There are described compounds of formula I, ##STR1## in which R.sub.3 represents hydrogen, or alkyl C 1 to 6, R.sub.5 represents hydrogen, hydroxy, alkoxy C 1 to 6, alkanoyloxy C 2 to 6, alkenyloxy C 2 to 6, nitro, -NR.sub.1 R.sub.2, halogen, alkyl C 1 to 6, hydroxy-alkyl C 1 to 6, or hydroxy-alkoxy C 1 to 6, PA1 An adjacent pair of X, Y and Z form a --(CH.sub.2).sub.4 --, --CH.dbd.CH--CH.dbd.CH--or --O(CH.sub.2).sub.3 --chain, each of the chains optionally being substituted by one or two C 1 to 6 alkyl groups, and the remaining substituent X or Z represents alkenyl C2 to 6 optionally substituted by phenyl; halogen; or alkyl C 1 to 9 optionally substituted by one or more of the groups hydroxy, halogen, carbonyl oxygen, phenyl, or alkoxy C 1 to 6, PA1 Or, when an adjacent pair of X, Y and Z form a chain substituted by one or two C 1 to 6 alkyl groups, the remaining substituent X or Z may be hydrogen, and PA1 R.sub.1 and R.sub.2, which may be the same or different, are each hydrogen or alkyl C 1 to 6, PA1 And pharmaceutically acceptable derivatives thereof. Processes for making the compounds and pharmaceutical, e.g. anti-allergic, compositions containing the compounds are also described.

This invention relates to new compounds, methods for their preparation and 
compositions containing them. 
A large number of monochromone-2-carboxylic acids, 
monochromone-2-(5-1H)-tetrazoles, and benzodipyran-2-carboxylic acids 
have, in the past, been suggested as of possible utility in the treatment 
of conditions involving antibody/antigen reactions, e.g. allergic asthma. 
(See for Example British Pat. Nos. 1,024,645; 1,032,362; 1,049,289; 
1,093,673; 1,223,690; 1,116,562; 1,147,976; 1,291,864; 1,389,227; 
1,321,879; 1,368,243; and 1,362,782 and French Pat. No. 1,481,033. In 
particular British Pat. specifications Nos. 1,029,213 and 1,230,087 are 
worthy of note. A number of these known compounds have been found to have 
activity in one or more of the various pharmacological tests used in this 
area of research, but have failed to be sufficiently well absorbed, or 
have been found to have other properties which are either unsatisfactory 
or inadequate, when administered oesophageally. A number of these 
monochromone compounds have also proved to have disadvantages when 
administered by inhalation, e.g. they are irritant or do not have adequate 
duration of action. In 1965 the bis-chromone compound di-sodium 
cromoglycate (British Pat. specification No. 1,144,905) was discovered and 
has subsequently been widely used for the inhalation therapy of allergic 
asthma. However inhalation therapy has, in certain instances, considerable 
disadvantages, e.g. in the use of complex devices for administration of 
the compound and the difficulty sometimes experienced by asthmatic 
subjects in inhaling powders. We have now found that a small and selected 
group of mono-chromone compounds are more readily absorbed when 
administered orally and/or possess other more advantageous properties, 
than structurally closely related known compounds. 
According to our invention we provide compounds of formula I, 
##STR2## 
in which R.sub.3 represents hydrogen, or alkyl C 1 to 6, 
R.sub.5 represents hydrogen, hydroxy, alkoxy C 1 to 6, alkanoyloxy C 2 to 
6, alkenyloxy C 2 to 6, nitro, --NR.sub.1 R.sub.2, halogen, alkyl C 1 to 
6, hydroxy-alkyl C 1 to 6, or hydroxy-alkoxy C 1 to 6, 
an adjacent pair of X, Y and Z form a --(CH.sub.2).sub.4 --, 
--CH.dbd.CH--CH.dbd.CH-- or --O(CH.sub.2).sub.3 -- chain, each of the 
chains optionally being substituted by one or two C 1 to 6 alkyl groups, 
and the remaining substituent X or Z represents alkenyl C 2 to 6 
optionally substituted by phenyl; halogen; or alkyl C 1 to 9 optionally 
substituted by one or more of the groups hydroxy, halogen, carbonyl 
oxygen, phenyl, or alkoxy C 1 to 6, 
or, when an adjacent pair of X, Y and Z form a chain substituted by one or 
two C 1 to 6 alkyl groups, the remaining substituent X or Z may be 
hydrogen, and 
R.sub.1 and R.sub.2, which may be the same or different, are each hydrogen 
or alkyl C 1 to 6, 
and pharmaceutically acceptable derivatives thereof. 
According to our invention we also provide a process for the production of 
a compound of formula I, or a pharmaceutically acceptable derivative 
thereof, which comprises, 
(a) cyclising a compound of formula II, 
##STR3## 
in which R.sub.5, X, Y and Z are as defined above, 
A.sup.1 and A.sup.2 represent the pairs of groups 
(i) --COCHR.sub.3 COCOR" and --OM or a halogen atom, or 
(ii) --H and --O--C(COR").dbd.CR.sub.3 --COR" 
R.sub.3 is as defined above, 
R" represents --OM, or a group which is hydrolysable thereto, and 
M represents hydrogen or an alkali metal, 
and if necessary or desired hydrolysing the group --COR", to a group 
--COOM, 
(b) selectively hydrolysing or oxidising a compound of formula III, 
##STR4## 
in which R.sub.3, R.sub.5, X, Y and Z are as defined above, and 
D is a group which is hydrolysable or oxidisable to a --COOH group, 
(c) selectively removing the groups A and B from a compound of formula IV, 
##STR5## 
or an ester thereof, 
in which R.sub.3, R.sub.5, X, Y and Z are as defined above, and 
A and B are both hydrogen or one of A and B is hydrogen and the other is 
halogen or hydroxy, 
(d) production of a compound of formula I in which R.sub.3, R.sub.5, X, Y 
and Z are as defined above, with the proviso that at least one of the 
substituents R.sub.3, R.sub.5, X, Y and Z is selected from the following 
significances: 
R.sub.3 =alkyl C 1 to 6; 
R.sub.5 =alkoxy C 1 to 6 or alkyl C 1 to 6; 
X or Z=alkyl C 1 to 9, or phenyl-alkyl in which the alkyl group contains 
from 1 to 6 carbon atoms; 
an adjacent pair of X, Y and Z form a chain substituted by one or two alkyl 
C 1 to 6 groups; 
by selective reduction of a corresponding compound of formula XX, 
##STR6## 
or an ester thereof, 
in which R.sub.3.sup.a, R.sub.5.sup.a, X.sup.a, Y.sup.a and Z.sup.a have 
the same significances as R.sub.3, R.sub.5, X, Y and Z above, save that at 
least one of R.sub.3.sup.a, R.sub.5.sup.a, X.sup.a, Y.sup.a and Z.sup.a is 
selected from the following significances: 
R.sub.3.sup.a =a group reducible to alkyl C 1 to 6; 
R.sub.5.sup.a =a group reducible to alkoxy C 1 to 6 or to alkyl C 1 to 6; 
X.sup.a or Z.sup.a =a group reducible to alkyl C 1 to 9, or a group 
reducible to phenyl-alkyl in which the alkyl group contains from 1 to 6 
carbon atoms; 
an adjacent pair of X.sup.a, Y.sup.a and Z.sup.a form a chain substituted 
by one or two groups reducible to an alkyl C 1 to 6 group, 
(e) production of a compound of formula I in which R.sub.5 is nitro, by 
nitration of a corresponding compound of formula I, or an ester thereof, 
in which R.sub.5 is hydrogen, 
(f) production of a compound of formula I in which R.sub.5 is amino by 
selective reduction of a corresponding compound of formula I, or an ester 
thereof, in which R.sub.5 is nitro, 
(g) production of a compound of formula I in which R.sub.5 is hydroxy, by 
hydrolysis of a corresponding compound of formula V, 
##STR7## 
or an ester thereof, 
in which R.sub.3, X, Y and Z are as defined above, and 
R.sub.5.sup.g is a group hydrolysable to an --OH group, 
(h) (i) production of a compound of formula I in which at least one of 
R.sub.5, X or Z is chlorine, bromine or iodine, by reaction of a 
corresponding compound of formula VI, 
##STR8## 
or an ester thereof, 
in which R.sub.3 is as defined above, and 
R.sub.5.sup.h, Xh, Yh and Zh have the same significances as R.sub.5, X, Y 
and Z above, save that at least one of R.sub.5.sup.h, Xh and Zh represent 
a diazonium cation, 
with cuprous chloride, cuprous bromide or an inorganic iodide respectively, 
(ii) production of a compound of formula I in which at least one of 
R.sub.5, X or Z is halogen, by treating a corresponding compound of 
formula I, or an ester thereof, in which R.sub.5, X or Z is another 
halogen, with an inorganic halide containing the desired halide ion, 
(iii) production of a compound of formula I in which at least one of 
R.sub.5, X or Z is fluorine, by thermal decomposition of a fluoroborate or 
hexafluorophosphate salt of a corresponding compound of formula VI, 
(i) production of a compound of formula I in which one or both of R.sub.1 
and R.sub.2 is alkyl C 1 to 6, by alkylation of a corresponding compound 
of formula I, or an ester thereof, in which R.sub.5 is --NR.sub.1 R.sub.2 
and none or one of R.sub.1 and R.sub.2 is alkyl C 1 to 6, 
(j) production of a compound of formula I in which an adjacent pair of X, Y 
and Z form a chain --CH.dbd.CH--CH.dbd.CH--, which chain is optionally 
substituted by one or two alkyl C 1 to 6 groups, by aromatisation of a 
corresponding compound of formula I, or an ester thereof, in which an 
adjacent pair of X, Y and Z form a chain --(CH.sub.2).sub.4 --, which 
chain is optionally substituted by one or two alkyl C 1 to 6 groups, 
(k) production of a compound of formula I in which at least one of X, Z or 
R.sub.5 is hydroxy-alkyl C 1 to 6, or in which R.sub.5 is hydroxy-alkoxy C 
1 to 6, by 
(i) selective reduction of a corresponding compound of formula VII, 
##STR9## 
or an ester thereof, 
in which R.sub.3 is as defined above, and 
R.sub.5.sup.k, Xk, Yk and Zk have the same significances as R.sub.5, X, Y 
and Z, save that at least one of R.sub.5.sup.k, Xk and Zk represent a 
group reducible to hydroxy-alkyl C 1 to 6, or R.sub.5.sup.k represents a 
group reducible to hydroxy-alkoxy C 1 to 6, 
(ii) selective hydrolysis of a compound of formula VIII, 
##STR10## 
or an ester thereof, 
in which R.sub.3 is as defined above, and 
R.sub.5.sup.l, Xl, Yl and Zl have the same significances as R.sub.5, X, Y 
and Z, save that at least one of R.sub.5.sup.l, Xl and Zl represent a 
group hydrolysable to hydroxy-alkyl C 1 to 6, or R.sub.5.sup.l represents 
a group hydrolysable to hydroxy-alkoxy C 1 to 6, 
(iii) production of a compound of formula I in which at least one of X, Z 
and R.sub.5 is hydroxy-alkyl C 2 to 6, or R.sub.5 is hydroxy-alkoxy C 2 to 
6, by hydration of a corresponding compound of formula IX, 
##STR11## 
or an ester thereof, 
in which R.sub.3 is as defined above, and R.sub.5.sup.m, Xm, Ym and Zm have 
the same significances as R.sub.5, X, Y and Z, save that at least one of 
R.sub.5.sup.m, Xm and Zm is alkenyl C 2 to 6, or R.sub.5.sup.m is 
alkenyloxy C 2 to 6, 
(l) production of a compound of formula I in which R.sub.5 is --OH and X 
and Y, or Y and Z respectively, together form a chain, by subjecting a 
corresponding compound of formula I, or an ester thereof, in which Y and 
Z, or X and Y respectively, together form a chain and R.sub.5 is --OH, to 
mildly basic, or to acidic conditions, 
(m) production of a compound of formula I in which R.sub.5 is alkoxy C 1 to 
6, alkenyloxy C 2 to 6 or alkanoyloxy C 2 to 6, or X or Z is alkoxy C 1 to 
6 -alkyl C 1 to 9, by alkylating, alkenylating or alkanoylating a 
corresponding compound of formula I, or an ester thereof, in which R.sub.5 
is --OH with a C 1 to 6 alkylating agent, a C 2 to 6 alkenylating agent or 
a C 2 to 6 alkanoylating agent, or by alkylating a corresponding compound 
in which X or Z is hydroxy-alkyl C 1 to 6 with a C 1 to 9 alkylating 
agent, 
(n) conversion of a compound of formula X, 
##STR12## 
or an ester thereof, 
in which R.sub.3, R.sub.5, X, Y and Z are as defined above, and 
R.sub.9 and R.sub.10 together form a .dbd.S or together form an 
--S(CH.sub.2).sub.n S-- chain, in which n is 2 or 3, 
to a corresponding compound of formula I, 
(o) production of a compound of formula I in which one of X and Z is 
alkenyl C 2 to 6 or phenyl alkenyl C 2 to 6, by condensation of a 
corresponding compound of formula XI, 
##STR13## 
or an ester thereof, 
in which R.sub.3 and R.sub.5 are as defined above, and 
Xb, Yb and Zb have the same significances as X, Y and Z above, save that 
one of Xb and Zb is an oxo-substituted alkyl C 1 to 5 group, 
with a compound of formula XII, 
EQU q.dbd.chr xii 
in which R is hydrogen, alkyl C 1 to 4 or phenyl-alkyl in which the alkyl 
contains from 1 to 4 carbon atoms, and 
Q is a trisubstituted phosphorous atom, 
(p) production of a compound of formula I in which X or Z is haloalkyl by 
reaction of a corresponding compound of formula I, or an ester thereof, in 
which X or Z is hydroxy-alkyl C 1 to 6, with a thionyl halide, or 
(q) production of a compound of formula I in which X or Z represents alkyl 
C 1 to 9 substituted by alkoxy C 1 to 6 by reacting a corresponding 
compound of formula I, or an ester thereof, in which X or Z represents 
alkyl C 1 to 9 substituted by a different alkoxy group or by hydroxy, with 
an appropriate C 1 to 6 alkanol, 
and if necessary or desired hydrolysing the ester of the compound of 
formula I to a compound of formula I and/or converting the compound of 
formula I to a pharmaceutically acceptable derivative thereof. 
