FI78068B - FOERFARANDE FOER FRAMSTAELLNING AV ALKYLETRAR. - Google Patents

Description

78068

Method for the preparation of alkyl ethers - Förfarande för framställning av alkyletrar

The invention relates to a process for the preparation of compounds of the formula RO-CH-CH-f Ν · (I), β-o-ch2-choh-ch2-nh-r1 and their salts, in which R represents lower alkyl optionally substituted by cycloalkyl and R 1 is isopropyl or tert-butyl, which process is characterized in that in the compound of the formula RO-CH-CH- / (II) • x / -O-CH2-CHOH-CH2-NH-R '· ^ * or a salt thereof, reducing the group -CH = CH- to -CH2 "CH2" by treatment with catalytically activated or generated hydrogen, lower alkanol or a mixture of such with water, and if desired converting the resulting free compound to a salt or the resulting salt to the free compound or another salt.

The withdrawn FI patent application 2510/68 describes the catalytic hydrogenation of the allyl group of 1- (allylphenoxy) -3-alkylaminopropan-2-olene to an n-propyl group. However, there were preconceptions to the application of this reaction to the starting materials of the formula II used according to the invention, since these are enol ethers which are known to cleave very easily to the corresponding aldehydes and to incorporate alcohols to form acetals. Thus, it was expected that the reduction of the invention, when it occurs at all, could only be performed using special precautions to prevent hydrolytic competing reactions.

The invention is thus based on the surprising finding that the reaction according to the invention results in the desired product in a high yield, without the need for special precautions dictated by the lability of the enol ether group. It is particularly advantageous that the process according to the invention can be carried out using conventional alkanols as solvents.

Residues and compounds marked "below" preferably contain up to 7 and especially up to 4 carbon atoms. Thus, lower alkyl has up to 7, preferably up to 4 carbon atoms and represents e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl.

Cycloalkyl has 3 to 7 ring members and denotes e.g. cyclopentyl, cyclohexyl or cycloheptyl, especially cyclopropyl.

Lower alkyl substituted by cycloalkyl may be substituted on an arbitrary carbon atom of a lower alkyl residue and denotes e.g. 1- or 2-cyclopropylethyl, 1-, 2- or 3-cyclopropylpropyl, 1- or 2-cyclopentylethyl, 1- or 2-cyclohexylethyl, however -pyy1imetyy1iä.

Salts of the starting materials are those prepared with suitable inorganic acids, such as mineral acids, e.g. hydrochloric acid, or organic acids, such as acetic acid.

The reduction according to the invention can take place, for example, by treatment with catalytically activated hydrogen, e.g. hydrogen in the presence of a hydrogenation catalyst, e.g. nickel, platinum or palladium catalyst, under reaction conditions in the presence of an inert solvent, e.g. lower alkanol, such as methanol.

The reduction may be carried out with further hydrogen, optionally with an alkali metal in a lower alkanol, e.g. sodium ethanol or lithium in tert-butanol, or with an amalgam, such as an alkali metal amalgam, e.g. sodium amalgam in the presence of water.

These reduction reactions are carried out, if necessary, by cooling or heating, e.g. in the temperature range of about -20 to about + 150 ° C and / or in a closed vessel under pressure and / or in an atmosphere of an inert gas, e.g. nitrogen.

Depending on the conditions and starting materials of the process, the compounds of the formula I are obtained in free form or in the form of their salts according to the invention, the compounds of the formula I or their salts optionally also being present as hemi-, mono-, sesqui- or polyhydrates. The acid addition salts of the compounds of the formula I can be converted into the free compounds in a manner known per se, for example by treatment with basic substances, such as alkali metal hydroxides, carbonates or hydrogen carbonates or ion exchangers. On the other hand, the free bases obtained may form acid addition salts with organic or inorganic acids, e.g. said acids, in particular those acids which are suitable for the formation of pharmaceutically acceptable, non-toxic salts being used.

