JP2000319229A - SYNSETIC METHOD FOR beta-KETOCARBOXYLATE AND beta- KETOCARBONITRILE - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject β-ketocarboxylate and β-ketocarbonitrile in high yield in a synthetic method suitable for an industrial scale useful for intermediate for dye or intermediate for photographic material by using a specific safety material which is easily obtainable and preferable for environment. SOLUTION: A β-ketocarboxylate of formula I (R1 and R3 are each an alkyl or alkenyl; R2 is H or a substituent) is synthesized in a synthesizing method carrying out a deacylation after reacting a compound of formula II with a carboxylic acid chloride in the presence of an organic solvent and (anhydrous) calcium chloride. A β-ketocarbonitrile of formula III (R4 is an alkyl or alkenyl; R5 is H or a substituent) is synthesized in a synthesizing method carrying out a cleavage after reacting a compound of formula IV with a carboxylic acid chloride in the presence of an organic solvent and calcium chloride. The preferable reaction temperature is -20 to 40 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for synthesizing β-ketocarboxylic acid esters and β-ketocarbonitrile which are effective as dye intermediates, photographic material intermediates, pharmaceutical intermediates and the like.

[0002]

2. Description of the Related Art In recent years, dye intermediates, photographic material intermediates,
There is an increasing demand for β-ketocarboxylic esters and β-ketocarbonitrile as pharmaceutical intermediates.

There are many known examples of the β-ketocarboxylic acid ester synthesis method, and they are roughly classified into a method using Claisen condensation in which a carboxylic acid ester and another carboxylic acid ester are condensed in the presence of a base, and a method using acetoacetic ester as a base. There are two general methods of performing a deacylation reaction after condensation with a carboxylic acid chloride in the presence.

In the Claisen condensation of the former, it is rare to give one reaction product in the reaction between compounds having α-hydrogen, and in many cases, a mixture is given, so that the yield is low. On the other hand, the method using acetoacetate and carboxylic acid chloride is easy to control the reaction and can be obtained at a higher yield than the reaction by Claisen condensation, so this method is generally used in industrial production. is there.

In the method using acetoacetate, J
ownnal of the American Ch
Electronic Society, vol. 67,219
8 (1945) report acylation of acetoacetate with carboxylic acid chloride and cleavage of the resulting acetylacetoacetate with ammonia or sodium methylate, but the yield was as low as 30-40%. As a means to improve it, British Patent No. B1,000,7
09 and Helvetica ChimicaAct
a, vol. 35.2280 (1952) discloses a method of reacting a carboxylic acid chloride of acetoacetic ester in the presence of magnesium alcoholate, followed by deacylation.
JP-A-5-148186 describes a method in which a carboxylic acid chloride of acetoacetate is reacted in the presence of calcium oxide or calcium hydroxide and then deacylated, but magnesium alcoholate is industrially sufficient. Although it has a high activity, it is difficult to obtain. Further, the method using calcium oxide or calcium hydroxide uses methylene chloride as a solvent, and is not environmentally preferable.

Although there are many known examples of the method for synthesizing β-ketocarbonitrile, the following four synthetic methods are common. α
A method of reacting a halogenoketone with a cyanide compound such as potassium cyanide, a method using Claisen condensation in which a carboxylic acid ester and carbonitrile are condensed in the presence of a base, amidating a β-ketocarboxylic acid ester with ammonia, and a dehydrating agent such as phosphorus oxychloride And a method in which a cyanoacetic acid ester and a carboxylic acid chloride are condensed in the presence of a base and then cleaved.

A method using a cyanide compound is not preferable for industrial use because of toxicity. In many cases, the Claisen condensation method rarely gives a single reaction product, and often gives a mixture, so that the yield is low and it is not industrially used. The method of deriving from β-ketocarboxylic acid ester is not preferable because a toxic substance such as phosphorus oxychloride must be used as a dehydrating agent for amide.

