JPH0797373A - Cyclic intermediate for producing phenol ether - Google Patents

Abstract

PURPOSE: To provide a compound useful as a cyclic intermediate for producing a beta xysorol useful as a control agent for the function of β-adrenaline.

CONSTITUTION: A targeted compound having a structure represented by formula I, [wherein R is 3-4C branched alkyl or 3-4C cycloalkyl; and R₁ is (substituted) aryl or 2-11C alkyl], preferably a compound having a structure represented by formula II. The targeted compound can be obtained, for example, by converting a p-hydroxy phenethyl alcohol to a phenoxide anion thereof by a base, reacting with an epihalohydrin, then reacting with a primary amine R.NH₂, and reacting with an appropriate aldehyde.

COPYRIGHT: (C)1995,JPO

Description

Detailed Description of the Invention

[0001]

The present invention relates to the synthesis of organic chemistry, in particular to the synthesis of pharmaceutical compounds, and more particularly to oxazolidinephenol alcohol compounds as cyclic intermediates for the production of phenol ethers.

[0002]

BACKGROUND OF THE INVENTION The compound 1- [4- [2- (cyclopropylmethoxy) -ethyl] phenoxy] -3-[(1-methylethyl) amino] -2-propanol is hereinafter referred to as betaxolol. , In recent years in the use of drugs in human and veterinary therapy, in the field of cardiovascular,
Mainly introduced as β-adrenergic inhibitor,
Proposed. It has the chemical formula:

[Chemical 3] It is represented by.

Including betaxolol, it has the following general formula I:

[Chemical 4] (Wherein m represents an integer of 2 to 5, n represents an integer of 1 to 4, and R represents 3 or 4 carbon atoms).
Represents a branched alkyl group or a cycloalkyl group having 3 or 4 carbon atoms. ), Its racemic and optically active forms, as well as the pharmaceutically acceptable acid addition salts thereof, are described in Canadian Patent No.
No. 2,981 in Synthelabo, along with its method of manufacture.

The conventional synthesis technique for betaxolol is
formula:

[Chemical 5] Starting from the readily available reagent p-hydroxyphenethyl alcohol and being converted to the hydrochloride salt of betaxolol by a 5-step sequential synthesis. The more acidic phenolic hydroxyl groups are chemically sequestered at the benzylic moiety by reaction of, for example, phenoxide with benzyl chloride. In the second step,
The hydroxyethyl group is subsequently etherified by reaction with cyclopropylcarbinyl halide to give the desired form for the final product at this position. The phenol position is then deprotected by hydrogenolysis and the phenol position is re-etherified with epihalohydrin to give the formula:

[Chemical 6] A compound represented by The fourth step product is then reacted with 2-aminopropane to give the betaxolol salt. Therefore, two of the five steps in the synthesis are protection and deprotection of the phenolic hydroxyl group. Each is a separate and necessary step.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel oxazolidinephenol alcohol compounds which can be used as intermediates in the synthesis of betaxolol and similar compounds.

[0006]

Clearly, the present invention provides a compound of the general formula III:

[Chemical 7] (In the formula, R represents a branched alkyl group having 3 or 4 carbon atoms or a cycloalkyl group having 3 or 4 carbon atoms, and R ¹ is an aryl group, a substituted aryl group, a direct alkyl group having 2 to 11 carbon atoms. A chain or branched alkyl group is represented by the formula (1), which relates to an oxazolidinephenol alcohol compound.

Particularly preferred oxazolidinephenol alcohol compounds according to the present invention have the formula:

[Chemical 8] It has a structure represented by.

According to the present invention, betaxolol and its analogues can be prepared by a novel process by using the oxazolidinephenol alcohol compound of formula III as an intermediate. The adoption of this new process has the advantage of avoiding the expensive and potentially dangerous hydrocracking and reducing the number of synthesis steps in the above-mentioned conventional method for producing betaxolol and the like.

