JP2002047257A - Method for manufacturing n,n-disubstituted-4- aminocrotonic acid ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for manufacturing N,N-disubstituted-4- aminocrotonic acid ester effectively on an industrial scale. SOLUTION: The method for manufacturing N,N-disubstituted-4-aminocrotonic acid ester comprises the reaction of 4-substituted oxycrotonic acid ester of formula (1) (wherein, R1 is an organic group; and G is a substituted oxycarbonyl group, acyl group or alkylsulfonyl group) with a secondary amine of formula (2) (wherein, R2 and R3 are each identical to or different from each other, and are each a hydrocarbon group, or they bond to each other and form a ring together with adjacent nitrogen atom) with the result of obtaining a compound of formula (3) (wherein, R1, R2 and R3 are same as described in the above formulae). The reaction may be carried out in the presence of a palladium compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing N, N-disubstituted-4-aminocrotonates useful as fine chemical intermediates for pharmaceuticals, agricultural chemicals and the like, and raw materials for polyamides and the like.

[0002]

2. Description of the Related Art As a method for producing an N, N-disubstituted-4-aminocrotonate, for example, Bull. Soc. Chim.
rance, 1959, pp. 1645-1650 and Ann. Fac. Sci. Univ.
Clcrmont. Chim., 1960, p. 80, describes the reaction of ethyl 4-chlorocrotonate with diethylamine to give N, N-
A method for producing ethyl diethyl-4-aminocrotonate is disclosed. Although this method is an advantageous method for synthesizing the target compound, there are some problems in obtaining the starting material, 4-halocrotonic acid ester. That is,
A typical method of synthesizing 4-halocrotonates is halogenation of crotonates with N-halosuccinimide or the like. In this case, a halogen-containing solvent such as carbon tetrachloride is used. These halogen-containing solvents have a large burden on the environment, and there is a limit to their future industrial use.

Ann. Chim (Paris), 1960, pp. 845-904, describes N, N-dimethyl-4-amino-2-butyric acid.
A method of obtaining N, N-dimethyl-4-aminocrotonic acid by reduction with a Pd catalyst has been reported. However, this method is not industrially advantageous because it requires the use of an acetylene compound requiring careful handling.

Further, Bull. Soc. Chim. France. 1964
Year, pp. 144-148, N, N-diethyl-4-amino-
By reacting 1-bromo-2-propene with metallic magnesium followed by treatment with carbon dioxide, N, N
A method for producing ethyl diethyl-4-aminocrotonate is disclosed. In this method, since the Grignard reagent is used, the by-product magnesium compound is
Generates at least equimolar with the substrate. Further, since it is necessary to use metallic magnesium which requires careful handling, it is still difficult to say that the method is industrially advantageous.

On the other hand, J. Org. Chem., 1991, 1014-1019
Page, J. Org. Chem., 1996, pages 5567-5573,
A method for synthesizing N-benzyl-4-aminocrotonate from (p-nitrobenzenesulfoxy) crotonate and benzylamine is described. However, these documents do not describe a method for obtaining an N, N-disubstituted-4-aminocrotonate.

[0006]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a method for industrially and efficiently producing an N, N-disubstituted-4-aminocrotonate. Another object of the present invention is to provide a method for producing an N, N-disubstituted-4-aminocrotonate with a high selectivity while suppressing the generation of by-products.

[0007]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have reacted a crotonate derivative having a specific substituent at the 4-position with a secondary amine. By this, it is found that N, N-disubstituted-4-aminocrotonate can be efficiently produced,
The present invention has been completed.

That is, the present invention provides the following formula (1)

Embedded image (Wherein R ¹ represents an organic group, G represents a substituted oxycarbonyl group, an acyl group or an alkylsulfonyl group) and a 4-substituted oxycrotonate represented by the following formula (2):

Embedded image (Wherein, R ² and R ³ may be the same or different and each represent a hydrocarbon group or may be bonded to each other to form a ring together with an adjacent nitrogen atom) And reacting with the following formula (3)

Embedded image (Wherein R ¹ , R ² , and R ³ are the same as described above). A method for producing an N, N-disubstituted-4-aminocrotonate ester is provided.

