JPS6056706B2 - Method for producing 1-alkyl-2-aminoalkylpyrrolidine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 1-alkyl-2-aminoalkylpyrrolidines.

In the formula, R1 represents an alkylene group, and R2 represents an alkyl group. The 1-alkyl-2-aminoalkylpyrrolidine is a compound known as a synthetic intermediate for various pharmaceuticals, industrial chemicals, etc. It has been proposed that 1-ethyl-2-aminomethylpyrrolidine can be obtained by heating 1-ethyl-3-chloropyrrolidine hydrochloride with ammonia (
(U.S. Pat. No. 3,031,452).

However, in this known method, 1-ethyl-3-hydroxypepyridine is produced as a by-product, and it is difficult to separate this by-product, making it unsuitable as a synthetic intermediate for pharmaceuticals that require particularly high purity. There is a drawback. Furthermore, as an improvement on the above-mentioned known method, a method for producing the compound of formula (1) using the following reaction steps has also been proposed (
(Special Publication No. 46-27457). In the above formula, R1 and R2 are as defined above. However, the above improved method has a low yield of the compound of formula (1) (approximately 18 to
50% yield) and requires industrially expensive reagents (potassium phthalimide and potassium iodide).

The present inventors conducted various studies on industrially advantageous production methods for 1-alkyl-2-aminoalkylpyrrolidine of the above formula (1), and found that benzoic acid, which is extremely easily available industrially, and 2-alkyl-2-aminoalkylpyrrolidine The present inventors have discovered that the compound of formula (1) can be obtained in extremely high yield from -tetrahydrofuranylalkylamine by the method described below, and have thus arrived at the present invention.

That is, according to the present invention, the 1-alkyl-2-aminoalkylpyrrolidine of the above formula (1) is (a) benzoic acid or a reactive derivative thereof, where R1 is as defined above. - reacting with thionyl chloride the N-(7-tetrahydrofuranyl)alkylbenzoic acid amide of the resulting formula, in which R1 is as defined above; (c) reacting an N-dichloroalkylbenzoic acid amide of the formula, in which R1 is as defined above, with an alkylamine of the formula, in which R2 is as defined above; d) Then N-( of the formula thus obtained, in which R1 and R2 are as defined above)
It is produced by treating ``-alkyl-25-pyrrolidinyl)alkylbenzoic acid amide with an alkali metal hydroxide to cleave the amide bond.

In this specification, the J alkyl group may be linear or branched, and lower groups having up to 1 carbon atom, particularly up to 5 carbon atoms, are preferred, such as methyl, ethyl, n- or IsO-propyl, n-, I
Included are sO-, Sec- or tert-butyl, n-pentyl and the like, with ethyl being particularly preferred for R2.

In addition, 1 alkyl group may be either linear or branched, and lower groups having up to 5 carbon atoms are particularly preferred, such as methylene, ethylene, propylene,
Examples include methylethylene, butylene, methylpropylene, dimethylethylene, etc., with methylene being particularly preferred for R1. In the present invention, first, benzoic acid or a reactive derivative thereof is reacted with 2-tetrahydrofuranylalkylamine of the formula (■) or a reactive derivative thereof.

As reactive derivatives of benzoic acid, any of those used for activating carboxyl groups during amidation reactions in the field of peptide chemistry can be used, and examples include the following.

(1) In the acid halide formula, X1 is a halogen atom, especially a chlorine atom, (I
i) In the ester formula, R1 is a lower alkyl group, in particular a methyl or ethyl group; or an active ester residue, such as - (YNO2
CH2CNl or -N/I, (11i) mixed acid anhydride, where R, is an organic or inorganic acid residue, such as acetyl,
Acyl group such as propionyl; group -COOR5 (in the formula, R
5 is a lower alkyl group having 6 or less carbon atoms): or (wherein R6 and R7 are the same or different and each represents an alkyl group, an aryl group or an aralkyl group, or R6 and R7 are taken together) represents an alkylene group or an o-phenylene group),
*(Iv) Active amide
\o/ ゜゛゜゜V- In the formula, R1 is as defined above, (Ji) phosfluoramidite compound,
In the formula, R1, 2 and R7 are as defined above;
8 represents a substituted or unsubstituted 1-imidazolyl group or 1-pyrazolyl group, (v) acid azide. Also, as the reactive derivative of the amine of the formula (■),
Any of those used for activating amino groups during amidation reactions in the field of peptide chemistry can be used, and examples include the following.

