JPS624386B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to N-(1'-alkyl-2'-pyrrolidinyl)alkylbenzoic acid amide and a method for producing the same. formula In the formula, R ₁ represents an alkylene group, and R ₂ represents an alkyl group. The 1-alkyl-2-aminoalkylpyrrolidine is a compound known as a synthetic intermediate for various pharmaceuticals, industrial chemicals, etc. , for example 1-ethyl-2-aminomethylpyrrolidine is 1-ethyl-2-aminomethylpyrrolidine.
It has been proposed to obtain 3-chloropyrrolidine hydrochloride by heating with ammonia (U.S. Pat.
3031452 specification). However, in this known method,
Since 1-ethyl-3-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 that particularly require high purity. Furthermore, as an improvement on the above-mentioned known method, a method for producing the compound of formula () using the following reaction steps has also been proposed (Japanese Patent Publication No. 46-27457). Reaction formula A In the above formula, R ₁ and R ₂ are as defined above. However, the above improved method has a low yield of the compound of formula () (about 18-50% yield based on the raw material tetrahydrofuranylalkyl chloride) and requires industrially expensive reagents (potassium phthalimide and iodine). There are drawbacks such as the need for potassium oxide). The present inventors have discovered that 1-alkyl- of the above formula ()
As a result of conducting various studies on industrially advantageous production methods for 2-aminoalkylpyrrolidine, we found that from benzoic acid and 2-tetrahydrofuranylalkylamine, which are extremely easily available industrially, the formula We have discovered that the compound () can be obtained in extremely high yield, and have arrived at the present invention. That is, according to the present invention, 1 of the above formula ()
-Alkyl-2-aminoalkylpyrrolidine is
(a) Benzoic acid or its reactive derivative with the formula (b) is reacted with 2-tetrahydrofuranylalkylamine or a reactive derivative thereof, in which R ₁ is as defined above, and (b) the resulting formula is In the formula, R ₁ is as defined above, the N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide of is reacted with thionyl chloride, and (c) the formula to produce reacting an N-dichloroalkylbenzoic acid amide of the formula R 2 -NH 2 (), wherein R ₁ is as defined above, with an alkylamine of the formula R ₂ -NH ₂ (), where R ₂ is as defined above; (d) Then the formula thus obtained In the formula, R ₁ and R ₂ are as defined above. Treating the N-(1'-alkyl-2'-pyrrolidinyl)alkylbenzoic acid amide with an alkali metal hydroxide to cleave the amide bond. Manufactured by. The compounds of the invention are intermediate compounds used in the above methods. In this specification, the "alkyl group" may be linear or branched, and the number of carbon atoms
Lower ones with up to 10, especially up to 5 carbon atoms are preferred, such as methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or
Included are tert-butyl, n-pentyl and the like, with ethyl being particularly preferred for _R2 . Further, the "alkylene group" may be linear or branched, and lower alkylene groups having up to 5 carbon atoms are particularly preferred, such as methylene, ethylene, propylene, methylethylene, butylene, Examples include methylpropylene, dimethylethylene, etc., but R ₁
Among these, methylene is preferred. 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. (iv) Acid halide (ii) _ester where R ₁ is a lower alkyl group, especially a methyl or ethyl group; or an active ester residue, such as -CH ₂ CN,

【formula】 or

[Formula], (iii) mixed acid anhydride In the formula, R ₄ is an organic or inorganic acid residue, such as an acyl group such as acetyl or propionyl;
COOR ₅ (wherein R ₅ is a lower alkyl group having 6 or less carbon atoms); or

[Formula] (In the formula, R ₆ and R ₇ are the same or different,
each represents an alkyl group, an aryl group or an aralkyl group, or R ₆ and R ₇ together represent an alkylene group or an o-phenylene group); In the formula, R ₃ represents a substituted or unsubstituted 1-imidazolyl group or 1-pyrazolyl group, (v) acid azide Furthermore, as the amine-reactive derivative of the above formula (), any derivative used for activating an amino group during an amidation reaction in the field of peptide chemistry can be used; for example, the following may be used: It will be done. (i) Isocyanate (or isothiocyanate) where R ₁ is as defined above, (ii) phosphazo compound or In the formula, R ₁ is as defined above; (iii) phosphoroamidite compound In the formula, R ₁ , R ₆ and R ₇ are as defined above. (iv) Phosfluoramidate compounds or In the formula, R ₁ , R ₆ and R ₇ are as defined above. 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. amides such as; halogenated hydrocarbons such as dichloromethane and chloroform;
Preferably, the reaction is carried out in dimethyl sulfoxide or the like. 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 ethyl-N'-diethylaminopropylcarbodiimide, N.N'-dicyclohexylcarbodiimide, etc.; a combination of triarylphosphin and disulfide; and 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 (), or between a free substituted benzoic acid and a free amine of the formula ().
