Claims
- 1. 4-Hydroxy-alpha'-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol,1-hydroxy-2-naphthalenecarboxylate.
- 2. 4-Hydroxy-alpha'-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol and its physiologically acceptable salts and solvates.
- 3. A pharmaceutical composition comprising the compound of claim 1 together with one or more physiologically acceptable carriers or excipients.
- 4. A pharmaceutical composition comprising at least one of the compounds of claim 2, together with one or more physiologically acceptable carriers or excipients.
- 5. 4-Hydroxy-alpha'-[[[6-(3-phenylpropoxy)hexyl]amino]methyl]1,3-benzenedimethanol and its physiologically acceptable salts and solvates.
- 6. A pharmaceutical composition comprising at least one of the compounds of claim 5, together with one or more physiologically acceptable carriers or excipients.
- 7. A method of treating a patient suffering from a disease associated with reversible airways obstruction which comprises administering to the patient an effective amount of the compound of claim 1.
- 8. A method of treating a patient suffering from a disease associated with reversible airways obstruction which comprises administering to the patient an effective amount of at least one of the compounds of claim 2.
- 9. A method of treating a patient suffering from a disease associated with reversible airways obstruction which comprises administering to the patient an effective amount of at least one of the compounds of claim 5.
- 10. A method according to claim 7, wherein the disease is asthma or chronic bronchitis.
- 11. A method according to claim 8, wherein the disease is asthma or chronic bronchitis.
- 12. A method according to claim 9, wherein the disease is asthma or chronic bronchitis.
Priority Claims (4)
| Number |
Date |
Country |
Kind |
| 8310477 |
Apr 1983 |
GBX |
|
| 8317087 |
Jun 1983 |
GBX |
|
| 8329568 |
Nov 1983 |
GBX |
|
| 8401889 |
Jan 1984 |
GBX |
|
INTERMEDIATE 2
This application is a continuation of U.S. Ser. No. 06/932,359, filed on Nov. 19, 1986, which is a continuation of U.S. Ser. No. 06/601,444 filed Apr. 18, 1984.
This invention relates to phenethanolamine compounds having a stimulant action at .beta..sub.2 -adrenoreceptors, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Certain phenethanolamine compounds are known to possess either stimulant or blocking actions at .beta.-adrenoreceptors. For example, British Patent Specification No. 1200886 describes a group of such phenethanolamines of general structure: ##STR3## where, inter alia, X.sub.1 is hydroxyalkyl, R.sub.1 and R.sub.2 is each a hydrogen atom, and R.sub.3 is straight or branched C.sub.1-6 alkyl, aralkyl or aryloxyalkyl. One compound from within this particular group has been developed for clinical use. This is salbutamol [(.alpha..sup.1 -tert-butylaminomothyl)-4-hydroxy-m-xylene-.alpha..sup.1,.alpha..sup.3 -diol; X.sub.1 =CH.sub.2 OH, R.sub.1 =--H; R.sub.2 =--H; R.sub.3 =t-butyl, above] which at the present time is widely prescribed for the treatment of conditions such as bronchial asthma and chronic bronchitis. The success of salbutamol devolves from its profile of action, in particular its potency, coupled with a selective stimulant action at .beta..sub.2 -adrenoreceptors.
All .beta..sub.2 -stimulants currently used in clinical practice suffer from the disadvantage that they have a relatively short duration of action when administered by inhalation. A .beta..sub.2 -stimulant with a relatively long duration of action would therefore offer a significant advance in the treatment of bronchial asthma and related disorders.
In a search for new .beta.-stimulants with advantageous properties, we have now found a novel group of phenethanolamine derivatives, which differ structurally from the group of compounds described in British Patent Specification No. 1200886, and which in our tests have shown a potent selective stimulant action at .beta..sub.2 -adrenoreceptors, and, in addition, have an advantageous profile of action.
Thus, the present invention provides compounds of the general formula (I) ##STR4## wherein m is an integer from 2 to 8 and
It will be appreciated that the compounds of general formula (I) possess one or two asymmetric carbon atoms, namely the carbon atom of the ##STR5## group and, when R.sup.1 and R.sup.2 are different groups, the carbon atom to which these group are attached.
The compounds according to the invention thus include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds in which the carbon atom in the ##STR6## group is in the R configuration are preferred.
In the general formula (I), the chain --(CH.sub.2).sub.m -- may be, for example, --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.6 -- or --(CH.sub.2).sub.7 --, and the chain --(CH.sub.2).sub.n -- may be, for example, --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 -- or (CH.sub.2).sub.6 --.
Preferably the sum total of the number of carbon atoms in the chains --(CH.sub.2).sub.m -- and --(CH.sub.2).sub.n is 6 to 12 inclusive and may be, for example, 7, 8, 9 or 10. Compounds wherein the sum total of m+n is 7, 8 or 9 are particularly preferred.
Preferred compounds of general formula (I) are those wherein m is 3 and n is 6, or m is 4 and n is 3, 4 or 5, or m is 5 and n is 2, 3, 4 or 5, or m is 6 and n is 2 or 3.
R.sup.1 and R.sup.2, for example, may each be methyl, ethyl, propyl, or isopropyl groups except that if one of R.sup.1 and R.sup.2 is a propyl or isopropyl group, the other is a hydrogen atom or a methyl group. Thus, for example, R.sup.1 may be a hydrogen atom or a methyl, ethyl or propyl group. R.sup.2, for example, may be a hydrogen atom or a methyl group.
R.sup.1 and R.sup.2 are each preferably a hydrogen atom or a methyl group.
A preferred group of compounds is that wherein R.sup.1 and R.sup.2 are both hydrogen atoms. In another preferred group of compounds R.sup.1 is a hydrogen atom and R.sup.2 is a C.sub.1-3 alkyl group, particularly a methyl group. In yet another preferred group of compounds R.sup.1 and R.sup.2 are both methyl groups.
The chain ##STR7## in general formula (I) may be, for example --(CH.sub.2).sub.4 O(CH.sub.2).sub.4 --, (CH.sub.2).sub.5 O(CH.sub.2).sub.2 -- --(CH.sub.2).sub.5 O(CH.sub.2).sub.3, --(CH.sub.2).sub.5 O(CH.sub.2).sub.4 --, ##STR8## where R.sup.1 is methyl, ethyl or propyl.
Examples of the optional substituents which may be present on the phenyl group represented by Ar include bromine, iodine or, in particular, chlorine or fluorine atoms, or methyl, ethyl, methoxy or ethoxy groups. In general, Ar is preferably an unsubstituted phenyl group. According to another preference, Ar is a phenyl group substituted by one substituent, particularly a fluorine or chlorine atom or a methoxy or methyl group.
Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxybenzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, p-toluenesulphonates, methanesulphonates, ascorbates, salicylates, acetates, fumarates, succinates, lactates, glutarates, gluconates, tricarballylates, hydroxynaphthalenecarboxylates e.g. 1-hydroxy- or 3-hydroxy-2-naphthalenecarboxylates, or oleates. The compounds may also form salts with suitable bases. Examples of such salts are alkali metal (e.g. sodium and potassium), and alkaline earth metal (e.g. calcium and magnesium) salts.
The compounds according to the invention have a selective stimulant action at .beta..sub.2 -adrenoreceptors, which furthermore is of a particularly advantageous profile. The stimulant action was demonstrated in the guinea-pig, where compounds were shown to cause relaxation of PGF2.alpha.-contracted isolated trachea. In another test, compounds of the invention were shown to afford protection against histamine-induced broncho-constriction when administered by inhalation or by an oral route in conscious guinea-pigs. In both tests, compounds according the invention have shown a particularly long duration of action. The selective action of compounds of the invention was demonstrated in the rat or guinea pig. Where compounds were shown to have little or no effect on isolated rat or guinea pig left atria (.beta..sub.1 -adrenoreceptor tissues) at concentrations where they cause relaxation of PGF.sub.2.alpha. -contracted isolated trachea. Compounds according to the invention have also been shown to inhibit the anaphylactic release of spasmagens and inflammagens from sensitised human tissues e.g. lung fragments.
The compounds according to the invention may be used in the treatment of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis.
The compounds according to the invention may also be used for the treatment of premature labour, depression and congestive heart failure, and are also indicated as useful for the treatment of inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma, and in the treatment of conditions in which there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
A particularly important group of compounds by virtue of the advantageously long duration of action they have shown in our tests, has the formula (Ia): ##STR9## in which R.sup.1 and R.sup.2 are as defined for general formula (I);
A preferred group of compounds of formula (Ia) is that wherein R.sup.1 and R.sup.2 is each a hydrogen atom.
In another preferred group of compounds of formula (Ia) R.sup.1 is a hydrogen atom or a methyl group and R.sup.2 is a methyl group.
In a further group of compounds of formula (Ia) R.sup.1 and R.sup.2 each is a hydrogen atom and Ar is phenyl or phenyl substituted by a methoxy group, or more preferably a fluorine or chlorine atom.
A particularly preferred group of compounds has the formula (Ia) in which R.sup.1 and R.sup.2 each is a hydrogen atom or a methyl group, m is 4 or 5, n is 2, 3 or 4, and Ar is phenyl or phenyl substituted by a chlorine or fluorine atom or a methoxy or methyl group and the physiologically acceptable salts and solvates thereof.
Particularly important compounds are:
The invention accordingly further provides compounds of formula (I) and their physiologically acceptable salts and solvates for use in the therapy or prophylaxis of diseases associated with reversible airways obstruction in human or animal subjects. The invention also provides compounds of formula (I) and their physiologically acceptable salts and solvates and compositions containing them in association with instructions for their use in the therapy or prophylaxis of diseases associated with reversible airways obstruction in human or animal subjects.
The compounds according to the invention may be formulated for administration in any convenient way. The invention therefore includes within its scope pharmaceutical compositions comprising at least one compound of formula (I) or a physiologically acceptable salt or solvate thereof formulated for use in human or veterinary medicine. Such compositions may be presented for use with physiologically acceptable carriers or excipients, optionally with supplementary medicinal agents.
The compounds may be formulated in a form suitable for administration by inhalation or insufflation, or for oral, buccal, parenteral, topical (including nasal) or rectal administration. Administration by inhalation or insufflation is preferred.
For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
For buccal administration the composition may take the form of tablets, drops or lozenges formulated in conventional manner.
The compounds of the invention may be formulated for parenteral administration. Formulations for injections may be presented in unit dosage form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
For topical administration the pharmaceutical composition may take the form of ointments, lotions or creams formulated in a conventional manner, with for example an aqueous or oily base, generally with the addition of suitable thickening agents and/or solvents. For nasal application, the composition may take the form of a spray, formulated for example as an aqueous solution or suspension or as an aerosol with the use of a suitable propellant.
The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride.
Where pharmaceutical compositions are described above for oral, buccal, rectal or topical administration, these may be presented in a conventional manner associated with controlled release forms.
A proposed daily dosage of active compound for the treatment of man is 0.0005 mg to 100 mg, which may be conveniently administered in one or two doses. The precise dose employed will of course depend on the age and condition of the patient and on the route of administration. Thus a suitable dose for administration by inhalation is 0.0005 mg to 10 mg, for oral administration is 0.02 mg to 100 mg, and for parenteral administration is 0.001 mg to 2 mg.
The compounds according to the invention may be prepared by a number of processes, as described in the following wherein m, n, Ar, R.sup.1 and R.sup.2 are as defined for general formula (I) unless otherwise specified. In the general processes (1) to (3) described below the final step in the reaction may be the removal of a protecting group. Suitable protecting groups and their removal are described in general process (4) below.
According to one general process (1), a compound of general formula (I) may be prepared by alkylation. Conventional alkylation procedures may be used.
Thus, for example, in one process (a), a compound of general formula (I) in which R.sup.1 is a hydrogen atom may be prepared by alkylation of an amine of general formula (II): ##STR10## (wherein R.sup.3, R.sup.5 and R.sup.6 each is a hydrogen atom or a protecting group and R.sup.4 is a hydrogen atom) followed by removal of any protecting group where present.
The alkylating reaction (a) may be effected using an alkylating agent of general formula (III): ##STR11## (wherein L represents a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy).
The alkylation is preferably effected in the presence of a suitable acid scavenger, for example, inorganic bases such as sodium or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine or pyridine, or alkylene oxides such as ethylene oxide or propylene oxide. The reaction is conveniently effected in a solvent such as acetonitrile or an ether e.g. tetrahydrofuran or dioxan, a ketone e.g. butanone or methyl isobutyl ketone, a substituted amide e.g. dimethylformamide or a chlorinated hydrocarbon e.g. chloroform at a temperature between ambient and the reflux temperature of the solvent.
According to another example (b) of an alkylation process, a compound of general formula (I) in which R.sup.1 represents a hydrogen atom may be prepared by alkylation of an amine of general formula (II), as previously defined except that R.sup.4 is a hydrogen atom or a group convertible thereto under the reaction conditions, with a compound of general formula (IV):
Examples of suitable groups represented by R.sup.4 which are convertible into a hydrogen atom are arylmethyl groups such as benzyl, .alpha.-methyl benzyl and benzhydryl.
Suitable reducing agents include hydrogen in the presence of a metal catalyst such as platinum, platinum oxide, palladium, Raney nickel or rhodium, on a support, such as charcoal, using an alcohol, e.g. ethanol or an ester e.g. ethyl acetate or an ether e.g. tetrahydrofuran, or water, as reaction solvent, or a mixture of solvents, e.g. a mixture of two or more of those just described, at normal or elevated temperature and pressure, for example from 20.degree. to 100.degree. C. and from 1 to 10 atmospheres.
Alternatively when one or both of R.sup.3 and R.sup.4 are hydrogen atoms, the reducing agent may be a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminium hydride. Suitable solvents for the reaction with these reducing agents will depend on the particular hydride used, but will include alcohols such as methanol or ethanol, or ethers such as diethyl ether or tert-butyl methyl ether, or tetrahydrofuran.
When a compound of formula (II) wherein R.sup.3 and R.sup.4 are both hydrogen atoms is used, the intermediate imine of formula (V) may be formed: ##STR12## (wherein R.sup.6 and R.sup.5 are as defined for formula (II)).
Reduction of the imine using the conditions described above, followed, where necessary, by removal of any protecting groups, gives a compound of general formula (I).
Where it is desired to use a protected intermediate of general formula (II) it is particularly convenient to use hydrogen and a metal catalyst as described above with protecting groups R.sup.3, R.sup.5 and R.sup.6 which are capable of being converted to a hydrogen atom under these reducing conditions, thus avoiding the need for a separate deprotection step. Suitable protecting groups of this type include arylmethyl groups such as benzyl, benzhydryl and .alpha.-methylbenzyl.
In a second general process (2), a compound of general formula (I) may be prepared by reduction. Thus, for example, a compound of general formula (I) may be prepared by reducing an intermediate of general formula (VI): ##STR13## (wherein R.sup.5 is as defined for general formula (II) and at least one of X, X.sup.1, X.sup.2, X.sup.3 and X.sup.4 represents a reducible group and the other(s) take the appropriate meaning as follows, which is X is CH.sub.2 OR.sup.6, X.sup.1 is --CH(OH)--, X.sup.2 is --CH.sub.2 NR.sup.3, X.sup.3 is --CR.sup.1 R.sup.2 (CH.sub.2).sub.m-1 -- and X.sup.4 is --(CH.sub.2).sub.n-1 --) followed where necessary by removal of any protecting groups.
Suitable reducible groups include those wherein X is a group --CO.sub.2 R.sup.7 (wherein R.sup.7 represents a hydrogen atom, or an alkyl, aryl or aralkyl group) or --CHO, X.sup.1 is a group --C.dbd.O, X.sup.2 is a group --CH.sub.2 NY-- (wherein Y represents a group convertible to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl, benzhydryl or .alpha.-methylbenzyl), or an imine (--CH.dbd.N--) group or a group --CONH--, and X.sup.3 is a group --CO(CH.sub.2).sub.m-1 --, or a group --CR.sup.1 R.sup.2 X.sup.5 -- where X.sup.5 is C.sub.2-7 alkenylene or C.sub.2-7 alkynylene, or X.sup.2 --X.sup.3 -- is a group --CH.sub.2 N.dbd.CR.sup.2 (CH.sub.2).sub.m-1, and X.sup.4 is C.sub.2-6 alkenylene or C.sub.2-6 alkynylene. In one convenient aspect of the reduction process, the group R.sup.5 may be a group convertible to hydrogen under the reducing conditions employed and may be for example an arylmethyl group such as benzyl, benzhydryl or .alpha.-methylbenzyl.
The reduction may be effected using reducing agents conveniently employed for the reduction of carboxylic acids, aldehydes, esters, ketones, imines, amides, ethylenes, acetylenes and protected amines. Thus, for example, when X in general formula (VI) represents a group --CO.sub.2 R.sup.7 or --CHO this may be reduced to a group --CH.sub.2 OH using a hydride such as diborane or a complex metal hydride such as lithium aluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride, sodium borohydride, diisobutylaluminium hydride or lithium triethylborohydride in a solvent such as an ether, e.g. tetrahydrofuran or diethyl ether, or a halogenated hydrocarbon e.g. dichloromethane at a temperature from 0.degree. C. to the reflux.