The general process for producing betaxolol and its analogues using the oxazolidinephenol alcohol compound of the present invention will be described below. First, p-
Hydroxyphenethyl alcohol is synthesized at its phenolic end. The primary alcohol group does not require protection during the synthesis of the phenolic end, as the phenolic group is much more reactive than the primary alcohol group. First, p
-Hydroxyphenethyl alcohol is converted with a base to its phenoxide anion, which is then reacted with epihalohydrin to form a compound of formula I. Therefore,

[Chemical 9] (In the formula, X represents a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom.).

Next, the compound represented by the formula I is converted to a primary amine R.NH ₂ (wherein R is a branched alkyl group having 3 or 4 carbon atoms or a cycloalkyl group having 3 or 4 carbon atoms). Represents a compound of formula II. Therefore,

[Chemical 10] The fact that intermediate I does not need to be isolated or purified is an important advantageous feature of the production process using the intermediate of the present invention. It is only necessary to filter the inorganic by-products, remove the solvent and excess alkylating agent and proceed to make intermediate II in the same reaction vessel.

Now, to complete the synthesis of compound II to the desired phenol ether base, the secondary alcohol-amine group must be protected until the primary alcohol is properly etherified. . According to the present invention, this synthesis is accomplished by the reaction of compound II with a suitable aldehyde to give a compound of general formula III below. Therefore,

[Chemical 11] Where R has the meaning given above and R ¹
Represents an aryl group, a substituted aryl group or a linear or branched alkyl group having 2 to 11 carbon atoms. ) It is not necessary to isolate the compound II before the reaction to form the intermediate III, so that the reaction can again proceed in the same reaction vessel, after simple removal of the solvent. The resulting oxazolidine ring provides a stable but easily removable protecting group for the secondary alcohol-amine groups required in the final molecule, while the primary alcohol functionality is worked up to the desired final. Produces a product.

The primary alcohol group is then suitably etherified with, for example, a base and a cycloalkylcarbinyl halide to form a protected phenol ether compound of formula IV. Therefore,

[Chemical 12]

[Chemical 13]

Thereafter, in a final step, compound IV is subjected to acid hydrolysis to act to deprotect and produce the final phenol ether base. This acid hydrolysis step can be carried out as a separation step, but is preferably carried out near the completion of the work of the previous esterification step.

The production process using the intermediates according to the invention can thus avoid the undesired hydrogenolysis in the conventional production process, with the attendant risks and inconveniences. The process described above provides a process scheme that reduces the total number of synthetic steps to 4 (when deprotection occurs near the completion of the etherification of the primary alcohol). Since it is not necessary to isolate and purify intermediates I, II, III and possibly IV, the steps can be carried out in rapid succession in sequence. In the case of the preparation of at least intermediates I, II, III and IV, the solvent and the reaction products dissolved therein are removed, possibly excess reagents are removed by distillation from higher boiling solvents, and The reaction mixture then simply needs to be filtered, as it is taken directly to the next stage of the process. Therefore, from a practical point of view,
Process. The first step is a multi-step preparation of intermediate IV from p-hydroxyphenethyl alcohol, and the second step is the preparation and recovery of betaxolol or its analogues. Moreover, all steps provide high yields of the desired product.

In the first step of the process, p-hydroxyphenethyl is first used in a suitable solvent with a base.
Converts alcohol to its phenoxide anion. As the base, the most preferable one can be selected from various inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydride and potassium hydride. Specific examples of suitable solvents include acetonitrile, lower aliphatic alcohols (straight or branched chain), acetone, 2-butanone,
Tetrahydrofuran, dimethylformamide, dimethyl sulfoxide benzene, toluene and the like are included. The reaction is suitably carried out under reflux. When the reaction is complete, the mixture is cooled, filtered and excess solvent distilled off. Intermediate I is formed as a white solid.

