GB1595503A - N-bisphenethylamine derivatives - Google Patents

Description

(54) N, N-BISPHENETHYLAMINE DERIVATIVES (71) We, SMITHKLINE CORPORA TION, of 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, United States of America, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement :- This invention concerns substituted N, N-bisphenethylamines which are useful intermediates in the preparation of compounds having diuretic and/or cardiovascular activity described and claimed in British Patent Application 46184/77. (Serial No. 1, 595,502).

According to the present invention there are provided compounds of the formula

where R, is halo, e. g. chloro, or trifluoromethyl ; R, and R,, which are the same or different, are Cl~5 alkyl, e. g. methyl, or together represent methylene or ethylene ; and R4 is hydrogen or 1-3 substituents selected from trifluoromethyl, halo, methyl, ethyl, methoxy, e. g. paramethoxy, ethoxy, acetoxy and hydroxy. R2O and R30 are preferably in the 3-and 4positions.

The compounds of formula I above are conveniently prepared by heating equimolar amounts of a styrene oxide of formula

with a phenethylamine of formula

which is either known or can be prepared by methods known to the art, either alone or in an inert organic solvent, for example tetrahydrofuran. Preferably, the heating is effected on a steam bath or at reflux temperature for from 12 to 24 hours. The required styrene oxide is conveniently prepared by reaction of the ylide derivative from sodium hydride and trimethylsulfonium iodide with the appropriately-substituted benzaldehyde.

The following Examples are given by way of illustration. All temperatures are in degrees Centigrade.

EXAMPLE 1 A mixture of 100 g (0.55 mol) of 3,4dimethoxy-phenylethylamine and 66.2 g (0.55 mol) of styrene oxide in 200 ml of tetrahydrofuran was refluxed overnight.

The solvent was removed in vacuo. About 500 ml of n-butyl chloride was added to the residue and the mixture cooled slightly.

Filtration furnished N- [2- (3,4dimethoxyphenyl) ethyl]-2-phenyl-2- hydroxy-ethylamine, m. p. 92-93 .

The above prepared phenethylamine, 71. 5 g (0.238 mol), was dissolved in 400 ml of acetic acid and the solution was cooled. To this solution was added 16. 9 g (0.238 mol) of chlorine gas over a 30 to 45 minute period.

The reaction mixture was poured into water, made basic with 40% sodium hydroxide solution and about 250 ml of ether added to the stirred solution. The resulting solid was filtered to give N- [2 (2-chloro-4, 5-dimethoxyphenyl)- ethyl]-2-phenyl-2-hydroxy- ethylamine, m. p. 110-113 .

EXAMPLE 2 Isovanillin (200 g, 1. 32 mole) was suspended in 1200 cc chloroform. Chlorine (103 g, 1. 45 mole) was added by means of three 500 cc portions of carbon tetrachloride, in which it was dissolved. The suspension was stirred vigorously during the addition and the reaction was kept around 25 by a water bath. The suspension was stirred for 22 minutes after the completion of the addition of chlorine. The precipitate was filtered and crystallized from methanol, then recrystallized from isopropanol/ethyl acetate. Yield 98.7 g (40%, m. p. 204-206 ) of 2-chloro-3-hydroxy-4-methoxy benzaldehyde.

The aldehyde product (189.3 g, 1. 02 mole) was suspended in 1 1. of dry dimethylformamide, 350 g of potassium carbonate was added. 145 cc (124 g, 1. 54 mole) of dimethyl sulfate was added dropwise over a 20 minute period. After the addition the reaction was heated on the steam bath for 5 minutes. 70 cc of water were added and the reaction was again heated for 5 minutes on the steam bath. The mixture was then poured into ice water and the precipitate was collecte. It was crystallized from acetic acid/water (800 cc-50 cc). A second crop was obtained from the mother liquor.

Yield 180 g (90 Ó) of 2-chloro-3, 4dimethoxybenzaldehyde after drying, m. p.

69-70 .

The dimethoxybenzaldehyde (180 g, 0. 9 mole) was dissolved in 500 cc warm acetic acid. 61 g (. 8 mole) of ammonium acetate was added, followed by 160 cc of nitromethane. The reaction was heated vigorously on the steam bath for 3 hours.

Water was then added to the cloud point, while still heating, and the solution was cooled and scratched. The A-nitrostyrene began to oil out and then crystallized. The solution was cooled. The yellow crystals were collecte and dried in a vacuum oven.

Yield 175 g (80 (í m. p. 88-91 ) of 2chloro-3, 4-dimethoxy-nitro- styrene.