It can also be carried out with reactive derivatives of amines such as those mentioned 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
The reflux temperature of the reaction mixture is between about -20°C and preferably between 0°C and 180°C, and the pressure is advantageously normal. 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-(2'-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-(2'-tetrahydrofuranyl)ethylbenzoic acid amide, N-(2'-tetrahydrofuranyl)propylbenzoic acid amide, N-[1'-(2 ″-tetrahydrofuranyl)ethyl]benzoic acid amide. Among these, N- ₍ 2′-tetrahydrofuranyl)methylbenzoic acid amide is particularly preferred. ), it can be converted to N-dichloroalkylbenzoic acid amide of formula ().The reaction of the compound of formula () with thionyl chloride is as follows:
Although it is possible to carry out the process in the presence of a solvent, it is generally advantageous to carry out the process in the absence of a solvent. Examples of solvents that can be used include benzene,
Examples include aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as carbon tetrachloride, chloroform and chlorobenzene. The temperature of the reaction is not critical, but is generally about 60
It is preferable to carry out the reaction under heating above .degree. C., advantageously carried out at the reflux temperature of the reaction mixture. The amount of thionyl chloride used is also not critical, but it is generally preferred to use it in an excess of at least 3 moles, preferably from 4 to 6 moles, per mole of the compound of formula (). Thus, this reaction allows the formula In the formula, R ₁ is as defined above. A compound of the formula () is produced, and the compound of the formula () can be isolated from the reaction system, but as soon as water is added to the reaction mixture, the compound of the formula () is formed. turns into a compound. The generated compound of formula () 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,
For example, means such as filtration, centrifugation, extraction, chromatography, and recrystallization can be used. The N-dichloroalkylbenzoic acid amide of the formula () thus obtained 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-(3′・6′-dichlorohexyl)benzoic acid amide, N-(4′・7′.dichlorheptyl)benzoic acid amide, N-(2'·5'-dichloro-1-methylpentyl)benzoic acid amide. Among these compounds, N-(2'.5'-dichloropentyl)benzoic acid amide is particularly preferred. The N-dichloroalkylbenzoic acid amide of the formula () thus produced is then reacted with an alkylamine of the formula R ₂ -NH ₂ (), where R ₂ is as defined above, to form a compound of the formula In the formula, R ₁ and R ₂ can be N-(1'-alkyl-2'-pyrrolidinyl)alkylbenzoic acid amide, as defined above. The reaction between the compound of formula () and the alkylamine of formula () can be carried out either in the presence or absence of a solvent. Examples of solvents that can be used include ethanol, isopropanol, n-butanol, tert.
