CS208498B2 - Method of making the phenylether compounds - Google Patents

Abstract

Propane derivs. of formula (I) are new. In (I) A is acyloxy or alkylsulphonyloxy (opt. substd. by >=1 halo), arylsulphonyloxy (opt. substd. by >=1 alkyl) or N3. Prepn. of (I), and analogues with A=OH or NH2 (or its acid addition salts) comprises first reaction of 2,6-dimethylphenol (IIe with propylene oxide in alkaline medium to give (I;A=OH). This may them be acrylated and the prod. reacted with alkali metal azide to give (I;A=N3) which is opt. reduced to (I;A=NH2). (I), and cpd. with A=OH, are useful as antiarrhythmics and sedatives, (I;A=NH2) is a known antiamythmic (without sedative activity). (I) are easily and simply prepd. from readily available materials without need for toxic reagents or special apparatus. They are prepd. in stable, pure form and (I;A=N3) is converted almost quantitatively to (I;A=NH2) of high purity at room temp. and pressure.

Description

(54) A method for producing phenylether compounds

The invention relates to a novel process for the preparation of phenylether compounds of the general formula I,

(I) where

A is hydroxy, C1-C4alkylcarbonyloxy in the alkyl moiety optionally substituted by halogen, alkylsulfonyloxyC1-4 alkyl, phenylsulfonyloxy, optionally substituted C1-C4 alkyl, azido or amino groups, and their editoral salts acids.

Compounds of formula X wherein A is amino or hydroxy are known from the literature, while the other of the above derivatives are novel.

The compounds of formula I possess valuable biological properties; in addition, some of them can also be used as important intermediates in the synthesis of other compounds of formula I.

For example, 1- (2,6-dimethylphenoxy-2-aminopropane (Formula I wherein A is amino)) and pharmaceutically acceptable acid addition salts thereof have beneficial effects in conditions of ventricular arrhythmia and may be advantageously used in particular in the treatment of ischemic 20Θ49Θ

206498 cardiac disorders, myocardial infarction, ventricular fibrillation and tachycardia (Brit. Heart, J. 22, 558-559 (1973); Lancet 1973/11, pp. 339-403, pp. 404-407; Brit. J. Clin Pharmacol., 1: 86-87, 229-232 (1974). The novel compound of formula I wherein A is azido has similar pharmacological effects.

Several methods for the preparation of 1- (2,6-dimethylphenoxy) -2-aminopropane are disclosed in British Patent No. 1,205,958. According to one of these methods, the compound produced is prepared by removing the protecting group (s) from the compound of formula (II). 3 (II) O-CH ₂ -CH-CH ₃

CH ₃ where

V is an amino group having one or two protecting groups.

Benzyl, phthalyl, toluenesulfonyl and formyl groups are mentioned as protecting groups in the cited British patent, but only the benzyl group is exemplified in the examples.

The starting compounds of formula XI can be prepared according to the aforementioned British patent by reaction of a compound of formula III,

CH, (III) ^ 3 where hal is a halogen atom, with a compound of formula IV,

B-H (IV) wherein

В has the meaning given above.

Compounds of formula (II) may also be prepared by reacting a ketone of formula (V)

(V) with a compound of formula VI,

H ₂ NQ (VI) where

Q is a protecting group contained in substituent B, under reducing conditions (British Patent No. 1,205,958).

The above process has the following disadvantages:

Hydrogenation of compounds of formula II wherein the protecting group is a benzyl group only thrives at 80 ° C at a pressure of at least 0.490 MPa and the desired amino compound is obtained only in an average yield (about 50-55%).

In addition, starting materials are difficult to prepare. Compounds of formula (II) are produced by reacting a compound of formula (III) with a compound of formula (IV), and double alkylation also occurs. as a consequence of the high reactivity of benzylamine, resulting in the formation of the bie-derivative of formula VII

(VII) as a by-product. In addition, this reaction, taking place in excess of the amine, involves the removal of the hydrohalide, leading to the formation of additional by-products. Even the products themselves are difficult to clean, since the yield is further reduced.

Compounds of formula (II) may also be prepared by reacting a ketone of formula (V) with an appropriately amine erythromide under reducing conditions. However, this procedure is not exemplified by the cited patent.