When X.sup.1 in general formula (VI) represents a --C.dbd.O group this may be reduced to a --CH(OH)-- group using hydrogen in the presence of a metal catalyst as previously described for process (1) part (b). Alternatively, the reducing agent may be, for example, a hydride such as diborane or a metal hydride such as lithium aluminium hydride, sodium bis(2-methoxyethoxy) aluminium hydride, sodium borohydride or aluminium hydride. The reaction may be effected in a solvent, where appropriate an alcohol e.g. methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as dichloromethane.
When X.sup.2 in general formula (VI) represents a CH.sub.2 NY group or the group --CH.dbd.N--, or --X.sup.2 --X.sup.3 represents --CH.sub.2 N.dbd.CR.sup.2 (CH.sub.2).sub.m-1 this may be reduced to a --CH.sub.2 NH-- or --CH.sub.2 NHCHR.sup.2 (CH.sub.2).sub.m-1 group using hydrogen in the presence of a metal catalyst as previously described for process (1) part (b). Alternatively, when X.sup.2 or --X.sup.2 --X.sup.3 is the group --CH.dbd.N-- or --CH.sub.2 N.dbd.CR.sup.2 (CH.sub.2).sub.m-1 this may be reduced to a --CH.sub.2 NH-- or CH.sub.2 NHCHR.sub.2 (CH.sub.2).sub.m-1 group using a reducing agent and conditions as just described for the reduction of X.sup.1 when this represents a --C.dbd.O group.
When X.sup.2 or X.sup.3 in general formula (VI) represents a --CONH-- or --CO(CH.sub.2).sub.m-1 -- group this may be reduced to a group --CH.sub.2 NH-- or --CH.sub.2 (CH.sub.2).sub.m-1 -- using a hydride such as diborane or a complex metal hydride such as lithium aluminium hydride or sodium bis(2-methoxyethoxy)aluminium hydride in a solvent such as an ether, e.g.-tetrahydrofuran or diethyl ether.
When X.sup.3 in general formula (VI) represents a group --CR.sup.1 R.sup.2 X.sup.5 -- this may be reduced to a group --CR.sup.1 R.sup.2 (CH.sub.2).sub.m-1 -- using hydrogen in the presence of a catalyst such as platinum or palladium on a support such as charcoal in a solvent such as an alcohol, e.g. ethanol or methanol, or an ester, e.g. ethyl acetate, or an ether, e.g. tetrahydrofuran, at normal or elevated temperature and pressure.
When X.sup.4 is C.sub.2-6 alkenylene or C.sub.2-6 alkynylene this may be reduced to --(CH.sub.2).sub.n-1 -- using hydrogen and a catalyst as just described. In this aspect of the reduction process, suitable starting materials of formula (VI) include those in which CR.sup.1 R.sup.2 X.sup.5 and/or X.sup.4 each contains one --C.dbd.C-- or --C.tbd.C-- linkage. Where both contain unsaturated linkages, these may be the same or different.
Particular examples of the reduction process are those in which a compound of general formula (I) in which --(CH.sub.2).sub.m -- represents --(CH.sub.2).sub.5 -- is prepared from a corresponding compound in which --(CH.sub.2).sub.m -- represents --CH.dbd.CH(CH.sub.2).sub.3 --, --C.tbd.C(CH.sub.2).sub.3 --, --(CH.sub.2).sub.2 CH.dbd.CHCH.sub.2 -- or --(CH.sub.2).sub.2 C.tbd.CCH.sub.2 --. In further examples, a compound of general formula (I) in which --(CH.sub.2).sub.n -- represents --(CH.sub.2).sub.4 -- or --(CH.sub.2).sub.3 -- may be prepared by reduction of a corresponding compound of general formula (I) in which --(CH.sub.2).sub.n -- represents --CH.sub.2 CH.dbd.CH--CH.sub.2, --CH.sub.2 C.tbd.CCH.sub.2, --CH.sub.2 CH.sub.2 CH.dbd.CH--, --CH.sub.2 CH.sub.2 C.tbd.C--, --CH.sub.2 CH.dbd.CH or --CH.sub.2 C.tbd.C--.
In the reduction processes just described the groups X and R.sup.5 in a compound of formula (VI) may together conveniently represent a group ##STR14## (where R.sup.8 and R.sup.9, which may be the same or different, each represents a hydrogen atom or an alkyl or aryl group. After the reduction is complete, cleavage of this group using e.g. a dilute acid in a solvent such as water at normal temperature yields a compound of formula (I).
According to a further general process (3), a compound of general formula (I) may be obtained by reaction of a compound of general formula (VII): ##STR15## (wherein Z represents a group ##STR16## and L, R.sup.5 and R.sup.6 are as previously defined, with an amine of general formula (VIII): ##STR17## (wherein Y.sup.1 is a hydrogen atom or a group convertible thereto by catalytic hydrogenation) followed by removal of any protecting groups where present, as described hereinafter.
Suitable Y.sup.1 groups convertible into a hydrogen atom include arylmethyl groups such as benzyl, benzhydryl or .alpha.-methylbenzyl.
The reaction may be effected in the presence of a suitable solvent for example an alcohol, such as ethanol, a halogenated hydrocarbon e.g. chloroform, a substituted amide e.g. dimethylformamide or an ether such as tetrahydrofuran or dioxan at a temperature from ambient to the reflux, optionally in the presence of a base such as an inorganic amine e.g. diisopropylethylamine or an inorganic base such as sodium carbonate.
The intermediate amines of general formula (VIII) and their acid addition salts are novel compounds and form a further aspect of the invention. A particularly preferred group of amines of general formula (VIII) are those in which the total number of carbon atoms in the groups represented by ##STR18## and (CH.sub.2).sub.n is from 7 to 13 inclusive.
In another general process (4), a compound of general formula (I) may be obtained by deprotection of a protected intermediate of general formula (IX): ##STR19## (wherein R.sup.3, R.sup.5 and R.sup.6 are as previously defined except that at least one of R.sup.3, R.sup.5 and R.sup.6 is a protecting group).
The protecting group may be any conventional protecting group, for example as described in "Protective Groups in Organic Chemistry", Ed. J.F.W. McOmie (Plenum Press, 1973). Examples of suitable hydroxyl protecting groups represented by R.sup.5 and R.sup.6 are aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl, and tetrahydropyranyl. Examples of suitable amino protecting groups represented by R.sup.3 are aralkyl groups such as benzyl, .alpha.-methylbenzyl, diphenylmethyl or triphenylmethyl and acyl groups such as trichloroacetyl or trifluoroacetyl.
The deprotection to yield a compound of general formula (I) may be effected using conventional techniques. Thus, for example, when R.sup.5, R.sup.6 and/or R.sup.3 is an aralkyl group this may be cleaved by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal). When R.sup.5 and/or R.sup.6 is tetrahydropyranyl this may be cleaved by hydrolysis under acidic conditions. Acyl groups represented by R.sup.3 may be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroacetyl, or trifluoroacetyl may be removed by reduction with, for example, zinc and acetic acid.
In a particular embodiment of the deprotection process (4), R.sup.5 and R.sup.6 may together represent a protecting group as in a compound of general formula (X): ##STR20## (wherein R.sup.8 and R.sup.9 are as previously defined).
A compound of general formula (X) may be obtained by treatment of a compound of formula (X) with a dilute acid, for example hydrochloric acid in a solvent such as water or an alcohol such as ethanol at normal or elevated temperature.
In the general processes (1) to (4) described above, the compound of formula (I) obtained may be in the form of a salt, conveniently in the form of a physiologically acceptable salt. Where desired such salts may be converted to the corresponding free base using conventional methods.
Physiologically acceptable salts of the compounds of general formula (I) may be prepared by reacting a compound of general formula (I) with an appropriate acid or base in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol e.g. methanol, ethanol or iso-propanol.
Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compounds of general formula (I), using conventional methods.
When a specific enantiomer of a compound of general formula (I) possessing one asymmetric carbon atom is required, this may be obtained by resolution of a mixture of enantiomers of a corresponding compound of general formula (I) using conventional methods.
Thus, in one example an appropriate optically active acid may be used to form salts with a mixture of enantiomers of a compound of general formula (I). The resulting mixture of isomeric salts may be separated, for example by fractional crystallisation, into the diastereoisomeric salts from which the required enantiomer of a compound of general formula (I) may be isolated by conversion into the required free base.
Alternatively, enantiomers of a compound of general formula (I) possessing one asymmetric carbon atom may be synthesised from the appropriate optically active intermediates using any of the general processes described herein.
When a compound of formula (I) contains two asymmetric carbon atoms, specific diasteroisomers or enantiomers thereof may be obtained from an appropriate asymmetric starting material or by separation of an appropriate mixture of isomers using techniques just described.
