DE2412798A1 - NEW PHENYLPROPYLAMINE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Cologne, March 7th, 1974 Kl / Ax

Takeda Chemical Industries, Ltd.,

27, Doshomachi 2-chome, Higashiku, Osaka (Japan).

New Phenylpropylamine Derivatives and Processes for Their

Manufacturing

The invention relates to new and valuable phenylpropylamine derivatives and a method for their production. The compounds according to the invention have the formula

(I)

R ^

12th

in which R and R are the same or different and for Hydrogen atoms, hydroxyl groups or methoxy radicals

3 Zl

stand, R ^ a phenyl radical or alkyl radical and R a

Is alkyl and R ^ and R are the same or different and for hydrogen atoms, alkyl radicals or hydroxyalkyl radicals with at least 2 carbon atoms with the proviso that in cases in which R is a hydrogen atom, the

5 6
R to R radicals are not methyl radicals.

It is known that narcotic analgesics such as morphine, codeine, meperidine, etc. have a strong analgesic effect

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to have. However, the use of these narcotic analgesics is associated with various unpleasant effects linked to their narcotic properties are. On the other hand, analgesics that do not have narcotic properties generally have a relatively weak analgesic effect, and drugs such as pentazocine cannot be taken orally administered.

It has been found that the compounds (I) according to the invention have an analgesic effect, which thereby it is characterized that the compounds have no antagonistic effect against nalorphine (N-allylnormorphine) and morphine as well as a strong analgesic effect also after the so-called Haffner method (German medical Wochenschrift, Volume 55, p. 731 (1929)) show that they are effective and have very low toxicity when administered orally and parenterally.

In the phenylpropylamine derivatives (I), the alkyl radicals for which Br to R stand can be straight-chain, branched or cyclic and, for example, methyl radicals, ethyl radicals, propyl radicals, isopropyl radicals, butyl radicals, sec, -butyl radicals, tert-butyl radicals, amyl radicals, hexyl radicals, dimethylallyl radicals Cyclopropylmethylreste, Cyclopentylreste and Cyclohexylreste be. The hydroxyalkyl radicals for which E and R can stand are alkyl radicals which are substituted by a hydroxyl group in any position, for example 2-hydroxyethyl radicals, 2-hydroxy-1-methylethyl radicals and 3-hydroxypropyl radicals.

The compounds (I) can be prepared, for example, by the following processes:

1) Implementation of propylamine derivatives of the formula

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(II)

in which all members have the meanings given above have with a compound of the formula

X ¹ "R ⁷ - OH (III)

Λ 7

in which X is a halogen atom and R 'is an alkylene radical

• 1
and X together with the hydroxyl group is a

Can form oxydo group, with formation of the compounds (I) in which at least one of the radicals R ^

6 7

and R is a hydroxyalkyl radical of the formula R-OH.

2) Implementation of propylamine derivatives (II) with a Compound of formula

R ⁸ X ² _CH-C0-R ⁹ (IV)

2 8 9

in which X is a halogen atom and R and R each represent a hydrogen atom or an alkyl radical; and subsequent reduction of the compound obtained to compounds of the formula (I), in. The at least one
the formula

at least one of the radicals R and R is a hydroxyalkyl radical

-CHCH ₂ -OH.
3) Alkylation of propylamine derivatives of the formula

(γ)

in which all members have the abovementioned meanings, to compounds of the formula (I) in which

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at least one of Ir and R is an alkyl radical.

4) Implementation of propylamine derivatives of the formula

H ,

IR
HO-C-CH ₀ CH ₀ -N ^ f. (VI)

in which all members have the meanings given above, or of dehydration products of these Derivatives with a phenyl compound of the formula

(VII)

1 2
in which R and R have the abovementioned meanings

have, in the presence of an acidic catalyst. 5) Reduction of compounds of the formula

-CH ₂ CH ₂ N ^ ^ ₁₁ (VIII)

Λ 4
in which R to R have the abovementioned meanings

OK 1Ί
and R and R each represent hydrogen atoms, alkyl radicals, hydroxyalkyl radicals or benzyl radicals and at least one of the radicals R and R is a benzyl radical, compounds of the formula (I) in which at least one of the radicals Έτ and R is a hydrogen atom are obtained .

6) Implementation of phenylpropionic acid derivatives of the formula

, 2

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1 H- in which R to R have the abovementioned meanings, or of reactive derivatives of these compounds with an amino derivative of the formula

R ⁵
^ (X)

in which R and R have the abovementioned meanings, to amide derivatives of the formula

(XI)

in which R to R have the abovementioned meanings, and reduction of the compounds obtained in this way (XI).

The reaction (1) and the first stage of the reaction (2) are carried out by combining the starting materials, that is, a propylamine derivative (II) and a compound (III) or (IV), preferably in a solvent of the kind exemplified below. The reaction proceeds usually at a temperature of not less than 0 ⁰ C, preferably at a temperature between room temperature and 150 ° C. The amount of the compound (III) or (IV) used is usually not less than 1 mole per mole of the compound (II). There is no particular upper limit. In general, an amount of from about 1 to 3 molar equivalents is useful. When a compound (IV) is used, a range of about 1.5 moles is appropriate for practical purposes. If this reaction takes place as a dehydrohalogenation reaction, ie if X

ρ
or X in the general formulas (III) and (IV)

Is halogen atom, there are cases where the reaction is 409839/1069

is advantageously carried out in the presence of a deacidifying agent or neutralizing agent. As a deacidifier For example, alkali hydrogen carbonates (e.g. sodium hydrogen carbonate and potassium hydrogen carbonate) are suitable, Alkali carbonates (e.g. sodium carbonate and potassium carbonate), alkali hydroxides (e.g. sodium hydroxide and potassium hydroxide), sodium amide, sodium hydride, alkali metals (e.g. sodium, potassium and lithium) and organic bases (e.g. pyridine, aldehyde collidine, Dimethylaniline and triethylamine).

