WO2008038637A1

WO2008038637A1 - Method for production of free amine

Info

Publication number: WO2008038637A1
Application number: PCT/JP2007/068583
Authority: WO
Inventors: Akira Nishiyama
Original assignee: Kaneka Corporation
Priority date: 2006-09-26
Filing date: 2007-09-25
Publication date: 2008-04-03
Also published as: JP5254799B2; JPWO2008038637A1

Abstract

Disclosed is a clean, simple, and general-purpose method for producing a free amine from a salt of an amine having 1 to 10 carbon atoms which may have a substituent with an acid, which does not need to use water or any organic solvent, and which is reduced in complicated operations as possible and therefore does not consume unnecessary energy. Specifically disclosed is a simple and general-purpose method which comprises the steps of adding an amino alcohol or a polyamine to a salt of an amine having 1 to 10 carbon atoms which may have a substituent with an acid and distilling the mixture, thereby producing a free form of an amine having 1 to 10 carbon atoms which may have the substituent.

Description

Specification

Method for producing free amin

Technical field

[0001] The present invention relates to a method for producing free amines, which obtains various amines useful as synthetic intermediates for pharmaceuticals and agricultural chemicals as free products.

Background art

[0002] As a general method for purifying an amine, a method of forming a salt from an amine and an acid and crystallization from an organic solvent is often used. Further, this method can be applied to form a salt from a racemic amine and an optically active acid, and precipitate the salt of one enantiomer as a crystal for optical desorption. Examples of a method for liberating an amine from a salt of an amine and an acid thus obtained include the following methods.

[0003] (1) A salt of an amine and an acid is dissolved in water and neutralized by adding an alkali such as sodium hydroxide or potassium carbonate, and then an organic solvent such as ethyl acetate, toluene, or methylene chloride is added. How to extract. Specifically, for example, (S) -1 monobenzyl 3-amino pyrrolidine and dibenzoyl L tartaric acid are dissolved in an aqueous sodium hydroxide solution to separate the free amine, and the aqueous layer is further separated into toluene. After extraction with the above, it was combined with the previous amine to concentrate, and free (S) -1 monobenzyl-3-aminopyrrolidine was obtained with a yield of 45% (Patent Document 1). Further, D-tartrate salt of (R) -3-amaminopyrrolidine was dissolved in a 40 wt% aqueous sodium hydroxide solution, extracted with ether, and then the ether was distilled off under reduced pressure. Subsequent vacuum distillation of the residue yields liberated (R) -3aminopyrrolidine in a yield of 22% (Patent Document 2).

[0004] (2) Amine and acid salt are dissolved in water, neutralized by adding an alkali such as sodium hydroxide or potassium carbonate, and then heated with normal pressure or vacuum to bring the amine together with water. How to remove. Specifically, for example, an aqueous solution of cyclobutylamine is obtained by adding a sodium hydroxide aqueous solution to a cyclobutylamine sulfate and steam distillation (Non-patent Document 1).

[0005] (3) A salt of an amine and an acid is dissolved or suspended in an alcohol solvent such as methanol or ethanol. Subsequently, a base such as sodium methoxide or sodium ethoxide is added for neutralization, and the precipitated inorganic salt is removed by filtration, and then an alcohol solution of free amine is obtained as a filtrate. Subsequently, free amine is obtained by concentrating or separating the amine and alcohol by distillation. Specifically, for example, (S) -3-amaminopyrrolidine dihydrochloride is added to a methanol solution of 28% sodium methoxide, the precipitated inorganic salt is filtered off, and the filtrate is concentrated at normal pressure. Further, the concentrated solution was distilled at atmospheric pressure to obtain liberated (S) -3-aminopyrrolidine.

% (Patent Document 3).

Patent Document 1: Japanese Patent Laid-Open No. 9 176115

Patent Document 2: JP-A-1 294633

Patent Document 3: JP-A-2-218664

Non-Patent Document 1: Org. Synth., V, 273 (1973).

Disclosure of the invention

Problems to be solved by the invention

[0006] Among amine compounds, an amine having 1 to 10 carbon atoms which may have a substituent is often miscible with water because the amino group in the molecule is a hydrophilic group. For this reason, when extracting amines as in the prior art (1), a large amount of organic solvent is required, and there are cases where the concentration and separation operation becomes complicated, for example, the commonly used organic solvent and amine are azeotroped (this application (See Comparative Example 1). In the case of the prior art (2), the amine can be obtained as an aqueous solution and cannot be used for a water-inhibiting reaction. Of course, it is possible to separate the amine and water, but in many cases, it is necessary to repeat the distillation operation a plurality of times (see Comparative Example 2 of the present application). Further, in the case of the prior art (3), a complicated inorganic salt filtration operation is essential, and in many cases, the inorganic salt cannot be completely removed by a single filtration operation. Furthermore, if the amine azeotropes with the alcohol, it is difficult to obtain a high-purity amine in high yield (see Comparative Example 3 of the present application).