Suitable methods for preparing the intermediate compounds used in the above general processes are described below. In the following discussion, Ar, m, n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, Y and Y.sup.1, Z, X, X.sup.1, X.sup.2, X.sup.3 and L are as defined above except where otherwise indicated. "Hal" represents a halogen atom. Where an intermediate with protected hydroxyl and/or amino groups is desired, this may be obtained using conventional protection methods, for example those described by McOmie (see process (4) above).
The intermediate compounds of general formula (III) may be prepared by reaction of an alcohol of general formula (XI):
The compounds of general formulae (XI) and (XII) are either known compounds or they may be made by methods analogous to those used for the preparation of the known compounds.
Intermediate aldehydes of general formula (IV) (in which R.sup.2 represents a hydrogen atom) may be prepared by oxidation of an alcohol of general formula (XIII):
Intermediate ketones of formula (IV) (in which R.sup.2 represents an alkyl group), may be prepared by reaction of a Grignard complex of a halide of formula (XIV):
Intermediate compounds of general formula (VI) for use in general process (2) may be prepared by a number of processes.
Thus for example intermediates of general formula (VI) in which X.sup.1 is a group --C.dbd.O may be prepared from a haloketone of formula (XV): ##STR21## by reaction with an amine of general formula (VIII). The reaction may be effected in a cold or hot solvent, for example tetrahydrofuran, tert-butyl methyl ether, dioxan, chloroform, dimethylformamide, acetonitrile or a ketone such as butanone or methylisobutylketone, or an ester, for example ethyl acetate preferably in the presence of a base such as diisopropylethylamine, sodium carbonate or other acid scavenger such as propylene oxide. When --(CH.sub.2).sub.m and/or --(CH.sub.2).sub.n -- in the amine of formula (VIII) contains an unsaturated linkage, an intermediate of formula (VI) in which X.sup.3 is --CR.sup.1 R.sup.2 X.sup.5 -- and/or X.sup.4 is C.sub.2-6 alkenylene or C.sub.2-6 alkynylene may be obtained in this process.
Intermediates of general formula (VI) in which X.sup.1 is a group --C.dbd.O may be reduced to the corresponding intermediate in which X.sup.1 is a group --CH(OH)-- using for example a metal hydride such as sodium borohydride in a solvent e.g. ethanol.
Iminoketones of general formula (VI) i.e. in which X.sup.2 is a group --CH.dbd.N-- may be obtained from a phenylglyoxal derivative of formula (XVI): ##STR22## by reaction with an amine of formula (VIII) in which Y.sup.1 represents a hydrogen atom, in a solvent such as benzene, tetrahydrofuran or an alcohol e.g. ethanol at temperatures up to the reflux. The phenylglyoxal derivatives of formula (XVI) may be obtained from a haloketone of formula (XV) by the action of a dialkylsulphoxide such as dimethylsulphoxide.
When X and R.sup.5 in the glyoxal of formula (XVI) together represent a group ##STR23## the iminoketone of formula (VI) so formed using this process subsequently may be reduced using a metal hydride such as sodium borohydride in a solvent such as ethanol to yield a compound of formula (X).
Intermediates of general formula (VI) in which X.sup.3 is a group --CO(CH.sub.2).sub.m -- may be prepared by acylation of an amine of formula (XVII): ##STR24## using an ester or an activated derivative of an acid of formula (XVIII):
Suitable activated derivatives include the acid chloride, an anhydride or imidazolide. The reaction may be optionally carried out in a solvent such as tetrahydrofuran, benzene or chloroform, optionally in the presence of a base such as pyridine or triethylamine. The acids (XVIII) may be used directly if a coupling agent such as dicyclohexylcarbodiimide is added.
Acids of formula (XVIII) may be obtained by treatment of an alcohol of general formula (XIII) with a suitable oxidising agent, for example pyridinium dichromate in a solvent such as dimethylformamide.
Intermediates of formula (VI) in which --X.sup.2 --X.sup.3 -- represents --CH.sub.2 N.dbd.CR.sup.2 (CH.sub.2).sub.m-1 may be obtained by reaction of an amine of formula (XVII) in which R.sup.3 is a hydrogen atom with a compound of formula (IV) preferably in a solvent such as acetonitrile.
Intermediates of formula (VI) in which X.sup.2 is --CONH-- may be prepared by reaction of an amine of formula (VIII) with an acid of formula (XIX) ##STR25## in the presence of a coupling agent such as dicyclohexylcarbodiimide.
Compounds of formula (VII) in which X represents a group ##STR26## may be prepared from a haloketone of formula (XX): ##STR27## by reduction using for example a metal hydride such as sodium borohydride in a solvent such as ethanol.
The halogen atom may be displaced to yield other compounds of general formula (VII) in which Z is a group ##STR28## where L is a leaving group other than a halogen atom.
Compounds of formula (VII) wherein Z represents ##STR29## may be prepared from the corresponding compound in which Z is ##STR30## by treatment with a base, for example an amine, which may be for example a compound of general formula (VIII), or an inorganic base such as sodium hydroxide in a solvent such as ethanol.
The amines of general formula (VIII) in which Y.sup.1 is a group convertible to hydrogen and R.sup.1 and R.sup.2 are both hydrogen atoms may be prepared by reaction of a compound of general formula (III) in which R.sup.2 is a hydrogen atom with an amine YNH.sub.2. The reaction may be effected in the absence or presence of a solvent such as a ketone e.g. butanone or methyl isobutyl ketone, an ether e.g. tetrahydrofuran or a substituted amide e.g. dimethylformamide, optionally in the presence of a base such as sodium carbonate or an organic amine e.g. triethylamine or N,N-diisopropylethylamine at temperatures between 0.degree. C. and the reflux. Where desired, subsequent reaction with hydrogen in the presence of a metal catalyst such as platinum in a solvent such as an alcohol e.g. ethanol yields a compound of formula (VIII) where Y.sup.1 is a hydrogen atom.
Alternatively, amines of formula (VIII) in which R.sup.1 is a hydrogen atom may be prepared by reductive alkylation of an amine Y.sup.1 NH.sub.2, in which Y.sup.1 is a group convertible into hydrogen with a compound of formula (IV), if necessary followed by conversion of the Y.sup.1 group to a hydrogen atom as just described.
The reaction may be effected by hydrogen in the absence or presence of a solvent such as an alcohol, e.g. ethanol with a metal catalyst such as platinum or palladium, or by use of a complex metal hydride such as sodium borohydride or sodium cyanoborohydride in an alcohol, for example, ethanol.
A process to afford amines of formula (VIII) in which R.sup.1 and R.sup.2 can both be alkyl groups uses an acid of formula (XXI): ##STR31##
The acid is converted via its chloride and azide by a Curtius reaction into the amine of formula (VIII) in which Y.sup.1 is a hydrogen atom. The reaction involves thermal rearrangement of the azide into an isocyanate, which is hydrolysed by treatment with an inorganic base, for example aqueous sodium hydroxide optionally in a solvent such as ethanol.
The acids of formula (XXI) can be prepared by alkylation of the acid (XXII): ##STR32## via its dilithio derivative with an alkylating agent of formula (XIV) in a solvent such as an ether, for example tetrahydrofuran at low temperature such as 0.degree. C. to ambient.
The compounds of formulae (II), (IV), (XVII), (XIX), (XX), (XXI) and (XXII) are either known compounds or may be obtained by analogous methods to those used for the preparation of the known compounds.
The following examples illustrate the invention.
Temperatures are in .degree. C. Thin layer chromatography (T.l.c.) was carried out over SiO.sub.2 and `dried` refers to drying using magnesium sulphate, except where otherwise stated.
The following abbreviations are used: DMF--dimethylformamide; THF--tetrahydrofuran; EA--ethyl acetate; ER--diethyl ether; CX--cyclohexane; HX--hexane; BR--brine; flash column chromatography [FCS]--on silica [FCTS]--on triethylamine-deactivated silica; T.l.c.EN--t.l.c. over triethylamine-deactivated SiO.sub.2.
Eluants used for chromatography and t.l.c. are:
[A]-CX-ER(19:1); [B]-CX-ER(9:1); [C]-ER-CX-triethylamine (60:40:1); [D]-CX-ER(1:4); [E]-CX-EA(19:1); [F]-CX-ER(4:1); [G]-ER; [H]-EA; [I]-EA-methanol-triethylamine(9:1:0.1); [J]-CX-ER(7:3); [K]-CX-EA(9:1); [L]-CX-ER (3:1); [M]-EA-CH.sub.3 OH-NH.sub.3 (9:1:0.1); [N]-EA-CH.sub.3 OH(9:1); [O]-CX-ER(1:1).
INTERMEDIATE 1 is .alpha..sup.1 -(aminomethyl)-4-hydroxy-1,3-benzenedimethanol.