The nitrostyrene (80 g, 0.33 mole) was dissolved in 800 cc of dry tetrahydrofuran.

Lithium aluminum hydride, as a 3.7 M solution (260 cc, 0.36 mole), was put in a 51.

3 neck flash which has been dried and flushed with argon. It was diluted with 500 cc of dry ether. The solution of the nitrostyrene was added in a thin stream. The flask was cooled in an ice bath so that the heat of reaction caused a gentle reflux of the ether. After addition, the reaction was refluxed one hour, then worked up by adding 36 cc of water, 36 cc of 10% sodium hydroxide and 108 cc of water sequentially and carefully, while cooling the reaction in ice.

The precipitate was collecte, washed well with ethyl ether and discarded. The ether-tetrahydrofuran mixture was evaporated.

The above reaction was repeated on 83 g of nitrostyrene. The two crude products were combined and distille at 0.5 mm to collect at 142155 the product containing fraction which was pure 2- (2-chloro 3,4-dimethoxyphenyl) ethylamine by t. l. c.

(80 g).

The phenethylamine (25.7 g, 0. 12 mole) was heated to 115'ion an oil bath. Styrene oxide (14.4 g, 0.12 mole) was added and the reaction was heated for 1 hour. After cooling to 30 , 2 : 1 petroleum ether/acetone was added to dissolve the oil ; N- [ (2- hydroxy-2-phenylethyl)]-N- [2- (2'- chloro-3', 4'-dimethoxyphenyl) ethyl]amine, crystallized out in 37% yield (15 g) m. p. 100101 .

EXAMPLE 3 2-Chloro-3, 4-dimethoxyphenethylamine (1. 0 g) was reacted with 0.70 g of p- methoxystyrene oxide as described above to give the hydroxyphenethylamine ; m. p.

118. 5-121 .

EXAMPLE 4 A mixture of 9.7 g of sodium hydride, 38 g of trimethylsulfonium iodide and 25.2 g (0.185 mol) of o-methoxy-benzaldehyde is reacted to give o-methoxystyrene oxide.

A mixture of 34 g of 2-chloro-3, 4dimethoxy-phenylethylamine and 28 g of o-methoxystyrene oxide is heated with stirring under argon on a steam bath overnight. Chilling and stirring yields the product N- [2- (2-chloro-3, 4dimethoxyphenyl) ethyll-2-hydroxy-2- (2-methoxyphenyl) ethylamine.

EXAMPLE 5 A mixture of 42.0 g of 57sodium hydroxide dispersed in oil and 700 ml of dimethyl sulfoxide is stirred at 70-75 for one to one and one-half hours. The solution is diluted with 700 ml of dry tetrahydrofuran and cooled to 0 , under nitrogen. A 200 g (1. 0 mol) sample of trimethylsulfonium iodide is added in portions, maintaining the temperature between 0-5 . The mixture is stirred for 15 minutes and then a solution of 70.4 g (0.50 mol) of o-chloro-benzaldehyde in 300 ml of dry tetrahydrofuran is added dropwise. The resulting mixture is stirred at room temperature for four hours, poured into water and extracted with ether. The extract is washed with brine, dried and evaporated in vacuo to leave o-chlorostyrene oxide.

A solution of 27.5 g of N-benzyl-2chloro-3,4-dimethoxyphenylethylamine and 23.3 g (0.15 mol) of m-chlorostyrene oxide in 500 ml of methanol is stirred and refluxed overnight. The methanol is removed in vacuo and the residual Nbenzyl-N- [2- (2-chloro-3, 4 dimethoxyphenyl) ethyl]-2-hydroxy-2- (2-chlorophenyl) ethylamine is reduced without further purification. This sample (0.01 mol) is dissolved in ether, acidified with ethereal hydrogen chloride and the hydrochloride precipitates. The latter is dissolved in 90 ml of methanol, the solution is added to a mixture of 0.5 g of palladiumon-charcoal in 10 ml of ethyl acetate and the mixture is hydrogenated at room temperature for 90 minutes at 60 psi. The reaction mixture is filtered and the filtrate evaporated in vacuo to yield N- [2- (2chloro-3,4-dimethoxyphenyl) ethyl]-2hydroxy-2- (2-chloro-phenyl) ethylamine hydrochloride.

EXAMPLE 6 Following the procedure of Example 5 and employing 42.0 g of 57% sodium hydride in mineral oil, 200 g (0.1 mol) of trimethylsulfonium iodide and 70.4 g (0.50 mol) of o-bromo-benzaldehyde there is obtain o-bromostyrene oxide.