The salts of the compounds of formula I are acid addition salts formed with suitable organic or inorganic acids. Examples of such acids are: hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, malic, tartaric, citric, ascorbic, maleic, fumaric, hydroxymaleic or pyruvic acid; phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acid; halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acid or sulfanilic acid; met ionin, tryptophan, lysine or arginine.

The starting materials of the formula II can be prepared, for example, starting from 4-hydroxybenzaldehyde III according to the following formula: 4 78068

OR

J n J *

H-C-0 H-C-0 H-C

I] I

/ \ / \ J jj (III) - ^ I l] -> ΐ II (VIII),

V V V

I I I

OH O-X / OH

\ / l "

GH

H-C-0 H-C

I I (VI) ✓ \ (IV), s \

I || 1 I II

• v · ^ #v · V o V o '/ \ I / \ 0-CH2-CH — CH2 O-CH2-CH - CH2 h J *

H-C

I (II),

I H

% / OH •

I I

O-CH2-CH-CH2-NH-R1 Accordingly, 4-hydroxybenzaldehyde III is reacted with epichlorohydrin in a conventional manner, e.g. an alkali metal such as alkali or alkaline earth metal hydroxides or carbonates, e.g. potassium carbonate, or metal alcoholates e.g. in the presence of a lower alkanolate, e.g. sodium methoxide, to 4-glycidyloxy-benzaldehyde IV.

5,78068

The obtained compound is then reacted with the formula / '\ s—' \ © P - CH - OR Hal ^ (V), r \ / 1 \ / ί ··· # \ • ·

I II

% / with a phosphonium halide in which Hal represents halogen, e.g. chlorine, to 4-glycidyloxystyryl-lower alkyl ether VI. This reaction is carried out in the presence of a strong base, e.g. an alkali metal lower alkanolate, optionally potassium tert-butylate in a suitable solvent, e.g. an ethereal solvent such as tetrahydrofuran.

The compound of formula VI is then reacted with an amine of formula N-R-j (VII) or a salt thereof, e.g. a salt formed with carbonic acid, to give a starting material of formula II. This reaction is carried out in a conventional manner, optionally in the presence of a suitable solvent, such as a lower alkanol, such as isopropanol.

One variation for the preparation of the starting material of formula VI is that the 4-hydroxy group in 4-hydroxybenzaldehyde is protected with an easily cleavable protecting group X and the protected compound IIIa obtained is reacted with a phosphonium halide of formula V. Subsequent work-up of the reaction mixture in the presence of water then cleaves the protecting group to give the compound of formula VIII.

Easily cleavable protecting groups are, for example, acyl residues of organic carboxylic acids, e.g. lower alkanoyl, such as acetyl, or carbonic acid half-esters, e.g. lower alkoxycarbonyl, further e.g. trityl or silyl residues, e.g. e.g. trimethylsilyl · 6 7 8 O 6 8 Such protecting groups are cleaved by water, possibly in the presence of basic substances or weak acids.

Basic substances are, for example, strong bases, e.g. oxides or hydroxides of alkali or alkaline earth metals, e.g. sodium or calcium hydroxide, metal alcoholates, e.g. formed with lower alkanols of alkali metals, such as sodium ethoxide, further organic amines, e.g. primary amines, e.g. isopropylamine, further ammonia. Weak acids include, for example, lower alkanecarboxylic acids such as acetic acid. Such acids preferably act under mild conditions, i. -10 to + 30 ° C, preferably +10 to + 25 ° C, care must be taken not to damage the ethanol ether group.

The resulting compound of formula VIII is then reacted with epichlorohydrin in a conventional manner with a basic substance, e.g. as described above, to give a compound of formula VI.