Further difficulties arise in the preparation of the ketone of formula V itself, since this compound is selected by reacting the salt of 2,6-dimethoxyphenol with chloroacetone or bromoacetone, which are highly toxic compounds (NI Sax: Handbook of Dangerous Maaeeials, Reinhold Hubl) Coop., New York, 1951, p. 94).

Briske Patent No. 1,205,958 also discloses the use of phthalyl, toluenesulfonyl and formyl protecting groups, but the use of these protecting groups is not exemplified by the examples.

According to another procedure described in the British Patent No. 1,205,958, the ketone of formula V is first treated with ammonia, hydroxylminine or hydrazine and the resulting compound of formula VIII,

(VIII)

CH ₃ \ ^J Y where

Y is hydrogen, hydroxy or amino, is reduced either by catalytic hydrogenation or by a suitable complex metal hydride to give 1- (2,6-dimethylphenoxy) -2-aminopropanol.

This procedure is also characterized by several disadvantages. it can be carried out only in moderate yields (51.5% for oxime and 44.3% for imine; no example is given for the reduction of hydrazone), and furthermore, as mentioned above, the starting ketone of formula V is difficult to prepare.

According to a further procedure described in the above-cio-viral Bris patent, 1- (2,6-dimethylphenoxy) ^-2- aminopropene can be prepared directly from 2,6-diylphenyl by reaction with 1-ethyllaairidine. However, no exemplary embodiment is given for this procedure in the breeding patent.

The disadvantage of this procedure is the use of 1-ethyl aziridine. This compound, like ethyl acetate, is highly toxic (see N.I. Sax: Handbook of Dangerous Maaterals, Sein Tribute Publ. Corp. New York, 1951, p. 328) and moreover is very easily polymerized. Polymerization also occurs simply by heating the mixture or by the action of trace moieties of cartridges (e.g. phenol).

In the next process, the arylphenol starting material IX described in British Patent No. 1,205,958 uses salts of 2,6-diluents. This salt is reacted with a compound of formula

Z-CH ₉ -CH-CH ² , ¹³ NH ³ (IX) wherein

Z is a reactive ester group such as halogen.

However, this procedure is also not exemplified by the exemplary embodiment.

The disadvantage of this process lies in the use of the compounds of the formula (IX), since they are difficult to prepare and are relatively easily subjected to di-e-ac, resulting in piperazine derivatives.

1- (2,6-Methylphono) Ц) 3-nitro-propanoate is disclosed in U.S. Pat. No. 3,979,460 as an undesired by-product, which is produced in a yield of 12% in the synthesis of 4,4 ' -hylamino. -3,3 '- ^ - ЬгсierildlfrIyl8tžlУilž. This patent does not disclose the physical constants of the hydroxyl compound. .

It has now been found that compounds of formula I wherein A is as defined above can be easily and in high yield prepared by the following process:

The 2,6-diethynoenol is reacted at a temperature in the range of from 50 to 100 ° C, preferably in the presence of an aqueous solution of sodium or potassium hydroxide, and in the presence of an organic solvent mixed with water at 60 ° C, reacted with propylene oxide and optionally of formula (I) wherein A is a hydroxy group acylates the acylating agent at a temperature in the range of from 0 to 50 ° C and optionally forms a compound of formula (I) wherein A is C 1-4 alkyl-C 1 -C 4 alkyl; an optionally substituted halogen or a C 1 -C 4 alkylsulphoronylonyl group or a phenyl sulfonyl group, optionally a C 1 -C 4 alkylsubstituted alkyl group, is reacted with water at the boiling point of the reaction mixture with water at the boiling point. with an alkali metal azide, preferably sodium or potassium azide, and optionally also a tonicity The compound of formula (I) in which A is an azido group is reduced and optionally the compound of formula (I) in which A is arninostapine is converted into its acid addition salt.