When A.sub.2 is a group --OM the cyclisation of process (a)(i) may be 
carried out by heating, or under basic or neutral conditions. It is 
however preferred to carry out the cyclisation in the presence of an acid, 
e.g. hydrochloric acid, and in a solvent which is inert under the reaction 
conditions, e.g. ethanol. The reaction may be carried out at from about 
20.degree. to 150.degree. C. The group --COR" is preferably an ester 
group, e.g. R" may be a lower alkoxy group. When A.sub.2 is halogen the 
cyclisation may be carried out in a solvent which is inert under the 
reaction conditions, preferably a high boiling polar solvent, e.g. 
pyridine, dimethylformamide or hexamethylphosphoramide. The reaction is 
preferably carried out with the aid of a strong base for example an alkali 
metal, e.g. sodium, hydride. The reaction is preferably carried out at a 
temperature of from about 80.degree. to 200.degree. C., in the absence of 
free oxygen, e.g. under an inert atmosphere such as nitrogen. 
The cyclisation of process (a)(ii) may be carried out by treating the 
compound of formula II with a cyclising agent, for example a dehydrating 
agent such as chlorosulphonic, polyphosphoric or sulphuric acid. The 
reaction is preferably carried out under anhydrous conditions and may be 
carried out at a temperature of from 0.degree. to 100.degree. C. 
Alternatively cyclisation may be achieved by converting the free carboxy 
groups of the compound of formula II to acyl halide groups and subjecting 
the resulting acyl halide to an intramolecular Friedel-Crafts reaction. 
In process (b) the group D may be, for example an ester, acid halide, amide 
or a nitrile group, which may be hydrolysed to a --COOH group. The 
hydrolysis may be carried out using conventional techniques, for example 
under mildly basic conditions, e.g. using sodium carbonate, sodium 
hydroxide, sodium bicarbonate, or under acidic conditions, e.g. a mixture 
of aqueous dioxan and hydrochloric acid, or hydrogen bromide in acetic 
acid. The hydrolysis may be carried out at a temperature of from about 
25.degree. to 120.degree. C. depending on the compounds used. 
Alternatively the group D may be an alkyl, e.g. a lower alkyl such as 
methyl, a hydroxymethyl, an aralkenyl, e.g. styryl, an acyl, e.g. a lower 
alkanoyl such as acetyl, or a formyl group. The oxidation may be carried 
out using conventional techniques which do not otherwise modify the 
molecule to such an extent that the yield of the desired product is 
uneconomical, for example an alkyl or a hydroxymethyl group may be 
oxidised using selenium dioxide, e.g. under reflux in aqueous dioxan; or 
chromic acid, e.g. under reflux in aqueous acetic acid. Aralkenyl groups 
may be oxidised using, for example neutral or alkaline potassium 
permanganate in aqueous ethanol, and acyl groups may be oxidised using, 
for example chromic acid or an aqueous hypochlorite, e.g. sodium 
hypochlorite. The formyl group may be oxidised using, for example chromic 
acid or silver oxide. 
When both A and B are hydrogen process (c) is a dehydrogenation and may be 
carried out by oxidation using a mild oxidising agent, for example 
selenium dioxide, palladium black, chloranil, lead tetraacetate or 
triphenyl methyl perchlorate. Alternatively the dehydrogenation of a 
compound of formula IV in which both A and B are hydrogen may be carried 
out indirectly by halogenation followed by dehydrohalogenation, e.g. by 
treatment with N-bromosuccinimide or pyridinium bromide perbromide to 
yield a compound of formula IV in which A is halogen and B is hydrogen, 
which is subsequently dehydrobrominated. When one of A and B is hydroxy 
the dehydration may be catalysed by an acid, e.g. sulphuric or oxalic 
acid; a base, e.g. potassium hydroxide; or a salt, e.g. potassium hydrogen 
sulphate; or N-bromosuccinimide. The reaction may be carried out in a 
solvent which is inert under the reaction conditions, e.g. a halogenated 
hydrocarbon, xylene, or glacial acetic acid. The reaction may be carried 
out at an elevated temperature, e.g. from 20.degree. to 150.degree. C. 
In process (d) the reduction may be hydrogenation, e.g. catalytic 
hydrogenation, for example using a palladium on charcoal or a Raney nickel 
catalyst in a suitable solvent, e.g. ethanol when, as we prefer, the group 
to be reduced is an alkenyl, a phenylalkenyl, an alkenyloxy or an 
oxo-substituted alkyl group. The reaction may conveniently be carried out 
at from about 20.degree. to 80.degree. C., preferably at greater than 
atmospheric pressure. Alternatively when the group to be reduced is an 
oxo-substituted alkyl group, e.g. a propionyl group, the reduction may be 
carried out using a metal hydride, e.g. sodium borohydride, in a suitable 
solvent, e.g. water, at a temperature of from about 20.degree. to 
100.degree. C. Thus in the starting material for process (d) we prefer at 
least one of R.sub.3.sup.a, R.sub.5.sup.a, X.sup.a, Y.sup.a and Z.sup.a to 
be selected from the following significances: 
R.sub.3.sup.a =alkenyl C 2 to 6 or oxo-substituted alkyl C 1 to 6; 
R.sub.5.sup.a =alkenyloxy C 2 to 6, oxo-substituted alkoxy C 1 to 6, 
alkenyl C 2 to 6 or oxo-substituted alkyl C 1 to 6; 
X.sup.a or Z.sup.a =alkenyl C 2 to 6, oxo-substituted alkyl C 1 to 6 or 
phenyl-alkenyl in which the alkenyl group contains from 2 to 6 carbon 
atoms; 
an adjacent pair of X.sup.a, Y.sup.a and Z.sup.a form a chain substituted 
by one or two alkenyl C 2 to 6 groups or substituted by one or two 
oxo-substituted C 1 to 6 alkyl groups. 
The nitration of process (e) may be carried out using concentrated or 
fuming nitric acid optionally in combination with concentrated sulphuric 
acid. The reaction may be carried out in an excess of the nitrating agent 
or in a solvent which is inert under the reaction conditions, e.g. acetic 
acid or sulpholane. The reaction may be carried out at a temperature of 
from about 0.degree. to 130.degree. C. Especial care should be taken when 
this process is applied to a starting material containing an aldehyde, 
alkenyl or phenyl-alkenyl group. 
The reduction of process (f) may be carried out by catalytic hydrogenation, 
e.g. using a palladium on charcoal (5% Pd) catalyst. The hydrogenation may 
if desired be carried out at a temperature of from about 10.degree. to 
50.degree. C. and at an elevated pressure, e.g. of up to about 50 
atmospheres. The hydrogenation may be carried out in a solvent which is 
inert under the reaction conditions, e.g. ethanol, acetic acid or a 
mixture thereof. The reduction may also be carried out by means of a 
chemical reducing agent, e.g. stannous chloride in acetic and hydrochloric 
acid, at a temperature of from about 20.degree. to 100.degree. C. 
In process (g) R.sub.5.sup.g may be an ether group -ORx in which Rx may be 
a straight or branched alkyl group, preferably containing from 1 to 10 
carbon atoms, e.g. a methyl or a t-butyl group. Alternatively the group Rx 
may be a benzyl group, in which the phenyl is optionally substituted, e.g. 
by a nitro group. Alternatively the group -ORx may be part of a mixed 
acetal, for example -ORx may be a tetrahydropyranyl ether. The -ORx ether 
groups may be removed by treatment of the compound of formula V with acid 
in a solvent which is inert under the reaction conditions. Thus when Rx is 
a methyl or straight-chain alkyl group, the ether may be treated with an 
acid, for example hydrogen bromide, in for example water, glacial acetic 
acid or trifluoracetic acid, at a temperature of from 0.degree. C. to the 
boiling point of the solvent employed. When Rx is a branched chain alkyl 
group, for example t-butyl, the ether may be treated with an acid, for 
example hydrogen chloride, in for example methanol, usually at about 
ambient temperature. When Rx is a phenylalkyl or substituted phenylalkyl 
group, the ether may be treated with an acid, for example hydrogen 
bromide, in for example water, glacial acetic acid or trifuoracetic acid, 
at a temperature of from 0.degree. C. to the boiling point of the solvent. 