A mixture of phenethyl alcohol (20 g), 1,6-dibromohexane (195 g) and tetrabutylammonium bisulphate (3.0 g) in 50% w/v NaOH solution (100 ml) was heated at 65.degree.-70.degree. for 4 h. The cooled reaction mixture was poured into H.sub.2 O (400 ml) and extracted with CX (2.times.300 ml). The dried extracts were evaporated in vacuo to give a yellow liquid which was purified by distillation under reduced pressure to give the title compound as a colourless liquid (26 g) b.p. 110.degree./0.1 mm. T.l.c. (EA) Rf 0.62.
NaH (46% dispersion in oil; 6.5 g) was added portionwise to a solution of 4-phenyl-1-butanol (15.0 g) and 1,6-dibromohexane (48.8 g) in THF (200 ml) under nitrogen. The resulting suspension was refluxed for 27 h and treated with H.sub.2 O (80 ml). The mixture was extracted with ER (2.times.200 ml) and the dried extract was evaporated to leave an orange oil. The oil was purified on a column of silica (800 ml) [A] to give a yellow oil which on distillation gave the title compound as a colourless oil (15.0 g) b.p. 90.degree.-95.degree./0.1 mm Hg.
INTERMEDIATE 4 is .alpha..sup.1 -[[bis(phenylmethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol.
A mixture of Intermediate 3 (10 g) sodium acetate trihydrate (34.8 g), H.sub.2 O (25 ml) and trioctylpropyl NH.sub.4 Cl (2 g) was stirred vigorously on a steam bath for 2.5 h. 2M NaOH (50 ml) and ethanol (50 ml) were added to the cooled mixture which was then stirred at RT for 30 min. The mixture was diluted with BR (200 ml), extracted with ER and the organic phase washed with H.sub.2 O (200 ml), BR (200 ml), dried and evaporated under reduced pressure to give the title alcohol as a yellow oil, (7.16 g). T.l.c. [G] Rf 0.73.
Pyridinium chlorochromate (4.1 g) was added to a solution of Intermediate 5 (3 g) in CH.sub.2 Cl.sub.2 (25 ml). The mixture was stirred at RT for 0.75 h, triturated with ER (75 ml), and filtered through hyflo. The filtrate was evaporated and the residue dissolved in ER (50 ml), filtered through silica and evaporated under reduced pressure to give a pale yellow oil. Purification by [FCS] (120 g) [B] gave the title compound as a colourless oil (1.65 g). T.l.c. [B] Rf 0.3.
A solution of benzylamine (16.64 g) and Intermediate 3 (11.27 g) in THF (45 ml) was kept at RT for 4 days, diluted with ER (450 ml), filtered and the filtrate evaporated to give a colourless oil which was purified by [FCS] [C] to give the title compound (9.94 g) as a colourless oil.
Analysis Found: C, 81.60; H, 10.1; N, 4.2. C.sub.23 H.sub.33 NO requires C, 81.35; H, 9.80; N, 4.15%.
A solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (1 g), Intermediate 7, (1.4 g) and N,N-diisopropylethylamine (0.8 g) in THF (10 ml) was kept at 23.degree. for 3 days. The mixture was diluted with ER (60 ml), washed with 8% NaHCO.sub.3 (50 ml) and BR (50 ml), dried and evaporated in vacuo to give an oil. Purification by [FCS] (40 g) [D] afforded the title compound as a viscous yellow oil (1.68 g). T.l.c. [D] Rf 0.42.
2-Methoxypropene (10 g) was added over 15 min to a stirred solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (5 g) and toluene-4-sulphonic acid (0.5 g) in CH.sub.2 Cl.sub.2 (100 ml) at 23.degree.. The mixture was stirred for 3 h, filtered through a wad of triethylamine-deactivated silica and evaporated to give an oil. Purification by [FCTS] (300 g) [E] afforded the title compound as an oil (4.8 g) which solidified on cooling. A small sample was crystallised from light petroleum (b.p. 60.degree.-80.degree.) to give white crystals m.p. 47.degree.-48.degree..
A solution of Intermediate 9 (1.6 g), Intermediate 7 (2.1 g) and N,N-diisopropylethylamine (1.2 g) in THF (15 ml) was kept at 23.degree. for 2 days. The mixture was diluted with EA (80 ml) washed with 8% NaHCO.sub.3 (50 ml) and BR (50 ml), dried (Na.sub.2 SO.sub.4) and evaporated in vacuo to give a yellow oil. Purification by [FCS] (150 g) [F] gave the title compound as a pale-yellow oil (2.2 g). T.l.c. [F] Rf 0.27.
A mixture of Intermediate 5 (4 g) and pyridinium dichromate (21.04 g) in DMF (50 ml) was stirred at RT for 15 h, diluted with H.sub.2 O (300 ml) and extracted with ER (2.times.100 ml). The extract was washed with H.sub.2 O (2.times.250 ml), dried, filtered through a bed of silica and evaporated in vacuo to give a colourless oil. Purification by [FCS] (80 g) [F] gave the title compound as a colourless oil (0.85 g). T.l.c. [F] Rf 0.27.
DMF (0.003 ml) and thionyl chloride (0.51 ml) were added to a solution of Intermediate 11 (0.89 g) in dry CH.sub.2 Cl.sub.2 (17 ml). The resultant solution was stirred at RT for 2.5 h and evaporated to dryness to give the acid chloride. Intermediate 1 (0.934 g) in THF was treated with ethyl (trimethylsilyl)acetate (3.57 ml). Tetrabutyl ammonium fluoride (0.9 ml) was added dropwise to the stirred suspension at 0.degree.. The resulting solution was stirred at RT for 2 h and added to a solution of the above acid chloride in THF (10 ml) under an atmosphere of nitrogen. Triethylamine (3.4 ml) was then added and the solution stirred at RT for 4 h, left to stand overnight, added to 2N hydrochloric acid (30 ml) and stirred for 15 min. The product was extracted into EA (3.times.25 ml) the extracts were washed with H.sub.2 O (25 ml), 8% NaHCO.sub.3 solution (25 ml) and BR (25 ml). The dried (Na.sub.2 SO.sub.4) organic layer was evaporated to dryness to give a brown oil which was chromatographed on silica (Merck art 7754, 40 g) [H] to give a pale yellow oil. The dried oil solidified to give the title amide as an off white solid (1.06 g), m.p. 96.degree.-97.5.degree..
Intermediate 7 (25 g) in absolute ethanol (250 ml) was hydrogenated over palladium on carbon (1 g) and platinum on carbon (1 g) catalysts. The mixture was filtered through Hyflo and evaporated under reduced pressure to give the title amine as a colourless oil (16.49 g).
T.l.c. EN(CH.sub.3 OH) Rf 0.3.
A solution of Intermediate 13 (0.49 g) in methanol (5 ml) was added over 15 min to a stirred suspension of methyl 5-(dihydroxyacetyl)-2-hydroxybenzoate in methanol (10 ml) at 23.degree.. The mixture was stirred for 10 min, evaporated in vacuo and the residue purified by [FCTS] (40 g) [G] to give the title imine as a dark-orange oil (0.61 g). The imine was unstable and should be used promptly after preparation.
T.l.c. EN[G] Rf 0.37.
NaBH.sub.4 (0.1 g) was added to a stirred solution of Intermediate 9 (0.6 g) in ethanol (20 ml) at 0.degree.. The mixture was stirred at 0.degree. for 1 h, diluted with H.sub.2 O (50 ml) and extracted with EA (2.times.25 ml). The extract was washed with BR (25 ml) dried and evaporated to give an oil which on trituration with HX afforded the title bromohydrin as a white solid (0.55 g) m.p. 84.degree.-85.degree. unchanged on recrystallisation from HX.
A mixture of Intermediate 15 (0.45 g), methanol (10 ml) and anhydrous K.sub.2 CO.sub.3 (0.25 g) was stirred at 23.degree. for 2 h. The mixture was diluted with ER (50 ml) filtered through a small wad of silica and evaporated in vacuo. The residual oil was dissolved in ER (50 ml), dried and evaporated to give the title epoxide as an oil (0.27 g).
T.l.c. (CX-EA 7:3) Rf 0.56.
A mixture of propargyl alcohol (10.0 g), (4-bromobutyl)benzene (38.0 g), aqueous NaOH (80 ml, 50% w/v), and tetrabutylammonium bisulphate (1.0 g) was stirred vigorously for 3 days, treated with H.sub.2 O (100 ml) and extracted with ER (2.times.200 ml). The dried extract was evaporated and the residue was purified on a column of silica (Merck 9385; 500 ml) [H] to give the title compound as a colourless oil (18.3 g). T.l.c. [A] Rf 0.2.