The implementation of compounds of the general Formula (II) with a compound of the general formula (IV) obtained compounds become the desired ones Compounds of general formula (I) reduced. This reduction can be done with any reducing agent be carried out provided the carbonyl group or Carboxylic acid ester group can thereby be converted into a methylene alcohol group. For example, can the reduction is advantageous as a catalytic reduction with a catalyst (e.g. Raney nickel, platinum oxide, Palladium on carbon, ruthenium on carbon, rhodium on carbon and copper chromium oxide), using nascent Hydrogen obtained by sharing a metal such as sodium, amalgamated sodium or amalgamated Aluminum, can be formed with water or alcohol, and using a hydrogenated Metal complex compound, e.g. lithium aluminum hydride, diethyl aluminum hydride, aluminum sodium hydride or Sodium borohydride. The reaction temperature and pressure, the type of solvent, the reaction time and other conditions will vary depending on the kinds of raw materials and the chosen reduction method.

In the method (3), the alkylation reaction of 409839/1069

Propylamine derivatives of the general formula (V) according to various alkylation processes necessary for the conversion from primary amines to secondary or tertiary amines which are known per se, can be carried out. For example can be the conversion into the secondary or tertiary amino derivatives by reaction of the substrate compound (V) with 1 to 2 or more molar equivalents of an alkyl halide (e.g. ethyl bromide and butyl iodide), a dialkyl sulfate (e.g. dimethyl sulfate and diethyl sulfate), a diazoalkane (e.g. diazomethane and diazoethane), an organic sulfonic acid alkyl ester or Formalin and a reducing agent (catalytic reduction, formic acid, formamide, etc.).

In the process (4-), propanolamine derivatives (VI) or their dehydration products with a phenyl compound (VII) implemented. Generally this reaction is carried out in the presence of an acidic catalyst, i. one of the catalysts, which are referred to by the collective term "Lewis acids", carried out. as acidic catalysts are, for example, inorganic acids (e.g. sulfuric acid, hydrogen chloride, Hydrogen fluoride, hydrogen bromide, hydrogen iodide, phosphoric acid, polyphosphoric acid, polyphosphoric acid ester, Acetic acid and acetic anhydride), metal halides (e.g. aluminum chloride, aluminum bromide, tin chloride, Boron trifluoride and arsenic trifluoride), phosphorus halides (e.g. phosphorus trichloride, phosphorus pentachloride and phosphorus pentafluoride) and suitable ones Mixtures of these compounds. Particularly advantageous among these Lewis acids are inorganic acids, . In particular sulfuric acid, polyphosphoric acid and acetic acid. If, for example, sulfuric acid is used, the acid concentration is simply of the order of magnitude which enables the desired condensation reaction to be carried out, i.e. generally at about

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50 % or more, preferably no less than about 75%.

This reaction can usually be carried out in the presence of one of the solvents mentioned below. If the Lewis acid to be used is liquid, it can also serve as a solvent at the same time. The reaction generally takes place at temperatures between room temperature and about 100 C _1, but it can also be carried out at a suitable temperature above or below this range.

The reduction in process (5) is generally referred to as a so-called catalytic reduction with a catalyst (e.g. Raney nickel, platinum oxide, palladium carbon, ruthenium on carbon, rhodium on carbon or copper chromium oxide) be performed. You can also use nascent hydrogen, which is common Use of a metal such as sodium, amalgamated sodium or amalgamated aluminum, for example is formed with water or alcohol, and by processes in which metal hydride complex compounds, e.g. aluminum lithium hydride, diethyl aluminum hydride, Aluminum sodium hydride and sodium borohydride can be used. The conditions of this reduction reaction, e.g. the temperature, the pressure, the type of solvent and the time chosen depending on the type of substrate material and the reduction method used.

In the method (6), phenylpropionic acid derivatives (IX) or their reactive derivatives are mixed with an amine derivative (X) reacted with the formation of intermediate compounds (XI). As reactive derivatives of the compounds (IX) are, for example, anhydrides, esters, acid halides and mixed anhydrides of the phenylpropionic acid derivatives (IX). This reaction can be done without

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Solvent can be carried out, however, is preferred worked in the presence of a solvent of the type mentioned below. The response is through use a deacidifying agent or dehydrating agent accelerated. Alkali hydrogen carbonates, for example, are suitable as deacidifying agents (e.g. sodium hydrogen carbonate and potassium hydrogen carbonate), Alkali carbonates (e.g. sodium carbonate and potassium carbonate), alkali hydroxides (e.g. sodium hydroxide and Potassium hydroxide), alkali amides (e.g. sodium amide), alkali hydrides (e.g. sodium hydride), alkali metals (e.g. sodium, potassium and lithium) and organic amines (e.g. pyridine, aldehyde collidine, dimethylaniline, trimethylamine and triethylamine). When the amino derivative (X) used as one of the starting compounds in Excess over the phenylpropionic acid derivative (IX) is used, it can at the same time the role of the deacidifying agent to play. As the dehydrating agent, toluenesulfonic acid, dicyclohexylcarbodiimide, etc. are used. particularly preferred, but other dehydrating agents, e.g. strong cation exchange resins and sulfuric acid can be used. The Compounds (XI) can be used under the same conditions as used in the method (2) "are reduced to the desired compounds (I).

In general, all of the reactions described above will be advantageous in the presence of a solvent carried out. All solvents that do not inhibit the reactions are suitable, e.g. water, alcohols (e.g. Methanol, ethanol, propanol, isopropanol, butanol and Amyl alcohol), acetone, methyl ethyl ketone, benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, Dimethyl sulfoxide, diglyme, pyridine, aldehyde collidine, triethylamine, dimethylamine, picoline, ether,

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Petroleum ether, petroleum benzine, ligroin, hexane, chloroform, Acetic acid and trifluoroacetic acid and mixtures of two or more solvents of this type.

