DE1959898A1 - ortho-substituted phenaethylamines and process for their preparation - Google Patents

Description

Process for their manufacture

The present invention is concerned with or-üho ^ substituted Phenylamines, especially with derivatives of 2-Hydroxyplienäthylamins, which have valuable pharmacological properties, with processes for their preparation and with therapeutic Compositions containing these compounds as an active ingredient.

Surprisingly, it has been found that compounds of the formula I

.CH ₂ -CH ₂ -NH-B

in the

Denotes hydrogen, hydroxy, chlorine or lower alkoxy or lower alkyl with at most 4 carbon atoms,
Is hydroxy, methoxy, acetoxy or propionoxy,

009825/2136

B denotes alkyl, isoalkyl or cycloalkyl, where each of these groups can contain 3 to 8 carbon atoms inclusive, or dj ^c i denotes group -CR ^ R ^ ri-, in which R ₃ , R ₄ and R ₅ each represent methyl or ethyl.

and their acid addition salts have valuable pharmacological properties own. Standard experiments "on warm-blooded animals have shown that compounds of the formula I and especially their physiologically compatible acid addition salts are able to lower blood pressure. From this one can conclude that the connections and their salts are useful as hypotensive agents in, for example, hypertension.

The terms "lower alkyl" and "lower alkoxy" mean alkyl and alkoxy groups containing from 1 to 4 carbon atoms. Examples of lower alkyl groups are thus methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. Methyl and ethyl are preferred. Examples of lower alkoxy groups are ethoxy, ethoxy-j isopropoxy and butoxy groups. The term "alkyl" means an aliphatic, "saturated, unbranched hydrocarbon radical which can contain 3 to 8 carbon atoms, inclusive, which radical can be linked to the nitrogen atom by means of the first, second or third carbon atom thereof. Examples of such alkyl groups are 1- and 2-propyl, 1- and 2-butyl and 1-, 2- and 3-pentyl, -hexyl, -heptyl and -octyl groups. "Isoalkyl" means a terminally branched, saturated carbon radical of the formula - (CH ₀ ) -CH (CH -) - ^ where η represents zero or an integer from 1 to inclusive 5. Such isoalkyl groups are isopropyl, isobutyl, isopentyl- (3-methylbutyl), isohexyl- (4- methylpentyl), isoheptyl (5-methylhexyl) and isooctyl (6-methylheptyl). Cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

A range of primary, secondary and tertiary ortho-substituted Phenethylamines are known. For these connections v / urde

009825/2136

however, no hypotensive activity was reported. So increase that known 2-hydroxyphenethylamine, its N-methyl and 'N, N-dimethyl derivatives the blood pressure, as do a great number of other phenethylaroins, known as synpathomimetic amines are known. The previously unknown N-ethyl-2-hydroxyphenethylamine was synthesized and tested; it also shows pressor activity.

Structurally related ortho-substituted phenethylamines are has been described, for example by Horii and Inoi, Yakugaku Zasshi, -T7, 1095 to 1100 (1957) and in US Pat. 2,525,674, wherein secondary amines, which differ from oc-methyl-ß-C2-methoxyphehyl) ethylamine and in Japanese Patent Publication No. 3572/61 which includes similar derivatives of β-14ethyl-β- (2-methoxyphenyl) ethylamine. Although for a number of these connections biological activity, no compound has been reported to have hypotensive properties. It is known that <x- (2-methoxyphenyl) -ß-methylaminopropane is a valuable therapeutic gown, but is contraindicated in hypertension, see Merck Index. 7, edition (1960), page 669.

Thus, the present invention is concerned with new derivatives of 2-hydroxy- and 2-kethoxypheric amine which have unexpected and valuable properties in that they show hypotensive activity in warm-blooded animals. ',

With regard to their preparation, compounds of the formula I can be classified into two groups, i) those types of the formula I ₁ which are encompassed by the formula Ia

Yes

009825/2 136

wherein R 'is hydroxy or methoxy and

R ₁ and B have the definition given under formula I,

and ii) such species of Formula I, and especially the hydrochlorides thereof, which are encompassed by the formula Ib

CH ₂ -CH ₂ -NH-B

Ib

wherein R ₁ "has the meaning given for R. under formula I,

excluding hydroxy,
'Rp "means acetoxy or just propionoxy and

B has the meaning given under formula I.

The compounds of the formula Ia and their acid addition salts are obtained by reducing a compound of the formula II

H-A-NH-B '

II

made in which

A denotes the carbonyl or methylene group, B ^{1 has} the meaning given for B and additionally also represents alkanoyl or is.oalkanoyl with 3 to 8 carbon atoms inclusive, provided that either only A or B ¹ contains a carbonyl group, and R ₁ and R ₂ 'have the meaning given under formula Ia, the reduction being carried out in an inert solvent with a complex Metallhydrid or borane or Dibcrsn, if desired, a product in which R _{1 is} lower alkoxy and / or R ₂ ' is methoxy , is converted into the corresponding compound in which R ₁ and / or R ₂ 'are hydroxy, by ether cleavage and , if desired, a reaction product is converted into an acid addition salt with an inorganic or organic acid rule. Π Λ Q ο ο r , *

"U9825 / 2136 ·

BATH ORIGINAL

The terms "alkanoyl" and "isoalkanoyl" mean alkarioyl radicals, the alkyl and isoalkyl groups as they are 'under formula I defined correspond.

The reduction is carried out with borane, diborane or a complex metal hydride, such as sodium borohydride, in the presence of aluminum chloride, lithium aluminum hydride, diisobutyl aluminum hydride and similar in the presence of an aprotic inert organic solvent, preferably an ethereal solvent, such as tetrahydrofuran, ethyl ether or the like carried out. It is advisable to exclude moisture, and especially then, if borane or diborane are used, to work in an inert atmosphere, for example in a nitrogen atmosphere. to Initially, the reaction is tempered by temperature control by cooling; The reaction is terminated by warming achieved, usually by heating the reaction mixture to boiling temperature. The product is made by customary procedures isolated. ■

The starting materials of the formula II are amides in which one of the groups A or B ¹ contains the carbonyl function.

Amides of the formula II, in which A is the carbonyl group, can

on nen, for example, by treatment of an isocumauone-C2-oxole, 2-dihydrobenzo / ~ b_7furans) of formula III

III

wherein R. has the meaning given under formula Ia, with an amine of the formula HpM-B, in which B has the meaning given under formula I, can be obtained. These amides are obtained by mixing the reactants, optionally in an inert solvent, for example benzene.

009825/2136

Slight heating, for example to reflux temperature, can can be used to speed up the reaction. The amides are grounded in crystalline or liquid form by customary processes Form isolated and are generally sufficiently pure to be subjected to the above-mentioned reduction process without further purification to be used ..

The isocoumarans of the formula III are known, or they can be made from known materials, as described in more detail in the examples.

The amides of the formula II, in which B ^{1 is} n-alkanoyl, can * by alkanoylating a primary amine of the formula IV

IV

wherein R. and R ₂ ^{1 have} the meaning given under formula Ia, are prepared. Suitable alkanoylating agents are, for example, n-alkanecarboxylic acid anhydrides; the alkanoylation processes used are known.

Ψ A number of primary amines of the formula IV are known; others can be prepared, for example, by reducing the corresponding phenylacetamides.

A number of compounds falling under the formula Ia. fall and represented by the formula Ic

CH ₀ CH ₀ NH-B "

²² Ic

009825/2136

where R- is hydrogen, hydroxy, chlorine or lower alkyl or lower alkoxy with at least 4 carbon atoms

- indicates, ·. :. ■■ '.. "■.' ^: ·. - ■ .- ■ '■. ■ .. ■

R ₂ ¹ denotes hydroxy or methoxy and

B "denotes alkyl or isoalkyl, where each of the groups Contains 3 to 8 carbon atoms inclusive, or Cycloalkyl of 5 to 8 carbon atoms, inclusive means,

and their acid addition salts can be prepared by a process which involves reducing a compound of formula V

CH-CH-N-Z

^ - ι t ι

P QX

wherein P and Q together represent a bond, X is hydrogen and

-ZX is alkyl, isoalkyl or cycloalkyl or Q and X together are a bond,
P hydrogen and

Z denotes alkylidene, isoalkylidene or cycloalkylidene and ■ R «and Rp ^{1 have} the definitions given above,

with activated hydrogen or a complex metal hydride, if desired, hydrolysis of a product containing lower alkyl groups to give the corresponding hydroxy derivative and, if desired, conversion of the product into an acid addition salts with an organic or inorganic acid .

