DE1493574B - Process for the preparation of new aminoketones - Google Patents

Description

V ^ n ₂ R ⁵
/ CH-CH- ^ R ⁶ R ⁸ /
\ CH ₃

1 2

The invention relates to a method for producing implements. Chlorine or bromine compounds are preferred new aminoketones of the general formula fertilize implemented. It is preferable to work here at elevated temperature in a solution

R 'medium in the presence of a basic reacting substance

, ρττ /-.TT ■ 5 fes, z. B. alkali alcoholate, sodium amide, potassium car-

'ι ² bonat or a tertiary amine.

R ² X ₃ il I ₄ . One can also proceed in such a way that one connects

using the general formula

IO R '

T) 2 - I

^R R ³ . .

in which Me denotes an alkali metal or the radical - MgHaI, with a compound of the general acid addition salts and quaternary ammonium formula
links. In this formula, R ', R ²

and R ^3, which are identical or different, are hydrogen 20 R

or a hydroxyl group, a methoxy group or /

Chlorine. R ⁴ is hydrogen or methyl or NC — CH CH ₂ —N ^ _r7

Ethyl residue. R ⁵ denotes hydrogen or a methyl I

rest. R ⁶ is hydrogen or a hydroxy radical. R ⁷ and R

R ^8, which are identical or different, mean water 25 II ^{X == / X} R ⁸

substance, a methyl radical, a methoxy group or CH ₃ R

Chlorine.

The new compounds are pharmaceutically valuable. This occurs in the presence of water full, especially for cardiovascular diseases - the new amino ketones.

units. They are excellently suited to the 30 Finally, one can also work in such a way that one improve heart function. a compound of the general formula

According to the invention, the compounds can manufacturers ₅

be made when you connect the all- R 'R

common Formula VV '

^K R ³ OR ⁴ H

R ³ OR ⁴ with a compound of the general formula

with a compound of the general formula 4 ° r> 7

y ^RS O = C-CH- ^

^H "~ \ R ⁷ H ₃ CR ⁶

γη γη \> / reducing condensed. Do you want to establish connections?

I Ig R ⁸ , in which the radicals R ', R ² and / or R ^{3 are} two

R CH3 _{O (j he} jrei hydroxyl or alkoxy groups so

together with formaldehyde or formaldehyde, a compound of the formula can also be used
converts remote substances. One works here with a preferred 5 °

wise at elevated temperature in the presence of an r '

Solvent.

You can also proceed in such a way that a compound of the general formula _{IV 3}
R '55 R

/ -C-CH-CH ₂ -Hal _w ith a compound of the general formula

R ³ OR ⁴ R ⁵

in which Hai means a halogen atom, with a 60 /

bond of the general formula NC — CH — CH ₂ —N _r7

R ⁵ I ■ \

/ R ⁴ CH - CH

H-N τ R ⁸

^HN R ⁷ 65 CH, R ^{6 R}

implement. In the presence of water, QH r6 R ⁸ also results in the new amino ketones.

The bases obtained in this way can be converted into their acid addition salts or quaternary in a manner known per se Ammonium compounds are transferred.

The bases obtained, which are usually obtained as racemates, are optionally converted into the optical active isomers separated.

In many cases it is also possible to proceed in such a way that optically active isomers are used as starting materials.

For example

480 g of acetophenone (4 mol), 60 g of paraformaldehyde (2 mol) and 188.8 g of hydrochloric acid amphetamine (1.1 mol) are refluxed for 2 ¹ I for _{2 hours in 250 ml of ethanol.} Most of the ethanol is evaporated off in vacuo, acetone or ether is added to the solution, the crystals which have precipitated out are separated off and recrystallized from isopropanol. 160 g of 3- [1-phenyl-propyl- (2) -amino] -1-phenylpropanon- (1) HCl are obtained

COCH ₂ CH ₂ NHCH-CH ₂
CH ₃

with a melting point of 162 ° C.
Example 2

150 g of acetophenone (1.33 mol) are mixed with 20 g of paraformaldehyde (0.66 mol) and 66 g of hydrochloric acid Nor-ephedrine (0.35 mol) boiled in 110 ml of ethanol. The reaction mixture is described as in Example 1 - refurbished. This gives 3- [l-phenyl-1-hydroxy-propyl- (2) -amino] -1-phenyl-propanone- (1) · HCl

