CH640212A5 - Process for the preparation of 1-amino-3-aryloxy-2-propanol derivatives - Google Patents

Abstract

Process for the preparation of the compounds of the formula VII Rb - OCH2 - CH(OH)CH2NH - R VII in a racemic or optically active form, starting from corresponding compounds of the formula V <IMAGE> over five or six reaction steps. The compounds of the formula VII are useful medicines having a ss-adrenoceptor-blocking action.

Description

The invention relates to the subject matter defined in the claims.

Examples of suitable meanings of Ra are alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, phenoxy, benzyloxy, phenoxy substituted by halogen with an atomic number from 9 to 35, alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms Benzyloxy. Ra preferably means alkoxy having 1 or 2 carbon atoms, 2,2,2-trichloroethoxy, unsubstituted phenoxy, or unsubstituted benzyloxy, in particular ethoxy or unsubstituted benzyloxy.

The cyclization of the compounds of formula II takes place under basic conditions, e.g. in the presence of sodium hydroxide, pyridine or triethylamine. One works at about 0 to 50 ° C, preferably at room temperature. The solvent used is e.g. Tetrahydrofuran, di-oxane, ethanol or methanol, or water.

The isopropylidene radical is split off from the compounds of the formula III analogously to known methods.

The introduction of a -CORa group into the compounds of the formula IV is carried out under Schotten-Baumann conditions.

The remaining reactions are carried out analogously to the known methods.

The compounds of formula V are known.

The compounds are preferably in optically active form. They preferably have the following configuration:

H

T /

CHn •• «•• ■« ('••••••• OH «v

• i 2 i \

0 0

1 I

The configuration of the starting material is retained.

The compounds of the formula I can be isolated and purified in a manner known per se, for example by recrystallization or column chromatography.

The compounds of formula VII have a blocker action on the β-adrenoceptors and can therefore u. a. for the prophylaxis and therapy of coronary diseases such as angina pectoris, for the treatment of cardiac arrhythmias and for conditions that lead to psychological

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see stress-induced, unwanted mobilization of fatty acid and glucose result.

One or more aromatic, heteroaromatic, cycloaliphatic or heterocycloaliphatic rings are optionally linked in Rb, it being possible for the linked rings to also be substituted. Rb means z. B. Phenyl.

Preferred residues Rb are residues of phenols, in particular of phenols, which do not contain any groups which are labile towards bases.

Suitable Rb radicals are e.g. B .:

a) 4-indolyl, optionally substituted in the 2-position by methyl or COOB, in which B is isopropyl;

b) phenyl, optionally substituted, e.g. by 2-acetyl-4-n-butyramido, allyl in the 2-, 3- or 4-position, 2-allyl-oxy, 2-cyano, 2-chloro-5-methyl, 2-chloro, 3,4-dichloro , 2,5-dichloro, 2-ethynyl, 2-ß-chloroallyl, 2-cis-y-chloroallyl, methyl in the 2-, 3- or 4-position, 2,3-dimethyl, 3,5-dimethyl , 2-bromo, 2-propynyloxy, 2-hydroxymethyl, 2-methyl-3-nitro, 2-phenoxy, methoxy in 2-, 3- or 4-position, methanesulfonamido, 3-cyclohexylureido, 2-methylthio, 2-tetrahydrofurfuryloxy , 3-n-butynyloxy, 2-cyclopropyl, 2-cyclopentyl, 4-methoxyethyl;

c) 2,3-dimethyl-4-benzo [b] furyl;

d) 1-naphthyl or 5,8-dihydro-l-naphthyl;

e) 1,2,3,4-tetrahydro-1,4-ethano-5-naphthyl;

f) 8-thiochromanyl;

g) 4-indanyl;

h) 7-indenyl;

i) 2,3-dihydro-l- (2H) -oxo-5-naphthyl;

j) cis-1,2,3,4-tetrahydronaphthalene-2,3-diol.

Particularly preferred Rb radicals are 4-indolyl and 2-methyl-4-indolyl.

The tosyloxy and mesyloxy groups represent examples of activated forms of the hydroxyl group of the compounds of the formula I. Halogen with an atomic number from 17 to 53 represents an example of an exchanged form of the hydroxyl group.

