JPS6044292B2 - Process for producing (L)-1-(4-hydroxyphenoxy)-2-hydroxy-3-isopropylamino-propane - Google Patents

Description

[Detailed description of the invention] The present invention is based on the formula It can be administered with

Pharmacological Tests The following compounds were tested and the pharmacological activity obtained for each was evaluated.

1 (L)-1-(4-hydroxyphenyl)-2-
Hydroxy-3-isopropylaminopropane hydrochloride (
Example 1 of the specification of the present application ■ (D)-1-(4-hydroxyphenyl)-2-hydroxy-3-isopropylaminopropane hydrochloride ■ (DL)-1-(4-hydroxyphenyl)-2-hydroxy-3- The isopropylaminopropane hydrochloride test method and results are described below.

A. Inotropic and chronotropic effects (stimulation of cardiac β-receptors) in the isolated atrium of a guinea pig (Grllneapig) 1. Test method The isolated right atrium of a spontaneously beating guinea pig and 2.
The heart rate (right atrium) and contraction width (left atrium) were continuously recorded in the isolated left atrium of Mole and Motu stimulated with a constant alternating current wave of 5 Hz (a). Equiaxial contraction under static tension of 5y).

50 mL of Krebs-Henseleit solution at 37C
A mixed gas of 95% oxygen and 5% monocarbon dioxide was passed through the organ bath containing the organ.

Compounds were added in portions and all dose-response curves were determined.

In another experiment, a beta-blocker (oxprenolol) 1
A dose-response curve of Compound 1 was determined in the presence of 0-6m0IIf (the β-blocker was added to the organ bath 3 minutes before the start of the measurement).

Results The maximum positive inotropic and chronotropic effects (efficacies) of the tested compounds were almost identical.

The contraction width is 10-13T1un (500-650T) on average.
n9), and the heart rate increased by an average of 59-73 beats/min (see Table 1). The three compounds are clearly different in terms of potency (EC5O = concentration required to reach half maximum efficacy).

Compound 1 is about 2 times more effective than Compound 1 and about 65 times more effective than Compound 2. In the presence of 10-6 moles of a beta-blocker (oxprenolol) (4 tests), the dose-response curve for compound ■ shifts to the right by about 300, and the EC5O for chronotropic effects is 1. .2×10-5
EC5O for m01 no e1 inotropic effect is 1.8×
10-5m011e, but efficacy was not affected (+64±6 doses/min, 12±1 garlic).

This clearly demonstrated that the mechanism of the positive inotropic and chronotropic effects of the racemate (compound ①) lies in the stimulation of cardiac β-1 receptors. Therefore, it is presumed that the effects of the optical isomers (compounds 1 and 2) are based on the same mechanism.

Toxicity 1 Substances and Methods Compounds 11■ and ■ were tested using TifMAGf mice and TifRAIf rats.

The average initial body weight is 19.8 for mice and 100 for f1 rats.
It was y.

Before starting the experiment, a constant room temperature of 22 ± 1°C and a relative humidity of 55 ±
Mice and rats were housed in a laboratory under conditions of 5.5% and 14 hours of light irradiation, and were habituated to the environment.

Animals were housed in groups of five in MacrOlOn cages and had access to standard pelleted food and drinking water at all times. Symptoms and mortality were recorded during a 15-day observation period after administration. LD5O was determined by probit analysis method (α匍Den A., MethOdsOfstat.
stica/Arlalysis. sJOhnWile
yandsOrlsll96O. s3rdprinti
nglpageS4O4~408). 2 Results Under the experimental conditions applied, compounds 11■ and ■ were slightly toxic.

Compound ■ is more toxic than compound 1 and compound ■, but
The latter two compounds were approximately equivalent in toxicity.

C. Conclusion From the results shown in Table 1, it can be said that Compound 1 is significantly superior to Compound ■ in terms of toxicity, considering that Compound 1 is twice as effective as Compound ■.

