JPS6280A - Production of phthalide compound - Google Patents

Abstract

PURPOSE:To obtain the objective compound in high yield suppressing the production of by-product, by using a specific amount of hydrochloric acid in the process for the production of a phthalide by the reaction of a trialkoxybenzoic acid with formaldehyde in the presence of hydrochloric acid. CONSTITUTION:The phthalide compound of formula III useful as an intermediate for tritoqualine (a medicine having anti-allergy action, etc.) is produced by reacting the trialkoxybenzoic acid of formula I (R<1>-R<3> are lower alkyl) with formaldehyde in the presence of hydrochloric acid. In the above process, the amount of the hydrochloric acid is selected to 1/100-1/200pts.wt. per 1pt. of the sum of formaldehyde and water in terms of hydrogen chloride. The by- production of 7-chloromethyl-4,5,6-trialkoxyphthalide can be suppressed and the yield of the objective compound can be improved by this process. The amount of formaldehyde is preferably 3-20mol per 1mol of the compound of formula I, and the reaction temperature is preferably 70-110 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing phthalides, and more particularly to phthalides useful as intermediates for the production of tritocpurine, etc., which have antiallergic effects. Concerning the manufacturing method.

(Prior art and problems to be solved) Conventionally, as a method for producing phthalides represented by the following general formula (II), trialkoxybenzoic acid represented by the following general formula (1) and formaldehyde are reacted in hydrochloric acid. However, in this method, the by-product 7-lyalomethyl-Hiro,j,4-)realkoxyphthalide is produced in almost equal amounts along with the target product, and the yield is said to be about 3P%. (British Patent No. 173.3j specification).

(In the formula O (+1), III), R1, R2 and R3 represent lower alkyl groups) (Means for solving the problem) Therefore, the present inventors solved the above reaction by reducing the production of the above-mentioned by-products. As a result of various studies aimed at suppressing the amount of hydrochloric acid and improving the yield, the present invention was achieved with the aim of achieving the objective by using a specific amount of hydrochloric acid.

C) 1. The gist of the present invention.

Trialkoxybenzoic acid represented by general formula (1) (wherein R1, R2 and R8 represent lower alkyl groups) is reacted with formaldehyde in the presence of hydrochloric acid to form the following general formula (ff
) ○ (In the formula, R1, R2, and R8 are as defined in the above general formula (I).) When preparing the phthalides represented by the formula, the above hydrochloric acid is converted into hydrogen chloride, and formaldehyde and water are mixed. A method for producing phthalides characterized by using 17too -t7xo times the total amount (weight ratio).

Hereinafter, one aspect of the present invention will be explained in detail.

As the raw material of the present invention, the following general formula (1) (in the formula R1
, R1 and R8 represent a lower alkyl group) where R1% R2 and R3 are a methyl group, an ethyl group,
A lower alkyl group having carbon number/-4 such as n-propyl group, 180-propyl group, n-butyl group, Hl, R2
, R3 may be the same or different, and trialkoxybenzoic acid is used. For example, when using phthalide as a raw material for tritocuprine, R
', R2, and R'' are all ethyl groups.

The above trialkoxybenzoic acid is usually j, 4t.

! It is obtained by reacting trihydroxybenzoic acid and dialkyl sulfuric acid in an aqueous medium in the presence of caustic alkali and hydrolyzing the alkyl ester of trialkoxybenzoic acid.

In addition, if different alkoxy groups are required, after isolating the monoalkoxybenzoic acid or dibrukoxybenzoic acid obtained by reducing the use of dialkyl sulfuric acid in the above reaction, it can be used in the same manner as with different dimethylkyl sulfuric acid. It can be obtained by reaction.

The formaldehyde used in the present invention may be an aqueous solution or a gas S1.An aqueous solution is usually used. Further, a formaldehyde polymer, such as Eva, formaldehyde, etc., which decomposes into formaldehyde in one reaction system may be used. Further, commercially available aqueous formaldehyde solutions usually contain methanol or the like as a stabilizer, or may be used as is.

The amount of formaldehyde used is usually λ to molar times, preferably 3 to molar times, relative to the starting material trial xybenzoic acid.
It is 2Q mole times. Note that the above usage amount is when a formaldehyde polymer such as paraformaldehyde is used.

This is the amount of formaldehyde assuming that the entire amount is decomposed into monomeric formaldehyde.

In the method of the present invention, the amount of hydrochloric acid used is 17 ioo based on the total of formaldehyde and water in terms of hydrogen chloride,
172o double amount (selected from the range of Ji weight ratio. 171
If the amount is less than 1,720 times, the reaction will be difficult to proceed; if the amount is more than 1,720 times, the production of by-products will increase rapidly.

The reaction temperature in the present invention is! 0-/koO℃.

Preferably #i70~/10°C. If the reaction temperature is too high, many by-products will be produced; conversely, if the reaction temperature is too low, 1
The reaction rate is slow and the reaction does not proceed well, which is not preferable.

Manen1 reaction time is usually 2 to 60 hours, preferably Hiroshi ~
It takes about 30 hours.

After the reaction is complete, the reaction mixture is usually cooled.