Alternatively, the ether may be hydrogenolysed, for example in the 
presence of a palladium/carbon catalyst in for example ethanol or glacial 
acetic acid, at a temperature of from about 0.degree. to 60.degree. C. 
When Rx is a part of a mixed acetal, the ether may be hydrolysed with an 
acid, for example 20% aqueous sulphuric acid, usually at about ambient 
temperature. 
The group -ORx may also represent an ester group, for example of formula 
-OCORy, in which Ry may be hydrogen, an alkyl group preferably containing 
from 1 to 10 carbon atoms (e.g. methyl) and optionally substituted by 
halogen (e.g. trifluoromethyl); or a phenyl group. The removal of the 
ester group may be carried out under acidic, or preferably under basic 
conditions, using for example, sodium carbonate or sodium hydroxide, in 
for example water or ethanol, at temperatures ranging from 0.degree. C. to 
the boiling point of the solvent employed. 
R.sub.5.sup.g may also be a diazo group, or a sulphonate group, for example 
a methane sulphonate or a p-toluene sulphonate group. The hydrolysis of 
the groups R.sub.5.sup.g, which are not groups -ORx, may be carried out 
under mildly basic conditions, for example using sodium hydroxide in a 
solvent which is inert under the reaction conditions, e.g. water or 
ethanol. Alternatively, when the group R.sub.5.sup.g is a diazo group, the 
hydrolysis may be carried out using an aqueous acidic medium, e.g. aqueous 
sulphuric acid. The reaction may be carried out at a temperature of from 
about 0.degree. C. to the boiling point of the solvent employed. 
The reactions of process (h) are particularly relevant to the production of 
compounds of formula I in which only R.sub.5 is halogen. 
The reaction of process (h)(i) may be carried out in the presence of the 
corresponding halogen acid, in a solvent, e.g. water, at a temperature of 
between about 0.degree. and 10.degree. C. We prefer the iodide to be an 
alkali metal, e.g. potassium, iodide. When an iodide is used no halogen 
acid need be present. 
Process (h)(ii) is particularly appropriate for the production of compounds 
of formula I in which R.sub.5 is fluorine. The inorganic halide may be an 
alkali metal, e.g. a sodium or potassium, halide such as potassium 
fluoride. The reaction may be carried out in a solvent which is inert 
under the reaction conditions, e.g. acetone, ethanol or dimethylformamide. 
Alternatively the inorganic halide may be an appropriate cuprous halide 
and the solvent may be, for example dimethylsulphoxide or 
.alpha.-picoline. The reaction may be carried out at a temperature of from 
about 20.degree. C. to the boiling point of the solvent employed. 
In process (h)(iii) the thermal decomposition may be carried out by 
subjecting the starting material, preferably in the absence of a solvent, 
to a temperature of from about 60.degree. to 200.degree. C. 
Process (i) may be carried out using an appropriate alkyl halide, e.g. an 
alkyl iodide such as methyl iodide; an alkyl sulphate, e.g. dimethyl 
sulphate; a trialkoxonium borofluoride, e.g. triethyloxonium borofluoride; 
or an alkoxy sulphonyl fluoride, e.g. methoxysulphonylfluoride. The use of 
a trialkoxoxonium borofluoride can only lead to mono-alkylamino products. 
The reaction may be carried out in a solvent which is inert under the 
reaction conditions, e.g. acetone or methylene chloride. The reaction may 
be carried out at a temperature of from about -20.degree. C. to the 
boiling point of the solvent employed, e.g. about 35.degree. C. When the 
alkyl group desired is a methyl group the reaction may be carried out 
using formaldehyde and formic acid under reflux. 
The selective dehydrogenation of process (j) may be effected by means of a 
suitable dehydrogenating agent, e.g. sulphur, selenium, or a metal 
catalyst, e.g. platinum or palladium. The metal catalyst may conveniently 
be used in the form of the finely divided metal adsorbed onto carbon, e.g. 
10% Pd/C. The reaction may be carried out either in the absence of a 
solvent or in a high boiling solvent, which is inert under the reaction 
conditions, e.g. naphthalene or quinoline. The reaction may be carried out 
at an elevated temperature, e.g. of from about 230.degree. to 350.degree. 
C. The reaction is preferably carried out using an ester starting 
material. 
In process (k)(i) we prefer one of R.sub.5.sup.k, Xk and Zk to represent 
epoxide substituted C 2 to 6 alkyl or an oxo-substituted C 1 to 6 alkyl 
group or R.sub.5.sup.k to represent epoxide substituted C 2 to 6 alkoxy or 
oxo-substituted C 1 to 6 alkoxy. The reduction may be carried out using a 
metal hydride, for example a borohydride such as sodium borohydride. The 
reaction may be carried out in a suitable solvent, for example water, 
bis(2-methoxyethyl)ether or a mixture thereof, and may conveniently be 
carried out at a temperature of from about 0.degree. to 40.degree. C. 
Alternatively the reduction may be carried out using hydrogen and a 
catalyst, e.g. palladium on carbon. The catalytic reduction my be carried 
out in a suitable solvent, e.g. ethanol, at a temperature of from about 
20.degree. to 100.degree. C. 
In process (k)(ii) we prefer at least one of R.sub.5.sup.l, Xl and Zl to 
represent a halo-alkyl C 1 to 6 group or, when a di-hydroxyalkyl group is 
required, an epoxy-alkyl C 2 to 6 group; or R.sub.5.sup.l to represent 
halo-alkoxy C 1 to 6. When a halo-hydroxy alkyl group is desired the 
hydrolysis of the epoxy-alkyl group may be carried out in the presence of 
an appropriate halogen acid, e.g. HCl. The hydrolysis may, for example, be 
carried out under mildly basic conditions, e.g. using sodium hydroxide, in 
a suitable solvent, e.g. ethanol or aqueous dioxan. The reaction may be 
carried out in the presence of a silver salt, e.g. silver acetate, and may 
be carried out at a temperature of from about 20.degree. to 100.degree. C. 
In process (k)(iii) the hydration may, for example, be carried out under 
acidic conditions, e.g. aqueous sulphuric acid; or using a combination of 
a borane and a peroxide, e.g. hexyl borane and hydrogen peroxide; or using 
a mercury compound in combination with a reducing agent, e.g. mercuric 
acetate and sodium borohydride. The reaction may be carried out in the 
absence of a solvent, or in a suitable solvent e.g. water. The reaction 
may be carried out at a temperature of from about 20.degree. to 
100.degree. C. 
Process (1) is a Wesseley-Moser rearrangement and is preferably carried out 
in an aqueous organic solvent, e.g. aqueous ethanol, and under acidic 
(e.g. HI) or weakly basic (e.g. NaHCO.sub.3 or Na.sub.2 CO.sub.3) 
conditions. The reaction is preferably carried out at a temperature of 
from about 20.degree. to 100.degree. C. The reaction passes through an 
intermediate of formula II(i). 
In process (m) the alkylating or alkenylating, agent may be a compound R-L 
in which R is alkyl C 1 to 6, or alkenyl C 2 to 6 and the alkanoylating 
agent may be a compound RyCOL in which Ry is alkyl C 1 to 5, L being a 
good leaving group, e.g. an anion forming group. Suitable anion forming 
groups include, for example, a halide, e.g. a bromide or iodide, or a 
sulphate, or, when an alkanoylating compound RyCOL is used, a sulphonate 
group. When an alkanoylating agent RyCOL is used L may also represent an 
alkyl ether group, e.g. a pivaloyl group. The reaction may be carried out 
in a suitable solvent, e.g. a lower alkanol such as ethanol; a ketone such 
as acetone or isobutylmethyl ketone; dimethylformamide or aqueous dioxan. 
The reaction may also be carried out in the presence of an acid binding 
agent, e.g. potassium carbonate, and optionally also in the presence of a 
catalyst, e.g. potassium iodide; suitably the reaction is carried out at a 
temperature of 25.degree. to 150.degree. C. Alternatively process (m) may 
be carried out using the starting compound of formula I (or preferably an 
ester thereof), in the form of a salt, e.g. a thallium or sodium salt of 
the hydroxy group. When a thallium salt is used the reaction may be 
carried out at an elevated temperature without a solvent or in a solvent 
which is inert under the reaction conditions, e.g. ethanol or 
dimethylformamide, and the product may be recovered from the reaction 
mixture by solvent extraction. 
In processes (n), when R.sub.9 and R.sub.10 together form a chain 
--S--(CH.sub.2).sub.n --S--, the conversion may comprise oxidative 
hydrolysis and may be carried out in an aqueous polar organic solvent, for 
example aqueous ethanol, acetone or tetrahydrofuran. The oxidative 
hydrolysis may be carried out in the presence of an oxidising agent, for 
example mercuric chloride, an N-halosuccinimide such as N-bromo- or 
N-chloro-succinimide, a per-acid such as periodic acid; or 
p-toluenesulphonchloramide or a salt thereof. When mercuric chloride is 
used the reaction may be carried out in the presence of a base, e.g. 
mercuric oxide, cadmium carbonate or calcium carbonate. N-halosuccinimides 
may be used alone or in the presence of a silver salt, e.g. silver 
perchlorate, or silver nitrate. The reaction may conveniently be carried 
out at a temperature of from about 15.degree. to 100.degree. C. 
When R.sub.9 and R.sub.10 together form a .dbd.S group the conversion may 
comprise (oxidative) hydrolysis and may be carried out in the presence of 
a heavy metal compound, e.g. a compound of group Ib, IIb or IIIb of the 
Periodic Table of Mendeleef, as catalyst. Suitable compounds include 
mercury, thallium and silver compounds, e.g. mercury (II) acetate or 
chloride, thallium (III) trifluoroacetate, or silver oxide. The reaction 
may be carried out in the presence of water and an organic solvent system 
such as acetone-acetic acid, alkanols, tetrahydrofuran/methanol, or 
tetrahydrofuran. Alternatively the reaction may be carried out by 
alkylation followed by hydrolysis. In such cases the reaction may be 
effected by (i) an alkyl halide or sulphonate (e.g. methyl iodide), in a 
moist solvent, e.g. acetone, (ii) an alkylfluorosulphonate and water in 
sulphur dioxide, or (iii) a trialkyl oxonium fluoroborate followed by 
aqueous sodium hydroxide. 
Process (o) is a Wittig synthesis and may be carried out in a solvent which 
is inert under the reaction conditions, e.g. dimethylsulphoxide, xylene, 
diethyl ether, tetrahydrofuran or a lower alkanol such as ethanol. The 
reaction may be carried out at a temperature of from about 20.degree. C. 
to the boiling point of the solvent employed. The reaction may be 
catalysed by a base, e.g. sodium hydride or lithium ethoxide. We prefer 
the group Q to be (C.sub.6 H.sub.5).sub.3 P or (C.sub.2 H.sub.5 O).sub.2 
OP. 