Furthermore, Compound 1 is tin times more effective than Compound (1) for each value in Table 1, and is also significantly superior to Compound (2) for each toxicity value. (L)-1-(4-hydroxyphenoxy)-2-hydroxy-3-(isopropylamino)-propane according to the invention is obtained by methods known per se.

Novel compounds can be obtained by reacting compounds of the formula with compounds of the formula.

In these formulas, one of the groups Y1 and Y2 is an amino group -NlI
2, the other is a reactively esterified hydroxyl group, and X1 is a hydroxyl group, or Y1 and X1
and Y form an epoxy group, and the absolute structure of this epoxide corresponds to (S) type 1, and Y
2 is a group -NH2. Reactively esterified hydroxyl groups are used in particular with strong inorganic or organic acids, especially hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, and also sulfuric acid or strong organic sulfonic acids such as benzenesulfonic acid, 4- It is a hydroxyl group esterified with a strong aromatic sulfonic acid such as bromobenzenesulfonic acid or 4-toluenesulfonic acid.

Incidentally, Y1 or Y2 is particularly a chlorine atom, a bromine atom or an iodine atom. The above reaction is carried out in a conventional manner.

When using reactive esters as starting materials, it is preferred to carry out the reaction in the presence of a basic condensing agent and/or with an excess of amine. Suitable basic condensing agents are, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as potassium carbonate,
and alkali metal alcoholates such as sodium methylate, potassium ethylate or potassium t-butylate. Furthermore, the novel compound is a compound represented by the formula (in which at least one of group A, Z2, and Z3 is a splittable group, and the remaining groups are hydrogen atoms). (or) 4
and/or obtained in the event of a division of Party B.

Such cleavable groups are in particular those which can be cleaved by solvolysis, reduction, thermal decomposition or fermentation.

Solvolytically cleavable groups are in particular groups which can be cleaved by hydrolysis, alcoholysis or acidolysis.

The hydrolytically cleavable group B is, for example, an acyl group, such as a carboxyl group that may be functionally modified (especially esterified), such as an alkoxycarbonyl group such as t-butoxycarbonyl group or ethoxycarbonyl group, or phenyl group. aralkoxycarbonyl groups such as lower alkoxycarbonyl groups, e.g. carbobenzoxy groups,
halogenocarbonyl groups such as chlorocarbonyl, as well as arylsulfonyl groups such as toluenesulfonyl and bromobenzenesulfonyl, and lower alkanoyl groups which may be halogenated (e.g. fluorinated) such as formyl, acetyl or a trifluoroacetyl group, or a benzoyl group, and a group which together with the oxygen atom in the formula forms an etherified hydroxyl group, such as a sugar group, such as a 1-aldopentosidyl group, or 1
-1-Aldohexisosidyl group such as glucopyranosidyl group, lower alkyl group such as methyl group or ethyl group, lower alkenyl group such as allyl group or methallyl group, or phenyl lower alkyl group such as benzyl group It is the basis.

4, which is a group that can be split by hydrolysis, is, for example, the group given to (B) above.

In this case, if 4 is an acyl group, 4 cannot be a hydrogen atom. 4 as a group that can be split by hydrolysis
is, for example, an acyl group as mentioned above, or a silyl group such as a cyano group or a trimethylsilyl group.

In addition to this, there are 2 other groups 4 that can be split by hydrolysis.
Also included are multiply bonded groups such as phosphoranylidene groups such as alkylidene groups, benzylidene groups or triphenylphosphoranylidene groups, in which case the nitrogen atom in the formula carries a positive charge. Compounds with groups which can be cleaved by hydrolysis may furthermore be used, for example, in which compounds are hydrogen atoms or have the meanings given above and Y is a carbonyl or thiocarbonyl group, or in particular aldehydes. There are also compounds represented by Y3, which is a divalent group formally obtained by substitution of a ketone with an oxo group.

