JP4652079B2 - Process for producing 2,2-disubstituted ethylenediamine derivatives - Google Patents

Description

  The present invention relates to a simple and efficient method for producing 2,2-disubstituted ethylenediamine derivatives.

  As a hair dye composition, it is known that a cyclic amine compound exhibits an excellent effect for decoloring or dyeing hair (see Patent Document 1). However, when 1,2-dimethyl-2-aminomethylpyrrolidine having an asymmetric carbon on the ring is to be synthesized, the conventional method requires a multi-step process of at least 6 steps as shown in the following formula. It was. (See Patent Document 2 and Non-Patent Document 1)

That is, proline (starting material) is asymmetric (first stage), treated with lithium diisopropylamide (LDA) to give lithium enolate, and methylated with methyl iodide to give 2-t-butyl-5- Methyl-1-aza-3-oxabicyclo [3.3.0] octane-4-one was synthesized (second stage) and hydrolyzed with hydrogen bromide to synthesize α-methylproline (third Stage), Boc (t-butoxycarbonyl) reaction (fourth stage), amidation reaction (fifth stage), reduction reaction (sixth stage), methylation, 1,2-dimethyl-2-amino There was a need to obtain methylpyrrolidine.
Moreover, in the process of said amidation reaction (5th step), reaction time requires a long time of 2 days. Furthermore, special reagents such as lithium diisopropylamide (LDA) and hydrogen bromide, which are not easy to handle, were necessary, and the overall yield was low (the yield of the reduction process was unknown).
Therefore, establishment of a simpler and more efficient production method for 2,2-disubstituted ethylenediamine derivatives has been desired.

International Publication No. 03/51322 Pamphlet International Publication No. 03/4467 pamphlet Dieter Seebach, et al., “Alkylation of amino acids without loss of optical activity: synthesis of proline derivatives substituted at the α-position-self-reconstruction of enantiomers”, J. Am. Chem. Soc., 105 , 5390-5398 (1983).

  An object of the present invention is to provide a simple and efficient method for producing a 2,2-disubstituted ethylenediamine derivative.

The inventors of the present invention can easily synthesize 2-aminonitro starting from an easily available amide by a one-step reaction known in the literature (see Japanese Patent Publication Nos. 49-24067 and 55-2426). By using the olefin derivative and 1,4-addition reaction of this with an alkylmagnesium halide, a substituent is introduced into the β-position of the nitro group of the 2-aminonitroolefin derivative, which is considered difficult to introduce sterically. By constructing an asymmetric carbon and then treating with a reducing agent, the reaction process and reaction time can be shortened, and 2,2-disubstituted ethylenediamine can be efficiently synthesized without the need for special reagents. I found.
That is, the present invention reacts a 2-aminonitroolefin derivative represented by the following general formula (1) with an alkylmagnesium halide and then treats with a reducing agent. A method for producing a 2-disubstituted ethylenediamine derivative is provided.

（式中、Ｒ¹及びＲ²は、それぞれ独立に、水素原子、水酸基又は置換基を有してもよい炭素数１〜１２の炭化水素基を示し、Ｒ³は、水素原子又は置換基を有してもよい炭素数１〜６の炭化水素基を示し、Ｒ⁴は、置換基を有してもよい炭素数１〜１２の炭化水素基を示し、Ｒ¹とＲ⁴、及びＲ²とＲ⁴は、互いに結合して環構造を形成してもよい。）

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group or a hydrocarbon group having 1 to 12 carbon atoms which may have a substituent, and R ³ represents a hydrogen atom or a substituent. a hydrocarbon group which may having 1 to 6 carbon atoms having, R ⁴ also have a substituent represents an optionally hydrocarbon group having 1 to 12 carbon atoms, R ¹ and R ^4, and R ² And R ⁴ may combine with each other to form a ring structure.)

（式中、Ｒ⁵は置換基を有してもよい炭素数１〜１２のアルキル基、又は置換基を有してもよい環状炭化水素基を示す。Ｒ¹〜Ｒ⁴は前記と同じである。）

(Wherein, R ⁵ is .R ¹ to R ⁴ represents an alkyl group, or an optionally substituted cyclic hydrocarbon group having 1 to 12 carbon atoms which may have a substituent the same as the is there.)

  According to the production method of the present invention, a 2,2-disubstituted ethylenediamine derivative can be produced simply and efficiently.

  The production method of the present invention is represented by the following reaction formula.

