JP2003183250A - Method for producing alicyclic hydrazine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially advantageously producing an alicyclic hydrazine compound useful as a raw material compound for a medicine, an agrochemical, a functional material, etc. <P>SOLUTION: This method for producing the compound represented by formula [I] (wherein, n denotes 3 or 4) comprises reacting a compound represented by formula [II] äwherein, X and X' denote each a leaving group; n denotes the same meaning as in formula [I]} with hydrazine. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing alicyclic hydrazine which is useful as a raw material compound for drugs, agricultural chemicals, functional materials and the like.

[0002]

As a method for producing alicyclic hydrazine,
Method for electrochemically reacting dihalogenated alkyl with nitrogen under catalyst [J. Chem. Soc. Chem. Comm., 1981, 20,
3959], a method of reacting a hydrazine derivative with a diol compound or an alicyclic ether [Patent 6023100]
4], a method using a Huffman rearrangement reaction using an alicyclic amine as a starting material [Chem. Pharm. Bull., 1983, 31 (2),
423], a method using hydroxysulfonic acid [Chem. Be
r., 1990, 123, 10], nitro, nitroso method [S
ynthesis, 1979, 423, J. Org. Chem., 1984, 49 (19),
3470] etc. are known. As a method for producing 1-aminopyrrolidine, a method is known in which 1,4-dichlorobutane and hydrated hydrazine are reacted in methanol in the alkaline region side. [JP-A-11-92465]

However, in the reaction of alkyl dihalide with nitrogen, an expensive catalyst and a special device are used, and
The yield is also low. The method of reacting a hydrazine derivative with a diol or an alicyclic ether is a reaction under high temperature and pressure, and the yield is not always satisfactory. Further, with respect to the Hoffman rearrangement and the reaction using hydroxysulfonic acid, the yield is low, and the method involving the nitro or nitroso form has problems in stability and toxicity.

[0004]

An object of the present invention is to provide a method for industrially advantageously producing an alicyclic hydrazine compound which is useful as a raw material compound for medicines, agricultural chemicals, functional materials and the like.

[0005]

The present invention provides: Formula [II]

[Chemical 5] (Wherein X and X ′ are leaving groups and n is 3 or 4) and hydrazine is reacted with the compound of the formula [I]

[Chemical 6] 1. A method for producing a compound represented by the formula (wherein n has the same meaning as described above) (claim 1), and Formula [II ']

[Chemical 7] (Wherein, X and X'represent a leaving group and n'represents an integer of 2 to 4) and hydrazine are reacted in the presence of a catalyst. ']

[Chemical 8] (Wherein, n ′ has the same meaning as described above), and a method for producing the compound (claim 2). Furthermore, in the above manufacturing method, 3. A production method (claim 3), which comprises reacting in a two-phase system of an organic solvent and water in the presence of a catalyst. The leaving group is a halogen atom or the formula RSO ₂ O-
4. In the production method (claim 4), R is an alkyl group or a phenyl group which may have a substituent. 5. A production method (Claim 5) in which the catalyst is a quaternary ammonium salt or crown ether, The production method (claim 6) according to any one of 1 to 5 wherein n is 3.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Formula [II] in the production method of the present invention
And the compound represented by [II '], the halogen atom of the leaving groups X and X'is a chlorine atom, a bromine atom,
Examples thereof include iodine atom. R is a linear or branched alkyl group having 1 to 20 carbon atoms, specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group, n-pentyl group, isopentyl group, neopentyl group, s-pentyl group, n-hexyl group, n-octyl group, n-nonyl group, n-decyl group, n-
Examples thereof include dodecyl group and branched structural isomers thereof. As the substituent of the phenyl group, a halogen atom such as chlorine and bromine, a linear or branched alkyl group having 1 to 20 carbon atoms, specifically, Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group, n-pentyl group, isopentyl group, neopentyl group, s-pentyl group, n-hexyl group, n- Examples thereof include an octyl group, an n-nonyl group, an n-decyl group, an n-dodecyl group and branched structural isomers thereof, and these substituents may be the same or different and may be plurally substituted.