In the second step of the process, intermediate I
Is reacted with the primary amine R.NH ₂ . The choice of the group R is
Determined by desired end product. When R represents an isopropyl group and the amine reactant represents isopropylamine, it is a more preferred case for the preparation of betaxolol. The process may be carried out without other solvents, Reactant I is dissolved in isopropylamine and the reaction is suitably carried out under reflux. At the end of this step of the process, all residual amine is removed from the mixture to minimize side reactions in successive steps of the process, for example by dissolving the compound in warm toluene and removing it under reduced pressure. Is the best.

Compounds and intermediates having an oxazolidine ring
Intermediate II is protected by reaction with the appropriate aldehyde to form III. Oxazolidine formation is a reversible reaction that requires the removal of water to complete the reaction. Therefore, preferred alderdos have the general formula R ¹ --CH
And O (in the formula, R ¹ represents an aryl group, a substituted aryl group or a linear or branched alkyl group having 2 to 11 carbon atoms). Preferred are a phenyl group, a lower alkyl-substituted phenyl group and a linear alkyl group having 4 to 8 carbon atoms. Most preferred is benzaldehyde, that is, ^{one in} which R ¹ represents a phenyl group because of reaction efficiency and ready availability. The reaction with benzaldehyde is clean, efficient, relatively fast and gives an intermediate with satisfactory stability, but in practice can be easily reversed under suitable conditions. It is a thing. The reaction is preferably carried out under reflux in the presence of an inert solvent such as benzene or toluene and using a small molar excess (eg 10-25%) of benzaldehyde. Although a large excess of benzaldehyde leads to a faster termination of the reaction, it tends to cause greater problems with the subsequent removal of excess benzaldehyde. Therefore, the intermediate III produced does not need to be isolated and purified. At the end of the reaction, the reaction mixture can simply be distilled off under reduced pressure and suctioned by a vacuum pump in order to remove excess benzaldehyde.

Intermediates for the synthesis of primary alcohol chains
Conversion of III requires operation under basic conditions. Thus a base, such as lithium hydride, potassium hydride, or sodium hydride or potassium t- butoxide was added, followed by the formula X- (CH ₂₎ -
Add the appropriate compound represented by CH (CH ₂ ) _m and solvent. When the desired product is betaxolol,
The reagent is cyclopropylcarbinyl halide (preferably chloride). The preferred solvent is selected from dimethyl sulfoxide, dimethylformamide, N-methyl-2-pyrrolidinone, glyme, tetrahydrofuran and the like. Most preferred are polar, aprotic solvents. The reaction proceeds satisfactorily at room temperature. Product, intermediate
IV may be isolated, for example, by pouring the reaction mixture into water, extracting with toluene, drying and evaporating, but such isolation is not essential.

Finally, intermediate IV is subjected to acid hydrolysis to release protection and the following general formula

[Chemical 14] To form a final product, such as betaxolol. This can be achieved by treatment with a suitable water-soluble inorganic or organic acid with a cosolvent such as isopropanol. The product may be isolated and purified according to conventional procedures.

[0020]

The present invention is further detailed by the following non-limiting examples. -Example-

Procedure 1 1- [4- (2-hydroxyethyl) phenoxy]-
2,3-epoxypropane 30.0 g of p-hydroxyphenethyl alcohol,
60 g of anhydrous potassium carbonate and 50.28 g of epichlorohydrin were heated to reflux in 250 ml of acetonitrile for 5 hours. After cooling, filtration and removal of the acetonitrile under reduced pressure, 300 ml of toluene are added and the toluene is removed under reduced pressure. The residual oil solidifies on standing and is used directly in the next step. Yield = 43.2 g, yield 1
00%. This solid, after recrystallization in water, was 56-58.
It has a melting point of 5 ° C.