Lie prepared in this way according to the invention Phenylpropylamine derivatives (I) can according to known Process (e.g. by extraction, distillation, recrystallization and chromatography) can be isolated and purified from the reaction mixture in the form of the free base or as salts with suitable acids. It is possible that the phenylpropylamine derivatives (I) according to the invention in the form of free bases are not always for pharmaceutical purposes are satisfactory. In these cases they can continue to be pharmaceutically acceptable Salts are converted. These salts can be prepared by methods known per se, for example by neutralization or double decomposition. Suitable acids for this purpose are inorganic acids, e.g. Hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and hydrobromic acid, inorganic carboxylic acids, e.g. oxalic acid, succinic acid, maleic acid, malic acid, tartaric acid, citric acid, lactic acid, nicotinic acid, Palmitic acid, stearic acid and salicylic acid, organic Sulfonic acids, e.g. methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and organophosphoric acids, e.g. Cytidylic acid, guanylic acid and inosinic acid.

The phenylpropylamine derivatives (I) have excellent analgesic, antipyretic and cough suppressants, among others Effects and are accordingly suitable, for example, as inalgesics, antitussives and antipyretics. Using of the compounds according to the invention as analgesics, antipyretics and / or antitussives is for example N-methyl-3- (3,4-dimethoxyphenyl) -3-methylamine either orally in the form of, for example, tablets, capsules and powders or non-orally in the form of suppositories in a normal daily dose of 10 to 1500 mg, preferably

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wise from 50 to 600 mg for the adult or as Injection solutions administered in a dose of 1 to 500 mg, preferably 10 to 500 mg, for the adult. However, the dose interval may vary with the disease and / or symptoms. All connections of the Formula (I) can be administered in approximately the doses mentioned above.

The invention is further illustrated by the following examples. In these examples the temperatures are all uncorrected and percentages are by weight.

example 1

10 g of N, 3-dimethyl-3- (3-methoxyphenyl) butylamine are added to 50 ml of ether solved. A solution containing 5 g of ethylene oxide is added dropwise to the solution. The mixture is left to stand for 48 hours and then concentrated. Here, N, 3-dimethyl-N- (2-hydroxyethyl) -3_ (3-methoxyphenyl) butylamine is used obtained as an oily product with a boiling point of 120 ° to 130 ° C./5 mm Hg.

Elemental Analysis: Calculated for Found:

In the manner described above, the following compounds can be made:

1) N, 3-Dimethyl-N- (2-hydroxypropyl) -3- (3-methoxyphenyl) -butylamine boiling point 130 ° C / 4 mm Hg 'from N, 3-dimethyl-3- (3-methoxyphenyl) butylamine and propylene oxide.

2) N, 3-dimethyl-N- (2-hydroxypropyl) -3- (3,4-dimethoxyphenyl) butylamine from boiling point 165 ° C / 1 mm Hg from N, 3 ~ dimethyl-3- (3,4-dimethoxyphenyl) butylamine and

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C. H 5 71 , 67 10.02 5 71 , 57 9.98 I. , 57 , 68

Propylene oxide.

Example 2

4.5 B N, 3 »3-trimethyl-3-phenylpropylamine are added to 30 ml of dimethylformamide solved. 2.6 g of anhydrous sodium carbonate and 3 »1 g of ethylene bromohydrin are added to the solution added. The mixture is heated to 150 ° C. for 5 hours while stirring. After the reaction, the mixture becomes Removal of the inorganic salt, filtered and concentrated. Water is added to the concentrate and extracted with benzene. The benzene is distilled off, and after the addition of dilute hydrochloric acid, the distillation residue is reduced under reduced pressure to Evaporated dry. Crystallization from ligroin results in N, 313-trimethyl-N- (2-hydroxyethyl) -3-phenylpropylamine-hydrochloride obtained from melting point 123 "to 125 ° C.

In the same way, the following compounds are made manufactured:

1) N-Isopropyl-2- (2-hydroxyethyl) -3,3-dimethyl-3-phenylpropylaminsuccinat of melting point 153-155 C from N-isopropyl-3-phenyl-3,3-dimethylpropylamine and ethylene odhydrin j.

2) N, 3 »3-trimethyl-N- (2-hydroxyethyl) -3- (3-methoxyphenyl) propylamine hydrochloride from a melting point of 89 to 93 ° C. from N, 3,3-trimethyl-3- (3-methoxyphenyl) propylamine and ethylene bromohydrin.

3) N-methyl-N- (2-hydroxyethyl) -3,3-dlmethyl-3- (4-methoxyphenyl) propylamine boiling point 130 ° C / 1 mm Hg from N-methyl-3,3-dimethyl-3- (4-methoxyphenyl) propylamine and ethylene fluorohydrin.

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N, 3,3-trimethyl-N- (2-hydroxyethyl) -3- (3-hydroxyphenyl) propylamine from N, 3,3-trimethyl-3- (3-hydroxyphenyl) propylamine and ethylene bromohydrin.

IR V cm " ¹ : 3250 (OH)

NMR (CDCl ₅ ) T: 2.80-3.40 (aromatic H), 5.05

(s, OH), 6.42, 7.50 (t, -NCH ₂ CH ₂ -O), 7.75 (s, NCH ₅ ), 7.55-8.35 (m, CH ₂ CH ₂ ) , 8.71 (s, CCH ₅ )

5) N, N-bis (2-hydroxyethyl) -3,3-dimethyl-3- (3-methoxyphenyl) propylamine from N- (2-hydroxyethyl-3,3-dimethyl-3- (3-methoxyphenyl) propylamine and ethylene bromohydrin.

6) N-Isopropyl-N- (2-hydroxyethyl) -3,3-dimethyl-3- (3-methoxyphenyl) propylamine from boiling point 135 to 145 ° C / 2 mm Hg from N-isopropyl-3,3-dimethyl-3- (3-methoxyphenyl) propylamine and ethylene chlorohydrin.

