JPS6338979B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula () (In the formula, A represents a perhalogenated lower alkylcarbonyloxy group, a lower alkylsulfonyloxy group, a lower alkyl-substituted phenylsulfonyloxy group, or an azido group) and a method for producing the same. The present invention also describes the above compounds as useful therapeutic agents.
(2,6-dimethylphenoxy)-2-amino-
It also concerns how to convert it to propane.

The novel compounds of the general formula () have useful biological activity and are also compounds used in the treatment of ventricular arrhythmias, 1-(2,6-dimethylphenoxy)-2
-Can be used as an important intermediate in the synthesis of amino-propane hydrochloride (Mexiletine).

As is well known, mexiletine base and its pharmaceutically acceptable acid addition salts exhibit beneficial effects in ventricular arrhythmia conditions and in ischemic heart disorders,
It can be applied particularly advantageously to the treatment of myocardial infarction, ventricular fibrillation and tachycardia ("Brit.Heart J." 35 , 558, 559
(1973); “Lancet” 1973/ , 339―403, 404―
407; "Brit.J.Clin.Pharmacol." 1 , 86-87, 229
-232 (1974)).

The anti-fibrillant effect of 1-(2,6-dimethylphenoxy)-2-azido-propane (in formula (), A = azide) is [B. Vargrafting
and JDCoignet (“Eur.J.of Pharmacol.” 6, 49
-55 (1969)) ED ₅₀ =
The effect is substantially the same as that of mexiletine at 150 mg/Kg (oral). This compound also has a suitable sedative effect as demonstrated by the method of S. Irwin (Science 136 , 123 (1962)). In this latter test, 1-(2,6-dimethylphenoxy)-
2-tosyloxy-propane (in formula (), A=
tosyloxy) was also found to be an effective sedative.

The novel compounds of general formula () can be converted into pharmaceutical compositions for oral or parenteral administration by methods well known in the art. This pharmaceutical composition includes tablets,
It may be a solid, semi-solid or liquid preparation, such as a coated tablet, capsule, injectable solution or suspension, suppository, etc., and, in addition to the active ingredient, customary pharmaceutically acceptable carriers, diluents, etc. and/or may contain auxiliary agents. As carriers or diluents, for example, water, non-toxic organic solvents, mineral or vegetable oils, starch, lactose, diatomaceous earth, cocoa butter and the like can be used. Among the adjuvants, the following may be mentioned:
Binders (such as microcrystalline cellulose, gum arabic and gelatin), disintegrants (such as alginic acid and corn starch), lubricants (such as magnesium stearate), flavoring agents (such as sucrose), ( antioxidants (such as ascorbic acid), preservatives, surfactants, and osmotic salts (such as sodium chloride).

As mentioned above, the novel compounds of general formula () can also be used as starting materials in the synthesis of 1-(2,6-dimethylphenoxy)-2-amino-propane as a valuable therapeutic agent. In the following, we will first discuss the known synthesis methods for this compound, and then describe the new method of preparation and its advantages.

Several methods are disclosed in GB 1205958 for the production of 1-(2,6-dimethylphenoxy)-2-amino-propane.

According to one of these methods, the desired product has the general formula () (wherein B is an amino group having one or two protecting groups) by removing the protecting groups of the compound. The cited reference mentions benzyl, phthalyl, toluenesulfonyl, and formyl groups as these protective groups, but the Examples only mention the cleavage of the benzyl group.

According to the above British patent specification, the starting material of the general formula () is of the general formula () (In the formula, Hal represents a halogen atom.) It can be produced by reacting a compound of the general formula () B-H () (In the formula, B is as defined above).

Compounds of general formula () are also compounds of formula () ₍ British Patent Specification No. 1205958).

The above method has the following disadvantages:
The addition reaction with water of the compound of the general formula () (in which the protecting group is benzyl) is carried out under a minimum of 5 atm.80
℃ and produces the desired amino compound in only moderate yields (approximately 50 to 55%).

Furthermore, the starting materials themselves are difficult to manufacture. When a compound of general formula () is prepared by reacting a compound of general formula () with a compound of general formula (), a double alkylation reaction also occurs due to the high reactivity of benzylamine, resulting in expression () A bis derivative of is produced as a by-product. In addition, the hydrohalide salt is removed since the reaction progresses with excess amine, resulting in the formation of addition by-products. These products themselves are difficult to purify, which further reduces yields.

They can also be prepared by reacting compounds of general formula () or ketones of formula () with appropriately protected amines under reducing conditions. However, this method is not exemplified in the cited patent specification.