In process (p) the reaction may be carried out in a solvent which is inert 
under the reaction conditions, e.g. a halogenated hydrocarbon solvent such 
as chloroform, or dichloromethane. The thionyl halide may be, for example, 
thionyl chloride. The reaction may be carried out at a temperature of from 
about 20.degree. to 90.degree. C. 
The alkoxide exchange of process (q) may be effected under, for example, 
acidic conditions, e.g. in the presence of hydrochloric acid, or may be 
effected under basic conditions, e.g. in the presence of the alkoxide ion 
corresponding to the desired alkoxy group. The reaction is preferably 
conducted in an excess of the alkanol corresponding to the desired alkoxy 
group, at a temperature of from about 20.degree. C. to the boiling point 
of the reaction mixture, e.g. about 160.degree. C. 
In processes (c) to (q) inclusive the ester may be, for example, a C 1 to 
10 alkyl ester. 
The compounds of formula II, in which A.sup.1 and A.sup.2 represent the 
groups --COCHR.sub.3 COCOR" nnd --OM or halogen, may be made by reacting a 
compound of formula XV, 
##STR14## 
in which R.sub.3, R.sub.5, X, Y, Z, and M are as defined above, with a 
compound of formula XVI, 
EQU R'CZ--CZR" XVI 
in which R" is as defined above, 
R' is a suitable leaving group, e.g. an alkoxy, halo, amino, alkylamino, 
substituted amino (e.g. an arylsulphonylamino group) or substituted 
alkylamino group, reactive with the carbanion of the --COCH.sub.2 R.sub.3 
group of the compound of formula XV, and 
each Z is a carbonyl oxygen atom, or one Z may represent two halogen atoms 
and the other a carbonyl oxygen atom, 
and if necessary hydrolysing the resulting compound to a compound of 
formula II. The preferred compounds of formula XVI are dialkyl oxalates, 
e.g. diethyl oxalate. 
The compounds of formula III may be made in a manner analogous to process 
(a)(i) using a starting material of formula XVII, 
##STR15## 
in which R.sub.3, R.sub.5, X, Y, Z, M and D are as defined above. 
The compounds of formula XVII may be made from known compounds in a manner 
analogous to that described above for the preparation of the corresponding 
compounds of formula II, using a compound of formula R'COD in which R' and 
D are as defined above, in place of the compound of formula XVI. 
Alternatively the compounds of formula III may, for example in the case of 
the acid halide, the amide and the nitrile, be made from compounds of 
formula I using conventional techniques, e.g. reaction of an ester of the 
compound of formula I with ammonia to produce the amide, followed by 
dehydration of the amide to form the nitrile. 
The compounds of formula IV in which both A and B are hydrogen may be made 
by cyclising a compound of formula XVIII, 
##STR16## 
in which R.sub.3, R.sub.5, X, Y, Z and M are as defined above, 
by treating the compound of formula XVIII with a base in a solvent which is 
inert under the reaction conditions. 
The compounds of formula XVIII may be made by reacting a compound of 
formula XV carrying a group --OM, with glyoxalic acid or an ester thereof. 
Alternatively the compounds of formula XVIII in which R.sub.3 is hydrogen 
may be made by reacting a compound of formula XIX, 
##STR17## 
in which R.sub.5, X, Y and Z are as defined above, 
with maleic anhydride in a solvent in the presence of a Lewis acid, e.g. 
AlCl.sub.3, and decomposition of the resulting complex with dilute acid. 
The compounds of formula IV in which both A and B are hydrogen may also be 
made by selective hydrogenation of a corresponding compound of formula I. 
The compounds of formula IV in which one of A and B is halogen may be made 
by halogenation of a corresponding compound of formula IV in which both A 
and B are hydrogen. The compounds of formula IV in which one of A and B is 
--OH may be made by treating a compound of formula II(i) in which A.sup.2 
is --OM with one equivalent of an inorganic acid, e.g. hydrochloric acid, 
in an inert solvent, e.g. ethanol, at a temperature of from about 
20.degree. to 80.degree. C. 
The compounds of formula VI may be made by conventional techniques from a 
corresponding compound of formula XXI, 
##STR18## 
or an ester thereof, 
in which R.sub.3 is as defined above, and 
R.sub.5.sup.a, Xa, Ya and Za have the same significances as R.sub.5, X, Y 
and Z above, save that at least one of R.sub.5.sup.a, Xa and Za represent 
an --NH.sub.2 group. 
The compounds of formula II in which A.sup.1 and A.sup.2 represents --H and 
--O--C(COR").dbd.CH--COR" may be made by reacting a compound of formula 
XIX, with a dialkyl acetylene dicarboxylate, in conventional manner, 
followed if necessary by hydrolysis of the reaction product. Compounds of 
formula II in which A.sup.1 and A.sup.2 represent --H and 
--O--C(COR").dbd.CR.sub.3 --COR" and may be made by reaction of a compound 
of formula XIX with an appropriate halo fumarate of formula 
R"OC(R.sub.3)C.dbd.C(halogen)COR" in which R.sub.3 and R" are as defined 
above. The halo fumarates may be made by dehydrogenation of the 
corresponding dihalosuccinic acid derivative. 
The compounds of formulae XX, V, VII, VIII, IX (some of which are compounds 
of formula I) and XI may be made by processes analogous to process (a) 
using starting materials which are known or which may be made from known 
compounds using conventional techniques. Alternatively some of these 
compounds may be made by other conventional techniques from known 
compounds or from compounds described in this specification, e.g. the 
compounds of formula VII having an epoxide substituent may be made by 
reacting the corresponding compound having an alkenyl substituent with a 
per acid. Compounds of formula X may be made by reacting a compound of 
formula I with a compound of formula HS(CH.sub.2).sub.n SH in which n is 
as defined above, or with phosphorus pentasulphide. 
The compounds of formulae X, XII, XV, XVI and XIX are either known or may 
be made from known compounds using conventional techniques. 
The compounds of formula I and the intermediates therefore may be isolated 
from their reaction mixtures using conventional techniques. 
Pharmaceutically acceptable derivatives of the compounds of formula I 
include pharmaceutically acceptable salts, esters and amides of the 
2-carboxylic acid group. Suitable salts include ammonium, alkali metal 
(e.g. sodium, potassium and lithium) and alkaline earth metal salts (e.g. 
calcium or magnesium), and salts with suitable organic bases, e.g. salts 
with hydroxylamine, lower alkylamines such as methylamine or ethylamine, 
with substituted lower alkylamines, e.g. hydroxy substituted alkylamines 
such as tris(hydroxymethyl)methylamine, or with simple monocyclic nitrogen 
heterocyclic compounds, e.g. piperidine or morpholine. Suitable esters 
include simple lower alkyl esters, e.g. the ethyl ester, esters derived 
from alcohols containing basic groups, e.g. di-lower alkyl amino 
substituted alkanols such as the .beta.-(diethylamino)-ethyl ester, and 
acyloxy alkyl esters, e.g. a lower acyloxy-lower alkyl ester such as the 
pivaloyloxymethyl ester, or a bis-ester derived from a di-hydroxy 
compound, e.g. a di(hydroxy-lower alkyl) ether, e.g. the 
bis-2-oxapropan-1,3-diyl ester. The pharmaceutically acceptable acid 
addition salts of the basic esters, and also of those compounds in which 
R.sub.5 is a group --NR.sub.1 R.sub.2, e.g. the hydrochloride, the 
hydrobromide, the oxalate, the maleate or the fumarate may also be used. 
The esters may be made by conventional techniques, e.g. esterification, 
transesterification or reaction of the acid, or a salt thereof, with an 
appropriate compound containing a good leaving group. The amides may be, 
for example, unsubstituted or mono- or di- C 1 to 6 alkyl amides and may 
be made by conventional techniques, e.g. reaction of an ester of the 
corresponding acid with ammonia or an appropriate amine. 
The compounds of formula I and pharmaceutically acceptable derivatives 
thereof are useful because they possess pharmacological activity in 
animals; in particular they are useful because they inhibit the release 
and/or action of pharmacological mediators which result from the in vivo 
combination of certain types of antibody and specific antigen e.g. the 
combination of reaginic antibody with specific antigen (see Example 27 of 
British Patent specification No. 1,292,601). In man, both subjective and 
objective changes which result from the inhalation of specific antigen by 
sensitised subjects are inhibited by prior administration of the new 
compounds. Thus the new compounds are useful in the treatment of asthma, 
e.g. allergic asthma. The new compounds are also useful in the treatment 
of so-called `intrinsic` asthma (in which no sensitivity to extrinsic 
antigen can be demonstrated). The new compounds are also useful in the 
treatment of other conditions in which antigen-antibody reactions are 
responsible for disease, for example, hay fever; certain eye conditions, 
e.g. trachoma; alimentary allergy, e.g. urticaria and atopic eczema; and 
gastointestinal allergy, especially in children, e.g. milk allergy. 
For the above mentioned uses the dosage administered will, of course, vary 
with the compound employed, the mode of administration and the treatment 
desired. However, in general, satisfactory results are obtained when the 
compounds are administered at a dosage of from 0.1 to 50 mg per kg of 
animal body weight in the test set out in Example 27 of British Patent 
specification No. 1,292,601. For man the indicated total daily dosage is 
in the range of from 1 mg to 3,500 mg preferably from 1 mg to 3,000 mg and 
more preferably from 1 mg to 600 mg, which may be administered in divided 
doses from 1 to 6 times a day or in sustained release form. Thus unit 
dosage forms suitable for administration (by inhalation or oesophageally) 
comprise from 0.17 mg to 600 mg, preferably 0.17 mg to 500 mg and more 
preferably from 0.17 mg to 100 mg of the compound preferably admixed with 
a solid or liquid pharmaceutically acceptable diluent, carrier or 
adjuvant. 
The compounds of formula I, and pharmaceutically acceptable derivatives 
thereof have the advantage that they are more efficacious in certain 
pharmacological models, or are more readily absorbed (as evidenced by 
plasma level, or by the ratio of the activity of the compounds when 
administered intestinally and intravenously in the test set out in Example 
27 of British Patent specification No. 1,292,601), or are longer acting as 
measured by plasma half-life or are more active when administered 
oesophageally than compounds of similar structure to the compounds of 
formula I. 
Preferred values of the substituents in formula I are: 
R.sub.3 =hydrogen; or straight or branched alkyl C 1 to 4, e.g. methyl or 
propyl; 
R.sub.5 =hydrogen; hydroxy; alkoxy C 1 to 3, e.g. methoxy or propoxy; 
acetoxy; allyloxy; nitro; amino; mono- or di-alkyl C 1 to 4 amino, e.g. 
dimethylamino or mono-ethylamino; chlorine or fluorine; straight or 
branched alkyl C 1 to 4, e.g. methyl; hydroxy-alkyl C 1 to 4, e.g. 
hydroxy-methyl; or hydroxy-alkoxy C 1 to 4, e.g. 2-hydroxy-propoxy, 
an adjacent pair of X, Y and Z (and more preferably X and Y) form a chain 
--(CH.sub.2).sub.4 --, --CH.dbd.CH--CH.dbd.CH--, --OCH.sub.2 CH.sub.2 
CH.sub.2 --, or such a chain substituted by one or two methyl or ethyl 
groups, and the remaining substituent X or Z represents hydrogen; 
straight, branched or cycloalkyl C 1 to 8, e.g. ethyl, n-propyl, n-hexyl, 
cyclohexylmethyl, cyclopentylethyl or cyclopentylmethyl; allyl or 
hex-1-enyl; halogen, e.g. bromine or chlorine; mono- or di-hydroxyalkyl C 
1 to 4, e.g. 2-hydroxy-propyl; chloro-alkyl C 1 to 4, e.g. chloropropyl; 
chloro-hydroxyalkyl C 1 to 4, e.g. chloro-hydroxypropyl; oxo-substituted 
alkyl C 1 to 4, e.g. formyl, propionyl or 3-oxo-butyl; phenyl-alkyl in 
which the alkyl contains from 1 to 3 carbon atoms, e.g. benzyl or 
phenylethyl; styryl; or alkoxy C 1 to 4-alkyl C 1 to 4, e.g. 
ethoxy-methyl. 