In the 2-aminonitroolefin derivative of the general formula (1) used as a starting material in the present invention, R ¹ and R ² each independently have ¹ hydrogen atom, a hydroxyl group, or a substituent. ~ 12 hydrocarbon groups.
As a C1-C12 hydrocarbon group, a C1-C12 linear, branched or cyclic alkyl group, a hydroxyalkyl group, an alkenyl group, an aromatic group etc. are mentioned.
Examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, n-octyl group, n -A decyl group, a cyclopentyl group, a cyclohexyl group, a cyclooctyl group, etc. are mentioned.
Examples of the hydroxyalkyl group include groups in which at least one hydrogen atom of the alkyl group has been substituted with a hydroxyl group. Specifically, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, 2 , 3-dihydroxypropyl group, 1-hydroxy-1-methylethyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group and the like. .
Examples of the alkenyl group include an allyl group, a propenyl group, various butenyl groups, various octenyl groups, various decenyl groups, various dodecenyl groups, cyclopentenyl groups, cyclohexenyl groups, and cyclooctenyl groups.
Examples of the aromatic group include a phenyl group and a benzyl group.

Moreover, as a substituent of the said C1-C12 hydrocarbon group, an amino group, an alkylamino group, an alkoxy group, a heterocyclic group, etc. are mentioned. Specific examples of the substituted hydrocarbon group having 1 to 12 carbon atoms include 2- (dimethylamino) ethyl group, 3- (dimethylamino) propyl group, 3- (diethylamino) propyl group, and 3-pyrrolidinylpropyl. Group, 3-piperidinopropyl group, 3-morpholinopropyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 2-hexyloxyethyl group, 2-methoxypropyl group, 3-methoxypropyl group, 2-methoxy A phenyl group etc. are mentioned.
Among these, R ¹ and R ² are preferably an alkyl group and a hydroxyalkyl group having 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and a methyl group, an ethyl group, A hydroxyethyl group is particularly preferred.

R < ³ > is a C1-C6 hydrocarbon group which may have a hydrogen atom or a substituent. Specific examples of R ³ include those similar to those having 1 to 6 carbon atoms among the specific examples of R ¹ . R ³ is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and more preferably a hydrogen atom.
R ⁴ represents an optionally substituted hydrocarbon group having 1 to 12 carbon atoms, and the same examples as the specific examples of R ¹ can be given.
R ¹ and R ⁴ , or R ² and R ⁴ may be bonded to each other via a carbon atom to form a ring structure in which N is a heteroatom. The formed ring structure is mainly —CH ₂ —, and in some cases, it may be —O—, —S—, —NH, or a combination of —CH ₂ — and these. .
Examples of the group in which R ¹ and R ⁴ or R ² and R ⁴ are bonded to each other to form a ring structure include 1-pyrrolidinyl group, piperidino group, hexamethyleneimino group and the like.

  Among the 2-aminonitroolefin derivatives represented by the general formula (1), a compound represented by the following general formula (3) is preferable.

（式中、Ｒ¹及びＲ³は前記と同じである。Ｒ⁶は、水素原子、水酸基、アミノ基、アルコキシ基、エステル基、又は置換基を有してもよい炭素数１〜１２の炭化水素基を示し、ｎは１〜３の整数を示す。）

(In the formula, R ¹ and R ³ are the same as described above. R ⁶ is a hydrogen atom, a hydroxyl group, an amino group, an alkoxy group, an ester group, or a carbon atom having 1 to 12 carbon atoms which may have a substituent. Represents a hydrogen group, and n represents an integer of 1 to 3.)

Examples of the alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, and a butoxy group. Examples of the ester group include a methyl ester group, an ethyl ester group, and a tert-butyl ester group. Further, the hydrocarbon group of good 1 to 12 carbon atoms have a substituent, are the same as specific examples of the R ¹ can be mentioned.
Specific examples of the compounds of the general formulas (1) and (3) preferably include nitromethylene pyrrolidines having an alkyl group having 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and more specifically. 1-methyl-2-nitromethylenepyrrolidine, 1-ethyl-2-nitromethylenepyrrolidine, 1-n-butyl-2-nitromethylenepyrrolidine and the like.
In the general formulas (1) and (3), the bonding positional relationship between R ⁵ and NO ₂ is not limited, and includes isomers (stereoisomers, planar isomers).

The alkyl magnesium halide used in the first step of the present invention is represented by the following formula (4).
R ⁵ -MgX (4)
In the general formula (4), R ⁵ may have a substituent having 1 to 12 carbon atoms, preferably a linear or branched alkyl group having 1 to 6 carbon atoms, or a cyclic carbon atom which may have a substituent. Indicates a hydrogen group. X represents a halogen atom, preferably a chlorine atom or a bromine atom. Examples of the substituent include an amino group, an alkoxy group, an ester group, an acyl group, and a phenyl group.
Specific examples of the hydrocarbon group having 1 to 12 carbon atoms, the alkoxy group, and the ester group include those similar to the above specific examples. R ⁵ is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms.

