CH651293A5 - Process for preparing aminopropanediol derivatives - Google Patents

Description

The present invention relates to a process for the preparation of therapeutically valuable aminopropanediol.

derivatives of the formula oh r

65

3 1

r -0-ch - ch-ch - n

\ 2 R

in which R1 and R2, which are identical or different from one another, each have a hydrogen atom or a straight-chain one

651293

4th

or branched alkyl radical having 1-4 carbon atoms and R3 is a cycloalkyl radical having 5-7 carbon atoms, a phenyl radical which may optionally contain one or more substituents from the group halogen, nitro, cyano, amino, acylamino, alkylamino or dialkylamino , where each alkyl group contains 1-4 carbon atoms, alkyl with 1-6 carbon atoms, alkenyl, alkoxy with 1-5 carbon atoms, unsaturated alkoxy, 2-methoxyethyl, alkoxyaryl, aryloxy, acyloxy, an indenyl -, Naphthyl, styryl-phenyl, indolyl, quinolyl, carbazolyl or the 5-oxo-5,6,7,8-tetrahydro-l-naphthyl radical or their salts.

The process according to the invention is characterized in that by reacting a 2,3-epoxypropylamine of the formula

/ R1

ch0-ch-ch0-n

V

is in common with a sulfonic acid of the formula, the advantage of the present process is that this side chain is initially produced in its entirety in the form of a well-crystallizing salt of a toluenesulfonic acid ester of high purity and stability, and with one in most cases relatively valuable phenol component in one reaction step to the desired end product.

The aminopropanedial derivatives of the formula I have hitherto been consistently prepared in such a way that hydroxalkylamine-io compounds or corresponding epoxides thereof are partially treated with. difficult to manufacture, i.e. expensive phenols. Since it is in the said hydroxyalkylamine compounds of the formula

, / r1

II

Halogen-CH2-CH-CH2-N OH

V

R-S03H

wherein R is alkyl with 1-6 C atoms, haloalkyl, aryl or substituted aryl, the salt of a sulfonic acid reester of the formula

? H ÎV

r-so -0-ch -ch-ch -h '

V

(+)

rso.

(-)

represents and this in a solvent with a hydroxy compound of the formula

R3-OH 1

to form the compound of the formula I, where the symbols R1, R2 and R3 in the formulas II, IV and V have the same meaning as in the formula I.

Water or an organic water-miscible polar solvent can advantageously be used as solvent in the second process step in the presence of alkalis such as alkali metal hydroxides or alkaline earth metal hydroxides or nitrogen bases. The reaction is carried out at temperatures of 20 to 150 ° C.

After the reaction has ended, the reaction product can be isolated by extraction with an organic solvent.

The process is therefore very simple since the starting materials and the solvents are cheap and the yield obtained is good. In addition, the desired end product is obtained in a very pure form, as a result of which the process described differs from almost all known regulations.

The process products have ß-adenergetic blocking activity and are therefore suitable for the treatment or prophylaxis of angina pectoris, cardiac arrhythmia and increased blood pressure. Since the majority of the ß-blockers known to date are the side chain of the formula

.1

R

-o-ch2-ch-ch2-n

OH

or the corresponding epoxides of the formula II by highly 20-reactive and partly. easily decomposable connection types, it represents a very significant technical advance

III is first to prepare the sulfonic acid ester salts, which have a practically unlimited shelf life, and only then to convert them with the valuable phenols to the end products.

25 put.

Compared to other known processes, the sulfonic acid ester also represents a leaving group with a significantly increased reaction rate compared to e.g. Halogens.

IV 30 The following examples illustrate the invention without restricting it.

Example la): 34.4 g (0.2 mol) of anhydrous p-toluenesulfonic acid are placed in 200 ml of ether and, while stirring, 12.9 g (0.1 mol) of N-tert-butyl-2,3-epoxypropylamine added dropwise 35 ether in 50 ml. The mixture is stirred for 5 hours at room temperature, the ether is decanted off and 200 ml of water are added to the residue. After some time, 43.0 g (91% of theory) of N-tert-butyl-N- (2-hydroxy-3-tosyloxypropyl) -V-ammonium tosylate are filtered off with suction and recrystallized from water. Melting point: 98 ° C.

Analysis according to the formula C21H31NO, S2. H20

Calc .: C 51.30% H 6.76% N 2.84% O 16.12% Found: C 50.94% H 6.68% N 2.86% O 26.03%

45 lb): 47.3 g (0.1 mol) of N-tert-butyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate together with 14.4 g (0.1 mol) 1-Naphthol in 500 ml 25% aqueous sodium hydroxide solution heated for 1 hour under reflux, cooled and extracted 3 times with 100 ml ether. The ether is washed with water, dried and after evaporation, 23.7 g (87% of theory) of l-tert-butylamino-3- (l-naphthoxy) -2-propanol are obtained, which are incorporated into the hydrogen oxalate , Melting point 230 ° C, can be transferred.