A number of terms used in the above definitions has been defined, in addition, the terms. "Alkylidene" and "Isoalkyliden" 1,1-alkylene groups, the "alkyl" and "isoalkyl ''respectively;" cycloalkylidene "means 1,1-cyclo- alkylene ^ the" cycloalkyl "corresponds.

009825/2136

The method is preferably carried out in the liquid phase, optionally in the presence of an inert solvent such as a lower alkanol, for example methanol, ethanol or Propanols If hydrogen is used for the reduction, then it is catalytically activated by a metallic catalyst, the metal being one of the palladium or platinum group. Suitable catalysts are, for example, platinum on charcoal or palladium on charcoal. It is beneficial at Print up to 100 atmospheres and at temperatures in the range to work from 20 to 100 ° C. The product is isolated from the reaction mixture by conventional methods, usually in Form of a salt, like the hydrochloride.

If a complex metal hydride is used, a solution of the Compound of formula V in a lower alkanol with sodium borohydride treated and the product isolated in a known manner.

The starting compounds of the formula V are prepared by mixing a phenylacetaldehyde, which _{is substituted in the phenyl ring according to the meanings of R 1} and R- ¹ , with an amine HpN-B ", where B" has the definition given under formula Ic, or by a phenylethylamine which is substituted in the phenyl ring according to the meanings of R ^ and Rp ', with a 2- or 3-alkanone or a cycloalkanone corresponding to the definitions given for "alkyl" and for the substituent B "under formula Ic "Cycloalkyl" mixed, if appropriate in solution. They are generally not isolated in bulk, but rather immediately subjected to the reduction described above.

/ ■ ■■

The necessary phenylacetaldehydes and phenethylamines are neither known nor produced by known chemical reactions.

The invention is also concerned with 2- (lower alkanoyloxy) -phenäthy1aminen and their hydrochloride salts of formula Ib

0Q982S / 2136

CH ₂ -CH ₂ -NH-B-HCl

Ib

Denotes hydrogen, chlorine, lower alkoxy or lower alkyl with a maximum of 4 carbon atoms,

Means acetoxy or propionoxy and

Is alkyl, isoalkyl or cycloalkyl, each of the groups containing 3 up to and including 8 carbon atoms, or the group -CR ₃ R ₄ R ₅ , in which R ₃ , R ₄ and R ₅ each represent methyl or ethyl.

Although these ester salts of the 2-hydroxy compounds produced by of the formula I are endowed with different physico-chemical properties, they are in relation to. their pharmacological activity that is hypotensive, the corresponding Very similar to phenols. These esters mentioned are valuable agents for the treatment of hypertensive conditions.

In the formula Ib contain the lower alkyl and lower alkoxy groups 1 to 4 carbon atoms inclusive; among the lower alkyl and lower alkoxy groups are the methyl, Ethyl, methoxy and ethoxy groups are preferred.

The ester salts of the formula Ib and the corresponding free bases are obtained by alkanoylating a compound of the formula VI "

CH ₂ -CH ₂ -NH-B

VI

009826/2136

where R ^ "and .B have the definition given above, with Acetyl or propionyl chloride, optionally prepared in the presence of the corresponding acid anhydride.

The alkanoylation is carried out by treating a salt of Formula VI with an acid chloride, optionally in the presence of the corresponding acid anhydride, produced at temperatures in the range from room temperature to 120 ° C. The product is isolated by removing the volatile constituents of the reaction mixture in vacuo and removing the residue from a lower alkanol, such as methanol or ethanol, optionally with dilution, with a lower dialkyl ether, such as diethyl ether, or a lower alkanone such as acetone, recrystallized.

The phenolic amine hydrochlorides of the formula VI can according to the process described in the first part of this application.

The following examples explain the invention in more detail without, however, restricting it. The temperatures are given in ° C.

example 1

a) Nn-propyl-2-hydroxyphenethylamine hydrochloride A solution of 19.32 g of Nn-propyl-2-hydroxyphenylacetamide (F = 65 ° C, decomp.) in 300 ml of anhydrous tetrahydrofuran is added dropwise over 1 hour to a stirred solution of 1 mol of boron in 300 ml of anhydrous tetrahydrofuran was added at 0 ° under nitrogen. After the addition is complete, the reaction mixture is refluxed for 4 hours. The cooled reaction mixture (0 °) is then carefully acidified by adding 700 ml of 3N hydrochloric acid and the tetrahydrofuran is removed by distillation under reduced pressure. The insoluble crude product is collected and air dried. Circum-

Installation of this material from ethanol / ether provides • 0 09825/2136

the above-mentioned propylamine hydrochloride, mp = 187 ° (dec.).

The starting material was produced as follows:

b) Nn-propyl-2-hydroxyphenylacetamide

A solution of 20 ml of n-propylamine in 50 ml of benzene is added dropwise to a stirred solution of 15 g of isocumarone in 150 ml of anhydrous benzene. After the addition v / ith the clear reaction mixture was stirred for 1/2 hour at room temperature and then heated on a steam bath, a v / _egg> tere 1/2 hours to reflux. The solvent is removed by distillation and the oily residue is vigorously stirred in 200 ml of petroleum ether (bp = 30 to 60 °), the product separating out as a colorless crystalline solid, melting point = 65 ° (decomposition).

Example 2

a) Nn-Butyl-2-Hydroxylphenethylamine Hydrochloride

A solution of 31 g of oily N-n-butyl-2-hydroxyphenylacetamide in 200 ml of anhydrous tetrahydrofuran is added dropwise to a solution of 1 pint of borane in 300 ml of tetrahydrofuran added at 0 under nitrogen. After the addition is complete, the reaction mixture is turned on for 4 hours Heated to reflux. 580 ml of aqueous Sn hydrochloric acid is carefully added to the reaction mixture, which has been cooled to 0 °, and the tetrahydrofuran is removed by distillation removed. The insoluble material is collected, washed with a little aqueous hydrochloric acid, and removed from methanol / Ether recrystallized, whereby the product of F = 190 ° (Decomp.) Receives.

The starting material was prepared as follows:

b) Nn-butyl-P- hyroxyphenylacetamide

A solution of 15 ml of n-butylanine in 50 ml of benzene is used . drop by drop, too. a stirred solution of 17 g of isocumarone in · 100 ml B.en.z.ol. at·. Room temperature added. After finishing

00982S / 2136 ^> -

BATH ORIGINAL

After the addition, the reaction mixture is left for 1/2 hour on Heated to reflux, and the solvents are removed by distillation under reduced pressure, the amide received as oil.

Game 3

a) N ~ Isopropyl-2-hvdroxvphenäthv1amin-hvdrochlorid A solution of 12 g of N-isopropyl-2-hydroxyphenylacetamide (melting point 117 to 118 °) in 125 ml of tetrahydrofuran is added dropwise to a stirred solution of 1 mol of borane in 188 ml of tetrahydrofuran 0 ° added under nitrogen. After the addition is complete, the reaction mixture is refluxed for 4 hours. The cooled reaction mixture is carefully acidified by adding 740 ml of aqueous 3N hydrochloric acid and the tetrahydrofuran is then removed by distillation. The aqueous residue is then made alkaline by adding 100 ml of 9N ammonium hydroxide solution, and the resulting solution is exhaustively extracted with ether. The combined extracts are dried over magnesium sulfate and concentrated under reduced pressure. The oily residue is taken up in 35 ml of ethanol, 7.8 ml of ethanolic 8,7N chlorine hydrogen is added, and the solution is diluted with 200 ml of ether. The precipitate, mp = 169 ° (dec.) Is collected and recrystallized from ethanol / ether to give the product as the hydrochloride, mp = 169.5 ° (dec.).

The starting material was prepared as follows:

b) N-1sopropv3-2-hydroxypheryl acetamide

A mixture of 19.8 g of isocumarone and 300 ml of isopropylamine • is refluxed for 1 hour, and the excess Amiη is then removed by distillation. The residue is dissolved in hot benzene and the benzene solution is evaporated until crystallization begins. The unusual

Crystals are collected and used with a second batch that was obtained by further concentration of the mother liquors, * united. Recrystallization de? Solid from benzene / hexane supplies the isopropylamide as colorless crystals, melting point = 117 to 118 °.