Particularly preferred compounds are those in which R.sub.3 is hydrogen, 
R.sub.5 is hydrogen, hydroxy, amino, mono- or di-alkyl amino, fluorine or 
alkoxy and the substituent X or Z which does not form part of a chain is 
propyl and an adjacent pair of X, Y and Z form a --(CH.sub.2).sub.4 -- or 
--CH.dbd.CH--CH.dbd.CH-- chain. 
Especially preferred compounds of formula I are those in which R.sub.5 is 
hydrogen, hydroxy, --NH.sub.2, --N(CH.sub.3).sub.2, --NHC.sub.2 H.sub.5, 
fluorine, chlorine or methoxy. 
We prefer the free acids of formula I. 
As a specific group of compounds of formula I we provide those in which 
R.sub.3 is hydrogen, R.sub.5 is hydrogen, alkyl or hydroxy, X and Y 
together form a --(CH.sub.2).sub.4 -- chain and Z is alkyl, alkenyl or 
halogen. As a further specific group of compounds we provide those of 
formula I in which R.sub.3 is hydrogen, R.sub.5 is hydrogen, hydroxy, 
nitro, --NR.sub.1 R.sub.2 or halogen, X and Y together form a 
--(CH.sub.2).sub.4 -- chain and Z is alkyl or alkenyl. 
According to the invention there is also provided a process for the 
production of a pharmaceutically acceptable salt of a compound of formula 
I, which comprises treating a compound of formula Ic, 
##STR19## 
in which R.sub.3, R.sub.5, X, Y and Z are as defined above, and 
E is a carboxylic acid group (or an ester thereof, or another salt 
thereof), a nitrile group, an acid halide group or an amide group, 
with a compound containing an available pharmaceutically acceptable cation 
and capable of converting the group E to a pharmaceutically acceptable 
salt of a carboxylic acid group. 
Compounds capable of converting the group E to a pharmaceutically 
acceptable salt of a carboxylic acid group include compounds, e.g. bases 
and ion exchange resins, containing pharmaceutically acceptable cations, 
e.g. sodium, potassium, calcium, ammonium and appropriate nitrogen 
containing organic cations. In general we prefer to form the 
pharmaceutically acceptable salt by treating the free acid of formula I 
with an appropriate base, e.g. with an alkaline-earth or alkali metal 
hydroxide, carbonate or bicarbonate in aqueous solution or by a 
metathetical process with an appropriate salt. When a strongly basic 
compound is used care should be taken, e.g. by keeping the temperature 
sufficiently low, to ensure that the compound of formula I is not 
hydrolysed or otherwise degraded. The pharmaceutically acceptable salt may 
be recovered from the reaction mixture by, for example, solvent 
precipitation and/or removal of the solvent by evaporation, e.g. by freeze 
drying. 
According to our invention we also provide a pharmaceutical composition 
comprising (preferably less than 80%, and more preferably less than 50% by 
weight) of a compound of formula I, or a pharmaceutically acceptable 
derivative thereof, in combination with a pharmaceutically acceptable 
adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or 
carriers are: for tablets capsules and dragees; microcrystalline 
cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, 
dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate 
and/or gelatin; for suppositories, natural or hardened oils or waxes; and 
for inhalation compositions, coarse lactose. The compound of formula I, or 
the pharmaceutically acceptable derivative thereof, preferably is in a 
form having a mass median diameter of from 0.01 to 10 microns. The 
compositions may also contain suitable preserving, stabilising and wetting 
agents, solubilizers, sweetening and colouring agents and flavourings. The 
compositions may, if desired, be formulated in sustained release form. We 
prefer compositions which are designed to be taken oesophageally and to 
release their contents in the gastrointestinal tract. 
Some of the compounds of formula I are asymetric and may therefore exist in 
the form of two (or more) optical isomers or a racemic or other mixture of 
such isomers. The various optical isomers may be resolved, wholly or 
partially, using conventional techniques, e.g. formation of a salt with an 
optically active base, e.g. cinchonidine, fractional crystallisation of 
the salt and subsequent regeneration of the free acid. 
The invention is illustrated, but in no way limited by the following 
Examples, in which the temperatures are in .degree.C.

EXAMPLE 1 
6,7,8,9-Tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
(a) 6-Acetyl-7-allyloxy-1,2,3,4-tetrahydronaphthalene 
A mixture of 6-acetyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene (2.0 g), 
allyl bromide (1.7 g), anhydrous potassium carbonate (2.2 g) and 
N,N-dimethylformamide (50 ml) was stirred at room temperature for 24 
hours. The mixture was then poured into ice/water (400 ml) and stirred. 
The precipitate was filtered off, washed with water and then dried to 
leave, as an off-white powder, 
6-acetyl-7-allyloxy-1,2,3,4-tetrahydronaphthalene (2.38 g), mp 
62.degree.-63.degree.. 
(b) 7-Acetyl-5-allyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene 
The product of step (a) (60.2 g) was heated in a fluidised sand-bath from 
140.degree.-200.degree. during 1 hour and was then further heated at 
200.degree. for 7 hours. The substance was allowed to cool and 
subsequently there was recovered as a brown oil, 
7-acetyl-5-allyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene (58.6 g). 
(c) 7-Acetyl-6-hydroxy-5-propyl-1,2,3,4-tetrahydronaphthalene 
5% Palladium/carbon catalyst (9 g) was added to a solution of the product 
of step (b) (115 g) in ethanol (500 ml). The mixture was shaken with 
hydrogen at an overpressure of 4 to 5 psi at room temperature for 1 hour. 
The catalyst was removed by filtration and the filtrate concentrated and 
cooled. The precipitated solid was filtered off and dried to give 
7-acetyl-6-hydroxy-5-propyl-1,2,3,4-tetrahydronaphthalene (96 g), mp 
52.degree.-53.degree.. 
(d) Ethyl 
6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
To a stirred solution of sodium ethoxide in ethanol, prepared from sodium 
(89.3 g) and ethanol (2.7 l) was added a solution of the product of step 
(c) (180 g) and diethyl oxalate (283 g) in ethanol (500 ml). The mixture 
was stirred and heated under reflux for 4 hours and then, after cooling, 
was poured into a stirred mixture of concentrated hydrochloric acid (500 
ml), water (10 l) and chloroform (1.5 l). The chloroform layer was 
separated and combined with a chloroform (1.5 l) wash of the aqueous 
layer. The chloroform solution was washed with water and then evaporated 
to a brown oil. A solution of this oil in ethanol (1 l) containing 
concentrated hydrochloric acid (1.5 ml) was heated under reflux for 1 
hour. On concentrating and cooling a precipitate was obtained. This 
precipitate was filtered off and the solid recrystallised from ethanol to 
give ethyl 
6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pryan-2-carboxylate 
(202 g), mp 98.degree.-99.5.degree.. 
(e) Sodium 
6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
A mixture of the product of step (d) (9.5 g) and sodium bicarbonate (2.8 g) 
in methanol (60 ml), and water (100 ml), was heated under reflux for 1.5 
hours. The mixture was evaporated and the residue was dissolved in water 
(500 ml). The solution was filtered, then acidified with hydrochloric acid 
and the resulting precipitated acid was filtered off, washed with water, 
dried and recovered as a white solid (8.2 g), which was dissolved in a 
solution of sodium bicarbonate (2.37 g) in water (50 ml). The solution was 
filtered, evaporated to low bulk and diluted with acetone. The solution 
crystallised upon cooling and scratching and gave, as a white powder, 
sodium 
6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
(4.9 g). 
(f) 6,7,8,9-Tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic 
acid 
A solution of the product of step (e) (0.3 g), in water (25 ml) was 
acidified with 2 N hydrochloric acid. The precipitated organic acid was 
filtered off washed with water and dried to give the title compound as a 
white solid, (0.24 g), mp 245.degree.-8.degree.. 
EXAMPLE 2 
Ethyl 
6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
A stirred solution of the product of Example 1(c) (5.75 g) and diethyl 
oxalate (7.3 g) in petroleum ether (60.degree.-80.degree.) (50 ml) was 
treated portionwise over 2 minutes with sodium hydride, (2.5 g of a 50% 
w/w suspension in oil). When effervescence subsided the mixture was 
stirred and heated under reflux for 10 minutes, cooled and treated with a 
solution of hydrogen chloride in ethanol (35 ml). This mixture was heated 
under reflux for 5 minutes then it was cooled, diluted with chloroform and 
sodium chloride was filtered off. The filtrate was evaporated and the 
residue was extracted into boiling petroleum ether 
(40.degree.-60.degree.). The petroleum ether extract was filtered, 
concentrated and cooled and crystallisation occurred. The product was 
filtered off and recovered as a cream solid, identified by mass 
spectroscopy, nuclear magnetic resonance spectroscopy and by thin layer 
chromatography as the title compound (6.0 g), mp 98.degree.-99.5.degree.. 
EXAMPLE 3 
Ethyl 
6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
(a) Ethyl 
10-allyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylate 
The product of Example 1(b) (58.6 g) was treated with sodium (29.4 g) and 
diethyl oxalate (93.1 g) in ethanol (1 l) using the conditions described 
in Example 1(d) to give ethyl 
10-allyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylate 
(50.2 g), as a pale yellow solid, mp 98.degree.-101.degree.. 
(b) Ethyl 
6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
A solution of the product of step (a) (20 g), in ethanol (120 ml), was 
treated with a 5% palladium on charcoal catalyst (100 mg), and shaken in a 
hydrogen atmosphere at 45 psi for 2 hours at room temperature. The 
catalyst was subsequently filtered off and the filtrate was evaporated. 
The residue solidified upon trituration with a little diethyl ether and 
the solid was twice crystallised from aqueous ethanol to give as white 
crystals, ethyl 
6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
(10 g), mp 98.degree.-99.5.degree.. 
EXAMPLE 4 
10-Ethyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
(a) 5-Ethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene 
5-Acetyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene (15.0 g) was heated at 
reflux in a mixture of dioxan (40 ml) and 50% HCl (50 ml) containing zinc 
amalgam (16.0 g) for 18 hours. The mixture was cooled, filtered and the 
filtrate was extracted with ether. The ether extracts were washed with 
water, dried (MgSO.sub.4), filtered and evaporated to dryness leaving a 
solid which crystallised from petroleum ether (60.degree.-80.degree.) to 
give 5-ethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene as pale yellow 
needles, 13.5 g (97%), mp 94.degree.-5.degree.. 
