DE1051281B - Process for the preparation of derivatives of 1-aryl-3-aminopropan-1-ols - Google Patents

Description

GERMAN

It is known that derivatives of I-aryl-3-aminopropanols- (I) can be prepared in that one either compounds of the I-aryl-3-dialkylaminopropanols- (l) type or of the des // - lets aminopropionic acid ester react with aryl or alkyltnagnesium halides. These methods are not technically advantageous, since the yields achieved are mostly unsatisfactory.

It has now been found that derivatives of I-aryl-3-aminopropanols- (l) can be obtained in a smooth reaction by reacting with diaryl or aryl alkyl ketones under the influence of molar amounts of strongly basic condensing agents alkyl nitriles or such aralkyl nitriles, their Alkyl radical contains at least 2 carbon atoms, added to ß, ß-t) \ - aryl or /? - aryl - /? - alkylhydracrylic acid nitriles, the nitriles thus obtained to 1,1-diaryl or 1-aryl-1-alkyl -3-aminopropan-1-ols are hydrogenated and, if appropriate, these bases are then substituted on the nitrogen in a manner known per se by alkyl or aryl radicals. The method according to the invention runs according to the following equation:

AryK
R '

Aryl,

R '

Aryl,
R '

Aryl,
R '

; CO + CH, - CN

X-CH
OH

Ri

X-CH-

OH

XN

XH ₉ -NH ₉

Ri

X —CH-CH ₂ -Ν:
OH

R,

Here, R denotes alkyl, cycloalkyl, aryl, R ₁ H, alkyl, cycloalkyl, aralkyl, R ₂ H, alkyl, cycloalkyl, aralkyl, R ₃ H, alkyl.

The both carbo and heterocyclic aryl groups can be substituted as desired and both the Aryl and also the alkyl groups can be identical to one another or different from one another; as well

Process for the preparation of derivatives of l-aryl -3- aminopropan-l-ols

Applicant:

Paint factories Bayer Aktiengesellschaft, Leverkusen-Bayerwerk

Dr. Hans Henecka, Dr. Rudolf Lorenz, Wupp er tal-Elb erfeld, and Dr. Rudolf Gösswald, Wuppertal-Vohwinkel, have been named as inventors

the two substituents of the keto group of the starting ketone can interrelate in any way be linked.

Strongly basic ones are used to add the diaryl or aryl alkyl ketones to alkyl or aralkyl nitriles Condensing agents such as sodium amide, sodium hydride, triphenylmethyl sodium or dialkylamino magnesium halides; Sodium amide has proven to be particularly advantageous here. As suitable Solvents or diluents for carrying out this addition are preferably open-chain or cyclic ethers in question, e.g. B. diethyl ether, tetrahydrofuran or dioxane. The implementations run smoothly even at ordinary temperature, in which case it is expedient to proceed in such a way that a mixture of the reaction components, if necessary dissolved in one of the agents mentioned, a suspension of the condensing agent in the same solvent in proportion to the reaction that occurs gradually adds, so that a temperature of the reaction mixture of about 30.degree. C. is established as a result of the exothermic reaction. If you use for condensation, for example sodium amide, the sodium salt of the tertiary formed separates out Carbinols mostly from precipitate; forms when the reaction mixture is stirred into water The free CarbinoL then undergoes hydrolysis

When using phenylacetonitrile as aralkyl nitrile, the addition to benzophen has proven to be beneficial shown that even during the work-up of the reaction mixture from the initially formed here too Carbinol very easily splits off water with the formation of a, /? - diplienyl-cinnamonitrile. In 2-position phenylated l-aryl-3-aminopropanols- (l)

809 767/503

are therefore not accessible after the claimed procedure.

The first stage of the new process, the addition of the labeled alkyl or aralkyl nitriles to diaryl or aryl alkyl ketones under the influence of strongly basic condensing agents, represents a special embodiment of the first stage of an aldol reaction, a so-called aldol addition The /?, /? - diaryl or /? - aryl - /? - alkylhydracrylic acid nitriles obtained with the new process are therefore aldol adducts with all of these substance group characteristic properties: Solutions of such aldol adducts in water or alcohols arise, especially in the presence of alkaline substances , with the components, they are by their addition arisen in an equilibrium whose setting speed of the nature of the materials and the surrounding conditions, especially temperature and type of alkaline additive, dependent (see for example Houben-Weyl, 4th edition, Vol IV / 2, p. 27; see also C. r., 243, p. 281 [1956]). In practice, this establishment of equilibrium in solvate systems, such as water or alcohols, means a partial breakdown of the adduct into the components. A second characteristic property of such aldol adducts, especially in acidic, but also in strongly alkaline solutions, is the easy transition of the aldol adduct to the aldol condensation product, a reaction which leads to the formation of an α, /? - unsaturated nitrile compound with elimination of water.