Means for solving the problem

In view of the above, as a result of intensive studies, the present inventor did not use water, organic solvent, or alcohol at all, and did not require complicated extraction operation, concentration operation, or filtration operation. To complete the present invention by developing a general and simple method for liberating amines from salts It came.

[0008] That is, the present invention includes a step of adding an amino alcohol or a polyamine to a salt of an amine and an acid having 1 to 10 carbon atoms which may have a substituent, and performing distillation. The present invention also relates to a method for producing the free form of ammine.

[0009] Further, the present invention is characterized in that an amino alcohol or a polyamine is added to a salt of an amine and an acid having 1 to 10 carbon atoms which may have a substituent, and distilled. The present invention relates to a method for obtaining a free form of ammine.

The invention's effect

[0010] According to the present invention, an organic solvent is not required for obtaining a free amine from a salt of an amine and an acid. In addition, wasteful energy is not consumed by reducing complicated concentration and filtration operations as much as possible. Furthermore, it is a simple and versatile method. Therefore, free amine can be obtained easily and efficiently at low cost.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, a free amine is obtained by adding an amino alcohol or a polyamine to a salt of an amine and an acid having 1 to 10 carbon atoms, which may have a substituent, and performing distillation. . It is not necessary to perform an extraction operation, a concentration operation, or a filtration operation by adding an amino alcohol or a polyamine to a salt of an amine and an acid and performing a direct distillation operation.

Here, the amine having 1 to 10 carbon atoms which may have the substituent is not particularly limited, and may be any of a chain amine and a cyclic amine. The substituent is not particularly limited as long as it is thermally stable and inactive with respect to amine. For example, hydroxyl group, carbon number;! -5 alkyloxy group, carbon number; An alkylthio group, a fluoro group, a cyano group, or a nitro group. Preferably, it is an amine having a boiling point of 250 ° C. or less at normal pressure, more preferably 200 ° C. or less at normal pressure. In addition, even if the material is thermally decomposed before being vaporized by heating at normal pressure, any material that can be vaporized under reduced pressure is included in the present invention.

[0013] Specific examples of the amine having 1 to 10 carbon atoms which may have the substituent include 2-amino 1-propanol, 1-amino-2-propanol, 2-amino-1-butanol, and 1-dimethylamine. Minnow 2-Propanol, Norinol, Mouth Icinol, Iso Mouth Icinol, ter t mouthful isinol, 2-aminocyclopentanol, 2-aminobutane, 2-methylbutylamine, 2-aminopentane, 2-aminohexane, 2-aminoheptane, 1-phenethylenamine, 1-phenylpropylamine, 2 —Phenylpropylamine, 3-aminopentaneditrinole, 3 aminotetrahydrofuran, 1,2 diaminopronone, 1,2 diaminoph, tan, 1,2-cyclohexanediamine, 2-methylpyrrolidine, 2-ethylpyrrolidine, 2-methylbiperidine, 3 methylbiperidine, 2 methylbiperazine, 2 methinoremonoreforin, 3 aminobi oral lysine, 3-aminobiperidine, 3-pyrrolidinole, 3-piperidinol, 3- (methylamino) pyrrolidine, 3- (ethylamino) pyrrolidine, 3 — (Dimethylamino) pyrrolidine, 3 (1 gin, 3- (aminomethyl) pyrrolidine, 3- (aminomethyl) piperidine, 2- (hydroxymethy

Examples include piperidine, 1 (2 pyrrolidinylmethyl) pyrrolidine, 3 quinuclidinol, and tetrahydrofurfurylamine. These may be optically active substances.

[0014] Preferably, it is 2 amino-1-butanol, 2 methylpyrrolidine, 2 methylbiperidine, 3-aminopyrrolidine, 3-aminobiperidine, or 3-pyrrolidinol, more preferably (S) -2-amino-1-butanol, (S) — 2-Methylpyrrolidine, (S) — 2-Methylbiperidine, (S) — 3-Aminopyrrolidine, (S) — 3-Aminobiperidine, (S) — 3-Pyrrolidinol, (R) — 2-Amino- 1-butanol, (R) -2-methylpyrrolidine, (R) -2-methinorepiperidine, (R) -3-aminopyrrolidine, (R) -3-aminobiperidine, or (R) -3-pyrrolidinol is there. Particularly preferred is (S) -3-amino pyrrolidine or (R) -3-amino pyrrolidine.

