SE449357B - INTERMEDIATES FOR USE IN THE PREPARATION OF 1-ARYLOXY-4-AMINO-2-BUTANOLS - Google Patents

Description

449 357 The compounds prepared by the compound of the present invention The present invention of formula I is characterized by a significant and significant pharmacological activity, which highlights their use. counteracting certain physiological abnormalities in animals and humans. The compounds are local anesthetics, alpha-adrenergic blocking agents, beta-adrenergic blocking agents and antiarrhythmics.

Thus, with the compounds of the present invention, then the new 1-aryloxy-4-amino-2-butanols, which are useful pharmacologically depending on the above types of activity, by procedure defined below. The definition of formula I includes symbols as well as where they otherwise appear in the descriptive one, the terms have the following meaning.

The term "lower alkyl" is intended to denote straight and branched groups with up to 8 carbon atoms, exemplified by such groups as methyl, ethyl, propyl, isopropyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl and the like.

The term "lower cycloalkyl" includes cyclic groups having up to 8 carbon atoms and including such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Reaction Scheme I - Preparation of 1-aryloxy-4-chloro-2-buta- noler (IV) Aron + clcnz-cnon-cnz-cnzcl _________ fÉL _; _ ¿p II III ' ArO-CH2-CHOH-CH2-CH2Cl IV 1-aryloxy-4-chloro-2-butanols (IV) are generally prepared by a basic aqueous solution or a basic aqueous-alcoholic solution of a phenol, a substituted phenol or an aryl compound having an acid hydroxyl group of formula II is treated with 1,4-dichloro-2-butanol III. The addition takes place at or below 70 ° C, preferably at about About 30 ° C to about 65 ° C, during a ten of from about 3 hours mar to about 8 hours. After the addition, the reaction medium is heated. 0 449 357 the mixture from about 50 ° C to about 75 ° C, preferably at 50 ° C for 6 hours to 48 hours, with a ten of 12-18 hours is usually appropriate. 1-aryloxy-4-chloro-2-butanol is isolated from the reaction mixture using a suitable organic solvents, for example ether, isopropyl ether or chloroform, evaporation of the solvent after drying to give 2- -butanol, which is suitably isolated, such as by distillation tion or crystallization. Alternatively, 1-aryloxy-4-chloro-2-bu- tanol is prepared by adding a basic aqueous solution of a mixing phenol or a compound with an acid hydroxy group and 1,4-dichloro-2-butanol in an amount per unit time so that the reaction the pH of the mixture is maintained from about 9.0 to about 10.5. preferably at a pH of 9.5 to 10.0. Products insulating race in the manner described above.

The examples given below illustrate the invention.

Example 1 4-chloro-1-phenoxy-2-butanol To a mixture containing 282 g (3 moles) of phenol, 1 liter water and 300 ml of 50% sodium hydroxide were slowly added with stirring at 60 ° C 443.36 g (3.1 mol)], 4-dichlorobutanol. If- stirring was continued at 60 ° C for 16 hours. The resulting the mixture was extracted twice with 1 liter of ether and the combined man-made ether extracts were washed with water to neutralize and dried overnight over sodium sulfate. The dried ether the mixture was concentrated to dryness under reduced pressure. The residue was distilled and 435 g of the product were collected at 135-138 ° C / 0.05 mm. The product was allowed to solidify and recrystallized using petroleum ether (60,110 ° C) to give a white crystalline solid, melting at 52-54 ° C.

Analysis: Calculated for C 10 H 13 ClO 2: C 59.86 H 6.53 'Obtained =' c 59.72 H 6.37 Example 2 4-clear-1- (2-chlorophemoxy-2-butanoic A To a mixture of 129 g (1 mol) of 2-chlorophenyl, 60 g of potassium hydride oxide, 100 ml of water and 400 ml of isopropanol were added 1Q3 mol § 185.9 g) 449 357 1,4-dichloro-2-butanol with stirring at 50 ° C. The resulting the mixture was heated on a steam bath at 65 ° C overnight and was extracted with 300 ml of isopropyl ether. The ether extracts were washed after every other with 1N sodium hydroxide, water and dried over sodium sulfate. The dried ether solution was concentrated the oily residue was distilled under reduced pressure, whereby 152 g of an oily residue were obtained (boiling point 130-131 ° C / 0.01 mm).