Example 2a): 34.4 g (0.2 mol) of anhydrous p-toluoisul-55 fonic acid are placed in 200 ml of ether and, while stirring, 11.5 g (0.1 mol) of isopropyl-2,3-epoxypropylamine in 50 ml Ether dropped. Working up analogously to Example la) Yield 40.4 g (88% of theory) of N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate. Melting point: 60 68-70 ° C.

Analysis according to the formula C20H29NO7S2. H20

Calc .: C 50.29% H 6.54% N 2.93%

Found: C 49.97% H 6.48% N 2.88%

65 2b): 45.9 g (0.1 mol) of N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate together with 14.4 g (0.1 mol) 1-Naphthol in 650 ml of 20% aqueous sodium hydroxide solution heated to reflux for 2 hours, cooled and

5

651293

Extracted 3 times with 100 ml ether. The ether is washed with water, dried and, after evaporation, 21.2 g (82% of theory) of l-isopropylamino-3- (l - naphthoxy) -2-propanol crystallize out. Melting point: 94-96 ° C (cy-clohexane).

Analysis according to the formula C16H21N02

Calc .: C 74.09% H 8.16% N 5.40%

Found: C 74.03% H 8.20% N 5.42%

Example 3a): 655 g (3.44 mol) of p-toluenesulfonic acid hydrate are placed in 1500 ml of methylene chloride and a solution of 200 g (1.72 mol) of isopropyl-2,3-epoxypropylamine in 600 ml of methylene chloride added so that the temperature does not exceed 15 ° C. After standing at room temperature for 5 hours, the methylene chloride is distilled off, the residue is taken up in water and, after cooling to 5 ° C., the product, N-isopropyl-N- (2-hydroxy-3-tosyloxy-propyl) -ammonium tosylate, is isolated.

3b): 12.0 g (0.083 mol) of 1-naphthol are dissolved in 200 ml of 10% NaOH and with 40 g (0.084 mol) of N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium -tosylate added. After standing for several hours at room temperature, virtually pure 1-isopropylamino-3- (1-naphthoxy) -2-propanol (melting point 95 ° C.) can be isolated. About 20% yield of product can be obtained from the mother liquor by extraction with ether of methylene chloride.

Example 4: 2.0 g of 2-allylphenol are dissolved in 30 ml of acetone and 4.0 g of potassium carbonate are added. After adding 4.8 g of N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate, the mixture is heated under reflux for 2 hours.

After taking up in methylene chloride, it is washed with 2N NaOH and water, dried over MgSO4 and the solvent is removed in vacuo. 1- (2-Allyl-phenoxy) -3-iso-propylamino-2-propanol, melting point 58-59 ° C hydrochloride melting point 107-109 ° C.

Example 5: 5.0 g of 2-chloro-5-methylphenol are dissolved in 50 ml of 10% NaOH and with a solution of 12.5 g of N-tert-butyl-N- (2-hydroxy-3-tosyloxypropyl) ) ammonium tosylate in 50 ml of methylene chloride. The two-phase system is stirred at room temperature for 18 hours, the organic phase is separated off, washed with water, dried and the solvent is removed in vacuo. The residue is treated with petroleum ether, 3-tert-butylamino-l- (2-chloro-5-methylphenoxy) -2-propanol is obtained, the hydrochloride melts at 222-224 ° C.

Example 6: 2.1 g of 3-N-dimethylaminophenol are dissolved in 30 ml of 10% NaOH and after the addition of 7.2 g of N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate Allow to stand for 12 hours at room temperature. The solution is saturated with potassium carbonate, etherified, the ether dried over MgSO4. After the solvent has been evaporated off, the residue is treated with petroleum ether to give 1- (3-dimethylamino-phenoxy) -3-isopropylamino-2-propanol with a melting point of 97-98 ° C.

