JPH09157268A - Production of 7-hydroxyisoflavone and its purification - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain 7-hydroxyisoflavone useful as an intermediate for osteoporosis medicines, etc., in a high purity and in a high yield without largely generating by-products by reacting dihydroxyphenylbenzylketone with methyl orthoformate, etc., in the presence of a base. SOLUTION: 2,4-Dihydroxyphenylbenzylketone is reacted with methyl orthoformate, propyl orthoformate or isopropyl orthoformate in the presence of a base such as piperidine, morpholine or pyrrolidine in a reaction organic solvent to obtain the 7-hydroxyisoflavone. 7-Propoxyisoflavone, 7- ethoxyisoflavone and 7-methoxyisoflavone contained in the 7-hydroxyisoflavone as by-products are heated and mixed with an alcohol such as methanol, left, and subsequently subjected to the separation of the supernatant or the filtration of the mixture at 20-50 deg.C to purify the 7-hydroxyisoflavone by removing by- products.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 7-hydroxyisoflavone, which is an intermediate of ipriflavone (7-isopropoxyisoflavone) which is a therapeutic agent for osteoporosis, and a method for purifying the same.

[0002]

2. Description of the Related Art As a method for producing 7-hydroxyisoflavone, dimethylformamide or isopropyl alcohol is used as a reaction medium in the presence of morpholine.
Method for producing 2,4-dihydroxyphenyl benzyl ketone by condensation with ethyl orthoformic acid ethyl ester
-507085) is known. This method produces 7-ethoxyisoflavone as a by-product.
When 7-isopropoxy isoflavone (ipriflavone) which is a drug substance is produced by isopropylating hydroxy isoflavone, 7-ethoxy isoflavone is mixed in the product. It is extremely difficult to remove 7-ethoxy isoflavone from 7-isopropoxy isoflavone. Therefore, studies have been made to remove 7-ethoxyisoflavone from 7-hydroxyisoflavone. In the above-mentioned patent, potassium carbonate is allowed to act on 7-hydroxyisoflavone in toluene to precipitate the resulting potassium salt of 7-hydroxyisoflavone (by dissolving 7-ethoxyisoflavone in toluene) to separate the compounds. Is going. Further, it is proposed that an appropriate amount of the solvent is distilled off from the reaction product, methanol and chloroform are added, and the mixture is strongly cooled. However, 7-hydroxyisoflavone is difficult to dissolve in toluene, and the reaction using potassium carbonate does not proceed smoothly. Thus, the method of treating with methanol or chloroform cannot sufficiently remove 7-ethoxyisoflavone.

[0003]

As described above, the conventional manufacturing method cannot be manufactured industrially at a low cost due to the production of by-products that are difficult to remove. Therefore, it is necessary to establish an inexpensive manufacturing method. Was wanted.

[0004]

Means for Solving the Problems In producing 7-hydroxyisoflavone, the inventor of the present invention used isopropyl alcohol as a reaction medium in the presence of morpholine.
As a result of intensive studies on a method for producing a target product by condensing 4-dihydroxyphenylbenzyl ketone and orthoformate ester, 1) When orthoformate isopropyl ester was used as the orthoformate ester, the obtained 7-hydroxyisoflavone was obtained. When 7-isopropoxy isoflavone is produced by reacting isopropyl bromide, 7-isopropoxy isoflavone does not contain impurities that are difficult to purify. 2) When ortho-formic acid methyl ester is used as ortho-formic acid ester, it is obtained. The obtained 7-hydroxyisoflavone contains 7-methoxyisoflavone, which can be easily removed and can also be removed from 7-isopropoxyisoflavone 3) Orthoformic acid propyl ester When used During 7-hydroxy isoflavone obtained, including 7-propoxy isoflavones, 7-
Remarkably easier to remove than ethoxy isoflavone 4) Even if ethyl orthoformate is used as the orthoformate ester, the reaction is carried out so that the 7-hydroxyisoflavone produced during the reaction is not exposed to a supersaturated state. Medium, by cooling and or by adding seed crystals, by precipitating crystals at any time and smoothing the stirring state,
The ability to suppress the production of 7-ethoxyisoflavone 5) The crude product extracted from the reaction system contains alcohols,
In particular, it was found that by-products can be removed by adding methanol and stirring sufficiently while heating, then filtering while heating, or separating the supernatant after standing while heating, and completed the present invention. In addition, there is an example in which methanol and chloroform are used in the examples of the above-mentioned patents, but both are cooled to 0 ° C. or lower and taken out,
No effect of removing the by-product is seen. Further, the patent does not describe hot filtration and hot separation. Purification by recrystallization with various organic solvents has also been tried, but in any case, there is no effect of removing the by-products, the purification yield is low, and there are many problems such as coloring when heated, It is totally unexpected that the product can be purified by washing with hot water.