Intermediate 17 (15.0 g) was added dropwise to a suspension of lithamide from lithium (0.61 g) in liquid ammonia (50 ml) at -33.degree.. The mixture was stirred for 2 h and bromochloropropane (13.9 g) in ER (10 ml) was added dropwise. The resulting suspension was stirred at -33.degree. for 3 h and ammonia was allowed to evaporate overnight. The residue was treated cautiously with H.sub.2 O (30 ml) and extracted with ER (3.times.50 ml). The dried extract was evaporated and the residue was distilled to give the title compound as a colourless oil (12.9 g) b.p. 140.degree.-150.degree./0.3 mmHg.
T.l.c. [A] Rf 0.2.
A mixture of Intermediate 18 (12.0 g) sodium iodide (20.0 g), and butanone (50 ml) was refluxed for 6 h and stirred at RT for 2 days, filtered and evaporated. The residue was dissolved in ER (50 ml) and washed with H.sub.2 O (50 ml) and aqueous sodium thiosulphate (50 ml). The dried organic phase was evaporated to leave the title compound as a pale yellow oil (12.6 g).
Intermediate 19 (8.66 g) was added dropwise to a solution of Intermediate 1 (6.7 g) and N,N-diisopropylethylamine (3.9 g) in DMF (250 ml) at 70.degree.. The mixture was heated at 70.degree. for 2 h and DMF was removed under reduced pressure. The residue was treated with aqueous NaHCO.sub.3 (1M; 200 ml) and extracted with EA (3.times.250 ml). The dried extract was evaporated and the residue was purified on a column of silica (Merck 9385; 250 ml) [I] to give a yellow oil. Trituration of the oil with ER gave the title compound as a white solid (4.3 g), m.p. 89.degree.-90.degree..
T.l.c. [M] Rf 0.2.
3-Phenylpropanol (3.00 g) and 1,6-dibromohexane (16.10 g, 10.2 ml) were stirred rapidly at RT with tetra-n-butylammonium hydrogen sulphate (0.5 g) and 12.5M aqueous NaOH (16 ml) for 30 h. The mixture was diluted with H.sub.2 O (80 ml), extracted with ER (3.times.100 ml), and the combined organic extracts were washed consecutively with H.sub.2 O (80 ml) and BR (80 ml). The dried extracts were evaporated and the residual oil purified by [FCS], eluting with CX (one columnful), followed by EA-CX (1:20) to give the title compound (5.35 g) as a colourless oil.
Analysis Found: C, 60.25; H, 7.8; Br, 26.45. C.sub.15 H.sub.23 BrO requires C, 60.2; H, 7.75; Br, 26.7%.
Intermediate 21 (317 g) was added to benzylamine (1116 ml) at a temperature of 115.degree.-125.degree. with stirring under nitrogen. Excess benzylamine was removed by distillation under reduced pressure. The residue was treated with methyl isobutyl ketone (1280 ml), the temperature adjusted to 50.degree. and 47% w/v hydrobromic acid (115 ml) in H.sub.2 O (800 ml) was added at 50.degree.-55.degree.. The aqueous phase was removed and the organic solution was washed with H.sub.2 O (3.times.800 ml) at 50.degree.. Distillation under reduced pressure and crystallisation of the residue from propan-2-ol afforded the title compound salt (318 g), m.p. 135.degree.-136.degree..
A solution of N,N-diisopropylethylamine (9.93 g) in CH.sub.2 Cl.sub.2 (15 ml) was added to a solution of methyl 5-bromoacetyl-2-hydroxybenzoate (10 g) and Intermediate 22 (14.87 g) in CH.sub.2 Cl.sub.2 (256 ml) at 16.degree.. The solution was stirred under nitrogen for 23 h at 20.degree., washed with H.sub.2 O (5.times.100 ml), dried and filtered. This solution of the title compound was used without further purification. T.l.c. (ER) Rf 0.7.
NaH (46% dispersion in oil; 1.36 g) was added portionwise to a solution of 2-methoxybenzenebutanol (5.0 g) and 1,6-dibromohexane (13.8 g) in THF (50 ml). The suspension was refluxed for 20 h and was treated cautiously with H.sub.2 O (20 ml). The resulting emulsion was extracted with ER (2.times.50 ml) and the dried extract was evaporated to leave a yellow oil. The oil was purified on a column of silica (Merck 9385, 600 ml) [A] to give the title compound as a colourless oil (5.6 g). T.l.c. [B] Rf 0.2.
(3-Bromopropyl)benzene (20 g) in THF (75 ml) was added dropwise to magnesium (2.43 g) at a rate to maintain gentle reflux. The mixture was stirred for 2 h at RT and oxetane (10 g) was added dropwise. The resulting suspension was stirred at RT for 2 h and at reflux for 16 h and poured into saturated aqueous NH.sub.4 Cl (100 ml). The mixture was extracted with ER (3.times.75 ml) and the dried extract was evaporated to leave a yellow oil. Distillation of the oil gave the title compound as a colourless liquid (6.05 g) b.p. 100.degree.-105.degree./0.4 mmHg. T.l.c. [O] Rf 0.3.
Dihydropyran (15.5 g) was added dropwise to a mixture of 4-chlorobutanol (20 g) and hydrochloric acid (18M, 1 drop) at RT. The mixture was stirred for 30 min and washed with H.sub.2 O (100 ml), aqueous NaHCO.sub.3 (1M, 50 ml) and BR (50 ml). The dried liquid was heated under reduced pressure to leave the title compound as a colourless liquid (31.9 g). T.l.c. [L] Rf 0.5.
NaH (3.85 g) was added portionwise to a mixture of Intermediate 25 (5.5 g), Intermediate 26 (30 g), potassium iodide (1 g) and THF (50 ml). The mixture was refluxed for 28 h and treated cautiously with H.sub.2 O (100 ml). The resulting emulsion was extracted with ER (3.times.100 ml) and the dried extract was evaporated to leave a yellow oil. Excess of Intermediate 26 was distilled from the mixture at 80.degree./0.4 mmHg and the residue was purified on a column of silica (300 ml) [B] to give the title compound as a colourless oil (2.7 g). T.l.c. [B] Rf 0.25.
A solution of Intermediate 27 (2.65 g) in methanol (20 ml) and 80% acetic acid (10 ml) was stirred at RT for 20 h. The solution was basified with aqueous NaOH (2M). The mixture was refluxed for 2 h and methanol was evaporated. The resulting emulsion was extracted with ER (2.times.50 ml) and the dried extract was evaporated to leave the title compound as a colourless oil (2.0 g). T.l.c. [O] Rf 0.3.
Methanesulphonyl chloride (0.4 g) was added dropwise to a solution of Intermediate 28 (0.8 g) and triethylamine (0.5 g) in CH.sub.2 Cl.sub.2 (5 ml) at 0.degree.. The mixture was stirred at RT for 25 min and filtered. The filtrate was washed with saturated aqueous NaHCO.sub.3 (20 ml) and BR (20 ml). The dried (Na.sub.2 SO.sub.4) organic phase was evaporated to leave the title compound as a yellow oil (1.0 g).
NaH (46% dispersion in oil; 4.2 g) was added portionwise to a solution of 2,6-dimethylbenzenethanol (6.0 g) and 1,6-dibromohexane (19.52 g) in THF (50 ml) under nitrogen. The mixture was refluxed for 18 h and treated cautiously with H.sub.2 O (20 ml). The resulting emulsion was extracted with ER (3.times.100 ml) and the dried extract was evaporated to leave a yellow oil. Excess 1,6-dibromohexane was removed under reduced pressure and the residue was purified on a column of silica (300 ml) [B] to give the title compound as a colourless oil (6.6 g) b.p. 110.degree.-115.degree./0.4 mmHg.
The following intermediates were prepared in a similar manner to Intermediate 21.
(3.3 g), b.p. 180.degree.-190.degree./0.5 torr, from 1,6-dibromohexane (8 g) and 4-(4-methoxyphenyl)butanol (2 g).
(3.2 g), b.p. 185.degree.-195.degree./0.3 torr, from 1,5-dibromopentane (8.5 g) and benzenepentanol (2 g).
(4.0 g), b.p. 169.degree./0.8 torr, from 1,6-dibromohexane (8.65 g) and 4-chlorobenzeneethanol (3.0 g).
(2.22 g), b.p. 170.degree./0.7 torr, from 1,6-dibromohexane (8.82 g) and Intermediate 42 (2.0 g).
(4.3 g), T.l.c. [B] Rf 0.3, from 1,8-dibromooctane (13.4 g) and benzeneethanol (20 g).
(2.7 g), T.l.c. [B] Rf 0.3, from 1,6-dibromohexane (9.0 g) and benzenepentanol (2.0 g).
(2.6 g), T.l.c. [B] Rf 0.25, from 1,6-dibromohexane (9.8 g) and 4-ethylbenzeneethanol (2.0 g).
(2.05 g) from 1,7-dibromoheptane (3.83 g) and 3-phenylpropanol (1.08 ml).
Analysis Found: C,62.6;H,8.4. C.sub.16 H.sub.25 BrO requires C,61.35;H,8.05%.
