JP2003335771A - Method for producing 6,7-dyhydroxycoumarin-3-carboxylic acid derivative, and its intermediate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially suitable method for producing 6,7- dihydroxycoumarin-3-carboxylic acid derivative from 6,7- methylenedioxycoumarin-3-carboxylic acid derivative in high yield by a simple method. <P>SOLUTION: The method for producing the 6,7-dyhydroxycoumarin-3-carboxy compound comprises (A) a step for reacting molecular chlorine with the 6,7- methylenedioxycoumarin-3-carboxy compound in the presence of a chlorine compound to provide 6,7-chloromethylenedioxycoumarin-3-carboxy compound, and (B) a step for subjecting the 6,7-chloromethylenedioxycoumarin-3-carboxy compound to hydrolysis and/or alcoholysis reaction to provide the 6,7- dihydroxycoumarin-3-carboxy compound. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 6,7-methylenedioxycoumarin-3-carboxy compounds,
The present invention relates to a method for producing a 6,7-dihydroxycoumarin-3-carboxy compound via a chloromethylenedioxycoumarin-3-carboxy compound as an intermediate. A 6,7-dihydroxy-3-carboxy compound is an important compound as a synthetic intermediate for pharmaceuticals, and specifically, for example, a modifier for penicillin or cephalosporin antibiotics (Patent Document 1), catechol- O
-A compound useful as a synthetic intermediate for a methyltransferase inhibitory activator (Patent Document 2) and the like.

[0002]

2. Description of the Related Art Conventionally, 6,7-dihydroxycoumarin-
Patent Document 2 discloses a method for producing a 3-carboxylic acid.
6,7-Dihydroxy-2-imino-obtained from 1,2,4-trihydroxybenzene and cyanoacetic acid ester
Non-Patent Document 1 discloses a production method of treating 2H-chromene-3-carboxylic acid ethyl ester with hydrochloric acid.
-A method for producing from trihydroxybenzene and diethyl malonate is described, but both are made from 1,2,4-trihydroxybenzene, which is industrially difficult to obtain in large quantities, and Since the compound has a plurality of hydroxyl groups that can participate in the reaction, there is a problem such as a side reaction. Further, Non-Patent Document 2 describes a method for producing a 6,7-methylenedioxycoumarin-3-carboxy compound, which is a starting material compound. There was no known method for producing a 6,7-dihydroxycoumarin-3-carboxy compound by using as a compound.

[0003]

[Patent Document 1] European Patent No. 62328

[Patent Document 2] International Publication No. 02/02548 Pamphlet

[Non-Patent Document 1] Chem. Ber. , 34, 190
1, p. 423

[Non-Patent Document 2] Bull. Chem. Soc. J
p. 1962, p. 1321-1323

[0004]

The object of the present invention is to produce a 6,7-methylenedioxycoumarin-3-carboxy compound in a high yield in a high yield by a simple method.
Industrially suitable 6,7-dihydroxycoumarin-3 for producing dihydroxycoumarin-3-carboxy compound
-Providing a process for producing a carboxy compound.

[0005]

The object of the present invention is (A)
In the presence of a chlorine compound, the general formula (1)

[0006]

[Chemical 5]

(7) In the formula, R represents a hydrogen atom or an alkyl group, 6,7-methylenedioxycoumarin-3-carboxy compound is reacted with molecular chlorine,
General formula (2)

[0008]

[Chemical 6]

(Wherein R has the same meaning as defined above), 6,7-chloromethylenedioxycoumarin-3-
A step of preparing a carboxy compound, and (B) the above 6,
A 7-chloromethylenedioxycoumarin-3-carboxy compound is subjected to a hydrolysis reaction and / or an alcoholysis reaction to give a compound represented by the following general formula (3).

[0010]

[Chemical 7]

(Wherein R has the same meaning as defined above), and a step of producing a 6,7-dihydroxycoumarin-3-carboxy compound represented by the formula 6,7-
It is solved by a method for producing a dihydroxycoumarin-3-carboxy compound.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the step (A) of the present invention,
The 6,7-methylenedioxycoumarin-3-carboxy compound represented by the general formula (1) is reacted with molecular chlorine in the presence of a chlorine compound to produce 6,6 represented by the general formula (2). The 7-chloromethylenedioxycoumarin-3-carboxy compound is prepared as an intermediate.