Preferable specific examples of the alkyl magnesium halide include methyl magnesium chloride, ethyl magnesium chloride, isopropyl magnesium chloride, n-butyl magnesium chloride, isobutyl magnesium chloride, t-butyl magnesium chloride, methyl magnesium bromide, ethyl magnesium bromide, isopropyl magnesium bromide. N-butylmagnesium bromide, isobutylmagnesium bromide, t-butylmagnesium bromide and the like. Among these, isopropyl magnesium chloride, n-butyl magnesium chloride, and methyl magnesium bromide are preferable from the viewpoint of availability.
The amount of alkylmagnesium halide used is usually in the range of 0.5 to 10 mol times the 2-aminonitroolefin derivative represented by the general formula (1) or (2) as the raw material. The range of 8 to 5 mole times is preferable, and the range of 1 to 1.5 mole times is more preferable.

As the reducing agent used in the second step of the present invention, a hydrogenation reagent can be used, such as lithium aluminum hydride (LiAlH ₄ ), sodium aluminum hydride (NaAlH ₄ ), diisopropylaluminum hydride. Inorganic hydrides. Among these, lithium aluminum hydride (LiAlH ₄ ) is preferable.
The amount of the reducing agent used is usually in the range of 0.5 to 10 mol times the 2-aminonitroolefin derivative represented by the general formula (1) as the raw material, and 0.8 to 5 mol. The range of double amount is preferable, and the range of 1 to 2 molar times is more preferable.

The solvent in the 1,4-addition reaction with an alkylmagnesium halide and the reduction reaction with a reducing agent varies depending on the alkylmagnesium halide and the reducing agent to be used, but an organic solvent generally used for an organometallic compound reaction can be used.
Examples of such organic solvents include alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, and tert-butanol, ether solvents such as diethyl ether, tetrahydrofuran (THF), and dioxane, chloroform, dichloromethane, dichloroethane, and trichloromethane. Halogen solvents such as benzene, toluene, xylene and other aromatic solvents, hexane and other hydrocarbon solvents, acetone, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPT) ), N-methylpyrrolidone and the like. Of these, ether solvents are preferred. These organic solvents can be used alone or in admixture of two or more.

The temperature of the 1,4-addition reaction and reduction reaction varies depending on the solvent used, but is usually -50 to 150 ° C, preferably a relatively mild temperature, for example 20 to 80 ° C, more preferably 25 to 70 ° C. It is. The reaction pressure can usually be carried out under normal pressure.
Although the reaction time varies depending on conditions such as reaction temperature, the 1,4-addition reaction is usually 1 to 20 hours, preferably 1 to 10 hours, and the reduction reaction is usually 1 to 15 hours, preferably 1 to 7 hours. It's time. The end point of the reaction can be confirmed, for example, by gas chromatography.
In the post-treatment / purification step after the reaction, filtration, extraction, drying, recrystallization, vacuum distillation, column purification, and the like can be appropriately selected and performed as necessary.

  Specific examples of the 2,2-disubstituted ethylenediamine represented by the general formula (2) obtained in the present invention include 1,2-dimethyl-2-aminomethylpyrrolidine and 1-ethyl-2--2 represented by the following formula. Methyl-2-aminomethylpyrrolidine, 1-methyl-2-isopropyl-2-aminomethylpyrrolidine, 1-methyl-2-n-butyl-2-aminomethylpyrrolidine, 1-hydroxyethyl-2-methyl-2-amino Examples include methylpyrrolidine, 1,2,5-trimethyl-2-aminomethylpyrrolidine, 1,2-dimethyl-5-n-butyl-2-aminomethylpyrrolidine and the like.

The 2,2-disubstituted ethylenediamine derivative has at least one asymmetric carbon, but may be an optical isomer (R-form or S-form) or a racemate.
The 2,2-disubstituted ethylenediamine derivative represented by the general formula (2) obtained in the present invention is useful as an intermediate for pharmaceutical synthesis, as an additive for hair cosmetics and skin cosmetics.

Example 1 [Production of 1,2-dimethyl-2-aminomethylpyrrolidine]
The reaction formula in this example is shown below.

To a 2 L four-necked eggplant flask equipped with a condenser, a dropping funnel and a thermometer, 60.00 g (0.422 mol) of 1-methyl-2-nitromethylenepyrrolidine and 240 mL of THF were added, purged with nitrogen, and stirred at 60 ° C. Thereto, 506 mL (0.506 mol) of methylmagnesium bromide (1.0 M, THF solution) was dropped from a dropping funnel. After completion of dropping, the mixture was stirred at 60 ° C. for 6 hours and ice-cooled to obtain a reaction solution.
Separately, 200 mL of THF was added to a 500 mL four-necked eggplant flask purged with nitrogen, stirred and cooled with ice, and 24.1 g (0.635 mol) of lithium aluminum hydride was slowly added to prepare a suspension. The obtained lithium aluminum hydride suspension in THF was transferred to a dropping funnel and added dropwise to the previously obtained reaction solution. After completion of the dropping, the dropping funnel was washed with 20 mL of THF three times and stirred at 60 ° C. for 3 hours. Thereafter, the mixture was ice-cooled, and when it became 10 ° C. or less, 250 mL of 2N hydrochloric acid was added to stop the reaction. Since salt was formed during the dropwise addition of hydrochloric acid and stirring became difficult, 400 mL of THF was added, and the salt was removed by filtration. The filtrate was made strongly alkaline by adding a 48% aqueous sodium hydroxide solution, and extracted three times with 200 mL of chloroform. The chloroform phase was dried over anhydrous sodium sulfate, filtered, concentrated, and dried under reduced pressure to obtain 54.7 g of 1,2-dimethyl-2-aminomethylpyrrolidine as a crude product. ^The compound was identified by ¹ H-NMR (400 MHz, solvent: deuterated chloroform, internal standard: nitromethane), and the yield was determined to be 29%.