[0015] Here, the acid in the salt of an amine having 1 to 10 carbon atoms which may have a substituent is not particularly limited, but specifically, for example, hydrogen fluoride, hydrogen chloride, odor Inorganic acids such as hydrogen iodide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, boric acid; formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, cyclohexane carboxylic acid, cycloacetic acid, dichloroacetic acid, trichloro Oral acetic acid, trifluoroacetic acid, acrylic acid, fumaric acid, maleic acid, benzoic acid, phthalic acid, oxalic acid, malonic acid, citrate, L tartaric acid, D tartaric acid, dibenzoyl L tartaric acid, diben Zoinole D-tartaric acid, di-p-toluoyl L-tartaric acid, di-p-toluoinole D-tartaric acid, (+)-camphoric acid, L-malic acid, D-malic acid, L-mandelic acid, D-mande Carboxylic acids such as Nore acid; methane sulfonic acid, ethane sulfonic acid, trifluoromethane sulfonic acid, benzene sulfonic acid, p toluene sulfonic acid, p black benzene sulfonic acid, m ditrobenzene sulfonic acid, camphor sulfonic acid, etc. A sulfonic acid is mentioned. Preferred are hydrogen chloride, hydrogen bromide, sulfuric acid, formic acid, acetic acid, oxalic acid, L tartaric acid, D tartaric acid, methanesulfonic acid, or p-toluenesulfonic acid.

[0016] Here, regarding the salt of an amine having 1 to 10 carbon atoms that may have the above-mentioned substituent and an acid, its production method is not particularly limited, but specifically, for example, an amino group of the amine. Is protected with a protecting group such as acetyl group, benzoyl group, phthaloyl group, methoxycarbonyl group, ethoxycarbonyl group, tert butoxycarbonyl group, or benzyloxycarbonyl group, for example, hydrogen fluoride, hydrogen chloride, odor Inorganic acids such as hydrogen iodide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, boric acid; methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p toluenesulfonic acid, p Deprotection with an acid such as acid, m sulfonic acid such as ditrobenzene sulfonic acid, camphor sulfonic acid, etc. Salts may be prepared with acids. Further, for the purpose of improving the purity of the amine, it may be produced by forming a salt with the acid and precipitating it as a crystal from a solvent. In addition, the racemic amines can be added to L-tartaric acid, D tartaric acid, dibenzoyl L, tartaric acid, dibenzoyl D It may be a salt of an optically active amine and an optically active acid formed by diastereomer salt formation with an optically active carboxylic acid such as L mandelic acid and D mandelic acid.

Next, the amino alcohols or polyamines added to this system will be described. The amino alcohols or polyamines to be added to the system may have a boiling point higher than that of the amine having 1 to 10 carbon atoms which may have the above substituents! /. Preferably, it may have a substituent! /, A boiling point of an amine alcohol or polyamine to be added is higher than the boiling point of an amine having 1 to 10 carbon atoms; Furthermore, the amino alcohols or poly Amines need to be sufficiently polar to dissolve the salt of the amine and acid.