The second stage according to the invention of the new process for the preparation of l-aryl-3-aminopropan-1-ols, the hydrogenation of the / 9, / 3-diaryl- or /? - aryl - /? Aryl-3-aminopropan-l-ols is expediently carried out in a neutral or weakly alkaline alcoholic solution of the disubstituted hydracrylic acid nitriles over Raney catalysts such as Raney nickel or Raney cobalt at temperatures of 50 to 100 ° C. under a hydrogen pressure of 50 to 150 atmospheres. This hydrogenation proceeds smoothly and with good yields, although it was to be expected that -the /?, /? - disubstituted hydracrylic acid nitriles as aldoI adducts in alcoholic solution would partially disintegrate again into the components, especially if the hydrogenation of the hydracrylic acid nitriles had already strongly basic oil -Aryl-3-aminopropanl-ol is formed and the decomposition of the starting material would be catalyzed by the reaction product. Surprisingly, even partial decomposition of this kind does not occur even if the hydrogenation over Raney nickel is carried out under the specified conditions to achieve the highest possible yields of primary amine in the presence of ammonia. The second side reaction to be expected when working in such a strongly alkaline solution, elimination of water to give the corresponding / ^ -substituted cinnamonitrile and its subsequent hydrogenation to an aminopropane derivative (compare, for example, BB, 20, p. 1129 [1897]), also occurs among the specified Hydrogenation conditions do not apply. Such a side reaction through dehydration was all the more to be expected since the ß, ß-Oi & ryl- or /? - aryl - / ^ alkylhydracrylic acid nitriles, due to their nature as tertiary carbinols, are particularly easily subject to dehydration to give ^ -substituted cinnamon nitriles.

The primary 1,1-diaryl- or 1-aryl-1-alkyl-3-aminopropanols (I) obtained according to the invention can be mono- or dialkylated on nitrogen by methods known per se; also can the tertiary 1,1-diaryl or I-aryl-1-alkyl-3-aminopropanols (l) obtained in this way convert into any O-acyl derivatives by acylation.

The products of the process are valuable, primarily spasmolytic substances; also are the products prepared according to the invention can be used in many ways as intermediates for further syntheses.

example 1

To a suspension of 66 g (1.69 mol) of finely powdered sodium amide in 300 ecm of dry ether a solution of 200 g (1.1 mol) of benzophenone and 77.5 g (1.89 mol) is gradually added dropwise with stirring Acetonitrile in 500 ecm of ether in such a way that a reaction temperature of 28 to 30 ° C is established. There if the sodium salt formed separates out voluminously, it is added gradually during the dropwise addition another 500 ecm of ether and then stir for a further 12 to 15 hours at room temperature. When careful When the reaction mixture is introduced into ice water, the water separates at the separating layer Ether separates /?, /? - Diphenylhydracrylsäurenitril, which is only moderately soluble in ether, in crystalline form. You vacuum off, wash with Water and a little ether and recrystallized from methanol for purification. Yield: 140 to 160 g of M.p. = 138.5 ° C

150 g ß, ß- diphenylhydracrylsäurenitril are mixed with 20% methanolic ammonia and after addition of 15 g Raney nickel in an autoclave at 80 to 100 ° C and 50 to 80 atm. H ₂ pressure hydrogenated until the end of the H ₂ uptake. The 1,1-diphenyl-3-aminopropan-l-ol formed separates out in crystalline form on cooling. It is filtered off with suction, separated from the admixed Raney nickel by boiling with methanol and, after concentrating and cooling, the methanol solution yields coarse, colorless crystals

M.p. = 142.5 ° C; Yield: 100 to 120 g.

By catalytic methylation (hydrogenation with 2.2 mol of formaldehyde in methanolic-aqueous solution via Raneynickel) one obtains 1,1-diphenyl-3-dimethylaminopropanol - (1) with a mp = 168 ° C (from Methanol).

Acetylation of this l, l-diphenyl-3-dimethylaminopropanols- (l) using pyridine acetic anhydride is obtained after customary work-up, the corresponding O-acetyl compound with a melting point of 109 ° C. (from a little petroleum ether).

The correspondingly obtained O-propionyl compound melts at 67 ° C and forms a hydrochloride from F. = 183 ° C.

The O-trimethylgalloyl compound obtained analogously with 3,4,5-trimethoxybenzoyl chloride melts 125 ° C (from ligroin).