Example 3

8.8 g of N, 3-dimethyl-3-phenylbutylamine are added to 50 ml of dimethylformamide solved. 15 g of sodium hydrogen carbonate and 6.6 g of bromoacetone are added to the solution. That Mixture is heated to 135 ° C for about 4 hours and then evaporated to dryness. Water is added to the residue in order to dissolve inorganic substances, whereupon with Ether is extracted. The ether layer is washed with water and dried. The ether is distilled off and the residue dissolved in 150 ml of methanol. Then will 2 g sodium borohydride added in small portions. The solution is left to stand at room temperature overnight. The next morning, the solution is refluxed for 1 hour to end the reaction. After addition the reaction mixture is extracted from water with ether. After a wash with water and dehydration the solvent is distilled off and the residue

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purified by chromatography on a silica gel column. Distillation under reduced pressure gives N, 3-dimethyl-N- (2-hydroxy-i-methylethyl) -3 - phenylbutylamine with a boiling point of 130 to 135 ° C./5 mm Hg.

Elemental analysis: C. H N 95 Calculated for C ₁₅ H ₂₅ NO: 76.54- 10.71 5, 84 Found: 76.66 10.49 5, Example 4

4.8 g of N-methyl-3- (3,4-dimethoxyphenyl) -3-iaethylbutylamine are added to 30 ml of dimethylformamide solved. 4.2 g of sodium carbonate are added to the solution. 2.5 g of ethyl chloroacetate are added dropwise with stirring, whereupon the mixture is stirred at 70 to 75 ° C. for a further 2 hours to complete the reaction. The reaction mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue becomes water Dissolution of the inorganic substances added, after which it is extracted with ether. The ether layer is with Washed with water and dried, whereupon the ether is distilled off. About 30 ml of a Get solution. This solution is added dropwise to a suspension of 0.63 g of lithium aluminum hydride in 50 ml added to dry ether. The mixture is 12 hours heated with stirring on the reflux condenser. The unreacted compound is decomposed with water and that Mixture then filtered. The filtrate is extracted with ether. The ether layer is washed with water and dehydrated. Finally, the solvent is distilled off. Here, N- (2-hydroxyethyl) -N, 3-dimethyl-3- (3,4- dimethoxyphenyl) butylamine as an oil with a boiling point of 198 to 200 ° C / 1.5 mm Hg.

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C. H N 68.28 9.67 4.98 68.18 9.63 5.12

Elemental analysis:
Calculated:
Found:

In the manner described in Example 4, the the following connections established:

1) N, 3,3-trimethyl-R- (2-hydroxyethyl) -3- (3-methoxy-4-hydroxyphenyl) propylamine with a boiling point of 170 ° C / 1 mm Hg from N, 3,3-trimethyl-3- (3-niethoxy-4-hydroxyphenyl) propylamine and ethyl chloroacetate.

2) N, 3-dimethyl-N- (2-hydroxyethyl) _3-ethyl-3- (3,4-dimethoxyphenyl) propylamine with a boiling point of 165 C / 1 mm Hg from N, 3-dimethyl-3-ethyl-3- (3,4-dimethoxyphenyl) propylamine and methyl chloroacetate.

3) N, 3,3-trimethyl-N- (2-hydroxy-1-methylethyl) -3- (3,4-dimethoxyphenyl) propylamine with a boiling point of 165 ° C./1 mm Hg from N, 3,3-trimethyl-3- (3,4 ™ dimethoxyphenyl) propylamine and ethyl 2-bromopropionate.

4) N, 3-dimethyl-N- (2-hydroxyethyl) -3-phenyl-3- (3, ^z idimethoxyphenyl) propylamine of boiling point 210 C / 1 mm Hg of N, 3 ~ dimethyl-3-phenyl-3- (3,4-dimethoxyphenyl) propylamine and isopropyl bromoacetate.

5) N, 3-dimethyl-N- (2-hydroxy-1-methylethyl) -3-phenyl-3- (3,4-dimethoxyphenyl) propylamine of boiling point 207 C / 1 mm Hg from H, 3-D: methyl-3-phenyl-3- (3,4-dimethoxyphenyl) propylamine and methyl 2-chloropropionate.

6) N, 3-Dimethyl-N- (2-hydroxy-1-methylethyl) -3-ethyl-3- (3,4-dimethoxyphenyl) propylamine boiling point 170 ° C / 1 mm Hg from N, 3-dimethyl-3-ethyl-3- (3,4-dimethoxyphenyl) propylamine and phenyl ~ 2-chloropropionate.

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Example 5

30 g of 3- (3j4-dimethoxyphenyl) -3-methylbutylamine are added to 50 ml of dimethylformamide solved. 6 g of methyl iodide are added to the solution. The mixture is 2 hours implemented at tree temperature with stirring. After the reaction has ended, inorganic substances are filtered off. The filtrate is concentrated under reduced pressure, N-methyl-3- (3> 4 - dimethoxyphenyl) -3-methylbutylamine is obtained as an oily product with a boiling point of 130 to 135 ° C / 2 mm Hg.

IR T? cm " ¹ : 3300 (-HH)
KMR (CGl ₄ ) T: 8.58 (-NH)

Elemental analysis: Calculated for Ο ^ Ηρ, ΝΟο: 5 »90 % N

Found: 5.70 % N

The following compounds were prepared using similar methylation procedures manufactured:

1) N-methyl-3- (3,4-dimethoxyphenyl) -3-phenylbutylamine Boiling point 195 to 196 ° 0/1 mm Hg

IR V cm " ¹ : 3320 (-NH)
NMR (CCl ₄ ) T: 8.28 (-NH)

2) N-methyl-3- (4-methoxyphenyl) -3-methylbutylamine hydrobromide, Melting point 138-139 ° C.

3) N-methyl-3 (4-hydroxy-3-methoxyphenyl) -3-methylbutylamine, Melting point 135 ° C.

4-) 315 »N-trimethyl-3- (3-methoxyphenyl) hexylamine, Boiling point 115 to 119 ° C / 0.2 mm Hg.

5) N-cyclopropylmethyl-3,5-dimethyl-3- (3-methoxyphenyl) -hexylaminoxalat, melting point 201-202 ⁰ C.