In the next step (B), the 6,7-chloromethylenedioxycoumarin-3-carboxy compound of the above formula (2) is subjected to a hydrolysis reaction and / or an alcoholysis reaction to give a compound of the general formula (3). A desired 6,7-dihydroxycoumarin-3-carboxy compound represented by

The 6,7-methylenedioxycoumarin-3-carboxy compound used in the step (A) of the present invention is represented by the above general formula (1). In the general formula (1), R is a hydrogen atom; an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, and a butyl group (these groups include various isomers). However, it is preferably a hydrogen atom, a methyl group or an ethyl group. The 6,
The 7-methylenedioxycoumarin-3-carboxy compound is a compound that can be easily synthesized according to the method described in Non-Patent Document 2 (see Reference Example 1).

Examples of the chlorine compound used in the step (A) of the present invention include phosphorus trichloride, phosphorus pentachloride, sulfuryl chloride, thionyl chloride and nitrosyl chloride.
Phosphorus trichloride and phosphorus pentachloride are preferably used. In addition, you may use these chlorine compounds individually or in mixture of 2 or more types.

The amount of the chlorine compound used is preferably 0.05 to 10 mol, more preferably 0.1 to 10 mol, based on 1 mol of the 6,7-methylenedioxycoumarin-3-carboxy compound. .

The amount of molecular chlorine used in the step (A) of the present invention is 6,7-methylenedioxycoumarin-3.
-Preferably 1 to 5 relative to 1 mol of the carboxy compound
It is 0 mol, more preferably 1 to 10 mol.

The step (A) of the present invention is preferably carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction and is itself difficult to be chlorinated. , Benzene, toluene, xylene, ethylbenzene, t-butylbenzene and other aromatic hydrocarbons; chlorobenzene and other halogenated aromatic hydrocarbons; n-hexane, n-heptane, n-octane, n-decane, cyclohexane , Cycloheptane, cyclooctane, and other aliphatic hydrocarbons; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and other halogenated aliphatic hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and other ethers; ethyl acetate , And carboxylic acid esters such as butyl acetate, but preferably aromatic Hydrocarbons, halogenated aliphatic hydrocarbons, carboxylic acid esters, more preferably aromatic hydrocarbons, carboxylic acid esters are used. In addition, you may use these solvents individually or in mixture of 2 or more types.

The amount of the solvent used is appropriately adjusted depending on the homogeneity and stirring property of the reaction solution, but is preferably 1 to 50 ml, and more preferably 1 g of the 6,7-methylenedioxycoumarin-3-carboxy compound. Is 2 to 20 ml.

The step (A) of the present invention comprises, for example, 6,7-
Stir while mixing a methylenedioxycoumarin-3-carboxy compound, a chlorine compound and a solvent, and supplying chlorine gas (which may be diluted with an inert gas such as nitrogen gas or argon gas) as molecular chlorine. It is carried out by a method such as reacting while. The reaction temperature at that time is preferably 25 to 150 ° C., more preferably 25 to 100 ° C.
The reaction pressure and the supply rate of chlorine gas are not particularly limited.

When a reaction solvent is used in the step (A) of the present invention, a solution containing a 6,7-chloromethylenedioxycoumarin-3-carboxy compound as a product is obtained. The solution is used as it is or after being concentrated, and then subjected to the next step (B). However, in some cases, the produced 6,7-chloromethylenedioxycoumarin-3-carboxy compound is filtered, for example, by filtration,
After being once isolated by a general method such as concentration, crystallization, recrystallization, distillation, and / or column chromatography, it may be subjected to the next step (B).

In the step (B) of the present invention, the 6,7-chloromethylenedioxycoumarin-3-carboxy compound represented by the formula (2) is subjected to a hydrolysis reaction and / or an alcoholysis reaction, The 6,7-dihydroxycoumarin-3-carboxy compound represented by the formula (3) is produced.