Note that the ketone Y3=0 is, for example, a di-lower alkyl ketone such as methyl ethyl ketone or acetone. The aldehyde Y3,=0 is, for example, a lower alkanal such as acetaldehyde or formaldehyde, or furthermore benzaldehyde. The above hydrolysis is carried out in a conventional manner, for example in the presence of a hydrolyzing agent, such as an acidic agent such as sulfuric acid or a hydrohalic acid, an aqueous solution of an inorganic acid such as hydrochloric acid or hydrobromic acid, or an organic acid such as a suitable hydrolyzing agent. in the presence of carboxylic acids e.g. alpha-halogenoalkanoic acids such as trifluoroacetic acid or chloroacetic acid, organic sulfonic acids such as benzenesulfonic acid or toluenesulfonic acid, or acidic ion exchangers, or basic agents e.g. sodium hydroxide. It is carried out in the presence of an alkali metal hydroxide such as.

Oxycarbonyl groups, arylsulfonyl groups and cyano groups can be cleaved advantageously with acidic agents such as hydrohalic acid. Particularly suitable for this purpose is cleavage using aqueous hydrochloric acid (optionally mixed with acetic acid). moreover. For example, a t-butoxycarbonyl group can be cleaved by treatment with a suitable acid such as trifluoroacetic acid under anhydrous conditions. The bases and (or) 4 and (
or) B is, for example, an α-arylalkyl group such as a benzyl group, or an α-aralkoxycarbonyl group such as a benzyloxycarbonyl group, which is prepared by hydrogenolysis in a conventional manner, particularly by catalysis. can be split using activated hydrogen in the presence of hydrogenation catalysts such as palladium, sometimes sulfided, on carbon, or Raney nickel. .

Other groups that can be split by hydrogenolysis are, for example, 2, 2,
A 2-halogenalkoxycarbonyl group such as a 2-trichloroethoxycarbonyl group, a 2-iodoethoxycarbonyl group, or a 2.2●2-tribromoethoxycarbonyl group, which is particularly treated by metallic reduction (so-called nascent hydrogen). In this case, the nascent hydrogen is obtained by the action of a metal or a metal alloy such as an amalgam on a hydrogen generating agent such as a carboxylic acid, an alcohol or water, in particular a combination of zinc or a zinc alloy with acetic acid. can be mentioned. Furthermore, 2
- Hydrogenolysis of the halogenalkoxycarbonyl group can also be carried out using divalent chromium compounds such as divalent chromium chloride or acetate. There are also arylsulfonyl groups such as toluenesulfonyl groups as groups that can be cleaved by reduction. This can be split in a conventional manner using nascent hydrogen, for example using an alkali metal such as lithium or sodium in liquid ammonia.
In particular, it can be split from a single N atom. When carrying out this reduction, care must be taken that other reducible groups are not affected. In particular, in the reaction with catalytically activated hydrogen using the non-sulfurized hydrogenation catalysts mentioned above, low temperatures e.g.
It is best to operate at 25°C. B and/or Z2 and/or Z3 as thermally cleavable groups are, for example, optionally substituted carbamoyl groups, but in particular unsubstituted carbamoyl groups. Suitable substituents are, for example, lower alkyl groups such as the methyl group, aryl lower alkyl groups such as the benzyl group or aryl groups such as the phenyl group. This thermal decomposition is carried out in a conventional manner, but attention should be paid to other heat-sensitive groups. A and/or B and/or B as radicals which can be cleaved by fermentation are, for example, optionally substituted carbamoyl groups, but in particular unsubstituted carbamoyl groups.

Suitable substituents are, for example, lower alkyl groups such as the methyl group, aryl lower alkyl groups such as the benzyl group or aryl groups such as the phenyl group. The fermentation is carried out in a conventional manner, for example using the enzymes urease or soybean extract or glucosidase, at about 20° C. or slightly elevated temperatures. Furthermore, new compounds can be obtained by reducing the --C=N double bond in a compound in which the nitrogen atom in the new compound is bonded by a double bond to one of its substituents. That is, the ring tautomer corresponding to (■) represented by the formula can be reduced.

