JPS6031831B2 - Method for producing 7-substituted-8-aminomethyl-isoflavone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 7-substituted-8-aminomethyl isoflavone complexes.

As is known, 7-alkoxy isoflavones can be used as animal feed additives due to their effect on metabolism.

(Hungarian Patent No. 162377). 7-Alkoxysoflavones are naturally occurring organic compounds with high biological activity, which play an important role in regulating cellular metabolism in animal bodies. When administered to living organisms, it confers significant vitamin-like activity. However, they are completely insoluble in water or aqueous media and only slightly soluble in organic solvents, which has hindered their practical application. The present invention is based on the general formula (1) (wherein R represents a C,-,8 alkyl group, and RI represents a C,
-4 alkyl group, and R2 represents a C, -4 hydroxyalkyl group or a picolyl group, or R
7-substituted-8-aminomethyl-isoflavone derivatives and their organic or concerning salts with inorganic acids.

In the above formula, R is preferably a methyl, ethyl, isopropyl or cetyl group.

The C,-,8 alkyl group may be linear or branched. A particularly preferred representative of a C,-4 hydroxyalkyl group is the hydroxyethyl group.

Advantageous representative examples of compounds having the general formula (1) are those in which R is methyl, isopropyl or cetyl;
represents a methyl group or a butyl group, R2 represents a Q-picolyl group, a Q-hydroxyethyl group, or an 8-hydroxyethyl group, or RI and R2 together with the adjacent nitrogen atom represent a morpholyl group, a pyrrolidino group, or or piveridino group.

The most advantageous examples of compounds having general formula (1) are as follows.

7-methoxy-8-(methyl-8-hydroxyethylamino)-methyl-isoflavone 7-methoxy-8-morpholinomethyl-isoflavone 7-isopropoxy-8
-Morlinomethyl-Isoflavone 7-Isopropoxy 8-(Methyl-8-Hydroxyethyl-amino)-Methyl-Isoflavone 7-Isopropoxy 8-Piveridinomethyl-Isoflavone 7-Isopropoxy 8-(n-
butyl-2'-/Q-picolyl/amino)-methyl-isoflavone 7-isopropoxy-8-pyrrolidinomethyl-isoflavone 7-cetyloxy-8-morpholy/methyl-isoflavone and salts of the above compounds.

As mentioned above, the compounds of general formula ql) form salts with organic or inorganic acids, among the salts are hydrochlorides, hydrosulfates, nicotinates, bi(bi)tartrates, citrates, There are gluconate and lactate.

Organic or inorganic acid addition salts of compounds having general formula (1) crystallize from aqueous solvents with water of crystallization.

The bound hydrochloride salt can give a 4 to 5% aqueous solution, and the salt with an organic acid can give a 0.5 to 1% aqueous solution. 5 to 1
More concentrated aqueous solutions can be obtained by adding 0% alcohol, glycerin or 4 to 5% glucose to the above solvents.

The compound of general formula (1) can be produced according to the present invention as follows.

a A compound having the general formula (0) (wherein R has the same meaning as defined above) is chloromethylated to obtain a compound having the general formula (0) (wherein R has the same meaning as defined above). , treated with a secondary amiso having the general formula (W) (wherein RI and R2 have the same meanings as defined above).

or b a compound having the general formula (m) (wherein R has the same meaning as defined above) and the general formula (W) (however,
RI and R2 each have the same meaning as above).

If desired, the resulting compounds of general formula (1) can be converted into acid addition salts with organic or inorganic acids. The starting material of general formula (0) is a known compound and is disclosed in Hungarian Patent No. 16237
7. In the first step of method a), 7-alkoxyisoflavones of general formula The chloromethylation is preferably carried out in the presence of a Lewis acid such as zinc chloride, aluminum chloride or stannous chloride. The reaction medium used is, for example, acetic acid or propionic acid.
to 100 degrees Celsius, preferably 85 to 95 degrees Celsius. Compounds of general formula (m) may be separated using known methods.

For example, the reaction mixture is concentrated and the product is precipitated with concentrated hydrochloric acid. A compound of general formula (2) can be reacted with a secondary amine of general formula (W) to give the desired final product of general formula (1).