- Alcohols such as butanol and ethylene glycol; ethers such as tetrahydrofuran, dioxane, and dimethoxyethane; amides such as dimethylformamide and dimethylacetamide; dimethyl sulfoxide (DMSO); organic amines such as triethylamine, pyridine, 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 the alkylamine of formula () used is also not critical and can be varied widely depending on the type of compound of formula () and/or the alkylamine of formula (), reaction conditions, etc.; The amount is at least equal to 1 mole, preferably 3 moles or more, per mole of the compound (2), and although there is no particular upper limit, it is wasteful to use a larger amount than necessary, and 10 moles 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 mechanism of the ring-closing reaction from a compound of formula () to a compound of formula () is not precisely known, for example,
When R ₁ is a methylene group, in the ring-closing reaction from a compound of formula () to a compound of formula (), an intermediate compound of formula as well as The presence of a compound in which R ₂ is as defined above is recognized. 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-(1'-ethyl-2'-pyrrolidinyl)methylbenzoic acid amide, N-(1'-methyl-2'-pyrrolidinyl)methylbenzoic acid amide, N-(1'-propyl-2'-pyrrolidinyl)methyl Benzoic acid amide, N-(1'-isopropyl-2'-pyrrolidinyl)
Methylbenzoic acid amide, N-(1'-butyl-2'-pyrrolidinyl)methylbenzoic acid amide, N-(1'-ethyl-2'-pyrrolidinyl)ethylbenzoic acid amide, N-(1'-butyl-2 '-pyrrolidinyl)ethylbenzoic acid amide, N-(1'-ethyl-2'-pyrrolidinyl)propylbenzoic acid amide, N-(1'-propyl-2'-pyrrolidinyl)propylbenzoic acid amide, N-[1' -(1″-propyl-2″-pyrrolidinyl)
Ethyl]benzoic acid amide, N-(1′-(1″-ethyl-2″-pyrrolidinyl)ethyl)benzoic acid amide. The above compound has the formula In the formula, R ₂₁ represents a lower alkyl group, and compounds of the following are preferred, especially N-(1'-ethyl-
2'-pyrrolidinyl)methylbenzoic acid amide is a preferred compound. The compound of formula () obtained as above is
According to the present invention, the amide bond is cleaved by treatment with an alkali metal hydroxide to form the desired 1-alkyl-2-aminoalkylamine of formula (). 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. These solvents are preferably anhydrous, but
The presence of small amounts of water (usually up to 5% by weight) can be tolerated without significantly inhibiting the reaction. Examples of alkali metal hydroxides that can be used include sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. In the present invention, the former two
It is preferable to use the The temperature during the above treatment is not critical and can vary widely depending on the type of compound of formula () and/or alkali metal hydroxide used and other reaction conditions, but is generally about 50°C. above, especially 60℃
It is advantageous to use temperatures in the range above 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 not critical and can vary widely depending on the type and reaction conditions of the compound of formula () and/or the alkali metal hydroxide, but generally the alkali metal hydroxide is It is appropriate to use the oxide in excess, for example it is advantageous to use at least 5 equivalents of alkali metal hydroxide, preferably in the range from 8 to 15 equivalents, per mole of compound of formula (). . Thus, 1-alkyl-2- of the formula ()
Aminoalkylpyrrolidine can be produced in high yield. Isolation of the compound of formula () from the reaction mixture can be easily carried out using methods known per se, such as extraction, chromatography, distillation, and the like. The compounds of formula () provided by the present invention are:
It 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 Add benzoyl chloride (14.15g) to benzene (42.4g).
ml), and tetrahydrofurfurylamine (10.1 g) and triethylamine (10.1 g) are added dropwise under cooling. After stirring at room temperature for 2 hours,
Add water 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℃
NMR (CDCl ₃ , δ); around 1.9 (4H, multiplet),
3.1~4.2 (5H, multiplet), 6.8 (1H, multiplet), 7.3
~7.9 (5H, multiplet). N-(2'-tetrahydrofuranyl)methylbenzoic acid amide can also be produced by the following method.
That is, benzoic acid (12.2 g) was mixed with dimethylformamide (60 ml) and triethylamine (10.6 g).