Similarly 2.71 g of N-benzyl-2chloro-3,4-dimethoxyphenethylamine and 2.33 g (0.015 mol) of o-bromostyrene oxide are reacted in methanol to give Nbenzyl-N- [2- (2-choro-3, 4dimethoxyphenyl)ethyl-2-hydroxy-2 (2-bromophenyl) ethylamine. The latter is converted to its hydrochloride, which is dissolved in 90 ml of methanol and hydrogenated over 1 g of 10% palladiumon-carbon in 10 ml of ethyl acetate at room temperature for six hours. The reaction mixture is filtered and evaporated in vacuo to leave N- [2- (2-chloro-3,4dimethoxyphenyl) ethyl]-2-hydroxy-2- (2-bromophenyl) ethylamine hydrochloride.

Substituting trifluoromethyl, fluoro, methyl, ethyl, ethoxystyrene oxides will give the compounds of this invention whose structures include the corresponding substituted I-phenyl moieties.

EXAMPLE 7 A mixture of 4.84 g of 50% of sodium hydride in mineral oil and 70 ml of dry dimethylsulfoxide was stirred at 65-70 for 80 minutes. After dilution with 70 ml of dry tetrahydrofuran, the mixture was cooled to 0 while a solution of 19.0 g (0.093 mole) of trimethylsulfonium iodide in 100 ml of dimethylsulfoxide was added. A solution of 12.6 g (0.0928 mole) of m-anisaldehyde in 40 ml of tetrahydrofuran was quickly added.

After stirring for 15 minutes at 0 and 1-1/2 hour at 25 , the mixture is poured into 1-1/2 1. of ice/water slurry and extracted well with water. The combined organic layers were washed with brine, dried and concentrated to give 13 g of crude epoxide. This is mixed with 13.0 g of 2- (2-chloro-3,4dimethoxyphenyl) ethylamine and heated at 110 for 4 hours. The product was chromatographed over silica gel with 3% methanol/chloroform. The product containing cuts were worked up to give 1.9 g of N- [2- (2-chloro-3, 4-dimethoxyphenyl) ethyl]-2-hydroxy-2- (m- methoxyphenyl) ethylamine, m. p.

95.5-96.5 .

The p-chlorophenyl congener melted at 99-100 . The p-methylphenyl congener melted at 117-118 .

EXAMPLE 8 A mixture of 8.0 g of 2-chloro-3,4dimethoxy-phenethylamine and 5.25 g of m-trifluoromethyl-a-methoxyphenethylbromide is heated at 100-105'for 21/2 hours. The product was partitioned between ethyl acetate and 5% sodium bicarbonate solution. The organic layer was removed, washed with brine, dried and concentrated. The residue was passed over 350 g of silica gel with 1 to 2% methanol/chloroform. The resulting product was an oil whose hydrochloride melted at 200-202 .

2-Chloro-3-hydroxy-4-methoxybenzaldehyde is treated with hydrogen bromide to give 2-chloro-3,4dihydroxybenzaldehyde which is converted to the methylenedioxy derivative with dibromomethane. The product is condensed with nitromethane and the resulting nitroethylene reduced to give the phenethylamine. This compound is condensed with p-methoxystyrene oxide to give the a-hydroxyphenethylamine.

Claims (9)

1. WHAT WE CLAIM IS : 1. Compounds of the formula

   where R, is halo or trifluoromethyl ; R, and R3, which are the same or different, are C, ~ alkyl or together represent methylene or ethylene ; and R, is hydrogen or 1-3 substituents selected from trifluoromethyl, halo, methyl, ethyl, methoxy, ethoxy, acetoxy and hydroxy.
2. 2. Compounds according to claim 1, where R2 and R3 are both methyl, and R, O- and, R, O- are in the 3-and 4positions.
3. 3. Compounds according to claim 2, in which R, is hydrogen or para-methoxy.
4. 4. Compounds according to any of the preceding claims in which R, is chloro.
5. 5. Compounds according to any of the preceding claims as herein specifically described in any of the Examples.
6. 6. A process for preparing compounds according to any of the preceding claims which comprises heating equimolar amounts of a styrene oxide of formula

   (where R, is as defined in claim 1) with a phenethylamine of formula

   (where R,, R and R, are as defined in claim 1) either alone or in an inert organic solvent.
7. 7. A process according to claim 6, wherein the solvent is tetrahydrofuran.
8. 8. A process for preparing compounds according to claim 1, substantially as herein described.
9. 9. Compounds according to claim I when prepared by a process according to any of claims 6 to 8.