The amino alcohols or polyamines are not particularly limited. Specifically, for example, 1-amino-2-butanol, 2 amino-1-butanol, 4 amino-1-butanol, 2-aminocyclohexanol, 4 amino-1 -Jetylaminopentane, 3-amino 2,2-dimethyl-1-propanol, 2-aminoethanol, 2- (2-aminoethoxy) ethanol, 2- (2-aminoethylamino) ethanol, N- (2 —Aminoethyl) aniline, N— (2-aminoethinole) morpholine, N— (2-aminoethinole) piperazine, 1 (2-aminoethyl) piperidine, 2 amino-2-ethynole 1,3 propanediol, 1 -(2 aminoethyl) pyrrolidine, 4 amino-2 methyl-1-butanol, 4- (aminomethyl) piperidine, 2 amino-2 methino 1, 3 propanediol, 2 amino-2 methyl 1 propanol, 2 aminomethyl pyridine, 3 aminomethyl pyridine, 4 aminomethyl pyridine, 2 amino 1-phenylethanol, 4 aminobiperidine, 2 amino 1 1,3-propanediol 3-amino-1,2-propanediol, 1-amino-2-propanol, 2-amino-1-propanol, 3-amino-1-propanol, N- (3-aminopropinole) cyclohexylamine, N- (3-aminopropinore) diethanol Amine, N— (3aminopropyl) morpholine, 1— (3aminopropyl) 1-2 Pipecoline, 3Aminobilysine, 4Amino-2,2,6,6 Tetramethinoleviperidine, 2Anilinoethanolol, 1 One benzil 3-aminopyrrolidine, N benzylethanolamine, one benzil Luo 3 pyrrolidinol, 1,2-bis (2-aminoethoxy) ethane, bis (2-aminoethyl) ether, N, N bis (2-aminoethynole) methylamine, N, N bis (2-aminoethyl) 1, 3 Propanadamine, bis (2aminoethyl) sulfide, bis (6aminohexyl) amine, 1,3-bis (aminomethyl) cyclohexane, 1,4-bis (aminomethyl) cyclohexane, 1,4 Bis (3aminopropoxy) butane, 1,2 bis (3aminopropoxy) ethane, bis [2- (3aminopropoxy) ethyl] ether, bis (3aminopropyl) etherole, N, N, one bis (3-Aminopropino) ethylenediamine, N, N bis (3-aminopropyl) methylamine, 1,4-bis (3-aminopropyl) piperazine, 1,6-bis (ethylamino) hexa , Bis (to Kisamechiren) Toriamin, 1- [bis (2-hydroxy E chill) Amino] 2-propanol, bis (2-hydroxy E chill) amino tris (hydroxymethyl) method Tan, N, N-bis (2-hydroxyethinole) ethylamine, N—n butylethanolamine, N—tert butinorethananolamine, N—n butynoleethylenediamine, 2, 2 ′ — ( Butylimino) diethanol, cinchonidine, cinchonine, 1,2-cyclohexanediamine, 1,3-cyclohexanediamine, 1,4-cyclohexanediamine, N-cyclohexylethanolamine, 1,4-diaminobutane, 3,3'-diamino Dipropylamine, 1,6-Diaminohexane, 1,2-Diamino1-2methylpropane, 1,3-Diaminopentane, 1,5-Diaminopentane, 1,2-Diaminopropane, 1,3-Diaminopropane, 1 , 3-Diamino 2 propanol, 1, 5 diazabicyclo [4, 3, 0] — 5 Nonene, 1, 4 diazabicyclo [2, 2, 2] octane, 1, 8 diazabi [5, 4, 0] —7 undecene, 2 di-n-butylaminoethanol, 3-(di-n-butylamino) propylamine, diethanolamine, 2 jetylaminoethanol, 3 jetylamino-1, 2 propanediol, 1-jetyl Amino-2 propanol, 3 Jetylamino-1 Propanol, N, N Jetinole 1, 3-Diaminopropane, N, N'-Gethinoreethylenediamine, N, N Jetyl N 'Methylethylenediamine, N, N Diisopropylethylene Diamine, 4-Dimethylamino-1-butanol, 2-Dimethylaminoethanol, 2- (2-Dimethylaminoethoxy) ethanol, 1- (2-Dimethylaminoethyl) 4-methylbiperazine, 2 Dimethylamino-2 methyl-1 Propanol, 3 (dimethylamino) 1, 2 Propanediol, 1-dimethyla Minol 2-propanol, 3-dimethylamino-1 propanol, 3-dimethylaminopyrrolidine, N, N dimethylethylenediamine, N, N'-dimethylethylenediamine, N, N 'dimethylbiperazine, 2 , 6 Dimethylbiperazine, N, N Dimethyl-1,3 Propanediamine, 2,2 Dimethyl-1,3 Propanediamine, N, N'-Diphenylethylenediamine, 1,2-Diphenylethylenediamine, 1,3 —Di-4-piperidylpropane, N-ethyljetanolamine, ethylenediamine, 2, 2, 2, 2 ,, 2, monoethylenediutrilotetraethanol, ethylene glycol bis (3-aminopropyl) ether, Nethylethylene Diamine, N-ethylbiperazine, 1-ethylenole, 3 pyrrolidinole, hexamethylenetetramine, homopiperazine, 2- (2 Rokishechiru) 1-methylpyrrolidine, N-(2-hydroxy-E chill) morpholine, 1 i (2-hydroxy-E chill) pyrrolidine, 2 [(hydroxymethyl) Amino] ethanol, 3 hydro Xyl 1-methylbiperidine, 4-hydroxy 1-methylbiperidine, 4-hydroxy-4 —phenylbiperidine, 3 hydroxypiperidine, 4 hydroxypiperidine, N— (2 hydroxypropinole) ethylenediamine, N— (3— Hydroxypropinole) ethylenediamine, N- (2-hydroxypropinole) morpholine, imidazole, isophoronediamine, 2- (isopropylamino) ethanol, N-isopropylinole 1,3-diaminopropane, N-isopropylethylenediamine , Lysine, 2- (methylamino) ethanol, 3- (methylamino) 1,

2-propanediol, 3- (methylamino) 1 propanol, 3- (methylamino) pyrrolidine, N-methyl-2,2'-diaminojetylamine, 2-methyl-1,5-diaminopentane, N-methyl-1,3-diaminopropane, N-methyljetanolamine, 4,4'-methylenbis (cyclohexylamine), 4,4'-methylenebis (2-methylcyclohexylamine), N-methylethylenediamine, N-methyl-D-glucamine, N-methylhomopiperazine, 1-methylbiperazine, 2-methylbiperazine, 1-methyl-2-piperidine methanol, 1-methyl-3-piperidinemethanol, 2-methyl-1,3-propanediamine,