That is, the present invention (1) is characterized in that 2,4-dihydroxyphenylbenzyl ketone is reacted with methyl orthoformate, propyl orthoformate or isopropyl orthoformate in the presence of a base. Method for producing isoflavone (2) Method for producing 7-hydroxyisoflavone according to the above item (1), wherein the base is piperidine, morpholine or pyrrolidine (3) Any of the above items (1) to (2) using an organic solvent as a reaction medium 7. The method for producing 7-hydroxyisoflavone according to any one of (1) to (4) a side reaction in crude 7-hydroxyisoflavone obtained by reacting 2,4-dihydroxyphenylbenzyl ketone and an alkyl orthoformate in the presence of a base. 7-propoxy isoflavone, 7-ethoxy existing as a substance In the purification method for removing isoflavone or 7-methoxyisoflavone, the mixture is heated and stirred with alcohols, allowed to stand, and then the supernatant liquid is separated or filtered for 20 to 5 times.
Purification method of 7-hydroxyisoflavone, which is characterized in that it is carried out in the range of 0 ° C. (5) The purification method according to the above (4), wherein the alcohol is methanol.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. (Description of Manufacturing Method) First, the manufacturing method, which is the first invention of the present invention, will be described. In this production method, isopropyl ester, propyl ester or methyl ester is used as the orthoformate ester. The amount of orthoformate ester used is 1 to 50 mol ratio, preferably 1 to 20 mol ratio, and particularly preferably 1 to 2,4-dihydroxyphenylbenzyl ketone (hereinafter abbreviated as PBZK).
~ 6 molar ratio. Although a base is used in the present invention, examples of the base that can be used include aliphatic, aromatic, alicyclic, heterocyclic secondary amine and / or tertiary amine, and specific examples thereof. Examples thereof include piperidine, morpholine, pyrrolidine, piperazine, pyridine, virazine, quinoline and the like. The amount of the base used is 0.01 to 20 mol ratio, preferably 0.1 to 5 mol ratio, and particularly preferably 0.2 to 2 mol ratio with respect to PBZK. The reaction temperature is 50 to 200 ° C., preferably 70 to 150 ° C.
Particularly preferably, it is 80 to 110 ° C. The reaction time is
It is 1 to 30 hours, preferably 3 to 15 hours, and particularly preferably 5 to 10 hours. Moreover, you may use an organic solvent as a reaction medium. Examples of organic solvents that can be used are dimethylformamide, dimethylacetamide,
Aprotic polar solvents such as dimethyl sulfoxide, protic polar solvents such as isopropyl alcohol, ethyl alcohol and methyl alcohol, nonpolar solvents such as benzene, toluene and xylene, and aromatic chlorinated compounds such as chlorobenzene and dichlorobenzene. To be The amount of the organic solvent used is 0 to 20 times (cc / g), preferably 0 to 5 times (cc / g), and particularly preferably 0 to PBZK.
~ 2 times (cc / g). Particularly when the solvent used is isopropyl alcohol, it is preferably 0 to 1 times (cc / g). Alcohols are produced as the reaction progresses,
It may or may not be distilled off at any time. The 7-hydroxyisoflavone produced will become supersaturated as the reaction progresses, though it may vary depending on the presence or absence of the reaction solvent, the type, and the amount, so the reaction temperature may be lowered or seed crystals may be added to prevent oversaturation. Then, crystals may be deposited at any time. If the reaction product is precipitated, the temperature may be raised to such an extent that the precipitate is not dissolved, because the reaction becomes difficult to proceed if it is cooled too much.