Example 2 [Production of 1-methyl-2-n-butyl-2-aminomethylpyrrolidine]
The reaction formula in this example is shown below.

To a 2 L four-necked eggplant flask equipped with a condenser, a dropping funnel and a thermometer, 42.50 g (0.299 mol) of 1-methyl-2-nitromethylenepyrrolidine and 100 mL of THF were added, purged with nitrogen, and stirred at 60 ° C. Thereto, 180 mL (0.360 mol) of n-butylmagnesium chloride (2.0 M, THF solution) was dropped from a dropping funnel. After completion of dropping, the mixture was stirred at 60 ° C. for 6 hours and ice-cooled to obtain a reaction solution.
Separately, 180 mL of THF was added to a 500 mL four-necked eggplant flask purged with nitrogen, stirred and ice-cooled, and 17.10 g (0.451 mol) of lithium aluminum hydride was slowly added to prepare a suspension. The obtained lithium aluminum hydride suspension in THF was transferred to a dropping funnel and added dropwise to the previously obtained reaction solution. After completion of the dropping, the dropping funnel was washed with 20 mL of THF three times and stirred at 60 ° C. for 3 hours. Thereafter, the mixture was ice-cooled, and when it became 10 ° C. or less, 250 mL of 2N hydrochloric acid was added to stop the reaction. Since salt was formed during the dropwise addition of hydrochloric acid and stirring became difficult, 200 mL of THF was added and the salt was removed by filtration. The filtrate was made strong alkaline by adding a 48% aqueous sodium hydroxide solution and extracted three times with 100 mL of chloroform. The chloroform phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by distillation under reduced pressure to obtain 5.8 g of 1-methyl-2-n-butyl-2-aminomethylpyrrolidine as a colorless transparent oil. ^The compound was identified by ¹ H-NMR (400 MHz, solvent: deuterated chloroform, internal standard: nitromethane), and the yield was determined to be 10%.

Claims (5)

A 2,2-disubstituted ethylenediamine derivative represented by the following general formula (2), which is treated with a reducing agent after reacting a 2-aminonitroolefin derivative represented by the following general formula (1) with an alkylmagnesium halide. Manufacturing method.

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, a hydroxyl group or a hydrocarbon group having 1 to 12 carbon atoms which may have a substituent, and R ³ represents a hydrogen atom or a substituent. R 1 represents a hydrocarbon group having 1 to 6 carbon atoms that may have a substituent, R ⁴ represents a hydrocarbon group having 1 to 12 carbon atoms that may have a substituent, and R ¹ and R ⁴ , or R ^2. And R ⁴ may combine with each other to form a ring structure.)

(Wherein, R ⁵ is .R ¹ to R ⁴ represents an alkyl group, or an optionally substituted cyclic hydrocarbon group having 1 to 12 carbon atoms which may have a substituent the same as the is there.) The method for producing a 2,2-disubstituted ethylenediamine derivative according to claim 1, wherein the 2-aminonitroolefin derivative is a compound represented by the following general formula (3).

(In the formula, R ¹ and R ³ are the same as described above. R ⁶ is a hydrogen atom, a hydroxyl group, an amino group, an alkoxy group, an ester group, or a carbon atom having 1 to 12 carbon atoms which may have a substituent. Represents a hydrogen group, and n represents an integer of 1 to 3.)   The method for producing a 2,2-disubstituted ethylenediamine derivative according to claim 1 or 2, wherein the 2-aminonitroolefin derivative is a nitromethylenepyrrolidine having an alkyl group having 1 to 6 carbon atoms or a hydroxyalkyl group.   The method for producing a 2,2-disubstituted ethylenediamine derivative according to any one of claims 1 to 3, wherein the alkylmagnesium halide has an alkyl group having 1 to 6 carbon atoms. The method for producing a 2,2-disubstituted ethylenediamine derivative according to any one of claims 1 to 4, wherein the reducing agent is lithium aluminum hydride.