3 Morpholino 1,2 propanediol, norephedrine, 2,2'oxybis (ethylamine), phenylalaninol, N-phenylethaneolamine, 1,2-phenolenediamine, 1,3-phenylenediamine N-phenylethylenediamine, phenyldarinol, 1-phenylbiperazine, 2 picolinolamine, 3 picolinolamine, 4 picolylamine, piperazine, 1-piperazine ethanol, 1-piperidineethanol, 2-piperidineethanol, 4- Piperidine ethanol, 2 piperidine methanol, 3 piperidine methanol, 4-piperidine methanol, 1-piperidine pentanol, 4-piperidinopiperidine, 2- (4-piperidyl) -2 propanol, prolinol, 4 (4 pyridyl) Morpholine, one (2-pyridyl) Perazine, 3-pyrrolidinol, 4-pyrrolidinopyridine, quinuclidinol, spartin, 1, 4, 7, 10 tetraazacyclododecane, N, N, Ν ', Ν, —tetraisopropyljetylenetriamine, tetrakis (dimethylamino) ) Ethylene, Ν, Ν

, Ν ', Ν, -Tetrakis (2-hydroxypropinole) ethylenediamine, Ν, Ν, Ν', Ν, tetramethyl 1,3-diaminobutane, Ν, Ν, Ν ', Ν'-tetramethyl 1 1, 4 —Diaminobtan, Ν, Ν, Ν ', N'—Tetramethyldiaminomethane, Ν, Ν, Ν', N'—Tetramethyl-1,3-diaminopropane, Ν, Ν, Ν ', N'— Tetramethylethylenediamine, triethanol Amines, triethylenetetramine, N, N, N'-triethylethylenediamine, 1, 3, 5-trimethylhexahydro-1, 3, 3, 5 triazine, N, N, N, trimethyl 1 N, 1 (2 hydroxy shetil) bis (2 aminoethyl) ether, 2, 6, 10 trimethinole 2, 6, 10 triazaundedecane, tris (2 aminoethyl) amine, tris (3 aminopropyl) amine, tris (dimethylamino) methane, tris ( Hydroxymethyl) aminomethane, tryptamine and the like. Two or more of these may be used in combination, and the mixing ratio is not particularly limited.

[0019] In order to release the target amine more efficiently, it is also derived from the structure of the amine, but as the amino alcohol or polyamine to be added, an aliphatic amine is preferable to an aromatic amine. Also, secondary amines are preferred over tertiary amines. Primary amines are even more preferred than secondary amines. In addition, polyamines such as triamine and tetramine, which are preferred to diamines over monoamino alcohols, are more preferred. As diamines, those having an amino group on the adjacent carbon are preferable.

[0020] In addition, liquids at 30 ° C are preferred from the viewpoint of ease of handling, for example, 2- (2-aminoethylamino) ethanol, N- (2-aminoethyl) morpholine, N- (2-amino Ethyl) piperazine, 1- (2-aminoethyl) piperidine, 1- (2-aminoethyl) pyrrolidine, N, N, 1-bis (3-aminopropyl) ethylenediamine, 1,4-bis (3-aminopropyl) pipera Gin, N—n Butynoleethylenediamine, 1,2-Cyclohexanediamine, 1,2-Diamino 2-methylpropane, N, N′-Dethylethylenediamine, N, N Diisopropylethylenediamine, N , N, Dimethinolepiperazine, N Ethinorepiperazine, Homopiperazine, N— (2 Hydroxypropinole) ethylenediamine, N— (3 Hydroxypropinore) Ethylenediamine, 2—Me Norre piperazine, piperidines Rajin, -1-piperazine eth no Honoré, N, N, Ν ', Ν, one tetrakis (2-hydroxypropyl) Echirenjiamin, triethylenetetramine Mi emissions, tris (2-aminoethyl) Amin and the like are preferable. In particular, 2- (2-aminoethylamino) ethanol or Ν, Ν, monobis (3-aminopropyl) ethylenediamine is preferable from the viewpoint of economy.

[0021] The amount of the amino alcohol or polyamine used may be set according to the number of amino groups contained in the amino alcohol or polyamine. If there is a single amino group, it should be used in an amount of 1 molar amount or more with respect to the salt of the amine and the acid. Is an amino group of polyamines (n represents a positive integer), 1 / n times the molar amount, preferably 1. It is preferable to use 3 / n times the molar amount or more, more preferably 1.5 / n times the molar amount or more.