Analysis: Calculated for C 10 H 15 ClO 2: C 51.08 H 5.15 Found: C 51.13 H 5.14 Exemgel 3 4-chloro-1- (3,5-dimethylphenoxy) -2-butanol To a mixture of 245 g (2 moles) of 3,5-dimethylphenol and 2 liters 2N sodium hydroxide was added 2.5 moles of 1,4-dichlorobutanol under stirring. ring at 65 ° C overnight. The solid precipitate that separated on cooling, it was filtered and washed with water until neutral reaction. Recrystallization from isopropyl ether gave 375 g of white crystalline solid, melting at 74-76 ° C.

Analysis = Calculated for c 12 H 17 ClO 2 = c 62.02 H 7.49 Received; C 63.96 H 7.66 Exemgel 4 4-chloro-1- (4-chloro-3-methylphenoxy) -2-butanol To a mixture of 286 g (2 mol) of 3-methyl-4-chlorophenol, 700 ml tertiary butanol, 700 ml of water and 3.0 moles of 1,4-dichloro-2-butanol sodium hydroxide (2.9 moles, 230 g in 700 ml of water) was added stirring at 40 ° C to maintain a pH of 9.5-10.0 during the course of the reaction. The addition took place for 10 hours and the reaction mixture was stirred at 40 ° C for 48 hours. The result- The reaction mixture was extracted with chloroform-sodium chloride at 25 ° C- The chloroform extract was washed with sodium sulfate.

The dried chloroform solution was concentrated and the residue was added under reduced pressure to give 110.9 g of product, which was distilled at 135-14300 / 0.007 mm and melted at 87- _. 89 ° C after recrystallization from isopropanol and petroleum ether (3o: so); Analysis: Calculated for C 11 H 14 Cl 2 O 2: C 53.03 rH 5.66 * Obtained = c 53.11 H 5.61 449357 Example 5 - 4-chloro-1- (4-chloro-2-methylphenoxy) -2-butahole 4-Chloro-1- (4-chloro-2-methylphenoxy) -2-butanol was prepared according to the procedure described in Example 4 using 105 g (0.74) mol) of 2-methyl-4-chlorophenol, 171.5 g (1.2 mol) of 1,4-dichloro-2-bu- tanol, 50.3 g of sodium hydroxide, 300 ml of water and 300 ml of tertiary butanol. This gave 84 g (45.5%) of a product which was distilled 1 irradiated at 13 ° C / 0.1 mm.

Analysis; Calculated for c11n14o¿c12 = c 53.03 H 5.66 Obtained = c 53.41 H s, 1o Example 6 4-chloro-1- (1-naphthyloxy) -2-butanol To a mixture of 1 mol (147 g) of 1-naphthol, 350 ml of water and 2 mol (112 g) of potassium hydroxide was added at 54 ° C 1 mol (143 g) of 1,4-dichloro- -2-butanol. The reaction temperature was kept below 60 ° C during addition of chlorobutanol. The reaction mixture was then heated to 65 ° C for 12 hours, after which it was mixed with 500 ml of water and 350 ml ml chloroform. The chloroform phase was separated, washed with water, dried over sodium sulfate, concentrated and residual oil was distilled under reduced pressure to give 128 g of a crystalline solid, which distilled at 162-165 ° C / 0.01 mm.

The solid was recrystallized from ether and petroleum. ether (30-60 ° C) to give a material melting at 75-77 ° C.