The saponification is preferably carried out under basic conditions, e.g. in the presence of an alkali metal hydroxide.

If the preparation of the starting compounds is not described, they are known or can be prepared by methods known per se or analogously to the methods described here or analogously to methods known per se.

In the following example, which explains the invention in more detail, all the temperatures are given in degrees Celsius and are uncorrected.

Example:

(2S) -1 - (Indol-4-yloxy) -3-isopropylamino-2-propanol (compound of the formula VII, starting from a compound of the formula V) a) (4S) -4-isopropylaminomethyl-2,2-dimethyl -l, 3-dioxo-lan (compound of the formula IV)

52.5 g of (4R) -2,2-dimethyl-1,3-dioxolane-4-carbaldehyde in 400 ml of methanol (prepared by reacting 1,2,5,6-diisopropylidene-D-mannitol with lead tetraacetate) become a suspension of 5.25 g of 10% palladium on carbon in 150 ml of methanol and 86 ml of isopropylamine was added dropwise under hydrogen over two hours. The mixture is hydrogenated at 1 atm until no more hydrogen is taken up, the catalyst is filtered off and the methanol is distilled off. The residue is stirred for five minutes with a solution of 95 g of Na2CO3 in 500 ml of water, extracted three times with methylene chloride, the organic phases are dried with Na2SO4 and the filtrate is concentrated. The yellowish oil is then distilled at 42 ° (0.1 mmHg). 56.7 g of colorless oil [a] D20 - 7.2 ° (2% methanol) are obtained.

b) N - [(4S) -2,2-dimethyl-1,3-dioxolan-4-ylmethyl] -N-iso-propylcarbamic acid ethyl ester (compound of the formula III)

150 g (4S) -isopropylaminomethyl-2,2-dimethyl-1,3-di-oxolane are dissolved in 1.51 methylene chloride and cooled to 0 ° from -5. 92 ml of ethyl chloroformate and 240 ml of 4N sodium hydroxide solution are simultaneously added dropwise to this solution over an hour and the suspension is stirred vigorously at 0 ° for 30 minutes. It is then acidified with cold 10% tartaric acid, the phases are separated and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are shaken twice with cold 2N NaOH, washed with water,

dried over Na2S04 and concentrated. Distillation of the residue gives the pure N - [(4S) -2,2-dimethyl-1,3-di-15 oxolan-4-ylmethyl] -N-isopropyl-carbamic acid ethyl ester (Sdpo, 6mmHg96 °), [a] D20 - 19.2 ° (1% MeOH).

c) ethyl {4S) -N- (2,3-dihydroxypropyl) -N-isopropylcarbamate (compound of the formula II)

115.7 g of N - [(4S) -2,2-dimethyl-l, 3-dioxolan-4-ylmethyl] -20 N-isopropylcarbamic acid ethyl ester are stirred in 500 ml of methanol and 115 ml of 4N HCl for two hours at 10 ° and concentrated in vacuo. The (2S) -N- (2,3-dihydroxypropyl) -N-isopropylcarbamic acid ethyl ester [a] D20 -19.9 ° (1% in methanol) (crude processed) is obtained. 25 d) (5S) -5-hydroxymethyl-3-isopropyl-2-oxazolidinone (compound of the formula I)

98.7 g of crude (2S) -N- (2,3-dihydroxypropyl) -N-iso-propylcarbamic acid ethyl ester are brought to pH 13 with 4N NaOH, left to stand at 20 ° for two hours and

30 extracted three times with methylene chloride. The organic phases are washed with 6m NaCl, dried over Na2SO4 and the solvent is distilled off. The title compound is obtained (mp. 56-59 ° - from methylene chloride / ether). [a] D20 + 49.1 ° (1% in methanol).

