CA1182131A - Process for producing alkyl ethers - Google Patents
Process for producing alkyl ethersInfo
- Publication number
- CA1182131A CA1182131A CA000388540A CA388540A CA1182131A CA 1182131 A CA1182131 A CA 1182131A CA 000388540 A CA000388540 A CA 000388540A CA 388540 A CA388540 A CA 388540A CA 1182131 A CA1182131 A CA 1182131A
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- formula
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrane Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
PROCESS FOR PRODUCING ALKYL ETHERS
Abstract The invention relates to a process for producing known compounds of the formula (I) wherein R is lower alkyl which is unsubstituted or substituted by cycloalkyl, and R1 is isopropyl or tert-butyl, and to salts thereof, which process comprises reducing in a compound of the formula
Abstract The invention relates to a process for producing known compounds of the formula (I) wherein R is lower alkyl which is unsubstituted or substituted by cycloalkyl, and R1 is isopropyl or tert-butyl, and to salts thereof, which process comprises reducing in a compound of the formula
Description
3~
C~ 117j~
~,,3--,.~
The invention relates to a process for producing co~pounds of the formula R-o-cH7-CH2-1~ i1 (I) ~.~ CH2-C~oa-c~2-NH-R
wherein R is lower alkyl which is unsubstituted or substituted by cycloalkyl, and Rl is isopropyl or tert-butyl, and to salts thereof, which process comprises reducing in a compound of the formula R-O-C~=CH-i~ i1 (II), ~ -o-cH~-cxoH-cH2-~H-Rl or in a salt thereof, the group -CH-CH- to the group -CH2-CH,-, and, if required, converting a resulting free ~.., compound into a salt, or a resulting salt into the free compound or into another salt.
Radicals and compounds designated as being "lower"
preferably contain up to 7, and particularly up to 4, carbon atoms. Lower alkyl thus has up ~o 7, preerably up to 4, carbon atoms, and is for example: methyl, ethyl, n-propyl~ isopropyl, n-butyl, n~pentyl or n-hexyl.
Cycloalkyl has 3-7 ring members, and is for example:
cyclopentyl, cyclohexyl or cycloheptyl, especially however cyclopropyl.
Lower alkyl substituted by cycloalkyl can be sub-stituted on any carbon atom of the lower alkyl radical, and is for example: 1- or 2-cyclopropylethyl, 1-, 2- or 3-cyclopropylpropyl, 1- or 2-cyclopentylethyl or 1- or
C~ 117j~
~,,3--,.~
The invention relates to a process for producing co~pounds of the formula R-o-cH7-CH2-1~ i1 (I) ~.~ CH2-C~oa-c~2-NH-R
wherein R is lower alkyl which is unsubstituted or substituted by cycloalkyl, and Rl is isopropyl or tert-butyl, and to salts thereof, which process comprises reducing in a compound of the formula R-O-C~=CH-i~ i1 (II), ~ -o-cH~-cxoH-cH2-~H-Rl or in a salt thereof, the group -CH-CH- to the group -CH2-CH,-, and, if required, converting a resulting free ~.., compound into a salt, or a resulting salt into the free compound or into another salt.
Radicals and compounds designated as being "lower"
preferably contain up to 7, and particularly up to 4, carbon atoms. Lower alkyl thus has up ~o 7, preerably up to 4, carbon atoms, and is for example: methyl, ethyl, n-propyl~ isopropyl, n-butyl, n~pentyl or n-hexyl.
Cycloalkyl has 3-7 ring members, and is for example:
cyclopentyl, cyclohexyl or cycloheptyl, especially however cyclopropyl.
Lower alkyl substituted by cycloalkyl can be sub-stituted on any carbon atom of the lower alkyl radical, and is for example: 1- or 2-cyclopropylethyl, 1-, 2- or 3-cyclopropylpropyl, 1- or 2-cyclopentylethyl or 1- or
2-cyclohexyl`ethyl, especially however cyclopropylmethyl.
Salts of starting materials are those with ~uitable inorganic acids, for instance mineral acids, for example hydrochloric acid, or organic acids, such as acetic acid.
The reduction according to the invention can be per~ormed for example by ~reatment with catalytically activated hydrogen, for example hydrogen in the presence of a hydrogenation catalyst, for example a nickel, platinum or palladium catalyst. The reduction is advan-tageously carried out in the presence o a solvent which i3 inert under the reaction conditions, for example in the presence of a lower alkanol, such as m~thanol.
It is also possible to perform the reaction with a suitable hydride reducing agent, for example with an alkali metal borohydride, such as sodium borohydride, in the course of which there is used a suitable solvent, for example an ethereal solvent, for instance tetrahydrouran.
Furthermore, the reducing reaction can be carried out by means of nascent hydrogen, for instance by means of an alkali metal in a lower alkanol, for example sodium in ethanol, or lithium in ~ert-butanol, or by means of an amalgam, such as an alkali me~al amalga~, ~or example sodium amalgam, in the presence of water.