Procedure 2 1- [4-[(2-hydroxyethyl)] phenoxy]
-3 [(1-methylethyl) amine] -2-propanol 10 g of 1- [4- (2-hydroxyethyl) phenoxy] -2,3-epoxypropane produced in step 1 in 50 ml of isopropylamine The mixture was heated at reflux for 16 hours. The amine is removed under reduced pressure, the residue is dissolved in warm toluene and the toluene is removed under reduced pressure. This oil solidifies on standing. Yield = 12.8 g 198
%). After recrystallization in petroleum ether, the solid is 77
It has a melting point of -78 ° C.

Procedure 3 2-Phenyl-3-isopropyl-5- [4- (2-hydroxyethyl) phenoxy] methyl] oxazolidine 26.2 g of 1- [4- (2-hydroxyethyl) phenoxy] from Procedure 2. -3-[(1-Methylethyl) amino] -2-propanol, 12.96 g of benzaldehyde and 200 ml of toluene are heated under reflux for 24 hours while azeotropically removing water. During the last hour of reflux, the solvent volume was reduced to 50 ml and the remaining solvent was removed under reduced pressure. Yield = 33.75 g (96% yellow oil).

Step 4 2-Phenyl-3-isopropyl-5-[[4- [2-
Cyclopropylmethoxy) ethyl] phenoxy] methyl] oxazolidine 2.0 g of 2-phenyl-3-isopropyl-5- [4-[(2-hydroxyethyl) phenoxy] methyl] oxazolidine from step 3 in 15 ml DMSO. Dissolves and contains 0.78 g of t-BuO ⁻ K ⁺ 15
ml DMSO was added. The solution was stirred for 1/2 hour and 0.64 g of chloromethylcyclopropane was added. 1
After stirring for 6 hours, a further 0.20 g of chloromethylcyclopropane and 0.33 g of t-BuO ^- K ⁺ are added and continuously stirred for 16 hours, with a final increment of 0.10 g of t-.
BuO ^- K ⁺ was added and stirred continuously for 8 hours. The reaction mixture is put into 150 ml of water to quench and 20 ml
The product was extracted twice with 1 part of toluene. Removal of the solvent under reduced pressure gave 2.25 g of a yellow oil. The yield is 96% of theory.

Procedure 5 1- [4- [2- (cyclopropylmethoxy) ethyl]
Phenoxy] -3-[(1-methylethyl) amino]-
2-Propanol 2.25 g of 2-phenyl-3-isopropyl-5-[[4- [2- (cyclopropylmethoxy) from Step 4]
10 ml of ethyl] phenoxy] methyl] oxazolidine
Dissolved in a mixture of isopropanol and 10 ml of 5% aqueous hydrochloric acid. The mixture was stirred at room temperature for 16 hours. Isopropanol is removed under reduced pressure and 30 ml of 1% hydrochloric acid is added. The aqueous phase was washed with 15 ml of toluene, then made basic and extracted twice with 10 ml of toluene. After removal of the solvent under reduced pressure, 1.3 g of white solid was obtained (crude yield of betaxolol base 74%). Betaxolol base was converted to its hydrochloride salt by dissolution in toluene and treatment with 1 equivalent of hydrochloric acid in isopropanol. Removal of isopropanol under reduced pressure and cooling of the toluene solution gave the betaxolol hydrochloride. 2% of this solid from acetone, 4 ml / g
The second time, when recrystallized with activated carbon treatment,
This gives a white crystalline solid with a melting point of 1.5-112.5 ° C.

 ─────────────────────────────────────────────────── ———————————————————————————————————————— Inventor Stephen Vigmond Canada M4V2G9, Ontario, Toronto, Avenue Road 291, Apartment 701

Claims (2)

[Claims] 1. A compound represented by the general formula III: (In the formula, R represents a branched alkyl group having 3 or 4 carbon atoms or a cycloalkyl group having 3 or 4 carbon atoms, and R ¹ is an aryl group, a substituted aryl group, a direct alkyl group having 2 to 11 carbon atoms. An oxazolidinephenol alcohol compound having a structure represented by a chain or a branched alkyl group.). 2. The formula: The oxazolidinephenol alcohol compound according to claim 1, which has a structure represented by: