Benzoate derivative of alpha naphthol preparation
Answers
Answered by
1
Unit
3,078,286 a NAPHTHfiL DERWATTVES -Wiiliam H. Hunter, Sandwich, Ronald .l'. Boscott, Deni,
Peter H. Sherman, Ramsgate, and Charics R. Worthing, Chadwell Heath, Engiand, assignors to Chas. Pfizer 63: Co, inc, New York, NY. No Drawing. Filed Apr. 4, H61, Ser. No. 109,521 Claims priority, application Great Britain Apr. 7, 1960 6 Claims. (Cl. 26t -4-iil5) wherein R is selected from the group consisting of --CH COR -cmonrn, 0320113,
and -CH CH OH; R is selected from the group consisting of lower alkyl having up to 6 carbon atoms, -CH OH, CH CH OH, -CH OO'CCH phenyl and --(CH O(CH ),.CH wherein x is an integer from 1 to 5, y is a whole number from 0 to 4 and x plus 3/ equals an integer from 1 to 5; R is a lower alkyl radical, preferably a straight chain one, having up to six carbon atoms; and R is an acyl radical.
The R acyl radical can be quite varied. For instance, it can be the acyl radical of a hydrocarbon acid or a hydrocarbon acid substituted by chloro, di-(lowcr alkyl) amino, w-carboxy or w-carboalkoxy. Also, benzoic acid along with its lower alkoxy, suliouic and carboxy substituted analogs; heterocyclic carboxylic acids; arylsulionic acids; carbamic acid and the N-(lower alkyl) carbamic acids; and aralkyl acids such as benzilic acid may be used.
Some of these acids impart additional properties to the a-naphthol derivatives of the invention. The nicotinate, isonicotinate and the half esters of succinic and phtnalic acids are water soluble and consequently are of interest for injection purposes. The higher alkanoyl esters such as palmitoyl, oleyl and lauroyl are oil soluble; they are valuable for intramuscular preparation.
The compounds of the present invention may be made by several methods. I. For example, compounds in which R represents CH COR may be made by:
(a) The reaction of the appropriate halo ketone, for example, the chloro or bromo-derivative, with the appropriate 4-acyl-1-naphthol. Examples of halo ketones which may be used in such a reaction are:
The reaction is carried out in an organic solvent, for example, acetone in the presence of an acid acceptor, for example, an alkali metal hydroxide, carbonate or bicarbonate. In order to obtain the highest yield, it is desirable that sufiicient acid acceptor is present to neutralize all the halo-acid formed during the reaction.
(b) The oxidation of the corresponding secondary alcohol, the preparation of which is described below, or,
(c) By the hydration of the appropriate acetylene compound.
ii. The compounds in which R represents 'CH CH OH) R;
(i.e. the secondary alcohols) may be made, for example, by:
(a) The reaction of the appropriate epoxide, for example, propylene oxide, or butylene oxide, in the presence of a suitable basic catalyst (for example, alkali metal hydroxides, carbonates, bicarbonates, formates or acetates) with the appropriate 4-acyl-l-naphthol. So dium acetate has been found particularly suitable for use in this reaction.
(b) The reaction of the appropriate chlorhydrin with the appropriate 4-acyl-naphthol, preferably in the presence of an acid acceptor. Within the scope of the present invention the R group of the OCH CH(OH)R group may be:
The product may then be recovered, for example, by pouring into Water, whereby the compound is precipi tated. The product may be purified further, for example, by distillation, if required.
iii. The compounds of the present invention in which R is OHQGHRZ 0R may be prepared by several general methods.
(a) For example, the secondary alcohol may be reacted With an acid halide, for instance the chloride. The reaction is conveniently carried out at room temperature in a solvent such as pyridine which is Water soluble and an acid acceptor. The product may then be recovered by pouring the reaction mixture into Water in which the pyridine dissolves and from which the ester is precipitated and may be recovered by filtration or by extraction by a suitable solvent.