As the amine agent of the general formula (W), preferably 8-methylaminoethanol, morpholine, piveridine, pyrrolidine or Q-n-butylamino-Q'-picoline can be used. The reaction is carried out at an elevated temperature, preferably at the boiling point of the reaction mixture. Preferably lower alkanols, such as methanol, ethanol or bupanol, or an excess of the amine of the general formula (W) can be used as reaction medium. The excess amount of amine also serves to scavenge hydrochloric acid liberated during the reaction. The resulting compounds of general formula (1) can be isolated by known methods.

The solvent is removed, preferably by pouring the mixture into water, and if necessary the product is precipitated from the residue. General formula (1)
The compounds can be converted into acid addition salts by known methods.

For example, it is reacted with a stoichiometric amount of a suitable acid in a solvent such as an alkanol such as methanol or ethanol. Compounds of general formula (1) can be used for the treatment of bone diseases.

Diseases of the heart and arms, such as those associated with hypoxia and hyperkapnia, such as corpulmonal
onale), Angina vectoris (angiMp
ec■ris), Emphisema (emp$ema), Pulmonary Ibrosis (Pyamamo female ry8brosi)
s), etc. It can also be used for the treatment of impaired blood supply. On the one hand, these compounds have a favorable influence on the processes of oxidative phosphorylation and energy conservation (oxygen sparing), and on the other hand, at the subcellular mitochondrial level they influence energy reinforcing transfer processes (calcium cycling and mineralization). do. 8-Aminomethyl derivatives significantly increase mitochondrial cytochrome C activity.

Compared to other 7-alkoxyisoflavone compounds, the new 8-aminomethyl derivatives of the present invention have the advantage of being water-soluble.

The compound of general formula (1) or its salt can be made into animal feed or feed additive containing it as an active ingredient.

To prepare these animal feeds or feed additives, the compound of general formula (1) or a salt thereof is added to the animal feed, or the compound of general formula (1) or a salt thereof is mixed with a suitable leapfrog or Mix with liquid carrier. The compounds of general formula (1) or their salts can also be used in pharmaceutical compositions containing them as active ingredients in admixture with inert carriers or liquid carriers, diluents and/or auxiliaries. .

These pharmaceutical compositions may be manufactured by methods well known in the pharmaceutical industry.

If desired, the compounds of general formula (1) can be mixed with other additives.

Additives such as bioactive substances such as vitamins,
Amino acids, choline chloride, inorganic acid salts, trace elements and other known biologically active substances may be used. Feed additives can generally be advantageously marketed in the form of premixes containing compounds of general formula (1) or their salts in admixture with other biologically active ingredients. Additionally, diluents, solvents, lubricants, carriers and formulation agents may be mixed with the active agent. Feed additives can be mixed with animal feed to form powders, powder mixtures, grains,
It can be made into a solution, emulsion, suspension, etc. General formula (1
) may also be mixed with the animal's drinking water. For use in human therapy, compounds of general formula (1) or salts thereof may be converted into pharmaceutical compositions.

Advantageously, they are used for oral administration, for example as tablets, coated tablets, powder mixtures, solutions, emulsions or suspensions. Pharmaceutical compositions which can be used for human therapy and dietary products may, in addition to the active ingredients having the general formula (1) or their salts, also contain other biologically active substances, primarily vitamins. Generally, the compounds of 1) or their salts are preferably formulated into tablets weighing from 100 to 200 o. These tablets may contain, in addition to the active ingredient, conventional excipients such as talc, starch, magnesium stearate, etc. The daily dosage will vary depending on the doctor's prescription and the patient's condition.

The biological effects of the compounds having general formula (1) are confirmed in the following tests.

Pharmaceutical and clinical studies show that 7-isopropoxy 8 at a dosage of 9/kg/day in 10
-When morpholinomethyl-isoflavone is orally administered to rats, it exhibits marked nitrogen crab properties.

In a swimming test after 45 days on male rats, animals show significantly increased swimming performance with daily oral administration of 9/k9 of Compound 5. The above compounds significantly reduce oxygen demand in resting rats.

In this study, animals are treated at a daily dose of 1 female/100 ta body weight for 4 weeks. The new compounds of the invention significantly increase calcium, phosphate and potassium retention.