35 Step b) can also be carried out using benzyl chloroformate or phenyl ester instead of ethyl ester, and thus steps 5) and 5) also give (5S) -5-hydroxymethyl-3-isopropyl-2- oxazolidinone (mp. 56-59 ° - from methylene chloride / ether 40 [a] D20 + 49.1 ° (1% in methanol).

e) (5S) -3-isopropyl-5-tosyloxymethyl-2-oxazolidinone (compound of the formula I in which the free hydroxyl group is activated in the form of the tosyloxy group)

32.8 g of p-toluenesulfonyl chloride are used for 30 Mi-4S grooves to give a solution of 24.8 g of (5S) -5-hydroxymethyl-3-

Isopropyl-2-oxazolidinone in 60 ml pyridine added at -5 ° and stored overnight at 0 °. The mixture is poured onto ice, the oil is extracted with methylene chloride and the organic phases are washed with 2H HCl and water. 50 After drying over Na2S04, the methylene chloride is removed and the residue is crystallized from methylene chloride ether. The (5S) -3-isopropyl-5-tosyloxymethyl-2-oxazolidinone (mp 77-79 °) [a] D20 + 51.8 ° (1% in MeOH) is obtained.

f) (5S) -5- (indol-4-yloxymethyl) -3-isopropyl-2-oxazolidi-non (compound of the formula VI)

A solution of 17.4 g of 4-hydroxyindole in 100 ml of N, N-dimethylformamide becomes a suspension of 6.3 g of Na-6o triumhydride (50% dispersion) and 50 ml of N, N-dimethylformamide under argon during a Dripped hour. The temperature must not exceed 35 °. The suspension is stirred for 1.5 hours at room temperature, 41 g (5S) -3-isopropyl-5-tosyloxymethyl-2-oxazolidinone in 50 ml of N, N-65 dimethylformamide are added dropwise and the mixture is stirred at 80 ° under argon overnight. The suspension is poured onto ice, shaken out with methylene chloride, the organic phases are washed with 2N NaOH and water and dried over Na2SO4

5

and concentrated on the rotor vapor. The residue is crystallized from methylene chloride ether. The (5S) -5- (indol-4-yloxymethyl) -3-isopropyl-2-oxazolidinone (mp. 139-142 °) [a] D20 + 56.7 ° (1% in MeOH) is obtained.

g) (2S) -l- (indol-4-yloxy) -3-isopropylamino-2-propanol s (compound of the formula VII)

A suspension of 19.5 g (5S) -5- (indol-4-yloxymethyl-3-isopropyl-2-oxazolidinone, 200 ml ethanol and 180 ml 4n

640212

NaOH is heated under reflux overnight, the solvent is distilled off and the residue is taken up in methylene chloride-water. The aqueous phase is extracted with methylene chloride, the combined organic phases are washed neutral with water, dried over Na2S04 and concentrated. The residue is crystallized from benzene. The (2S) -l- (indol-4-yloxy) -3-isopropylamino-2-propanol (mp. 93-94.5 °) [a] 54620 -4.8 ° (1% in methanol) is obtained.

Claims (23)