In producing the ketone of formula () itself, this compound is a highly toxic substance,
Additional difficulties arise because they are synthesized by reacting a salt of chloroacetone or bromoacetone with a salt of 2,6-dimethylphenol (NISax Handbook of Dangerous
Materials” Reinhold Publ.Corp., New York,
1951, p. 94).

British Patent Specification No. 1205958 also describes phthalyl,
The use of toluenesulfonyl and formyl protecting groups is mentioned, however, these methods are not illustrated by example.

According to another method disclosed in British Patent Specification No. 1205958, a ketone of formula () is first treated with ammonia, hydroxylamine or hydrazine and the resulting general formula () (wherein Y represents hydrogen, hydroxy or amino) is reduced to 1-
(2,6-dimethylphenoxy)-2-amino-
Get propane.

This method also has some disadvantages.
This water addition reaction can only be carried out with moderate yields (51.5% for oximes and 44.3% for imines, and there are no examples of reduction of hydrazones), and as mentioned above, the formula ( ) is difficult to produce.

According to another method disclosed in the above-mentioned British patent specification, 2,6-dimethylphenol is reacted with 1-methyl-aziridine.
1-(2,6-dimethylphenoxy)-2-amino-propane can be produced from 6-dimethylphenol. However, no examples of this method are given in the specification.

The disadvantage of this method is that it utilizes 1-methyl-aziridine. This compound is not extremely harmful like ethyleneimine (see NISax
“Handbook of Dangerous Materials”
Reinhold Publ. Corp., New York, 1951, 328
Page), and is also very susceptible to polymerization. The polymerization reaction occurs when the mixture is heated or even by the effect of trace amounts of acids (such as phenols).

Yet another method disclosed in GB 1205958 uses a salt of 2,6-dimethylphenol as the starting material. This salt has the general formula () (wherein Z is a reactive ester group such as a halogen). This method is also not exemplified.

The disadvantage of this process lies in the use of reactants of formula () which are difficult to prepare and are rather easy to dimerize, thereby forming piperazine derivatives.

1-(2,6-dimethylphenoxy)-2-hydroxy-propane is disclosed in U.S. Patent No. 3979460.
Although it is listed as an undesirable by-product in the
This results in a yield of 12 in the synthesis of 4,4'-hydroxy-3,3'-tetramethyl-diphenyl sulfide.
Generated in %. Physical constants of hydroxy compounds are not given in this patent specification.

It has been found that compounds of the general formula (), in which A is as defined above, can be prepared easily and in high yields by the method described below.

2,6-dimethylphenol is reacted with propylene oxide in an alkaline medium and the resulting compound is acylated and, if desired, the resulting general formula () (where A is a perhalogenated lower alkylcarbonyloxy group) , a lower alkylsulfonyloxy group, or a lower alkyl-substituted phenylsulfonyloxy group) is reacted with an alkali metal azide. If an amino compound has to be prepared, the 1-(2,6-dimethylphenoxy)-2-azido-propane obtained is reduced. This latter compound can be converted into its acid addition salt.

In our experience, 1-(2,6-dimethylphenoxy)-2-hydroxy-propane can be used to remove excess propylene oxide and water-soluble organic solvents.
- It was shown that it can be easily produced in good yield by adding it to an aqueous solution of dimethylphenol and stirring the resulting mixture under heat.
It is preferable to use sodium hydroxide or potassium hydroxide as the alkaline agent because it forms a soluble phenolate with the starting material.
For every mole of 2,6-dimethylphenol, 1.05 to 10 moles of alkali are generally used, preferably 1.2 moles. As a water-soluble organic solvent,
Lower alcohols or ketones, acetonitrile, tetrahydrofuran or dioxane, preferably ethanol or acetone can be used. This reaction is carried out at 20℃ or the boiling point of this reaction mixture,
Preferably, it can be carried out at a temperature of 50 to 60°C. If desired, the crude 1-(2,6-dimethylphenoxy)-2 obtained after working up this reaction mixture
-Hydroxy-propane with these general formulas ()
(wherein A is a perhalogenated lower alkylcarbonyloxy group, a lower alkylsulfonyloxy group or a lower alkyl-substituted phenylsulfonyloxy group).

As used herein, "lower alkyl" means alkyl having 1 to 4 carbon atoms.

1-(2,6-dimethylphenoxy)-2-hydroxy-propane is converted to perhalogenated lower alkylcarbonyloxy, lower alkylsulfonyloxy or lower alkyl substituted phenylsulfonyloxy derivatives by conventional acylation methods. (See also: ``Methoden der organischen''
Chemie”, Georg Thieme Verlag, 1952, No. 8
Volume, page 543).