Note that the compounds of formulas (■) and (■) can also coexist. The reduction is carried out in a conventional manner using, for example, a dilight metal hydride such as sodium borohydride or lithium aluminum hydride, a hydride such as borane or formic acid.

It should be noted that a mild reducing agent, in particular an alkali metal boron hydride such as sodium borohydride or preferably sodium cyanoborohydride, is used and an inert solvent is used under mild conditions, e.g. at room temperature or at moderately elevated temperature. It is advantageous to work in alkanols, such as ethanol or methanol, in ethers, such as diethyl ether, tetrahydrofuran or dioxane, or in water. Depending on the reaction conditions and the raw materials, the final products are obtained in free form or in the form of their acid addition salts, which are also according to the invention.

For example, basic, neutral or mixed salts and optionally also their 112-hydrate, monohydrate, dihydrate or polyhydrate are obtained. The acid addition salts of these new compounds can be converted into the free compounds by methods known per se, for example using basic agents such as alkalis or ion exchangers. The free bases obtained also form salts with organic or inorganic acids. For the formation of acid addition salts, particularly those acids suitable for the formation of therapeutically acceptable salts are used. Examples of such acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
Nitric acid, or fatty acids, cycloaliphatic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid , pyruvic acid, benzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halogenobenzenesulfonic acid, toluenesulfonic acid, sulfanilic acid or Cyclohexylamine sulfonic acid. These salts or other salts of the novel compounds, such as picrate salts, can also be used for the purification of the free bases obtained by the process of the invention.

That is, the free base is converted into a salt, which is separated, and the base is liberated from the salt again. Because of the close relationship between the free forms of these new compounds and their salt forms, references herein to the free compounds also refer to the corresponding salts, where relevant and appropriate. I hope you understand that. The present invention starts from the compound obtained as an intermediate at any stage of the process and performs the remaining steps or interrupts the process at any stage or generates or reacts the raw materials under the reaction conditions. This also concerns embodiments in which the components are optionally present in the form of their salts.

That is, a compound in which X1 is a hydroxyl group and Y1 is a group -NH2 in formula (■) can be appropriately reacted with acetone in the presence of a suitable reducing agent as mentioned above.

In this case, compounds of the formula (■) or (■) are obtained as intermediates, which are reduced by the process of the invention. Some of the raw materials mentioned above are known, but new ones can be obtained by methods known per se.

For example, a compound of the formula (in which X1 has the meaning given above and is a group cleavable by solvolysis, reduction, thermal decomposition or fermentation) and a compound of the formula (in which X1 and Y1 have the meanings given above, but preferably both form an epoxy group, and A is a reactively esterified hydroxyl group, such as the hydroxyl group mentioned above. By reacting to form a compound of the formula and then further splitting the group 4 by the method described above, it can be determined that X1 in formula (■) is a hydroxyl group and Y1 is a reactively esterified hydroxyl group. Alternatively, a raw material compound in which both X1 and Y1 form an epoxy group can be obtained.

Also, compounds of the formula (in which O has the meaning given above and Y1 is a reactively esterified hydroxyl group) and the formula (in which 4 has the meaning given above) or a hydrogen atom) in a customary manner and then splitting the (L) unit from the racemate thus obtained, for example by one of the methods mentioned above,
A compound is obtained in which B in formula (■) is a cleavable group, 4 is a hydrogen atom, and Z3 is a hydrogen atom or a cleavable group.

Furthermore, compounds of formula (■) and formula (in which A is a reactively esterified hydrogen group and X1 is a hydroxyl group or A.l!:.X1 is an epoxy group in both or when 4 is a hydrogen atom, A can be a direct bond together with the hydrogen atom of the amino group in the formula) by a conventional method. It is also possible to obtain a compound in which 4 in formula (■) is a cleavable group, O is a hydrogen atom, and O is a hydrogen atom or a cleavable group.