These reducing reactions are performed if necessary with cooling or heating, for example in a temperature range ....
o~ about -~0 to about ~150, and/or in a closed vessel under pressure, and/or i~ an inert gas, for example in a nitrogen atmosphere.
Depending on the process conditions and the starting materials, the compounds of the ormula I are obtained in the free form or in the form, likewise embraced by the inven~ion, of their salts; and the compounds of the ormula I or salts thereof can moreover also be in the form of hemi-, mono-, sesqui- or polyhydrates. Acid addition salts of the compounds of the formula I can be converted, in a manner known per se, or example by treatment with basic agents, such as with hydroxides, carbonates or hydrogen carbonates of alkali metals or with ion exchangers, into the free compounds. Alternatively, the free bases obtained can form acid addition salts with organic or inorganic acids, for example with the stated acids, the acid addition salts being produced by use in particular of those acids which are suitable for forming pharma-ceutically acceptable, nontoxic salts.
Salts of compounds of the formula I are acid addition salts with suitabLe organic or inorganic acids. The following may be mentioned as examples of such acids:
~ydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or he~erocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic~ lactic, malic, tartar~Lc, citric, ascorbic, maleic, f-unaric, hydroxymaleic or pyruvic acid; phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic, methanesulfonic, ethanesulfonic, hydroxy-ethanesulfonic or ethylenesulfonic acid; halobenzene-sulfonic, toluenesulfonic, naphthalenesulfonic acid or sulfanilic acid; or methionine, tryptophane, lysine or arginine.
Starting materials of the formula II can be obtained for example starting with 4-hydroxybenzaldehyde III
according ~o the~ following reaction scheme:
OR
H-C30 a-c=o ~-c~ .
li ( III) ~ ~ _ ~ i (VIII ), OH 0-~ / OH
(IIIa) OR
CH
H-C=C H--C
(VI) i~ 11 ~ i~ li T /\ i ~o\
O-CH -CH--CH O-C~7-CH--CH2 ~ OR
H C~
II), \
OH
Accordingly, 4-hydroxybenzaldehyde lII is reacted with epichlorohydrin in the customary manner, for example in the presence of basic agents, ~or instance hydroxides or carbonates of alkali metals or alkaline-earth metals, for exæmple potassium carbonate, or metal alcoholates, such as alkali metal-lower alkanolates, for example sodium methoxide, to give 4-glycidyloxybenzaldehyde IV.
~ ..
. .
~ 3 ~
The compound obtained is subsequently reacted with a phosphonium halide of the formula ~
P - CH2 - OR 8al ~) (V) ,,~
!~ I!
wherein Hal is halogen5 for example c~ ,lorine, ~o give a 4-glycidyloxystyryl-lower-alkyl ether VI. This reaction is performed in the presence of a s~rong base, for example an alkali metal-lower-alkanolate, for instance potassium tert-butyla~e, in a suitable solven~, for example an ethereal solvent, such as tetrahydrouran. This is followed by the reaction of a compound of the formula VI
with an amine of the formula H2N-Rl (VII), or with a salt thereof, for example that with carbonic acid, to obtain a starting material of the formula II. This reaction is carried out in the usual manner, optionally in the presence of a suitable solvent, for instance a lower alkanol, such as isopropanol.
A variant for producing a starting material of the formula VI is a procedure whereby the 4-hydroxy group in the 4-hydroxybenzaldehyde is protected by a readily detachable protective group X, and the resulting protected compound IIIa is then reacted with a phosphonlum halide of the for~:~ula V. In subsequent processing of the reaction mixture in the presence o~ water, the protective group is split off~ whereupon a compound of the formula VIII is obtained.
Readily detachable protective groups are for example:
acyl groups of organic carboxylic acids, for example lower alkanoyl, such as acetyl, or half-esters of carbonic acid, for example lower alkoxy carbonyl, also for example ~ 3 ~
trityl or silyl groups~ such as trimethylsilyl.
Protective groups of this kind are split off by means of water, op~ionally in the presence of basic agents or weak acids.
Basic agents are for example s~rong bases, for example the oxides or hydroxides of alkali metals or alkaline~
earth metals, for example sodium or calcium hydroxide~
metal alcoholates, for example those of alkali metals with lower alkanols, for instance sodium ethoxide, also organic amines, for example primary amines, such as isopropylamine, and also ammonia. Weak acids are for example lower alkanecarboxylic acids, such as acetic acid.
Such acids act preferably under mild conditionsj that is to say, in a temperature range of -10 to ~30, preferably from ~10 to +25C, care having to be taken to ensure that in the process the enol ether group is not attacked.
The resulting compound of the formula VIII is subsequently reacted with Ppichlorohydrin in the customary manner in the presence of basic agents, for example such as were described in the foregoing, to give a compound of the formula VI.