G in the formula (1) includes, for example, an alkoxycarbonyl group, a C _1-5 aliphatic acyl group, a C _1-4 alkylsulfonyl group and the like. The above reaction may be performed in the presence of a palladium compound.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound represented by the above formula (1), G represents a substituted oxycarbonyl group, an acyl group or an alkylsulfonyl group. Examples of the substituted oxycarbonyl group include, for example, an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group and a t-butoxycarbonyl group (such as a C _1-4 alkoxy-carbonyl group); Aryloxycarbonyl groups such as phenoxycarbonyl group and naphthyloxycarbonyl group (C _6-14
An aralkyloxycarbonyl group such as an benzyloxycarbonyl group (C
_7-19 aralkyloxy-carbonyl group, etc.). Preferred substituted oxycarbonyl groups include alkoxycarbonyl groups and the like.

Examples of the acyl group include a formyl group,
Acetyl group, trifluoroacetyl group, propionyl
Acyl groups such as a group, isobutyryl group and pivaloyl group
Group (C _1-5Aliphatic acyl group, etc.); benzoyl group, p-
Chlorobenzoyl group, p-nitrobenzoyl group, p-meth
Toxibenzoyl group, p-methylbenzoyl group, p-to
Fluoromethylbenzoyl and naphthoyl groups
Aromatic acyl group (C_7-15For example, an aromatic acyl group).
it can. Preferred acyl groups include C_1-5Aliphatic acyl group
Etc. are included.

The alkyl group contained in the alkylsulfonyl group may be linear or branched, and may have a substituent such as a halogen atom such as a fluorine atom. The “alkylsulfonyl group” in the present specification also includes an alkylsulfonyl group having a substituent such as a halogen atom (eg, a haloalkylsulfonyl group). Representative examples of the alkylsulfonyl group include, for example, a methanesulfonyl group, a trifluoromethanesulfonyl group, an ethanesulfonyl group, an n-propanesulfonyl group, a methylethylsulfonyl group, a t-butylsulfonyl group and the like. Preferred alkylsulfonyl groups include C _1-4 alkylsulfonyl groups.

In the compound represented by the formula (1),
R ¹ represents an organic group. The organic group is not particularly limited as long as it does not impair the reaction, and may be any of a hydrocarbon group, a heterocyclic group, and the like. Examples of the hydrocarbon group include a linear or branched alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, and a hexyl group. C _1-6 such as an alkyl group); a vinyl group, an alkenyl group (C _2-6 alkenyl group such as allyl group); an alkynyl group (C _2-6 alkynyl group such as propynyl group); cyclopentyl group, a cyclohexyl group, etc. An aryl group such as a phenyl group or a naphthyl group (C
_6-14 an aryl group); a benzyl group, a diphenylmethyl group, an aralkyl group (C _7-19 aralkyl group such as trityl group) and the like. Examples of the heterocyclic group include a 2-pyridyl group, a 4-pyridyl group, a 2-furyl group, a 2-thienyl group, a 2-tetrahydrofuranyl group,
An aromatic or non-aromatic heterocyclic group (including a condensed heterocyclic group) such as a tetrahydropyranyl group; Preferred R ¹ includes a hydrocarbon group having about ¹ to 6 carbon atoms (for example, an aliphatic hydrocarbon group), and a C _1-6 alkyl group is particularly preferred.

The 4-substituted oxycrotonate represented by the formula (1) is, for example, represented by the following formula (4)

Embedded image (Wherein R ¹ is as defined above) and a 4-hydroxycrotonate represented by the following formula (5) GX (5) (in the formula, X represents a halogen atom. G is as defined above. ) In the presence of a base such as triethylamine. The halogen atoms include, for example, chlorine, bromine and iodine atoms.

The reaction between the compound represented by the formula (4) and the compound represented by the formula (5) is carried out in an organic solvent such as toluene or methylene chloride at a temperature of about -10 ° C to 50 ° C. Will be The amount of the compound represented by the formula (5) is, for example, from 0.8 to 1 mol of the compound represented by the formula (4).
About 1.5 mol, and the amount of the base used is represented by the formula (4)
0.8 to 1.5 relative to 1 mole of the compound represented by
It is about a mole. The base may be used in a large excess with respect to the compound represented by the formula (4). After completion of the reaction, the reaction mixture was adjusted for liquidity, extracted, filtered, concentrated, crystallized, recrystallized,
By subjecting to conventional separation and purification means such as distillation and column chromatography, a 4-substituted oxycrotonate represented by the formula (1) can be obtained.