(1) isocyanate (or isothiocyanate) in which R1 is as defined above, (Ii) phosphazo compound or 3(Iv) phosfluoramidate compound or in the formula, R1, R6 and R7 are as defined above It is.

The amidation reaction between benzoic acid or its reactive derivative and the amine of formula (■) or its reactive derivative can be carried out according to various methods known per se.

For example, the amidation can be carried out by direct condensation of benzoic acid with an amine of formula (■).

Although the reaction can be carried out without a solvent, it is generally carried out in an inert organic solvent, such as hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane, dimethoxyethane and diglyme; dimethylformamide and dimethylacetamide. The reaction is preferably carried out in amides such as; halogenated hydrocarbons such as dichloromethane and chloroform; and dimethyl sulfoxide. The reaction temperature and pressure are not particularly limited and can be varied widely depending on the raw materials used, but the reaction temperature is usually about 0°C to the reflux temperature of the reaction mixture, preferably room temperature to 200°C. , the pressure is advantageously normal pressure. Further, the reaction can be carried out in the presence of a condensing agent, if necessary. Examples of condensing agents that can be used include Lewis acids, particularly silicon tetrachloride, trichlorophenylsilane, titanium tetrachloride, etc. Examples include N-diethylaminopropylcarbodiimide, N,N''-dicyclohexylcarbodiimide, etc.; combination of triarylphosphin and disulfide; strongly acidic ion exchange resin such as Amperite IR-12 Maki. A reactive derivative as described above and the formula (
It can also be carried out between a free amine of formula (2) or between a free substituted benzoic acid and a reactive derivative of the amine of formula (2) as described above.

This amidation can also be carried out without using a solvent if necessary, but it is usually advantageous to carry out in an inert organic solvent such as those mentioned above or a high boiling point alcohol (e.g. ethylene glycol, glycerin, etc.). be. Although the reaction temperature and pressure are not critical, the reaction temperature is usually about -
The 2CfC to reflux temperature of the reaction mixture is preferably from 0°C to 180°C, and the pressure is advantageously normal pressure. In this way, N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide of the formula (■) is obtained.

This product can be subjected to the next reaction as it is or after isolation. After the reaction, the compound of formula (■) can be easily separated and purified from the reaction mixture by methods known per se, such as filtration, extraction, recrystallization, and chromatography. The resulting N-(7-tetrahydrofuranyl)alkylbenzoic acid amide of formula (■) is a novel compound that has not been described in conventional literature, and representative examples thereof are as follows.

N-(2'-tetrahydrofuranyl)methylbenzoic acid amide, N-(7-tetrahydrofuranyl)ethylbenzoic acid amide, N-(7-tetrahydrofuranyl)propylbenzoic acid amide, N-0''(2''-tetrahydrofuranyl) ) Ethyl] benzoic acid amide.

Among these, N-(7-tetrahydrofuranyl)methylbenzoic acid amide is particularly preferred.

The compound of formula (■) obtained above is thionyl chloride (S
By reacting with OCl2), it is converted to N-dichloroalkylbenzoic acid amide of the formula (■). Although the reaction between the compound of formula (■) and thionyl chloride can be carried out in the presence of a solvent, it is generally advantageous to carry out the reaction in the absence of a solvent.

Examples of solvents that can be used include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as carbon tetrachloride, chloroform, and chlorobenzene. Although the temperature of the reaction is not critical,
It is generally preferred to carry out the reaction under heating above about 60°C, advantageously at the reflux temperature of the reaction mixture.

The amount of thionyl chloride used is also not critical, but
Generally, per mole of compound of formula (■), at least 3
It is preferred to use a molar excess, preferably 4 to 6 molar excess.

In this way, this reaction produces a compound of formula (■) in which R1 is as defined above under substantially anhydrous conditions, and this compound of formula (■) can also be isolated from the reaction system. However, when water is added to the reaction mixture, it immediately changes to the compound of formula (■) above.

The generated compound of formula (V) may be directly subjected to the next reaction, or may be temporarily isolated from the reaction mixture. Separation and purification of the compound of formula (■) can be carried out by methods known per se, including means such as p-filtration, centrifugation, extraction, chromatography, and recrystallization. The N-dichloroalkylbenzoic acid amide of the formula (■) thus obtained is also a novel compound that has not been described in any conventional literature, and representative examples thereof are as follows.