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Example 6

A mixture of 1.2 g of N-methyl-3- (3,4-dimethoxyphenyl) -3-phenylbutylamine, 0.46 g of 99% formic acid and 0.5 g of 37% formalin is refluxed for 12 hours. After cooling, the mixture is made alkaline with an aqueous potassium carbonate solution and then extracted with ether. The extract is washed with water and dehydrated, whereupon the solvent is distilled off. This gives N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-phenylbutylamine as a yellow oil with a boiling point of 160 ° C./1 mm Hg.

NMR (CDCl ₃ ) T: 2.74 (s, phenyl), 3.19-3.30 (m, aromatic ring), 6.13, 6.23 (each s, OCH ₃ ), 7.79 (s , -NCH ₃ , -CH ₂ CH ₂ -), 8.35 (s, -C-CH ₃ )

In the same way, the following compounds were made:

1) N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-phenylbutylamine from Boiling point 160 ° C / 1 mm Hg from 3- (3,4-dimethoxyphenyl) -3-phenylbutylamine, 99% formic acid and 37% formalin.

2) N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-methylbutylamine with a boiling point of 146 ° C / 1 mm Hg from N-methyl-3- (3,4-dimethoxyphenyl) -5-methylbutylamine, 99% formic acid and 37% formalin.

3) N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-methylbutylamine with a boiling point of 146 ° C / 1 mm Hg from 3- (3,4-dirnethoxyphenyl) -3-methylbutylamine, 99% formic acid and 37% formalin.

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Example 7

1) To a mixture of 30 ml of 85% phosphoric acid and 30 ml of concentrated sulfuric acid are 10.3 g (0.075 mol) of veratrole and, with stirring, 10.4 g (0.05 mol) of N-methyl-N- (3-hydroxy-3-methylbutyl) benzylamine. The mixture is left to react for 96 hours at room temperature. Then refer to the example 1 described manner, with N-benzyl-N-methyl-3- (3,4-dimethoxyphenyl) -3-methylbutylamine is obtained.

2) In 150 ml of ethanol 12 g (0.0317 mol) of N-benzyl-N-methyl-3- (3 » 4-dimethoxyphenyl) -3-methylbutylamine dissolved as in section (1). After adding 5% palladium carbon Let 7 / ate fabric bubble through the solution while stirring vigorously and allow the reaction to take place 24 hours a day. After the reaction has ended, the palladium carbon is filtered off and the Solvent removed from the filtrate under reduced pressure. This is N-methyl-3- (3 * 4-dimethoxyphenyl) -3-methylbutylamine as oil from boiling point 130 to 135 ° C /. 2 mm Hg obtained.

IR *> cm " ¹ : 3300 (-NH)
NMR (CCl ₄ ) T: 8.58 (-NH)

Elemental Analysis (for C ₁₄ H ₂₅ NO ₂ ): Calculated 5.90 % JS

Found 5.70% N

Example 8

1) To a mixture of 50 ml of 85% orthophosphoric acid and 50 ml of concentrated sulfuric acid 8.9 g (0.0645 mol) of veratrol given in the cold. Then 12 g (0.0543 mol) of N-methyl-N- (3-hydroxy-3-methylpentyl) benzylamine are added at room temperature added, followed by stirring for 6 days. This is N-benzyl-K-methyl-3- (3 »4-dimethoxyphenyl) -3-methylpentylamine from boiling

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-O

obtained point 194 to 195 C / 1 mm Hg.

NMR (CCl ₄ ) f: 2.79 (s, benzyl, aromatic ring), 3.30 (s, aromatic ring), 6.20 (s, -OCH,), 6.62 (s, benzyl, methylene group) , 7.90 (s, -NCH ₃ ), 8.23 (q, -CH ₂ CH ₃ ), 7.75- - 8.57 (m, -CH ₂ CH ₂ -), 9.33 (t, -CH ₂ CH ₃ )

Elemental analysis: Calculated for

C. H 15th E. 77 , 37 9, 95 4.01 77 , 17th 8th, 4.12

31 Found:

2) 10.2 g (0.03 mol) of the according to N-Benzyl-N-methyl-3- (3,4-dimethoxyphenyl) 3-methylpentylamine prepared in section (1) solved. After adding 5 g of 5% palladium-on-carbon, hydrogen is left in Bubble through the solution for 24 hours. After the reaction has ended, the palladium carbon is filtered off and the Solvent removed from the filtrate under reduced pressure. Here is N-methyl-3 - '(3 »4-dimethoxyphenyl) -3-methylpentylamine obtained from boiling point 140 to 145 ° C / 1 mm Hg.

¹ : 3300 (-NH)
NMR (CCl ₄ ) T: 9.02 (-NH)

Elemental Analysis (for C ^ ₅ H ₂₅ NO ₂ ): Calculated 5.57% N

Found 5.37 % N

Example 9

1) To a mixture of 80 ml of 85% orthophosphoric acid and 80 ml of concentrated sulfuric acid are given 16.5 g (0.12 mol) of veratrole in the cold. Under 26.9 g (0.1 mol) of N-methyl-N- (3-hydroxy-3-phenylbutyl) benzylamine are added with stirring. The mixture will Stirred for 6 days at room temperature, whereupon N-benzyl-N-

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C. H N 80.17 8.02 3.60 80.11 8.00 3.77

methyl-3- (3,4-dimethoxyphenyl) -3-phenylbutylamine from Boiling point 224 to 225 ° C / 0.5 mm Hg is obtained.

NMR (CCl ₄ ) T: 2.77, 2.82 (phenyl), 3.30, 3.42 (aromatic ring), 6.20, 6.32 (-OCH,), 6.60 (s, benzyl , aromatic ring), 7.77 (s, benzyl, methylene group), 7.87 (s, -NCH,), 2.40 (s, -CCH,)

Elemental Analysis: Calculated for Found:

2) 20 g (0.05 mol) of N-benzyl-N-methyl-3- (3,4-dimethoxyphenyl) -3-phenylbutylamine are dissolved in 200 ml of ethanol. After adding 10 g of 5% palladium carbon, hydrogen is bubbled through the solution with constant stirring. By working up in the manner described in Example 8 (2), N-methyl-3- (3,4-dimethoxyphenyl) -3-phenylbutylamine of boiling point 195 to 196 ⁰ C / 1 mm Hg is obtained.