HIGH

COCH ₂ CH ₂ NHCH
CH,

• HCl

with a melting point of 196 to 197 ° C. Example 3

30.8 g of p-chloro-acetophenone, 6 g paraformaldehyde and 20.1 g of 1-norephedrine HCl are boiled in 100 ml of ethanol, 2 ¹ J ₂ hours at reflux. The reaction mixture is worked up as described in Example 1. The 3- [1-phenyl-1-hydroxypropyl - (2) - amino] -1 - (ρ - chloro - phenyl) - propanone - (1) · HCl prepared in this way

. CH (OH)

COCH ₂ CH ₂ NHCH
CH,

HCl

the sucked off. This gives 3- [l-phenyl-l-hydroxypropyl - (2) - amino] -1 - (m - methoxy - phenyl) - propanone- (l) · HCl

20 OCH

10

CH (OH)

HCl

This salt can be recrystallized from methanol and has a melting point of 190 to 193 ° C.

Example 5

50 g of propiophenone, 8 g of paraformaldehyde and 30.2 g of 135 ml of isopropanol-HCl solution were added 1-norephedrine (pH 4.5) are refluxed for 4 hours. The reaction mixture is according to example 6 worked up. The obtained 3- [l-phenyl-1 - hydroxypropyl - (2) - amino] -1 - phenyl - 2 - methylpropanon- (l) · HCl

CH (OH) - ^ _{y /}
COCHCH ₂ NHCh
CH ₃ CH ₃

HCl

30 is recrystallized from methanol and melts at 191 to 193 ° C.

B e i s ρ i e 1 6

16.8 g (S-chloro-propiophenone are refluxed for 3 hours with 15.1 g 1-norephedrine, 150 ml isopropanol and 21 g K ₂ CO ₃ and filtered while warm. 3- [1-phenyl is obtained from the filtrate -1-hydroxy-propyl- (2) -amino] -1-phenylpropanon- (l). After recrystallization from isopropanol, the base has a melting point of 138 to 140 ° C. The HCl salt is formed from the base with isopropanol-HCl , which has a melting point of 195 ° C.

45

Example 7

27.2 g of p-hydroxy-acetophenone, 2 ¹ J boiled for ₂ hours, 6 g of paraformaldehyde, 20.1 g of 1-norephedrine HCl and 100 ml of ethanol under reflux; The N- [3-phenyl-3-hydroxypropyl- (2)] - / S-amino- (i} rhydroxy-propiophenone) HCl is isolated from the reaction mixture by the method given in Example 6. .

CH (OH)

HO

is recrystallized from methanol and melts at 205 to 207 ° C.

Example 4

45 g of m-methoxyacetophenone, 8 g of paraformaldehyde and 30.2 g of 1-norephedrine, brought to a pH of 4.5 with about 135 ml of isopropanol-HCl solution, are refluxed for 4 hours. The reaction mixture is cooled. The crystals become -COCH ₂ CH ₂ NHCH
CH ₃

HCl

Recrystallized from methanol, the compound melts at 210 ° C.

Examples

27.5 g of 3,4,5-trimethoxyacetophenone, 3.6 g of paraformaldehyde and 16.5 g of 1-norephedrine (pH 4.5) mixed with 65 ml of isopropanol-HCl solution are _{refluxed for 4V for 2} hours and as in the case of

game 6 worked up. The thus isolated N- [3-phenyl-3 - hydroxy - propyl - (2)] - β - amino - (3,4,5 - trimethoxypropiophenone) ■ HCl

OCH,

CH (OH)

= ^ v

) -F V-COCH ₂ CH ₂ NHCH

OCH,

CH,

HCl

COCHCh ₂ NHCH
CH ₃ CH ₃

OCH ₃
(V- COCH ₂ CH ₂ NHCH

CH (OH)

CH,

HC!