A furthe:r variant for producing the intermedia~es of the formulae VI and VIII consists of reacting 4-hydroxy-benzaldehyde III or the 0-protected intermediate IIIa, or the glycidyloxy compound IV, not as described with a compound of the formula V, but with a phosphine oxide of the formula 0~ ~. o \-=u/ \ 11 / P ~ CH2-OR (Va) \ / ' or wi~h a dialkylphosphonate of the formula o R20~ 11 / P -cH2 oR (~b), wherein R2 is lower alkyl, for example ethyl. Starting with 4-hydrox~benzaldehyde III, there is then obtained a compound of the formula VIIL, whîls~ the glycidyloxy co~pound IV leads in this manner to a compound of the fonmula VI.
These reactions are performed in a suitable solvent, for example a sclvent of aprotic nature, for instance in lower alkyl ethers of alkylene glycolsg for example 1,2-dimethoxyethane, in the presence of a strong base, preferably a metal lower alkanolate, for example an alkali metal-lower-alkanolate.
From JACS 84, 3944-3946 (1962) is known the reaction of epoxides with carbethoxymethylene-triphenylphosphorane, which reaction results in products which no longer have an epoxide ring, because the oxygen ~tom of the epoxide group is split off in the orm of triphenyl-phosphine oxide. By reaction of carbethoxymethylene-triphenyl-phosphorane with, for example, 1 octene oxide, there is thus obtained trans carbethoxy-2-hexylcyclopropane, whilst the reaction with cyclohexene oxide leads to 7-norcarane-carboxylic acid ethyl ester, and the reaction wi~h dl-st~rene oxide leads to trans carbethoxy-2-phenyl-cyclopropane.
It was accordingly not to be expected in the case of the reaction of a compound of the formula IV with, for example, a compound of the formula V, that the epoxide group would remain intactj but it was found that surprisingly the said.
reaction in which the epoxide group remains unaffected ~ 3 ~
produces a compound of the formula VI with good yields.
The starting materials are known~ or in cas~s where they are new they can be obtained by methods known per se, for exampl~ by methods analogous to those described in the examples. Thus, for example, s~arting materials o~
the formulae V, Va and Vb can be produced in a manner known per se. Gompounds of the formula V can be produced for example by reaction of triphenylphosphine (Vc) with a compound of the formula Hal-CH2-OR (Vd) 5 wherein Hal is halogen, for example chlorine. Phosphine oxides of the formula Va are obtainable for example by reaction of diphenylchlorophosphine of the formula ~-Cl (ve) with an acetal of formaldehyde, for example formaldehyde-dimethylacetal, whilst those of the formula Vb can be obtained by reaction of a trialkylphosphite of the formula R20 R 0~ 2 (Vf) with a halide of the formula (Vd). Thçse reactions are performed in the usual manner (cp. Tetrahedron Letters 978, pp. 3629-32).
Novel starting materials likewise form subject matter of the present invention. The invention relates also to intermediates obtainable by the processes of the invention.
The Examples which follow further illustrate the invention. Temperature values are given in degrees Centigrade.
To a solution of 600 mg (2.26 mmols) of l-isopropyl-amino-3-[4-(2-methoxy-ethenyl)-phenoxy]-2-propanol in 50 ml of methanoL arP added 60 mg of palladium-on-charcoal catalyst (10%), and the solution is hydrogenated at normal pressure and roQm temperature. After completion of the absorption of hydrogen, the catalyst is filtered off, and 2 N hydrochloric acid is added to the filtrate until the pH value is about 4; the solution is then concentrated by evaporation under reduced pressure, and the residue is recrystallised rom ethyl acetate to thus obtain the hydrochloride of l-isopropylamino-3-~4-(2-methoxyethyl)-phenoxy]-2-propanol, m.p. 83; yield: 650 mg, 95% of theory.
The starting material can be produced as follows:
a) A mixture of 122.12 g (1 mol) of 4-hydroxybenzaldehyde, 925 g (10 mols) of epichlorohydrin and 207 g of potassium carbonate is stirred for 14 hours at room temperature.
A~ter a further three hours at 75, the salts which have precipitated are filtered off, the unreacted epichlorohydrin is distilled off, and the crude product (199 g) remaining is chromatographed with toluene/ethyl acetate (95:5) on silica gcl. 4-Glycidyloxybenzaldehyde is isolated as oil, which crystallises fully after some time at a temperature of 5, m.p. 35-37; yield: 129.8 g, 73% of theory.
b) 3.04 g (25 mmols) of po~assium tert-butylate are added in two portions to a suspension (heated to 50 internal temperature) of 8.57 g (25 mmols) of triphenyl-methoxy-methylene-phosphonium chloride in 50 ml of absolute tetrahydrofuran, in the course of which there is an exothermic reaction and a red colouration of the reaction solution occurs. The internal temperature of 50 is maintained, and a solution of 3.56 g of 4-glycidyloxy-benzaldehyde in 20 ml of tetrahydrofuran is added dropwise, whereupon the colour of the reaction mixture changes to yellow. A further 8.57 g of triphenyl-methoxymethylene-phosphonium chloride and 3.04 g of potassium tert-bu~yla~e are subsequen~ly added, and the reac~ion mixture is refl~xed for 2 hours. After cooling, the salts are filtered off, the filtrate is concentrated by evaporation to leave an oil, and this is then chromatographed wi~h toluene on silica gel. Further processing yields 4-glycidyloxy-styrylmethyl ether in the form of oil which, with regard to the double bond, constitutes a mixture of the E/Z isomers; yield: 2.76 g, 67% of theory.
The NMR spectrum data are given for characterisation:
NMR: (100 MHz, CDC13): ~ = 7.5 d, 7.18 d, 6.8 - 6.95 m, 6.08 d, 5.8 d, 5.2 d, 4.20 dd, 3.95 ddd, 3.77 s, 3.68 s,
Salts of starting materials are those with ~uitable inorganic acids, for instance mineral acids, for example hydrochloric acid, or organic acids, such as acetic acid.
The reduction according to the invention can be per~ormed for example by ~reatment with catalytically activated hydrogen, for example hydrogen in the presence of a hydrogenation catalyst, for example a nickel, platinum or palladium catalyst. The reduction is advan-tageously carried out in the presence o a solvent which i3 inert under the reaction conditions, for example in the presence of a lower alkanol, such as m~thanol.
It is also possible to perform the reaction with a suitable hydride reducing agent, for example with an alkali metal borohydride, such as sodium borohydride, in the course of which there is used a suitable solvent, for example an ethereal solvent, for instance tetrahydrouran.
Furthermore, the reducing reaction can be carried out by means of nascent hydrogen, for instance by means of an alkali metal in a lower alkanol, for example sodium in ethanol, or lithium in ~ert-butanol, or by means of an amalgam, such as an alkali me~al amalga~, ~or example sodium amalgam, in the presence of water.
These reducing reactions are performed if necessary with cooling or heating, for example in a temperature range ....
o~ about -~0 to about ~150, and/or in a closed vessel under pressure, and/or i~ an inert gas, for example in a nitrogen atmosphere.
Depending on the process conditions and the starting materials, the compounds of the ormula I are obtained in the free form or in the form, likewise embraced by the inven~ion, of their salts; and the compounds of the ormula I or salts thereof can moreover also be in the form of hemi-, mono-, sesqui- or polyhydrates. Acid addition salts of the compounds of the formula I can be converted, in a manner known per se, or example by treatment with basic agents, such as with hydroxides, carbonates or hydrogen carbonates of alkali metals or with ion exchangers, into the free compounds. Alternatively, the free bases obtained can form acid addition salts with organic or inorganic acids, for example with the stated acids, the acid addition salts being produced by use in particular of those acids which are suitable for forming pharma-ceutically acceptable, nontoxic salts.
Salts of compounds of the formula I are acid addition salts with suitabLe organic or inorganic acids. The following may be mentioned as examples of such acids:
~ydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or he~erocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic~ lactic, malic, tartar~Lc, citric, ascorbic, maleic, f-unaric, hydroxymaleic or pyruvic acid; phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic, methanesulfonic, ethanesulfonic, hydroxy-ethanesulfonic or ethylenesulfonic acid; halobenzene-sulfonic, toluenesulfonic, naphthalenesulfonic acid or sulfanilic acid; or methionine, tryptophane, lysine or arginine.
Starting materials of the formula II can be obtained for example starting with 4-hydroxybenzaldehyde III
according ~o the~ following reaction scheme:
OR
H-C30 a-c=o ~-c~ .
li ( III) ~ ~ _ ~ i (VIII ), OH 0-~ / OH
(IIIa) OR
CH
H-C=C H--C
(VI) i~ 11 ~ i~ li T /\ i ~o\
O-CH -CH--CH O-C~7-CH--CH2 ~ OR
H C~
II), \
OH
Accordingly, 4-hydroxybenzaldehyde lII is reacted with epichlorohydrin in the customary manner, for example in the presence of basic agents, ~or instance hydroxides or carbonates of alkali metals or alkaline-earth metals, for exæmple potassium carbonate, or metal alcoholates, such as alkali metal-lower alkanolates, for example sodium methoxide, to give 4-glycidyloxybenzaldehyde IV.
~ ..
. .
~ 3 ~
The compound obtained is subsequently reacted with a phosphonium halide of the formula ~
P - CH2 - OR 8al ~) (V) ,,~
!~ I!
wherein Hal is halogen5 for example c~ ,lorine, ~o give a 4-glycidyloxystyryl-lower-alkyl ether VI. This reaction is performed in the presence of a s~rong base, for example an alkali metal-lower-alkanolate, for instance potassium tert-butyla~e, in a suitable solven~, for example an ethereal solvent, such as tetrahydrouran. This is followed by the reaction of a compound of the formula VI
with an amine of the formula H2N-Rl (VII), or with a salt thereof, for example that with carbonic acid, to obtain a starting material of the formula II. This reaction is carried out in the usual manner, optionally in the presence of a suitable solvent, for instance a lower alkanol, such as isopropanol.