Example 4

^a ) ■ N-sec-butyl-2-hydroxyphenethylamine hydrochloride A solution of 12.44 g of N-sec .'-Butyl-S-hydroxyphenylacetamide (F = 63 °) in 150 ml of anhydrous tetrahydrofuran is added dropwise over 1 hour added to a stirred solution of 1 mol of borane in 180 ml of anhydrous tetrahydrofuran at 0 under nitrogen. After the addition is complete, the reaction mixture is refluxed for 4 hours. The reaction mixture, cooled to Ό, is then acidified by adding 580 ml of 3N hydrochloric acid, and the tetrahydrofuran is removed by distillation under reduced pressure. The remaining aqueous mixture is then adjusted to p = 9 with aqueous ammonia and extracted with ether. The ether extracts are washed once with water and dried over anhydrous magnesium sulfate. The ether is removed on a rotary evaporator and the residue is further dried by azeotropic distillation with benzene. The amine. is obtained as an oil and dissolved in 300 ml of anhydrous ether. Hydrogen chloride gas is passed through the cooled (0) and vigorously stirred ethereal solution for 1 hour. The mixture is then stirred at room temperature for an additional hour and the insoluble hydrochloride is collected by filtration, mp = 148 ° (dec.). Recrystallization from ethanol / ether gives the product, mp = 149 ° (decomp.).

The starting material was prepared as follows:

b) N-sec-butyl-2-hydroxyphenylacetamide

A solution of sec-bufcylamine in 50 τηΐ benzene is added dropwise to a stirred solution of 15 g of isocumarone in

00982S / 2136

100 ml of anhydrous benzene were added. After the addition is complete, the reaction mixture is refluxed on a steam bath for 1/4 hour and then the solvent is removed by distillation. The remaining oil is stirred in petroleum ether (boiling point 30 ° to 60 °) at 0 ° for 1 hour, the amide separating out as a colorless crystalline solid, melting point 63.

c) From N-isobutyl-2-hydroxyphenylacetamide, prepared according to the process from isocumarone and isobutylarriin specified in part b), obtained according to the method described in part a), the hydrochloride of N-isobutyl-2-hydroxy- ^ phenethylamine, F = 235 to 236 ° .-

d). If, instead of sec-butylamine, as described in part b), isoamylamine is used, the amide thus obtained is reduced according to the process described in part a), N- (3-methylbutyl) -2-hydroxyphenethylamine hydrochloride is obtained, F = 215 to 216 ° (dec.).

e) If 4-methylpentylamine is used instead of sec-butylamine in the process described in part b) and reduces the amide thus obtained according to the process described in part a), this gives N ~ (4-methylpentyl) -2-hydroxyphenethylamine-

K hydrochloride, F = 137-138.5 °.

w / - ■

Example 5

a) N-tert-Buty 1-2-hyclroxyphenäthylamin-hydrochlorid A solution of, 28 g of N-tert-Butyl-2-hydroxyphenylacetamid in 125 ml Tetrahydrofuran is added dropwise to a stirred solution of 1 Hol of borane in 400 ml Tetrahydrofuran given at 0 ° _i under nitrogen. After the addition, the reaction mixture is refluxed for 4 hours. The cooled reaction mixture is acidified by the careful addition of 800 ml of aqueous 3N hydrochloric acid, and the tetrahydrofuran is then removed by distillation. It settles in

009825/2136

this

Oil from and / partially crystallizes on standing. The insoluble Material is dried by azeotropic distillation with ethanol / benzene and the residue is triturated with ether. The crystalline material is recrystallized from ethanol / ether to give the product, mp = 239 ° (decomp.).

The starting material was prepared as follows:

b) N-tert-butyl-2-hydroxyphenylacetamide A solution of 18.3 g of 2-hydroxyphenylacetic acid lactone in 175 ml of tert-butylamine is refluxed for 15 hours and then the excess amine is removed by distillation. The residue is dissolved in benzene and evaporated to dryness under reduced pressure to give the amide which does not require further purification.

Example 6

a) N-Cyclopropyl-2-hydroxynhenäthylflT.in hydrochloride A solution of 19.12 g of N-cyclopropyl-2-hydroxyphenäthylacetamid (F = 125 °, decomp.) in 250 ml of anhydrous tetrahydrofuran is for 1 hour to a stirred solution of 1 mol of borane in 250 ml of anhydrous tetrahydrofuran was added at 0 ° under nitrogen. When the addition is complete, the mixture is refluxed for 4 hours. The reaction mixture, cooled to 0 °, is then acidified by adding 7 ml of Sn hydrochloric acid, and the tetrahydrofuran is removed by distillation under reduced pressure. The residue is adjusted to p = 9 with dilute aqueous ammonia and extracted exhaustively with ether. The combined ether extracts are washed once with water and dried over anhydrous magnesium sulfate. Removal of the Xether on a rotary evaporator yields the desired amine as an oil. Anhydrous hydrogen chloride is passed through a stirred solution of the amine in 500 ml of anhydrous ether for 1 hour. The colorless crystalline hydrochloride that forms is collected and mixed with it

00982 5/2 x 1 3 a:: -;

BATH ORIGINAL

1959838

Ether washed. Recrystallization from methanol / ether provides «Yes product, F = 168 °.

The starting material was prepared as follows:

b) N-Cyclopropyl - ^ - hydroxyphenylacetamide A solution of 20 q cyclopropylamine in 50 ml benzene is added dropwise over 15 minutes to a stirred solution of 20 g isocumarone in 100 ml anhydrous benzene. The mixture is stirred at room temperature for 1/2 hour and then refluxed at steam bath temperature for 15 minutes. The solvent is removed by distillation, and 50 ml of petroleum ether are added to the hot mixture. The amide separates out on cooling. It is collected and washed well with benzene, F = 125 (decomp.).

Example 7

a) N-Cyclopenty1-2-hydroxyphenäthy1amin-hydrochlorid · A solution of 13.16 g of N-Cyclopentyl-2-hydroxyphenylacetamid (F = 128 °, dec.) in 200 ml of anhydrous tetrahydrofuran is added dropwise over 1 hour to a stirred solution of 1 mol of Borah in 130 ml of anhydrous tetrahydrofuran was added at 0 ° under nitrogen. After the addition is complete, the reaction mixture is refluxed for 4 hours. The reaction mixture, cooled to 0 °, is carefully acidified with 550 ml of 3N hydrochloric acid, and the tetrahydrofuran is removed by distillation under reduced pressure. The aqueous mixture that remains is allowed to stand for 15 hours and the insoluble material is collected and air-dried. Recrystallization from ethanol / ether gives the product, F = 201 ° (decomp.,) ..

The starting material was prepared as follows;

b) N-Cyclopenty1-2-hydroxyphenylacetamide A solution of 15 ml of cyclopentylamine in 50 ml of benzene becomes

00982 5/2136

dropwise to a stirred solution of 15 g of isocumarone added in 100 ml of anhydrous benzene. When the addition is complete, the resulting clear reaction mixture will open up refluxed on a steam bath for 1/2 hour, and then be Removed approx. 50 ml of the solvent by distillation. The solid that forms on cooling is collected and washed well with cold benzene. Pas Amid has one F = 12 8 ° (dec.).

Example 8

a) N-Isopropyl ^ -hydroxy-S-methoxYphenäthylamine hydrochloride A solution of 19.3 g of N-isopropyl ^ -hydroxy-S-methoxyphenylacetamide (melting point 135 ° to 136 °) in 350 ml of anhydrous tetrahydrofuran is added dropwise over 1 hour a stirred solution, cooled to 0 °, of 1 mol of borane in 300 tnl of anhydrous tetrahydrofuran was added under nitrogen. After the addition is complete, the mixture is refluxed for 4 hours. The reaction mixture, cooled to 0 °, is acidified with 700 ml of aqueous 3N hydrochloric acid, and the tetrahydrofuran is then removed by distillation under reduced pressure. The mixture is cooled, adjusted by addition of aqueous ammonia to p _H 9, and extracted with ether. The ether extracts are washed with water and dried over anhydrous magnesium sulfate * Removal of the ether on a rotary evaporator yields the isopropylamine as a colorless oil. Anhydrous hydrogen chloride is bubbled through a stirred solution of the amine in 500 ml of anhydrous ether for 1 hour, and the mixture is then stirred for an additional hour. The Amih hydrochloride is collected, washed with ether, air-dried and recrystallized from methanol / ether, mp = 179 to 180 °.

The starting material was manufactured as follows:

009825/2 136

b) 2, S-dimethoxy'-phenylacetyl chloride

A solution from. 101 g of 2,3-dimethoxyphehylacetic acid in 300 ml of benzene is added dropwise to a stirred solution 'of 100 ml of thionyl chloride in 200 ml of benzene. After the addition is complete, the mixture is refluxed for 2 hours heated, and excess reagent and solvent be on a rotary evaporator at room temperature removed, whereby the acid chloride is obtained without further Cleaning can be used in the next stage.

c.) 7-Methoxy-2-oxo-2,3-dihydrobenzo / ~ b 7furan

A solution of 43 g of 2,3-dimethoxyphenylacetyl chloride in * 200 ml of carbon disulfide slowly turns into a suspension of 53.2 g of anhydrous aluminum chloride in 1400 ml of carbon disulfide added at 0 °. After the addition has ended, the mixture is stirred at 0 for 24 hours. The mixture is v / ird then into a mixture of 500 ml of concentrated hydrochloric acid and ice poured, the carbon disulfide layer is separated and the aqueous layer is washed with ether. The organic extracts are combined, washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provides an oily residue which is distilled in vacuo. That Product is collected at 115 ° / O, 005 torr, and is used immediately ._ /fixed.

d) N ~ Isopropyl-2-hydroxy-3-methoxyphenylacetamide A solution of 22 ml of isopropylamine in 50 ml of benzene is added dropwise over 1/2 hour to a stirred solution of 22 g of 7-methoxy-2-oxo-2,3-dihydrobenzo / ~ b_7furan in 150 ml of benzene was added. After the addition is complete, the solution is refluxed at steam bath temperature for 15 minutes and then concentrated to half its volume. The mixture is stirred vigorously and 50 ml of petroleum ether are added. The solid is collected and washed well with cold benzene. Air drying gives the desired amide, mp = 135-136 °.

003826/2 "! 36

e) If n-butylamine is used instead of isopropylamine in the in part d) described method and reduces the resulting arnid according to the method described in part a), this gives W-n-butyl ^ -hydroxy-S-methoxyphenethylamine hydrochloride, F = 177 to 178 degrees.

Example 9

a) N- Isopropyl-2-hydroxy-3-methylphenylacetamide CF = 141 to 142.5 °) in 60 ml of dry tetrahydrofuran added dropwise to a stirred solution of 1 mol of borane in 175 ml of tetrahydrofuran under nitrogen at 0 °. After the addition is complete, the reaction mixture is heated at reflux temperature for 4 hours. 250 ml of aqueous 3N hydrochloric acid is carefully added to the cooled reaction mixture, and then the tetrahydrofuran is removed by distillation under reduced pressure until crystallization begins. The reaction mixture is allowed to stand for 15 hours and the resulting pesticide is collected and dried by azeotropic distillation with ethanol / benzene. Two recrystallizations from methanol / ether yield the product, F = 181 to ie?, 5 °.

The starting material was prepared as follows:

b) o-To] ν 1 glyoxylic acid chloride

A solution of 112.5 g of o-cresol in 560 ml of anhydrous Benzene is added 'over 50 minutes to a stirred solution of .14 3.3 g of oxalyl chloride in 1030 ml of benzene, with is kept at reflux temperature by external heating. After the addition has ended, the reaction mixture is refluxed for 8 hours. The benzene (solvent.) And Excess oxalyl chloride is removed by distillation and the residue is distilled under reduced pressure, whereby the acid chloride, 2-hydroxy-3-methylphenyiglyoxalic acid chloride, as yellow oil, bp = 106 / iö Torr.

009825/21

1953898

n ^ ⁵ receives 1.5123.

c) 2,3-Dioxo-7-methyl-2,3-dihydrob; jnzo / ~ b_7furan

A solution of 148.1 g of o-tolylchloroglyoxalate in 180 ml of 1,1,2,2-tetrachloroethane is used over a period of 90 minutes to an ice-cold suspension of 115 g of aluminum chloride given in 420 ml symmetrical tetrachloroethane. the The reaction mixture is then stirred for 15 hours at room temperature. 400 ml of aqueous 3N hydrochloric acid and then Water are added to the chilled mixture, "The Mixture is diluted with a little chloroform to separate the emulsion ^ and the organic layer is separated. the organic layer is made with 3N hydrochloric acid, then washed with water and finally with a little saturated sodium chloride solution. The solution is made over magnesium sulfate dried and most of the solvent is stripped off under reduced pressure. The residue becomes carbon tetrachloride diluted, and the yellow crystals which separate out are collected and dried, F = 97 up to 128 °.

d) 2-Hydroxy ~ 3-rne thy! mandelic acid lac ton

A mixture of 30 g of 2,3-dioxo-7-methyl-2,3-dihydrobenzo- / b_7furan and 3 g of 10% palladium on charcoal in 750 ml of acetic acid is shaken under hydrogen at atmospheric pressure ml of hydrogen have been consumed, the uptake of hydrogen ceases. The filtered solution is stripped from the solvent under reduced pressure. The residue is dissolved in ether and washed with sodium bicarbonate solution and then with a little water. The solution is dried over magnesium sulfate and stripped of solvent under reduced pressure to give the lactone as a yellow oil.

e) 7-Hethvl-2-oxo-2,3-dihydrobenzo / ~ b 7furan

A mixture of 1.61 g of red phosphorus, 0.537 g of iodine and 20 ml of glacial acetic acid will stand at room temperature for 25 minutes.

009825/2136

left, and a solution of 7.3 g of 2-hydroxy-3-methylmandelic acid lactone in 9 ml of acetic acid and 0.54 ml of water are then added. The resulting reaction mixture is stirred for 3 hours under reflux. The reaction mixture is filtered hot and the filtrate is stirred into a well Solution of 2.5 g of sodium bisulfite in 100 ml of water poured. After the mixture has been stirred for 1 hour, the crystalline product is collected, washed well with water

ο -3 and dried. Sublimation at 80/5 χ 10 Torr the lactone as pale yellow crystals, mp = 95 to 96.5 °.

f) N-Isopropy 1-2-hydr oxy t-3-nrte thy! p h e nyl acetamide 15 ml of isopropylamine are added to a stirred solution of 15 g of 7-methyl-2-oxo-l, 2-dihydrobenzo / ~ b_7furan in 130 ml of dry benzene. The resulting solution is stirred at room temperature for 15 minutes, then at 50 ° for 1 hour and finally for 2 hours at reflux temperature. The benzene is removed under reduced pressure until crystallization begins, and the mixture is then left to stand for 15 hours. The collected white crystalline amide has a.F = 141 to 142.5 ° after drying.

Example 10

a) Nn-Octyl-2-hydroxyphenäthvlamin-hydrochlorid A solution of 22.6 g of Nn-octyl-2-hydroxyphenylacetamide (F = 42 to 49 °) in 60 ml of tetrahydrofuran is added dropwise to a solution of 3N-Borane in 172 ml Tetrahydrofuran was added at 0 under nitrogen. When the addition is complete, the reaction mixture is refluxed for 4 hours. To the cooled reaction mixture, 250 ml of aqueous 3N hydrochloric acid are carefully added, and the tetrahydrofuran is then distilled off. The product separates out of the aqueous residue and is collected, dried by azeotropic distillation with benzene / ethanol and recrystallized twice from methanol / ether, melting point 107 to 109 °.

00382S / 2136

The starting material was prepared as follows:

b) Nn ~ Qctyl-2-hydroxyphenylacetamide

12 ml of n-octylamine become a solution of 12 g of isocumarone added in 130 ml of benzene, and the resulting slightly yellow solution is stirred for 4 hours at 70 ° and then for 2 days at Room temperature. The reaction mixture is concentrated under reduced pressure. A solution to the lagging Oil in ether is treated with aqueous 3N hydrochloric acid and then washed with water, dried over magnesium sulfate and finally concentrated under reduced pressure to give a heavy oil which slowly crystallizes, F = 42 to 49 °.

Example 11

a) N-Cycloocty1-2-hydroxyphenethylamine hydrochloride . A solution of 26.3 g of N-isopropyl-2-hydroxyphenylacetamide (F = 96-108 °) in 80 ml of anhydrous tetrahydrofuran is added dropwise to a solution of 1 mol of borane in 202 ml of tetrahydrofuran at 0 ° under nitrogen. After the addition is complete, the reaction mixture is refluxed for 4 hours. 295 ml of aqueous 3N hydrochloric acid are carefully added to the cooled reaction mixture and the solvent is then removed by distillation. The precipitate is collected and then washed with aqueous 3N hydrochloric acid. The solid is dried by azeotropic distillation with ethanol / benzene and then recrystallized from methanol / ether, the product being obtained as white crystals, F. = 133 to 137 ° (dec

The starting material was prepared as follows:

b) N-Cycloocty1-2-hydroxyohenylacetami d A mixture of 15 g of isocumarone, 20 ml of cyclooctylamine and 150 ml of benzene is refluxed over power, and the solvent is then reduced by distillation under reducing

009825/2136

temp pressure removed. ' The residue is dissolved in ether and first with aqueous 2N hydrochloric acid and then with Water washed. The essential solution is over ϊ-iagnesiumsulfat dried and concentrated under reduced pressure to give the amide as a heavy oil which crystallizes obtained, F = 96 to 108 °.

Example 12

Reduction of the following amides:

N-isopropyl-2,6-dihydroxypheny / acetamide, mp = 90 ° (decomp.),
N-Isopropyl-2-hydroxy-5-methylphenylacetamide, mp = 145 ° (decomp.), N-isopropyl-2-hydroxy-4-methoxyphenylacetamide, mp = 85 ° (decomp.), N-isopropyl-2-hydroxy -5-methoxyphenylacetamide (oil) and
N-Isopropyl - ^ - hydroxy-S-chlorophenyiacetamide, m.p. 178 to 179 °

with diborane in tetrahydrofuran in the manner described in Examples 1 to 11 gives the following amines:

a) N-Isopropyl- ^ jo'-dihydroxyphenathylamine hydrochloride, F =
144 ° (decomp.),

b) N-isopropyl ^ -hydroxy-B-methylphenäthylamine hydrochloride, F = 162 ° (dec.),

c) N »isopropyl-2-hydroxy-4-methoxyphenethylamine hydrochloride, F - 152 ° (dec.),

d) N-isopropyl ^ -hydroxy-S-methoxyphenethylamine hydrochloride, F = 117 ° (dec.),

e) N-isopropyl- 2-hydroxy-5-chlox "ph en a thy lamina-hydro chloride,
F = 199 ° (dec.).

The required starting materials are obtained from the following isocoumarones and the appropriate amines as described in the previous examples:
S-oxo-4-hydroxy-2,3-dihydrobenzo / ~ b_7furan,
2-oxo-5-methyl-2,3-dihydro likewise / "b_7furan,
2-oxo-5-methoxy-2,3-dihydrobenzo / ~ b_7furan,
2-oxo-5-chloro-2,3-dihydrobenzo / ~ b 7furan *
2-oxo-6-methoxy-2,3-dihydrobenzo (b] furan.

009825/2136

The required isocoumarones can be prepared as follows will:

2,6-Dimethoxypheny! Acetonitrile, which is for example from 2,6-dimethoxybenzoic acid by esterification, reduction of the benzyl alcohol with borane, conversion into the benzyl chloride can be obtained with thionyl chloride and treatment with sodium cyanide, is hydrolyzed with sodium hydroxide, 2,6-Dimethoxypheny! acetic acid, F = 149 to 150 °. This is treated with 46% hydrobromic acid, whereby 2,6-Dihydroxyphenylacetic acid is obtained, which then with p-toluenesulfonic acid to the 2-oxo-4-hydroxy-2,3-dihydrobenzo / ~ "b_7f uran, F = 138 to 140 ° is cyclized. 2-oxo-5-methyl-2,3-dihydrobenzo / ~ b_7furan, F = 73 to 74 °, is obtained in an analogous manner from 2-methoxy-5-methylphenylacetonitrile.

2-Oxo-5-chloro-2,3-dihydrobenzo / ~ b_7furan, F = 132 °, obtained from 2-hydroxy-5-chlorophenylacetic acid by ring closure with p-toluenesulfonic acid.

2-Oxo-5-methoxy-2,3-dihydrobenzo / ~ b_7furan, F = 90 to 91 °, is made from 2,5-dimethoxyphenylacetyl chloride by adding a Solution of 23.2 g of the acid chloride in 100 ml of carbon disulfide to a suspension of 28 g of anhydrous aluminum Chloride in 700 ml of the same solvent under nitrogen and obtained at 0 °. After the addition is complete the mixture was stirred at 0 ° for 24 hours and then with a Mixture of 400 ml of hydrochloric acid and ice decomposes. The aqueous layer is separated and extracted with chloroform, and the combined extracts and the organic Layer with water, aqueous sodium hydroxide and again washed with water. Kach dry over magnesium sulfate the organic solution is evaporated under reduced pressure to obtain the desired compound, die'by distillation at 115 to 117 ° / O, O5 Torr, further purified, can be. -,. -,

009825/2136

BATH ORIGINAL

Example 13-

Nn-Butyl-S-chloro ^ -hydroxyphc-näthylarTiin hydrochloride a) A solution of 31.7 g of Nn-butyl-S-chloro - ^ - hydroxyphenylacetamide in 160 ml of anhydrous tetrahydrofuran is added dropwise to a stirred and cooled to 0 ° 1 -molar solution of borane in 288 ml of the same solvent added under a protective layer of nitrogen. After the addition is complete, the resulting mixture is refluxed for 4 hours. The mixture, cooled to 0 °, is carefully acidified with 380 ml of aqueous 3N hydrochloric acid, and the solvent is reduced under reduced pressure. Pressure removed. After standing overnight, the precipitate is collected and dried. Recrystallization from methanol / ether gives the product as colorless crystals, melting point = 130.5 ° to 132 °.

b) Similarly, 2-Οχο-7-π ^ ηγ1-2,3-dihydrobenzo / ~ * b 7-furan is obtained and n- butylamine N-rn-butyl-2-hydroxy-3-methyl phenyl acetamide, F = 52 to 54, which, as described in part a), is reduced, using N-n-butyl-2-hydroxy-3-methylphenethylamine hydrochloride, F = 130 to 131 °.

c) Nn-butyl-5-chloro-2-hydroxyphenylacetamide

A mixture of 28 g of 2-oxo-5-chloro-2,3-dihydrobenzo / ~ "b_7-furan and 28 ml of n-butylamine in 280 ml of anhydrous benzene is refluxed for 3 hours. The mixture is then reduced to half of its original pressure Concentrated by volume, and petroleum ether becomes clouded admitted. The solid is collected by filtration, washed with cold benzene and dried, whereby the amide, F = 107 to 109 °, is obtained.

Example 14 N-n-hexyl-2-hydroxyphenethylamine hydrochloride

Using n-hexylamine instead of n-butylamine in the process of Example 2, the title compound is obtained as

009825/2136

- 26 the hydrochloride with an F = 112 ° (decomp.).

Example 15

N-isopropyl -? - hydroxyphenäthy3 g n in hydrochloride A solution of 9.7 g of N-isopropyl-2-hydroxyphenylacetamide in 75 ml of anhydrous tetrahydrofuran is added dropwise ml at room temperature to a stirred suspension of 3.8 g Lithiumaluminiumnydrid in 100 of the same Solvent added. After the addition is complete, the resulting mixture is stirred at room temperature overnight and then refluxed for 4 hours. Excess lithium aluminum hydride is destroyed by carefully adding 25 ml of isopropanol to the cooled mixture. 150 ml of aqueous 3N hydrochloric acid are then added and the solvents are removed by distillation under reduced pressure. The solid is collected, washed with 3N hydrochloric acid and dried. Recrystallization from methanol / ether gives the product as colorless crystals, temperature = 169 to 171 °, a mixed melting point with an authentic sample shows no melting point depression.

Example 16

N-n-butyl-2-hydroxyphenethylamine hydrochloride

ψ A solution of 3.5 ml of butyric anhydride in 15 ml of anhydrous benzene is added dropwise to a stirred mixture of 3.0 g of 2-hydroxyphenethylamine and 1.6 ml of triethylamine in 30 ml of _: benzene; After the addition is complete, the mixture is refluxed for 3 hours. The cooled mixture is washed with potassium bicarbonate solution and then with water. After drying over magnesium sulfate, the solution was concentrated to give the N- (2-hydroxyphenethyl) butyramide as an oil which slowly solidified, F = 70.