N-(7,5″-dichloropentyl)benzoic acid amide,
N-(3″,6″-dichlorohexyl)benzoic acid amide, N(-4″,7″-dichloroheptyl)benzoic acid amide, N-(7,5′-dichloro-1-methylpentyl)
Benzoic acid amide.

Among these compounds, N-(2'',5''-dichloropentyl)benzoic acid amide is a particularly preferred compound.

The N-jikugugoa 1 of the formula (■) thus generated
(2) Nalbenzoic acid amide can then be reacted with an alkylamine of formula N-('alkyl-7-pyrrolidinyl)alkylbenzoic acid amide, where R2 is as defined above.

The reaction between the compound of formula (■) and the alkylamine of formula (■) can be carried out in the presence or absence of a solvent.

Examples of solvents that can be used include ethanol, isopropanol, n-butanol, Ter
Alcohols such as t-butanol and ethylene glycol; Ethers such as tetrahydrofuran, dioxane, and dimethoxyethane; Amides such as dimethylformamide and dimethylacetamide; Dimethylsulfoxide (
DMSO); triethylamine, pyridine, colicin,
Organic amines such as picoline; polar solvents such as water are preferably used. Although the reaction temperature is not critical, it is generally advantageous to carry out the reaction under heating, preferably at a temperature of about 60° C. or higher, particularly 80° C. or higher, up to the reflux temperature of the reaction mixture.

Further, the reaction pressure is not particularly limited and is usually carried out at normal pressure, but it may be carried out under reduced pressure or increased pressure if necessary.
The amount of alkylamine in formula (■) used is also not critical;
Although it can vary widely depending on the type of the compound of formula (■) and/or the alkylamine of formula (■), reaction conditions, etc., it is usually at least equimolar to 1 mole of the compound of formula (V), The amount is preferably 3 moles or more, and there is no particular upper limit, but it is wasteful to use a larger amount than necessary;
A mole or less is sufficient.

Furthermore, in the reaction, an acid binder may be used instead of using an excessive amount of the alkylamine. Although the exact mechanism of the ring-closing reaction from the compound of formula (V) to the compound of formula (■) is not known, for example, when R1 is a methylene group, the compound of formula (■) is converted to the compound of formula (■). In the ring-closing reaction to , the presence of a compound in the formula in which R2 is as defined above is recognized as an intermediate.

The compound of formula (■) thus obtained can be separated from the reaction mixture if necessary and then subjected to the reaction in the final step of the present invention.

The separation can be carried out according to conventional methods, such as filtration, centrifugation, chromatography, extraction, and distillation. The resulting compound of formula (■) is also a novel compound that has not been described in conventional literature, and representative examples thereof are as follows.

N-(choichiethynol2''-pyrrolidinol)methylbenzoic acid amide, N-('-methyl-7-pyrrolidinyl)methylbenzoic acid amide, N-(1''-propyl-2'')
-pyrrolidinyl) methylbenzoic acid amide, N-('-isopropyl-7-pyrrolidinyl) methylbenzoic acid amide, N-(1''-butyl-2''-pyrrolidinyl) methylbenzoic acid amide, N-('1-ethyl-7-pyrrolidinyl )
Ethylbenzoic acid amide, N-('-butyl-2'-pyrrolidinyl)ethylbenzoic acid amide, N-('monoethyl-2'-pyrrolidinyl)propylbenzoic acid amide, N-(
“-propyl-2″-pyrrolidinyl)propylbenzoic acid amide, N-[1″-(1″″-propyl-7-pyrrolidinyl)ethyl]benzoic acid amide, N-0゛-(11-
Ethyl-7-pyrrolidinyl)ethylbenzoic acid amide.

Preferred are the above compounds in which R2l represents a lower alkyl group, with N-(1''-1ethyl-7-pyrrolidinyl)methylbenzoic acid amide being particularly preferred.

According to the present invention, the compound of formula (■) obtained as described above can be treated with an alkali metal hydroxide to
The amide bond is cleaved, and the desired 1 of formula (1) is obtained.
-Alkyl-2-aminoalkylamine.

The treatment with the alkali metal hydroxide is advantageously carried out in a substantially water-free inert organic solvent which is capable of dissolving at least a portion of the alkali metal hydroxide.