A variant for producing a starting material of the formula VI is a procedure whereby the 4-hydroxy group in the 4-hydroxybenzaldehyde is protected by a readily detachable protective group X, and the resulting protected compound IIIa is then reacted with a phosphonlum halide of the for~:~ula V. In subsequent processing of the reaction mixture in the presence o~ water, the protective group is split off~ whereupon a compound of the formula VIII is obtained.
Readily detachable protective groups are for example:
acyl groups of organic carboxylic acids, for example lower alkanoyl, such as acetyl, or half-esters of carbonic acid, for example lower alkoxy carbonyl, also for example ~ 3 ~
trityl or silyl groups~ such as trimethylsilyl.
Protective groups of this kind are split off by means of water, op~ionally in the presence of basic agents or weak acids.
Basic agents are for example s~rong bases, for example the oxides or hydroxides of alkali metals or alkaline~
earth metals, for example sodium or calcium hydroxide~
metal alcoholates, for example those of alkali metals with lower alkanols, for instance sodium ethoxide, also organic amines, for example primary amines, such as isopropylamine, and also ammonia. Weak acids are for example lower alkanecarboxylic acids, such as acetic acid.
Such acids act preferably under mild conditionsj that is to say, in a temperature range of -10 to ~30, preferably from ~10 to +25C, care having to be taken to ensure that in the process the enol ether group is not attacked.
The resulting compound of the formula VIII is subsequently reacted with Ppichlorohydrin in the customary manner in the presence of basic agents, for example such as were described in the foregoing, to give a compound of the formula VI.
A furthe:r variant for producing the intermedia~es of the formulae VI and VIII consists of reacting 4-hydroxy-benzaldehyde III or the 0-protected intermediate IIIa, or the glycidyloxy compound IV, not as described with a compound of the formula V, but with a phosphine oxide of the formula 0~ ~. o \-=u/ \ 11 / P ~ CH2-OR (Va) \ / ' or wi~h a dialkylphosphonate of the formula o R20~ 11 / P -cH2 oR (~b), wherein R2 is lower alkyl, for example ethyl. Starting with 4-hydrox~benzaldehyde III, there is then obtained a compound of the formula VIIL, whîls~ the glycidyloxy co~pound IV leads in this manner to a compound of the fonmula VI.
These reactions are performed in a suitable solvent, for example a sclvent of aprotic nature, for instance in lower alkyl ethers of alkylene glycolsg for example 1,2-dimethoxyethane, in the presence of a strong base, preferably a metal lower alkanolate, for example an alkali metal-lower-alkanolate.
From JACS 84, 3944-3946 (1962) is known the reaction of epoxides with carbethoxymethylene-triphenylphosphorane, which reaction results in products which no longer have an epoxide ring, because the oxygen ~tom of the epoxide group is split off in the orm of triphenyl-phosphine oxide. By reaction of carbethoxymethylene-triphenyl-phosphorane with, for example, 1 octene oxide, there is thus obtained trans carbethoxy-2-hexylcyclopropane, whilst the reaction with cyclohexene oxide leads to 7-norcarane-carboxylic acid ethyl ester, and the reaction wi~h dl-st~rene oxide leads to trans carbethoxy-2-phenyl-cyclopropane.
It was accordingly not to be expected in the case of the reaction of a compound of the formula IV with, for example, a compound of the formula V, that the epoxide group would remain intactj but it was found that surprisingly the said.
reaction in which the epoxide group remains unaffected ~ 3 ~
produces a compound of the formula VI with good yields.
The starting materials are known~ or in cas~s where they are new they can be obtained by methods known per se, for exampl~ by methods analogous to those described in the examples. Thus, for example, s~arting materials o~
the formulae V, Va and Vb can be produced in a manner known per se. Gompounds of the formula V can be produced for example by reaction of triphenylphosphine (Vc) with a compound of the formula Hal-CH2-OR (Vd) 5 wherein Hal is halogen, for example chlorine. Phosphine oxides of the formula Va are obtainable for example by reaction of diphenylchlorophosphine of the formula ~-Cl (ve) with an acetal of formaldehyde, for example formaldehyde-dimethylacetal, whilst those of the formula Vb can be obtained by reaction of a trialkylphosphite of the formula R20 R 0~ 2 (Vf) with a halide of the formula (Vd). Thçse reactions are performed in the usual manner (cp. Tetrahedron Letters 978, pp. 3629-32).
Novel starting materials likewise form subject matter of the present invention. The invention relates also to intermediates obtainable by the processes of the invention.
The Examples which follow further illustrate the invention. Temperature values are given in degrees Centigrade.
To a solution of 600 mg (2.26 mmols) of l-isopropyl-amino-3-[4-(2-methoxy-ethenyl)-phenoxy]-2-propanol in 50 ml of methanoL arP added 60 mg of palladium-on-charcoal catalyst (10%), and the solution is hydrogenated at normal pressure and roQm temperature. After completion of the absorption of hydrogen, the catalyst is filtered off, and 2 N hydrochloric acid is added to the filtrate until the pH value is about 4; the solution is then concentrated by evaporation under reduced pressure, and the residue is recrystallised rom ethyl acetate to thus obtain the hydrochloride of l-isopropylamino-3-~4-(2-methoxyethyl)-phenoxy]-2-propanol, m.p. 83; yield: 650 mg, 95% of theory.