This material was then, as described in part b) of Example 2, reduced, the amine hydrochloride, F =

held that in j <

009025/2133

188.5 to 190 °, which in every respect with the in

Example -2 was identical to the product described.

Example 17

a) H -Isopropyl-P-methoxvphenetyr / larnin-hydro c hlorid A solution of 14.5 g of N-isopropyl-2-methoxyphenylacetamide in 200 ml of anhydrous tetrahydrofuran is added dropwise over 1 hour to a stirred solution of 1 mol of borane in 140 ml of the same solvent at 0 ° and under nitrogen, added. After the addition is complete, the mixture is refluxed for 4 hours. 500 ml of aqueous 3N hydrochloric acid are carefully added to the cooled mixture (0 °) and the solvent is then removed by distillation under reduced pressure. Aqueous ammonia is added to the mixture until it has a basic reaction (p "8 to 9) and then extracted with ether. These extracts are washed once with water and then dried over anhydrous magnesium sulfate. Removal of the ether under reduced pressure yields the aniine as a colorless oil. Water-free hydrogen chloride is passed through the stirred solution of this amine in 500 ml of anhydrous ether for 1 hour. The mixture is stirred at room temperature for an additional hour and the insoluble amine hydrochloride is collected. Recrystallization from ethanol / ether gives N-isopropyl-P-methoxyphenethylamine hydrochloride as colorless needles, F = 1 (51 ° (decomp.).

Similarly, the following are obtained from the corresponding acetamides Amine hydrochloride:,.

b) N-Isopropyl-Z-methoxy-S-chlorophenäthylarr.in hydrochloride, F »" 171 to 172 °, ·

c) N-Isopropyl ^^ - dimethoxyphcnäthylamin-hydrochlorid, F = 182 ° (decomp.),

d) N-isopropyl ^ -methoxy-S-methylpher.äthylairiin-hydrochloride,

■■ '■' · 009825/2 136 "" ■ ~ "* °°°" ^r ' ^Λ '

e) N-n-butyl ^ -methoxy-S-chlorophenethylamine hydrochloride, F = ISO up to 191 °,

f) K-Isopropyl-2,3-dimethoxyphenärhylamine hydrochloride, F = 121 ° (decomp.),

g) N-isopropyl-2, S-dirnethoxyphenethylainin hydrochloride, F = 138 ° (decomp.),

h) N-n-butyl-2,3-dimethoxyphenethylamine hydrochloride, F = 135 °.

The starting materials were obtained in the following way:

A solution of 24 g of thionyl chloride in 50 ml of benzene is added " fenv / ice to a stirred solution of 24.9 g of 2-methoxyphenylacetic acid placed in 200 ml of anhydrous benzene. After completion then the mixture is refluxed for 2 hours and then stirred for 1 more hour at room temperature. Excess reagent and the solvent are reduced under reduced Pressure removed, and what remained darkened Oil is distilled at 100 ° / l, 5 Torr, 2-methoxyphenylacetyl chloride, which is again distilled at 85 ° / 0.5 torr is received.

A solution of 15 ml of isopropylamine in 50 ml of ether is added dropwise to a stirred and cooled solution of 15.5 g of 2-methoxyphenylacetyl chloride in 350 ml of anhydrous "ether given. After the addition is complete, the mixture is 15 minutes heated to reflux and the solid removed by filtration. The ether solution is washed well with water and then dried over anhydrous magnesium sulfate. distance of the ether under reduced pressure gives N-isopropyl-2-methoxyphenylacetamide as a colorless solid, mp = 108 ° (decomp.).

Similarly, from isopropylamine and

00982 5/2 13 6

BATH ORIGINAL

1) 2-methoxy-5-chlorophenylacetic acid,

2) 2,6-dimethoxyphenylacetic acid (obtained (by hydrolysis of 2,6-dimethoxyphenyl acetonitrile),

3) 2,3-dimethoxyphenylacetic acid,

4) 2-methoxy-5-methylphenylacetic acid (obtained from 5-methylsalicylic acid by etherification and esterification with dimethyl sulfate, reduction of the resulting methyl 2-methoxy-5-methylbenzoate to the corresponding benzyl alcohol and chain extension by nitrile synthesis),

5) 2,5-dimethoxyphenylacetic acid and

6) from n-butylamine and 2-methoxy-5-chlorophenylacetyl chloride:

N-Isopropyl-2-methoxy-5-chlorophenylacetamide, F = 132, N-Isopropyl-2,6-dimethoxyphenylacetamide, F = 137, N-Isopropyl-2,3-dimethoxyphenylacetamide, F = 116, N-Isopropyl-2-methoxy ~ 5-methylphenylacetamide, F = 108, N-Isopropyl-2,5-dimethoxyphenylacetarr.id, F «100 ° (dec.) and N-n-Butyl-2'-methoxy-5-chlorophenylacetamide, F = 104 bis 105 °.

In a similar way one obtains from

7) 2,3-dimethoxyphenylacetic acid and n-butylamine the following Amide: N-n-Buty1-2,3-dimethoxyphenylacetamide, F-72 °.

009825/2136

Example 1 8 '. ■ ■

K-Isopropyl-2-Hydroxypher.ät'nylarnirihepi: anoat . ■■: ■■ - ·

A solution of 10.0 g of N-isopropyl-2-hydroxyphenethylamine hydrochloride in i-ethanol one equivalent of aqueous' Sodium Hydroxide Treated. The resulting mixture is concentrated to dryness and the residue is extracted with isopropanol . The extracts are concentrated under reduced pressure to give the free base.

A solution of this free base in methanol is treated with 6.6 g of heptane carboxylic acid. The resulting solution is concentrated, giving a heavy oil which slowly crystallizes. Provide two recrystallizations from ether the salt as white crystals, F = 93.5 to 95.5 °.

Example 19

N-Isopropyl-2,3-dihydroxypher.äthylamiri-hvdroch lorid A mixture of 1 g of N-isopropyl-2-hydroxy-3-methoxyphenethylamine hydrochloride in 30 ml of concentrated aqueous hydrochloric acid is heated in a sealed tube for 3 hours at 160 ° . Concentration of the resulting solution under reduced pressure gives the product, which is recrystallized from methanol / ether, F = 145 °.

Example 20

N-isopropyl-2-hydroxyohenethylamine hydrochloride a) A mixture of 0.8 g of N-isopropyl-2-methoxyphenethylamine hydrochloride and 30 ml of concentrated hydrochloric acid is heated to 160 ° in a sealed tube for 3 hours. The resulting clear solution is concentrated under reduced pressure, and the solid obtained is recrystallized from methanol / ether, the product being obtained as colorless crystals, mp = 168 to 169 ° (decomposition. The compound was identical in every respect to the compound, which was produced according to Example 3.

009825/2136

^BA ®

mm YY ^ mm

In a similar way one gets from

N-isopropyl-2-methoxy-5-chlorophenethylamine hydrochloride, N-Isapropyl ^ .G-dimethoxyphenäthylerp.inr-hydrochloride, N-Isopropy l-2-ir.ethoxy-5-methyl-phene-thy-larnine-hydrochloride and N-n-Butyl ^ -methoxy-S-chlorophenylarein hydrochloride

the following products:

b) N-isopropyl - ^ - hydroxy-B-chlorophenethy] amine hydrochloride, F = 199 ° (dec.),

c) N-Isopropy1-2,6-dihydroxyphenethy1amine hydrochloride, F = 144 ° (decomp.),

d) N-isopropyl ^ -hydroxy-S-methylphenäthylamine hydrochloride, F = 162 ° (dec.) And

e) N-n-Butyl - ^ - hydroxy-S-chlorophenethylamine hydrochloride, F -131 up to 132 °.

Example 21

a) N-Isopropy] -P-acetoxyphonäthylaTiin-hydrochlorid

A mixture of 1.0 g of N-isopropyl-2-hydroxyphenethylamine hydrochloride and 10 ml of acetyl chloride is kept at room temperature for 72 hours. The resulting solution will concentrated under reduced pressure, last traces of Acetyl chloride is removed by codestruction with benzene. A white solid is obtained, mp = 136.5 to 138 °. Recrystallization from acetone gives the analytically pure one Ester, m.p. 138-140 °.

b) -In an analogous manner, one obtains from propionyl chloride and N-isopxopyl-2-hydroxyphenethylamine the ti-isopropyl-2-propionoxyphenethylamine hydrochloride, F = "- 129.5 to 132 °.

