JPS6310143B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing oxyphenyl malonic acid half ester (4) by the following reactions.

[reaction path] (In this specification, X represents a p-methoxybenzyl or tetrahydropyranyl group, ^R1 represents a p-methoxybenzyl group, ^R2 represents an alkyl group, and Z represents an alkali metal.) [Summary of the Invention] That is, This invention has the general formula: The oxyphenylacetic acid compound represented by is alkali metalized with an alkali metal salt of hexaalkyldisilazane, etc., and then treated with carbon dioxide to form the general formula: Oxyphenylmalonate (2) represented by
The general formula obtained by applying acid to this is: This invention relates to a method for producing a novel oxyphenyl malonic acid half ester (3) represented by:

Moreover, this invention also provides the general formula: It also includes an optional step of reacting the oxyphenylacetic acid compound (1) represented by the formula with an alkali metal salt of hexa-lower alkyldisilazane to replace one hydrogen at the α-position with an alkali metal.

That is, compound (1) is converted to an alkali metal in this optional step, reacted with carbon dioxide to form oxyphenyl malonate (2), and reacted with acid to form oxyphenyl malonic acid half ester (3). Continuous manufacturing steps are also included in the invention.

[Description of each step] The production method of the present invention includes an optional first step of converting the oxyphenylacetic acid compound (1) to an alkali metal by reacting with an alkali metal salt of hexaalkyldisilazane, an alkali metal compound of the compound (1): From the second step of producing oxyphenyl malonic acid salt (2) by introducing carbon dioxide into the salt (2) and the third step of producing oxyphenyl malonic acid half ester (3) by reacting the salt (2) with an acid. Become.

This entire process can be carried out continuously in the same container, making it economical to operate.

(First step) In this optional step, oxyphenylacetic acid compound (1)
is reacted with an alkali metal salt of hexaalkyldisilazane (1 to 3 equivalents, preferably 1.5 to 2 equivalents) in a suitable anhydrous solvent to form an alkali metal.

This reaction is preferably carried out under anhydrous conditions, in a nitrogen stream, and under cooling.

As the hexaalkyldisilazane, hexamethyldisilazane, hexaethyldisilazane, hexapropyldisilazane, etc. can be used. These can be easily produced by the method described in Journal of the American Chemical Society 66 , 1707 (1944).

Examples of alkali metal salts include sodium salts, lithium salts, and potassium salts.

The alkali metal salt of hexaalkyldisilazane can be easily produced, for example, by reacting hexaalkyldisilazane with an alkali metal amide (particularly sodium amide) in an anhydrous solvent under a nitrogen stream.

As the solvent, hydrocarbons (benzene, toluene, xylene, n-hexane, etc.), ethers (diethyl ether, glyme, diglyme, tetrahydrofuran, etc.), dimethylformamide, etc. are used singly or as a mixture. Toluene, dimethylformamide, tetrahydrofuran, n-hexane and the like are suitable.

(Second Step) In the second step, oxyphenyl malonate (2) is produced by allowing carbon dioxide to act on the alkali metalated oxyphenyl acetic acid compound in the above-mentioned solvent.

To introduce carbon dioxide into the reaction solution, carbon dioxide gas may be directly introduced, but it is also convenient to use dry ice.

(Third Step) In the third step, the oxyphenyl malonic acid salt (2) obtained in the previous step is reacted with an acid to produce the oxyphenyl malonic acid half ester (3).

As the acid, acids commonly used for liberating carboxylic acid salts, such as hydrochloric acid and sulfuric acid, can be used.

[Advantages of the invention] This invention has the following points: raw materials are easily available, there is little risk of ignition, the reaction temperature is relatively high, a safe solvent can be used, the reaction time is short, the operation is simple, It has many advantages including high yield.

[Uses of the product] The oxyphenyl malonic acid half ester (3) obtained by the production method of the present invention can be used, for example, to produce diester compounds (4), other types of ester compounds (5), (6), which are industrial raw materials, by the following reaction. ), etc.