The hydrolysis reaction and / or alcoholysis reaction carried out in the step (B) of the present invention can be carried out by using commonly used methods, conditions and apparatus for hydrolysis and / or alcoholysis. Preferably, the hydrolysis reaction is carried out under acidic conditions containing an acid and water. The reaction liquid obtained in the step (A) (6,7-chloromethylenedioxycoumarin-3 which is the product of the step)
-A solution containing a carboxy compound, which may be concentrated), is used as it is, it is not necessary to newly add an acid, and only water may be added.

The amount of water used is appropriately adjusted depending on the homogeneity and agitation property of the reaction solution, but the amount used in step (A) is 6,7.
-Methylenedioxycoumarin-3-carboxy compound 1
With respect to g, preferably 1 to 50 g, more preferably 2
~ 20g.

When the alcoholysis reaction is carried out in the step (B) of the present invention, the alcohol is an aliphatic saturated alcohol having 1 to 4 carbon atoms, for example, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, N-butyl alcohol, isobutyl alcohol and the like are used, and preferably methanol, ethanol, propyl alcohol and isopropyl alcohol are used.

The amount of alcohol used in the alcoholysis reaction is the amount of the 6,7-methylenedioxycoumarin-3-carboxy compound used in step (A) 1
With respect to g, preferably 1 to 50 g, more preferably 2
~ 20g.

In the step (B) of the present invention, for example, the 6,7-chloromethylenedioxycoumarin-3-carboxy compound obtained in the step (A) or a reaction solution containing the same (may be concentrated) And water and / or alcohol (if necessary, an acid may be added), and if necessary,
The reaction may be performed with stirring. The reaction temperature at that time is
Preferably 5 to 100 ° C, more preferably 25 to 70 ° C
And the reaction pressure is not particularly limited. Further, this step may be performed in an atmosphere of a gas that is not reactive with the reaction system, for example, an inert gas such as nitrogen gas or argon gas.

After the above step (B), the final product, the 6,7-dihydroxycoumarin-3-carboxy compound, is filtered, concentrated, crystallized, recrystallized, distilled, and / or
Alternatively, it is isolated and purified by a general method such as column chromatography.

[0029]

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

Reference Example 1 (3-methoxycarbonyl-6,
Synthesis of 7-methylenedioxycoumarin) In a flask having an internal volume of 50 ml equipped with a stirrer, a thermometer, a dropping funnel and a Dean-Stark device, in a nitrogen atmosphere, 2.56 g (30.06 mmol) of piperidine and 25 ml of cyclohexane were added. Was added and mixed, and 1.81 g (30.14 mmol) of acetic acid was slowly added dropwise to this mixture while stirring. Further, 5.00 g (30.10 mmol) of 2-hydroxy-4,5-methylenedioxybenzaldehyde was added to this mixture, and the resulting water was reacted for 2 hours while being distilled off under reflux (70-80 ° C). It was After completion of the reaction, the reaction solution was cooled to room temperature, 50 g of ethyl acetate and 50 g of ice water were added, and the mixture was stirred. The precipitated crystals were separated by filtration and washed with water,
After drying at 50 ° C. under reduced pressure, yellow crystals of 3-methoxycarbonyl-6,7-methylenedioxycoumarin 0.8.
99 g was obtained (isolated yield: 95%). In addition, 3-methoxycarbonyl-6,7-methylenedioxycoumarin is a novel compound having the following physical properties.

¹ H-NMR (CDCl ₃ , δ (ppm)); 3.805 (3 H, s), 6.
218 (2H, s), 7.166 (1H, s), 7.410 (1H, s), 8.691 (1H, s) CI-MS (m / e); 249 (MH ⁺ ) Elemental analysis; Carbon 57.85%, hydrogen 3.24 % (Theoretical value (C ₁₂ H ₈ O ₆ ); carbon 58.07%, hydrogen 3.25%)