As such an inert organic solvent, lower alcohols such as methanol, ethanol, n-propanol, n-butanol, methoxyethanol, ethoxyethanol, ethylene glycol, propylene glycol, diethylene glycol, glycerin, etc. are most suitable. Among these, methanol, ethanol, ethylene glycol and glycerin are particularly conveniently used. Although these solvents are preferably anhydrous, the presence of a small amount of water (usually up to 5% by weight) is acceptable as long as the reaction is not significantly inhibited. Usable alkali metal hydroxides include sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., and in the present invention, it is particularly desirable to use the former two. The temperature during the above treatment is not strict and can be varied widely depending on the type of compound of formula (■) and/or alkali metal hydroxide used and other reaction conditions, but is generally about 50C. It is advantageous to use temperatures in the range above, in particular above 6 C) up to the reflux temperature of the reaction mixture. There are no particular restrictions on the pressure during this treatment, but atmospheric pressure is usually sufficient, and reduced pressure or increased pressure can be used as necessary.The amount of the alkali metal hydroxide used is also critical. However, it is generally appropriate to use an excess of the alkali metal hydroxide, although it can be varied widely depending on the type and reaction conditions of the compound of formula (■) and/or the alkali metal hydroxide. For example, it is advantageous to use at least 5 equivalents of alkali metal hydroxide, preferably in the range of 8 to 15 equivalents, per mol of the compound of formula (■).Thus, 1- Alkyl-2-aminoalkylpyrrolidine can be produced in high yield.

Isolation of the compound of formula (1) from the reaction mixture can be easily carried out using methods known per se, such as extraction, chromatography, distillation, and the like. The compound of formula (1) provided by the present invention includes various industrial chemicals,
It can be used as a synthetic intermediate for pharmaceuticals.

The present invention will be further explained below with reference to Examples.

Example 1 Benzoyl chloride (14.15y) was mixed with benzene (
42.4 ml), tetrahydrofurfurylamine (10.1 fl) and triethylamine (10.1 fl)
f) is added dropwise while cooling.

After stirring at room temperature for 2 hours, water is added to the reaction solution. The organic layer is washed with water and dried with Glauber's salt. When the solvent is distilled off under reduced pressure, N-(7!'-tetrahydrofuranyl)methylbenzoic acid amide (20.1y) is obtained as crystals. Melting point ~90℃. NMR (CDCl3, δ): Around 1.9 (4
H1 multiplet), 3.1-4.2 (5H, multiplet), 6
．． 8 (1H, multiplet), 7.3-7.9 (5H1 multiplet). N-(2″-tetrahydrofuranyl)methylbenzoic acid amide is also produced by the following method.

That is, benzoic acid (12.2 g) was mixed with dimethylform,
amide (60ml) and triethylamine (10.6
f) and isopropyl chloroformate (12.85'
) is added dropwise under cooling. After stirring at room temperature for 1 hour, it was cooled again and tetrahydrofurfurylamine (10.6y
) is added dropwise. Stir at room temperature for 2 hours. After that, the reaction solution was poured into water and extracted with benzene. The organic layer is washed with water and dried with Glauber's salt. When the solvent was distilled off, N-(7-tetrahydrofuranyl)methylbenzoic acid amide (20.0y) was obtained. Melting point ~90℃. N-(2'-tetrahydrofuranyl)methylbenzoic acid amide (40y) obtained above was heated under reflux for 4 hours with thionyl chloride (76.7y).

Pour the reaction solution into ice water and neutralize with potassium carbonate. The precipitated crystals are collected, washed with water, and then dried to form N1 (7.5″
-dichloropentyl)benzoic acid amide (47.2f) is obtained. Melting point 56-57°C. NMR(CDCl3,δ
): around 2.0 (4H1 multiplet), 3.8 to 4.3 (5
H1 multiplet), around 6.9 (1H1 multiplet), 7.3~
7.9 (5H1 multiplet). N-(7,5″
-dichloropentyl)benzoic acid amide (23.9fI)
is heated with 70% ethylamine solution (23.9 ml) and ethanol (23.9 ml) for 2 hours.

Claims (1)