Does not cause estrogen and androgen side effects. Does not affect the function of the thyroid gland and adrenal cortex. Administration of the new compounds of the invention increases the activity of the glycolytic oxygen system. It acts on NAD-dependent substrate oxidation, improving the efficiency of oxidation by having a stimulatory effect on feedback mechanisms that reduce the intensity of oxidation in the resting state or increase the intensity of oxidation in the activated state. Thus, it increases the energy-intensive expansion of the mitochondria and the droplet properties of Q-glycerophosphate. Increases the oxidative capacity of all substrates of the liver mitochondria.

The results show that the Warburg device can effectively increase the weight of livestock when mixed into animal feed at a rate of 2 quarts/quart.

Each 30 castrated male chickens are tested.

The test will continue for 35 days.

The test compound is mixed into the feed at a concentration of 2 quarts.
During the pre-treatment period (1 week) and 1 week after the start of the test, the animals are fed with feed, and thereafter fed with fattening feed.
The composition of these feeds is as follows. Feeding: Corn 60.0%, 45% soybean 20.0%, alfalfa powder 2%, 65% fish meal 10.0%, yeast 3.3%, calcium phosphate 0.6%, lime 23%, salt 0.3 %, Vitamin Premix 11.0%, Mineral Premix 1
0.5%.

Breeding feed: Corn 50.0%, wheat 14.9%, 45%
Soybean 12.5%, peanut grit 9.0%, alfalfa powder 20%, 65% fish meal 4.5%, meat meal (45%)
%) 3.0%, calcium phosphate 1.0%, lime 1.8
%, salt 0.3%, vitamin premix 00.5%, mineral premix 10.5%.

The composition of the vitamin premix used is as follows.

Vitamin Bremix 1 Vitamin Premix 0 Vitamin A 2000,0001U 1,200,0001○ Vitamin ○ 3400,0001U 300,00010 Vitamin E 4,0001U 2,0001U Vitamin K 3400
Phosphorus 400 increase vitamin B, 400 phosphorus 2002 several vitamin B
2800 Phosphorus 700 Vitamin B31,200 Phosphorus 2,00
0' Vitamin B6-400 Male 500Z Cubicumin B,
210 Foundation 4 items Niason 4,000 Female 5,000 Z Cucorin Chloride 100,000 Approximately 100,000 Yubatetracin 6,000 Female 4,000 Item Etquin Methyl-Quinoline 25,000 Item 25,000 Furazolidone 20
,000 Ardinone 25,00
The zero-use mineral premix has the following composition. Manganese 20.000 9 Iron 2.000 Female Zinc 8.000
Both feeds have the following guaranteed properties.

Dry matter weight 86%, starch equivalent 69.5k9/quart, crude protein 19.5%, digestible crude protein (calculated value) 1
7.1%. The compound to be detected is a powder obtained by milling.
Divide into stages and mix with feed.

First, a concentrate containing 100Q-like active ingredients is prepared.
Next, it is diluted to give a final active ingredient concentration of 2. After the second mixing step, the feed is analyzed to ensure that the active ingredients are evenly distributed. During the study, weights are taken weekly in a temperature and humidity controlled room.

The results of these tests are summarized in the following table.

Compound "A": 7-isopropoxy 8-morpholinomethyl-isoflavone nicotinate Compound "8": 7-isopropoxy 8-(methyl-8
-Hydroxyethylamino)-methyl-isoflavone nicotinate Compound "C": 7-Methoxy-8-(methyl-8-hydroxyethylamino)-methyl-isoflavone nicotinate This invention is further illustrated in the following non-limiting examples. Explain in detail.

Example 1 7-methoxy-8-chloromethyl-isoflavone24.
0 ml of paraformaldehyde is added to a suspension containing 50.4 ml of 7-toxyisoflavone in 500 cc of glacial acetic acid.

The mixture is heated to 90 degrees Celsius. 1.5 days of zinc chloride and 1
A mixture with 50 cc of concentrated hydrochloric acid is added to the above solution over a period of 2 hours, the mixture is heated for a further 2 hours at 90-99 C, the mixture is clarified and filtered over 1.09 charcoal powder.