The starting material can be produced as follows:
a) A mixture of 122.12 g (1 mol) of 4-hydroxybenzaldehyde, 925 g (10 mols) of epichlorohydrin and 207 g of potassium carbonate is stirred for 14 hours at room temperature.
A~ter a further three hours at 75, the salts which have precipitated are filtered off, the unreacted epichlorohydrin is distilled off, and the crude product (199 g) remaining is chromatographed with toluene/ethyl acetate (95:5) on silica gcl. 4-Glycidyloxybenzaldehyde is isolated as oil, which crystallises fully after some time at a temperature of 5, m.p. 35-37; yield: 129.8 g, 73% of theory.
b) 3.04 g (25 mmols) of po~assium tert-butylate are added in two portions to a suspension (heated to 50 internal temperature) of 8.57 g (25 mmols) of triphenyl-methoxy-methylene-phosphonium chloride in 50 ml of absolute tetrahydrofuran, in the course of which there is an exothermic reaction and a red colouration of the reaction solution occurs. The internal temperature of 50 is maintained, and a solution of 3.56 g of 4-glycidyloxy-benzaldehyde in 20 ml of tetrahydrofuran is added dropwise, whereupon the colour of the reaction mixture changes to yellow. A further 8.57 g of triphenyl-methoxymethylene-phosphonium chloride and 3.04 g of potassium tert-bu~yla~e are subsequen~ly added, and the reac~ion mixture is refl~xed for 2 hours. After cooling, the salts are filtered off, the filtrate is concentrated by evaporation to leave an oil, and this is then chromatographed wi~h toluene on silica gel. Further processing yields 4-glycidyloxy-styrylmethyl ether in the form of oil which, with regard to the double bond, constitutes a mixture of the E/Z isomers; yield: 2.76 g, 67% of theory.
The NMR spectrum data are given for characterisation:
NMR: (100 MHz, CDC13): ~ = 7.5 d, 7.18 d, 6.8 - 6.95 m, 6.08 d, 5.8 d, 5.2 d, 4.20 dd, 3.95 ddd, 3.77 s, 3.68 s,
3.33 m, 2.70 - 2.95 m.
c~ 4.73 g (80 mmols) of isopropylamine are added to the solution of 1.95 g (9.47 mmols) of 4-glycidyloxy-styryl-methyl ether in 40 ml of isopropanol, and the mixture is heated at an internal temperature of 70 for three hours.
The unreacted isopropylamine and the solvent are afterwards distilled off, and the oil remaining is crystallised from 60 ml of ether/n-hexane (1:1) to thus yield 1 isopropyl-amino~3-[4-(2-methoxy-ethenyl) phenoxy]-2-propanol;
m.p. 84-86; yieLd: 2.12 g, 84% of theory.
The 4-glyeidyl-styrylmethyl ether described under b) can be produced also in the following manner:
d) 4.o6 g of 0,N-bis-(trimethylsilyl~-acetamide are added to a soLution o~ 2.2 g (18 mmols) of 4-hydroxybenzaldehyde in 80 ml of absolute tetrahydrofuran and 10 ml of diglyme, and the mixture is held for 30 minutes at 65, during which the 4-trimethylsilyloxy-benzaldehyde is formed. There are subsequently added 6.86 g of triphenyl-methoxymethylene-~ 3 ~
phosphonium chloride and then 1.08 g of sodium methylatein two portions; ~he mixture is refluxed for 4 hours, and afterwards stirred overnight at room temperatureO
~he salts which have precipitated are fiLtered off, the solvent is largely evaporated off, and the residue is taken up in 50 ml of methylene chloride; the solution is washed 3 times with 50 ml of water each time, the organic phase is evaporated off, and the residue is chromato-graphed with toluene/ethyl acetate on basic aluminium oxide. The first fractlons contain triphenylphosphine, triphenylphosphine oxide and unreacted 4-hydroxybenzaldehyde and are discarded. The product is the~ eluted with toluene/ethyl acetate (1:2), and the resulting fractions 9 - 15 yield, after drying under high vacuum, 4-hydroxy-styrylmethyl ether as light-yellow oil; yield: 1.48 g, 55% of theory. The NMR spectra are given for characteris-ation: NMR: (100 MHz, CDC13): 7.35 - 7.90 (aromatic H) 6.75 - 7~20 (aromatic H), 6.o5 d, 5.80 d, 5.18 d, 3.72 s, 3.66 s.
e) A mixture of 15 g (0.1 mol) of 4-hydroxystryrylmethyl ether, 92.5 g (1 mol) of epichlorohydrin and 21 g of potassium carbonate is stirred for 12 hours at room temperature and subsequently at 75 for a further 2 hours;
the salt which has precipitated is filtered off, unreacted epichlorohydrin is distilled off, and the resulting oil is chromatographed with toluene!ethyl acetate on silica gel to thu~ obtain 4-glycidyloxy-qtyrylmethyl ether, which is identical to the product obtained according to Example 1 b);
yield: 16.9 g, 82~/o of theory.