[0022] Specifically, if there are two amino groups, they are used in an amount of 0.5 moles or more with respect to the salt of the amine and the acid, and if there are three amino groups, the amine and the acid are used. If the salt is used in an amount of 0.34 times the molar amount or more and 4 amino groups are used, the amount of 0.25 times the molar amount or more of the salt of the amine and the acid may be used.

[0023] Further, in the case where the salt of an amine and an acid has m protons (m represents a positive integer), the amino alcohol or polyamine is preferably added in an amount of m / n-fold molar amount or more. It is preferable to use 1 · 3 m / n-fold molar amount or more, more preferably 1.5 · 5 m / n-fold molar amount or more. For example, if there are two protons such as oxalic acid, m becomes 2.

[0024] The upper limit of the amount of the amino alcohol or polyamine used is not particularly limited. However, from the viewpoint of economy, the salt of the amine and the acid is preferably used as long as the amino compound to be added has one amino group. When the amount of amino group is 5 or less, and the number of amino groups is one, the number of amino groups to be added may be 1 / n times that of one amino group (n is the same as above). Of course, when the acid in the salt of amine and acid has m protons (m is the same as above), the upper limit of the amount of aminoamino or polyamine having n amino groups is (5m) A molar amount of / n is preferred.

[0025] As a method for adding the amino alcohols or polyamines, it is preferable to start distillation after adding the amino alcohols or polyamines to the salt of the amine and the acid. Further, aminoanols or polyamines may be further added after the start of distillation.

[0026] The distillation method of the present invention may be either atmospheric pressure distillation or reduced pressure distillation. Amines obtained by distillation contain acids, and may contain amino alcohols or polyamines in some cases. In this case, re-distillation should be performed to increase the purity of the target amine.

Example

[0027] The present invention will be described more specifically with reference to the following examples. Not limited to examples only

[0028] (Comparative Example 1) (R) — 3-—A: (E) —3-

When 36.0 g (2.7 equivalents) of a 30 wt% aqueous sodium hydroxide solution was added to 15.91 g (100 mmol) of (R) -3-aminopyrrolidine dihydrochloride, a homogeneous solution was obtained. This was heated to 40 ° C. and extracted three times with 50 mL of tetrahydrofuran, and the organic layers were combined. When the recovery rate was calculated by measuring the amount of (R) -3-aminopyrrolidine in the organic layer, it was 14%, and the rest remained in the aqueous layer.

[0029] (Comparative Example 2) 3-Aminopyro _]; (£) —3-

When 36.0 g (2.7 equivalents) of a 30 wt% aqueous sodium hydroxide solution was added to 15.91 g (100 mmol) of (R) -3-aminopyrrolidine dihydrochloride, a homogeneous solution was obtained. This was heated and concentrated at 70 ° C. under reduced pressure of 10 to 20 mMHg to obtain 20.5 g of an aqueous solution of (R) -3-aminopyrrolidine. When the amount of (R) -3-aminopyrrolidine in the aqueous solution was measured, the content was 15.0% by weight, and 36% in terms of recovery.

[0030] (Comparative Example 3) (R) -3-Aminopyrrolidine from (R) -3-Aminopyrrolidine disalt

(R) -3-Aminopyrrolidine dihydrochloride (15.91 g, 100 mmol) was suspended in methanol (15 mL), and 28 wt% sodium methoxide / methanol solution (46.30 g, 2.4 equivalents) was added thereto. This was heated to 40 ° C and stirred for 1 hour, and then 50 mL of tetrahydrofuran was added and cooled to 5 ° C. The inorganic salt (sodium chloride) precipitated after stirring at 5 ° C for 30 minutes was filtered off under reduced pressure and washed with 50 mL of tetrahydrofuran. The filtrate was concentrated under normal pressure heating (external temperature: 110 ° C., internal temperature: ˜85 ° C.) to obtain a yellow liquid as a residue. To this was added 50 mL of tetrahydrofuran, concentrated again under normal pressure heating (external temperature: 110 ° C, internal temperature: ~ 85 ° C), and the residue was distilled at atmospheric pressure, so that the external temperature: ~ 180 ° C. The inner temperature: ~ 140 ° C as a colorless liquid 13. Olg was obtained, and the outside temperature: 180 ~; 190 ° C, the inner temperature: 140 ~; 145 ° C as a fraction of colorless liquid 1. 56g When the amount of (R) -3-aminopyrrolidine in each fraction was measured, the content was 12.7% by weight (recovery: 19%) and 89.3% by weight (recovery: 16 %)Met. [0031] (Comparative Example 4) (R) — 3—A: (R) — 3-from hydrochloride

(R) — A mixture (slurry) of 3-95aminopyrrolidine dihydrochloride 7953 g (50 mmol) and dibenzylamine (boiling point: 300 ° C) 29.55 g (3 equivalents) under a reduced pressure of 35 mmHg at 190 ° C However, the distillate could not be confirmed.