The monkey solution was evaporated under reduced pressure to a final volume of 100 cc, 20 cc of concentrated hydrochloric acid was added to the residue, and the mixture was cooled in an ice bath.
The separated crystals are collected, washed with 80% acetic acid, and dried under reduced pressure.
The crude product 51.8 was reconsolidated from hot methanol. Jun 7
-Methoxy-8-chloromethyl-isoflavone is obtained.
Melting point 146 to 148 degrees C. Example 27 - Methoxy 81 (
Methyl-8-hydroxyethyl-amino)monomethyl-isoflavone 8 cc of 8-methylaminoethanol 15
．． 0 evening of 7-methoxy-8-chloromethyl-isoflavone is added to a suspension containing 150 cc of methanol and the mixture is boiled for 3 hours.

The resulting solution was poured into 450 cc of water to cool the aqueous mixture, and the separated product was washed with 20% aqueous methanol and dried. 15.2 hours of the title compound was obtained. melting point 72-7
4 vessels C (reconstituted with methanol). Example 3 7-Methoxy-8-morpholinomethyl-isoflavone and salt 35 cc of morpholine are added to a suspension containing 60.02 of 7-methoxy-8-chloromethyl-isoflavone in 600 cc of methanol and the mixture is stirred. Heat to boil.

Solids dissolve in 20 minutes. After boiling for 3 hours, add the slightly yellow solution to 2400 cc of water while stirring.

The mixture is cooled and the separated precipitate is collected, washed with 20% aqueous methanol and dried. 67.1 evening 7-methoxy-
Obtain 8-morpholinomethyl-isoflavone.

Melting point: 179 to 180 degrees C (recrystallized from methanol). 7
-Methoxy-8-morpholinomethyl-isoflavone hydrochloride 17.59 of 7-methoxy-8-morpholinomethyl-isoflavone is suspended in 160 cc of anhydrous methanol and heated to boiling with stirring.

A mixture of 5 cc of concentrated hydrochloric acid and 15 cc of methanol is added to the suspension to completely dissolve the solids.

After boiling for 15 minutes, the mixture was clarified with charcoal powder, passed hot, the passed liquid was diluted with 15 cc of benzene, 66% of the solvent was distilled off at atmospheric pressure, and the residue was heated to -10°C. Cool, separate the separated salt, wash with methanol, dry,
7-Methoxy-8-morpholinomethyl-isoflavone hydrochloride was obtained on 16.9 pm.

Melting point is 240 to 242 degrees Celsius. 7-Methoxy 8-Morpholy/Methyl-Isoflavone Nicotinate 140 7
-Methoxy 8-morpholinomethyl-isoflavone 1
A suspension containing 50 mg of nicotinic acid dissolved in 40 cc of hot anhydrous isopropanol in 15 cc of isopropanol is added to the solution.

Boil the slightly yellow solution for 15 minutes, cool and crystallize the product. The product was filtered at minus 10 degrees Celsius, washed with isopropanol, and dried to obtain 7-methoxy-8-morpholinomethyl-isoflavone-nicotinate for 18.3 days. Melting point 157 to 1 degree C (reconsolidated from 85% isopropanol). Example 4 7-Isof.

Ropoxy-8-chloromethyl-isoflavone 50.0 g of 7-isopropoxy isoflavone is dissolved in 560 cc of acetic acid with gentle heating.

To this solution was added 24 hours of paraformaldehyde, the mixture was heated to 90 degrees C, 1.5 hours of zinc chloride and 150 degrees C.
A mixture of cc of concentrated hydrochloric acid is added dropwise to the above mixture at 90 to 95 degrees C with constant stirring. The mixture was heated to 90 or 95 degrees Celsius for an additional hour, then clarified with charcoal, heated, and evaporated under reduced pressure to a final volume of 1
50 to 160 cc and 20 cc of concentrated hydrochloric acid are added to the residue and the mixture is cooled in an ice bath with stirring.
The separated crystals were collected and washed with 80% acetic acid to give 50.6 hours of the title compound. Melting point 125 to 12 mother rhombus C. Example 5 7-isopropoxy-8-morpholinomethyl-isoflavone and salt A mixture of 7-isopropoxy-8-chloromethyl-isoflavone, 164 cc of absolute alcohol and 20 cc of morpholine was heated to boiling point. ,
The resulting solution is boiled for 3 hours and poured very slowly into 700 cc of stirred water.