Analysis: Calculated for C 14 H 15 O 2 Cl: C 67.07 H 6.03 Found: C-67.19 H 6.19 Example 7 I I 4-Chloro- (4-biphenylyloxy) -2-butanol To a solution of 1 mol (158 g) of 4-phenylphenol, 100 g of sodium hydride oxide and 500 ml of water were added 1 mol (143.02 g) of 1,4-dichloro-2- ëbutanol with stirring at 4000. The resulting mixture , heated to 6800 in a steam bath for 6 hours, cooled and was extracted with 300 ml of chloroform. The chloroform extract was washed with water to neutral reaction, dried over sodium sulfate and concentrated to dryness. The solid residue is recrystallized. was lysed with isopropanol to give 180 g of a white crystalline tallin, solid mass, melting at 12É-124 ° C; 449 357 Analysis: Calculated for C 16 H 17 ClO 2: C 69.44 H 6.19 Obtained: C 69.79 H 6.22 Exemgel 8 4-chloro-1- (3-trifluoromethylphenoxy) -2-butanol To a mixture of 0.5 mol (75 g) of m-trifluoromethylphenol, 1 mol (56 g) potassium hydroxide, 100 ml water and 400 ml isopropanol 0.6 mol (84 g) of 1,4-dichloro-2-butanol while stirring at a temperature below 55 ° C. The resulting reaction mixture was heated at 65 ° C for 20 hours and mixed with 2 liters of water and extracted with 400 ml of isopropyl ether. The ether extract washes taken with 0.5 N sodium hydroxide and then with water, dried over sodium sulfate and distilled under reduced pressure. Des- allowed to collect at 120-124 ° c / 0.01 mm and solidified at room temperature temperature and melt at 50-52 ° C.

Analysis: Calculated for C ClF 0: C 49.18 H 4.50 11H12 3 2 Obtained = 5 c 49.35 H 4.47 Example 9 4-chloro-1- (4-chlorophenoxy) -2-butanol --Chloro-1- (4-chlorophenoxy) -2-butanol was prepared using the procedure described in Example 7 from 45 g (0.5 mol) of β-chloro- -phenol, 72 g (0.5 mol) of 1,4-dichloro-2-butanol, 40 g (1.0 mol) of sodium rium hydroxide and 400 ml of water to give 85 g (36.1%) of a product which melted at 62-6400 after recrystallization from isopro- panel.

Analysis: Calculated for c 10 H 15 ClO 2 = c 51.09 H 5.14 Obtained: C 51.76 H 5.12 Exemgel 10 f § 3 4-chloro-1- (2-methoxyphenoxy) -2-butanol To a mixture of 2 moles (248.26 g) of 2-methoxyphenol, 4 moles (160 g) sodium hydroxide, 250 ml of water and 1 liter of isopropanol were added 2.2 mol (314.64 g) 1,4-dichloro-2-butanol. The mixture was boiled under reflux overnight. The reaction mixture was extracted with 1 liter of isopropanyl, dried over sodium sulfate and distilled reduced pressure. The distillate was collected at 136-138 ° C / 0.015 mm (396.8 g), solidified to a white crystalline solid, which melted at 48-5 ° C. 5 5 1449 357 Analysis: Calculated for C 11 H 14 O 3 Cl: C 57.52 .H 6.14 Found: C 57.49 H 6.54 Using Examples 1-10 shown above, starting from the appropriate femol II and 1,4-dichloro-2-butanol III were prepared differently 1-aryloxy-4-chloro-2-butanols IV.

Example11 4-chloro-1- (2-methyl-5-chlorophenoxy) -2-butanol with a boiling point of 135- 138 ° C / 0.5 mm was prepared from 2-methyl-5-chlorophenol and 1,4-dichloro- -2-butanol.

Example_12 4-chloro-1- (2-naphthyloxy) -2-butanol, m.p. 101-102 ° C was prepared from 2-naphthol and 1,4-dichloro-2-butanol.

Example_l§. 4-chloro-1- (4-acetylaminophenoxy) -2-butanol, m.p. 128 ° C was prepared from 4-acetylaminophenol and 1,4-dichloro-2-butanol.

Example 14 - 4-chloro-1- (4-methoxyphenoxy) -2-butanol, m.p. 61-63 ° C was prepared from 4-methoxyphenol and 1,4-dichloro-2-butanol.

Example 15 4-chloro-1- (3-chloro-2-pyridyloxy) -2-butanol, m.p. At 58 ° C, 3-chloro-2-hydroxypyridine and 1,4-dichloro-2-bu- tanol.