Example 2 The following compounds are obtained by a procedure analogous to that described in Example 1:
a) from 700 mg (2.5 mmols) of 1-isopropylamino~3-[4-(2-. . ~ .
~ 3 ethoxy-ethenyl~-phenoxy]-2-propanol~ isopropylamino-3-[4-(2-ethoxy-ethyl)-phenoxy]-2-propanol as hydrochLoride, m.p. 102; yield: 760 mg, 97% o~ theory;
b) from 760 mg (2.5 mmols) of 1-isopropylamino-3-[4-(2-cyclopropylmethoxy-ethenyl)-phenoxy]-2-propanol:-l-isopropylamino-3-[4-(2-cyclopropylmethoxy-ethyl)-phenoxy]-2-propanol as hydrochloride, m.p. 116 (~rom acetone);
yield: 765 mg, 89% of th~ory.
The star~ing materials mentioned under the Examples a) and b~ can be obtained in substantially the same yields, using procedures analogous to those described under Examples lb~ ~ e), by the use of triphenyl-ethoxymethylene-phosphonium chloride and triphenyL-cyclopropylmethoxy-methylene~phosphonium chloride, respectively.
c~ 4.73 g (80 mmols) of isopropylamine are added to the solution of 1.95 g (9.47 mmols) of 4-glycidyloxy-styryl-methyl ether in 40 ml of isopropanol, and the mixture is heated at an internal temperature of 70 for three hours.
The unreacted isopropylamine and the solvent are afterwards distilled off, and the oil remaining is crystallised from 60 ml of ether/n-hexane (1:1) to thus yield 1 isopropyl-amino~3-[4-(2-methoxy-ethenyl) phenoxy]-2-propanol;
m.p. 84-86; yieLd: 2.12 g, 84% of theory.
The 4-glyeidyl-styrylmethyl ether described under b) can be produced also in the following manner:
d) 4.o6 g of 0,N-bis-(trimethylsilyl~-acetamide are added to a soLution o~ 2.2 g (18 mmols) of 4-hydroxybenzaldehyde in 80 ml of absolute tetrahydrofuran and 10 ml of diglyme, and the mixture is held for 30 minutes at 65, during which the 4-trimethylsilyloxy-benzaldehyde is formed. There are subsequently added 6.86 g of triphenyl-methoxymethylene-~ 3 ~
phosphonium chloride and then 1.08 g of sodium methylatein two portions; ~he mixture is refluxed for 4 hours, and afterwards stirred overnight at room temperatureO
~he salts which have precipitated are fiLtered off, the solvent is largely evaporated off, and the residue is taken up in 50 ml of methylene chloride; the solution is washed 3 times with 50 ml of water each time, the organic phase is evaporated off, and the residue is chromato-graphed with toluene/ethyl acetate on basic aluminium oxide. The first fractlons contain triphenylphosphine, triphenylphosphine oxide and unreacted 4-hydroxybenzaldehyde and are discarded. The product is the~ eluted with toluene/ethyl acetate (1:2), and the resulting fractions 9 - 15 yield, after drying under high vacuum, 4-hydroxy-styrylmethyl ether as light-yellow oil; yield: 1.48 g, 55% of theory. The NMR spectra are given for characteris-ation: NMR: (100 MHz, CDC13): 7.35 - 7.90 (aromatic H) 6.75 - 7~20 (aromatic H), 6.o5 d, 5.80 d, 5.18 d, 3.72 s, 3.66 s.
e) A mixture of 15 g (0.1 mol) of 4-hydroxystryrylmethyl ether, 92.5 g (1 mol) of epichlorohydrin and 21 g of potassium carbonate is stirred for 12 hours at room temperature and subsequently at 75 for a further 2 hours;
the salt which has precipitated is filtered off, unreacted epichlorohydrin is distilled off, and the resulting oil is chromatographed with toluene!ethyl acetate on silica gel to thu~ obtain 4-glycidyloxy-qtyrylmethyl ether, which is identical to the product obtained according to Example 1 b);
yield: 16.9 g, 82~/o of theory.
Example 2 The following compounds are obtained by a procedure analogous to that described in Example 1:
a) from 700 mg (2.5 mmols) of 1-isopropylamino~3-[4-(2-. . ~ .
~ 3 ethoxy-ethenyl~-phenoxy]-2-propanol~ isopropylamino-3-[4-(2-ethoxy-ethyl)-phenoxy]-2-propanol as hydrochLoride, m.p. 102; yield: 760 mg, 97% o~ theory;
b) from 760 mg (2.5 mmols) of 1-isopropylamino-3-[4-(2-cyclopropylmethoxy-ethenyl)-phenoxy]-2-propanol:-l-isopropylamino-3-[4-(2-cyclopropylmethoxy-ethyl)-phenoxy]-2-propanol as hydrochloride, m.p. 116 (~rom acetone);
yield: 765 mg, 89% of th~ory.