When the reaction of taking out the product is completed, excess orthoformate ester, excess base, organic solvent used as a reaction medium and the like may be distilled off under reduced pressure. In the reaction solution, alcohols such as isopropyl alcohol,
Add ethyl alcohol, methyl alcohol, especially methyl alcohol. The amount of alcohol is relative to PBZK
0.1 to 30 times (cc / g), preferably 0.5 to 3 times (cc / g), particularly preferably 0.7 to 1.5 times (cc
/ G) at 10 ° C. to reflux temperature, preferably 20 ° C. to reflux temperature, particularly preferably 30 ° C. to reflux temperature for 0.1 minutes to 10 days, preferably 10 minutes to 2 days, and more preferably 20. Minutes to 20 hours, particularly preferably 30 minutes to 10 hours
After sufficient stirring for a long time, the mixture is allowed to stand and the supernatant liquid is extracted or filtered. Isopropyl alcohol,
Since ethyl alcohol is present, a new alcohol
You may perform the said operation, without adding a tool. The temperature treatment conditions of the reaction liquid with alcohols will be specifically described below. It may be carried out at a low temperature with a low stirring speed, but it takes 10 to 30 under reflux because it takes time to extract the by-product.
For 10 minutes to 5 hours, preferably 30 minutes
Take from 3 minutes to 3 minutes. Then, the mixture is cooled to 10 to 50 ° C, preferably 30 to 40 ° C, and at the same temperature for 10 minutes to 3 days,
Preferably 30 minutes to 24 hours, particularly preferably 1 to
After stirring for 2 hours, the mixture is left standing and the supernatant liquid is extracted. Or,
Filter. The filter cake is washed with alcohol. The amount of cleaning alcohol is 0.1 to 5 relative to the raw material PBZK.
Times (cc / g), preferably 0.5 to 3 times (cc / g)
g).

(Purification Method) Next, the purification method of the second invention of the present application will be described. Examples of the alcohols that can be used in the purification method of the present invention include lower alcohols such as isopropyl alcohol, ethyl alcohol and methyl alcohol. Methyl alcohol is particularly preferable. These alcohols include ethyl acetate, butyl acetate, ethyl propionate, butyl propionate and other esters, acetone, methyl ethyl ketone, methyl isobutyl ketone and other ketones, acetonitrile and other nitriles, toluene, xylene and other aromatic compounds. You may mix and use hydrocarbon etc. A crude product of crude 7-hydroxyisoflavone obtained by reacting 2,4-dihydroxyphenylbenzyl ketone with an alkyl orthoformic acid ester in the presence of a base, or an undried product containing alcohols in a dry conversion of 7-
1 to 30 times (cc /
g), preferably 2 to 10 times (cc / g), particularly preferably 3 to 7 times (cc / g), and added under atmospheric pressure or pressure at 20 to 150 ° C, preferably 30 to 100 ° C.
Then, 0.1 minutes to 10 days, preferably 10 minutes to 2 days,
More preferably, the mixture is treated with stirring for 20 minutes to 20 hours and then 20 to
The solution is allowed to stand at 50 ° C, preferably 30 to 50 ° C, and the supernatant liquid is extracted or filtered. Next, the most optimal treatment conditions with the above alcohols will be described. 6 under normal pressure or under pressure
0 to 150 ° C., preferably 60 to 100 ° C. for 10 minutes
Stir for 10 hours, preferably 30 minutes to 5 hours, particularly preferably 1 to 3 hours, 10 minutes to 5 hours, preferably
20 to 50 ° C., preferably 3 to 30 minutes to 3 hours
Cool to 0-40 ° C. After stirring at the same temperature for 10 minutes to 3 days, preferably 30 minutes to 24 hours, and particularly preferably 1 to 2 hours, the mixture is left standing and the supernatant liquid is extracted. Alternatively, it is filtered at the same temperature. The filter cake is washed with alcohol. The amount of cleaning alcohols is 0.1 to 5 times (cc / g) with respect to the dry-converted 7-hydroxyisoflavone before purification,
It is preferably 0.5 to 3 times (cc / g). The purity of 7-hydroxyisoflavone can be easily measured by HPLC (high performance liquid chromatography).