The 4-hydroxycrotonate represented by the formula (4) used as a raw material in the above reaction is, for example, a 4-halo-3 such as a corresponding 4-chloro-3-hydroxybutanoate. -It can be obtained by allowing a base such as sodium ethoxide to act on hydroxybutanoate. The reaction is carried out in a suitable solvent such as ethanol at a temperature of about -10C to 100C. The amount of the base used is 4-halo-3
-0.1 to 1 mol of hydroxybutanoic acid ester
It is about 1.5 mol. After the completion of the reaction, the reaction mixture is subjected to conventional separation and purification means such as liquid property adjustment, extraction, filtration, concentration, crystallization, recrystallization, distillation, and column chromatography, whereby the reaction mixture is represented by the formula (4). A 4-hydroxycrotonate can be obtained.

In the secondary amine represented by the above formula (2), the hydrocarbon groups represented by R ² and R ³ include the above-mentioned R
Examples include the hydrocarbon groups shown in ¹ . Preferred hydrocarbon groups include hydrocarbon groups having about 1 to 6 carbon atoms (eg, aliphatic hydrocarbon groups). In particular, R
² , and R ³ is preferably a C _1-6 alkyl group.

R ² and R ³ may be bonded to each other to form a ring together with an adjacent nitrogen atom. The number of members of the ring is, for example, about 3 to 15 members. As such a ring, an aziridine ring, an azetidine ring, a pyrrolidine ring, a piperidine ring,
Examples thereof include an imidazolidine ring, a piperazine ring, and a morpholine ring.

In the production method of the present invention, the amount of the secondary amine represented by the formula (2) depends on its kind, reaction mode,
Depending on the reaction rate and the like, for example, 4 represented by the formula (1)
-0.1 mol per mol of the substituted oxycrotonate.
It can be selected from a wide range of about 1 to 100,000 moles,
Usually, 0.5 to 1,000 mol (for example, 0.8 to 10
0 mol), preferably about 0.8 to 10 mol.

The reaction may be carried out in the presence or absence of a solvent. The solvent does not inhibit the progress of the reaction,
There is no particular limitation as long as it dissolves the reaction components,
For example, water, alcohols (eg, methanol, ethanol, 2-propanol, n-butanol, t-butyl alcohol, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), ethers (eg, 1,4
-Dioxane, tetrahydrofuran, diethyl ether, etc.), nitriles (e.g., acetonitrile, benzonitrile, etc.), sulfoxides (e.g., dimethyl sulfoxide, etc.), sulfones (e.g., sulfolane, etc.), aliphatic hydrocarbons (e.g., pentane, Hexane,
Octane), aromatic hydrocarbons (eg, benzene,
Toluene and the like, and halogen-containing compounds (for example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, bromoform, chlorobenzene, and bromobenzene) can be used. The amount of the solvent is not particularly limited as long as the reaction components (such as the 4-substituted oxycrotonate (1)) can be dissolved. For example, with respect to 1 part by weight of the 4-substituted oxycrotonate (1),
It can be selected from a range of about 1 to 1,000 parts by weight.

When the secondary amine represented by the formula (2) has a boiling point of room temperature or lower (for example, dimethylamine or the like), it can be blown into the reaction system as a gas,
It can be added to the reaction system in the form of an aqueous solution.

In the method of the present invention, when a palladium compound is added to the reaction system, side reactions are remarkably suppressed, and the desired N, N-disubstituted-4-aminocrotonate can be obtained with a high selectivity. Can be. Examples of the side reaction include N, N-disubstitution-
The secondary amine represented by the formula (2) is Michael-added to 4-aminocrotonate to form N, N, N ', N'.
A reaction in which a tetra-substituted-3,4-diaminobutanoic acid ester is formed. The above side reaction suppressing effect is particularly remarkable when G is a substituted oxycarbonyl group or an acyl group.

The palladium compound includes a simple substance of palladium metal and a compound or complex (including a complex salt) containing palladium element. The valence of palladium is not particularly limited, and is usually about 0 to 4, preferably about 0 to 2.
For example, divalent palladium and an appropriate reducing agent may be added to the system to generate zero-valent palladium in the system and then subject to the reaction. Suitable reducing agents include phosphines such as triphenylphosphine and tributylphosphine, hydrazines such as hydrazine, carbon monoxide, hydrogen and the like.