Similarly, the following links are obtained at Use of the corresponding 2.-hydroxyphenethylamine:

up to 104 °,

c) N-eycjeoetyl - ^^ - aGefcö'jiyphenäth.ylamine hydrochloride,: F = 1O2

009825/2 136

BATH ORIGINAL

d) N-Cyclopentyl-2-acetoxyphenethylamine hydrochloride, F = 141 °,

e) N-isopropyl ^ -acetoxy-S-chlorophenethylamine hydrochloride, F = 196 to 197 ° and

f) N-n-Butyl-Z-acetoxy-B-chlorophenMthylamine-hydrochloride, F = 159 to 160.5 °.

Beis piel 22

N- Isopropyl ^ -pcetoxyphenethylarein hydrochloride A solution of 10.0 g of H-isopropyl-2-hydroxyphenethylamine hydrochloride, 25 ml of acetylene chloride and 25 ml of acetic anhydride is heated to 100 ° for 22 hours. The cooled reaction mixture is concentrated under reduced pressure and the residue is dissolved in a little methanol. The resulting solution is diluted with ether and the solution treated with dry hydrogen chloride gas until an insoluble oil begins to form. The mixture is then stored at 0 °, the oil crystallizing. Further dilution with ether yields the ester hydrochloride, F = 138.5 ° (decomp

Example 23

N-Isopropyl-2-hydroxynhenethylamine hydrochloride A mixture of 4.0 g of 2-hydroxyphenethylamine, 10% palladium on animal carbon and 175 ml of acetone is heated to 70 ° C. under a pressure of 90 atmospheres of hydrogen for 18 hours. The resulting solution is filtered and concentrated under reduced pressure to give an oil. The oil is dissolved in a little methanol and the solution becomes. treated with ethanolic hydrogen chloride and diluted with anhydrous ether, giving the asnine hydrochloride, which is recrystallized from metharide / ether, F = 157 bis

Example 24

N-IEopropyl-2-hydroxy-3-chlorophenethylamine

A mixture of 3.1 g of 2-hydroxy ~ 3-chlorophenethylamine, 225 ml

009826/2 13S

Acetone and 0.5 g of 10% palladium on charcoal are used in 60 ° and 100 atmospheres of hydrogen heated for 8 1/2 hours. The filtered reaction mixture is reduced under reduced pressure Concentrated pressure to obtain the desired amine, F = 130 to 165 ° C (dec.).

Better results are obtained with platinum-on-animal charcoal than Catalyst.

The necessary starting material can be obtained according to the following procedure:

A mixture of 65.3 g of c-chlorophenol and 46.9 g of 2-methoxy-1,3-butadiene in 450 ml of anhydrous benzene is heated in an autoclave at 160 ° C. under nitrogen for 22 hours. The mixture is then diluted with 1,100 ml of ether and the resulting solution is washed with 6% aqueous sodium hydroxide (2 × 450 ml). After drying over anhydrous magnesium sulfate, the ethereal solution is concentrated to give a yellow oil which, in vacuo is distilled. 36.9 g of a fraction to 72 ° C / O passed ₅ 3 Torr "at 65, is re-distilled at 72 to 75 ° C / O, 15 Torr to give 29.5 g of 2-Hethoxy-2- ntethyl-8-chlorochroman is obtained.

A mixture of 29.5 g of 2-I'4ethoxy-2-methyl-S-chlorochroman in 220 ml of ether and 295 ml of aqueous 2N hydrochloric acid is stirred at ambient temperature until the IR spectrum indicates hydrolysis is complete (18 hours). The ether layer is separated, quickly with 10% sodium bicarbonate solution and then washed with v / ater. After drying over sodium sulfate, the solution is concentrated, whereby Methyl-o-hydroxy-m-chlorophenethyl ketone is obtained as an oil.

50 ml of anhydrous pyridine become a solution of 10 g Methyl-o-hydroxy-m-chlorophore ethyl ketone in 50 ml abs, ethanol admitted. 10 g of hydroxylamine hydrochloride are then added

009825/2138

- 34 - 1359898

added to the stirred mixture, which is then refluxed for 3 hours. The mixture is under reduced '
Pressure concentrated and the residue washed with water to remove the pyridine hydrochloride. The collected white crystals are dried in vacuo over phosphorus pentoxide, iiethyl-o-hydroxy-m-chlorophenethylketoxime, F = 102 to 1H ⁰ C _{1 being} obtained.

A mixture of 13.4 g of methyl-o-hydroxy-m-chlorophenethyl ketoxime and 436 g of polyphosphoric acid is at 140 C 1/2
Hour held. The mixture is then cooled in an ice bath and 670 ml of concentrated ammonium hydroxide in 500 ml of water are slowly added. The mixture is then extracted with chloroform and the combined chloroform extracts are washed with water and dried over magnesium sulfate. Distilling off the chloroform under reduced pressure Pressure delivers N ~ 2-hydroxy-3-chlorophenethylacetamide, F = 131 to 145 ° C.

A mixture of 6.7 g of N ^ 2-hydroxy-3-chlorophenethylacetamide and 300 ml of concentrated hydrochloric acid is poured over
Heated to reflux overnight. The cooled .mixture is with
aqueous ammonia until the basic reaction (p "10 to 11) is added and the mixture is extracted with ether. The United Aetherx

»Tracts are dried over magnesium sulphate. Distilling off the ether under reduced pressure gives the crude product, which is recrystallized from isopropanol
2-Hydroxy-3-chlorophenethylamine, melting point 162 ° C. (decomp.) Is obtained.

Example 25

N-Cyclopentyl-, N-Cyclooctyl- and N-sec-butyl-2-hydroxy- > phenylamine hydrochloride

Using the procedure described in Example 23, so obtained from 5 g of 2-hydroxyphenethylamine and 20 ml of cyclopentanone or 20 ml of cyclooctanone in 100 ml of ethanol or 80 ml 2-butanone the following products:

009825 / 213S

a) N-Cyclopentyl-2-hydroxyphenäthylemin-hydfochlorid,
F = 201 ° (dec.),

b) N-CycloGctyl-2- "hydroxyphenethylarain hydrochloride, F =
132 to 137 ° (dec.),

c.) K ^t -2-butyl-2- hydroxyphenathylamine hydrochloride j F = 149 ° (decomp.).

Example 26

anrin hydrochloride

a) A mixture of 10 g of 2-hydroxyphenylacetaldehyde, 10% strength Pd la'di circulating animal charcoal and 50 ml of n-propylamine was used in 65 ° heated under 95 atmospheres of hydrogen for 18 hours. The catalyst was filtered off and the resulting solution concentrated under reduced pressure. That back— Permanent oil was taken up in methanol, with ethanolic Heated hydrogen chloride and the solution was diluted with ether. The resulting solid was from methano / ether recrystallized, whereby the amine hydrochloride was obtained as white crystals, mp = 187 ° (decomp.).

If you used n-octylamine, isopropylamine or cyclooctylamine instead of n-propylamine in the above process, see above you get:

b) N-n-octyl - ^ - hydroxyphenethylamine hydrochloride, F = 108 bis

e) N-Is®pr © pyl-2 "hydroxyphenethylamine hydrochloride, F = 166 up to 168 ° (dec,),

d) N-Cyclooctyl-2-hydroxyphenethylamine hydrochloride, F = up to 136 ° (decomp.). Λ

Example 27 V: .- ^; ■: ν · ^:. .

H-isopropyl - 2.3-dirr. ethoxyphenä t hylamine ~ hydrochloride
a) A mixture of 5.0 g of 2,3-pimethoxyphenylacetaldehyde,
10? 6% palladium on charcoal and 50 ml isopropylamine

009825/2 136

was heated under 90 atmospheres of hydrogen at 75 for 18 hours. After the catalyst had been removed and the solvent had been distilled off under reduced pressure, the residue was taken up in methanol; Ethanolic hydrogen chloride was added and the solution was diluted with ether. The precipitate was recrystallized, giving the amine hydrochloride, melting point 121 ° (Zsrs.) «

If you use 2,5-dimethoxyphenylacetaldehyde instead of the 2,3-dimethoxy derivative in the above procedure gives:

b) N-iscpropyl-2,5-dirnethoxyphenethylamine hydrochloride, F = 138 ° (dec. 5.

c) The above products are also _s obtained when the imines formed as intermediates are reduced with sodium borohydride "

As already stated, the compounds of the formula I have hypotensive activity. This activity can be carried out in test animals such as the rat, the cat or the dog by usual pharmacological Test procedures are shown.