Zki ^ mos! have shown that 1- (2,6-dimethylphrolo) 3-hydroxypropanoate can be easily and in good yield prepared by adding an excess of propylene oxide and an organic water-soluble solvent to the aqueous alkali solution of 2,6-zeryl-2-ol, and the resulting mixture was stirred while glancing. Sodium hydroxide or potassium hydroxide is preferably used as the alkaline reagent since it forms soluble phenoins with the starting material. Typically, 1.05 to 10 -oles, preferably 1.2 -oles, is used per mole of 2,6-methyl-1-ol. The water-soluble organic solution used may be a lower alcohol or ketone, acetontril, anane or dioxane, preferably ethanol or acetone. The reaction may be carried out at temperatures ranging from 20 ° C to the boiling point of the reaction mixture, preferably at a temperature ranging from 50 to 60 ° C. The crude 1- (2,2-dimethyphrolo [eta] < 3 &gt; -2-nitro) naphthane obtained after the treatment of the reaction network may optionally be prepared for the preparation of those compounds of formula I wherein A is alpha-alkoxy, alkylsulpholyololyl or aryl.

The terms acyloxy, and alkylsulfoiyrloiyric group and β-methylsulfonyloxy-10-β-α are used in the present description in the broadest sense, ie include all derived groups. removal of the hydrogen atom from the carboxylic acid, allylsulfonic acid and arylsulfonic acid. The hydroxycearbyl moieties of these groups may be substituted by one or more groups such as halogen atoms, alkyl groups, etc.

1- (2, N-Dimethylphenoxy) -2-pyridylpropane can be converted to the corresponding acyloxy-, alkylsulfonyloxy- or arylsulfonyloxy derivatives customary. acylation procedures (see Houben-Weyl: Methoden der Organischen Chemie, Georg Thieme, 1952, Vol. 8, p. 543) «

The acylation is preferably carried out in pyridine. or in a mixture of dichloroethane and triethylmin at a temperature below 10 ° C. The acylated compounds are formed in a very pure state in very high yields (above 98%). Alternatively, the acyl derivatives can be used directly for the preparation of 1- (2,6-diethylphthioxt) -2-azidopropane (Formula I wherein A = azido).

The az compound is prepared by reacting a compound of formula (I) wherein A is acyloxy, alkylsulfonoyl, or a γ-β-α-γ-γ group with a metal azide, preferably sodium azide, in the presence of water and a water-soluble organic solvent, preferably ethyl ether . The resulting 1- (2,6-dimethylphenoxy-2-azidesprspai) is surprisingly stable (it can be distilled and does not decompose even if heated to 200 ° C) and is obtained in good yields (83-89%). Alternatively, the compound can be used directly, without any further purification, to prepare the corresponding α-formate.

The amino compound, i.e. 1- (2,6-diisulfonyloxy) -2-minspspane, is prepared by reduction of the corresponding azido-4-formate according to a known method (see Methoden der organischen Chemie,

Georg Thieme ,. 1957, vol. 11/1, pp. 262, 539 and 1 002). The reduction is preferably. by catalytic hydrogenation.

The latter reaction afforded 1- (2,6-ethylphenyl) -2-η-Jinopropane as the sole product as a base, without any by-products in almost a yield. The reaction can be easily monitored by thin-layer chromatography. The reaction proceeds easily and does not require any special equipment.

The new method according to the invention offers the following main advantages:

1. all starting materials are easy to prepare, mean-palnje easily and not harmful to health,

2. reactions can be carried out easily without the use of any special equipment. and are carried out in exceptional yields,.

3. all compounds of formula (I) are stable substances which are easy to handle and, although in the raw state, are sufficiently pure for further transformation,

4. Reduction of 1- (2,6-ethylphenethoxy) -2-azidespropanoate to the appropriate amine can be carried out at room temperature under an atherospheric temperature in nearly quadratic yield to give the pure compound.

5. 1 '(2,6-Diethylphenyl) 22amphenylpropane is readily isolated from the reaction bands.

The invention is explained in more detail below. Examples, however, its scope is not in any way limited. .