IR V cm "" ¹ : 3320 (-NH)
NMR (CCl ₄ ) Γ: 8.28 (-NH)

Elemental analysis: (3 HN

Calculated for C ₁₉ H ₂₅ NO ₂ : 76.22 8.42 4.68 Found: -76.04 8.22 4.65

Example 10

1) 25.5 g (0.136 mol) of o-bromoanisole and 31 g (0.15 mol) of N-methyl-N- (3-hydroxy-3-methylbutyl) benzylamine are added to 100 ml of 80% sulfuric acid while cooling will. The mixture is stirred for 7 days at room temperature. The procedure is then continued in the manner described in Example 2, N-benzyl-N-

409839/1069

methyl-3- (3- "bromo-4-methoxyphenyl) -3-diethylbutylamine from Boiling point 194 ° C / 0.5 mm Hg is obtained.

NMR (CDCl ₅ ) T: 2.48-3.26 (m, benzyl, more aromatic

Ring), 2.71 (s, aromatic ring), 6.12 (s, -OCH,), 6.53 (s, benzyl, methylene group), 7.60 - 8.30 (m, -CH ₂ CH ₂ -), 7.83 (s, -NCH ₅ ), 8.72 (s, -C-CH ₅ )

Elemental analysis:

Calculated for C _on H _oC -NOBr:

2Ü 2b

Found:

2) 14 g (0.037 mol) of N-benzyl-N-methyl-3- (3-bromo-4-methoxyphenyl) -3-methylbutylamine are dissolved in 200 ml of ethanol. After adding 8 g of 5% palladium carbon, hydrogen is bubbled through the solution with constant stirring. The procedure is then continued in the manner described in Example 8 (2), N-methyl-3- (4-methoxyphenyl) -3-methylbutylamine hydrobromide having a melting point of 138 to 139 ^° C. being obtained.

NMR (CDCl ₅ ) T: 1.05 (broad singlet, -NH), 2.67,

3.10 (aromatic ring), 6.18 (s, -OCH ₅ ), 7.10 - 7.90 (m, -CH ₂ CH ₂ -), 7.40 (s, -NCH ₅ ), 8, 62 (s, -C-CH ₅ )

C. H I. 63.83 6.97 3.73 64.12 6.83 3.98

Elemental analysis: I ₂₀ NO. HBr) C. 11 I.
I. 17th 7th H N Calculated for C ₁₅ I. : 54, 99 7th , 69 4.86 Found: example 53 , 54 4.94

.1) A mixture of 12.4 g (0.1 mol) of guaiacol and 15.5 g (0.075 mol) of N-methyl-N- (3-hydroxy-3-methylbutyl) benzylamine becomes a mixture of 30 ml of concentrated sulfuric acid and 30 ml of 85% orthophosphoric acid in the cold given. The mixture is at 96 hours

409839/1089

Stirred room temperature, whereupon the in Example 1 described manner further worked and an oily product is obtained.

A small amount of ether is added to this oil. The mixture is left to stand overnight while cooling with ice. Here, N-benzyl-N-methyl-3- (4-hydroxy-3-methoxyphenyl) -3-methylbutylamine is obtained in the form of crystals of melting point 111 ⁰ C.

IE Ό cnT ¹ : 3400 (-OH)

NMR (CCl ^) T: 2.82 (s, aromatic ring), 3.11-3.38

(m, benzyl, aromatic ring), 4.45 (broad singlet, -OH), 6.20 (s, OCH ₃ ), 6.63 (s, benzyl, methylene group), 7.60 8.40 (m, -CH ₂ CH ₂ -), 7.92 (s, -NCH ₃ ), 8.72 (s, -C-CH ₃ )

Elemental analysis: Calculated for C ₂₀ H ₂ Found:

2) 5 g (0.016 mol) of N-benzyl-N-methyl-3- (4-hydroxy-3-methoxyphenyl) -3-methylbutylamine are added to 150 ml of ethanol solved. After adding 4 g of 5% palladium carbon, a catalytic reduction is carried out. This reaction gives N-methyl 1-3- (4-hydroxy-3-methoxyphenyl) -3-methylbutylamine of melting point 134 ° C.

IR l) cm ": 3240 (-NH), about 2400 (broad, -OH) NMR (CDCl ₃ ) X-. 5.6 (s, - -OH, -NH)

El em en tar analysis: (3 HN

Calculated for C ₁₃ H ₂₁ NO ₂ : 69.92 9.48 6.27 Found: 69.46 9.38 6.26

c_ H I. 76.64 8.69 4.47 76.85 8.73 4.68

409839/108

Example 12

16 g (0.054 mol) of N-benzyl-N-methyl-3- (4-methoxyphenyl) -3-methylbutylamine are dissolved in 150 ml of ethanol solved. After adding 5% palladium-carbon, hydrogen is left in Bubble through the solution for 8 hours. The procedure is then continued in the manner described in Example 9 (2), where N-methyl-3- (4-methoxyphenyl) -3-methylbutylamine with a boiling point of 110 ° C / 2 mm Hg.

IH "Pcm" ¹ : 3250 (-NH)

Elemental analysis (for Ο ^, Η ^ ΝΟ): Calculates 6.76 % N

Found 6.75 % N

Example 13

5 »5 g of veratrole are added to 50 ml of 80% sulfuric acid and 4 g of N-methyl-3,3-dimethylallylamine are added. That The mixture is stirred at room temperature for 12 hours to complete the reaction. The reaction mixture is on Given ice, neutralized with sodium carbonate and filtered. The filtrate is extracted with ether. .Of the The extract is washed with water, dehydrated and freed from the solvent, whereby N-methyl-3- (3i4 ~ dimethoxyphenyl) -3-methylbutylamine as an oil from the boiling point 130 to i35 ° C / 2 mm Hg is obtained.