g) and isopropyl chloroformate (12.85
g) is added dropwise while cooling. After stirring at room temperature for 1 hour, it is cooled again and tetrahydrofurfurylamine (10.6 g) is added dropwise. After stirring at room 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 was distilled off, N-(2'-tetrahydrofuranyl)methylbenzoic acid amide (20.0 g) was obtained. Melting point 88-90
℃. N-(2'-tetrahydrofuranyl)methylbenzoic acid amide (40 g) obtained above was heated under reflux with thionyl chloride (76.7 g) for 4 hours. Pour the reaction solution into ice water and neutralize with potassium carbonate. When the precipitated crystals are collected, washed with water and dried, N-
(2',5'-dichloropentyl)benzoic acid amide (47.2 g) is obtained. Melting point 56-57℃. NMR
(CDCl ₃ , δ); around 2.0 (4H, multiplet), 3.3~
4.3 (5H, multiplet), around 6.9 (1H, multiplet), 7.3
~7.9 (5H, multiplet). The N-(2'.5'-dichlorobentyl)benzoic acid amide (23.9 g) obtained above is heated with 70% ethylamine solution (23.9 ml) and ethanol (23.9 ml) for 20 hours. Ethylamine is distilled off as much as possible under reduced pressure and heated for 4 hours. 4 to the reaction solution
% caustic soda solution and then extraction. The organic layer was washed with water and dried with sodium sulfate. When the solvent is distilled off, N-
(1'-Ethyl-2'-pyrrolidinyl)methylbenzoic acid amide (18.9 g) is obtained as an oil.
NMR (CDCl ₃ , δ); 1.11 (3H, triplet, J=
7Hz), around 1.8 (4H, multiplet), 1.9 to 3.5 (7H,
multiplet), 7.3-7.9 (5H, multiplet). N-(1'-ethyl-2'-pyrrolidinyl)methylbenzoic acid amide (120 g) was dissolved in ethanol (600 ml).
and potassium hydroxide (300 g) under reflux for 4 hours. The precipitated crystals are removed, and the solvent of the liquid 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. Distillation of the residue under reduced pressure yields an oil (60.8 g) with a bp ₂₀ of 60-61°C. NMR ( _CDCl3 , δ); 1.09
(3H, triplet, J=7Hz), 1.5-3.8 (11H, multiplet).

Claims (1)

[Claims] 1 formula N-(1'-alkyl-2'-pyrrolidinyl)alkylbenzoic acid amide represented by: However, in the formula R ₁
represents an alkylene group, and R ₂ represents an alkyl group. 2. N-(1'-alkyl-2'-pyrrolidinyl)methylbenzoic acid amide, wherein R ₁ is a methylene group, as set forth in claim 1. 3. In claim 1, R ₂ is an ethyl group, N-(1'-ethyl-2'-pyrrolidinyl)alkylbenzoic acid amide. 4 In claim ₁ , N- ₍ 1'-
Ethyl-2'-pyrrolidinyl)methylbenzoic acid amide. 5 formula A formula characterized by reacting an N-dichloroalkylbenzoic acid amide represented by the formula with an alkylamine represented by the formula R ₂ -NH ₂ () A method for producing N-(1'-alkyl-2'-pyrrolidinyl)alkylbenzoic acid amide represented by However, in the formula, R ₁ represents an alkylene group, and R ₂ represents an alkyl group. 6. The method according to claim 5, wherein the reaction is carried out in the presence or absence of a solvent. 7 Claim 6, wherein the solvent is a polar solvent
The method described in section. 8. Claim 5, wherein the reaction is carried out at a temperature range of about 60°C to the reflux temperature of the reaction mixture.
The method described in section. 9 Alkylamine of formula () is replaced with N- of formula ()
Claim 5, wherein at least 3 moles are used per mole of dichloroalkylbenzoic acid amide.
The method described in section. 10 (a) Benzoic acid or its reactive derivative with the formula (b) the resulting formula: When N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide represented by is reacted with thionyl chloride, (c) the formula to be produced is A formula characterized by reacting an N-dichloroalkylbenzoic acid amide represented by the formula with an alkylamine represented by the formula R ₂ -NH ₂ () A method for producing N-(1'-alkyl-2'-pyrrolidinyl)alkylbenzoic acid amide represented by
However, R ₁ represents an alkylene group, and R ₂ represents an alkyl group. 11 The reaction of (b) above is carried out in the absence of a solvent,
A method according to claim 10. 12. The method according to claim 10, wherein the reaction (b) is carried out at the reflux temperature of the reaction mixture. 13. At least 3 mol, preferably 4-6 mol of thionyl chloride in the reaction (b) above is used per 1 mol of N-(2'-tetrahydrofuranyl)alkylbenzoic acid amide represented by formula (),
A method according to claim 10. 14. The method according to claim 10, wherein the reaction product of (b) above is treated with water.