After cooling, the separated crystals are concentrated and washed with 20% aqueous alcohol. After drying, 37.7 hours of 7-isopropoxy-8-morpholinomethyl-isoflavone was obtained. melting point 12
6 to 12 motherhood C (recondensed from methanol).・7-isopropoxy-8-morpholinomethyl-isoflavone hydrochloride monohydrate 10.0 mL of 7-isopropoxy-8-morpholinomethyl-isoflavone was dissolved in 50 cc of hot anhydrous ethanol, and mixed with 28 cc of concentrated hydrochloric acid. Add a mixture with 10 cc of absolute alcohol.

After boiling for 0.5 hour, the mixture is clarified with activated charcoal and the liquid is cooled.

Remove the separated material and wash it with 96% alcohol. After drying for 10.1 days, 7-isopropoxy-8-morpholinomethyl-isoflavone hydrochloride monohydrate was obtained. Melting point 223-224C. 7-Isofurapoxy 8-morpholinomethyl-isoflavone hydrosulfate 1.45cc
A mixture of concentrated sulfuric acid (d=1.84) and 10 cc of methanol is added dropwise to a warm solution containing 10.0 m of 7-isobrapoxy-8-morpholinomethyl-isoflavone in 40 cc of methanol.

The mixture is boiled for 0.2 hours. During this time, the crystalline end product begins to separate. The mixture is stirred and cooled in an ice bath, and the separated crystals are collected. Wash with anhydrous methanol and dry at 60° C. to obtain 7-isopropoxy-8-morpholinomethyl-isoflavone hydrosphate. Melting point (195) -228 - 230 degrees C
. 7-isopropoxy-8-morpholinomethyl-isoflavone nicotinate 10.0 g of 7-isopropoxy-8-morpholinomethyl-isoflavone was dissolved in 40 cc of hot isopropanol, 35 g of nicotinic acid was dissolved in 10 c.
The suspension containing c in isopropanol is added to the solution.

The reaction mixture was boiled with 1 powder, added with activated carbon, and further boiled with 0.
Continue boiling for an hour. Temperature of monkey fluid at minus 10 degrees Celsius
Cool to , collect the precipitated crystals, wash with isopropanol,
Dry in a vacuum dessicator. 11.5 hours of 7-isopropoxymorpholinomethyl-isoflavone nicotinate was obtained.

Melting point 133-13 degrees C. 7-isopropoxy-8-morpholinomethyl-isoflavone is reconcentrated with 4 times the amount of 85% isopropanol.

The compound takes up 1 mole of water of crystallization. This cannot be removed even after drying in a desiccator. 7-isopropoxy-8-morpholinomethyl-isoflavone nicotinate 1
Obtain hydrate.

Melting point: 106℃) to 108℃. 7-isoproboxy8
-morpholinomethyl-isoflavone ditartrate hydrate 1
Dissolve 0.0 ml of 7-isobropoxy-8-morpholinomethyl isoflavone in 40 cc of hot isopropanol, stir this solution, and add 4.0 ml of tartaric acid to 10 cc of isopropanol. Add to the suspension.

A rapid crystallization of the final product begins after a few seconds. 1
After boiling for 5 minutes, the mixture is cooled, the crystals are filtered, washed with isopropanol and dried.

13. Obtain 7-isopropoxy-8-morpholinomethyl-isoflavone ditartrate hydrate on the third day.

Melting point 184 to 186 degrees C. 7-Isopropoxy 8-
Morpholinomethylisofurapon citrate hydrate 10
．． 0 ml of 7-isopropoxy-8-morpholinomethyl-isoflavone is dissolved in 50 cc of hot 85% isopropanol and a suspension containing 6.5 ml of citric acid in 15 cc of 85% isopropanol is added.

The clear solution obtained by boiling for 15 minutes is diluted with 10 cc of dry benzene, volatile components are distilled off under atmospheric pressure, and the remaining solution is clarified with charcoal powder and stirred with koji to initiate crystallization. .