The acylation reaction is preferably carried out in pyridine or in a mixture of dichloroethane and triethylamine at a temperature below 10°C. The acylated compounds are produced in excellent yields (>98%) and in very pure form. If desired, the acyl derivatives can be used directly in the preparation of 1-(2,6-dimethylphenoxy)-2-azido-propane (formula (), A=azido).

The azide compound is a compound of the general formula () (in which A is a perhalogenated lower alkylcarbonyloxy group, a lower alkylsulfonyloxy group, or a lower alkyl-substituted phenylsulfonyloxy group), which is a metal azide, preferably sodium azide. and water and a water-soluble organic solvent, preferably ethylene glycol monomethyl ether or ethylene glycol monoethyl ether. Obtained 1-
(2,6-dimethylphenoxy)-2-azido-
Propane is extremely stable (distilled and
(does not decompose even when heated to 200 °C) and is formed in good yields (83 to 89%). If desired, this compound can be used directly without further purification to prepare amino derivatives.

Amino compounds, namely 1-(2,6-dimethylphenoxy)-2-amino-propane, are prepared by reducing azide compounds by known methods (see Houben-Weyl, “Methoden der
Organischen Chemie” Georg Thieme Verlag,
1957 Vol. 11/1 No. 262, 539 and 1002). Reduction is preferably carried out by catalytic hydrogenation.

In this latter reaction, 1-(2,6-dimethylphenoxy)-2-amino-propane base is obtained as a single product without by-products in an almost quantitative yield. This reaction can be easily monitored by thin layer chromatography. This reaction is easy to perform and does not require special equipment.

The novel process according to the invention offers the following important benefits: 1. All starting materials are easy to produce, easy to handle and are not harmful to health.

2 This reaction can be easily carried out without the use of special equipment and is carried out in excellent yields.

3. All compounds of the general formula () are stable substances that are easy to handle, and even their crude state is sufficient for their subsequent conversion reactions.

4 1-(2,6-dimethylphenoxy)-2-
The reduction of azido-propane to the amine can be carried out almost quantitatively at room temperature under atmospheric pressure and produces pure compounds.

5 1-(2,6-dimethylphenoxy)-2-
Amino-2-propane can be separated very easily from the reaction mixture.

The examples given below are intended to illustrate the invention and are not intended to limit its scope.

Example 1 1-(2,6-dimethylphenoxy)-2-hydroxy-propane 2,6-dimethylphenol 12.2g (0.1 mol)
was dissolved in a solution of 4.2 g (0.105 mol) of sodium hydroxide in 20 ml of water. Ethanol 25% to this solution
ml and 8.7 g (0.15 mol) of propylene oxide were added and the mixture was stirred at 60° C. for 12 hours. Cool this mixture, add 200ml of benzene and water.
200ml was added and the organic layer was separated. This aqueous layer was extracted with 200 ml of benzene. These benzene solutions were combined, washed with 200 ml of water, dried over sodium sulfate, and dried under reduced pressure (40 ml) from a steam bath.
evaporated to dryness (mmHg). Oily substance 14.6g (81
%) was obtained. This crude product could be used directly in the acylation reactions described in Examples 2-5. This crude 1-(2,6-dimethylphenoxy)-
2-Hydroxy-propane can be purified by distillation (boiling point 84°C). R _f = 0.6 (chromatography on a layer of Merck grade silica gel 0.1 to 0.3 mm thick in a 6:1 mixture of benzene and pyridine; developed with o-toluidine after chlorination; see Z.
Anal. Chem.” 148 , 181 (1955)).

Analysis C ₁₁ H ₁₆ O ₂ (Molecular weight = 180.24) Calculated value C: 73.30% H: 8.95% Measured value C: 73.60% H: 9.07% Example 2 1-2,6-dimethylphenoxy)-2-(4
-methylphenylsulfonyloxy)-propane The crude 1-(2,
9.0 g (0.05 mol) of 6-dimethylphenoxy)-2-hydroxy-propane were dissolved in 50 ml of dry pyridine and 19.0 g (0.1 mol) of tosyl chloride was added portionwise to this solution while cooling with ice.
During this addition, the temperature of the mixture should be kept below 10°C. When the addition is complete, remove the cooling bath and allow the mixture to warm to 20-25°C.
The mixture was stirred at the same temperature for 1 hour. At the end of the reaction, the mixture was poured onto 100 g of crushed ice and the product was extracted with 200 ml of benzene. The benzene solution was washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. The obtained crystal residue was recrystallized from 20 ml of isopropanol.
16.5g (98.7g) of 1-(2,6-dimethylphenoxy)-2-(4-methyl-phenylsulfonyloxy)-propane (melting point 63-64°C) was produced. The crude product with a melting point of 59-61°C could be used directly in the reaction described in Example 6.