As hydrazine, generally, hydrazine hydrate is preferably used, but its hydrochloride, sulfate, carbonate, hydrobromide or the like can also be used. The amount of hydrazine used is not particularly limited as long as it is equimolar or more to the compound represented by the formula [II] or [II '], but is preferably 2 to 20 times by mole. In addition, hydrazine may also be used as a deoxidizing agent.

The method of the present invention can also use a phase transfer catalyst. Specific examples of the phase transfer catalyst used include quaternary ammonium salts, onium salts such as quaternary phosphonium salts, and crown compounds. The quaternary ammonium salt is composed of a C1 to C18 linear or optionally branched alkyl group and / or aralkyl group which are independent on the nitrogen atom.
Represents an ammonium salt having one substituent, tetraalkylammonium halide, tetraalkylammonium sulfate, tetraalkylammonium hydrogen sulfate, tetraalkylammonium acetate, aralkyltrialkylammonium halide, aralkyltrialkylammonium sulfate, aralkyltrialkyl hydrogensulfate. Examples thereof include ammonium and aralkyltrialkylammonium acetate. More specifically, tetra-chloride
n-amyl ammonium, tetrabutyl ammonium chloride, tetraethyl ammonium chloride, tetra-n-chloride
Octyl ammonium, tetra-n-propyl ammonium chloride, tetra-n-hexyl ammonium chloride, tetra-n-heptyl ammonium chloride, tetrapentyl ammonium chloride, -n-hexadecyl trimethyl ammonium chloride, myristyl trimethyl ammonium chloride, dodecyl trimethyl ammonium chloride , Lauryl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, benzyl tributyl ammonium chloride, tetra-n-amyl ammonium bromide, tetrabutyl ammonium bromide, tetraethyl ammonium bromide, tetra-n-octyl ammonium bromide, tetra-n bromide -Propylammonium, tetra-n-hexylammonium bromide, tetra-n-heptylammonium bromide, tetrapentylammonium bromide , N-hexadecyltrimethylammonium bromide, myristyltrimethylammonium bromide, dodecyltrimethylammonium bromide, lauryltrimethylammonium bromide, benzyltriethylammonium bromide, benzyltributylammonium bromide, tetra-n-amylammonium iodide , Tetrabutylammonium iodide, tetraethylammonium iodide, tetra-n-octylammonium iodide, tetra-n-propylammonium iodide, tetra-n-hexylammonium iodide, tetra-n-heptylammonium iodide, iodide Tetrapentyl ammonium, i-n-hexadecyl trimethyl ammonium iodide, myristyl trimethyl ammonium iodide, dodecyl trimethyl ammonium iodide, iodide Uryl trimethyl ammonium, benzyl triethyl ammonium iodide, benzyl tributyl ammonium iodide, tetra-n-amyl ammonium sulfate, tetrabutyl ammonium sulfate, tetraethyl ammonium sulfate, tetra-n-octyl ammonium sulfate, tetra-n-propyl ammonium sulfate, sulfuric acid Tetra-n-hexyl ammonium, tetra-n-heptyl ammonium sulfate, tetrapentyl ammonium sulfate, n-hexadecyl trimethyl ammonium sulfate, myristyl trimethyl ammonium sulfate, dodecyl trimethyl ammonium sulfate, lauryl trimethyl ammonium sulfate, benzyl triethyl ammonium sulfate, sulfate Benzyltributylammonium, Tetra-n-amylammonium hydrogensulfate, Teto hydrogensulfate Rabutyl ammonium, tetraethyl ammonium hydrogen sulfate, tetra-n-octyl ammonium hydrogen sulfate, tetra-n-propyl ammonium hydrogen sulfate, tetra-n-hexyl ammonium hydrogen sulfate, tetra-n-heptyl ammonium hydrogen sulfate, tetrapentyl ammonium hydrogen sulfate , Hydrogensulfate-n-hexadecyltrimethylammonium, myristyltrimethylammonium hydrogensulfate, dodecyltrimethylammonium hydrogensulfate, lauryltrimethylammonium hydrogensulfate, benzyltriethylammonium hydrogensulfate, benzyltributylammonium hydrogensulfate, tetra-n-amylammonium acetate, acetic acid Tetrabutylammonium, tetraethylammonium acetate, tetra-n-octylammonium acetate, tetra-n-pro-acetate Le ammonium acetate tetra -n- hexyl ammonium, acetate tetra -n- heptyl ammonium acetate tetrapentylammonium,
Acetic acid-n-hexadecyltrimethylammonium, myristyltrimethylammonium acetate, dodecyltrimethylammonium acetate, lauryltrimethylammonium acetate, benzyltriethylammonium acetate, benzyltributylammonium acetate, etc. can be exemplified.
Examples of the quaternary phosphonium salt include tetraethylphosphonium chloride, tetraethylphosphonium bromide, tetraethylphosphonium iodide, tetrabutylphosphonium bromide, tetraphenylphosphorium bromide, triphenylbenzylphosphonium bromide and the like, and as a crown compound, 15 Examples thereof include crown ethers such as crown-5 and 18-crown-6, cryptands, and the like. The amount of phase transfer catalyst used is determined by the formula [II] or [II ']
Although it is not particularly limited as long as it is 1 equivalent or less in molar ratio with respect to the compound represented by, it is preferably used in the range of 0.05 to 30 mol%.