The crystal-containing mixture is cooled on ice, and the crystals are filtered, washed with dry isopropanol, and dried to obtain 7-isopropoxy-8-morpholinomethyl-isoflavone citrate hydrate (14.1). Melting point 151-15 C. 7-isopropoxy 8-morpholinomethyl-isoflavone gluconate 10.0 ml of 7-isopropoxy 8-morpholinomethyl-isoflavone was dissolved in 50 cc of dry salt isopropanol and 10 cc of 50% gluconic acid. Add aqueous solution.

The mixture is 0. After boiling and concentrating the resulting solution, product separation begins. Cool the concentrate, collect the separated crystals, wash with ice-cold 85% isopropanol, and store at 60 degrees C.
After drying at 15.5 pm, snow-white crystalline 7-isopropoxy-8-morpholinomethyl-isofurapone gluconate was obtained. Melting point: 131 to 133 degrees C. Example 6 7-isopropoxy-8-(methyl-8-hydro).

A mixture of 20.0 g of 7-isopropoxy-8-chloromethyl-isoflavone, 16 cc of 8-methylamino/ethanol and 100 cc of absolute ethanol is refluxed for 6 hours.

The bright yellow solution is clarified with charcoal powder, filtered through a sieve, and the liquid is dried under reduced pressure. The remaining material of 31.0 mL is stirred with 31 cc of 50% aqueous acetone and the pH of the mixture is brought to 8 with concentrated hydrochloric acid.

Finally, cool to minus 10 degrees Celsius. The separated crystals are collected, washed with 50% aqueous acetone, and dried in a desiccator. 7-isopropoxy-8-(methyl-8-hydroxyethyl-amino)-monomethyl-isoflavone was obtained.

Melting point is 80 to 81 degrees C. 7 - Isopropoxy 81 (
Methyl-8-hydroxyethyl-amino)-methyl-isoflavone hydrochloride monohydrate 10.0 mg of 7-isopropoxy-8-chloromethyl-isoflavone was dissolved in 50 cc of absolute ethanol as in Example 5. The mixture is reacted with 8 cc of 8-methylaminoethanol.

The reaction mixture was evaporated to dryness, leaving a resinous residue of 15 ml, which was dissolved in 100 ml of hot 1N hydrochloric acid and salted out with 120 ml of sodium chloride to precipitate the product. The mixture is cooled, the separated crystals are removed, dried, and reconsolidated from twice the amount of methanol. 6.4 7-isopropoxy-8-(methyl-B-hydroxyethylamino)-
Obtain methyl isoflavone hydrochloride monohydrate.

The melting point is (78)-164-166 degrees C. 7-isopropoxy 8-(methyl-3-hydro.

30.0 g of 7-isopropoxy-8-(methyl-8-hydroxyethylamino)-methyl-isoflavone is dissolved in 90 cc of hot isopropanol.

10. Add a suspension of 2 ml of nicotinic acid in 32 cc of isopropanol.

After boiling for 15 minutes, the mixture was cooled to -10°C and stirred, and the separated crystals were collected, washed with isopropanol, dried in a vacuum dessicator, and dried at 26.0 pm at 7 pm.
-Isopropoxy-8-(methyl-3-hydroxyethylamino)-methyl-isoflavone nicotinate is obtained.

Melting point is 120 to 121 degrees Celsius. 7-isopropoxy-8
-(Methyl-8-hydroxyethylamino)monomethyl-isoflavone ditartrate hydrate 10.0 ml of 7-isopropoxy-8-(methyl-B-hydroxyethyl-amino)-methyl-isoflavone was heated to 40 cc. A suspension containing 4.1 ml of tartaric acid in 10 cc of isopropanol is added.

The mixture is boiled for 0.2 hours, during which time crystallization of the final product begins. After cooling, the crystals were collected, washed with isopropanol, dried, and 7-isopropoxy-8-(methyl-8-hydroxyethylamino)
- Obtain methyl isoflavone ditartrate hydrate. Melting point 134 to 136 degrees C. Example 7 7-isopropoxy-8-piveridinomethyl-isoflavone and its nicotinate A mixture of 10.0 ml of 7-isopropoxy-8-chloromethyl isoflavone, 50 cc of anhydrous ethanol and 10 cc of piverizine 6
After refluxing for a period of time, the solution is clarified with charcoal powder, and the liquor is cooled to -10°C.