(3.2 g), T.l.c. (CX-EA 4:1) Rf 0.43, from 1,6-dibromohexane (9.5 g) and Intermediate 44 (2.5 g).
(4.12 g), T.l.c. (ER- HX 1:79) Rf 0.16, from 1,6-dibromohexane (11.71 g) and 3-chlorobenzeneethanol (2.5 g).
(4.71 g), T.l.c. (ER- CX 1:79) Rf 0.22, from 1,6-dibromohexane (14.28 g) and 3-(2-fluorophenyl)-1-propanol (3.0 g).
A Grignard reagent was prepared from 4-bromo-1-fluorobenzene (8.0 g), magnesium turnings (1.10 g), and iodine (one small crystal) in THF (40 ml). Oxetane (2.3 g) in THF (10 ml) was added at RT and the reaction mixture was heated at reflux overnight. The cooled solution was poured into aqueous saturated NH.sub.4 Cl (100 ml), extracted with ER (2.times.150 ml) and the combined, dried (Na.sub.2 SO.sub.4) extracts were evaporated. The residual oil was purified by flash chromatography over silica gel (Merck 9285, 5.0 cm wide column), eluting with ER- CX (1:5.fwdarw.1:3). The resultant oil was further purified by distillation to give the title compound (3.15 g) as a colourless oil, b.p. 150.degree./0.8 torr.
A solution of n-butyllithium in HX (1.6M, 6.5 ml) was added over 5 min to a stirred suspension of [3-(1-methoxy-1-methylethoxy)propyl]triphenylphosphonium bromide (4.8 g) in dry THF (25 ml) at 0.degree. under nitrogen. The mixture was stirred at 0.degree. for 45 min, treated with a solution of piperonal (1.2 g) in dry THF (5 ml) and stirred at 0.degree. to 23.degree. over 1 h. ER (70 ml) was added, the mixture filtered through silica and the filtrate evaporated in vacuo to give a yellow oil which was dissolved in a mixture of THF-H.sub.2 O-2M hydrochloric acid 25:5:1 (31 ml) and kept at 23.degree. for 0.5 h. The mixture was diluted with 8% NaHCO.sub.3 (30 ml), extracted with ER (2.times.50 ml) and the extract was washed with BR (50 ml), dried and evaporated in vacuo to afford the title alcohol as a yellow oil (1.05 g) (E:Z ratio of 3:2). T.l.c. [O] Rf 0.22.
A solution of Intermediate 43 (3.5 g) in absolute ethanol (50 ml) was hydrogenated at RT and atmospheric pressure over 10% palladium on carbon catalyst (200 mg). Hydrogen absorption (392 ml) ceased after 45 min, the solution was filtered and the filtrate evaporated in vacuo to give the title alcohol as a colourless oil (3.5 g).
T.l.c. (EA-CX (3:2)) Rf 0.49.
The following intermediates were prepared in a similar manner to Intermediate 21.
(2.44 g), T.l.c. [K] Rf 0.68, from 1,4-dibromobutane (8.6 g) and benzenebutanol (2 g).
(2.46 g), T.l.c. [K] Rf 0.58 from 1,4-dibromobutane (7.89 g) and benzenepentanol (2 g).
(6.2 g), T.l.c. (CX-ER 40:1) Rf 0.29, from 1,7-dibromoheptane (10.5 g) and benzeneethanol (50.0 g).
(2.19 g) T.l.c. [K] Rf 0.48, from 1,5-dibromopentane (7.8 g) and 4- ethylbenzeneethanol (1.7 g).
(8.51 g) T.l.c. [K] Rf 0.56 from 1,6-dibromohexane (24.2 g) and 4- methylbenzeethanol (4.5 g).
(2.85 g), T.l.c. [K] Rf 0.41, from 1,4-dibromobutane (10.6 g) and benzeneethanol (2 g).
(3.8 g), T.l.c. [K] Rf 0.46 from 1,5-dibromopentane (11.3 g) and benzeneethanol (2 g).
(2.8 g), T.l.c. [K] Rf 0.44 from 1,5-dibromopentane (10.2 g) and benzenepropanol (2 g).
4-Phenylbutanol (5.80 g) was stirred in 1,5-dibromopentane (52 ml) and 5N NaOH solution (50 ml), and tetrabutyl ammonium bisulphate (0.87 g) was added and the reaction mixture was stirred at RT for 72 h. (After 42 h the NaOH layer was replaced by a fresh solution). The two layers were separated and the aqueous phase was extracted with ER (3.times.50 ml). The combined organic layers were dried (Na.sub.2 SO.sub.4), and evaporated to give a clear liquid. Excess 1,5-dibromopentane was removed by distillation at 60.degree. 1.00 mmHg. The residue was chromatographed on a silica (70-230 mesh, 30 g) column using CX as eluant, with a slowly increasing quantity of ER until the title compound was obtained, which on evaporation gave a colourless oil (3.26 g). T.l.c. (CX-ER (99:1)) Rf 0.15.
4-Methoxybenzeneethanol (5.0 g) and 1,6-dibromohexane (23.7 g) were stirred rapidly at RT with tetra-n-butyl ammonium bisulphate (0.94 g) and 12.5M aqueous NaOH (30 ml) for 16 h. The mixture was diluted with H.sub.2 O (125 ml), extracted with ER (3.times.150 ml) and the combined organic extracts were washed consecutively with H.sub.2 O (125 ml), BR (125 ml), dried and evaporated to give an oil (24.6 g). The oil was purified by [FCS] eluting with ER-CX (0:100.fwdarw.4:96) to give the title compound as a colourless oil (8.30 g). T.l.c. (CX-ER (40:1)) Rf 0.33.
A solution of Intermediate 51 (2.0 g) in ER (15 ml) was added dropwise to magnesium (0.18 g). The mixture was refluxed for 1 h, cooled and added during 40 min to acetic anhydride (1.4 g) in ER (10 ml) at -78.degree.. The suspension was stirred at -78.degree. for 2 h, warmed to -10.degree. and treated with saturated aqueous NH.sub.4 Cl (20 ml). The mixture was extracted with ER (2.times.25 ml) and the extract was washed with 5% NaOH (20 ml) and BR (20 ml). The dried extract was evaporated and the residue was purified on a column of silica (100 ml) [L] to give the title compound as a colourless oil (0.70 g). T.l.c. [L] Rf 0.25.
The following ketones were prepared in a similar manner: (Intermediates 57, 62 and 64 are described after Intermediate 65)
(1.15 g) from Intermediate 53 (3.0 g) and acetic anhydride (2 g). T.l.c. [L] Rf 0.25.
(1.3 g) from Intermediate 57 (3.5 g) and acetic anhydride (2.6 g). T.l.c. [L] Rf 0.25.
(1.3 g) from Intermediate 45 (3.0 g) and acetic anhydride (2.3 g). T.l.c. [L] Rf 0.35.
(4.35 g) from Intermediate 51 (7.0 g) and propionic anhydride (6.53 g). T.l.c. (CX-ER 7:1) Rf 0.22.
(2.25 g) from Intermediate 51 (5.0 g) and butyric anhydride (6.75 g). T.l.c. [B] Rf 0.2.
(1.88 g) from Intermediate 62 (6.0 g) and acetic anhydride (4.2 g), b.p. 172.degree./0.7 Torr.
(2.17 g) from Intermediate 64 (5.5 g) and acetic anhydride (3.66 g). T.l.c. [F] Rf 0.18.
A mixture of 3-phenylpropanol (2 g), tetrabutylammonium bisulphate (0.5 g) 1,4-dibromobutane (9.5 g) and 50% NaOH (11 ml) was stirred at RT for 22 h, diluted with H.sub.2 O (250 ml) and extracted with ER (250 ml). The organic phase was washed successively with H.sub.2 O (250 ml) and BR (250 ml), dried and evaporated under reduced pressure to give a colourless oil. Purification by [FCS] [120 g], eluting with CX followed by [K] afforded the title compound as a colourless oil (2.72 g).
T.l.c. (CX - EA 1:9) Rf 0.51.
4-Fluorobenzeneethanol (10.0 g), 1,5-dibromopentane (29 ml), tetra-n-butylammonium hydrogen sulphate (3.2 g, 9 mmol), and aqueous 12.5M NaOH (109 ml) were stirred vigorously at RT overnight. The mixture was diluted with H.sub.2 O (400 ml), extracted with ER (3.times.200 ml), and the combined organic extracts were evaporated. The residual oil was purified by [FCS] eluting with CX - ER (100:0.fwdarw.100:6), to give the title compound as a colourless oil (14.37 g). T.l.c. (ER-CX, 19:1) Rf 0.22.