Example 12

45 g of 4-methoxy-acetophenone, 8 g of paraformaldehyde and 30.2 g with 115 ml of isopropanol-HCl solution 1-norephedrine adjusted to pH 5 is refluxed for 4 hours. The reaction mixture is worked up as in Example 6. The isolated N- [3-phenyl-3-hydroxypropyl- (2)] - / 3-amino-4-methoxy-acetophenone · HCl

is recrystallized from ethanol and melts at 175 to 177 ° C.

Example 9

45 g of 4 - hydroxy - propiophenone, 8 g of paraformaldehyde and 30.2 g with 80 ml isopropanol-HCl solution neutralized 1-norephedrine are refluxed for 4 hours. The reaction mixture 200 ml of acetone are then added. The precipitated N - [3 - phenyl - 3 - hydroxy - propyl - (2)] - α-methyl- / S-amino- (p-hydroxy-propiophenone) · HCl

CH ₃ O - ^ "V-COCH ₂ CH ₂ NHCH

COCHCH ₂ NHCh

I I -HCl

CH ₃ CH ₃

is recrystallized from methanol. F. 204 to 206 ⁰ C. Example 10

50 g of 4-methoxy-propiophenone, 8 g of paraformaldehyde and 30.2 g of 1-norephedrine adjusted to a pH of 4.5 with 80 ml of isopropanol-HCl solution are refluxed for 4.5 hours. The resulting N- [3-phenyl-3-hydroxypropyl - (2)] - α - methyl - β - amino - (ρ - methoxypropiophenone) ■ HCl

CH, O

is, as described in Example 6, isolated. Recrystallized from methanol, the compound melts at 206 to 209 ^° C.

B e i s ρ ie I 11

45 g of 2-methoxy - acetophenone, 8 g of paraformaldehyde, 37.5 g of 1-norephedrine HCl and 100 ml of isopropanol are refluxed for 5 hours. The reaction mixture is worked up as described in Example 6. The isolated N- [3-phenyl-3-hydroxy-propyl- (2)] -β- amino-2-methoxy-propiophenone · HCl

CH (OH) -

HCl CH,

HCl

is recrystallized from methanol and melts at 199 to 201 ⁰ C.

Example 13

41 g of ο-hydroxy-acetophenone, 8 g of paraformaldehyde and 30.2 g of 1-norephedrine adjusted to a pH of 5 with 115 ml of isopropanol-HCl solution are _{refluxed for 4V for 2} hours. As already described in Example 6, the resulting N- [3-phenyl-3-hydroxypropyl- (2)] - ß-amino-2-hydroxypropiophenone · HCl

? ^H CH (OH) -

COCH ₂ CH ₂ NHCH
CH,

HCl

isolated and recrystallized from methanol. F. 214 to 217 ° C.

Example 14

25 g of 2-hydroxy-4-methoxy-acetophenone, 4.3 g of paraformaldehyde and 20.7 g of 1-norephedrine adjusted to a pH of 3.5 with 95 ml of isopropanol-HCl solution are refluxed for 5 hours . The resulting N- [3-phenyl-3-hydroxypropyl- (2)] -β- amino-2-hydroxy -4-methoxypropiophenone · HCl

^0H CH (OH) -

CH, O

COCH ₂ CH ₂ NHCH
CH,

HCl

is isolated as in Example 6. Recrystallized from methanol, the compound melts at 212 bis 213 ° C.

Example 15

39.4 g of p-hydroxy-butyrophenone, 6.6 g of paraformaldehyde and 30.2 g of 1-norephedrine adjusted to a pH of 6 with 115 ml of isopropanol-HCl solution are _{refluxed for 4 1/2} hours. After cooling, 40 ml of acetone are added. The isolated N- [3-phenyl-3-hydroxy-pro-Pyl - (2)] - α - ethyl - β - amino - 4 - hydroxy - propiophenone · HCl

HO-

is recrystallized from ethanol and melts at 163 to 165 ° C.

COCHCh ₂ NHCH
C ₂ H ₅ CH ₃

HCI

is recrystallized from methanol and melts at 204 to 206 ° C.