(In the formula, ^R3 is an ester group such as a 5-indanyl group that is more difficult to remove than ^R1 .) Hereinafter, embodiments of the present invention will be explained with reference to Examples.

Reference Example 1 Production of sodium hexaalkyldisilazane 10.5 ml (50.36 mmol) of hexamethyldisilazane (hereinafter abbreviated as HMDS) and 2.5 g of sodium amide are added to 50 ml of anhydrous toluene, and the mixture is heated under reflux for 3 hours under a nitrogen stream. After cooling, filter it.
HMDS - toluene solution of alkali metal salt (hereinafter referred to as
HMDS-Na solution) is obtained as a pale yellow transparent liquid.

Example 1 Production of p-(p-methoxybenzyloxy)phenylmalonic acid p-methoxybenzyl ester Toluene solution of HMDS-Na obtained in Reference Example 1 10
A solution of 1.57 g (4 mmol) of p-(p-methoxybenzyloxy)phenyl acetic acid p-methoxybenzyl ester dissolved in 12 ml of anhydrous toluene was added dropwise to the solution of 1.57 g (4 mmol) of p-methoxybenzyl ester (p-(p-methoxybenzyloxy) phenyl acetate) dissolved in 12 ml of anhydrous toluene under a nitrogen atmosphere and ice-cooled, and the solution was stirred at room temperature for 35 minutes. After stirring, cool on ice again. Gradually add a large excess of dry ice to this, stir for 20 minutes, then add a saturated aqueous sodium bicarbonate solution, stir vigorously under ice cooling, and then filter. Add the precipitate to 10 ml of toluene.
After washing 3 times with 15 ml of water and 3 times with 15 ml of water, dissolve in 40 ml of 1N hydrochloric acid and 120 ml of ethyl acetate while stirring on ice. Separate the organic layer and wash three times with 20 ml of water each.
The aqueous layer is further extracted with 20 ml of ethyl acetate, washed, and combined with the organic layer. The organic layer was dried with 20 g of sodium sulfate, and the solvent was distilled off under reduced pressure.
1.62 g of crystalline residue are obtained. This was recrystallized from 15 ml of ether-petroleum ether (3:2) and washed to give 1.549 g of the target compound (yield: mp 128-130°C).
88.7%). In addition, from the mother liquor, mp121~
Obtain 0.021 g (yield 1.20%) of the target compound at 123°C.

Total yield: 1.57g (yield 89.9%) IR: νmax (KBr) 3260, 1740, 1612, 1585,
1511, 1250, 1168 cm ^-1 NMR: δppm (d ₆ -acetone) 3.78s6H,
4.75s1H, 5.05s2H, 5.15s2H Example 2 Production of p-tetrahydropyranyloxyphenylmalonic acid P-methoxybenzyl ester p-hydroxyphenylacetic acid methyl ester
3.32 g (20 mmol) and dihydropyran 5.5
ml (3.0 equivalents) was dissolved in 2.5 ml of toluene, 1 mg of p-toluenesulfonic acid/H ₂ O was added, and the mixture was stirred at room temperature for 1.5 hours. To this, add 30 ml of toluene solution of 0.3 ml of 4.1N sodium methoxide/methanol and 3.0 ml of anise alcohol, attach a calcium chloride tube, and heat under reflux for 20 minutes. After cooling, add this
Add dropwise to HMDS-Na solution (2.23 molar equivalents) at 10°C over 5 minutes and stir at 20°C for 40 minutes. The reaction solution was cooled to below -60°C, 20g of dry ice was added, and stirred at the same temperature for 10 minutes, then at 0°C for 15 minutes,
Add water, collect the precipitated crystals by filtration, and wash with 40 ml of water and then 4 ml of toluene. The filtrate is separated into an organic layer and an aqueous layer, and the organic layer is shaken with an aqueous sodium bicarbonate solution. Combine the water layer with the previous water layer and wash with toluene.
Combine with the previous crystals and add ethyl acetate and phosphoric acid to adjust the pH to 3-4. Separate the aqueous layer and wash with ethyl acetate. The washing liquid and the extract were combined, washed with water and then with a saturated aqueous sodium carbonate solution, and then washed with carbon tetrachloride.
Crystallization from ethyl acetate gives the desired compound.

