JPS6144886A - N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide and a method for producing the same.

RR In the formula, R8 represents an alkylene group, and R7 represents an alkyl group. 1-Alkyl-2-aminoalkylpyrrolidine is a compound known as a synthetic intermediate for various pharmaceuticals, industrial chemicals, etc. For example, l-ethyl-2-aminomethylpyrrolidine has been proposed to be obtained by heating 1-ethyl-8-chloropyrrolidine hydrochloride with ammonia (
U.S. Patent No. 3,081.452 EJ4). However, in this known method, 1-ethyl-8-hydroxypiperidine is produced as a by-product, and it is difficult to separate the by-product.
It has the disadvantage that it is unsuitable as a synthetic intermediate for pharmaceuticals, which requires particularly high purity. Furthermore, as an improvement method of the above-mentioned known method, the above-mentioned formula (
A method for producing compound I) has also been proposed (Japanese Patent Publication No. 46-27457).

Reaction formula A In the above formula, R and R1 are as defined above.

However, the above improved method has a low yield of the compound of formula (I) (yield of about 18-50% based on the raw material tetrahydrofuranyl alkyl chloride), and the reagent (7 The inventors have discovered an industrially advantageous method for producing 1-alkyl-2-aminoalkylpyrrolidine of the above formula (I). As a result of various studies, we have found that the compound of formula (I) can be obtained in extremely high yield from benzoic acid and 2-tetrahydrofuranylalkylamine, which are very easily available industrially, by the method described below. This discovery led to the present invention.

That is, according to the present invention, 1-alkyl-2-aminoalkylpyrrolidine of the above formula (Il) is (a) benzoic acid or a reactive derivative thereof, where Rlt- is as defined above. (b) react with 2-tetrahydro7ranylalkylamine or its reactive M conductor, in which the N-(2'
-Tetrahydrofuranyl)alkylbenzoic acid amide is reacted with thionyl chloride to form (C) an N-dichloroalkylbenzoic acid amide of the formula Rt NHt, where R1#-i is as defined above.
(6) in which R is as defined above; (d) then the N-(
It is produced by treating 1'-alkyl-2'-pyrrolidinyl)alkylbenzoic acid amide with an alkali metal hydroxide to cleave the amide bond. The compounds of the present invention are mesosomal compounds used in the methods described above.

In this specification, the "alkyl group" may be either linear or branched, and preferably has a lower carbon number of up to 10 carbon atoms, particularly a lower carbon number of up to 5 carbon atoms, such as methyl , ethyl, n- or 1so-propyl, n-
1iso -1sec- or tert-butyl, n
-pentyl and the like are included, with ethyl being particularly preferred for R1. Further, the "alkylene group" may be either linear or branched, and lower alkylene groups having up to 6 carbon atoms are particularly preferred, such as methylene, ethylene,
Examples include propylene, methylethylene, butylene, methylpropylene, dimethylethylene, etc., and methylene is especially preferred for R1.

In the present invention, first, benzoic acid or a reactive derivative thereof is reacted with 2-tetrahydrofuranylalkylamine of the formula (I) 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) Acid halide COX 1(■-a) In the formula, Xl is a halogen atom, especially a chlorine atom. (11) Ester C0OR3(Vll-b) In the formula, R is a lower alkyl group, especially a methyl group or Ethyl group; or active ester residue, such as (button) In the mixed acid anhydride formula, R1 is an organic or inorganic acid residue, such as acetyl,
Acyl group such as propionyl; group -COOR5 (in the formula, R
sII'i is a lower alkyl group having 6 or less carbon atoms); or, in different schemes, each represents an alkyl group, an aryl group, or an aralkyl group, or ViRi and R7 together represent an alkylene group or fd o -represents a phenylene group), in the trunk) active amide formula, R@Ld H-substituted or unsubstituted 1-imigzoly/I
' group or dl-pyrazolyl group, (V) acid azide;
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) Incyanate (or isothiocyanate) [2R, -N=C=0 (or S)Cm-8) in the formula, R1 is as defined above, (11) Phos7azo compound or in the formula , R1d is as defined above, (in) a phosphoroamidite compound, where R1
, R6 and R7 are as defined above.

(IV) Phosfluoroamyl y'-) compound or compound in which 1<1, R6 and R2 are as defined in 6rI.