Example 1

1- (2,6-Dimethylphenoxy) -2-hydroxypropane

12.2 g (0.1 mol) of 2,6-dimethylphenol are dissolved in a solution of 4.2 g (0.105 mol) of sodium hydroxide in 20 ml of water. 25 ml of toluene and 8.7 g (0.15 mol) of propylene oxide were added to the obtained solution, and they were stirred at 60 ° C for 12 hours. The reaction mixture is cooled, 200 ml of benzene and 200 ml of water are added and the organic phase is separated. The aqueous phase is extracted with 200 ml of benzene. The benzene solutions are combined, washed with 200 ml of water, dried over sodium sulphate and evaporated to dryness on a steam bath at 5 mm Hg. 14.6 g of an oily substance are obtained, which corresponds to a yield of 81% of theory. This crude product can be directly used in the acylation reactions described in Examples 2 to 5. The crude 1- (2,6-diethylphenyl) -2-hydroxypropane can be overruled by pretreatment. Boiling point 84 DEG C., Rf = 0.6 (chromatographically on a layer of silica 0.1 to 0.3 mm thick in a mixture of benzene and pyridine 6.1, detection with o-toidine after chlorination; see FIG. also Z. And Chem Chem 148. p. 181 (1955)) Alialysis - for C ^ HH ^Og (mol.hmoon = 180.24):

calculated: - 73.30% C, 8.95% H; found: C, 73.60; H, 9.07.

Example 2

1- (2,6-Dimethylphenyl) -2- (4-methylphenylsulfonyloxy) propane

9.0 g (0.05 mol) of crude 1- (2,6-dimethylphenoxy) -S-hydroxypropane, obtained as described in Example 1, are dissolved in 50 ml of anhydrous pyridine and the solution is added under ice-cooling in an ice bath. in small portions of 19.0 g (0.1 mol) of tosyl chloride. The temperature of the mixture should be kept below 10 ° C during the addition. After the addition was complete, the cooling bath was rubbed off, the mixture was allowed to reach 20-25 ° C and stirred at this temperature for 1 hour. After the reaction. The reaction mixture is poured into 100 g of crushed ice and the product is extracted with 200 ml of benzene. The benzene solution is washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The crystalline residue obtained is recrystallized from 20 ml of isopropanol to give 16.5 g of 1- (2,6-dimethylphenoxy) -2- (4-methylphenylsulfonyl) propane, m.p. 63-64 ° C. Yield 98.7% of theory. The crude product having a melting point of 59-61 ° C can be directly used in the reaction described in Example 6.

Rf = 0.8 (directly on a 0.1 to 0.3 mm thick silica gel layer in benzene / pyridine 6: 1, detection with o-toluidine after chlorination).

Analysis for ^C 22 ^H 22 ^SO 4 (mol. Wt. 334.42): Calculated: 64.64 ° C, 6.63% H, 9.59% S;

found: 64.84% C. 6.86% H. 9.86% S.

Example 3

1- (2'-Dimethylphenoxy) -2-methylsulphonoyloxy propane

The procedure is as described in Example 2, except that 11.4 g (0.1 mol) of maeyl chloride is added dropwise to a solution of 1- (2,6-dimethylthioxy) -2-hydroxypropane in pyridine. The reaction mixture was worked up as in Example 2 to give 12.8 g (99.1% of theory) of 1- (2,6- (6,6-enoxy) -2-methanesulfonyloxypropane). This crude product can be directly reacted in the reaction described in Example 7.

Rf = 0.8 (chromatographically on a silica gel layer 0.1 to 0.3 mm thick in benzene / pyridine 6: 1, detection with o-toluidneem after chlorination).

Analysis for C ^ HH ^^^S (M h 258.33): Calculated: C 55.78, H 7.02, S 12.41;

found: 56.20 «C, 7.52% H, 12.14 * S.

Example 4

1- (2,6-Dimethylphenoxy) -2-trifluoroacetio thiooypropane

The procedure is as described in Example 2, except that 18.1 g (0.1 mol) of trichloroacetyl chloride is added dropwise to a solution of 1- (2,6-dimethylphenooy) -2-hydrooypropane in pyridine. The reaction mixture was worked up as described in Example 2 to give 16.1 g of crude oily 1- (2,6-dimethylphenoxy) -4-trichloroacetyloy / propane which was used in the procedure described in Example 8 without purification. corresponds to 98.9% of theory The crude product can be pretreated by boiling at 146 DEG C. under 0.5 mm Hg.

Rf = 0.85 g (Chromatography on silica gel, 0.1 to 0.3 mm thick in benzene / pyridine 6: 1, detection of 1-toluide after chlorination).

Analysis: Calculated: 47.95% C, Found: 48112% C, (Mo.m. 325.62):

4.64 &apos; H, 32.67% Cl; H, 4.92; CL, 32.48.