The oily unreacted raw material trialkoxybenzoic acid and the reaction product are solidified. Next, filter this with ft? ! & The target product t- can be obtained by washing the solid matter preferably with an aqueous alkali solution to remove the unreacted raw material trialkoxybenzoic acid contained therein. Cooling of the reaction mixture is usually 5O-O<0>C. Washing with an alkaline aqueous solution is usually carried out at 60 to io<0>C, for example, by sprinkling washing or suspension washing, preferably suspension washing, usually at 0. J ~ 3 hours time digit. Examples of the alkalis used include ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. 1. Preferably, ammonia, sodium hydroxide or sodium carbonate is used. The concentration of alkaline aqueous solution is usually o,
r~30% by weight, preferably /-J-% by weight.

The desired product obtained by the above reaction may be treated with, for example, methanol or ethanol, as required.

The purity of the target product can be improved by washing or recrystallizing it with a solvent such as and an aqueous solution thereof.

In addition to the above method, you can also directly add to the reaction mixture.

Method 1, etc., in which an organic solvent is added, the unreacted raw material triplekoxybenzoic acid and the reaction product are extracted, the organic layer is washed with an alkaline aqueous solution to remove the unreacted trialfoxybenzoic acid, and the organic solvent is distilled off to the hole diameter. It is also possible to obtain the desired product depending on the method. In this case, the organic solvent used for extraction is, for example, alkanes such as methylene chloride, chloroform, and dichloroethane; benzene, toluene, xylene, and chlorobenzene.

Aromatic hydrocarbons such as nitrobenzene; ethers such as diethyl ether and dibutyl ether; esters such as ethyl acetate and butyl acetate; and the like.

The unreacted raw material trialkoxybenzoic acid removed by the above alkaline washing can be easily recovered by acid precipitation of the alkaline washing solution and can be used as a raw material for the next phthalidation. Acid precipitation is caused by the pH of the alkaline cleaning solution.
H is below.

Preferably, it is carried out until J, j or less. The acid used in acid precipitation is usually sulfuric acid, hydrochloric acid, etc. After acid precipitation, triple koxybenzoic acid is recovered by filtering the precipitated crystals according to a conventional method and washing with water if necessary.

Among the phthalides represented by the general formula (II) obtained in this way, those in which R1, R2% and R3 are all ethyl groups can be reacted with nitrofluorocarbons such as copper nitrate in acetic anhydride as shown in the reaction formula below. Become.

#, J, J-) Liethoxy 7-nitrophthalide is obtained, and then condensed with cotarunine in a solvent, reduced with tin-hydrochloric acid, etc., and epimerized if necessary, to produce anti-allergic, etc. This can lead to tritoqualin, which is useful as a medicine.

(Triethoxyphthalide) () Liethoxynitrophthalide) (Tritocuprine) (Examples) The present invention will now be described in more detail with reference to Examples.
The present invention is not limited to this.

Example 1 3,ll,j-triethoxybenzoic acid 10.0? (o,
o3y mol), 31% formalin aqueous solution W30d (formaldehyde 0.3? mol), concentrated! After heating a mixture of acid λ, ti (in terms of hydrogen chloride, /3 times the weight of the total of formaldehyde and water) for 3 hours under reflux, an additional 3j%
Add 30y of formalin aqueous solution (0.31 mol of formaldehyde) and 2.1* concentrated hydrochloric acid (in terms of hydrogen chloride, /36 times the amount of formaldehyde and water combined), heat under reflux for 6 hours in the same way, and add ! Thiformalin aqueous solution/jWII (formaldehyde o, i tamole) was added and reacted in the same manner for 7 hours.

After cooling this to room temperature, 100 d of water was added and extracted three times with chloroform lθθd. After washing the organic layer with water, the raw material was recovered in a saturated sodium bicarbonate water bath.

Next, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off.

By recrystallizing the crystals thus obtained with methanol solution, 7.1 lf (yield: t) of Hiroshij-,4-triethoxyphthalide was obtained.

(mp, /2j -/2J, jo) Also, by silica gel column chromatography from the recrystallization mother liquor, the by-product 7-chloromethyl-≠, 7.7
-Driethoxyphthalide 0. t/l (yield jchi) was obtained.

Incidentally, the saturated aqueous sodium bicarbonate solution from which the raw materials were recovered was treated with hydrochloric acid, and the precipitated crystals were filtered, thereby recovering Bucchinensis and Coor.

Comparative Example 3, ≠, j-triethoxybenzoic acid 80 (J, mmol) tJj% formalin aqueous solution λ, Jd (32 mmol formaldehyde) and concentrated hydrochloric acid/, Jw (in terms of hydrogen chloride, formaldehyde and water i7'r for the total
2 times the weight) and allowed to react under heating and reflux for 3 hours. After cooling this, water is added, the crystals are filtered, washed with water, and recrystallized from ethanol, ≠,! , Otsu-toso triethoxyphthalide 011 (yield 39%) was obtained.

(mp, //?-/220) In addition, the by-product 7-chloroI methyl-
! ,j,j-triethoxyphthalide O6≠3t (yield 36%) was obtained.

(Effect of the invention) According to the method of the present invention, the production of by-products is suppressed.

And phthalides can be obtained in high yield.

Applicant: Mitsubishi Chemical East Co., Ltd. Representative Patent Attorney Hase - 1 other person

Claims (1)

[Claims] (1) Trialkoxybenzoic acid represented by the following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1, R^2 and R^3 represent lower alkyl groups) The acid is reacted with formaldehyde in the presence of hydrochloric acid to form the following general formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R^1, R^2 and R^3 are as above) General formula ( I
) as defined in ). ) A method for producing phthalides, characterized in that the above-mentioned hydrochloric acid is used in an amount (weight ratio) of 1/100 to 1/20 times the total of formaldehyde and water in terms of hydrogen chloride.