Example 2

A mixture is added dropwise to a suspension of 100 g (2.56 mol) of sodium amide in 600 ecm of dry ether of 200 g (1.66 mol) of acetophenone and 117 g (2.86 mol) of acetonitrile such that the reaction temperature adjusts to about 30 ° C. After adding a further 600 ecm of ether, the reaction mixture is stirred 12 to 15 hours at room temperature, then wears out carefully in ice water and separates the aqueous layer, which is shaken out again with ether. From the combined ethereal solutions an oily residue is obtained, which is fractionally distilled in vacuo: after a forerun

(Acetophenone) is obtained at _{b.p. 2i5} = 125 to 130 ° C. 150 g /? - methyl - /? - phenylhydracrylic acid nitrile as a pale oil which soon crystallizes. F. = 60 ° C (from ether - petroleum ether).

A mixture of 110 g /? - methyl - /? - phenylhydracrylsäurenitril, 60 ecm methanol and 250ccm20% methanolic ammonia is after the addition of 10 g Raney nickel at 80 ° C and 60 to 80 atm. H ₂ pressure hydrogenated in a stirred autoclave. After the _{uptake of H 2 has} ended, the Raney nickel is separated off after cooling and methanol and excess ammonia are evaporated off in vacuo at 40 ° C., 2-phenyl-4-aminobutanol- (2) being obtained as a residue which crystallizes easily. F. = 73 to 75 ° C after recrystallization from ether-petroleum ether; Yield: 85 to 90 g.

20 g of this primary base are dissolved in 65 g of technical formic acid (85%) with ice cooling and this solution is mixed with 26.7 g of 30% strength formaldehyde solution. After standing for several hours, the solution will warmed up on the steam bath overnight, then evaporated in vacuo, the residue dissolved in water, the base deposited with concentrated potash solution and isolated with ether. By distillation the residue of the ether solution is obtained

2-phenyl-4-dimethylaminobutanol- (2) as a water- _{white oil with a boiling point of lj7} = 92 ° C; Yield: 19 g.

60 g of 2-phenyl-4-am.inobutanol- (2), dissolved in 200 ecm of acetone, are hydrogenated after adding 5 g of Raney nickel for 1.5 hours at 80 ° C and 60 to 90 atmospheres. H ₂ , the 2-phenyl-4-isopropylaminobutanol- (2) formed in this way is obtained after the usual work-up, initially as a slightly viscous, water-white oil with a boiling point of ₀₆ = 98 to 100 ° C. which solidifies in crystalline form. M.p. = 57 to 58 ° C; Yield: 68 g.

The 2-phenyl-4-isopropylmethylaminobutanol- (2) obtained therefrom by N-methylation is a pale oil with a boiling point of ₂ = 115 ° C.

Example 3

If the benzophenone in Example 1 is replaced by the equivalent amount of p-methoxybenzophenone, the β- phenyl- β -p-methoxyphenylhydracrylic acid nitrile, melting at 132 ° to 133 ° C., is obtained in an analogous procedure by adding acetonitrile into the 1-phenyl-lp-methoxyphenyl-3-aminopropanol- (l) with a temperature of 108 ° C. By methylation according to the information in Example 1, 1-phenyl-lp-methoxyphenyl-3-dimethylaminopropanol ( l) from m.p. = 115 to 116 ° C

The ß- phenyl- β- o-methoxyphenylhydracrylic acid nitrile obtained analogously from o-methoxybenzophenone and acetonitrile melts at 118 to 120 ° C and changes into 1-phenyl -1 - ο - methoxyphenyl - which melts at 126 to 127 ° C during the hydrogenation. 3-aminopropanol- (l). The corresponding dimethylamino compound obtained analogously to Example 1 has a melting point of 134.degree

If the 1-phenyl-l-o-methoxyphenyl-

3- aminopropanol- (l) in acetone as described in Example 2, then I-phenyl-1 is formed -o-methoxyphenyl-3-isopropylaminopropanol- (1) with a melting point of 153 to 155 ° C. Methylation gives from this the 1-phenyl-l-o-methoxyphenyl-3-isopropylmethylaminopropanol- (l) with a temperature of 71 ° C.