Example 1 (3-methoxycarbonyl-6,
Synthesis of 7-dihydroxycoumarin) 3-methoxycarbonyl-synthesized in the same manner as in Reference Example 1 in a nitrogen atmosphere in a flask having an internal volume of 25 ml equipped with a stirrer, a thermometer, a dropping funnel and a gas introduction tube.
1000 mg of 6,7-methylenedioxycoumarin (4.
03 mmol) and 10 ml of toluene, and mixed,
170 mg of phosphorus trichloride (1.
21 mmol) was gently added dropwise. Further, after heating the mixed solution to 50 ° C., chlorine gas is added to
The reaction was performed while feeding at a feed rate of 0.4 g / hr over time. Next, this reaction liquid was cooled to room temperature, 10 g of ice water was added thereto, the temperature of this reaction liquid was raised to 50 ° C. again, and a hydrolysis reaction was carried out for 3 hours. After completion of the reaction, when the reaction solution was cooled to room temperature, crystals were precipitated, so crystals were filtered, washed with water, and dried at 50 ° C. under reduced pressure to give yellow crystals.
899 mg of methoxycarbonyl-6,7-dihydroxycoumarin was obtained (isolated yield: 94%).

Example 2 (3-ethoxycarbonyl-6,
Synthesis of 7-dihydroxycoumarin) In Example 1, the starting material was 3-ethoxycarbonyl-
1000 mg of 6,7-methylenedioxycoumarin (3.
The reaction was performed in the same manner as in Example 1 except that the amount was changed to 82 mmol). As a result, yellow crystals of 3-ethoxycarbonyl-6,7-dihydroxycoumarin 904 mg
Was obtained (isolated yield: 95%). In addition, 3-ethoxycarbonyl-6,7-dihydroxycoumarin is a novel compound having the following physical properties.

¹ H-NMR (DMSO-d ₆ , δ (ppm)); 1.289 (3H, t, J =
7.08Hz), 4.251 (2H, q, J = 7.08Hz), 6.761 (1H, s), 7.170
(1H, s), 8.547 (1H, s), 8.609 (1H, s), 9.00 to 11.00 (2H, b
rs) CI-MS (m / e) ； 251 (MH ⁺ )

Example 3 (Synthesis of 3-carboxy-6,7-dihydroxycoumarin) In a flask having an internal volume of 25 ml equipped with a stirrer, a thermometer, a dropping funnel and a gas introduction tube, in a nitrogen atmosphere, 3
-Carboxy-6,7-methylenedioxycoumarin 10
00 mg (4.29 mmol) and 10 ml of toluene were added thereto and mixed, and the mixture was stirred and phosphorus trichloride 1.
38 g (10.05 mmol) was gently added dropwise. Further, the temperature of this mixed liquid was raised to 50 ° C., and then chlorine gas was reacted for 5.5 hours while supplying 0.4 g / hour. The obtained reaction solution was cooled to room temperature, 10 g of ice water was added thereto, and the reaction solution was added to 5 times again.
The temperature was raised to 0 ° C. and the hydrolysis reaction was carried out for 0.5 hours. After the completion of the reaction, the reaction solution was cooled to room temperature to precipitate crystals, which were filtered, washed with water, and dried at 50 ° C. under reduced pressure.
980 mg of 3-carboxy-6,7-dihydroxycoumarin, which is a yellow crystal, was obtained (isolated yield: 100%).

Example 4 (3-methoxycarbonyl-6,
Synthesis of 7-chloromethylenedioxycoumarin) 3-methoxy synthesized in the same manner as in Reference Example 1 in a nitrogen atmosphere in a flask having an internal volume of 25 ml equipped with a stirrer, a thermometer, a dropping funnel and a gas introduction tube. Carbonyl-6,7-methylenedioxycoumarin 1000 mg
(4.03 mmol) and 10 ml of toluene were added and mixed, and 170 mg of phosphorus trichloride was added while stirring the mixture.
(1.21 mmol) was gently added dropwise. Furthermore,
The temperature of this mixed liquid was raised to 50 ° C., and then chlorine gas was supplied thereto at a supply rate of 0.4 g / hour for 4 hours for reaction. After completion of the reaction, crystals were precipitated when the reaction solution was cooled to room temperature, so crystals were filtered, washed with toluene and n-hexane in that order, and then dried at 25 ° C. under reduced pressure to give yellow crystals of 3-methoxycarbonyl-6,7. 762 mg of chloromethylenedioxycoumarin was obtained (isolated yield: 64
%). In addition, 3-methoxycarbonyl-6,7-chloromethylenedioxycoumarin is a novel compound specified by the following physical properties.