Example 16 4-Chloro-1- (5-chloro-2-pyridyloxy) -2-butanol was prepared from 5-chloro-2- -hydroxypyridine and 1,4-dichloro-2-butanol. s Example 17 4 -.k10r-1l (xinaen-s-yloxy) -z-butanol with a melting point of 56-5 ° C was prepared from §-hydroxyindene and 1,4-dichloro-2-butanol.

Example 18 4-chloro-1- (3-chlorophenoxy) -2-butanol, m.p. 60-62 ° C was prepared from 3-chlorophenol and 1,4-dichloro-2-butanol. 449 357 Example 19 4-chloro-1- (2-ethoxyphenoxy) -2-butanol with a boiling point of 130-132 ° C / 0.01 mm was prepared from 2-ethoxyphenol and 1,4-dichloro-2-butanol.

Example 20 4-chloro-1- (4-acetylphenoxy) -2-butanol, m.p. 125-128 ° C was prepared from 4-acetylphenol and 1,4-dichloro-2-butanol.

Exemgel 21 I _ - 4-chloro-1- (o-phenylphenoxy) -2-butanol with a boiling point of 156 ~ 160 ° C / 0.25 mm was prepared from o-phenylphenol and 1,4-dichloro-2-butanol.

The preparation of the 1-aryloxy-4-amino-2-butanols of formula I follows the following reaction scheme: Reaction Scheme 2 - Preparation of 1-aryloxy-4-amino-2-butanols ArO-CH 2 -CHOH-CH 2 -Cl-Iz-Cl + HNR 1 R 2 -_--- f o Iv v_.

Aro-cH2-cHoH-cr12-cr12-NR1112 IN where all included symbols are previously defined; In the reaction sequence, 1-aryloxy-4-chloro-2-butanol (IV) was reacted with an amine (V) to give the new 1-aryloxy-4-amino-2-buta- nolerna (I). The previous reaction can be carried out by (A) heating a mixture of the chlorine compound and the amine with a solution; IN in a steel container, (B) heating a mixture of the chlorine compound and the amine with a solvent in a steel container re, (C) refluxing a mixture of the chlorine compound, and a solvent at atmospheric pressure or (D) heating of the mixture of chlorine compounds and the amine without a solvent part at atmospheric pressure and at ambient temperature. The selection since the process obviously depends somewhat on the type of amine reactant. _ Thus, when the amine is a low molecular weight volatile amine, it is preferred processes A or B and the bomb contents are heated from around 100 ° C to about 150 ° C for a period of from about 12 hours to about 24 hours. When the amine is a high molecular weight,

Claims (1)

449 357 non-volatile amine or a low volatility amine, process C or D is preferred and the reaction mixture is refluxed * at the boiling temperature of the solvent used or the mixture is heated at about 100 to about 150 ° C. The reaction time can be varied, the reaction time being somewhat shorter when the chlorine compound and the amine reactant are allowed to react together in the absence of a solvent and where a higher reaction temperature is used. The reaction product is isolated in each case by conventional acid-base extraction procedures and the free base is converted, if desired, to a pharmaceutically acceptable acid addition salt, which can be further purified by crystallization from suitable solvents or solvent systems. 1-aryloxy-4-amino-2-butanols, which do not form well-defined salts, can be purified by vacuum distillation. A new chemical compound for use as an intermediate in the preparation of pharmaceutically active compounds of the formula Ar-O-CH2-CHOH-CH2-CH2-NR1R2, wherein Ar represents 1-naphthyl, 2-naphthyl, inden-4- (or - 5-) yl, 3-or--5-) chloro-2-pyridyl, phenyl with chlorine, methyl, phenyl, methoxy, ethoxy, acetyl or acetylamino mono- or disubstituted phenyl, and wherein R 1 represents lower alkyl, phenyl, benzyl, phenethyl, methylbenzyl, phenylpropyl, 2-hydroxymethyl--2-propyl, adamantyl or lower cycloalkyl, where R 2 represents hydrogen and R 2 together with the attached or lower alkyl, where R the nitrogen atom forms a heterocyclic radical, characterized in that it has the formula Ar-O-CH 2 -CHOH-CH 2 -CH 2 -Cl, where Ar has the meaning given above.