The compound containing a palladium element includes, for example, inorganic acid salts such as palladium sulfate, palladium nitrate and palladium phosphate; halides such as palladium chloride and palladium bromide; palladium formate, palladium acetate, palladium lactate and oxalic acid Examples include fatty acid salts such as palladium and palladium naphthenate, and organic acid salts such as palladium thiocyanate. Among these, palladium nitrate, palladium chloride, palladium acetate and the like are preferable.

Examples of the palladium complex include a complex or a complex salt in which a ligand is coordinated to the above-mentioned palladium metal simple substance or the compound containing the above-mentioned palladium element. As the ligand, phosphorus compounds such as phosphine (for example, trialkylphosphine such as tri-n-butylphosphine; triarylphosphine such as triphenylphosphine), nitrile, OH (hydroxo), alkoxyl group (methoxy, ethoxy group, etc.) ), Acyl group (acetyl,
Propionyl group, etc.), alkoxycarbonyl group [methoxycarbonyl (acetato), ethoxycarbonyl group, etc.], acetylacetonato, cyclopentadienyl group,
Halogen atom (chlorine, bromine, etc.), CO, oxygen atom, H
Examples include ₂ O (aquo) and nitrogen-containing compounds (for example, NH ₃ (ammine), NO, NO ₂ (nitro), NO ₃ (nitrat), ethylenediamine, pyridine, phenanthroline, etc.). In the palladium complex, one or more of the same or different ligands may be coordinated. The palladium metal alone or the palladium element-containing compound and the ligand can be appropriately combined to form a complex.

As a typical example of the palladium complex,
Acetylacetonato palladium (II), tetraamminepalladium (II) chloride, bis (ethylenediamine) palladium (II) chloride, tetrachloropalladium (II)
Potassium salt, potassium tetranitropalladium (II), dichlorobis (trialkylphosphine) palladium (II), dimethylbis (triethylphosphine) palladium (II), biscyclopentadienyl palladium (II), tricarbonylcyclopentadienyl Palladium (I), dichloro-μ-bis [bis (dimethylphosphino) methane] dipalladium (I), tetrakis (triphenylphosphine) palladium (0), bis (tricyclohexylphosphine) palladium (0), tetrakis (triethyl) (Phosphito) palladium (0), carbonyltris (triphenylphosphine) palladium (0), bis (cycloocta-1,5-diene) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like. .

When the palladium compound is used, the system may be a homogeneous system or a heterogeneous system. The palladium compound may be used in a form supported on a carrier. Examples of the carrier include a porous carrier such as activated carbon, zeolite, silica (eg, silica gel), alumina, silica-alumina, and bentonite.

The amount of the palladium compound to be used can be appropriately selected within a range not to impair the reaction, but is usually 0.001 to 1 mol per 1 mol of the 4-substituted oxycrotonate represented by the formula (1). Preferably it is about 0.01 to 0.5 mol, more preferably about 0.01 to 0.2 mol.

As the reaction proceeds, the reaction system contains the formula (1)
Acid corresponding to the compound of (G-OH; carbonate monoester,
(Carboxylic acid or sulfonic acid). To neutralize (capture) this acid, a base may be added to the system. Bases include inorganic bases and organic bases. Examples of the inorganic base include hydroxides of alkali metals or alkaline earth metals (such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide), and carbonates of alkali metals or alkaline earth metals (sodium carbonate). , Potassium carbonate, magnesium carbonate, calcium carbonate, etc.) and alkali metal bicarbonates (sodium bicarbonate, potassium bicarbonate, etc.).

Examples of the organic base include carboxylate salts of alkali metals or alkaline earth metals (eg, sodium acetate, potassium acetate, magnesium acetate, calcium acetate), alkali metal alkoxides (eg, sodium methoxide, sodium ethoxide), and the like. Amines (for example,
Tri C _1-4 alkylamines such as triethylamine,
Tertiary amines such as N, N-diC _1-4 alkylaniline such as N, N-dimethylaniline); and basic heterocyclic compounds (eg, nitrogen-containing heterocyclic compounds such as pyridine). No. In addition, instead of these bases,
The acid may be neutralized by using an excess of the secondary amine represented by the formula (2). These bases can be used alone or in combination of two or more.