(b) Methyl 
10-ethyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylate 
A solution of the product of step (a) (12.7 g), dimethylacetylene 
dicarboxylate (10.2 g) in dioxan (50 ml) containing `Triton B` (40% 
aqueous solution of benzyltrimethylammonium hydroxide, 10 drops) was 
heated on a steam bath for 20 minutes. Water (100 ml) was added and the 
mixture was extracted with ether. The extracts were dried (MgSO.sub.4), 
filtered and the filtrate was evaporated to dryness. This left, as an 
orange oil, a mixture of the maleate and fumarate esters. (Nuclear 
magnetic resonance spectroscopy showed a predominance of the fumarate, the 
isomer required for cyclisation to the chromone derivative). 
This mixture of maleate and fumarate (19.7 g) was heated at 100.degree. in 
polyphosphoric acid (200 g) for 18 hours. The mixture was poured into ice 
and the resulting solution was extracted with ethyl acetate. The organic 
extracts were washed well with water, dried (MgSO.sub.4), filtered and 
evaporated to dryness leaving an oil. This oil was taken up in ether and 
cooled to 0.degree. when methyl 
10-ethyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylate 
crystallised as off-white needles, 3.3 g. 
(c) 10-Ethyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylic 
acid 
A mixture of the product of step (b) (3.0 g) and sodium bicarbonate (3.0 g) 
in water (100 ml) was heated at reflux for 3 hours. The solution was 
cooled and acidified and the resulting white solid was filtered and dried 
to give the title compound 2.4 g (84%), mp 269.degree.-271.degree.. 
(d) Sodium 
10-ethyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylate 
The product of step (c) (2.14 g) was dissolved in a solution of sodium 
bicarbonate (0.66 g) in water (50 ml). The resulting solution was filtered 
and freeze-dried leaving an off-white solid which was further dried in 
vacuo at 80.degree. giving the desired sodium salt (95%). 
EXAMPLE 5 
6,7,8,9-Tetrahydro-5-nitro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxy 
lic acid 
(a) Ethyl 
6,7,8,9-tetrahydro-5-nitro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylate 
Ethyl 
6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
(9.4 g) was dissolved in concentrated sulphuric acid (100 ml) and cooled 
to room temperature, and fuming nitric acid (3 ml) was added dropwise, 
with stirring. The resulting mixture was stirred for a further 3 hours and 
then poured into water (2 l). The resulting yellow semi-solid was 
extracted into ether. The organic layer was washed with water, dried 
(sodium sulphate) and evaporated to give a yellow solid of moderately pure 
ethyl 
6,7,8,9-tetrahydro-5-nitro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylate (8.5 g; 79%). An analytically pure sample (5 g) was obtained on 
recrystallisation from cyclohexane, mp 140.degree.-2.degree.. 
(b) 
6,7,8,9-Tetrahydro-5-nitro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylic acid 
The ester product of step (a) (720 mg) and sodium bicarbonate (200 mg) in 
water (10 ml) and ethanol (5 ml) were heated under reflux for 2 hours. The 
ethanol was removed and the aqueous solution was made up to 50 ml with 
water, and acidified producing a semi-solid precipitate. The solid was 
recrystallised from ethanol to give an off-white solid shown to be an 
analytically pure sample of the title acid, mp 265.degree.-7.degree. 
(decomposition 261.degree.). Yield 220 mg (33%). 
(c) Sodium 
6,7,8,9-tetrahydro-5-nitro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylate 
The acid product of step (b) above (0.2 g) was converted into the 
corresponding sodium salt (0.15 g), by the method described in Example 
4(d). 
EXAMPLE 6 
5-Amino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxy 
lic acid 
(a) Ethyl 
5-amino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylate 
The product of Example 5(a) (20 g) in ethanol (150 ml) and acetic acid (150 
ml) was hydrogenated for 2 days at 30 psi and room temperature using 5% 
palladium on charcoal (2 g) as catalyst. The reaction mixture was filtered 
through a super-cel filter aid and the filtrate was evaporated. The crude 
product was treated with water (1 l) and ether (1 l) and transferred to a 
separating funnel. The ether layer was run off, washed with water (1 l), 
saturated aqueous sodium bicarbonate solution (3.times.500 ml), water (1 
l), dried (sodium sulphate) and evaporated to yield a red solid (18 g). 
This solid was recrystallised from petroleum ether (40.degree.-60.degree.) 
to give red needles of a pure sample of the title ester (13.1 g; 71.5%), 
mp 78.degree.-81.degree.. 
(b) Sodium 
5-amino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylate 
The ester of step (a) (4.5 g) was converted into its corresponding sodium 
salt (3.2 g) by the method of Example 1(e). 
(c) 
5-Amino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylic acid 
The salt of step (b) (3.0 g) was converted into the corresponding acid (2.5 
g) mp 285.degree. (decomp) by the method of Example 1(f). 
EXAMPLE 7 
5-Amino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxy 
lic acid 
Stannous chloride dihydrate (132 g) was dissolved in concentrated HCl (400 
ml) and to this solution was added the product of Example 5(a) (30 g) 
followed by glacial acetic acid (400 ml). The whole mixture was heated on 
a steam bath for 2 hours, poured onto ice water (1,500 ml) and the 
precipitated solid was filtered, washed with water and dried in vacuo at 
95.degree. to give 
5-amino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylic acid as an orange solid, (21 g; 84%) mp 285.degree. (decomp). 
EXAMPLE 8 
(a) 
6,7,8,9-Tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylic acid 
The product of Example 6(a) (6.0 g) in 50% (v/v) sulphuric acid (30 ml) at 
0.degree. was treated, whilst being stirred, over 15 minutes with a 
solution of sodium nitrite (1.4 g) in water (10 ml). Stirring at 0.degree. 
was continued for 30 minutes, then the solution was poured, in aliquots, 
into a 50% (v/v) sulphuric acid solution at 120.degree. over a period of 
20 minutes. The reaction mixture was allowed to warm slowly (over 30 
minutes) to 140.degree. after which time it was cooled to room 
temperature. The solution was extracted with chloroform and both layers 
were filtered through a super-cel filter aid. The chloroform layer was 
treated with saturated sodium bicarbonate precipitating the sodium salt of 
the 5-hydroxy acid. The red-brown solid was filtered off and combined with 
the bicarbonate washings and a second bicarbonate extract of the 
chloroform layer. This suspension was treated with concentrated 
hydrochloric acid to precipitate the free acid, which was extracted back 
into chloroform (5.times.100 ml). The chloroform extracts were combined 
and washed with water, dried (sodium sulfate) and evaporated to yield a 
yellow solid (2.8 g; 51%). A pure sample of the title compound (2.1 g; 
38.2%) was obtained in two crops on recrystallisation of the crude product 
from ethanol mp 260.degree.-2.degree.. 
(b) Sodium 
6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylate 
The product of step (a) (1.4 g) was suspended in water (20 ml) and sodium 
bicarbonate (356 mg) was added over 10 minutes. When homogeneity had been 
achieved the mixture was freeze-dried to yield a yellow solid which was 
shown to be a pure sample of the desired sodium salt (1.4 g; 93%). 
EXAMPLE 9 
6,7,8,9-Tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylic acid 
(a) Ethyl 
6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylate 
A solution of the product of Example 6(a) (13.5 g) in concentrated 
sulphuric acid (120 ml) was stirred at 8.degree. while a solution of 
sodium nitrite (3.4 g) in water (7 ml) was added dropwise. The solution 
was then stirred at 8.degree. for 30 minutes, poured slowly into 50% v/v 
sulphuric acid (200 ml) at 115.degree.-125.degree. and the temperature of 
the resulting mixture maintained for 30 minutes. The mixture was then 
partly cooled and added to water (300 ml) with stirring. The precipitated 
solid was filtered off and recrystallised from ethanol. The solid obtained 
was dried, suspended in a mixture of ethanol (150 ml) and concentrated 
sulphuric acid (2 ml) and refluxed with stirring for 20 hours. The mixture 
was concentrated and cooled. The precipitated solid was filtered off, 
recrystallised from ethanol and dried to give ethyl 
6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylate (4.5 g) mp 136.degree.- 138.degree.. 
(b) 
6,7,8,9-Tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylic acid 
A refluxing solution of ethyl 
6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylate (45.4 g) in ethanol (600 ml) was stirred whilst adding a solution 
of sodium bicarbonate (11.5 g) in water (300 ml) over 15 minutes. After 
refluxing a further 4 hours, an additional quantity of sodium bicarbonate 
solution (1.5 g in 30 ml water) was added and the mixture refluxed for a 
further 1 hour. The hot solution was acidified with dilute hydrochloric 
acid and the yellow precipitate filtered off. The damp solid was 
recrystallised from acetone to give 
6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylic acid (34.0 g) mp 265.degree.-268.degree.. 
EXAMPLE 10 
(a) 
5-Chloro-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylic acid 
Ethyl 
5amino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxy 
late (7.2 g) in concentrated hydrochloric acid (90 ml) was treated with 
sodium nitrite (1.8 g) in water (15 ml) with stirring at 0.degree. over 15 
minutes. 
The resulting diazonium salt-suspension/solution was added to a stirred 
solution of cuprous chloride (freshly prepared by standard techniques from 
9 g of cupric sulphate) at 0.degree.. The mixture was gradually heated to 
120.degree. over 90 minutes, and then allowed to cool to room temperature. 
The resulting sand-coloured solid was filtered off and washed with water. 
The solid was dissolved in saturated sodium bicarbonate solution and 
heated on a steam bath for 30 minutes. The solution was acidified (HCl) 
and the precipitate was filtered off (4.9 g) and recrystallised twice from 
ethanol and then twice from acetic acid to give the title compound (2.6 g; 
37.6%) mp 269.degree.-71.degree.. 
(b) Sodium 
5-chloro-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylate 
The product of step (a) (2.27 g) suspended in water (15 ml) was treated 
with sodium bicarbonate (0.594 g). The resulting solution was filtered and 
reduced to a 10 ml bulk on the rotary evaporator. Acetone (70 ml) was 
added causing crystallisation to occur. A pale yellow solid (1.15 g; 
47.4%) was obtained in two crops, which were blended and shown to be pure 
sodium salt. 
EXAMPLE 11 
(a) 10-Allyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylic 
acid 
The product of Example 3(a) (6.6 g) and sodium bicarbonate (1.78 g) were 
heated under reflux for 1 hour in a mixture of water (100 ml) and methanol 
(50 ml). The hot solution was filtered and the filtrate was evaporated to 
yield a white solid, which was taken up in water. The resulting solution 
was acidified with concentrated hydrochloric acid and the white solid was 
filtered off and washed well with cold water. On drying in a vacuum oven, 
an off-white powder of moderately pure title compound m.p 
235.degree.-7.degree. (6.0 g; 100%) was obtained. A pure sample of the 
compound was obtained as cream-coloured crystals after two 
recrystallisations from ethanol. Yield (4.7 g; 79%) m.p 
238.degree.-240.degree.. 