Another variation for the preparation of intermediates of formulas VI and VIII is that the 4-hydroxy-20-sibenzaldehyde III or vast, its O-protected intermediate lila or glycidyloxy compound IV, instead of being reacted as shown with a compound of formula V, is reacted formula • 0

\ / \ M

With phosphine oxide of the formula ·· \ Il ^ P - CH2-0R (Va) \ / ··· or of the formula

O

R-0 ·. Vb 2 \

P - CH - OR

with a dialkyl phosphonate according to r20 '2 7 78068, in which 1 * 2 denotes lower alkyl, e.g. ethyl. Starting from 4-hydroxybenzaldehyde III, a compound of formula VIII is obtained, while glycidyloxy compound IV thus leads to a compound of formula VI.

These reactions are carried out in a suitable solvent, e.g. of an aprotic nature, such as Lower alkyl ethers of alkylene glycols, e.g. 1,2-dimethoxyethane, in the presence of a strong base, preferably a metal, e.g. alkali metal lower alkanolate.

JACS 84-3944-3946 (1962) discloses the reaction of epoxides with carbethoxymethylene triphenylphosphorane, which results in products that no longer contain an epoxide ring because the oxygen atom of the epoxide group is loh-15 in the form of triphenylphosphine oxide. Thus, upon reaction with carbethoxymethylene triphenylphosphorane, e.g.

Accordingly, it could not be expected that when the compound of formula IV is reacted with e.g. the compound of formula V, the epoxide group would be retained; rather, it was surprisingly found that said reaction leads in good yields to the compound of formula VI while retaining the epoxide group.

The starting materials are known or, if they are new, can be prepared according to methods known per se, as described above, e.g. as described in the examples. Thus, for example, the starting materials of the formulas V, Va and Vb can be prepared in a known manner. Compounds of formula V may be prepared, e.g., by reacting triphenylphosphine (Vc) with compounds of formula 35, Hal-CH 2 "0R (Vd) wherein Hai 8 78068 represents halogen, e.g. chlorine. Phosphine oxides of formula Va may be prepared e.g. diphenylchlorophosphine of the formula · - · \ „/ \ V-Cl (Ve) \ / • m · to react with a formaldehyde acetal, e.g. formaldehyde dimethyl acetal, while formulas of formula Vb can be prepared by reacting

Ro0 2 X

Trialkyl phosphite of P-ORo Vf r20-2 to react with a halide of formula (Vd). These reactions are performed in a conventional manner (cf. Tetrahedron Letters 1978, pages 3629-10 32).

The novel starting materials are also the subject of the invention. The invention also relates to intermediates obtainable according to the process.

The following examples illustrate the invention. Temperatures 15 are shown in degrees Celsius.

Example 1; To a solution of 600 mg (2.26 mmol) of 1-isopropylamino-3- (4- (2-methoxyethenyl) phenoxy) -2-propanol in 50 ml of methanol is added 60 mg of palladium-on-carbon catalyst ( 10%) and hydrogenated at normal pressure and room temperature. After uptake of hydrogen, the catalyst is filtered off, 2-n is added to the filtrate. hydrochloric acid to a pH of about 4, the solution is evaporated under reduced pressure and the residue is recrystallized from ethyl acetate. 1-Isopropylamino-3- (4- (2-triethyldidyl) phenoxy) -25 2-propanol hydrochloride, m.p. 83 °; yield 650 mg, 95% of theory.

9 78068 The starting material can be prepared as follows: a) A mixture of 122.12 g (1 mole) of 4-hydroxybenzaldehyde, 925 g (10 moles) of epichlorohydrin and 207 g of potassium carbonate is stirred for 14 hours at room temperature. After a further three hours at 75 °, the precipitated salts are filtered off, the excess epichlorohydrin is distilled off and the residual crude product (199 g) is chromatographed on toluene / ethyl acetate (95: 5) on silica gel. 4-Glycidyloxy-benzaldehyde is isolated as an oil which, after some time, crystallizes out at 5 °. Mp 35-37 °; yield 129.8 g, 73% of theory.