(b) Alternatively, the secondary alcohol may be reacted, under conditions similar to those in the preceding paragraph, wtih the appropriate acid anhydride, for example, according to the formulas:
3,078,286 a NAPHTHfiL DERWATTVES -Wiiliam H. Hunter, Sandwich, Ronald .l'. Boscott, Deni,
Peter H. Sherman, Ramsgate, and Charics R. Worthing, Chadwell Heath, Engiand, assignors to Chas. Pfizer 63: Co, inc, New York, NY. No Drawing. Filed Apr. 4, H61, Ser. No. 109,521 Claims priority, application Great Britain Apr. 7, 1960 6 Claims. (Cl. 26t -4-iil5) wherein R is selected from the group consisting of --CH COR -cmonrn, 0320113,
and -CH CH OH; R is selected from the group consisting of lower alkyl having up to 6 carbon atoms, -CH OH, CH CH OH, -CH OO'CCH phenyl and --(CH O(CH ),.CH wherein x is an integer from 1 to 5, y is a whole number from 0 to 4 and x plus 3/ equals an integer from 1 to 5; R is a lower alkyl radical, preferably a straight chain one, having up to six carbon atoms; and R is an acyl radical.
The R acyl radical can be quite varied. For instance, it can be the acyl radical of a hydrocarbon acid or a hydrocarbon acid substituted by chloro, di-(lowcr alkyl) amino, w-carboxy or w-carboalkoxy. Also, benzoic acid along with its lower alkoxy, suliouic and carboxy substituted analogs; heterocyclic carboxylic acids; arylsulionic acids; carbamic acid and the N-(lower alkyl) carbamic acids; and aralkyl acids such as benzilic acid may be used.
Some of these acids impart additional properties to the a-naphthol derivatives of the invention. The nicotinate, isonicotinate and the half esters of succinic and phtnalic acids are water soluble and consequently are of interest for injection purposes. The higher alkanoyl esters such as palmitoyl, oleyl and lauroyl are oil soluble; they are valuable for intramuscular preparation.
The compounds of the present invention may be made by several methods. I. For example, compounds in which R represents CH COR may be made by:
(a) The reaction of the appropriate halo ketone, for example, the chloro or bromo-derivative, with the appropriate 4-acyl-1-naphthol. Examples of halo ketones which may be used in such a reaction are:
The reaction is carried out in an organic solvent, for example, acetone in the presence of an acid acceptor, for example, an alkali metal hydroxide, carbonate or bicarbonate. In order to obtain the highest yield, it is desirable that sufiicient acid acceptor is present to neutralize all the halo-acid formed during the reaction.
(b) The oxidation of the corresponding secondary alcohol, the preparation of which is described below, or,
(c) By the hydration of the appropriate acetylene compound.
ii. The compounds in which R represents 'CH CH OH) R;
(i.e. the secondary alcohols) may be made, for example, by:
(a) The reaction of the appropriate epoxide, for example, propylene oxide, or butylene oxide, in the presence of a suitable basic catalyst (for example, alkali metal hydroxides, carbonates, bicarbonates, formates or acetates) with the appropriate 4-acyl-l-naphthol. So dium acetate has been found particularly suitable for use in this reaction.
(b) The reaction of the appropriate chlorhydrin with the appropriate 4-acyl-naphthol, preferably in the presence of an acid acceptor. Within the scope of the present invention the R group of the OCH CH(OH)R group may be:
The product may then be recovered, for example, by pouring into Water, whereby the compound is precipi tated. The product may be purified further, for example, by distillation, if required.
iii. The compounds of the present invention in which R is OHQGHRZ 0R may be prepared by several general methods.
(a) For example, the secondary alcohol may be reacted With an acid halide, for instance the chloride. The reaction is conveniently carried out at room temperature in a solvent such as pyridine which is Water soluble and an acid acceptor. The product may then be recovered by pouring the reaction mixture into Water in which the pyridine dissolves and from which the ester is precipitated and may be recovered by filtration or by extraction by a suitable solvent.
(b) Alternatively, the secondary alcohol may be reacted, under conditions similar to those in the preceding paragraph, wtih the appropriate acid anhydride, for example, according to the formulas:
Similar questions