The amidation reaction between benzoic acid or a reactive derivative thereof and the amine of formula (l'lI) or a reactive derivative thereof can be carried out according to a method known per se.

For example, the amidation can be carried out by face-to-face condensation of benzoic acid with an amine of formula (till). Although the reaction can be carried out without a solvent, it is generally carried out in an inert organic solvent, such as benzene, toluene, xylene, etc. Preferably, the reaction is carried out in hydrogen ashing such as; ethers such as tetrahydrofuran, dioxane, dimethoxyethane and guigrime; amides such as dimethylformamide and dimethylacetamide; halogenated hydrocarbons such as dichloromethane and chloroform; dimethyl sulfoxide and the like.

There are no particular restrictions on the reaction temperature and pressure, and they can be varied widely depending on the raw materials used. However, usually the reaction temperature is about 0°C to the reflux temperature of the reaction mixture, preferably room temperature to 200°C, and the pressure is preferably normal pressure. Moreover, the reaction can be carried out in the presence of a combination agent if necessary, and condensing agents that can be used include, for example, Lewis acids, especially silicon tetrachloride, trichlorophenylsilane, titanium tetrachloride, etc., N-ethyl -N'-diethylaminopropylcarpodiimide, N,N'-dicyclohexylcarbodiimide, etc.; a combination of triarylphosphine and disulfide; strongly acidic ion exchange resins such as Amberlite IR-120.

The amidation may be carried out between a reactive derivative of benzoic acid as described above and a free amine of the formula (2), or between a free substituted benzoic acid and a reactive derivative of the amine of formula (2) as described above. You can do it even if you go between them. This amidation can also be carried out without using a solvent if necessary, but usually an inert organic solvent such as those mentioned above or a high boiling point alcohol (e.g. ethylene glycol, glycerin, etc.) is used.
It is advantageous to do it inside. Although the reflection temperature and pressure are not critical, the reaction temperature is usually from about -20°C to the reflux temperature of the reaction mixture, preferably from 0°C to 180°C, and the pressure is advantageously normal pressure.

In this way, the N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide of the formula (Iv) is obtained.

This product can be subjected to the next reaction as it is or after isolation. After the reaction, separation and purification of the 2-fold compound from the reaction mixture can be carried out by methods known per se, for example -
This can be easily accomplished by methods such as extraction, recrystallization, and chromatography.

The resulting N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide of formula QV) 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-(2'-tetrahydrofuranyl)ethylbenzoic acid amide, N-(2'-tetrahydrofuranyl)propylbenzoic acid amide, N-Cl'-(2 “-tetrahydrofuranyl)ethyl”
Benzoic acid amide.

Among these, N-(2'-tetrahydrofuranyl)methylbenzoic acid amide is particularly preferred.

The compound of formula (Iv) obtained above is thionyl chloride (
Upon reaction with 5OCIl, it can be converted to N-dichloroalkylbenzoic acid amide of the formula ff).

Although the reaction of the compound of formula (lv) with 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 conduct the reaction at a temperature of about 60° C. or higher, advantageously at the reflux temperature of the reaction mixture.

The amount of thionyl chloride used is also not critical, but
In general, it is preferred to use H in excess of at least 8 mol, preferably from 4 to 6 mol, per mol of the compound of formula (2).

Thus, this reaction produces a compound of the formula, where R and R are as defined above, under substantially anhydrous conditions, and this compound (formed) can also be isolated from the reaction system. , when water is added to the reaction mixture, it immediately changes to a compound of formula (V).

The resulting compound of formula ff) may be subjected to the next reaction as it is, or may be temporarily isolated from the reaction mixture. Separation and purification of the compound of formula (v) can be carried out by methods known per se, for example, means such as p-filtration, centrifugation, extraction, chromatography, recrystallization, etc. can be used.

The thus obtained N-dichloroalkylbenzoic acid amide represented by the formula ff) is also a novel compound that has not been described in conventional literature, and representative examples thereof are as follows.

N (2' + 5'-dichloropentyl)benzoic acid amide, N-(8',6'-dichlorohexyl)benzoic acid amide, N-(4',?'-dichlorheptyl)benzoic acid amide, N -(2',5'-dichloro-1-methylpentyl)benzoic acid amide.