Analysis according to the formula c14H24N2o2

Calc .: C 66.33% H 9.59% N 11.10%

Found: C 66.81% H 9.89% N 11.16%

Example 7: 3.0 g of 2-hydroxyquinoline are dissolved in 40 ml of 10% KOH and 7.5 g of N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate are added. To

Heating for 3 hours at 30 ° C. is allowed to stand for a further 12 hours at room temperature, extracted with ether, the organic phase washed with water, dried and the ether removed in vacuo. The 1-isopropyl-amino-3- (8-quinolinyloxy) -2-propanol is obtained as a colorless oil with the following spectroscopic data:

1 H NMR Spectrum (CDC13): 1.00 (s, CH3), 1.11 (s, CH3) 7.00-7.50 (m4H), 8.13 (d, 1H), 8.83 ( d, 1H) ppm.

Analysis according to the formula C15H20N2O2

Calc .: C 69.20% H 7.74% N 10.76%

Found: C 68.76% H 7.48% N 10.52%

Example 8: 5.0 g of 4-hydroxystilbene are dissolved in 100 ml of 20% NaOH at the boil. After adding 12.0 g of N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium stylate, the mixture is kept at 80 ° C. for a further 20 minutes. After cooling, a further 100 ml of 10% NaOH are added and then extracted with ether. The organic phase is washed with water, dried and evaporated to dryness. L- (4-Stilboxy) -3-isopropyl-amino-2-propan.ol of melting point 113-114 ° C. is obtained.

Analysis according to the formula C20H25NO2

Calc .: C 77.14% H 8.09% N 4.50% - Found: C 77.11% H 7.82% N 4.43%

Example 9: 3.5 g of 4-methoxyphenol are dissolved in 50 ml of methanol and 3.5 g of sodium methylate are added. After adding 8.4 g of N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate, the mixture is stirred at room temperature for 24 hours. The precipitate is filtered off, the filtrate is evaporated to dryness and the residue is taken up in methylene chloride / water. After the organic phase has dried, the solvent is removed and the residue is crystallized using petroleum ether. 1 [4- (2-methoxyethyl) phenoxy] 3-isopropylamino-2-propanol is obtained in the form of deliquescent crystals with the following spectroscopic data:

^ H NMR Spectrum (CDC13): 1.00 (s, CH3), 1.11 (s, CH3), 3.30 (s, CH3), 6.70-7.20 (m, 4H) ppm .

Analysis according to the formula C15H2SN03

Calc .: C 67.38% H 9.43% N 5.24%

Found: C 67.01% H 9.32% N 5.33%

Example 10: 4.0 g of 2-cyanophenol are dissolved in 40 ml of 10% NaOH, with 10.0 g of N-tert. Butyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate were added and the mixture was left to stand at room temperature for 24 hours. It is extracted with ether, the ether is washed, dried and removed in vacuo. The l- (2-cyanophenoxy) -3-tert.butylamino-2-propanol is obtained as a colorless oil.

Example 11: 0.3 g of NaOH are dissolved in 5 ml of water and 0.3 g of 4-hydroxyindole is added. After filtration of the somewhat cloudy solution, 0.5 g of NaCl is added and, after its dissolution, 1.2 g of N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate are added. After standing at room temperature for 20 hours, the product formed is filtered off with suction and washed with water. Recrystallization from ethanol gives colorless crystals with a melting point of 169-171 ° C. of 1 - (4-indolyloxy) -3-isopropylamino-2-propanol.

Analysis according to the formula

Calc .: C 67.71% H 8.12% N 11.28%

Found: C 67.43% H 8.12% N 11.06%

5

10th

15

20th

25th

30th

35

40

45

50

55

60

V

Claims (13)