Alternatively, a compound of formula (■) and a compound of the formula (in which Y has the meaning given above and A is a 7-reactively esterified hydroxyl group, such as the above-mentioned group) can be prepared by a conventional method. A compound in which 4 and Y in formula (■) have the meanings given above is produced by the reaction.

) Furthermore, for example, compounds of the formula (■) in which B is preferably a group cleavable by solvolysis, thermal decomposition or fermentation and have the corresponding meanings given above, and compounds of the formula or ( In these formulas, X1 is a hydroxyl group and A is a reactively esterified hydroxyl group, such as the groups mentioned above, or A and X1 together form an epoxy group. A group 4 that can be cleaved by solvolysis, thermal decomposition or fermentation after reaction by a conventional method.
Compounds of formula (■) or (■) are made by splitting, for example, by the methods described above.

Pharmaceutical preparations containing the new compounds according to the invention as medicaments, e.g. these compounds or their salts, e.g. in admixture with a pharmaceutical organic or inorganic solid or liquid carrier suitable for enteral administration, e.g. oral administration or parenteral administration. It can be used in the form of

Carriers include substances that do not react with these new compounds, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, benzyl alcohol, gum, polyalkylene glycol, petrolatum, cholesterin or other known pharmaceutical carriers. Can be mentioned. These pharmaceutical preparations can be, for example, in the form of tablets, dragees, capsules, suppositories, ointments, creams or liquids, as solutions (e.g. elixirs or syrups, suspensions or emulsions). may be sterilized and/or they may contain auxiliary agents such as preservatives, stabilizers, wetting agents, emulsifiers, salts or buffers to adjust the osmotic pressure.In addition, they may be subjected to other treatments. The preparations can also be used as veterinary medicine and they can be obtained by conventional methods. about 10-100 mgIp.0., preferably about 2
0-40mg1p. 0. It is.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 1- with a melting point of 157-160℃/186-18rC
6.0 q of diastereomer of [p-(β-D-glycopyranosidyloxy)-phenoxy]-3-isopropylamino-2-propanol is dissolved in 20 mt of sulfuric acid and heated to 80° C. for 3 hours.

The reaction mixture is cooled, made alkaline with concentrated ammonia, saturated with sodium chloride and extracted with ethyl acetate. The extract is dried with sodium sulfate and concentrated in an aspirator vacuum. The residue is crystallized from -acetate. Thus [α]r=-0
．． 9±0.5% (c=1.0% Ylv in methanol)
(-)-1-(4-hydroxyphenoxy-2-hydroxy-3-isopropylaminopropane 2.0 V) is obtained. Neutral fumarate salt prepared from this using fumaric acid is prepared from a mixture of methanol and ether. It crystallizes.The melting point is 210-211℃ and [α] 0=-21.
c=1.01% Ylv) in 5±0.5 ml. The raw materials necessary for this reaction are prepared as follows.

Hydroquinone-β-glucopyranoside 27.2V (a)
．． Dissolve 1 mole of potassium carbonate and 250 ml of epichlorohydrin in 1.01 ml of ethanol, and dissolve 6.9 f of potassium carbonate (0.05
mol) and heat under reflux for 6 hours.

The precipitate thus deposited is filtered off with suction. Concentrate the filtrate in an aspirator vacuum. Dissolve the residue in ethanol and filter. The filtrate is cooled and ether is added until it begins to become cloudy. The reaction product thus precipitated is filtered off with suction and washed with ether. The 4-(2,3-epoxypropoxy)-phenyl-β-D-glycopyranoside is thus dissolved. obtained as a mixture of two possible diastereomers. This diastereomeric mixture 25y is dissolved in 300 ml of methanol and isopropylamine 18
．． Add 5 g and heat under reflux for 6 hours. The reaction mixture is then completely evaporated. The residue is dissolved in 35 ml of water and a solution of 11.6 y of cyclohexylsulfamic acid in acetone is added. Add acetone to this solution until it becomes cloudy. The reaction product thus begins to crystallize. Leave at 0°C for 1 hour for complete crystallization. The precipitated crystals are separated by suction filtration and recrystallized from aqueous acetone. This is the diastereomer that requires no further treatment in Example 2. The mother liquors obtained in the above crystallization step were combined and concentrated in an aspirator vacuum to form a syrup, which was mixed with 50% water
Dissolve in m1.