Example 16

13.5 g of β-Cl- propiophenone are added to a solution of 13.3 g of 1-ephedrine in 80 ml of isopropanol and the mixture is refluxed for 2 hours. The N - [3 - phenyl - 3 - hydroxy - propyl - (2)] - N - methyl- / 5-aminopropiophenone -HCl / = ^ precipitates from the cooled reaction mixture

'CH (OH)

COCH ₂ CH ₂ N-CH H ₃ C CH ₃

HCl

crystalline. Recrystallized from ethanol, the compound melts at 146 to 149 ° C.

Example 17

26.8 g of acetophenone, 6.6 g of paraformaldehyde and 18.5 g of [3- (4-methyl-phenyl) -propyl (2)] - amine · HCl are heated in 200 ml of isopropanol for 2 '/ ₂ hours. The isopropanol is then concentrated and, with the aid of ether-acetone, the N- [3- (4-methylphenyl) propyl- (2)] - (S-aminopropiophenone · HCl , - ·.

CH ₂ - ^ V-CH ₃

20th

25th

COCH ₂ CH ₂ NHCH CH,

HCl

brought to crystallize. Recrystallized from isopropanol, the compound melts at 170 to 171 ^° C.

Example 18

33.9 g of p-Cl-acetophenone, 6.6 g of paraformaldehyde and 18.5 g of [3 - (4 - methyl - phenyl) - propyl - (2)] - amine · HCl are boiled and worked up as in Example 21. The resulting N- [3- (4-methylphenyl) propyl (2)] - ß-amino-4-chloropropiophenone ■ HCl

CH ₂ -

COCH ₂ CH ₂ NHCH

CH

3

CH,

HCl

is recrystallized from a mixture of methanol-isopropanol and melts at 200 to 201 ⁰ C.

Claims (1)

Claim: Process for the preparation of new aminoketones of the general formula R ' R ³ C-CH-CH ₂ Il I OR ⁴ 55 6o R ⁵ CH- / ~ X R ⁷ CH, R ⁶ R ⁸ their acid addition salts and quaternary ammonium compounds, where R ', R ² and R ^{3 are} identical or different and are hydrogen, a hydroxyl group, a methoxy group or chlorine, R ^{4 is} hydrogen, a methyl or ethyl radical, R ^{5 is} hydrogen or a methyl radical, R ^{6 is} hydrogen or a hydroxy radical and R ⁷ and R ^{8 are} identical or different and are hydrogen, a methyl group, a methoxy group or chlorine, characterized in that. one in a manner known per se a) a compound of the general formula R ' "VC-CH ₂ R ³ Ö R ⁴ with a compound of the general formula R ⁵ Η — Ν CH- CH
CH ₃ R ⁶ R ⁷ R ⁸ reacts together with formaldehyde or formaldehyde-supplying substances or b) a compound of the general formula R 'R ² ' R ³ VC-CH-CH ₂ -HaI
OR ⁴ in which Hai denotes a halogen atom, with a compound of the general formula Η — Ν R ^{5 S} CH
CH ₃ R ⁶ R ⁷
R ⁸ implements or c) a compound of the general formula
R ' R ³ where Me is an alkali metal or the remainder - MgHaI, with a compound of 109 518/382 general formula rs NC-CH-CH ₂ -N R ⁴ CH- CH ₃ R ⁶ implements or
d) a compound of the general formula R 'Ζ ^{5 iX} R ³ OR ⁴ H with a compound of the general formula R ⁷ O = C-CH- / ~~ X H ₃ CR ^{6 R8} reducing condensed or ίο e) a compound of the general formula _in ^ _{the Regte R /> r2 and} / _or r3 _{two or} are groups of three hydroxyl or alkoxy, ^ £ _{Ver indung al ge} i ^ _e ^P _a ^P _n i _Forme R ⁵ NC-CH-CH ₂ -N converts and the bases obtained, if appropriate, in their acid addition salts or quaternary Ammonium compounds transferred and bases obtained, which as a rule: as Accumulate racemates, optionally separates into the optically active isomers.