The method using a cyanoacetic acid ester and a carboxylic acid chloride also has a drawback that the yield is low with sodium alcoholate conventionally used as a base.
To improve it, J. Org. Chem. , 19
In 85, 50 and 2622, the yield was improved by using an organic tertiary amine as a base and anhydrous magnesium chloride as a catalyst. However, for industrial use, anhydrous magnesium chloride has a drawback that it is difficult to handle because it is in a lump and it is difficult to obtain an anhydrous powder because of its high water absorption.

[0009]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to handle β-ketocarboxylates and β-ketocarbonitrile, to obtain them easily, to use industrially preferable safe materials and to industrially produce them in high yield. It is an object of the present invention to provide a synthesis method suitable for the above.

[0010]

The above object of the present invention is achieved by the following constitution.

(1) In a method for synthesizing a β-keto carboxylic acid ester represented by the following general formula (1), an acetoacetic ester represented by the following general formula (2) is prepared by reacting an acetoacetic ester with an organic solvent and calcium chloride. A method for synthesizing a β-ketocarboxylic acid ester, which comprises reacting with a chloride and then deacylating the compound for synthesis.

[0012]

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[Wherein, R ¹ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, R ² represents a hydrogen atom, Or a substituent, and R ³ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group. ]

[0014]

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Wherein R ² and R ³ have the same meanings as R ² and R ^{3 in} formula (1). (2) In a method for synthesizing β-ketocarbonitrile represented by the following general formula (3), a cyanoacetic ester represented by the following general formula (4) is subjected to carboxylic acid chloride in the presence of an organic solvent and calcium chloride. And then cleaved to give β
A method for synthesizing β-ketocarbonitrile, which comprises producing ketocarbonitrile.

[0016]

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[In the formula, R ⁴ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, and R ⁵ represents a hydrogen atom. Or a substituent. ]

[0018]

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Wherein R ⁴ and R ⁵ have the same meanings as R ⁴ and R ^{5 in} formula (3). Hereinafter, the present invention will be described in detail. In the general formula (1), the substituted or unsubstituted alkyl group for R ¹ is a methyl group, an ethyl group, a propyl group,
Examples thereof include a butyl group, an octyl group, an ethoxyethyl group, and a trifluoromethyl group.

Examples of the substituted or unsubstituted alkenyl group include an ethenyl group, an allyl group and a butenyl group.

Examples of the substituted or unsubstituted aryl group include a phenyl group, a tolyl group, a chlorophenyl group and a biphenyl group.

Examples of the substituted or unsubstituted heterocyclic group include a pyrrolyl group, a picolyl group, a thienyl group, an imidazolyl group, an N-methylimidazolyl group, a furanyl group, a pyridinyl group, a benzothiazolyl group, a thiadiazolyl group and a benzothiazolyl group.

Examples of the substituent represented by R ² include an alkyl group (methyl group, ethyl group, propyl group, butyl group, octyl group, ethoxyethyl group, trifluoromethyl group, etc.), an alkenyl group (ethenyl group, allyl group). Group, butenyl group, etc.), alkynyl group (ethynyl group, propynyl group,
Butynyl group), an aralkyl group (benzyl group, o-bromobenzyl group, etc.), an aryl group (phenyl group, tolyl group, chlorophenyl group, biphenyl group, etc.), a heterocyclic group (pyrrolyl group, thienyl group, imidazolyl group, Furanyl group, pyridinyl group, benzothiazolyl group, thiadiazolyl group, benzothiazolyl group, etc.), cyano group, alkoxy group (methoxy group, ethoxy group, phenoxy group, ethoxyethoxy group, poly (ethyleneoxy) group, etc.),
Carbonyl group (acetyl group, propionyl group, octanoyl group, lauroyl group, stearoyl group, acetoacetyl group, benzoyl group, thienylcarbonyl group, etc.), ester group (methoxycarbonyl group, ethoxycarbonyl group, phenoxycarbonyl group, methoxycarbonyloxy group , Ethoxycarbonyloxy group, acetoacetyloxy group, phenoxycarbonyloxy group, etc.), amide group (acetamido group, propionamide group, octanoylamino group, benzoylamino group, etc.), sulfonyl group (methanesulfonyl group, ethanesulfonyl group, Tosyl group), amino group (amino group, ethylamino group, diethylamino group, dioctylamino group, etc.), alkylthio group (methylthio group, ethylthio group, benzylthio group, etc.), arylthio group (Such as phenylthio group).

The substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, and substituted or unsubstituted aryl group represented by R ³ are the same as those represented by R ¹ .

In the general formulas (3) and (4), R ⁴ is the same as R ^{1 in the} general formula (1), and R ⁵ is the same group as R ^{2 in the} general formula (1).

The calcium chloride used in the present invention can be favorably used in the form of powder or granules as long as it is anhydrous.

Generally, the amount used is 10 moles per acetoacetate or cyanoacetate.
There is no particular limitation as long as it is 1% or more, but it is particularly preferable to use it in an amount of 80 mol% to 120 mol%.

Solvents usable in the present invention include alcohols such as methanol, ethanol and propanol, acetonitrile, acetone, ethyl acetate, toluene, tetrahydrofuran, dimethylformamide, and the like.
Dimethyl sulfoxide and the like. Chloroform, dichloromethane, benzene and the like can also be used, but it is not preferable from the viewpoint of the environment. A particularly preferred solvent is acetonitrile.

The base that can be used in the present invention may be any commonly used base. For example, organic bases such as triethylamine, pyridine, morpholine,
Although an inorganic base such as potassium carbonate and sodium acetate can be used, a base soluble in a solvent is preferable. Particularly preferred are organic bases such as triethylamine, pyridine and morpholine.

The amount of the base used is not particularly limited as long as it is at least the amount necessary for neutralizing the acid generated by the reaction.

In the synthesis method of the present invention, it is preferable to add a carboxylic acid chloride to a mixed solution in which a solvent, an acetoacetate ester or a cyanoacetate ester, a base and calcium chloride are added in an arbitrary order.

The reaction temperature of the present invention is not particularly limited as long as it is from -20 ° C to the reflux temperature of the solvent, but is preferably 40 ° C or lower to control the reaction.

The acetylacetoacetate ester produced in the reaction between the general formula (2) and the carboxylic acid chloride is deacetylated by a known method to obtain the general formula (1). Deacetylation can be easily performed by a method using an alcoholate base such as sodium methoxide or a method using an alkali such as potassium hydroxide.

The acetyl cyanoacetate produced by the reaction of the general formula (4) with a carboxylic acid chloride is decarboxylated by a known method to obtain the general formula (3). Examples of a method for producing β-ketocarbonitrile by cleavage include a method of refluxing with a solvent in the presence of water. In that case, the solvent may be water, dimethyl sulfoxide, a polar solvent such as dimethylformamide, ethanol, butanol,
Any solvent that is miscible with water, such as an alcoholic solvent such as diethylene glycol, may be used. Particularly, preferred solvents include dimethylsulfoxide and dimethylformamide.

[0035]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to examples, but the present invention is not limited to these examples.

Example 1 6.5 g (0.05 mol) of ethyl acetoacetate, 5.6 g (0.05 mol) of calcium chloride powdered in a mortar
l), 8.4 ml of triethylamine (0.06 mol
l), a mixture of 50 ml of acetonitrile was stirred under ice cooling. 5.3 g (0.05 mol) of butyric acid chloride in it
And the temperature is returned to room temperature. Ethyl acetate and diluted hydrochloric acid were added to the reaction solution, and the ethyl acetate layer was separated, neutralized and concentrated. 2.7 g of sodium methoxide in the concentrate
(0.05 mol) was added to 50 ml of methanol, and the mixture was stirred at room temperature for 5 hours. After stirring, ethyl acetate and water were added, the ethyl acetate layer was separated, concentrated, and distilled under reduced pressure (10 m
mHg Bp 78-80 ° C.), as a colorless liquid, 5.2 g of methyl butyroyl acetoacetate (yield 7).
2%).

The same reaction was carried out except that granular calcium chloride was used instead of calcium chloride powdered in a mortar, and ethyl butyroyl acetoacetate was converted to 5.1.
g (70% yield).