(b) Sodium 
10-allyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxyic 
The product of step (a) (3.0 g) was converted into its sodium salt (2.9 g) 
by the method of Example 4(d). 
EXAMPLE 12 
6,7,8,9-Tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
The product of Example 11(a) (6.2 g) was hydrogenated at 15 psi for 21/2 
hours at room temperature after which time hydrogen ceased to be absorbed. 
The fawn-coloured solid so obtained (6.0 g; 97%) was recrystallised from 
ethanol to give an analytically pure fawn solid m.p 245.degree.-8.degree. 
(decomp), (5.2 g; 72%), identical to that obtained by the method of 
Example 1(f). 
EXAMPLE 13 
5-Dimethylamino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2 
-carboxylic acid 
(a) Ethyl 
5-dimethylamino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran- 
2-carboxylate 
The product of Example 6(a) (1.65 g) was dissolved in calcium chloride 
dried methylene chloride (15 ml) at -20.degree., and 
methoxy-sulphonylfluoride (1.14 g=0.86 ml) was added with stirring. The 
mixture was stirred at -20.degree. for 1 hour, then at room temperature 
for 3 hours, at which time a further aliquot of methoxy sulphonylfluoride 
(0.25 ml) was added. Stirring was continued at room temperature overnight. 
The reaction mixture was washed with water (100 ml), saturated aqueous 
sodium bicarbonate (2.times.100 ml), water (100 ml) and dried (anhydrous 
sodium sulphate) to yield a brown oil which was boiled with petroleum 
ether (60.degree.-80.degree.), filtered and the filtrate evaporated to 
give a brown oil which crystallised to a brown solid (1.3 g; 73%). This 
solid was a pure sample of ethyl 
5-dimethylamino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran- 
2-carboxylate mp 61.degree.-62.5.degree.. 
(b) 
5-Dimethylamino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran- 
2-carboxylic acid hydrochloride 
The product of step (a) (1.8 g), sodium bicarbonate (0.5 g), water (20 ml), 
and ethanol (12 ml) were heated under reflux for 3 hours. The ethanol was 
removed on the rotary evaporator and the resulting solution was acidified 
(to pH 4). The resulting solution was then evaporated to a volume of 10 
ml, causing crystallisation of the (approximately) hemihydrochloride. The 
buff solid was filtered off and combined with a similar solid obtained 
from a larger scale (6.0 g) hydrolysis of the starting ester. The combined 
solids were dissolved in 50% (vol/vol) hydrochloric acid (25 ml), 
evaporated and dried to yield after recrystallisation from water, the 
desired hydrochloride (3.6 g; 50%) mp 209.degree. (decomp). 
EXAMPLE 14 
5-Ethylamino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-ca 
rboxylic acid 
(a) Ethyl 
5-ethylamino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-c 
arboxylate 
Triethyloxonium borofluoride (2.7 g) in calcium chloride dried methylene 
chloride (25 ml) was added dropwise to a solution of the product of 
Example 6(a) (4.7 g) in methylene chloride (15 ml) over 15 minutes, with 
stirring, at 0.degree.. The mixture was allowed to attain ambient 
temperature, then it was stirred for 2.5 hours. It was then poured into 
water and washed with water (50 ml), saturated aqueous sodium bicarbonate 
(2.times.50 ml), water (50 ml) and dried (anhydrous sodium sulphate) to 
yield a brown oil which crystallised from petroleum ether 
(60.degree.-80.degree.) as brown needles (3.6 g; 71%). This solid (1.0 g) 
was recrystallised from petroleum ether (60.degree.-80.degree.) to yield 
an analytically pure sample (600 mg; 60% recovery) of ethyl 
5-ethylamino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-c 
arboxylate as brown needles mp 91.5.degree.. 
(b) 5-Ethylamino-6,7,8,9-tetrahydro-4-oxo-10-propyl-naphtho[ 
2,3-b]pyran-2-carboxylic acid 
The product of step (a) (1.2 g), sodium bicarbonate (340 mg), water (15 ml) 
and ethanol (15 ml) were heated under reflux for 80 minutes. The ethanol 
was removed on the rotary evaporator and the solution was acidified (with 
concentrated HCl) to pH 1. The brown solid was filtered off and combined 
with a similar solid obtained from a larger scale (4.8 g) hydrolysis of 
the ester. The combined solids were recrystallised from ethanol to give a 
pure sample of the title compound (4.2 g; 77%) mp 213.degree.-16.degree.. 
EXAMPLE 15 
(a) 4-Oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
The product of Example 1(d) (10 g) and sulphur (3 g) were heated at 
230.degree.-245.degree. for 2 hours. A further quantity (0.5 g) of sulphur 
was added and heating was continued between 265.degree. and 250.degree. 
for 1 hour. The product was dissolved in ethanol and treated with 
decolourising charcoal. A dark brown solid crystallised from the filtered 
and cooled ethanol solution. Recrystallisation (three times) from ethanol 
gave a moderately pure sample of ethyl 
4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate as pale brown needles 
(3.9 g; 39.6%). This solid (3.9 g) was heated under reflux with sodium 
bicarbonate (1.5 g), water (100 ml) and ethanol (50 ml) for 2 hours. The 
ethanol was removed on the rotary evaporator and the resulting solution 
was acidified (with concentrated HCl) to yield a brown solid which was 
recrystallised twice from chloroform, then twice from acetone to yield a 
nearly pure sample of the title acid (0.7 g; 20%) as light brown needles 
mp 265.degree.-7.degree.. 
(b) Sodium 4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
The product of step (a) (0.6 g) was converted into its corresponding sodium 
salt (0.55 g) by the method of Example 4(d). 
EXAMPLE 16 
5-Fluoro-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylic acid 
(a) Ethyl 
5-diazoniumhexafluorophosphate-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-napht 
ho[2,3-b]pyran-2-carboxylate 
Ethyl 
5-amino-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylate (20 g) was suspended in concentrated HCl (40 ml) at 5.degree. and a 
solution of sodium nitrite (5.0 g) in water (20 ml) was added dropwise 
over 30 minutes maintaining the temperature between 5.degree. and 
10.degree.. Hexafluorophosphoric acid (10 g of a 65% aqueous solution=15 
ml) was added, causing a sticky solid to precipitate. The aqueous solution 
was decanted and the residue was triturated with methanol/ether to give a 
fawn solid, which was filtered off and washed with aliquots of water, 
methanol and ether, to yield a pale fawn solid (8.1 g; 31%) of ethyl 
5-diazoniumhexafluorophosphate-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-napht 
ho[2,3-b]pyran-2-carboxylate mp 120.degree.-1.degree. (decomp). A further 
6.4 g, 25% of this compound was recovered from the washings. Total yield 
14.5 g (56%). 
(b) Ethyl 
5-fluoro-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylate 
The product of step (a) (14.5 g) was heated at 125.degree.-140.degree. for 
several minutes until nitrogen evolution had ceased. The black solid (10.8 
g) was purified by column chromatography (on silica). Toluene/ethyl 
acetate eluted a pale yellow solid (2.5 g; 23%) of moderately pure ethyl 
ester mp 126.degree.-129.degree.. Two recrystallisations from cyclohexane 
gave the required product (1.8 g), mp 132.degree.-4.degree.. 
(c) 
5-Fluoro-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylic acid 
The ester of step (b) (2.49 g) was converted into the corresponding acid 
(1.5 g; 66%), mp 249.degree.-253.degree., by the method of Example 5(b). 
(d) Sodium 
5-fluoro-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylate 
The product of step (c) (1.0 g) was converted into its sodium salt (0.85 g) 
by the method of Example 4(d). 
EXAMPLE 17 
(a) 
6,7,8,9-Tetrahydro-4-oxo-10-(2-hydroxypropyl)-4H-naphtho[2,3-b]pyran-2-car 
boxylic acid 
The product of Example 11(b) (12.0 g) was dissolved in water (800 ml) and 
mercuric acetate (12.5 g) was added. This mixture was stirred and heated 
on a steam bath overnight. Sodium bicarbonate (3.3 g) sodium chloride (30 
gm) and dioxan (750 ml) were added and heating was continued until 
solution was complete. Sodium borohydride (3.0 g) was added and mercury 
was precipitated. The mixture was acidified to pH 7 and the mercury was 
removed by decantation. Acidification of the filtrate was continued to pH 
1 and the solution was evaporated to small bulk giving a solid which was 
filtered off. This solid was washed well with hot ethyl acetate and the 
solid which remained undissolved, being the required compound, was 
collected and dried (2.5 g; 21%) mp 235.degree.. 
(b) Sodium 
6,7,8,9-tetrahydro-4-oxo-10-(2-hydroxypropyl)-4H-naphtho[2,3-b]pyran-2-car 
boxylate 
To a solution of sodium bicarbonate (0.668 g) in water (20 ml) was added 
the product of step (a) (2.401 g) and the resulting solution was 
freeze-dried. The white deliquescent solid obtained was crystallised from 
ethanol to give the desired sodium salt (1.6 g, 62%). 
EXAMPLE 18 
(a) 
7,8,9,10-Tetrahydro-5-hydroxy-4-oxo-6-propyl-4H-naphtho[1,2-b]pyran-2-carb 
oxylic acid 
The product of Example 9(a) (6.6 g) was heated with aqueous sodium 
bicarbonate (4.0 g) in water (50 ml) and ethanol (5 ml) at reflux for 24 
hours. The resulting solution was evaporated to small volume and allowed 
to cool. The solid deposited was filtered off, dissolved in water and the 
aqueous solution was acidified to give the title compound (4.4 gm, 66%), 
mp 226.degree.-7.degree.. 
(b) Sodium 
7,8,9,10-tetrahydro-5-hydroxy-4-oxo-6-propyl-4H-naphtho[1,2-b]pyran-2-carb 
oxylate 
The product of step (a) (4.316 g) was dissolved in a hot solution of sodium 
bicarbonate (1.21 g) in water (50 ml) and the resulting solution was 
cooled at 5.degree. overnight. The solid which crystallised was filtered 
off and dried to give the desired sodium salt as a yellow solid (4.2 g, 
90%). 
EXAMPLE 19 
10-Bromo-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
(a) 7-Acetyl-5-bromo-1,2,3,4-tetrahydro-6-hydroxynaphthalene 
A mixture of aluminium chloride (8.15 g) and 
7-acetyl-1,2,3,4-tetrahydro-6-hydroxynaphthalene (4.75 g) in 
dichloromethane (250 ml) was cooled to -10.degree.. A solution of bromine 
(6.0 g) in dichloromethane (150 ml) was then added over 1 hour with 
constant stirring. The reaction mixture was allowed to warm to room 
temperature overnight, dilute HCl (400 ml) was added and the organic layer 
was separated, washed with water and dried (MgSO.sub.4). The solvent was 
filtered and the filtrate was evaporated to dryness leaving an oil which 
solidified on cooling to give 
7-acetyl-5-bromo-1,2,3,4-tetrahydro-6-hydroxynaphthalene (5.3 g, 79%) mp 
127.degree.-130.degree.. 