The solvent used in this reaction is represented by the formula [II]
It is not particularly limited as long as it is inactive to the compound represented by, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, s-butanol, isobutanol, acetone, methyl ethyl ketone, methyl Ketones such as isobutyl ketone, nitriles such as acetonitrile and benzonitrile,
Halogen solvents such as methylene chloride, chloroform, dichloroethane and chlorobenzene, hydrocarbon solvents such as benzene, toluene, xylene, hexane and cyclohexane, ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate, diethyl ether, THF
And the like, nitro solvents such as nitrobenzene, polar solvents such as DMF, DMA, NMP, and the like. These may be used alone or in combination of two or more, and may also be used in mixture with water.

The solvent used when the reaction is carried out in a two-phase system with water using a phase transfer catalyst is not particularly limited as long as it is a solvent that is not completely mixed with water to form a homogeneous system. Solvents with low solubility are preferred, and [I
A solvent that dissolves the compound represented by I ′] is preferable. Specifically, halogen-based solvents such as methylene chloride, chloroform, dichloroethane and chlorobenzene, hydrocarbon-based solvents such as benzene, toluene, xylene, hexane and cyclohexane, ester-based solvents such as methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate. Examples thereof include solvents, ketone-based solvents such as methyl isobutyl ketone, ether-based solvents such as diethyl ether, nitrile-based solvents such as benzonitrile, and nitro-based solvents such as nitrobenzene. One or more species can be mixed with water and used. Even if the solvent has a polar group and is considered to have a high affinity with water, it is not completely miscible with water if it has a large proportion of non-polar groups in the molecule, so it should be used in this reaction. it can.

The amount of the solvent used is not particularly limited as long as the compound represented by the formula [II] or [II '] can be dissolved or stirred in the reaction system.

In this reaction, hydrazine can also be used as a deoxidizing agent, but a base can also be used separately. The base used is sodium hydroxide,
Inorganic hydroxides such as potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate,
Inorganic bases such as inorganic carbonates or bicarbonates such as magnesium carbonate, calcium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc., tertiary amines such as triethylamine, tri-n-butylamine, pyridine, picoline, lutidine, etc. A pyridine derivative etc. can be illustrated.

The amount of the base used is not particularly limited as long as the total amount with the excess hydrazine is 2 mol or more, but it is 2 to 1
It is preferably used in the range of 0 equivalent.

The reaction temperature is 0 ° C to the reflux temperature, preferably 10 to 30 ° C. Further, the pressure is preferably normal pressure. If the reaction temperature is too low, the reaction is slow and it takes a long time to complete the reaction.