R _f =0.8 (chromatography on a layer of Merck grade silica gel 0.1 to 0.3 mm thick in a 6:1 mixture of benzene and pyridine, developed with o-toluidine after chlorination).

Analysis C ₁₈ H ₂₂ SO ₄ (molecular weight 334.42) Calculated value C: 64.64% H: 6.63% S: 9.59% Measured value C: 64.84% H: 6.86% S: 9.86% Example 3 1-(2,6-dimethyl fluoride) (enoxy)-2-methanesulfonyloxy-propane Worked as described in Example 2. However, 1-
Mesyl chloride 11.4g in pyridine solution of (2,6-dimethylphenoxy)-2-hydroxy-propane
(0.1 mol) was added dropwise. The reaction mixture was worked up as described in Example 2 and 1-(2,6-dimethylphenoxy)-
2-methanesulfonyloxy-propane 12.8g
(99.1%). This crude product is Example 7
can be used directly in the reactions described in .

R _f = 0.8 (chromatography on a 0.1 to 0.3 mm thick layer of Merck grade silica gel in a 6:1 mixture of benzene and pyridine, o
-Developed with toluidine) Analysis C ₁₂ H ₁₈ O ₄ S (molecular weight 258.33) Calculated value C: 55.78% H: 7.02% S: 12.41% Measured value C: 56.20% H: 7.52% S: 12.14% Example 4 1-( 2,6-Dimethylphenoxy)-2-trichloroacetyloxy-propane The procedure was carried out as described in Example 2. However, the difference is that 18.1 g (0.1 mol) of trichloroacetyl chloride is added to the pyridine solution of 1-(2,6-dimethylphenoxy)-2-hydroxy-propane.
was added dropwise. The reaction mixture was worked up as described in Example 2 to yield 16.1 g (98.9%) of crude oily 1-(2,6-dimethylphenoxy)-2-trichloroacetyloxy-propane, which could be applied without purification in the treatment described in Example 8.
This product could be purified by distillation. (boiling point 146℃/0.4
mmHg) R _f = 0.85 (chromatography on a 0.1 to 0.3 mm thick layer of Merck grade silica gel in a 6:1 mixture of benzene and pyridine: after chlorination o-
Analysis C ₁₃ H ₁₅ Cl ₃ O ₃ (molecular weight 325.62) Calculated value C: 47.95% H: 4.64% Cl: 32.67% Measured value C: 48.12% H: 4.92% Cl: 32.48% Example 5 1-( 2,6-dimethylphenoxy)-2-
(4-methyl-phenylsulfonyloxy)-
11.1 g (0.11 mol) of propane triethylamine were added to the crude 1-(2,6-
9.0 g (0.05 mol) of dimethylphenoxy)-2-hydroxy-propane in 100 ml of dry dichloroethane
Added to the solution inside. This solution was stirred under ice cooling,
and tosyl chloride in 50 ml of dry dichloroethane.
It was added dropwise to a solution of 19.0 g (0.1 mol). When the addition is complete, remove the cooling bath and cool the reaction mixture for 20
Warm it to 25℃ or 25℃, and then heat it at the same temperature.
Stir for hours. At the end of the reaction, the mixture was decomposed with 100 g of crushed ice and the layers were separated from each other. The dichloroethane layer was washed with water, dried over sodium sulfate and evaporated to dryness in vacuo.
The crystalline residue was recrystallized as described in Example 2.
16.55 g (98.9%) of 1-(2,6-dimethylphenoxy)-2-(4-methyl-phenylsulfonyloxy)-propane (melting point 58-61°C) was obtained. This compound corresponds to the product obtained according to Example 2 and could be used directly in the reaction described in Example 6.