The reaction between the compound represented by the formula (1) and the compound represented by the formula (2) is usually carried out at normal pressure to 500 atm.
0MPa), preferably normal pressure to 100 atm (10MPa)
a), more preferably at about normal pressure to 10 atm (1 MPa). The reaction may be performed under reduced pressure if necessary from the viewpoint of the apparatus or operation.

The reaction temperature is not particularly limited as long as it is not lower than the melting point of the system and not higher than the boiling point under the reaction pressure employed.
For example, -30 ° C to 200 ° C, preferably -10 ° C to 10 ° C
The reaction proceeds at about 0 ° C. even under mild conditions of about room temperature (−5 ° C. to 40 ° C.).

The N, N-disubstituted -4- represented by the formula (3)
The production of the aminocrotonate can be carried out by any conventional method such as a batch system, a semi-batch system, and a continuous system. Further, the produced N, N-disubstituted-4-aminocrotonate is filtered, concentrated, distilled, extracted, ion-exchanged, electrodialyzed, crystallized, recrystallized, adsorbed, membrane-separated, centrifuged, chromatographically ( Column chromatography, etc.) or a combination thereof.

The N, N-disubstituted-4-aminocrotonic acid ester derivatives thus obtained are useful as intermediates in fine chemicals such as pharmaceuticals and agricultural chemicals and as raw materials for polyamides.

[0035]

According to the present invention, a corresponding N, N-disubstituted-4-aminocrotonate is prepared from a specific N-substituted oxycrotonate which is easily available or prepared and a secondary amine. Can be industrially efficiently produced. Also, by adding a palladium compound into the system, by-products such as N, N, N ', N'-tetrasubstituted-3,4-diaminobutanoate can be remarkably suppressed, and the target compound has a high selectivity. Can be obtained at Further, the method of the present invention is extremely industrially advantageous because it uses highly versatile and easy-to-handle materials.

[0036]

The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the invention thereto. The NMR spectrum is B
Using RUKER AM500, 500MHz ⁽¹ H-
NMR) was measured using trimethylsilane (TMS) as an internal standard. In the following spectral data,
“Me” represents a methyl group, “Et” represents an ethyl group, “A
"c" represents an acetyl group. Also, N, N-dimethyl-4
The formation ratio between ethyl-aminocrotonate and ethyl N, N, N ', N'-tetramethyl-3,4-diaminobutanoate was determined by gas chromatography. The analysis conditions at that time are shown below. Stationary phase: 5% Thermon 1000 + 1% KOH / Chromosorb W (AW-
DMCS) 60-80mesh, φ3.2mm × 2.1m Mobile phase: N ₂ head pressure 1kgf / cm ² (98.1kP
a) Column temperature; 150 ° C Detector: FID

Reference Example 1 Synthesis of ethyl 4-hydroxycrotonate In a 300 mL four-necked flask, 7.5 g of sodium ethoxide was charged under a nitrogen atmosphere.
5 mL was added to form a solution. To this solution, add 4-
37.0 g of ethyl chloro-3-hydroxybutanoate are
The system was dropped so that the temperature of the system did not exceed 10 ° C. After completion of the dropwise addition, the system was stirred at room temperature for 2 hours and at 60 ° C. for 2 hours. After completion of the reaction, 5 mL of 35% hydrochloric acid was added to the reaction mixture. The pH of the system was 4. 100 mL of water was added thereto to form a solution, which was concentrated under the conditions of 40 ° C./60 mmHg (8 kPa). 100 mL of ethyl acetate was added to the residue thus obtained, and an organic layer was obtained by an extraction operation. Re-enter the aqueous layer for 100
Extracted with mL of ethyl acetate. Combining these organic layers,
The mixture was concentrated under the conditions of 40 ° C./40 mmHg (5.3 kPa), and the intended ethyl 4-hydroxycrotonate was added.
89 g were obtained. The yield was 88%. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (t, J = 7.1 Hz, 3H, E
t), 3.14 (bs, 1H, OH), 4.19 (q, J = 7.1Hz, 2H, E
t), 4.32 (bs, 2H, OCH ₂ ), 6.08 (td, J = 2.0, 15.7H
z, 1H, COCH =), 7.02 (td, J = 3.9, 15.7Hz, 1H, OCH ₂ C
H =)