[Claims] 1 N-(1'-alkyl-2'-pyrrolidinyl)alkylbenzoic acid amide represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) is treated with an alkali metal hydroxide. The formula ▲ is characterized in that the amide bond is cleaved by
There are chemical formulas, tables, etc. ▼ Method for producing 1-alkyl-2-aminoalkylpyrrolidine represented by (I). However, R_1 represents an alkylene group, and R_2 represents an alkyl group. 2. N-(1'-lower alkyl-2'-pyrrolidinyl) represented by the formula (II-a), which has the formula ▲mathematical formula, chemical formula, table, etc., as a compound of formula (II).
Claim 1 using methylbenzoic acid amide
The method described in section. However, R_2_1 represents a lower alkyl group. 3. The method according to claim 1, wherein the above treatment is carried out in the presence of a lower alcohol. 4. The method according to claim 3, wherein the lower alcohol is methanol, ethanol, ethylene glycol or glycerin. 5. The method according to claim 1, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide. 6. The method of claim 1, wherein the treatment is carried out under substantially anhydrous conditions. 7. The method according to claim 1, wherein at least 5 mol of the alkali metal hydroxide is used per 1 mol of the compound of formula (II). 8. The method of claim 1, wherein said treatment can be carried out at about 50°C to the reflux temperature of the reaction mixture. 9 Formula (c) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ N-dichloroalkylbenzoic acid amide represented by (V) is expressed as formula R_2
-N-(1'-alkyl-2'-pyrrolidinyl) represented by (II) is reacted with an alkylamine represented by -NH_2 (VI), and (d) the formula thus obtained ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ N-(1'-alkyl-2'-pyrrolidinyl) represented by (II) Formula ▲ Formula, characterized in that an alkyl benzoic acid amide is treated with an alkali metal hydroxide to cleave the amide bond,
There are chemical formulas, tables, etc. ▼ Method for producing 1-alkyl-2-aminoalkylpyrrolidine represented by (I). However, R_1 represents an alkylene group, and R_2 represents an alkyl group. 10. The method according to claim 9, wherein the reaction (c) is carried out in the absence of a solvent. 11 Performing the reaction (c) above in the presence of a polar solvent,
A method according to claim 9. 12. The method of claim 9, wherein the reaction (c) is carried out at about 60° C. to the reflux temperature of the reaction mixture. 13 (b) Formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ When N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide represented by (IV) is reacted with thionyl chloride, (c) Formula produced ▲ Numerical formula, There are chemical formulas, tables, etc. ▼ N-dichloroalkylbenzoic acid amide represented by (V) is expressed by the formula R_2-NH
Reacted with an alkylamine represented by _2(VI),
(d) Then, the formula thus obtained ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The N-(1'-alkyl-2'-pyrrolidinyl)alkylbenzoic acid amide represented by (II) is treated with an alkali metal hydroxide. A method for producing 1-alkyl-2-aminoalkylpyrrolidine represented by the formula (I), which includes numerical formulas, chemical formulas, tables, etc., characterized by cleaving the amide bond. However, R_1 represents an alkylene group, and R_2 represents an alkyl group. 14. The method according to claim 13, wherein the reaction (b) is carried out in the absence of a solvent. 15. The method according to claim 13, wherein the reaction (b) is carried out in the presence of an inert organic solvent. 16. The method according to claim 13, wherein the reaction (b) is carried out at 60° C. to the reflux temperature of the reaction mixture. 17 In the reaction (b) above, thionyl chloride is converted to the formula (
IV) N-(2'-tetrahydrofuranyl)
14. The process according to claim 13, wherein at least 3 mol, preferably 4-6 mol, are used per mol of alkylbenzoic acid amide. 18. The method of claim 13, wherein the reaction product of (b) above is treated with water. 19 (a) Benzoic acid or its reactive derivative is expressed by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) 2-
Reaction with tetrahydrofuranylalkylamine or its reactive derivative, (b) Obtained formula ▲ Numerical formula, chemical formula, table, etc. ▼ N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide represented by (IV) is reacted with thionyl chloride When reacted with (c), the formula ▲Mathematical formulas, chemical formulas, tables, etc. are available▼N-dichloroalkylbenzoic acid amide represented by (V) is expressed by the formula R_2-NH
Reacted with an alkylamine represented by _2(VI),
(d) Then, the formula thus obtained ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The N-(1'-alkyl-2'-pyrrolidinyl)alkylbenzoic acid amide represented by (II) is treated with an alkali metal hydroxide. A method for producing 1-alkyl-2-aminoalkylpyrrolidine represented by the formula (I), which includes numerical formulas, chemical formulas, tables, etc., characterized by cleaving the amide bond. However, R_1 represents an alkylene group, and R_2 represents an alkyl group. 20. The method according to claim 19, wherein the reaction (a) is carried out in the absence of a solvent. 21. The method according to claim 19, wherein the reaction (a) is carried out in the presence of an inert organic solvent. 22. The method according to claim 19, wherein the reaction (a) is carried out in the presence of a condensing agent. 23. The method according to claim 19, wherein the reaction (a) is carried out at 0° C. to the reflux temperature of the reaction mixture.