Example 5

1- (2,6-Dimethylphenoxy) -2- (4-ethylphenylsulfonyl ^, lnylloy) propane

To a solution of 9.0 g (0.05 mol) of crude 1- (2,6-dioethylphenol) -2-hydroxypropane obtained as described in Example 1 in 100 ml of anhydrous dichloromethane (11.1 g of 0.11 mol) is added. triethylamine. The solution was stirred with flight cooling and a solution of 19.0 g (0.1 mole) in 50 ml of anhydrous Sichlrttaoz was added dropwise. After the addition was complete, the cooling bath was removed, the temperature of the reaction mixture was allowed to rise to 20-25 ° C, and the reaction mixture was stirred at this temperature for 1 hour. After completion of the reaction, the reaction mixture is quenched with 100 g of crushed ice and the phases are separated. The dichloroethane layer was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crystalline residue was recrystallized as described in Example 2 to give 16.55 g of 1- (2,6-dl-methyl-1-phenoxy) -2- (4'-methylphenylsulfonylooy) propane, m.p. 58-61 ° C. The quantity obtained corresponds to a yield of 98.9% of theory. This compound is identical to the product of Example 2 and can be used directly in the reaction described in Example 6.

Example 6

1- (2,6 "Dimethylphenoxy) -2-azidopropao

8.36 g (0.025 mol) of crude 1- (2,6-diethylphenooy) -2- (4'-ethylphenyl sulfoyl) propyl, prepared as described in Example 2 or 5, was span in 50 ml of ethyl glycol alcohol ethyl ether. A solution of 3.25 g (0.05 mol) of sodium azide in 15 ml of water was added all at once, and the resulting mixture was heated under reflux for 5 hours. The mixture was allowed to cool, 100 ml of water and 100 ml of chloroform were added and the organic phase was separated. The chloroform solution is washed with 200 ml of water, dried over sodium sulfate and evaporated to dryness under a pressure of 5 to 50 psi on a steam bath. 4.6 g of crude 1- (2,6-dimethylphenoxy) 208498 are obtained

-2-azidopropane, which can be used immediately in the reaction described in Example 9 without further purification. This amount corresponds to a yield of 89.6% of theory. The product may be predetermined therefrom; boiling point 106 ° C at a pressure of 93.32 Pa.

Rf = 0.75 (chromatographically on a silica gel layer 0.1 to 0.3 mm in thickness in a 6: 1 mixture of benzene and pyridine, detectable by o-toluddno after chlorine).

Analysis for G ^H ^N ^O O (molar mass 205.25):

calculated: 64.37% C, 7.37% H, 20.47% N; Found:% C, 64.65;% H, 7.48;% N, 20.30.

Example 7

1- (2,6-Dimethyl-phenooyl) -2-azidopropene

The procedure is as described in Example 6, except that instead of 1- (2,6-trimethyllenooy) -2- (4-methylphenylsulfonylamino) propane propane, 6.46 g (0.025 mol) of crude 1- (2,6-dimethylphenyl) is used as starting material. enoxy) -2-methanesulfoxyro [theta] 3propane, prepared as described in Example 3. The reaction mixture was worked up as described in Example 6 to give 4.3 g (corresponding to a yield of 83.8% of theory) of crude 1- (2,6- diethylphenooyl-2-azidopropane identical to the product of Example 6.

Example 8,

1- (2,6-Dime tyllenooy) 2-azidopropane

The procedure was as described in Example 6, except that instead of b- (2,6-di-m-1-m-2-en-2-en-2-di-m-2-m-4-m-2-m-1-m-1-m-1-m-1-m). The starting material was 1,14 g (0.025 mole) of crude 1- (2,6-dimethyllenoDoO-2-tri). The mixture was worked up as described in Example 6 to give 4.5 g of crude 1- (2,6-dimethylphenoic) -2-azidopropane, identical to the product obtained in Example 6. The quantity corresponds to a yield of 87.7% of theory.

