JP3013022B2 - Method for producing alkyl 3-phthalidylideneacetate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the synthesis of oxophthalazinyl acetic acids which are useful as aldose reductase inhibitors for the treatment of various chronic complications derived from diabetes such as diabetic cataract, retinopathy, neuropathy and the like. The present invention relates to a method for producing an alkyl 3-phthalidylideneacetate as an intermediate.

[0002]

2. Description of the Related Art
The following are known as methods for producing phthalidylideneacetic acid alkyl esters. A method in which potassium acetate is reacted with phthalic anhydride in acetic anhydride, then treated with thionyl chloride, and then esterified with an alcohol (US Pat. No. 2,483,371). A
ust. J. Chem. , 1975, 28 , 2499-
2510), reacting phthalic anhydride with a Zn-Cu bond and monobromoacetic acid ethyl ester (Reformatosky reaction)
Followed by dehydration with concentrated sulfuric acid (J. Org. Che).
m. , 1991 , 56 , 2587-2589;
JP-A-4-3173) and a method of reacting malonic acid diethyl ester with phthalic anhydride in tonene (JCS Perkin I,
1977 , 84-90) and the like.

However, the method has a large number of steps, a low yield, and uses thionyl chloride. The method uses triphenylphosphorane and cis-
This gives a mixture of trans isomers. In the method, the yield of the Reformatsky reaction is low, and there is a problem of metal drainage because Zn or Cu is used. Further, the reaction becomes two steps. The method is not industrially advantageous because it involves two steps and the yield is very low (13%). Although the cause of the low yield of this method is not clear,
Ethyl Cyano (phthalidylidene) acetat similar to 1st process
Looking at the synthesis example of e, since the yield is only 9%, the reaction rate in the first step of the diethyl malonate method can be expected to be similarly low. Furthermore, since only the ester on one side is selectively hydrolyzed to obtain only the desired Z-isomer, it is assumed that the yield is naturally low. In addition, there is a concern about the by-product of the E-body in the second step. Therefore, a more industrially advantageous 3-
At present, there is a demand for the development of a method for producing an alkyl phthalidylidene acetate.

[0004] It is an object of the present invention to provide a novel method capable of industrially and advantageously producing high-purity alkyl 3-phthalidylideneacetate from inexpensive raw materials in a simple and high yield.

[0005]

Means for Solving the Problems In order to achieve the above object, the present inventors have studied various methods for producing alkyl 3-phthalidylideneacetate. By using a malonic acid monoalkyl ester or a salt thereof in place of the malonic acid dialkyl ester as in the above, it is possible to use a reagent which is difficult to perform post-treatment, and a method which is free from metal wastewater in one step from inexpensive raw materials. And that the desired alkyl 3-phthalidylideneacetate can be produced in high yield.
The present invention has been completed as a result of further research based on these findings.

That is, the gist of the present invention is to provide (1) a method for producing an alkyl 3-phthalidylideneacetate by reacting phthalic anhydride and a malonic ester, wherein the malonic ester is MOCO-CH ₂ -COOR (provided that M represents a hydrogen atom, K, Na, Li, or NH ₄ ,
R represents a lower alkyl group having 1 to 5 carbon atoms. (3) a method for producing an alkyl 3-phthalidylideneacetate, characterized by using a monoalkyl malonate or a salt thereof represented by the following formula (2): (2) wherein the malonate is monoethyl malonate or ethyl potassium malonate; (1) The method according to (1) or (2), wherein at least one selected from the group consisting of pyridine, triethylamine, piperidine and ammonium acetate is added as a catalyst. Method,
About.

Hereinafter, the present invention will be described in detail.
The scheme of this reaction is as follows.

[0008]

Embedded image

The phthalic anhydride used in the production method of the present invention can be industrially available at low cost. The choice of the malonic ester to be reacted with phthalic anhydride forms the basis of the present invention. Malonic acid esters usable in the present invention has the general formula MOCO-CH ₂ -C
Malonic acid monoalkyl ester represented by OOR or a salt thereof. Here, M represents a hydrogen atom, K, Na, Li or NH ₄ . R represents a lower alkyl group having 1 to 5 carbon atoms, that is, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and s.
ec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, or neopentyl group.

Preferred examples of the malonic ester usable in the present invention include monoethyl malonate, ethyl potassium malonate, monomethyl malonate,
Methyl potassium malonate and the like are mentioned, and these are industrially available. In addition, these are commonly used (for example,
C. A. , 47 , 12296) can be easily produced from malonic acid diethyl ester or the like.