[0009]

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

Example 1 In a 200 cc four-necked flask equipped with a stirrer, a thermometer, a calcium chloride tube, and a reflux condenser, 25 cc of isopropyl alcohol, 30 g (0.132 mol) of PBZK, and 30.8 g (0 0.162 mol) and 2.4 cc of morpholine,
Stirred for hours. Next, 30 cc of methanol was added, and the mixture was stirred under reflux for 30 minutes, cooled to 10 ° C over about 1 hour, stirred at the same temperature for 1 hour, and filtered under reduced pressure. Wash with 70 cc of methanol. Drying with hot air at 50 ° C., 28.3 g of 7-hydroxyisoflavone (yield 90.1%, melting point 215 ° C., HPL
C area purity (hereinafter the same) 99.6%) was obtained. When 7-isopropoxyiosoflavone was synthesized using the obtained 7-hydroxyisoflavone, HPLC purity was 9
The target product was obtained at 9.95%, and by-products derived from the raw materials could not be detected.

Example 2 In a 200 cc four-necked flask equipped with a stirrer, a thermometer, a calcium chloride tube, and a reflux condenser, 25 cc of isopropyl alcohol, 30 g (0.132 mol) of PBZK, and 17.2 g (0 .162 mol),
Morpholine 2.4 cc was added, and the mixture was reacted with stirring at 80 to 90 ° C. for 7 hours. Next, 30 cc of methanol was added, and the mixture was refluxed.
Stir for 30 minutes, cool to 35 ° C. over about 1 hour, stir at the same temperature for 2 hours, and then filter under reduced pressure. Wash with 70 cc of methanol. After drying with hot air at 50 ° C., 27.6 g of 7-hydroxyisoflavone (yield 87.9%, HPLC purity 99.6).
%, 7-methoxyisoflavone content 0.2%). When 7-isopropoxyiosoflavone was synthesized from the obtained 7-hydroxyisoflavone, HPLC
Purity 99.95%, 7-methoxyisoflavone 0.03
%was.

Example 3 In a 200 cc four-necked flask equipped with a stirrer, a thermometer, a calcium chloride tube, and a reflux condenser, 25 cc of isopropyl alcohol, 30 g (0.132 mol) of PBZK, and 30.8 g (0% of propyl orthoformic acid ester). 0.162 mol) and 2.4 cc of morpholine,
Stirred for hours. Next, 30 cc of methanol was added, and the mixture was stirred under reflux for 30 minutes, cooled to 40 ° C. over about 1 hour, stirred at the same temperature for 2 hours, and then filtered under reduced pressure. Wash with 70 cc of methanol. After drying with hot air at 50 ° C., 27.8 g of 7-hydroxyisoflavone (yield 88.5%, HPLC purity 99.4).
%, 7-propoxy isoflavone content 0.07%)
I got

Example 4 Production of 7-Hydroxyisoflavone Using Orthoformate Ethyl Ester In a 200 cc four-necked flask equipped with a stirrer, thermometer, calcium chloride tube, and reflux condenser, 25 cc of isopropyl alcohol and 30 g of PBZK (0. 132 mol), orthoformic acid ethyl ester 24 g (0.162 mol), and morpholine 2.4 cc were added, and the mixture was stirred at 80 to 90 ° C. for 7 hours. Next, 30 cc of methanol was added, and the mixture was stirred under reflux for 30 minutes, cooled to 40 ° C. over about 1 hour, stirred at the same temperature for 2 hours, and then filtered under reduced pressure. Wash with 70 cc of methanol. 50 ℃
Dried with hot air with 27.6 g of 7-hydroxyisoflavone
(Yield 87.9%, HPLC purity 99.6%, 7-ethoxyisoflavone content 0.2%). Purification method In a 300 cc four-necked flask equipped with a stirrer, a thermometer, and a reflux condenser, this 7-hydroxyisoflavone 27.6 was added.
g and 166 cc of methanol were added, and the mixture was stirred under reflux for 1 hour, cooled to 35 ° C. over 1 hour, stirred at the same temperature for 2 hours, filtered under reduced pressure, and the cake was washed with 50 cc of methanol. After drying in hot air at 50 ° C., 25.1 g of 7-hydroxyisoflavone (purification yield 91.0% by weight, HPLC purity 99.8%, 7-ethoxyisoflavone content 0.0
5% by weight) was obtained.