In the manner described above, the following Connections made:

1) N-Methy1-3- (3,4-dimethoxyphenyl) -3-phenylbutylamine, Boiling point 195 to 196 ° C / 1 mm Hg.

• 2) N-methyl-3- (4-methoxyphenyl) -3-methylbutylamine hydrobromide, Melting point 138-139 ° C.

3) N-methyl-3- (4-hydroxy-3-methoxyphenyl) -3-methylbutylamine, Melting point 135 ° C

4G9839 / 106Ö

2412738

4) N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-phenylbutylamine, Boiling point 160 ° C / 1 mm Hg.

5) N-Methy1-3- (3, 4-dimethoxyphenyl) -3-nie thy Ineptylamin, Boiling point 155 ° C / 2 mm Hg.

6) N, N-dimethyl-3- (3,4-dimethoxyphenyl) -3-methylbutylamine, Boiling point 146 ° C / 1 mm Hg.

Example 14

A mixture of 2.25 S 3-methyl-3 »3-diphenylpΓopylamin _t 2.3 6 99% formic acid and 3.4 g 37% formalin is refluxed for 12 hours. After cooling, the reaction mixture is made alkaline with sodium carbonate and extracted with ether. After washing with water and drying, the solvent is distilled off from the ether layer under reduced pressure, NiN-dimethyl ^ -methyl ^^ amine having a boiling point of 138 ° C / 1 mm Hg is obtained.

Elemental analysis: ϊ ₂ , Ν: 85 G H 5 N Calculated for Cj “I 85 , 32 9.15 5 , 53 Found: example , 04 9.28 , 3o 15th •

A mixture of 6.3 g of N-benzyl-3-me ^<fchyl-3,3 - cLiphenylpropylamin, 2.3 g of formic acid and 3.4 g of 37% formalin is heated for 10 hours a reflux condenser. After cooling, the reaction mixture is made alkaline with aqueous ammonia and extracted with ether. After washing with water and drying, the ether extract is freed from the solvent by distillation. The oil remaining as residue is dissolved in 100 ml of methanol. 5 g of 5% palladium carbon are added to the solution, whereupon hydrogen gas is bubbled through

409839/1069

leaves until gas uptake ceases. The reaction mixture is filtered and the piltrate evaporated under reduced pressure to give an oily residue. After the addition of ethanolic hydrochloric acid to the residue, the solution is evaporated under reduced pressure to give N, 3-dimethyl-3,3-diphenylpropylaminhydrochlorid of melting point 189-190 ⁰ G is obtained.

Elemental analysis: ₃₁ N.HC1): 74 C. H N Calculated for C ₁₇ H, 74 , 03 8.04 5.08 Found: example 16 , 00 7.91 5.03

1) To a solution of 1.21 g of N-methylbenzylamine in 20 ml of dry chloroform are added in portions to 3.2 g of anhydrous sodium carbonate and 2.3 g of 3,3-dimethyl-3- (3,4-dimethoxyphenyl) propionyl chloride given. The mixture obtained is refluxed for 2 hours heated, whereupon the toluene is distilled off. The residue is dissolved in 100 ml of water and the solution extracted with chloroform. The extract is dried and the solvent is distilled off. The one here The oily residue obtained is dissolved in 30 ml of tetrahydrofuran. The resulting solution becomes one dropwise Suspension of 0.6 g of lithium aluminum hydride in 100 ml of tetrahydrofuran was added with stirring, followed by 5 hours is heated on the reflux condenser. The reaction mixture is cooled with ice and with 50 ml of water and then with 20 ml of a 20% aqueous solution of sodium hydroxide are added. The separated tetrahydrofuran layer is washed with water and dried, followed by the solvent is distilled off under reduced pressure. Here is N-benzyl-3,3, N-trimethyl-3- (3,4-dimethoxyphenyl) propylamine obtained from the boiling point 166 ° C / 0.3 mm Hg.

4Q9839 / 10S3

C. H N 80.74 9.15 4.71 80.62 9.24 4.88

Elemental analysis:
Calculated for C ₂₀ H ₂
Found:

2) The N-benzyl-3,3, N-trimethyl-3- (4-methoxyphenyl) propylamine obtained in this way is reacted in the manner described in Example 7 (2), wherein N, 3,3-trimethyl-3- (3,4-dimethoxyphenyl) propylamine in Form of an oil with a boiling point of 130 to 135 ° C / 2 mm Hg is obtained.

Example 17

1) To a solution of 1.21 g of N-benzylamine in 40 ml of chloroform, 3.5 g of potassium carbonate and 0.8 ml Given water. After cooling, 2.8 g of 3-methyl-3,3-diphenyl-propionyl chloride are added in portions to the mixture added while stirring. The mixture is then stirred for a further 3 hours at room temperature. From the The solvent is distilled off in the reaction mixture. The residue is dissolved in 50 ml of tetrahydrofuran, followed by drying with potassium carbonate. The solution is added dropwise to a suspension of 0.6 g of lithium aluminum hydride added to 50 ml of tetrahydrofuran while stirring. The mixture is taken overnight left to the same conditions of the reaction. The next morning, the reaction mixture is 1 hour on The reflux condenser is heated and then ethyl acetate is added to decompose excess lithium aluminum hydride, whereupon 50 ml of water are added. The tetrahydrofuran layer is separated off and the aqueous layer remaining as residue with 30 ml of tetrahydrofuran extracted. The combined tetrahydrofuran layer is dried and the solvent is distilled off, whereby an oily residue is obtained. Hydrochloric acid is added to the residue, whereupon it under reduced pressure

409839 / 1OSiJ

- cy -

is evaporated. Here, N-benzyl-3, N-dimethyl-3,3-diphenylpropylamine hydrochloride with a melting point of 142 to 144 ^° C. is obtained.