Reference Example 2 Synthesis of ethyl 4- (methanesulfonyloxy) crotonate In a four-necked flask having a capacity of 500 mL, 20.76 g of ethyl 4-hydroxycrotonate and 20.11 g of triethylamine were added.
g and 60 mL of toluene were charged, and the system was set to a nitrogen atmosphere. This solution was added to methanesulfonyl chloride 2 under ice cooling.
A solution of 2.8 g dissolved in 60 mL of toluene was added dropwise over 1.5 hours. The temperature of the system rose to 13 ° C.
After the completion of the dropwise addition, the system was kept at 5 ° C. and stirred for 2 hours.
After completion of the reaction, 120 mL of water was added to the reaction mixture, and an organic layer was obtained by a liquid separation operation. The organic layer was washed twice with 120 mL of water and then concentrated to obtain 28.6 g of crude ethyl 4- (methanesulfonyloxy) crotonate. The yield was 86%. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (t, J = 7.2 Hz, 3H, E
t), 3.06 (s, 3H, Me), 4.22 (q, J = 7.2Hz, 2H, Et),
4.86 (dd, J = 1.9, 4.8Hz, 2H, OCH ₂ ), 6.14 (td, J =
1.9, 15.7Hz, 1H, COCH =), 6.92 (td, J = 4.8, 15.7Hz,
1H, OCH ₂ C H =)

Reference Example 3 Synthesis of ethyl 4-acetoxycyclotonate A 100 mL four-necked flask was charged with 2.0 g of ethyl 4-hydroxycrotonate, 1.7 g of triethylamine and 10 mL of toluene, and the system was set to a nitrogen atmosphere. To this solution, 1.27 g of acetyl chloride was added with toluene 5 under ice cooling.
The solution dissolved in mL was dropped over 30 minutes. After completion of the dropwise addition, stirring was continued for 1.5 hours while cooling the system with ice. After the completion of the reaction, the reaction mixture was washed three times with 15 mL of water.
The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 2.59 g of ethyl 4-acetoxycyclotonate. The yield was 100%. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (t, J = 7.1 Hz, 3H, E
t), 2.11 (s, 3H, Ac), 4.21 (q, J = 7.1Hz, 2H, Et),
4.73 (dd, J = 1.9, 4.5Hz, 2H, OCH ₂ ), 6.02 (td, J =
1.9, 15.9Hz, 1H, COCH =), 6.93 (td, J = 4.5, 15.9Hz,
1H, OCH ₂ C H =)

Reference Example 4 Synthesis of ethyl 4- (ethoxycarbonyloxy) crotonate In a 100 mL four-necked flask, 1.54 g of ethyl 4-hydroxycrotonate and 1.49 of triethylamine were added.
g and methylene chloride (10 mL) were charged, and the system was set to a nitrogen atmosphere. To this solution was added 1.43 ethyl chlorocarbonate under ice cooling.
g in methylene chloride (5 mL) was added dropwise over 15 minutes. After completion of the dropwise addition, stirring was continued for 3 hours while the system was cooled with ice. After the reaction was completed, the reaction mixture was washed three times with 10 mL of water. The organic layer thus obtained was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the desired 4-
Ethyl (ethoxycarbonyloxy) crotonate 1.6
9 g were obtained. The yield was 71%. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (t, J = 7.0 Hz, 3H, E
t), 1.32 (t, J = 7.1Hz, 3H, Et), 3.06 (s, 3H, Me),
4.20 (q, J = 7.1Hz, 2H, Et), 4.23 (q, J = 7.0Hz, 2H,
Et), 4.78 (dd, J = 1.8, 4.6Hz, 2H, OC H 2 CH =), 6.07
(Td, J = 1.8, 15.9Hz, 1H, COCH =), 6.93 (td, J = 4.6,
15.9Hz, 1H, OCH ₂ C H =)