[0032] (Example 1) iR) _— 3-Aminopyrrolyl ”(R) —3-Aminopyro _];

(R) —3-Aminopyrrolidine dihydrochloride 7. 953 g (50 mmol), 2- (2-aminoethinoreamino) ethanol (boiling point: 243.7 ° C.) 15.60 g (3 equivalents) The colorless homogeneous solution was heated to 180 ° C. under a reduced pressure of 60 mmHg to obtain 4.416 g of colorless liquid at an outflow temperature of 90 to 120 ° C. When the amount of (R) -3-aminopyrrolidine in this liquid was measured, the content was 89.9% by weight (recovery rate: 93%). Further, this liquid was distilled under reduced pressure. When heated to 120 ° C under reduced pressure of 55 mmHg, an effluent temperature of 82-88 ° C was obtained as a colorless liquid. When the amount of (R) -3-aminopyrrolidine in this liquid was measured, the content was 100% by weight (recovery: 86%, total recovery: 80%).

[0033] (Example 2) (R) -3-Aminopyrrolidine from (R) -3-Aminopyrrolidine disalt

(R) —3-Aminopyrrolidine dihydrochloride 7 · 953 g (50 mmol), N-methyljetanolamine (boiling point: 246–248 ° C) 17. 87 g (3 eq) A color uniform solution was obtained. When this solution was heated to 185 ° C under a reduced pressure of 55 mmHg, 8.9506 g of a colorless liquid was obtained at an effluent temperature of 155 ° C. When the amount of (R) -3-aminopyrrolidine in this liquid was measured, the content was 17.0% by weight (recovery rate: 35%).

[0034] (Example 3) Net loss of (R) -3-pyrrolidinol from (R) -3-pyrrolidinol hydrochloride

(R) —3-Pyrrolidinole hydrochloride 6. 179 g (50 mmol), 2- (2-aminoethynoleamino) ethanol (boiling point: 243.7 ° C) 15. 60 g (3 eq) mixture (colorless homogeneous solution) ) Was heated to 185 ° C. under reduced pressure of 35 mmHg to yield 21.649 7 g of colorless liquid at an effluent temperature of ˜155 ° C. Furthermore, this liquid was distilled under reduced pressure. Add to 155 ° C under reduced pressure of 40 mmHg Upon heating, 6.765g of colorless liquid was obtained at an effluent temperature of ~ 138 ° C. Further, this liquid was distilled under reduced pressure. When heated to 145 ° C under a reduced pressure of 38 mmHg, 3.5491 g of a colorless liquid was obtained at an outlet temperature of 133 ° C. When the amount of (R) -3 pyrrolidinol of this liquid was measured, the content was 78.8% by weight, which was 64% in terms of recovery.

[0035] (Example 4) Defeat of (S) -2-amino-1-butanol from (S) -2-amino-1-butanol acetate

(S) — 2 Amino 1-butanol acetate 7 · 457 g (50 mmol), N, N, monobis (3aminopropyl) ethylenediamine (boiling point: 165 ° C / 10 mmHg) 8. 715 g (l equivalent) When the colorless homogeneous solution was heated to 150 ° C under a reduced pressure of 40 mmHg, a colorless liquid of 4 · 5945 g force S was obtained at an outflow temperature of 95 ° C. When the amount of (S) -2-amino-1-butanol in this liquid was measured, the content was 93.4% by weight, which was 96% in terms of recovery.

(Example 5) of 2 methylbiperidine from 2 methylbiperidine methanesulfonate

2 Methylbiperidine methanesulfonate 9 · 759g (50mmol), 2- (2aminoethylamino) ethanol (boiling point: 243.7 ° C) 15. 60g (3eq) mixture (colorless homogeneous solution) When heated to 170 ° C at normal pressure, 3.680 g of colorless liquid was obtained at an effluent temperature of 80-99 ° C. When the amount of 2-methylbiperidine in this liquid was measured, the content was 100% by weight, and it was 78% when converted to recovery.

[0037] (Example 6) 2-methylbiperidine methanesulfone salt from 2-

2 Methylbiperidine methanesulfonate 9 · 759 g (50 mmol), 2- (2 aminoethoxy) ethanol (boiling point: 218–224 ° C) 10. 514 g (2 equivalents) of a mixture (colorless homogeneous solution) When heated to 175 ° C at normal pressure, 3.5579 g of colorless liquid was obtained at an outflow temperature of 110 ° C. When the amount of 2-methylbiperidine in this liquid was measured, the content was 96.6% by weight, and 69% in terms of recovery.