b) To a suspension of 8.57 g (25 mmol) of triphenylmethoxymethylene phosphonium chloride in 50 ml of absolute tetrahydrofuran heated to an internal temperature of 50 ° is added 3.04 g (25 mmol) of potassium tert in two portions. -butylate, whereby the reaction is exothermic and the reaction solution turns red. Maintain at an internal temperature of 50 ° and add dropwise a solution of 3.56 g of 4-glycidyloxy-benzaldehyde in 20 ml of tetrahydrofuran, after which it turns yellow. 8.57 g of triphenylmethoxymethylene phosphonium chloride and 3.04 g of potassium tert-butylate are then added and the reaction mixture is heated under reflux for 2 hours. After cooling, the salts are filtered off, the filtrate is evaporated to an oil and chromatographed on toluene on silica gel. After work-up, 4-glycidyloxy-styrylmethyl ether is obtained as an oil which is a mixture of E / Z isomers with respect to the double bond; yield: 2.76 g, 67% of theory. To characterize the NMR spectral values, the following is shown: NMR: (100 MHz, CDCl 3): δ = 7.5 d, 7.18 d, 6.8-6.95 m, 6.08 d, 5.8d, 5.2 d , 4.20 dd, 3.95 ddd, 3.77 s, 3.68 s, 3.33 m, 2.70 - 2.95 m.

10 78068 c) To a solution of 1.95 g (9.47 mmol) of 4-glycidyloxystyryl methyl ether in 40 ml of isopropanol is added 4.73 g (80 mmol) of isopropylamine and heated at an internal temperature of 70 ° for three hours. The excess isopropylamine and solvent are then distilled off and the residual oil is crystallized from 60 ml of ether / n-hexane (1: 1) to give 1-isopropylamino-3- (4- (2-methoxyethenyl)). -phenoxy) -2-propanol; mp 84-86 °; yield: 2.12 g, 84% of theory.

The 4-glycidyloxy-styryl methyl ether shown in b) can also be prepared as follows: d) To a solution of 2.2 g (18 mmol) of 4-hydroxybenzaldehyde in 80 ml of absolute tetrahydrofuran and 10 ml of diglyme is added 4 .06 g of Ο, Ν-bis- (trimethylsilyl-15) acetamide and the mixture is kept at 65 ° for 30 minutes to give 4-trimethylsilyloxybenzaldehyde. 6.86 g of triphenylmethoxymethylene phosphonium chloride are then added, followed by 1.08 g of sodium methylate in two portions, the mixture is heated under reflux for 4 hours and then stirred overnight at room temperature.

Filter off the precipitated salts, evaporate the solvent carefully, add residue 50 of any methylene chloride, wash the solution 3 times with 50 ml of water each time, evaporate the organic phase and chromatograph the residue with toluene / ethyl acetate in basic alumina. The first fractions contain triphenylphosphine, triphenylphosphine oxide and unreacted 4-hydroxybenzaldehyde, which are removed. The product 30 is then eluted with toluene / ethyl acetate (1: 2) to give fractions 9-15 after drying under high vacuum to give 4-hydroxystyryl methyl ether as a pale yellow oil; yield: 1.48 g, 55% of theory.

To characterize, NMR spectral values are shown: 35 NMR: (100 MHz, CDCl 3): 7.35 to 7.90 (aromatic H) 6.75 to 11,78068 7.20 (aromatic H), 6.05 d, δ, 80 d, 5.18 d, 3.72 s, 3.66 s.

e) A mixture of 15 g (0.1 mol) of 4-hydroxystyryl methyl ether, 92.5 g (1 mol) of epichlorohydrin and 21 5 g of potassium carbonate is stirred for 12 hours at room temperature and then for a further 2 hours at 75 °. , the precipitated salts are filtered off, the excess epichlorohydrin is distilled off and the oil obtained is chromatographed on toluene / ethyl acetate on silica gel to give 4-glycine-10-yloxy-styrylmethyl ether, which is identical to the product prepared in Example 1b); yield: 16.9 g, 82% of theory.