The separated crystals were collected, washed with absolute ethanol, and dried at 60°C to obtain 7-isopropoxy-8-piveridinomethyl-isoflavone on September 06th. Melting point is 138 degrees C. 7-isopropoxy-8-piveridinomethyl-isoflavone nicotinate monohydrate
A suspension containing 1.3 g of nicotinic acid in 5 cc of 85% isopropanol, dissolved in hot isopropanol, is added after stirring the above solution.

0. After boiling for an hour, the mixture is cooled, and the separated crystals are washed with 85% isopropanol and dried in a desiccator.

4. Obtain 7-isopropoxy-8-piveridinomethyl-isoflavone nicotinate monohydrate.

Melting point: 1 degree C from paper. Example 8 7-isopropoxy-8-(n-butyl-2-Q-picolyl/-amino)-methyl-isoflavone hydrochloride 10.
7-isopropoxy-8-chloromethyl-isoflavone, 50 cc of absolute alcohol, and 6 cc of Q-n-
The mixture with butylamino-Q'-picoline is refluxed for 2 hours.

The mixture is clarified by hot charcoal treatment, filtered through a sieve, and the moat liquor is evaporated to dryness under reduced pressure. 16.7 ml of dendritic material is dissolved in 35 cc of acetone. The solution is made strongly acidic with concentrated hydrochloric acid and diluted with water to crystallize. After cooling, the crystals are filtered, washed with aqueous acetone, and dried in a vacuum desiccator. 8.6 hours of the title compound was obtained. Melting point: 108 to 110 degrees C (recrystallized from methanol). Example 9 7-isopropoxy-8-pyrrolidinomethyl-isoflavone and salt 5 cc of pyrrolidine were added at 10.0 tm.
Isopropoxy 8-chloromethyl-isoflavone and 5
Add to the suspension containing 0 cc of absolute ethanol.

The mixture is refluxed for 3 hours. The solids already melt at 50°C. This orange solution is clarified with charcoal powder, filtered through a sieve, and 100 cc of water is added to the warm solution. The product is divided as described in Example 5. 10. Obtain 7-isopropoxy-8-pyrrolidinomethyl-isoflavone for 5 days.

Melting point: 115°C to 116°C. 7-Isopropoxy 8
-pyrrolidinomethyl-isoflavone hydrochloride hydrate 25c
Add concentrated hydrochloric acid (d=1.19) to 10 cc of anhydrous ethyl
7-isopropoxy-8-
Add pyrrolidinomethyl-isoflavone to a warm solution containing 38 cc of absolute ethanol.

The resulting mixture is boiled for 0.2 hours. The cooled and separated crystals are separated as described in the second paragraph of Example 5. 10. Obtain 7-isopropoxy-8-pyrrolidinomethyl-isoflavone hydrochloride hydrate at 25 o'clock.

Melting point is 218 to 220 degrees Celsius. 7-Isopropoxy 8
-pyrrolidinomethyl-isoflavone nicotinate 10.
Dissolve 7-isopropoxy-8-pyrrolidi/methyl-isoflavone from 09 in 30 cc of warm dry isopropanol, and add a suspension containing 3.4 mol of nicotinic acid in 10 cc of dry isopropanol. do.

The reaction mixture is boiled for 15 minutes and processed as described in Example 5, paragraph 4. 12. Obtain 7-isobropoxy-8-pyrrolidinomethyl-isoflavone nicotinate at 60 o'clock.

Melting point 156 to 1 degree C. 7-isopropoxy-8-pyrrolidinomethyl-isoflavone ditartrate hydrate 4.0
40 cc of 7-isopropoxy-8-pyrrolidinomethyl isoflavone was added to a suspension of 10.0 ml of tartaric acid in 10 cc of 85% isopropanol while stirring.
Add to a hot solution containing isopropyl alcohol.

The crystals immediately begin to separate. 0. After boiling for a while, the mixture was cooled, the crystals were collected, washed with cold 85% isopropanol, dried at 60°C under atmospheric pressure, and washed with 7-isopropoxy-8-pyrrolidinomethyl at 14.30 pm. Obtain isoflavone ditartrate hydrate.