The following substances are obtained analogously from m-methoxybenzophenone: /? - phenyl - /? - m-methoxyphenylhydracrylic acid nitrile, mp = 86 to 88 ° C; 1-phenyl-lm-methoxyphenyl-3-aminopropanol- (l), b.p. _{0> 01} = 195 ° C; I-Phe-

nyl-l-m-methoxyphenyl-3-dimethylaminopropanol- (l), m.p. = 145 ° C

Example 4

To a suspension of 33 g (0.845 mol) of finely powdered sodium amide in 150 ecm of dry ether a solution of 120 g (0.554 mol) of p-chlorobenzophenone and 39 g of acetonitrile is gradually added dropwise with stirring (0.95 mol) in 250 ecm of dry ether such that a reaction temperature of 28 to 30 ° C is set. After stirring for 12 to 15 hours at room temperature, the reaction mixture is carried Carefully pour it into ice water, the majority of the / 5-phenyl - /? - p-chlorophenylhydracrylic acid nitrile formed precipitates in crystalline form; M.p. = 146 ° C (from dilute methanol); Yield 111.7g.

25.7 g of this hydracrylonitrile are dissolved in 300 ecm of methanol and in the presence of 20 g of Raney cobalt at 70 ° C. and 80 to 50 atm. H ₂ pressure hydrogenated for 1 hour until 2 moles of H _{2 are} absorbed. From the methanolic solution separated from the contact, 1-phenyl-lp-chlorophenyl-3-aminopropanol- (I) with a melting point of 105 to 107 ° C. is obtained after conventional work-up

By catalytic methylation (hydrogenation with 2.2 mol of formaldehyde in methanolic-aqueous solution via Raneynickel) the I-phenyl-1 - ρ - chlorophenyl - 3 - dimethylaminopropanol - (1) from M.p. = 127 ° C

93 .beta.-phenyl -beta-m-chlorophenyl-hydracrylsäurenitril, mp = ° C; of m-chlorobenzophenone obtained analogously the following substances obtained 1-phenyl-1-m-chlorophenyl-3-aminopropanol- (l), m.p. = 85 to 86 ° C, and I-phenyl-1 - m - chlorophenyl - 3-dimethylaminopropanol- (l), m.p. = 128 ° C

The following substances are obtained analogously from O '-chlorobenzophenone: / 5-phenyl - ^ - o-chlorophenyl-hydracrylic acid nitrile, mp = 90 to 92 ° C; l-phenyl-lo-chlorophenyl-3-aminopropanol- (l), m.p. = 117 ° C; 1-phenyl-lo ^ chlorophenyl-3-dimethylaminopropanol- (l), m.p. = 120 to 121 ° C

Example 5

From cyclohexylphenyl ketone and acetonitrile, using sodium amide as the condensing agent and following the procedure described in Example 1, the β- phenyl-β-cy clohexylhydracrylsäurenitril with a melting point of 110 ° to 112 ° C. is obtained. The hydrogenation of this nitrile in methanolic solution over Raney cobalt as a catalyst results in accordance with the procedure described in Example 4, the l-phenyl-l-cyclohexyl-3-aminopropanol- (l) with a temperature of 90 to 91 ° C .; the corresponding dimethylamino compound shown as usual with a temperature of 152 to 153 ° C forms an easily soluble hydrochloride with a temperature of 212 ° C.

B e i s ρ i e 1 6

A solution of 44 g of pyridyl (4) phenyl ketone and 17 g of acetonitrile in 120 ecm of absolute ether at 28 to 30 ° C. is gradually added dropwise to a suspension of 14.4 g of finely powdered sodium amide in 70 ecm of dry ether, and then 12 up to 15 hours at room temperature. When the reaction mixture is introduced into ice water, the β- phenyl - ^ - pyridyl- (4) -hydracrylic acid nitrile separates from the

M.p. = 185 ° C (from dilute methanol) crystalline; Yield: 38 g.

When hydrogenating over Raney cobalt in the procedure described in Example 4, this results the l-phenyl-l-pyridyl- (4 ') -3-aminopropanol- (l) from

M.p. = 143 ° C (from methylcyclohexane). The corresponding

Claims (1)