[0038] (Example 7) of 2-methylbiperidine from 2-methylpiperinidine methanesulfone

2 Methylbiperidine methanesulfonate 9.759 g (50 mmol), diethanolamine ( Boiling point: 217 ° C / 150mmHg) When a mixture of 514g (2 equivalents) (colorless homogeneous solution) is heated to 185 ° C at atmospheric pressure, a colorless liquid is obtained at an outflow temperature of 95 ° C 3. 1669g It was. When the amount of 2-methylbiperidine in this liquid was measured, the content was 95.2% by weight and 61% when converted to recovery.

(Example 8) 2-methylbiperidine derived from 2-methylpiperinidine methanesulfone

A mixture consisting of 9.759 g (50 mmol) of 2-methylbiperidine methanesulfonate and 11.92 g (2 equivalents) of N-methyljetanolamine (boiling point: 246-248 ° C) (colorless homogeneous solution) at atmospheric pressure When heated to 185 ° C, 1.5668 g of a colorless liquid was obtained at an effluent temperature of 90 ° C. When the amount of 2-methylbiperidine in this liquid was measured, the content was 88.7% by weight and 28% in terms of recovery.

[0040] (Example 9) 2-methylbiperidine methanesulfone

2-Methylbiperidine methanesulfonate 9 · 759g (50mmol), N, N, monobis (3-aminopropyl) ethylenediamine (boiling point: 165 ° C / 10mmHg) 8. 715g (l equivalent) When the colorless homogeneous solution was heated to 150 ° C at normal pressure, 4.1061 g of colorless liquid was obtained at an outflow temperature of 110 ° C. When the amount of 2-methylbiperidine in this liquid was measured, the content was 95.4% by weight, and 79% in terms of recovery.

Claims

The scope of the claims

[1] The amine having a step of adding an amino alcohol or a polyamine to a salt of an amine and an acid having 1 to 10 carbon atoms which may have a substituent and distilling the amine. A method for producing a free form of

[2] Amino alcohols or polyamines 2- (2-aminoethylamino) ethanol, N- (2-aminoethinole) morpholine, N- (2-aminoethinole) piperazine, 1- (2-amino) Noethyl) piperidine, 1- (2 aminoethyl) pyrrolidine, N, N, monobis (3-aminopropyl) ethylenediamine, 1,4 bis (3-aminopropynole) piperazine, N- n-butylethylenediamine, 1,2 —Cyclohexanediamine, 1,2-diamino-2-methylpropan, N, N'-jetylethylenediamine, N, N diisopropylethylenediamine, N, N'-dimetinorepiperazine, Nethinorepiperazine , Homopiperazine, N- (2-Hydroxypropinole) ethylenediamine, N— (3 Hydroxypropinole) ethylenediamine, 2-Methylbiperazine, Pipera At least one selected from the group consisting of gin, 1-piperazine ethanol, N, N, Ν ', Ν, -tetrax (2-hydroxypropyl) ethylenediamine, triethylenetetramine, and tris (2-aminoethyl) amine. The method of claim 1.

Yes

[3] The acid is hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, boric acid, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, cyclohexanecarboxylic acid. Acid, black acetic acid, dichloroacetic acid, trichroic acetic acid, trifluoroacetic acid, acrylic acid, fumaric acid, maleic acid, benzoic acid, phthalic acid, oxalic acid, malonic acid, citrate, L tartaric acid, D-tartaric acid, dibenzoyl L , Dibenzoyl D tartaric acid, G ρ Toluoi Lu L—tartaric acid, di ρ—toluoyl D—tartaric acid, (+) — camphoric acid, L—malic acid, D malic acid, L mandelic acid, D mandelic acid, methanesulfonic acid , Ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, ρ toluenesulfonic acid, ρ-black benzenesulfonic acid, m ditrobenzenes The method according to claim 1 or 2, which is at least one selected from the group consisting of sulfonic acid and camphorsulfonic acid.

[4] The number of carbon atoms which may have the above-mentioned substituents;! To 10 amin is (S) -2-amino-1-1-butanol mononole, (S) -2-methinolepyrrolidine, (S)- 2—Metinoleviperidine, (S) —3 aminopylori Gin, (S) -3-aminobiperidine, (S) -3-pyrrolidinol, (R) -2-amino-1-butanol, (R) -2-methylpyrrolidine, (R) -2-methylbiperidine, (R) The method according to any one of claims 1 to 3, which is —3-amino pyrrolidine, (R) -3-aminobiperidine, or (R) -3-pyrrolidinol.

[5] A free form of the above-mentioned amine, characterized by adding an amino alcohol or a polyamine to a salt of an amine and an acid having 1 to 10 carbon atoms which may have a substituent and distilling it. How to get.