Add this solution to Amperlite IRA-4008 (strongly basic ion exchanger with trimethylammonium groups, particle size 0).
．． Filter through a 200 ml column of 38-0.457077 mm. The column is washed with water until the free base is completely eluted from it. The aqueous eluate is completely evaporated in an aspirator vacuum and recrystallized three times from a mixture of methanol and isopropanol. Thus 1-[p-(
Another diastereomer of β-D-glucopyranosidyloxy)-phenoxy-3-isopropylamino-2-propanol (melting point 157-160°C/186-
189'C) is obtained. Example 2 Tablets containing 10 mg of active substance are manufactured in a conventional manner with the following composition.

Component Amount (M9) (-)-1-(4-hydroxyphenoxy)-2-hydroxy-3-isopropylaminopropane

10 wheat starch 60 lactose 50 colloidal silicic acid
5 talc
9 Magnesium stearate
1↓ 135 Preparation (-)-1-(4-hydroxyphenoxy)-12-hydroxy-3-isopropylaminopropane is mixed with a portion of wheat starch, lactose and colloidal silicic acid and the mixture is passed through a sieve.

Another portion of wheat starch is made into a paste with 5 times the amount of water on a water bath and this paste is mixed with the above powder mixture and kneaded until a soft mass forms. The soft mass is passed through a sieve with a mesh size of approximately 37 w1n, dried and the dry granules are passed through the sieve again.

This is mixed with the remaining wheat starch, talc and magnesium stearate and the mixture is compressed into slotted tablets weighing 135 m9. Example 3 (a) A 5% solution of 1.6y of 1-isopropylamino-5-hydroxy-3-(4-benzyloxy-phenoxy)-propane hydrochloride dissolved in 160ml of ethanol.
Hydrogenation is carried out under normal pressure in the presence of 0.2y of palladium on carbon.

After the calculated amount of hydrogen has been absorbed, the catalyst is filtered off and the filtrate is evaporated to dryness. The remaining amount is 45.6T of 0.1N Kasei sorter liquid! Dissolve in Ll and extract with ethyl acetate. After drying the organic phase with magnesium sulphate, it is evaporated and the residue is recrystallized from ethyl acetate. Thus, (L)-1-. (4-hydroxyphenoxy)-2-hydroxy-3-(isopropylamino)-propane is obtained. [α] Bas 0 = -1 no ±
1p, [α] = +2 + 1 [(methanol, c = 0.
940). Dissolve 0.7y of (L)-1-(4-hydroxy-phenoxy)-2-hydroxy-3-(isopropylamino)-propane thus obtained in 5wL1 of methanol, and add 9.1ml of a 4% methanol solution of fumaric acid.
Add. Add ether to the solution until cloudy and cool. The crystals thus formed are filtered off with suction and dried to yield (L)-1-(4-hydroxyphenoxy)-2-hydroxy-3-(isopropylamino)-propane 112 fumarate having a melting point of 209-211°C. [
α] milk 0 = -232 ± 1 les, [α] 偲 = -68 ± 1 [(
methanol, c=1.061). The above raw materials are made as follows.

A few drops of pyridine are mixed into a melt of 100 y of 5,6-anhydro-1,2-0-isopropylidene-α-D-glucofuranose and 100 y of hydroquinone-monobenzyl ether heated to 120°C, and at this time mixed with hot water. External cooling is used to maintain the internal temperature below 140°C.

