (0.4 mol) of cis-2-butene-1,4-diol,
83.8 g (0.8 mol) of triethylamine, 416.6 g of ethyl acetate
Was added to a reaction vessel, and 91.8 g (0.8 mol) of methanesulfonyl chloride was dropped in an ice bath (5 ° C to 10 ° C) over 30 minutes.
After completion of the dropwise addition, the temperature was raised to 50 ° C., and the reaction was further performed for 2 hours.
Subsequently, 171.7 g (1.6 mol) of benzylamine was added and reacted at room temperature for 2 hours. After completion of the reaction, the precipitated solid was separated by filtration, 42.0 g of 35% hydrochloric acid aqueous solution was added to the filtrate, and unreacted benzylamine was removed by filtration as a hydrochloride, and the obtained filtrate was concentrated under reduced pressure. As a result, 52.2 g (82.0% yield) of N-benzyl-3-pyrroline was obtained.

[0020]

According to the process of the present invention, cis-2-butene-1,4-diol which is inexpensive and easily available is used as a starting material.
This is an economically advantageous production method in which pyrrolines can be efficiently obtained by a simple method without a complicated processing step. Moreover, the obtained N-substituted-3-pyrroline compounds can be used as various synthetic intermediates, and are useful in the field of medicine and agrochemicals.

Claims (8)

[Claims] An N-substituted-3-pyrroline compound represented by the general formula (1): (R ¹ represents an alkyl or alkenyl group having 1 to 6 carbon atoms, an optionally substituted phenyl group, or an alkyl or alkenyl group having an aromatic substituent.) Bottom, cis-2-
Reacting the butene-1,4-diol and a halide source (first step), and further the general formula (2) primary amine R ¹ -NH ₂ · · · (2) represented by (R ¹ is A step (second step) of performing a cyclization reaction by using an alkyl group or alkenyl group having 1 to 6 carbon atoms, an optionally substituted phenyl group, or an alkyl group or an alkenyl group having an aromatic substituent. )). A method for producing an N-substituted-3-pyrroline compound, comprising: 2. The method for producing an N-substituted-3-pyrroline compound according to claim 1, wherein the first step and the second step are performed continuously. 3. A method according to claim 1, wherein the base used in the first step is a tertiary organic amine.
A method for producing a substituted-3-pyrroline compound. 4. The method for producing an N-substituted-3-pyrroline compound according to claim 3, wherein the tertiary organic amine is triethylamine. 5. A halogen source used in the first step is a sulfonyl halide represented by the general formula (3): R ² —SO ₂ Z (3) (where R ² is an aliphatic carbon having 1 to 6 carbon atoms). 5 represents a hydrogen group, an aromatic hydrocarbon group which may be substituted, or a hydrocarbon group substituted with an aromatic hydrocarbon group, and Z represents a halogen atom). The method for producing an N-substituted-3-pyrroline compound according to any one of the above. 6. The N-substituted-3 compound according to claim 5, wherein the substituent Z of the sulfonyl halide is a chlorine atom.
-A method for producing a pyrroline compound. 7. The method for producing an N-substituted-3-pyrroline compound according to claim 6, wherein the sulfonyl halide is methanesulfonyl chloride. 8. The method according to claim 1, wherein the number of moles of the primary amine represented by the general formula (2) is in excess with respect to the number of moles of the starting material cis-2-butene-1,4-diol. 8. The method for producing an N-substituted-3-pyrroline compound according to any one of items 7 to 7.