The star~ing materials mentioned under the Examples a) and b~ can be obtained in substantially the same yields, using procedures analogous to those described under Examples lb~ ~ e), by the use of triphenyl-ethoxymethylene-phosphonium chloride and triphenyL-cyclopropylmethoxy-methylene~phosphonium chloride, respectively.
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a compound of the formula (I) wherein R is lower alkyl which is unsubstituted or substituted by cycloalkyl, and R1 is isopropyl or tert-butyl, and salts thereof, which process comprises reducing in a compound of the formula (II) or in a salt thereof, the group -CH=CH- to the group -CH2-CH2-, and, if required, converting a resulting free compound into a salt, or a resulting salt into the free compound or into another salt.
2. A process according to Claim 1, wherein the reducing reaction is performed by means of catalytically activated hydrogen.
3. A process according to Claim 1 or 2, wherein the reducing reaction is performed by means of hydrogen in the presence of a hydrogenation catalyst.
4. A process according to Claim 1 or 2, wherein the reducing reaction is performed in the presence of a palladium catalyst.
5. A process according to Claim 1, wherein the reducing reaction is performed with a hydride reducing agent.
6. A process according to Claim 5, wherein the reducing reaction is performed by means of an alkali metal boron hydride.
7. A process according to Claim 6, wherein the reducing reaction is performed by means of sodium borohydride.
8. A process according to Claim 1, wherein the reducing reaction is performed by means of nascent hydrogen.
9. A process according to Claim 8, wherein the reducing reaction is performed by means of an alkali metal in a lower alkanol.
10. A process according to Claims 8 and 9, wherein the reducing reaction is performed by means of lithium in tert-butanol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH7945/80-0 | 1980-10-24 | ||
| CH794580A CH643527A5 (en) | 1980-10-24 | 1980-10-24 | Process for the preparation of 1-alkylamino-3-(4-(2-lower alkoxy-ethyl)phenoxy)-2-propanols |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1182131A true CA1182131A (en) | 1985-02-05 |
Family
ID=4332776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000388540A Expired CA1182131A (en) | 1980-10-24 | 1981-10-22 | Process for producing alkyl ethers |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS5799560A (en) |
| AT (1) | AT379377B (en) |
| CA (1) | CA1182131A (en) |
| CH (1) | CH643527A5 (en) |
| DK (1) | DK155881C (en) |
| FI (1) | FI78068C (en) |
| NO (1) | NO152901C (en) |
| SE (1) | SE8106254L (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016172353A1 (en) * | 2015-04-21 | 2016-10-27 | Ndsu Research Foundation | Epoxy resin derived from vanillin and thermosets therefrom |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE384853B (en) * | 1972-04-04 | 1976-05-24 | Haessle Ab | PROCEDURE FOR THE PREPARATION OF NEW AMINES |
| SE354851B (en) * | 1970-02-18 | 1973-03-26 | Haessle Ab | |
| FR2330383A1 (en) * | 1975-11-06 | 1977-06-03 | Synthelabo | NEW PHENOL SUBSTITUTE ETHERS, THEIR SALTS, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM |
-
1980
- 1980-10-24 CH CH794580A patent/CH643527A5/en not_active IP Right Cessation
-
1981
- 1981-10-21 FI FI813286A patent/FI78068C/en not_active IP Right Cessation
- 1981-10-22 SE SE8106254A patent/SE8106254L/en not_active Application Discontinuation
- 1981-10-22 CA CA000388540A patent/CA1182131A/en not_active Expired
- 1981-10-23 DK DK468981A patent/DK155881C/en active
- 1981-10-23 AT AT0453581A patent/AT379377B/en not_active IP Right Cessation
- 1981-10-23 NO NO813580A patent/NO152901C/en unknown
- 1981-10-24 JP JP56169452A patent/JPS5799560A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016172353A1 (en) * | 2015-04-21 | 2016-10-27 | Ndsu Research Foundation | Epoxy resin derived from vanillin and thermosets therefrom |
Also Published As
| Publication number | Publication date |
|---|---|
| FI813286L (en) | 1982-04-25 |
| DK468981A (en) | 1982-04-25 |
| JPS5799560A (en) | 1982-06-21 |
| CH643527A5 (en) | 1984-06-15 |
| SE8106254L (en) | 1982-04-25 |
| NO152901B (en) | 1985-09-02 |
| DK155881B (en) | 1989-05-29 |
| NO152901C (en) | 1985-12-11 |
| ATA453581A (en) | 1985-05-15 |
| FI78068B (en) | 1989-02-28 |
| AT379377B (en) | 1985-12-27 |
| DK155881C (en) | 1989-10-09 |
| FI78068C (en) | 1989-06-12 |
| NO813580L (en) | 1982-04-26 |
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