640212 1 I 2 I! 2nd in which R has the meaning given in claim 1, under Schotten-Baumann conditions introduces a group -CORa, in which Ra has the meaning given in claim 1 25, B) splitting off the isopropylidene radical from the corresponding compounds of the formula m obtained in this way and defined in claim 1, C) the compound 30 obtained in this way, defined in claim 1, fertilize the formula II to the corresponding compounds in claim 1 cyclized compounds of formula I, D) either i) the compounds of the formula I thus obtained directly to the corresponding compounds defined in claim 1 35 fertilize the formula VI or ii) activates or exchanges the hydroxy group in the compounds of the formula I thus obtained and then the compounds of the formula I thus obtained with the hydroxyl group in activated or exchanged form 40 corresponding compounds of formula VI defined in claim 1 and E) the compounds of formula VI thus obtained are saponified. 2. Process for the preparation of the compounds of formula VII defined in claim 1 in racemic or optically active form, characterized in that A) in corresponding compounds of formula IV 2 II a 0 f yj \ / c / \ III CH. CH. wherein R has the above meaning and Ra denotes a group which is split off during intramolecular oxazolidinone formation, cleaves off the isopropylidene residue, B) the compounds of formula II thus obtained, HIGH2CH (OH) CH2NR-C-Ra O II V NO where R has the meaning given above, cyclized, C) either i) the compounds of the formula I thus obtained directly to the corresponding compounds of the formula VI, - OCH2 - CH - CH2 V NO VI reacted group in activated or exchanged form to the corresponding compounds of formula VI • and D) the compounds of formula VI thus obtained are saponified. 2nd PATENT CLAIMS 1. Process for the preparation of the compounds of formula VII, Rb-OCH2-CH (OH) CH2NH-R VII where R stands for a group which is resistant to a reductive amination and Rb stands for an optionally substituted aromatic ring, in racemic or optically active form, characterized in that A) from corresponding compounds of the formula III, CR "- CH - CH" NR - C - R 3. Process for the preparation of the compounds of formula VII defined in claim 1 in racemic or optically active form, characterized in that A) in corresponding compounds of formula V, 50 55 CH2 - CH - CHO in which Rb and R have the meaning given above, or ii) activates or exchanges the hydroxy group in the compounds of the formula I thus obtained and then the compounds of the formula I thus obtained with the hydroxy group O O X ch3 ch3 introduces the group R, which stands for a group which is stable at 6o of a reductive amination, by reductive amination, B) introduces a group CORa, in which Ra has the meaning given in claim I, into the compounds of formula IV thus obtained and defined in claim 2, 65 C) from the corresponding compounds of formula III thus obtained and defined in claim 1 cleaves the isopropylidene residue, D) the compounds thus obtained and defined in claim I fertilize the formula II to give the corresponding compounds of the formula I as defined in claim 1, E) either i) the compounds of the formula I thus obtained are reacted directly to the corresponding compounds of the formula VI defined in claim 1 or ii) the hydroxy group in the compounds of the formula I thus obtained is activated or exchanged and then the compounds thus obtained Reacts compounds of formula I with the hydroxy group in activated or exchanged form to the corresponding compounds of formula VI defined in claim 1 and F) the compounds of formula VI thus obtained are saponified. 4. The method according to claim I, characterized in that Rb is 1-naphthyl, 5,8-dihydro-l-naphthyI or 2,3-di-hydro-1 (2H) -oxo-5-naphthyI. 5. The method according to claim I, characterized in that Rb is indol-4-yl. 6. The method according to claim 1, characterized in that R is alkyl. 7. The method according to claim I, characterized in that Ra alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, phenoxy, benzyloxy, by halogen with an atomic number of 9 to 35, alkyl with 1 to 4 carbon atoms or alkoxy phenoxy or benzyloxy substituted with 1 to 4 carbon atoms. 8. The method according to claim 1, characterized in that Ra means alkoxy having 1 to 4 carbon atoms. 9. The method according to claim 1, characterized in that in the compounds of formula I the hydroxy group is activated in the form of the mesyloxy or tosyloxy group. 10. The method according to claim 1, characterized in that in the compounds of formula I the hydroxyl group is replaced by a halogen atom with an atomic number of 17 to 53. 10th 11. The method according to claim 1, characterized in that one carries out the saponification of the compounds of formula VI in the presence of a base. 12. The method according to claim 11, characterized in that one carries out the saponification in the presence of an alkali metal hydroxide. 13. The method according to claim 11, characterized in that one carries out the saponification in the presence of an alkali metal hydride. 14. The method according to claim 1, characterized in that one carries out the saponification at reflux temperature. 15. The method according to claim 1, characterized in that one carries out the saponification in the presence of sodium hydroxide and ethanol. 15 CH2 - CH - CH2 - NHR 0 0 X IV CH, in which R and Ra have the above meaning, under basic conditions, at about 0 to about 50 ° C. and in the presence of a solvent, to give corresponding compounds of the formula I, HO - CH "- CH - CH- 16. The method according spoke 1, characterized in that one carries out the ether formation with 4-hydroxyindole. 17. The method according to claim 1, characterized in that one carries out the ether formation in dimethylformamide. 18. The method according to claim 1, characterized in that one carries out the ether formation in the presence of sodium hydride. 19. The method according to claim 1, characterized in that one carries out the ether formation at a temperature of 35 ° C. 20. The method according to claim I, characterized in that one carries out the ether formation under argon. 21. The method according to claim 1, characterized in 640 212 net that the compounds produced are in racemic form. 22. The method according to claim I, characterized in that the compounds produced have the following optically active form: H T / CH .. •••••• C «•••••• .CHv I 2 A 0 o 23. The method according to claim 1, characterized in that the compounds prepared are in the form of the free base.