The amounts of the above-mentioned phthalic anhydride and malonic ester used in the present invention are usually equimolar, but malonic acid alkali metal salts such as ethyl potassium malonate and ethyl sodium malonate are used as malonic esters. When is used, phthalic anhydride is preferably used in an amount of 1.5 to 2.5 times, particularly preferably 2 times, in order to neutralize the by-produced metal ions. Of course, other neutralizing agents can be used.

In the reaction of the present invention, a catalyst is added to promote the reaction. Examples of such a catalyst include pyridine, triethylamine, piperidine, and ammonium acetate. One or more of these are used, and pyridine is particularly preferably used. When an alkali metal salt or an ammonium salt of malonic acid such as ethyl potassium malonate is used, the reaction itself proceeds without addition of a catalyst because the salt itself acts as a catalyst. The amount of the catalyst used is usually about 0.01 to 1 with respect to phthalic anhydride and malonic ester 1, and when the reaction solvent is also used, it is usually 1 to 2 with respect to phthalic anhydride and malonic ester 1.
0.

The reaction in the present invention is carried out in an inert solvent, for example, an aromatic hydrocarbon such as toluene or benzene, or an ether such as diethyl ether or methyl isopropyl ether. When used, pyridine or the like also serves as a solvent, so that it is not necessary to further add another solvent.

The reaction temperature in the reaction of the present invention is as follows:
There is no particular limitation as long as there is no adverse effect on the progress of the reaction. Usually, room temperature to 120 ° C., and in order to increase the reaction rate, 50 to 120 ° C. are preferable. When the reaction is carried out under reflux, the upper limit of the reaction temperature is usually the boiling point of the reaction solvent. The reaction time in the reaction of the present invention is usually 1 to 10 hours, depending on the reaction temperature, and is terminated when the phthalic anhydride as a raw material has disappeared.

After completion of the reaction, the intended alkyl 3-phthalidylideneacetate is isolated from the reaction solution by a conventional method. For example, when the reaction is carried out in an organic solvent such as toluene, water is added to the reaction-terminated liquid, shaken and allowed to stand. The organic layer is separated, toluene is distilled off, and then recrystallized from ethanol or the like. Let it. At this time, if the target substance is relatively insoluble in the organic layer, water is added, ammonium bicarbonate is added to neutralize phthalic acid by-produced, and the resulting mixture is filtered to remove crystals. Obtainable. When the reaction is performed in a pyridine solvent, an acetic acid aqueous solution is added to the reaction solution to dissolve the pyridine, and then cooled,
The precipitated crystals are collected by filtration and recrystallized.

[0016]

The present invention will be described in more detail with reference to the following Examples and Reference Examples, but the present invention is not limited by these Examples and the like.

Example 1 118.5 g (0.8 mol) of phthalic anhydride and 68.1 g (0.4 mol) of ethyl potassium malonate were added to pyridine 12
Added to 5 ml and heated at 90-100 ° C for 2 hours. The amount of phthalic anhydride used was twice the molar amount of ethyl potassium malonate in order to neutralize KOH produced as a by-product. After the generation of carbon dioxide gas disappeared, the mixture was cooled to room temperature, and 600 ml of a 10% aqueous acetic acid solution was added. After cooling to 10 ° C., the precipitated crystals were collected by filtration. After washing with 100 ml of water, it was dried under reduced pressure to obtain 54.0 g (0.247 mol) of ethyl (Z) -3-phthalidylideneacetate (melting point: 132〜).
134 ° C). The yield was 61.7%. The physical properties are as follows. EI-MS, 218 (M ⁺ ), 190, 173, 14
6. NMR (60 MHz, CDCl ₃ ), δ (ppm):
1.3 (3H, t), 4.3 (2H, q), 5.9 (1
H, s), 7.7-8.1 (4H, m)

EXAMPLE 2 59.2 g (0.4 mol) of phthalic anhydride, 26.4 g (0.2 mol) of malonic acid monoethyl ester and pyridine 1
5.8 g (0.2 mol) is added to 200 ml of toluene,
Heat under reflux for 4 hours. After completion of the reaction, 100 ml of water was added, and the organic layer was separated. 5% acetic acid aqueous solution 100m
The organic layer was washed with 1 and toluene was distilled off under reduced pressure. The residue was recrystallized from ethanol to obtain 32.7 g (0.15 mol) of (Z) -3-phthalidylideneacetic acid ethyl ester. The yield was 75%.