[0015]

The present invention will be described in detail below with reference to Examples.
The present invention is not limited to the following production examples. Example 1 Production of N-aminopiperidine 288.8 g (0.7 mol) of pentane ditosylate,
701 g (14.0 mol) of hydrated hydrazine and 1400 ml of methanol were added, and under normal pressure, it was 8.5 at 25-30 ° C.
Reacted for hours. After the reaction, the reaction mixture was analyzed by gas chromatography to find that it contained 67.6 g of the desired product. Yield 96.4 mol%. Methanol was distilled off and water 1
After adding 10 ml, add 2 ml with 700 ml of chloroform.
Once, extracted twice with 350 ml. After distilling off chloroform, the residue was distilled under reduced pressure, and it was confirmed by NMR that this was N-aminopiperidine. NMR spectrum data (CDCl ₃ , δppm) ¹ H: 1.20-1.35 (br, 2H), 1.54 (m,
4H), 2.10-2. 75 (br, 4H), 2.85-3.00 (br, 2H) ^13C : 23.2,26.0,61.0

Example 2 Production of N-aminopiperidine 1.0 g (2.4 mmol) pentane ditosylate, 2,4 g (48 mmol) hydrated hydrazine, 5 ethanol
After adding ml, the mixture was reacted under normal pressure at 25 to 30 ° C. for 9.5 hours. After the reaction, the reaction solution was analyzed by gas chromatography to find that it contained 0.87 g of the desired product. Yield 89.7 mol%.

Example 3 Preparation of N-aminopiperidine 0.52 g (2.3 mmol) dibromopentane, 2.17 g (43 mmol) hydrated hydrazine, ethanol 1
0 ml was added and the reaction was carried out at 25-30 ° C. for 7 hours under normal pressure. After the reaction, the reaction mixture was analyzed by gas chromatography to find that it contained 0.21 g of the desired product. Yield 9
2.0 mol%.

Example 4 Preparation of N-aminopiperidine 0.5 g (2.2 mmol) dibromopentane, 2.16 g (43 mmol) hydrated hydrazine, 10 methanol
ml was added and the reaction was carried out at 25-30 ° C. for 8 hours under normal pressure.
After the reaction, the reaction solution was analyzed by gas chromatography and found to contain 0.21 g of the desired product. Yield 94.
3 mol%.

Example 5 Production of N-aminopiperidine 1.0 g (2.4 mmol) of pentane ditosylate was dissolved in 7 ml of toluene and 0.2 g (4 m) of hydrated hydrazine was added.
mol), 0.06 g (0.2 mmol) of benzyltriethylammonium bromide and 0.4 g (2.8 mmol) of 28% NaOH aqueous solution were added, and the mixture was reacted at room temperature for 3 hours and then refluxed for 5 hours. After the reaction, the reaction mixture was analyzed by gas chromatography to find that it contained 0.16 g of the desired product. Yield 66.5 mol%.

Example 6 Preparation of N-aminopyrrolidine 6.5 g (50 mmol) of dichlorobutane was added to 5 parts of toluene.
Dissolve in 0 ml, water 10 ml, hydrated hydrazine 6.1 g
(120 mmol), benzyltriethylammonium bromide 1.7 g (7.5 mmol), 28% NaOH
An aqueous solution (17.1 g, 120 mmol) was added, and the mixture was reacted under reflux for 25 hours. After the reaction, the reaction mixture was analyzed by gas chromatography to find that it contained 3.1 g of the desired product. Yield 72 mol%.

[0021]

EFFECTS OF THE INVENTION According to the production method of the present invention, alicyclic hydrazine, which is useful as an intermediate for medicines and agricultural chemicals, can be produced in high yield under mild conditions and is excellent as an industrial production method. .

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C054 AA02 BB10 CC06 DD01 EE01                       FF01                 4C069 AA23 BC23                 4H039 CA42 CH10

Claims (6)

[Claims] 1. The formula [II]: (Wherein X and X ′ are leaving groups and n is 3 or 4) and hydrazine is reacted with the compound of the formula [I] (In the formula, n has the same meaning as described above). 2. The formula [II ']: (Wherein, X and X'represent a leaving group and n'represents an integer of 2 to 4) and hydrazine are reacted in the presence of a catalyst. '] [Chemical 4] (In the formula, n ′ has the same meaning as described above). 3. The method according to claim 1, wherein the reaction is carried out in a two-phase system of an organic solvent and water in the presence of a catalyst. 4. The leaving group is a halogen atom, or a compound represented by the formula RSO.
₂ O- (wherein R represents an alkyl group or a phenyl group which may have a substituent).
3. The manufacturing method according to any one of 3 above. 5. The production method according to claim 1, wherein the catalyst is a quaternary ammonium salt or a crown ether. 6. The manufacturing method according to claim 1, wherein n is 3.