Example 5 When the reaction and purification were carried out in the same manner as in Example 4 except that 25 cc of ethanol was used in place of isopropyl alcohol in the production of 7-hydroxyisoflavone in Example 4, both yield and purity were obtained. Similar results to 4 are obtained.

Example 6 Except that a mixture of 10 cc of methanol and 15 cc of toluene was used in place of isopropyl alcohol in the preparation of 7-hydroxyisoflavone in Example 4,
When the reaction and purification are carried out in the same manner as in Example 4, the same results as in Example 4 are obtained in terms of yield and purity.

Example 7 Production of 7-Hydroxyisoflavone Using Orthoformate Ethyl Ester In a 200 cc 4-necked flask equipped with a stirrer, thermometer, calcium chloride tube, reflux condenser, 8 cc of isopropyl alcohol, 30 g of PBZK (0. 132 mol), ethyl orthoformate 24 g (0.162 mol), morpholine 17
cc was added, and the mixture was stirred at 80 to 90 ° C. for 3.5 hours. While distilling off the produced ethanol, raise the reaction temperature to 10
Keep at 5 ° C., react for 2 hours, then reduce pressure to 80-90
Excess morpholine was distilled off at ℃, then methanol 90
cc was added, and the mixture was stirred under reflux for 30 minutes, and after about 1 hour,
After cooling to 40 ° C. and stirring at the same temperature for 2 hours, vacuum filtration was performed. Wash with 70 cc of methanol. Drying with hot air at 50 ° C., 27.6 g of 7-hydroxyisoflavone (yield 87.9%, HP
LC purity was 99.6% and 7-ethoxy isoflavone content was 0.2%). Purification method In a 300 cc four-necked flask equipped with a stirrer, a thermometer, and a reflux condenser, this 7-hydroxyisoflavone 27.6 was added.
g and 166 cc of methanol were added, and the mixture was stirred under reflux for 1 hour, cooled to 40 ° C. over 1 hour, stirred at the same temperature for 2 hours, filtered under reduced pressure, and the cake was washed with 50 cc of methanol. After drying in hot air at 50 ° C., 25.1 g of 7-hydroxyisoflavone (purification yield 91.0% by weight, HPLC purity 99.8%, 7-ethoxyisoflavone content 0.0
5% by weight) was obtained.

[0017]

Industrial Applicability A process for producing high-purity 7-hydroxyisoflavone in a high yield has been established.

Claims (5)

[Claims] 1. A process for producing 7-hydroxyisoflavone, which comprises reacting 2,4-dihydroxyphenylbenzyl ketone with orthoformic acid methyl ester, orthoformic acid propyl ester or orthoformic acid isopropyl ester in the presence of a base. 2. The method for producing 7-hydroxyisoflavone according to claim 1, wherein the base is piperidine, morpholine or pyrrolidine. 3. The method for producing 7-hydroxyisoflavone according to claim 1, wherein an organic solvent is used as a reaction medium. 4. A 7-propoxy isoflavone, 7 present as a by-product in a crude 7-hydroxy isoflavone obtained by reacting 2,4-dihydroxyphenyl benzyl ketone with an alkyl orthoformate in the presence of a base.
-In the purification method for removing ethoxy isoflavone or 7-methoxy isoflavone, the mixture is heated and stirred with alcohols and then allowed to stand, and then the supernatant liquid is separated or filtered.
A method for purifying 7-hydroxyisoflavone, which is carried out in the range of 0 to 50 ° C. 5. The alcohol as claimed in claim 4, which is methanol.
Purification method as described.