¹ H-NMR (CDCl ₃ , δ (ppm)); 3.962 (3 H, s), 7.
113 (1H, s), 7.246 (1H, s), 8.049 (1H, s), 8.544 (1H, s) CI-MS (m / e); 283 (MH ⁺ )

Example 5 (3-ethoxycarbonyl-6,
Synthesis of 7-chloromethylenedioxycoumarin) In Example 4, the starting material was 3-ethoxycarbonyl-
1000 mg of 6,7-methylenedioxycoumarin (3.
The reaction was performed in the same manner as in Example 4 except that the amount was changed to 82 mmol). As a result, 669 mg of 3-ethoxycarbonyl-6,7-chloromethylenedioxycoumarin, which was a yellow crystal, was obtained (isolated yield: 60%). Note that 3-ethoxycarbonyl-6,7-chloromethylenedioxycoumarin is a novel compound specified by the following physical property values.

¹ H-NMR (DMSO-d ₆ , δ (ppm)); 1.295 (3H, t, J =
7.08Hz), 4.272 (2H, q, J = 7.08Hz), 6.957 (1H, s), 7.739
(1H, s), 8.547 (1H, s), 8.667 (1H, s)

Example 6 (3 using alcoholysis reaction)
-Synthesis of methoxycarbonyl-6,7-dihydroxycoumarin) In a flask with an internal volume of 25 ml equipped with a stirrer, a thermometer, a dropping funnel and a gas introduction tube, in a nitrogen atmosphere, the same method as in Reference Example 1 was used to synthesize 3 -Methoxycarbonyl-
1000 mg of 6,7-methylenedioxycoumarin (4.
(03 mmol) and 10 ml of toluene were added and mixed, and the mixture was stirred with 166 mg of phosphorus trichloride.
(1.21 mmol) was gently added dropwise. Furthermore,
The temperature of this reaction solution was raised to 50 ° C., and then chlorine gas was supplied to the reaction solution at a supply rate of 0.4 g / hour for 3 hours for reaction. The obtained reaction liquid was cooled to room temperature, 10 ml of methanol was added thereto, and the reaction liquid was heated to 50 ° C. again and reacted for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, 10 ml of dimethylformamide was added thereto to make a uniform solution, and this was quantified by an absolute calibration curve method using high performance liquid chromatography. It was confirmed that 894 mg of methoxycarbonyl-6,7-dihydroxycoumarin was contained (yield: 94%).

[0041]

According to the present invention, by a simple method,
From 6,7-methylenedioxycoumarin-3-carboxy compound, 6,7-dihydroxycoumarin-3 was obtained in high yield.
Industrially suitable 6,7 for producing carboxy compounds
A method for producing a dihydroxycoumarin-3-carboxy compound can be provided.

Claims (3)

[Claims] (A) The following general formula (1): (In the formula (1), R represents a hydrogen atom or an alkyl group.) 6,7-methylenedioxycoumarin-
The 3-carboxy compound is reacted with molecular chlorine in the presence of a chlorine compound to give a compound represented by the following general formula (2): (In the formula (2), R is the same as the above.) The step of adjusting the 6,7-chloromethylenedioxycoumarin-3-carboxy compound represented by the formula, and (B) the 6,7-chloro. A methylenedioxycoumarin-3-carboxy compound is subjected to a hydrolysis reaction and / or an alcoholysis reaction to give the following general formula (3): (In the formula (3), R has the same meaning as described above.) 6,7-dihydroxycoumarin-3-carboxyl compound characterized by comprising a step of producing a 6,7-dihydroxycoumarin-3-carboxy compound. -3-A method for producing a carboxy compound. 2. The method for producing a 6,7-dihydroxycoumarin-3-carboxy compound according to claim 1, wherein the chlorine compound used in the step (A) is selected from phosphorus trichloride and phosphorus pentachloride. 3. The following formula (4): (However, in the above formula (4), Et represents an ethyl group.) 3-ethoxycarbonyl-6,7
-Dihydroxycoumarin.