First crystal: 5.65g (70.6%) mp115-118℃ Second crystal: 0.80g (10.0%) mp115-118℃ TLC: Rf = 0.68 (Developing solvent: n-heptane-ethyl acetate-acetic acid (15:15: 1); Colored with _I2 ).

NMR: δppm ( _CD3SOCD3 ) 2.5~ _2.0m9H ,
3.70s3H, 4.70s1H, 5.03s2H, 5.46brs1H, 6.6
-7.3m. Reference Example 2 Production of 4-methoxybenzyl 5-indanyl p-(p-methoxybenzyloxy)phenylmalonate ester p-methoxybenzyl p-(p-methoxybenzyloxy)phenylmalonate obtained in Example 1 1.5 g (3.44 mmol) of ester in methylene chloride 10
ml, add 0.48 ml (3.44 mmol) of triethylamine and 0.29 ml (3.44 mmol) of oxalyl chloride at -15°C under stirring in a nitrogen stream, and stir at the same temperature for 20 minutes and then at 0°C for 10 minutes. ,
Obtain the corresponding acid chloride solution.

5-hydroxyindan 415 mg (3.10 mmol)
was dissolved in 10 ml of methylene chloride, and 0.25 ml (3.10 mmol) of pyridine was dissolved at 0°C under stirring in a nitrogen stream.
Then, the above acid chloride solution was added, stirred for 1 hour, and then extracted with ethyl acetate. The extract is washed successively with 2N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on 10% hydrous silica gel, eluted with benzene, and then washed with n-hexane to obtain the target compound.
Obtain 950 mg (50% yield).

mp106~107℃.

NMR: δppm (CDCl ₃ ) 2.07m2H, 2.80t (6Hz)
4H, 3.72s3H, 4.75s1H, 4.90s2H, 5.10s2H Reference Example 3 Production of p-hydroxyphenylmalonic acid 5-indanyl ester p-(p-methoxybenzyloxy)phenylmalonic acid p-methoxy obtained in Reference Example 2 benzyl 5
-4.41 g of indanyl ester in anhydrous methylene chloride
Dissolve in 90 ml of anisole 9 at 0°C in a nitrogen stream.
ml and 9 ml of trifluoroacetic acid and stirred at the same temperature for 40 min.
After stirring for a minute, concentrate under reduced pressure. The residue is crystallized from n-hexane and washed with n-hexane to quantitatively obtain the target compound.

IR: νmax (KBr) 3425, 1750, 1700cm ^-1 NMR (CD ₂ OD) δ: 2.00m2H, 2.80t (6Hz)
4H, 4.82s1H, 6.63~7.43 (m, 7H)

Claims (1)

[Claims] 1. General formula: (In the formula, X is a p-methoxybenzyl or tetrahydropyranyl group, ^R1 is a p-methoxybenzyl group, and Z is an alkali metal atom.) General formulas characterized by summing: (In the formula, X and R ¹ have the same meanings as above.) A method for producing an oxyphenyl malonic acid half ester. 2 General formula: (In the formula, X represents a p-methoxybenzyl or tetrahydropyranyl group, ^R1 represents a p-methoxybenzyl group, and Z represents an alkali metal atom.) The oxyphenylacetic acid compound represented by the general formula: The manufacturing method according to claim 1, which is produced by reacting an alkali metal salt of hexaalkyldisilazane with an oxyphenyl acetic acid compound represented by the formula (wherein, X and R ¹ have the same meanings as defined above).