Example 2:

According to the procedure described in Example 1, the following compounds are obtained: a) 700 mg (2.5 mmol) of 1-isopropylamino-3- (4- (2-ethoxyethenyl) phenoxy) -2-propanol are obtained in 1- isopropylamino-3- (4- (2-ethoxy-ethyl) -phenoxy) -2-propanol as hydrochloride, m.p. 102 °; yield: 760 mg. 97% of theory, 20 b) 760 mg (2.5 mmol) of 1-isopropylamino-3- (4- (2-cyclopropylmethoxyethenyl) -phenoxy) -2-propanol 1-isopropylamino-3- ( 4- (2-cyclopropylmethoxy-ethyl) -phenoxy) -2-propanol as hydrochloride, m.p. 116 °, (from acetone); yield 765 mg, 89% of theory.

The starting materials shown in Examples 2 a) and b) can be prepared according to the methods described in Examples 1b) to e) using triphenyl ethoxymethylene phosphonium chloride or triphenylcyclopropylmethoxymethylene phosphonium chloride in substantially the same yields.

12 78068

Example 3:

To a solution of 2.12 g (8 mmol) of 1-isopropylamino-3- [4- (2-methoxyethenyl) phenoxy] -2-propanol in 40 ml of abs. tetrahydrofuran, 4.74 g (74 mmol) of tert-butanol are added and the mixture is heated to reflux. Then 0.56 g (80 mg of atoms) of lithium metal cut into small pieces and washed with anhydrous tetrahydrofuran are added in several portions. Finally, heat to reflux until no starting material is detected in the thin layer chromatography. The excess lithium is then filtered off, the filtrate is evaporated to one third of the original volume and the residue is partitioned between water and ethyl acetate. The vinegar ester extracts are evaporated in vacuo to a volume of 50 ml.

After gaseous hydrogen chloride is derivatized, 1-iopropylamino-3- [4- (2-methoxyethyl) phenoxy] -2-propanol hydrochloride, m.p. 83 °, yield 2.15 g (88.5% of theory). Example 4:

To a solution of 700 mg (2.5 mmol) of 1-isopropylamino-3- [4- (2-ethoxyethenyl) phenoxy] -2-propanol in 55 ml of anhydrous ethanol is added 69 mg (0.003 mg of atoms) of sodium metal in small batches. When the reaction is complete, the solution is evaporated to dryness under reduced pressure, the residue is dissolved in 50 ml of ethyl acetate and washed with 40 ml of water. After drying over sodium sulfate, gaseous hydrogen chloride is introduced to crystallize 1-isopropylamino-3- [4- (2-ethoxyethyl) phenoxy] -2-propanol hydrochloride, m.p. 102®, · yield 710 mg, (90.6% of theory).

Example 5:

To a solution of 760 mg (2.5 mmol) of 1-isopropylamino-3- [4- (2-cyclopropylmethoxyethenyl) phenoxy] -2-propanol in 45 ml of 96% ethanol is added 3 mmol. an amount equivalent to sodium metal of 2% sodium amalgam. After standing for about J hours, 20 ml of water are added dropwise and the reaction mixture is allowed to stand at room temperature for 24 hours. The solution is then decanted from the separated mercury

Claims (4)

1. Process for Preparation of Compounds of Form In-RO-CH -CH -f Ν · (I), O - O-CH2-CHOH-CH2 -butyl, and salts thereof, characterized in that in a compound of the formula RO-CH-CH- · N. (II) O-CH2-CHOH-CH2-NH-R1 or in a site thereof, reduces the -CH a seed with water, and optionally transfer a poured free compound to one site, or a poured salt to the free compound or to another site. Process according to Claim 1, characterized in that the reduction takes place in the presence of a palladium catalyst. Process according to Claim 1, characterized in that the reduction takes place by means of an alkali metal in a lower alkanol. Method according to claim 3, characterized in