EXAMPLE 3 118.5 g (0.8 mol) of phthalic anhydride and 68.1 g (0.4 mol) of ethyl potassium malonate were added to 25 parts of toluene.
0 ml and heated at 90-100 ° C. for 7 hours. After the generation of carbon dioxide gas has ceased, cool to room temperature
Poured into 0 ml. Then, ammonium bicarbonate 3
1.6 g (0.4 mol) was added for neutralization. The crystals were collected by filtration, washed with 100 ml of water, and further added with 50 ml of ethanol.
Washed with ml. The crystals are dried under reduced pressure to give (Z) -3
-Phthalidylideneacetic acid ethyl ester 69.8 g (0.
32 mol). The yield was 80.0%.

Example 4 14.8 g (0.1 mol) of phthalic anhydride and te malonic acid
9.9 g (0.05 mol) of rt-butyl potassium was added to 200 ml of toluene, and the mixture was heated under reflux for 6 hours. After completion of the reaction, 100 ml of water was added, and the organic layer was separated. The organic layer was further washed with 100 ml of a 5% aqueous ammonium bicarbonate solution, and toluene was distilled off under reduced pressure. Next, the residue was purified by column chromatography to obtain 6.4 g (0.026 mol) of (Z) -3-phthalidylideneacetic acid tert-butyl ester. The yield was 52%.

Example 5 The procedure of Example 3 was repeated except that ethyl sodium malonate was used instead of ethyl potassium malonate. The reaction and treatment were carried out in the same manner to obtain 56.5 g of ethyl (Z) -3-phthalidylideneacetic acid (06.5 g). .259 mol). The yield was 64.8%.

Example 6 The reaction and treatment were carried out in the same manner as in Example 3 except that ethyl ammonium malonate was used instead of ethyl potassium malonate, and 45.8 g of (Z) -3-phthalidylideneacetic acid ethyl ester was obtained. .21 mol). The yield was 52.5%.

Reference Example 21.8 g (0.1 mol) of ethyl (Z) -3-phthalidylideneacetate obtained in Example 1 was added to ethanol 1
Added to 50 ml. 5. 80% hydrazine hydrate
3 g (0.1 mol) was added dropwise and reacted for 5 hours under heating and reflux. After the completion of the reaction, the mixture was cooled to room temperature, and the crystals were collected by filtration. After drying under reduced pressure, 2-oxo-3H-phthalazin-1-yl-acetic acid ethyl ester 20.9 g (0.09
Mol) (mp 181 ° C). The yield was 90.0%. Its physical properties were as follows. EI-MS, 232 (M ⁺ ), 159, 130, 10
2. NMR (60 MHz, DMSO-d ₆ ), δ (PP
M): 1.2 (3H, t), 4.0 (2H, s), 4.
1 (2H, q), 7.7 to 8.3 (4H, m),
9 (1H, s)

[0024]

According to the production method of the present invention, high-purity and high-purity alkyl 3-phthalidylideneacetate is obtained in one step from phthalic anhydride and monoalkyl malonate or a salt thereof, which are inexpensive raw materials. Can be manufactured. According to the method of the present invention, the reaction activity of the monoalkyl malonate, which is a reaction reagent, is extremely high, and the yield is up to 80%.
% And good. In addition, since the reaction mechanism is different from the diethyl malonate method, a Z-isomer can be selectively obtained. Furthermore, there is no problem of metal drainage as in the conventional method, so that it is industrially advantageous.

──────────────────────────────────────────────────続 き Continuation of front page (56) References JP-A-64-3173 (JP, A) Chem. Soc. , Perkin Trans. 1, 1982 (8), p. 1855-1863. Chem. Soc. , Perkin Trans. 1, 1977 (1), pp. 84-90 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 307/88 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A method for producing an alkyl 3-phthalidylideneacetate by reacting phthalic anhydride and a malonic ester, wherein the malonic ester is MOCO-
CH ₂ —COOR (where M is a hydrogen atom, K, Na, L
i or NH ₄ , and R represents a lower alkyl group having 1 to 5 carbon atoms. A method for producing an alkyl 3-phthalidylideneacetate, characterized by using a monoalkyl malonate represented by the formula (1) or a salt thereof. 2. The method according to claim 1, wherein the malonic ester is malonic acid monoethyl ester or ethyl potassium malonate. 3. The method according to claim 1, wherein at least one selected from the group consisting of pyridine, triethylamine, piperidine and ammonium acetate is added as a catalyst.
Or the production method according to 2.