651293 1 H \ oh h ch3 characterized in that 8-hydroxyquinoline is reacted with N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate. 1 ch0-ch-ch, -n V with a sulfonic acid of the formula R-S03H II III H- characterized in that 7-dioxyindene is reacted with 25 N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate. 2. The method according to claim 1, characterized in that in the second process stage, water or an organic, water-miscible polar solvent is advantageously used in the presence of alkalis, such as alkali metal hydroxides or alkaline earth metal hydroxides, or nitrogen bases. \ "2 (+) rso, (-) characterized in that 4-hydroxyindole is reacted with 40 N-isopropyl-N- (2-hydroxy-3-tosyloxy propy I) ammonium tosylate. 2nd PATENT CLAIMS 1. Process for the preparation of therapeutically valuable aminopropanediol derivatives of the formula OH 0-CH, -CH-eH ~ -NH-CH on Ri ./ 3 25th 0-CH2-CH-CH2-NH-CH. OH CH, characterized in that 1-naphthol is reacted with N-iso-propyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate 30. 16. The method according to any one of claims 1 to 3 for the preparation of a compound of the formula 35 CH30CH2CH2- ^ ^ -OCH2CHCH2NHCH (CH3) 2 QH characterized in that 4-methoxyethylphenol is reacted with N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) -ammo-40 nium-tosylate. 17. The method according to any one of claims 1 to 3 for the preparation of a compound of the formula CH, / 45 0-CH2-CH-CH2-NH-CH ^ CH, CH2 = CH-CH2 characterized in that 2-allylphenol with N-iso- propyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate. / 3rd V 15 characterized in that 3-methyl-phenol is reacted with N-isobutyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosy-lat. 15. The method according to any one of claims 1 to 3 for the preparation of a compound of the formula "CH, / 3rd 0-CH2-CH-CH2-NH-CHv OH CH CH, I J 0-CH2-CH-CH? -NH-C-CH, CI v • c i 3 OH CH_. characterized in that 2-chloro-5-methyl-phenol is reacted with N-tert-butyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate. 14. The method according to any one of claims 1 to 3 for the preparation of a compound of the formula 0-CH, -CH-CH, -NH-CH CH, / 3rd 0-CH2-CH-CH2-NH-CH ^ OH CH3 CH = CH O characterized in that 4-hydroxystilbene is reacted with N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate. 3rd 651293 3. Process according to claims 1 or 2, characterized in that the reaction with the hydroxy compound of the formula R3-OH is carried out at a temperature of 20 to 150 ° C. / 3rd \ / -3 i / c r -0-ch9-ch-ch_-n xr2 H3C O? / CH3 \ ch, in which R1 and R2, which are the same or different from one another, each represent a hydrogen atom or a straight-chain or branched alkyl radical having 1-4 C atoms, and Rs is a cycloalkyl radical having 5-7 C atoms, a phenyl radical which, if appropriate one or more substituents from the group halogen, nitro, cyano, amino, acylamino, alkylamino or dialkylamino, each alkyl group containing 1-4 carbon atoms, alkyl with 1-6 carbon atoms, alkylene, alkoxy with 1-5 carbon atoms, unsaturated alkoxy, 2-methoxyethyl, alkyloxyaryl, aryloxy, acyloxy, an indenyl, naphthyl, styrylphenyl, indolyl, quinoyl, carbazolyl or the 5-oxo 5,6,7,8-tetrahydro-l-naphthyl radical or of their salts, characterized in that by reacting a 2,3-epoxypropylamine of the formula ch3 o-co-ch3 4. The method according to any one of claims 1 to 3 for the preparation of a compound of the formula CH3 0-CH2-CH-CH2-NH-C-CH3 CH, characterized in that 2-cyano-phenol with N-tert. Butyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate. 5. The method according to any one of claims 1 to 3 for the preparation of a compound of the formula 0-ch2-ch-ch2-nh-ch oh ch, 6. The method according to any one of claims 1 to 3 for the preparation of a compound of formula ch3 o-ch9-ch-ch_-nh-ch ( c. , c \ oh ch3 wherein R is alkyl with 1-6 C atoms, haloalkyl, aryl or substituted aryl, the salt of a sulfonic acid ester of the formula h oh I. r-s02-0-ch2-ch-ch2-n V «1 7. The method according to any one of claims 1 to 3 for the preparation of a compound of the formula IV represents and this in a solvent with a hydroxy compound of the formula R3-OH V to form the compound of the formula I, where the symbols R1, R2 and R3 in the formulas II, IV and V have the same meaning as in the formula I. 8. The method according to any one of claims 1 to 3 for the preparation of a compound of formula ch3 o-ou-ch-ch.-n-ch / ' 9. The method according to any one of claims 1 to 3 for the preparation of a compound of the formula CH3 0-CH2-CH-CH2-NH-C-CH3 OH CH- characterized in that 8-hydroxy-l, 2,3,4-tetra-hydro-naphthalene-l-one with N-tert-butyl-N- (2-hydroxy-3-to-syloxypropyl) ammonium tosylate. 10. The method according to any one of claims 1 to 3 for the preparation of a compound of the formula CH, 0-CH2-CH-CH2-NH-CH ^ ^ OH CH, characterized in that 4-hydroxy-carbazole is reacted with N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) ammonium tosylate. 10th characterized in that 2,3,6-trimethyl-4-0-acetoxyphenol is reacted with N-isopropyl-N- (2-hydroxy-3-tosyloxy-propyl) ammonium tosylate. 11. The method according to any one of claims 1 to 3 for the preparation of a compound of the formula CH, 12. The method according to any one of claims 1 to 3 for the preparation of a compound of formula CH, 13. The method according to any one of claims 1 to 3 for the preparation of a compound of the formula characterized in that 3-dimethylamino-phenol with N-isopropyl-N- (2-hydroxy-3-tosyloxypropyl) -ammo-55 nium- tosylate.