Example 6 1-(2,6-dimethylphenoxy)-2-azido-propane Crude 1-(2,6-dimethylphenoxy)-2-(4
-Methyl-phenylsulfonyloxy)-propane (8.36 g (0.025 mol)) was dissolved in 50 ml of ethylene glycol monomethyl ether. A solution of 3.25 g (0.05 mol) of sodium azide in 15 ml of water was added in one portion and the resulting mixture was refluxed for 5 hours. The mixture was allowed to cool, mixed with 100 ml of water and 100 ml of chloroform, and the organic layer was separated. The chloroform solution was washed with 200 ml of water, dried over sodium sulfate, and dried on a steam bath under reduced pressure (40 to 60 mm Hg).
It was evaporated to dryness. 4.6 g of crude 1-(2,6-dimethylphenoxy)-2-azido-propane
(89.6%), which could be used directly in the reaction described in Example 9. This product was purified by distillation. (boiling point 106°C/0.7 mmHg) R _f =0.75 (chromatography on a layer of Merck grade silica gel 0.1 to 0.3 mm thick in a 6:1 mixture of benzene and pyridine; after chlorination o-
Analysis C ₁₁ H ₁₅ N ₃ O (molecular weight: 205.25) Calculated value C: 64.37% H: 7.37% N: 20.47% Measured value C: 64.65% H: 7.48% N: 20.30% Example 7 1-( 2,6-dimethylphenoxy)-2-azido-propane Worked as described in Example 6. However, 6.46 g (0.025 mol) of crude 1-(2,6-dimethylphenoxy)-2-methanesulfonyloxy)-propane obtained as described in Example 3 was added
6-dimethylphenoxy)-2-(4-methyl-
phenylsulfonyloxy)-propane was used as the starting material instead. This reaction mixture was treated as described in Example 6 to yield 4.3 g of crude 1-(2,6-dimethylphenoxy)-2-azido-propane.
(83.8%), which was the same as the product obtained according to Example 6.

Example 8 1-(2,6-dimethylphenoxy)-2-azido-propane Treated as described in Example 6. However, 1-
(2,6-dimethylphenoxy)-2-(4-methyl-phenylsulfonyloxy)-propane was replaced with the crude 1-(2,6-
8.14 g (0.025 mol) of dimethylphenoxy)-2-trichloroacetyloxy-propane was used as starting material. The reaction mixture was treated as described in Example 6 to yield 4.5 g (87.7%) of crude 1-(2,6-dimethylphenoxy)-2-azido-propane.
was obtained, which was consistent with the product obtained according to Example 6.

Example 9 1-(2,6-dimethylphenoxy)-2-amino-propane hydrochloride 1 g of charcoal-supported palladium catalyst was added to the crude 1-(2,6-dimethylphenoxy)-2-amino-propane hydrochloride prepared in any of Examples 6 to 8. C)-2-azido-propane 4.1g
(0.02 mol) in 100 ml of ethanol. Hydrogen was slowly bubbled continuously through the flask and the mixture was shaken at 20-25°C for 5 hours before adding water. This reaction progresses with 0.1
Monitored by chromatography on a layer of torque grade silica gel from 0.3 to 0.3 mm thick.
The spots were developed with o-toluidine after chlorination.

At the end of the reaction the catalyst was filtered off and washed with a small amount of 70% aqueous ethanol. The solution was acidified to PH=1 with concentrated hydrochloric acid and then evaporated to dryness under reduced pressure (40 mm Hg) on a steam bath. The obtained crude 1-(2,6-dimethylphenoxy)-
2-amino-propane hydrochloride crystals 4.4g (100%)
was dissolved in 10 ml of isopropanol under heating, the solution was filtered, and 50 ml of dry ether was added to the liquid at about 40° C., and the product began to crystallize. The mixture was cooled on ice, the crystals were filtered, washed with a little ether and dried. The obtained purified 1-(2,6-dimethylphenoxy)-
2-Amino-propane hydrochloride melted at 201-203°C.

Claims (1)

[Claims] 1 General formula () (wherein A is a perhalogenated lower alkylcarbonyloxy group, a lower alkylsulfonyloxy group, a lower alkyl-substituted phenylsulfonyloxy group, or an azido group). 2 1-(2,6-dimethylphenoxy)-2-
The compound according to claim 1, which is (4-methyl-phenylsulfonyloxy)-propane. 3 1-(2,6-dimethylphenoxy)-2-
The compound according to claim 1, which is methanesulfonyloxy-propane. 4 1-(2,6-dimethylphenoxy)-2-
The compound according to claim 1, which is trichloroacetyloxypropane. 5 1-(2,6-dimethylphenoxy)-2-
The compound according to claim 1, which is azido-propane. 6 General formula () (In the formula, A represents a perhalogenated lower alkylcarbonyloxy group, a lower alkylsulfonyloxy group, a lower alkyl-substituted phenylsulfonyloxy group, or an azido group). phenoxy) -
2-Hydroxy-propane is acylated or sulfonated, and optionally the resulting general formula ( Production of a compound of the general formula (), which is characterized by reacting the compound (which is an oxy group) with an alkali metal azide.