Example 1 Production of ethyl N, N-dimethyl-4-aminocrotonate [Production method using dimethylamine aqueous solution and ethyl 4- (methanesulfonyloxy) crotonate] A four-necked flask having a capacity of 500 mL was used. Crude 4 obtained in Reference Example 2
26. Ethyl-(methanesulfonyloxy) crotonate
45 g and 135 mL of toluene were charged, and the system was set to a nitrogen atmosphere. A solution in which 34.5 g of a 50% by weight aqueous dimethylamine solution was dissolved in 53 mL of ethanol was added dropwise to this solution over 1 hour under ice cooling. The temperature of the system rose to 7 ° C., and the system separated into two layers with the dropwise addition. After completion of the dropping,
The mixture was further stirred for 0.5 hour while maintaining the temperature. After completion of the reaction, an 8% by weight aqueous sodium hydrogen carbonate solution 5 was added to the reaction mixture.
3 mL was added, and an organic layer was obtained by a liquid separation operation. The organic layer was concentrated to obtain 13.4 g of ethyl N, N-dimethyl-4-aminocrotonate. The yield was 67%. The main by-product is N, N, N ', N'-tetramethyl-3,4-produced by Michael addition of dimethylamine to ethyl N, N-dimethyl-4-aminocrotonate.
It was ethyl diaminobutanoate. Ethyl N, N-dimethyl-4-aminocrotonate and N, N, N ', N'-tetramethyl-3,4-based on the area of the gas chromatogram
The formation ratio with ethyl diaminobutanoate is the former: the latter =
1: 0.090.

Example 2 Production of ethyl N, N-dimethyl-4-aminocrotonate [Production method using dimethylamine THF (tetrahydrofuran) solution and ethyl 4- (methanesulfonyloxy) crotonate] 10 mL of a 2M-dimethylamine THF solution (manufactured by Aldrich) was charged into a one-necked flask,
The system was under a nitrogen atmosphere. This solution was added with ice cooling under Reference Example 2
A solution obtained by dissolving 1.00 g of the crude ethyl 4- (methanesulfonyloxy) crotonate obtained in 5 above in 5 mL of toluene was added to
It was added dropwise over a period of minutes. After completion of the dropwise addition, the system was maintained at 5 ° C., and further stirred for 5 hours. After completion of the reaction, 10 mL of toluene and 20 mL of water were added to the reaction mixture, and an organic layer was obtained by a liquid separation operation. The organic layer thus obtained was washed twice with 10 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the desired N, N-dimethyl-4.
0.575 g of ethyl aminocrotonate were obtained. The main by-product is N, N-dimethyl-4-aminocrotonate, which is formed by Michael addition of dimethylamine to N, N-dimethyl-4-aminocrotonate.
It was ethyl N, N ', N'-tetramethyl-3,4-diaminobutanoate. Ethyl N, N-dimethyl-4-aminocrotonate and N, N based on the area of the gas chromatogram
The formation ratio with respect to ethyl N, N ', N'-tetramethyl-3,4-diaminobutanoate is the former: the latter = 1: 0.014.
Met.

Example 3 Production of ethyl N, N-dimethyl-4-aminocrotonate [Production method using dimethylamine THF solution and ethyl 4-acetoxycyclotonate] Palladium chloride was added to a 50-mL two-necked flask in a two-necked flask. 05
8 g, 0.151 g of triphenylphosphine, 6 mL of toluene, and 0.504 g of ethyl 4-acetoxycyclotonate obtained in Reference Example 3 were charged, and the system was set to a nitrogen atmosphere. To this solution, 5.8 mL of a 2M-dimethylamine THF solution (manufactured by Aldrich) was added dropwise over 10 minutes under ice cooling. After completion of the dropwise addition, stirring was continued for 1 hour under ice cooling and for 3 hours at room temperature. After completion of the reaction, 10 mL of a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and an organic layer was obtained by liquid separation. The organic layer was concentrated to obtain 0.554 g of a brown liquid. Analysis by ¹ H-NMR indicated that the reaction mixture contained 0.355 g of the starting material ethyl 4-acetoxycyclotonate and 0.047 g of the target compound, ethyl N, N-dimethyl-4-aminocrotonate. The yield of ethyl N, N-dimethyl-4-aminocrotonate was 13%. In gas chromatography, N, N, N ',
Ethyl N'-tetramethyl-3,4-diaminobutanoate was not detected.

Example 4 Production of ethyl N, N-dimethyl-4-aminocrotonate [Production method using dimethylamine THF solution and ethyl 4- (ethoxycarbonyloxy) crotonate] In a two-necked flask having a capacity of 50 mL. Palladium chloride 0.06
1 g, 0.152 g of triphenylphosphine, 6 mL of toluene, and 0.623 g of ethyl 4- (ethoxycarbonyloxy) crotonate obtained in Reference Example 4 were charged, and the system was set to a nitrogen atmosphere. To this solution, 6.1 mL of a 2M dimethylamine THF solution (manufactured by Aldrich) was added under ice-cooling for 10 minutes.
It was added dropwise over a period of minutes. After completion of the dropwise addition, stirring was continued at room temperature for 3 hours. After completion of the reaction, 10 mL of a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and an organic layer was obtained by liquid separation. The organic layer was concentrated to 0.737 g of a yellow liquid.
I got Analysis by ¹ H-NMR indicated that the reaction mixture contained 0.44 g of the target compound, ethyl N, N-dimethyl-4-aminocrotonate. The yield of ethyl N, N-dimethyl-4-aminocrotonate was 91%. Ethyl N, N-dimethyl-4-aminocrotonate and N, N, N ', N'- based on the area of the gas chromatogram
The production ratio with ethyl tetramethyl-3,4-diaminobutanoate was the former: the latter = 1: 0.004.

Example 5 Purification of ethyl N, N-dimethyl-4-aminocrotonate 9.2 g of the crude ethyl N, N-dimethyl-4-aminocrotonate obtained in Example 1 was distilled under reduced pressure by a conventional method. Boiling point 82
By collecting a fraction at −84 ° C./11 mmHg (1.46 kPa), 4.7 g of ethyl N, N-dimethyl-4-aminocrotonate was obtained. The area-based purity of the gas chromatogram was 93%. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (t, J = 7.1 Hz, 3H, E
t), 2.25 (s, 6H, Me), 3.06 (dd, J = 1.6, 6.2Hz, 2H,
NCH ₂ ), 4.19 (q, J = 7.1 Hz, 2H, Et), 5.96 (td, J =
1.6, 15.6Hz, 1H, COCH =), 6.94 (td, J = 6.2, 15.6Hz,
1H, NCH ₂ C H =)

Example 6 Production of ethyl 4-piperidinocrotonate In a 30-mL two-necked flask, 0.358 g of the crude ethyl 4- (methanesulfonyloxy) crotonate obtained in Reference Example 2 was charged under a nitrogen atmosphere. And 3 mL of toluene were added to form a solution. To this solution was added 0.29 piperidine under ice-cooling.
A solution in which 3 g was dissolved in 2 mL of toluene was added dropwise over 20 minutes. After completion of the dropwise addition, the system was maintained at 5 ° C.
Stirred for hours. After completion of the reaction, the reaction mixture was
Washing was repeated twice to obtain an organic layer. The organic layer was concentrated to obtain 0.238 g of ethyl 4-piperidinocrotonate. The yield was 70%. The main impurity in the organic layer was raw material ethyl 4- (methanesulfonyloxy) crotonate. No by-products due to Michael addition could be identified. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (t, J = 7.3 Hz, 3H, E
t), 1.4-1.5 (m, 2H, -N (CH ₂ ) ₂ C H _2- ), 1.5-1.7 (m, 4
H, -NCH ₂ C H _2- ), 2,4-2.5 (bs, 4H, NC H ₂ ), 3.12 (d,
J = 6.4Hz, 2H, NC H ₂ -CH =), 4.19 (q, J = 7.3Hz, 2H, E
t), 5.96 (d, J = 15.6Hz, 1H, COCH =), 6.97 (td, J =
6.4, 15.6Hz, 1H, NCH ₂ C H =)

Claims (3)

[Claims] [Claim 1] The following formula (1) (Wherein R ¹ represents an organic group, G represents a substituted oxycarbonyl group, an acyl group or an alkylsulfonyl group), and a 4-substituted oxycrotonate ester represented by the following formula (2): ] (Wherein, R ² and R ³ may be the same or different and each represent a hydrocarbon group or may be bonded to each other to form a ring together with an adjacent nitrogen atom) And reacting with the following formula (3) (Wherein R ¹ , R ² , and R ³ are the same as above), and a method for producing an N, N-disubstituted-4-aminocrotonate ester. 2. The N, N-disubstituted-4-amino according to claim 1, wherein G in the formula (1) is an alkoxycarbonyl group, a C _1-5 aliphatic acyl group or a C _1-4 alkylsulfonyl group. A method for producing crotonic acid esters. 3. The method for producing an N, N-disubstituted-4-aminocrotonate according to claim 1, wherein the reaction is carried out in the presence of a palladium compound.