To administer the compounds of the formula I, preferably in the form of their pharmaceutically acceptable acid addition salts, they can be incorporated into compositions and unit dosage forms «

Pharmaceutically acceptable acid addition salts include salts derived from an amine of the formula I and one of the derive from the following acids: hydrochloric acid, hydrochloric acid, Sulfuric acid, phosphoric acid, methanesulfonic acid, Acetic acid, lactic acid, succinic acid, malic acid, maleic acid, aconitic acid, phthalic acid, tartaric acid, emboxylic acid, enanthic acid and similar acids «The use of the hydrochloride salts is preferred; · Other pharmaceutically acceptable salts can be obtained from this or from the free bases by customary methods

. 009825/2136

produced v.'erden.

The term "unit dose form" as used in the specification and the claims used refers to physically discrete units that are used as uniform doses for Mammals are suitable, each unit having a predetermined Amount of active material. Contains calculated as is that the desired therapeutic effect is achieved, in conjunction with the required pharmaceutical Diluents, solvents, or carriers. The usual pharmaceutical unit dosage forms for oral or parenteral Administration are, for example, tablets, capsules, powders, suspensions, solutions, syrups and the like, and include sustained release preparations made by known methods.

The following examples describe the manufacture of unit doses sforms »

Example 28 Components Quantity / capsule

N-isopropyl-2-hydroxyphenethylamine-

hydrochloride 10 mg

Corn starch 50 mg

The aforementioned ingredients are mixed and put in Two-piece hard gelatine capsules filled. Other pharmaceutically acceptable salts of the active ingredient can alternatively be used.

009825/2136

Example 29

Components Menqe / tablet N-Isopropyl ~ 2-acetoxyphenäthylarnIn = ·
hydrochloride . 25 mg Cornstarch 130 rag Lactose 160 mg colloidal silicon dioxide 4 mg gelatin 5 mg Magnesium stearate 1 mg

The aforementioned ingredients are intimately mixed and compressed into tablets containing 25 mg of the active ingredient and are suitable for oral administration. The tablets can be notched so that smaller doses can be given.

009825/2136

Claims (1)

(I) wherein R ^ hydrogen, hydroxy, chlorine or lower alkoxy or lower alkyl with a maximum of 4 carbon atoms . tefc,. . '. . ■■■■■ .-. ·. '■■ ^; .. ■■ - ^: ■■■ ■■ ·. · ■■ λ '. ■■. '; ■ - -. ■:' R ~ is hydroxy, methoxy, acetoxy or propionoxy and B denotes alkyl, isoalkyl or cycloalkyl, each containing 3 to 8 carbon atoms inclusive, or denotes the group -CR ₃ R ₄ R ₅ , in which R ₃ , R ₄ and R ₅ each represent methyl or ethyl, And the acid addition salts of it. 2 »connection according to claim 1, characterized in that the acid addition salt is a pharmaceutically acceptable one Salt is. . 3 «connection according to claim 1 and 2, characterized in that that Rr only denotes hydroxy or kethoxy. 4. A compound according to claim 1 and 2 _r characterized in that is '
that R- different from hydroxy and R_ only represents acetoxy or propionoxy, as the hydrochloride. 5. Compound according to claim 1 and 2, characterized in that that B represents alkyl or isoalkyl, each 3 up to and including Contains 8 carbon atoms, or cycloalkyl 009825/2136 indicates -with 5 to 8 carbon atoms, and Rp is only hydroxy or methoxy. 6. Process for the preparation of compounds of Formal Ia (Ia) wherein R ₁ denotes hydrogen, hydroxy or chlorine or lower W is alkoxy or lower alkyl with a maximum of 4 Konlenstpff- represents atoms, Rp ^{9 is} hydroxy or methoxy and B represents alkyl, isoalkyl or cycloalkyl, each containing 3 to 8 carbon atoms inclusive, or the group -CR ₃ R ₄ R _{5 represents} , v / orin R ₃ , R ₄ and R ₅ each represent methyl or ethyl, and their acid addition salts, characterized in that a compound of the formula II CH ₂ -A-NH-B ' (II) wherein A is the carbonyl or methylene group, B "has the meaning given above for B and, in addition, can also mean alkanoyl or isoalkanoyl having 3 to 8 carbon atoms inclusive, provided that only one of A. and B ^{1 contains} a carbony group, and R ^ and R ₂ 'have the meanings given above, 009825/2136 is reduced in an inert solvent by a complex metal hydride or by borane or diborane, if desired a product in ^ at R ,. low alkoxy and / or methoxy, Rp ', * represents hydroxy into the corresponding compound wherein R ^ and / or R _n, is converted by Ather.spaltung and gewürischtenfalls the product into an acid addition salt with an inorganic or organic acid is ungewande'ic . 7. The method according to claim 6 _S, characterized in that a compound of the formula II in which the carbonyl group is represented by the symbol A is used. 8. The method according to claim 6, characterized in that a compound of the formula II is used in which the symbol B ^{1 represents} an alkanoyl or isoalkanoyl group. 9. The method according to claim 6, characterized in that borane or diborane are used as reducing agent. 10. The method according to claim 6, characterized in that a complex metal hydride is used as a reducing agent, 11. The method according to claim 6, characterized in that a product which contains low alkoxy and / or methoxy groups, subject to the splitting of the ether. 12. The method according to claim 11, characterized in that the low alkoxy group represents methoxy and the ether cleavage is effected by acid hydrolysis. 13. Process for the preparation of compounds of the formula Ic h "ch" nh-b " ^{2 2} (ίο wherein 009825/2136 R _{1 is} hydrogen, hydroxy, chlorine or lower alkyl or represents lower alkoxy with a maximum of 4 carbon atoms, Rp ^{1 is} hydroxy or methoxy and B "means alkyl or isoalkyl, each having 3 to 8 carbon atoms contains, inclusive, or means cycloalkyl with 5 to 8 carbon atoms inclusive, and their acid addition salts, characterized in that a compound of formula V »^ CH ₀ -CH-KZ ρ I ^ TT PQX (V) wherein P and Q together represent a bond, X means hydrogen and -ZX denotes alkyl, isoalkyl or cycloalkyl 'or Q and X together denote a bond, P means hydrogen and Z represents alkylidene, isoalkylidene or cycloaikylidene, and R. and R 'have the meaning given above, ' Is reduced with ¹ catalytically activated hydrogen or a complex metal hydride, if desired a product that contains low alkoxy and / or methoxy groups is hydrolyzed to the corresponding hydroxy derivative and if desired the product is converted into an acid addition salt with organic or inorganic acid. 14. The method according to claim 13, characterized in that catalytically activated hydrogen is used. 15. The method according to claim 14, characterized in that the catalyst is a metal from the palladium group or platinum and the method at a pressure in the range of 00982 5/2 136 1 to 'ICO atmospheres and in a temperature range of 20 to 90 ° C. 16. The method according to claim 15, characterized in that a compound of formula V is used in which X is hydrogen. 17. The method according to claim 15, characterized in that Compounds of the formula V are used, in which P is hydrogen » 18o Process according to Claim 13 _1, characterized in that a complex metal hydride is used. 19. The method according to claim IB, characterized in that the complex metal hydride is sodium borohydride » 20. Process for the preparation of a compound of the formula Ib -NH-B • HCl wherein R ₁ * 'represents hydrogen, chlorine, lower alkoxy, lower alkyl or lower alkanoyloxy with a maximum of 4 carbon atoms, R "means acetoxy or propionoxy, B denotes alkyl or cycloalkyl, each containing 3 to 8 carbon atoms inclusive, or represents the group -CR ₃ R ₄ R ₅ , in which R ₃ , R ₄ and R ₅ each denote methyl "or ethyl, characterized in that a compound of the formula VI 009825/2136 CH ₂ -CH ₂ -IJH-B · HCl wherein ge
R .. "and B have the meanings mentioned above, with a lower alkanoyl chloride, optionally in the presence of the corresponding lower alkanecarboxylic acid anhydride, is alkanoylated 21. Therapeutic composition with hypotensive effect in fe warm-blooded animals, characterized in that it is a therapeutically effective amount of a compound of the formula I according to claims 1 and 2 together with a pharmaceutical acceptable diluents or carriers therefor and in dosage forms suitable for internal administration are, is compounded. 009825/2136