4-Methoxybenzenepropanol (7.5 g) and 1,5-dibromopentane (30.5 g) were stirred rapidly at RT with tetra-n-butylammonium bisulphate (1.02 g) and 12.5M aqueous NaOH (36 ml) for 16 h. The mixture was diluted with H.sub.2 O (170 ml), extracted with ER (3.times.200 ml) and the combined organic extracts were washed consecutively with H.sub.2 O (170 ml) and BR (170 ml), dried and evaporated to give an oil (34.8 g). The oil was purified by [FCS] eluting with ER - CX (0:100.fwdarw.4:96) to give the title compound as a colourless oil (8.83 g). T.l.c. (CX-ER 79:1) Rf 0.1.
1,1-Dimethylpropargylamine (8.5 g) was added dropwise to a suspension of lithamide [from lithium (1.7 g)] in liquid ammonia (100 ml) at -33.degree.. The mixture was stirred for 90 min and a solution of [3-(2-bromoethoxy)propyl]benzene (21.5 g) in ER (30 ml) was added dropwise. The suspension was stirred for 4 h and ammonia was allowed to evaporate overnight. The residue was treated with H.sub.2 O (100 ml) and extracted with ER (3.times.100 ml). The dried extract was evaporated and the residue was distilled to give the title compound as a colourless oil (3.0 g) b.p. 160.degree.-165.degree./0.2 mmHg. T.l.c. (ER) Rf 0.3.
A solution of methyl 5-(bromoacetyl)-2-hydroxybenzoate (3.3 g) Intermediate 66 (2.9 g) and N,N-diisopropylethylamine (1.55 g) in EA (50 ml) was refluxed for 3 h, filtered and evaporated. The residue was dissolved in ER (50 ml), filtered, and added dropwise to a suspension of LiAlH.sub.4 (2 g) in ER (100 ml) at 0.degree. under nitrogen. The mixture was stirred at 0.degree. for 1 h at RT for 1 h and was treated cautiously with H.sub.2 O (10 ml). The mixture was acidified to pH 1 with hydrochloric acid (2M), and basified with solid KHCO.sub.3 to pH8. The ER layer was decanted off and the aqueous slurry was extracted with CHCl.sub.3 (3.times.500 ml). The dried extract was evaporated to leave an orange oil. The oil was purified on a column of silica (300 ml) eluted with EA - methanol - triethylamine (93:7:1) to give the title compound as a white solid (0.88 g) m.p. 108.degree.-109.degree.. T.l.c. [M] Rf 0.25.
n-Butyllithium in HX (1.6M; 172 ml) was added dropwise to diisopropylamine (27.5 g) in THF (40 ml) at -78.degree. under nitrogen. The mixture was warmed to 0.degree., stirred for 45 min, and isobutyric acid (12.0 g) was added dropwise. The resulting suspension was stirred at RT for 4 h and Intermediate 51 (25.0 g) was added dropwise. The mixture was stirred for 16 h at RT, treated slowly with hydrochloric acid (2M; 350 ml), and extracted with ER (2.times.250 ml). The dried extract was evaporated and the residue was purified on a column of silica (Merck 9385; 300 ml) [B] to give the title compound as a colourless oil (17.0 g). T.l.c. [L] Rf 0.35.
Ethyl chloroformate (3.26 g) in acetone (10 ml) was added to a solution of Intermediate 68 (8.0 g) and triethylamine (3.03 g) in acetone (100 ml) and H.sub.2 O (10 ml) at 0.degree.. The mixture was stirred for 40 min at 0.degree. and sodium azide (2.25 g) in H.sub.2 O (25 ml) was added dropwise. The resulting suspension was stirred at RT for 30 min, diluted with H.sub.2 O (200 ml), and extracted with toluene (2.times.200 ml). The dried (Na.sub.2 SO.sub.4) extract was evaporated to half-volume, heated at 70.degree.-80.degree. for 2 h, and toluene was removed under reduced pressure. The resulting isocyanate in benzyl alcohol (20 ml) was heated at 80.degree.-83.degree. for 60 h and benzyl alcohol was removed under reduced pressure (1 Torr). The residue was purified in a column of silica (Merck 9385; 300 ml) eluted with CX - ER (17:3) to give the title compound as a colourless oil (7.45 g). T.l.c. [L] Rf 0.25.
A solution of Intermediate 69 (6.8 g) in ethanol (100 ml) was hydrogenated over 10% palladium on charcoal (0.5 g) for 40 min filtered, and evaporated to give the title compound as a colourless oil (4.3 g).
Dimethylamine (33% in ethanol, 156 ml) was added to a stirred suspension of methyl 5-(bromoacetyl)-2-(phenylmethoxy)benzoate (105.8 g) in absolute ethanol (1 l) and THF (1 l). The resulting solution was stirred at RT for 2 h, treated with NaBH.sub.4 (25 g) and stirred at RT overnight. The solvent was removed in vacuo and H.sub.2 O (500 ml) was added to the residue. The mixture was extracted with EA (2.times.500 ml), the combined extracts were washed with H.sub.2 O and BR, dried (Na.sub.2 SO.sub.4) and concentrated in vacuo. The product was purified twice by [FCS] eluted with EA-methanol-triethylamine (80:20:1) to give the title compound as a fawn solid (59.8 g) m.p. 79.degree.-81.degree..
Intermediate 71 (50 g) in hot methanol (250 ml) was mixed with (-)-di-p-toluoyl tartaric acid, monohydrate (60 g) in hot methanol (250 ml). The resulting precipitate was collected by filtration and recrystallised three times from methanol (25 ml/gram) to give the title compound as white needles (16.4 g). m.p. 169.degree.-170.degree. [.alpha.].sub.D.sup.18.2.degree. -103.3.degree.(c 0.51 in CH.sub.3 OH).
Intermediate 72 (16.4 g) was partitioned between EA (175 ml) and 6N ammonium hydroxide (8.4 ml) in H.sub.2 O (175 ml). The organic layer was washed with 8% NaHCO.sub.3 (2.times.100 ml), BR, dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to give the title compound as a viscous oil (7.9 g) T.l.c. (EA-methanol-triethylamine 80:20:1) Rf=0.23.
Intermediate 73 (7.85 g) and methyl iodide (17.5 ml) in acetone (55 ml) was stirred at reflux under nitrogen for 3 h. The acetone was removed in vacuo and CHCl.sub.3 (100 ml) was added to the residue. The resulting precipitate was collected by filtration and dried in vacuo (12.2 g). Recrystallisation from methanol gave the title compound as an off-white solid (4.5 g) m.p. 85.degree.-120.degree. [.alpha.].sub.D.sup.20.2 -32.2.degree. (c 0.7 in DMSO).
A warm suspension of Intermediate 74 in dry acetonitrile (200 ml) was treated with tetramethylammonium fluoride-bi-methanol solvate (5.5 g) and stirred at reflux, with continuous removal of the distillate, for 2.5 h. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo to a semi-solid. Dry ER (100 ml) was added and the mixture was refiltered. The filtrate was concentrated to an oil which was purified by [FCS] eluting with CX-EA-triethylamine 80:20:1 to give the title compound as a colourless oil (1.98 g). [.alpha.].sub.D.sup.23.3.degree. +19.9.degree. (c 0.86 in benzene).
T.l.c. (CX-EA-triethylamine 80:20:1) Rf=0.14.
Intermediate 75 (1.9 g) and Intermediate 22, free base (2.17 g) in methanol (50 ml) were stirred at reflux, under nitrogen, for 6 h. The solvent was removed in vacuo and the residual oil was purified by [FCS] eluting with CX-EA-triethylamine 75:25:1 to give the title compound as a pale yellow oil (2.1 g). [.alpha.].sub.D.sup.20.6.degree. -62.4.degree. (c 0.74 in T.l.c.
(CX-EA-triethylamine 80:20:1) Rf=0.12.
Intermediate 76 (2.0 g) in dry THF (40 ml) was added to a stirred suspension of LiAlH.sub.4 (300 mg) in dry THF (40 ml) at RT, under nitrogen. The reaction mixture was placed in an oil-bath, preheated to 80.degree., and stirred at reflux for 5 min. The cooled mixture was treated cautiously with H.sub.2 O (40 ml) and ER (40 ml). The phases were separated and the aqueous phase was re-extracted with ER (50 ml). The combined organic phases were washed with H.sub.2 O and BR, dried (Na.sub.2 SO.sub.4) and concentrated in vacuo. [FCS] using CX-EA-triethylamine 66:33:1 as eluant gave the title compound as a clear, colourless oil (1.70 g). [.alpha.].sub.D.sup.21.degree. -64.6.degree. (c 0.6 in CHCl.sub.3) T.l.c. (CX-EA-triethylamine 66:33:1) Rf=0.15
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Continuations (2)
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Number |
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| Parent |
932359 |
Nov 1986 |
|
| Parent |
601444 |
Apr 1984 |
|
Patent Grant
4992474