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

The N-dichloroalkylbenzoic acid amide of the formula ff) thus produced is then reacted with an alkylamine of the formula %(), where R7 is as defined above, to give the N-dichloroalkylbenzoic acid amide of the formula ff)
R1 and R, Vi are as defined above, N-(1'
-alkyl-2'-pyrrolidinyl)alkylbenzoic acid amide.

The reaction between the compound of formula ff) 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, inpropertool,
alcohols such as n-butanol, tert-butanol, and ethylene glycol; ethers such as tetrahydrofuran, dioxane, and dimethoxyethane; atridos such as dimethylformamide and diterthylatothemide; dimethyl sulfoxide (DMSO); triethylamine, pyridine, Organic amines such as collidine and 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 of formula (W) used is also not critical,
Although it can be varied widely depending on the type of compound of formula ff) and/or the alkylamine of formula (11), reaction conditions, etc., it is usually at least equimole per mole of compound of formula ff), preferably It is 8 moles or more, and there is no particular upper limit, but it is wasteful to use more than necessary, and 1
0 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 root cause of the ring-closing reaction from the compound of formula (v) to the compound of (II) is not precisely known, for example, when R1 is a methylene group, the ring closure reaction from the compound of formula ff+ to the compound of formula (II) is unknown. In the 1311 W reaction, the presence of a compound of formula is observed in the middle.

The compound of formula (II) thus obtained can be separated from the reaction mixture if necessary and then subjected to the final step of the reaction of the present invention. The separation can be carried out according to conventional methods, such as p-filtration, centrifugation, chromatography, extraction, and distillation.

The resulting compound of formula (b) is also a novel compound that has not been described in conventional literature, and representative examples thereof are as follows.

N-(1'-ethyl-27iroricinyl)methylbenzoic acid amide, N-(1'-methyl-21-pyrrolidinyl)methylbenzoic acid amide, N-(1'-7'ropyru-2'-pyrrolidinyl)methylbenzoic acid Amide, N-(1'-iapropyl-2'-pyrrolidinyl)methylbenzoic acid amide, N-(1'-butyl-2'-pyrrolidinyl)methylbenzoic acid amide, N-(1'-ethyl-2'-pyrrolidinyl) ) Ethylbenzoic acid amide, N-(1'-phthyl-2'-pyrrolidinyl)ethylbenzoic acid amide, N-(1'-ethyl-21-pyrrolidinyl)propylbenzoic acid amide, N-(1'-propyl-2') -pyrrolidinyl)propylbenzoic acid amide, N-CI'-(1''-propyl-2〃-pyrrolidinyl)
Ethyl]benzoic acid amide, N-(1'-(1〃-ethyl-2''-pyrrolidinyl)ethyl]benzoic acid amide.

Preferred are the above compounds in which Rt1Vi represents a lower alkyl group, with N-(1'-ethyl-2'-pyrrolidinyl)methylbenzoic acid amide being particularly preferred.

According to the present invention, the compound of formula (II) obtained as described above is treated with an alkali metal hydroxide to cleave the amide bond, and the desired 1- converted into alkyl-2-aminoalkylamines.

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-7'ropanol, fi-butanol, methoxyethanol, ethoxyethanol, ethylene glycol, propylene glycol, diethylene glycol, chrycerin, etc. are most suitable. Among these, methanol, ethanol, ethylene glycol and glycerin are particularly conveniently used. Preferably, these solvents are anhydrous, or the presence of small amounts of water (usually up to 5% by weight) can be tolerated so long as the reaction is not significantly inhibited.

Examples of alkali metal hydroxides that can be used include sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., and in the present invention, the use of the former two is particularly desirable.

The temperature during the above process is not exact, and the formula used ([
Although it can vary widely depending on the type of compound and/or alkali metal hydroxide in 1) and other reaction conditions,
It is generally advantageous to use temperatures in the range from about 50° C. and above, especially from 60° C. 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 not critical and can vary widely depending on the type and reaction conditions of the compound of formula (II) and/or the alkali metal hydroxide, but generally the alkali metal It is appropriate to use the hydroxide in excess; for example, 5 equivalents, preferably 8 to 15 equivalents of the alkali metal hydroxide, per mol of the compound of formula (II). is advantageous.

In this way, the 1-alkyl-2-aminoalkylpyrrolidine of formula (I) can be produced in high yield. ``This isolation of the compound of formula (I) from the reaction mixture is carried out by
This can be easily carried out using methods known per se, such as extraction, chromatography, distillation, and the like.