Example 9

N- (2,6-dimethylphenooyl) -2-amino-propane

To a solution of 4.1 g (0.02 mol) of crude 1- (2,6-methylphenoxy) -2-anodopropane, prepared by any of the procedures described in Examples 6-8, in 100 ml of ethanol is added 1 g of catalyst, · Made of palladium on active salt. Hydrogen was bubbled through the reaction mixture slowly and continuously and the mixture was hydrogenated with shaking at room temperature for 5 hours. 20-25 ° C. The progress of the reaction is monitored by chromatography on a layer of silk cable having a thickness y ranging from 0.1 to 0.3 mm in a 6: 1 mixture of benzene and pyridine. Spot detection is performed by o-toluddnnem po. cHoraci. ’

After completion of the reaction, the catalyst was removed by filtration and washed with a small amount of 70% aqueous ethanol. The filtrate got a shake! to pH = 1 with concentrated hydrochloric acid, then drained to dryness under reduced pressure (50 psi). The resulting crude crystalline 1-iodo-4-formylphosphoyl-4-amino-propane hydrobromide in an amount of 4.4 g (corresponds to yield).

100% of theory) was dissolved in 10 ml of isopropanol under ice, the solution was filtered and 50 ml of anhydrous ether was added to the liirate at about 40 ° C, whereupon the product soon began to crystallize. The mixture was cooled with ice, the crystals were collected by filtration, washed with a small amount of ether and dried. The melting point of the resultant pure HCl salt was 1- (2,6-, 6, 6, 10, 9)

Example 10

1- (2,6-Dimethylphenoxy) -2-isobutoxycarbonylpropane

The procedure is as described in Example 2, but a solution of 10.6 g (0.1 mol) of isobutyric acid chloride is added to the starting 1- (2,6-dimethylphenyl) -2-hydroxydepropene. in pyridine. The reaction mixture was as described in Example 2 to give

12.25 g (97.9% of theory) of crude oils .alpha.-1- (2,6-dimethyl-ethylene) -2-iso-butoxycarbone / propane. This product can be used for the reaction of Example 3 without further purification. After purification by distillation, the product has a boiling point of 104 DEG C. at a pressure of 0.99 Pa.

Example 11

1- (2,6-Dimethylphenyl) -2-phenylsulphonyloxypropane

9.0 g (0.05 mol) of crude was dissolved in 20 ml of anhydrous pyridine. 1- (2,6-Dimethylenoxy) -2-} ydrooypropain prepared according to the procedure of Example 1. To the resulting solution was added 9.18 g (0.052 mol) of benzenesulphonic acid chloride at a temperature, and the reaction mixture was stirred in a water bath for 5 hours. temperature 50 ° C. After cooling, 50 ml of water and 300 ml of benzene are added to the reaction mixture, the resulting base is separated from the aether, the organic phase is washed with 200 ml of water, dried over sodium sulphate and evaporated to dryness. 15.6 g (yield 97.5% of theory) of slow-setting 1- (2,6-dimethylphentoy) -2-phenylsulphosyloxypropanes are obtained. This product can be used immediately for the reaction of Example 3. After recrystallization from isopropyl alcohol, the melting point of the product is in the range of 61 to 63 ° C.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of lenylether compounds of the general formula I, CH ₃ where A is hydroxy, (C1-C4) alkyl, (C1-C4) alkyl, optionally halogenated, (C1-C4 ₎ alkyl, (C1-C4) alkyl, (phenyl) sulfoxyrolo (C1-C4) alkyl, or (C1-C4) alkyl; and the acid addition salts thereof, characterized in that 2,6-dimethylenol is left at a temperature in the range of from 50 to 100 ° C, preferably in the presence of an aqueous solution of sodium or potassium hydroxide and in the presence of an organic solvent. mixed with water at 60 ° C, reacted with propylene oxide and optionally the resulting compound of formula (I). wherein A is hydroxy, acylated with an acylating reagent at a temperature in the range of from 0 to 50 ° C, and optionally forming the compound of formula 1 wherein A is C 1 -C 4 alkyl, optionally halogen or C 1 -C 4 alkylsulfonyl. or optionally substituted C1-C4 alkyl, reacted in the presence of water and an organic solvent miscible with water at the boiling point of the reaction mixture with an alkali metal azide, preferably sodium or potassium azide, and optionally in this manner. the compound of formula (I) wherein A is cis-bipin is obtained, and optionally a compound of formula (I) wherein A is is obtained. amino skipine, to be converted into its acid addition salt.