Elemental Analysis: Calculated for Found:

2) The N-benzyl-3, N-diinethyl-3,3-diphenylpropylamine hydrochloride prepared in the described manner is reacted in the manner described in Example 7 (2), whereby 3, N-dimethyl-3,3- diphenylpropylamine hydrochloride with a melting point of 189 "to 190 ⁰ C is obtained.

C. H N 78.77 7.71 3.83 78.58 7.84 3.77

409839/1069

Claims (1)

Patent claims 1 · Compounds of the formula 1 2
in which E and E are identical or different and represent hydrogen atoms, hydroxyl groups or methoxy radicals, Ir is a phenyl radical or alkyl radical and E is an alkyl radical and E ^ and E, which are identical or different, each represent hydrogen atoms, alkyl radicals or hydroxyalkyl radicals with at least 2 C atoms are available with the proviso that in cases in which E is a hydrogen atom is, Br to E are not methyl radicals at the same time, and physiologically harmless salts of these compounds. 2. Compounds according to claim 1 of those mentioned in claim 1 1 2
Formula in which E and E both represent methoxy radicals. 5. N, 3-Dimethyl-N- (2-hydroxypropyl) -3- (3,4-dimethoxyphenyl) -butylamine 4. N, 3-dimethyl-N- (2-hydroxyethyl) -3- (3,4-dimethoxyphenyl) butylamine 5. N, 3-dimethyl-N- (2-hydroxyethyl) -3-ethyl-3- (3,4-dimethoxyphenyl) propylamine 6. N, 3,3-Trimethyl-li (2-hydroxy-1-methylethyl) -3- (3, ^z "- dimethoxyphenyl) propylamine 7. N, 3-Dimethyl-N- (2-hydroxyethyl) -3-phenyl-3- (3,4-dimethoxyphenyl) propylamine 409839/1069 8. N, 3-Mmethyl-N- (2-hydroxy-1-methylethyl) 3-phenyl-3- (3,4-dimethoxyphenyl) propylamine 9. N, 3-Mmethyl-N- (2-hydroxy-1-methylethyl) -3-ethyl-3- (3,4-dimethoxyph. Enyl ) propylamine 10. N, 3-Dimethyl-3-pheny1-3- (3,4-dimethoxyphenyl-propylamine 11. N, N, 3-a? Rimethyl-3-plienyl-3- (3,4-dimethoxyphenyl) propylamine 12. N, 3-Dimethyl-3-ethyl-3- (3, ^ - dimethoxyplienyl) propylamine 13. N _J N, 3-trimethyl-3-phenyl-3- (3, ^ - dimetlioxyphenyl) propylamine 14. N _i N ₁ 3-trimethyl-3-ethyl-3- (3,4-dimethyl-oxyp] ienyl) propylamine 15. Compounds according to claim. 1 with the one mentioned there 1 p Formula in which R and R both represent hydrogen atoms stand.
16 '. N, 3 _t 3-trimethyl-N- (2-hydroxyethyl) -3-phenylpropylamine 17. N, 3-Dimethyl-N- (2-hydroxyethyl) -3-phenylpropylamine 18. N ₁ N _i 3-Ti ^> iniethyl-3 ~ phenylpropylamine 19. N, 3-Dimethyl-3-phenylpropylamine 20. N, 3,3-trimethyl-N- (2-hydroxyethyl) -3- (3-niethoxyphenyl) propylamine 21. N-Cyclopropylmethyl-3-methyl-3-isobutyl-3- (3-niethoxyphenyl) propylamine 22. N-Cyclopropylmethyl-3-methyl-3-propyl-3- (3-methoxyphenyl) propylamine 409839/1069 23. Process for the preparation of compounds according to claims 1 to 22, characterized in that one a) Propylamine derivatives of the formula 1 2
in which R and R are identical or different and each represent hydrogen atoms, hydroxyl groups or 5
Methoxy radicals, R a phenyl radical or alkyl 4 5 radical, R is an alkyl radical and Br is a hydrogen atom or an alkyl radical or a hydroxyalkyl radical having at least 2 carbon atoms, with a compound of the formula i 7
X -R'-OH, 1 7 in which X is a halogen atom and R is an alkylene radical and X together with the hydroxyl group is Can form oxido group to compounds of the formula 6 7 (I) converts, in which R is a group of the formula R-OH is, or
b) compounds of the formula 3 tT Q τ- * ι sy * ^ -Π. Jx Jx 8 9
in which R and R ^y each represent hydrogen atoms or alkyl radicals and the other members have the meanings given above, reduced to compounds of the formula (I) in which R is a group of the formula -CH-CH ₂ -OH
409839/1069 is, or
c) propylamine derivatives of the formula in which all members have the meanings given above, with the formation of compounds of Formula (i) alkylated in which at least one of the radicals R ^ and R is an alkyl radical, or d) propanolamine derivatives of the formula S ³ 5 I *> 2 2 in which all members have the abovementioned meanings, or dehydration products of these derivatives with a Pheny! compound of the formula 1 2
in which R and R have the abovementioned meanings, reacts or in the presence of an acidic catalyst e) compounds of the formula 1 4
in which R to R have the abovementioned meanings 409839/1069 have and R and R each represent hydrogen atoms, Alkyl radicals, hydroxyalkyl radicals or benzyl radicals 10 and at least one of the radicals R and R is a benzyl radical, reduced to compounds of the formula (I) in which at least one of the radicals R and R is a hydrogen atom, or f) Phenylpropionic acid derivatives of the formula CH ₂ COOH 1 4-in which R to R have the abovementioned meanings, or reactive derivatives of these compounds with an amine derivative of the formula in the Ή? and R have the abovementioned meanings to form amide derivatives of the formula Ε - C-CH _n CON ^ c- I ² ^ T? ^6th 1 6
in which R to R have the abovementioned meanings, and the compounds obtained in this way are reduced to the compounds (I). 409839/1069