When the exothermic reaction subsided, the reaction mixture was stirred at 140°C for an additional 3 min, then cooled to 80°C, and diluted with 500 mL of methanol.
1 and then add water until it starts to become cloudy. The crystals precipitated after being left at 0°C for several hours are filtered off with suction and recrystallized from methanol to give 1,210-isopropylidene-6-0-(4-benzyloxyphenyl) with a melting point of 99-102'C. )-α-D-glucofuranose is obtained.

R on silica gel thin layer plate, value = 0.25 (system:
15:1 mixture of methylene chloride and methanol).゛) 1.2 dissolved in 800ml of glacial acetic acid and heated to 70℃
-0-isopropylidene-6-0-(4-benzyloxyphenyl)-α-D-glucofuranose 127.3y
Add 500ml of water dropwise to the solution while stirring, and heat to 70°C.
Stir for a further 14 hours and then evaporate to dryness in an aspirator vacuum.

If the crystalline residue is recrystallized from glacial acetic acid 1', the melting point is 1
6-0-(4-benzyloxyphenyl)-D-glucose at 64-168°C is obtained. R on silica gel thin layer plate, value = 0.61 (methanol), [α] 0 = -62 value ± 1. (Methanol, c=0.985).
g) This 6-0-(4-benzyloxyphenyl)-D
- 36.2 y of glucose is suspended in a mixture of 600 ml of methanol, 10 ml of glacial acetic acid and 60 ml of water, to which sodium metaperiodate is added in small portions with external cooling and stirring, and at about 25°C So 2 (2
) Stir for a while.

The insoluble material is filtered off, the filtrate is evaporated to dryness, the residue is dissolved in chloroform, the solution is washed with water, dried over magnesium sulphate and the solvent is evaporated in an aspirator vacuum. The residue is dissolved in 150 ml of methanol and added dropwise into a solution cooled to -5 DEG C. of 3.8 y of sodium boron hydride dissolved in a mixture of 150 ml of methanol and 40 ml of water. After standing for an additional hour at about 25° C., the reaction mixture was evaporated to dryness, the residue was dissolved in chloroform and washed with ice-cold hydrochloric acid and water, and after drying over magnesium sulfate the solvent was removed in an aspirator vacuum. evaporates inside. If the residue is recrystallized from chloroform, 1-(4-benzyloxyphenoxy)-saturated 3-dihydroxypropane having a melting point of 134 to 138°C is obtained.

Rf value on silica gel thin layer plate = 0.32 (system:
15:1 mixture of methylene chloride and methanol). (
e) 1 dissolved in 20 ml of pyridine and cooled to -10°C
-(4-benzyloxyphenoxy)-? ● P-tosyl chloride 5.7 g pyridine 3 while stirring in a solution of 8.2 da 3-dihydroxypropane and avoiding moisture.
0 ml solution was added dropwise over 4 hours and about 250 ml of
Leave it alone for 1 second with C.

The reaction mixture is diluted with chloroform and water, the organic phase is separated and washed with ice-cold hydrochloric acid, water, saturated sodium bicarbonate solution and again water, dried over magnesium sulfate and freed from the solvent. 25 ml of silica gel
19 of methylene chloride and ethyl acetate on a 0q column:
1 and the product was purified by chromatography using a mixture of ethyl acetate and petroleum ether. Recrystallization from a mixture of 1-(4-benzyloxyphenoxy), ie, 1-hydroxy-3-p-tosyloxy-propane, having a melting point of 70 to 74°C, is obtained. R on silica gel thin layer plate, value = 0.36 (system: 19:1 mixture of methylene chloride and ethyl acetate), [α]? = 11 acids ±1
(chloroform, c=1.631). ethanol 40
A solution of 3.8 f of 1-(4-benzyloxyphenoxy) monohydro-hydroxy-3-p-tosyloxy-propane dissolved in a mixture of mt and 4 ml of isopropylamine is kept at 50 DEG C. for 30 hours and then evaporated to dryness.