Dimethylamino compound melts at 150 ° C (from dilute alcohol). ? Was obtained analogously: / - phenyl- / J-pyridyl- (3) -hydracrylsäurenitril, F. = 176 ride to 179 ° C (Hydrochlo; 1 - phenyl -1 - pyridyl - (3 ') - 3 - aminopropanol- ( 1), mp = 154 ° C, and l -l -phenyl -pyridyl- (3 ') - 3-AminoPro-Panol- (I) _j F. = 154 ° C, and 1-phenyl-1 -pyridyl- (3 ') - 3-dimethyl aminopropanol - (1), m.p. = 146 ° C, as well as /; - Phenyl - /? - pyridyl- (2) -hydracrylic acid nitrile, m.p. = 92 ° C, l -phenyl - l -pyridyl- (2 ') -3-aminopropanol- (l), mp = 112 ° C, and l -phenyl- l -pyridyl- (2') -3-dimethylaminopropanol- (l), mp = 100 ° C. Example 7 When a suspension of 14 g of sodium amide in 75 ecm of absolute ether is gradually added to a solution of 45 g of thienyl (2) phenylketone and 16.7 g of acetonitrile in 300 ecm of dry ether, the / 3-phenyl / S-thienyl is obtained - (2) hydracrylic acid nitrile with a temperature of 91 to 92 ° C (from dilute alcohol). 14.5 g of the aforementioned nitrile are extracted from a Soxhlet thimble in -a boiling solution of V ₁₀ mol of Li-alanate in 500 ecm of ether and thus to 1-phenyl-I-thienyl- (2 ') - 3-aminopropanol - ( l) hydrogenated. Working up is carried out in such a way that the reaction mixture is broken down with ice water, the mass obtained is extracted several times after shaking off the ethereal layer with ethyl acetate and the combined extracts are evaporated to dryness in vacuo. The residue is dissolved in dilute acetic acid, this solution is washed with ether and then the base is separated off in crystalline form by adding dilute sodium hydroxide solution. Yield 9.5 g; F. = 136 ° C (from methylcyclo- hexane). . . Examples If the acetonitrile in Example 1 is replaced by the equimolar amount of propionitrile, β, β -diphenyl-α-methylhydracrylic acid nitrile with a melting point of 124 ° C. (from methylcyclohexane) is obtained in an analogous manner. From this, the l, l -diphenyl-2-methyl-3-aminopropanol - (l) with a temperature of 112 ° C (from methylcyclohexane), its corresponding Ν, Ν-dimethylamino compound at 91 to 93 °, can be prepared in the manner described above C (from dilute alcohol) melts. Example 9 A solution of 100 g of fluorenone and 39 g of acetonitrile in 250 ecm of absolute ether is added dropwise to a suspension of 33 g of sodium amide in 150 ecm of absolute ether in such a way that the reaction temperature is set at 28 to 30 ° C. After stirring for 12 to 15 hours at room temperature, the reaction mixture is poured into ice water and shaken, with the addition of further ether, until the precipitate that initially forms is dissolved again. The ether solution dried over sodium sulphate gives an oil after evaporation of the ether, which crystallizes on trituration with petroleum ether. Yield of 9-oxy-9'-cyanomethyl fluorene: 118 g; F. = 110 to ^{III 0} C (from ether — petroleum ether). In the hydrogenation carried out as described above, 9-oxy-9 - /? - aminoethyl fluorene is obtained therefrom from F. = 117 ° C The associated Ν, Ν-dimethylamino compound melts at 104 to 106 ° C, while the N-isopropylamino compound is obtained as an oil, its methanesulfonate at 196 to 198 ° C melts. Example 10 By condensation of benzophenone and hydrocinnamonitrile using sodium amide as coindensation agent, the procedure described in Example 1 gives a -benzyl-β, β- diphenylhydracrylic acid nitrile with a melting point of 172 ° C., which in the catalytic hydrogenation in methanolic ammonia over Raney nickel as a catalyst which gives 1,1-diphenyl-2-benzyl-3-aminopropanol - (1) melting at 116 ° C. The l, l -dipfaenyl-2-benzyl-3-dimethylaminopropanol - (l) obtained therefrom by catalytic methylation melts at 92 ° C. PATENT CLAIM: Process for the preparation of derivatives of the l-aryl-3-aminopropan-l-ols of the general formula AryL ; c-ch-ch ₂ -n; Oh in which R is an alkyl, cycloalkyl or aryl radical, R _{1 is} hydrogen or an alkyl, cycloalkyl or aralkyl radical and R ₂ and R _{3 are} hydrogen or an alkyl, cycloalkyl or aralkyl radical, the aryl radicals being carbo- or heterocyclic * Can be natural, characterized in that corresponding ketones of the general formula aryl — CO — R ₁ , where aryl and R have the meaning given above, are alkylnitriles under the influence of molar amounts of strongly basic condensing agents or those aralkylnitriles whose alkyl content has at least 2 carbon atoms contains, added, the thus obtained /?, /? - disubstituted hydracrylonitriles to corresponding I-aryl-3-aminopropan-l-ols in a neutral to alkaline medium at temperatures of about 50 to 100 ° C and catalytically hydrogenated these primary amines in converts in a manner known per se into N-alkyl, N-aralkyl, Ν, Ν-dialkyl or N-alkyl-N-aralkyl derivatives. Considered publications:
Reports German former Ges., 34, p. 1963 (1901).