The melting point is 166°C to 168°C. Example 107-Cetyloxy-8-chloromethyl-isofurapone 23.0 7-
Cetyloxyisoflavone and 6.09 paraformaldehyde are dissolved in 460 cc of hot acetic acid.

A mixture of 0.4 ml of zinc chloride and 40 cc of concentrated hydrochloric acid,
Add to the above solution within 2 hours at 90 to 95 degrees Celsius.

The mixture is stirred for an additional 2 hours at 90-95 degrees Celsius.
The mixture is clarified with activated carbon, hot-drained and the flow is cooled. The resulting shiny globules have a fat-like feel.
The sample is drained, washed with 80% acetic acid, and dried in a vacuum dessicator. 19.0 mL of the title compound was obtained. Melting point is 85 to 8
6 degrees C (recondensed from absolute alcohol). Example 11 7-Cetyloxy-8-morpholinomethyl-isoflavone and its salts 15. A mixture of 7-cetyloxy-8-chloromethyl-isoflavone, 50 cc of absolute ethanol and 10 cc of morpholine is refluxed for 6 hours.

Solids dissolve slowly. The red solution was clarified with hot charcoal powder, and the Sarugashi solution was cooled and then placed in an ice-salt bath. Collect the separated crystals, wash with absolute ethanol, and dry in a vacuum desiccator. 15.5 minutes of 7-cetyloxy-8-morpholinomethyl-isoflavone was obtained. The melting point is 93 C) and 94 C. 7-cetyloxy-8-morpholinomethyl-isoflavone hydrochloride lcc of a mixture of concentrated hydrochloric acid and 3 cc of absolute alcohol was prepared by adding 11.0 minutes of 7-cetyloxy-8-morpholinomethyl-isoflavone to 20 cc of absolute alcohol. Add to hot solution.

The clear solution is boiled for 0.25 hours and then cooled. Collect the separated salt, wash with 96% alcohol, dry, and 6.
7-cetyloxy-8-morpholinomethyl-isoflavone hydrochloride was obtained for 3 nights. The melting point is (151)-187-1
89 degrees C. 7-cetyloxy-8-morpholinomethyl-isoflavone nicotinate 1.3 g of nicotinic acid 5 c
The suspension of 7-cetyloxy-8-morpholinomethyl-isoflavone in 2.8 cc of isopropanol was added to the hot solution of 7-cetyloxy-8-morpholinomethyl-isoflavone in 2.8 cc of isopropanol, and the mixture was boiled for 0.2 hr. do.

The mixture is cooled, immersed in ice cubes, and the separated crystals are collected.
Wash with isopropanol and dry under vacuum. 4.8 evening 7
-Cetyloxy-8-morpholinomethyl-isoflavone nicotinate is obtained.

Claims (2)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R represents a C_1_-_1_8 alkyl group, R_1 represents a C_1_-_4 alkyl group, and R_2 represents a C_1_-_4 alkyl group
_1_-_4 represents a hydroxyalkyl group or a picolyl group, or R^1 and R^2 may together with adjacent nitrogen atoms constitute a piperidine group, a morpholino group or a pyrrolidino group] A method for producing compounds or their salts, in which a compound having the general formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R^1 and R^2 each have the meanings defined above), and if desired, the resulting general formula (I) A method characterized in that any compound is converted into a salt by reacting with an organic or inorganic acid. (2) General formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R represents a C_1_-_1_8 alkyl group, R^1 represents a C_1_-_4 alkyl group, and R^2 represents a C
_1_-_4 represents a hydroxyalkyl group or a picolyl group, or R^1 and R^2 may together with adjacent nitrogen atoms constitute a piperidino group, a morpholino group or a pyrrolidino group] A method for producing compounds or their salts, which comprises preparing a compound having the general formula (II) ▲Mathematical formula, chemical formula, table, etc.▼ (in the formula, R has the meaning as defined above) in an acetic acid or propionic acid medium. Chloromethylation with formadehyde and concentrated hydrochloric acid gave the general formula (III
) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R in the formula has the meaning as defined above) Compounds having the general formula (IV) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (R^1 in the formula) and R^2 each have the meaning as defined above) and, if desired, the resulting compound of general formula (I) is reacted with an organic or inorganic acid to form a salt. A method characterized by converting.