Example 2 The procedure of Example 1 was repeated except that butyric acid chloride was replaced by 5.3 g (0.05 mol) of isobutyric acid chloride. 5.3 g of methyl i-butyroyl acetoacetate
(75% yield).

Example 3 6.5 g (0.05 mol) of ethyl acetoacetate of Example 1
6.5 g of ethyl 2-methylacetoacetate instead of l)
(0.05 mol), 8.5 g of o-methoxybenzoyl chloride instead of butyric acid chloride (0.05 mol)
l) The procedure was the same except for the use. The amount of ethyl o-methoxybenzoylacetoacetate was 6.2 g (87%).

Example 4 5.3 g (0.05 mol) of ethyl cyanoacetate, 5.6 g (0.05 mol) of calcium chloride powdered in a mortar
l) A mixture of 14 ml (0.1 mol) of triethylamine and 50 ml of acetonitrile is stirred under ice cooling. 5.3 g (0.05 mol) of butyric acid chloride is dropped therein, and the liquid temperature is returned to room temperature as it is. Ethyl acetate and diluted hydrochloric acid were added to the reaction solution, and the ethyl acetate layer was separated and concentrated. 16 ml of DMSO and 4 ml of water are added to the concentrate, and the mixture is refluxed for 3 hours. After refluxing, ethyl acetate and water were added, and the ethyl acetate layer was separated, concentrated, and distilled under reduced pressure (10 mmHg Bp 1).
02-106 ° C) to obtain 4.2 g (80% yield) of butyroyl acetonitrile as a colorless liquid.

Example 5 The procedure of Example 4 was repeated except that butyric acid chloride was replaced with 5.3 g (0.05 mol) of isobutyric acid chloride. The yield of i-butyroyl acetonitrile was 4.4 g (85% yield).

Comparative Example 1 Synthesis was carried out in the same manner as in Example 1 except that calcium chloride of Example 1 was omitted. As a result, ethyl butyroyl acetoacetate was 3.0 g (yield 42%).

Comparative Example 2 The same procedure as in Example 4 was carried out except that the calcium chloride used in Example 4 was omitted. The yield of butyroyl acetonitrile was only 1.1 g (20% yield). .

As described above, the synthesis method of the present invention handles β-ketocarboxylic acid esters and β-ketocarbonitrile, and can be industrially produced in high yield using easily available and safe materials.

[0045]

According to the present invention, β-ketocarboxylic acid esters and β-ketocarbonitrile are handled and easily available.
It was possible to provide a synthesis method suitable for industrial production in high yield by using environmentally preferable safe materials.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4H006 AA02 AC44 BA06 BA37 BA50 BA51 BA69 BB11 BB12 BB14 BB16 BB17 BB20 BB21 BC10 BC34 BR10 BT10 QN30

Claims (2)

[Claims] 1. A method for synthesizing a β-ketocarboxylic acid ester represented by the following general formula (1):
A method for synthesizing a β-ketocarboxylic acid ester, which comprises reacting an acetoacetic ester represented by the formula with a carboxylic acid chloride in the presence of an organic solvent and calcium chloride, followed by deacylation for synthesis. Embedded image (In the formula, R ¹ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group,
R ² represents a hydrogen atom or a substituent, and R ³ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group. [Chemical formula 2] Wherein, R ² and R ³ has the same meaning as R ² and R ³ in the general formula (1). ] 2. A method for synthesizing β-ketocarbonitrile represented by the following general formula (3), wherein a cyanoacetic acid ester represented by the following general formula (4) is carboxylated in the presence of an organic solvent and calcium chloride. A method for synthesizing β-ketocarbonitrile, comprising reacting with a substance and cleaving to produce β-ketocarbonitrile. Embedded image Wherein R ⁴ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group,
R ⁵ represents a hydrogen atom or a substituent. [Formula 4] Wherein, R ⁴ and R ⁵ have the same meanings as R ⁴ and R ⁵ in the general formula (3). ]