The residue is dissolved in methylene chloride, the solution is washed with caustic soda solution and then with water, dried over magnesium sulfate and the solvent is evaporated. Thus 1-isopropylamino? -Hydroxy-3-(4-benzyloxyphenoxy)-propane is obtained. This is recrystallized from a mixture of methylene chloride and petroleum ether. Melting point is 9
1 to 93 C. This compound is dissolved in a small amount of ethanol, an alcoholic solution of hydrochloric acid is added until the pH is 4 and ether is added until it becomes cloudy.

Upon cooling, 1-isopropylamino-5-hydroxy-3-(4-benzyloxyphenoxy)-propane hydrochloride crystallizes. Filter this by suction and dry it. Melting point 161
~163℃, [α]? = -190, [α] Takashi = -573
±1 [(methanol, c=4.903). The present invention has been described in detail above, but the specific configuration of the present invention can be summarized as follows. 1) The method according to claim (a), wherein a hydroxyl group esterified with hydrohalic acid, sulfuric acid or sulfonic acid is used as the reactively esterified hydroxyl group.

2) A method according to the preceding claims, in which a group which can be cleaved by solvolysis, reduction, thermal decomposition or butyric fermentation is used as the cleavable group.

3) hydrolysis as a group cleavable by solvolysis;
A method according to any of the preceding claims and (2) above, using a group that is cleavable by alcoholysis or acidolysis.

(4) As a compound having a group that can be cleaved by hydrolysis, the formula (in this formula, B is a hydrogen atom or a group that can be cleaved by hydrolysis, and Y is a carbonyl group, a thiocarbonyl group, an aldehyde or Any of the above claim (b) and the preceding paragraph (2) or (3) using a compound represented by Y3, which is a divalent group Y3 obtained formally by substitution of a ketone with an oxo group. Method described in Crab.

5) Formula or a Schiff base represented by the formula or a ring tautomer corresponding to the formula (■) represented by the formula [Formula (■)
The method according to claim (c), wherein the compounds () and (■) may coexist.

(6) The remaining process steps are carried out starting from the compound obtained as an intermediate at any stage of the process, or the process is interrupted at any stage, or the raw materials are produced under the reaction conditions, or Process according to the preceding claims and any one of the preceding clauses (1) to (5), in which the reaction components are used optionally in the form of their salts.

(7) X1 in formula (■) is a hydroxyl group, and Y1
The method according to the preceding item (6), wherein a compound in which is a group -NH2 is reacted with acetone in the presence of a reducing agent to obtain a compound of formula (1).

]) A method according to the preceding claims and any of the preceding clauses (1) to (7) for making the new compound in free form.

J) A method according to the preceding claims and any one of the preceding clauses (1) to (7), in which the new compound is prepared in the form of its salt. 0 A process according to the preceding claims and any of the preceding clauses (1) to (7) and (9) for making the new compound in the form of its therapeutically useful salt.

Claims (1)

[Claims] Primary formula (I): (L) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (L)-1-(4-hydroxyphenoxy)- represented by (I)
A method for producing 2-hydroxy-3-(isopropylamino)propane and its salt, comprising (a) the following formula (II): (L
) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Compounds represented by (II) and formula (III): Y_2-OH(CH_3)_2(III) [In the above formula, one of the groups Y_1 and Y_2 is an amino group - N
H_2 and the other is a reactive esterified hydroxyl group; either X_1 is a hydroxyl group or Y_1 cooperates with X_1 to form an epoxy group, provided that in the latter case the absolute The configuration corresponds to the (S)-form; Y_2 is a group -NH_2]; or (b) the following formula (IV): (L)
▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the above formula,
At least one of the groups Z_1, Z_2 and Z_3 is a cleavable group, and the remaining groups are hydrogen atoms), in which the groups Z_1 and/or Z_3
_2 and (or) Z_3; or (c) a compound derived from the above novel compound (I), in which the nitrogen atom is bonded to one of its substituents through a double bond. in the compound, characterized in that this -C=N- double bond is reduced and, if desired, the free base obtained is converted into its salt, or the salt obtained is converted into the free base, A method for producing a compound represented by formula (I) and a salt thereof.