The compound of formula (I) provided by the present invention can be used as a synthetic intermediate for various industrial chemicals and pharmaceuticals.

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

Example 1 Benzoyl chloride (1415g) was mixed with benzene (42.4d
) and tetrahydrofurfurylamine (1o, 1
9) and triethylamine (10,19) are added dropwise under 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. The solvent was distilled off under reduced pressure to obtain N-(2'-tetrahydrofuranyl)methylbenzoic acid amide (20.1 g) as crystals.

Melting point 88-90°C NMR (CDC11s +δ); 1.
Around 9 (4H9 multiplet), 8.1 to 4.2 (5H, multiplet), 6.8 (LH, multiplet), 73 to 7.9 (5H, multiplet)
, multiplet).

N-(2'-tetrahydrofuranyl)methylbenzoic acid amide is also produced by the following method.

That is, benzoic acid (12,29) was mixed with dimethylformamide (60 ml') and triethylamine (10,6
9) and isopropyl thalolformate (12.85g).
) is added dropwise under cooling. After stirring at room temperature for 1 hour, it was cooled again and tetrahydrofurfurylamine (10, fH
+) dropwise. After stirring at military temperature for 2 hours, 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 is distilled off, N-(2'-tetrahydro7ranyl)
Methylbenzoic acid amide (20.0 g) is obtained. Melting point: 88-90°C.

The N~(2'-tetrahydrofuranyl)methylbenzoic acid amide (40 g) obtained above was mixed with thionyl chloride (76,7
9) and heat under reflux for 4 hours. Pour the reaction solution into ice water and neutralize with potassium carbonate. The precipitated crystals are collected, washed with water, and then dried to obtain N-(2',5'-dichloropentyl)benzoic acid amide (47,29). Melting point 56-57°C.

NMR (CDC1x+a); around 2ko (4H
, multiple i), 8.8 to 4.8 (5H, multiplet), 6.9
Near (IH5 multiplet), 78-7.9 (5H, multiplet)
N-(2',5'-dichloropentyl) obtained above
Benzoic acid amide (2 & 9 g) is heated with a 70% ethylamine solution (23,9fnI) and ethanol (2 & 9rnI) for 20 hours. Distill as much of the ethylamine as possible under reduced pressure and heat for 4 hours. Add 4% caustic soda to the reaction solution. After adding the liquid and liquid, extract with benzene. The organic layer is washed with water and dried with sodium sulfate. Bath U is removed in 4 steps.
Ethyl-2'-pyrrolidinyl)methylbenzoic acid amide (
18,11) is obtained as an oil. NMR (CDC
1x + etc.); 1.11 (8H9 triple line IJ = 7H2),
Around 1.8 (4H9 multiplet), 1.9 to 3.5 (7H,
multiplet), 7.8-7,9 (5H, multiplet).

N-(1'-ethyl-2'-hyrolidinyl)methylbenzoic acid amide (1209) was dissolved in ethanol (600me)
and potassium hydroxide (800 g) and heated under reflux for 4 hours. The precipitated crystals are removed, and the solvent of liquid F is distilled off as much as possible under reduced pressure, followed by extraction with benzene. After washing with water, drying with sodium sulfate and distilling off the solvent. When the residue is distilled under reduced pressure, 1) i) z. An oil (60.8 g) is obtained at 60-61 °C. NMR (CDCIIs, δ); 1.091H, triplet, J=7Hz), 15-8.8 (IIH, multiplet).

Claims (1)

[Claims] 1. N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (IV). However, R_1 represents an alkylene group. 2. N-(2'-tetrahydrofuranyl)methylbenzoic acid amide according to claim 1, wherein R_1 is a methylene group. 3. Characterized by reacting benzoic acid or its reactive derivative with 2-tetrahydrofuranylalkylamine or its reactive derivative represented by the formula ▲Mathematical formula, chemical formula, table, etc.▼(III)
A method for producing N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide. However, R_1 represents an alkylene group. 4. The method according to claim 3, wherein the reaction is carried out in the absence of a solvent. 5. The method according to claim 3, wherein the reaction is carried out in the presence of an inert organic solvent. 6. carrying out the above reaction at the reflux temperature of the reaction mixture;
A method according to claim 3. 7. The method according to any one of claims 3 to 6, wherein the reaction is carried out in the presence of a condensing agent.