(b) Ethyl 
10-bromo-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylate 
The product of step (a) (5.3 g) was treated with sodium (2.3 g) and diethyl 
oxalate (7.3 g) under the conditions of Example 1(d) to give the title 
ester (5.0 g; 72%), mp 130.degree.-132.degree.. 
(c) 10-Bromo-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylic 
acid 
The ester product of step (b) (4.2 g) was converted into the corresponding 
carboxylic acid (3.2 g; 83%), mp 188.degree.-191.degree., by the method of 
Example 5(b). 
(d) Sodium 
10-bromo-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylate 
The acid product of step (c) (2.8 g) was converted into the corresponding 
sodium salt (2.7 g; 89%), by the method of Example 4(d). 
EXAMPLE 20 
6,7,8,9-Tetrahydro-5-methoxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylic acid 
(a) Methyl 
6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylate 
A mixture of the product of Example 8(a) (34.4 g), methanol (1000 ml) and 
concentrated sulphuric acid (5 ml) was heated to reflux temperature and a 
homogeneous solution was obtained. Refluxing was continued for a further 
18 hours. The solution was then allowed to cool and the methanol was 
evaporated in vacuo to give a brown solid. This solid was dissolved in 
acetone and the solution was treated with charcoal. Filtering off the 
charcoal and evaporation of the acetone gave a yellow solid which was 
recrystallised from methanol to give methyl 
6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylate (20.6 g). 
(b) Methyl 
6,7,8,9-tetrahydro-5-methoxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylate 
To a solution of the product of step (a) (20.6 g) in dry acetone (1000 ml) 
was added powdered anhydrous potassium carbonate (9.91 g) and methyl 
iodide (20.3 ml) and the stirred reaction mixture was refluxed gently. 
Further quantities of the reagents were added as follows:- 
at 24 hours, methyl iodide, (20.3 ml), 
at 48 hours, methyl iodide, (20.3 ml), 
at 96 hours, potassium carbonate (4.5 g). 
After refluxing for 118 hours the reaction mixture was allowed to cool, the 
potassium carbonate was filtered off and the acetone was removed by 
evaporation in vacuo. The resulting yellow solid was dissolved in ether 
and the ethereal solution was washed with water. The organic solution was 
then dried (magnesium sulphate) and filtered, and the ether was evaporated 
in vacuo. The crude product was recrystallised twice from petroleum ether 
(60.degree.-80.degree.) to give methyl 
6,7,8,9-tetrahydro-5-methoxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylate as a fawn solid (13.8 g), mp 92.degree.-93.degree.. 
(c) 
6,7,8,9-Tetrahydro-5-methoxy-4-oxo-10-propyl-4H-naphtho-[2,3-b]pyran-2-car 
boxylic acid 
The product of step (b) (2 g) was hydrolysed to the corresponding acid 
(1.55 g), mp 228.degree.-229.degree., by the method of Example 5(b). 
(d) Sodium 
6,7,8,9-tetrahydro-5-methoxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylate 
The acidic product of step (c) (1.1 g) was converted into its sodium salt 
(1.0 g), by the method of Example 4(d). 
EXAMPLE 21 
6,7,8,9-Tetrahydro-3-methyl-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylic acid 
(a) 5,6,7,8-Tetrahydro-2-propionoxynaphthalene 
To a stirred solution of 5,6,7,8-tetrahydro-2-hydroxy naphthalene (44.5 g) 
in dry pyridine (200 ml) was added propionic anhydride (45.6 g). The 
mixture was heated on a steam bath for 2 hours, left overnight, then 
poured into stirred 5N hydrochloric acid and extracted with chloroform. 
The chloroform extract was washed with N HCl, with water, dried 
(MgSO.sub.4), filtered and evaporated to leave the title product, (61 g) 
as a pale brown oil. 
(b) 5,6,7,8-Tetrahydro-2-hydroxy-3-propionylnaphthalene 
To a mixture of aluminium chloride (120 g) and sodium chloride (52.6 g) at 
160.degree. was added, over 10 minutes, the product of step (a) (60 g). 
The mixture was then heated at 180.degree. for 30 minutes, cooled and 
poured onto ice. The precipitate was extracted into ether and the extract 
was filtered and evaporated. The residue was twice crystallised from 
petroleum ether (40.degree.-60.degree.) to give 
5,6,7,8-tetrahydro-2-hydroxy-3-propionylnaphthalene, (14.5 g) as a pale 
brown solid, m.p. 57.degree.-58.degree.. 
(c) 2-Allyloxy-5,6,7,8-tetrahydro-3-propionylnaphthalene 
The product of step (b) (14.5 g) was treated with allyl bromide (11.5 g) 
under the conditions of Example 1(a) to give the title compound (18.8 g) 
as a pale brown oil, whose structure was confirmed by MS and NMR 
spectroscopy. 
(d) 1-Allyl-5,6,7,8-tetrahydro-2-hydroxy-3-propionylnaphthalene 
The product of step (c) (18 g) was thermally rearranged to the title 
compound (17 g), by the method of Example 1(b). 
(e) Ethyl 
10-allyl-6,7,8,9-tetrahydro-3-methyl-4-oxo-4H-naphtho[2,3-b]pyran-2-carbox 
ylate 
The product of step (d) (17 g) was treated with sodium (8 g) and diethyl 
oxalate (25.5 g) under the conditions of Example 1(d) to give the title 
ester (16 g) as a pale brown oil, which was characterised by NMR 
spectroscopy. 
(f) Ethyl 
6,7,8,9-tetrahydro-3-methyl-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylate 
The product of step (e) (16 g) was hydrogenated over palladium on charcoal 
catalyst, under the conditions of Example 3(b), to give the title ester 
(16.2 g), as a low melting brown solid. 
(g) 
6,7,8,9-Tetrahydro-3-methyl-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylic acid 
A mixture of the product of step (f) (16.2 g), glacial acetic acid (80 ml) 
and 5 N hydrochloric acid (20 ml) was heated and stirred on a steam bath 
overnight, and then evaporated. The residue was extracted with aqueous 
sodium bicarbonate and the extract was filtered and then acidified. 
Precipitated material was isolated by decantation and was triturated with 
water, dried, then triturated with an ether/petroleum ether 
(40.degree.-60.degree.) mixture. There remained as an insoluble off-white 
solid, 
6,7,8,9-tetrahydro-3-methyl-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylic acid, (3.5 g), m.p 162.degree.-4.degree.. 
(h) Sodium 
6,7,8,9-tetrahydro-3-methyl-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylate 
A solution of sodium bicarbonate (0.78 g) in water (30 ml) was added to the 
product of step (g) (2.8 g). The resulting solution was filtered then 
evaporated to small volume and diluted with acetone. Crystallisation 
occurred and the resulting crystals were filtered off and recovered as an 
off-white solid, which was the desired sodium salt (2.65 g). 
EXAMPLE 22 
7,8-Dihydro-4-oxo-10-propyl-4H,6H-benzo[1,2-b:5,4-b']dipyran-2-carboxylic 
acid 
(a) 6-Acetyl-2,3-dihydro-7-allyloxy-4H(1) benzopyran 
6-Acetyl-2,3-dihydro-7-hydroxy-4H(1) benzopyran (20 g) was treated with 
allyl bromide (12.1 ml), under the conditions of Example 1(a), to give the 
title compound (23.9 g: 99%), mp 62.degree.-64.degree.. 
(b) 6-Acetyl-2,3-dihydro-7-hydroxy-8-allyl-4H(1) benzopyran 
The allyl ether of step (a) (23.9 g) was heated at 200.degree.-210.degree. 
for 1.25 hours. The reaction mixture was cooled, diluted with water and 
extracted with ether. The ethereal extract was washed with water, dried 
and the solvent evaporated to give 23.3 g of the product, mp 
67.degree.-71.degree. (97.5%). 
(c) 6-Acetyl-2,3-dihydro-7-hydroxy-8-propyl-4H(1) benzopyran 
The compound from step (b) (10 g) was dissolved in ethanol (200 ml) and 
hydrogenated in the presence of 5% palladium on charcoal (1.0 g) at 45 psi 
until hydrogen uptake had ceased. The catalyst was filtered off and the 
filtrate evaporated to give 9.6 g of the desired product mp 
62.degree.-66.degree. (95.2%). 
(d) Ethyl 
7,8-dihydro-4-oxo-10-propyl-4H,6H-benzo[1,2-b:5,4-b']dipyran-2-carboxylate 
The product of step (c) (9.6 g) was treated with sodium (4.71 g) and 
diethyl oxalate (15.0 g), under the conditions of Example 1(d), to give 
the title ester (10.7 g: 82.6%), mp 100.degree.-103.degree.. 
(e) 
7,8-Dihydro-4-oxo-10-propyl-4H,6H-benzo[1,2-b:5,4-b']dipyran-2-carboxylic 
acid 
The ester from step (d) (8.0 g) was hydrolysed to the corresponding acid 
(5.9 g) mp 261.degree.-262.degree. (decomp), using the conditions of 
Example 5(b). 
(f) Sodium 
7,8-dihydro-4-oxo-10-propyl-4H,6H-benzo[1,2-b:5,4-b']dipyran-2-carboxylate 
The acid of step (c) (4.64 g) was added to sodium bicarbonate (1.354 g), in 
water (200 ml). The solution was filtered and the filtrate was 
freeze-dried to give 4.15 g of the sodium salt which analysed as a 
dihydrate. 
EXAMPLE 23 
5-Allyloxy-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylic acid 
A stirred solution of the product of Example 8(a) (1.5 g) in 
dimethylformamide (15 ml) was treated with a 50% w/w oil dispersion of 
sodium hydride (0.5 g). This mixture was slightly warmed and the resulting 
suspension was treated with a solution of allyl bromide (7 g) in 
dimethylformamide (10 ml). After stirring at room temperature for 10 
minutes the mixture was heated under reflux for 5 minutes then evaporated. 
The residue was treated with water (30 ml), methanol (10 ml) and sodium 
bicarbonate (0.8 g) and heated under reflux for 1.5 hours. The mixture was 
evaporated, diluted with water and the aqueous solution was filtered then 
acidified with hydrochloric acid. Precipitated material was triturated 
with water, dried and the title compound recovered as a yellow powder (1.4 
g) mp 162.degree.-8.degree. (molecular weight 342, structure confirmed by 
Mass Spectroscopy). 
EXAMPLE 24 
(a) 
6,7,8,9-Tetrahydro-4-oxo-5-propoxy-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylic acid 
A solution of the product of Example 23 (1.4 g) in ethanol (25 ml) was 
treated with a 5% palladium on charcoal catalyst (50 mg) and hydrogenated 
at 45 psi/room temperature for 5 hours. Catalyst was filtered off and the 
ethanolic filtrate was evaporated to low bulk, treated with sodium 
bicarbonate (0.8 g) and water (30 ml), and heated under reflux for 1 hour. 
The solution was evaporated, diluted with water and filtered and the 
filtrate was acidified. The precipitated acid was filtered off, washed 
with water, dried and the title compound recovered as a pale yellow powder 
(1.4 g), mp 208.degree. (decomp). 
(b) Sodium 
6,7,8,9-tetrahydro-4-oxo-5-propoxy-10-propyl-4H-naphtho[2,3-b]pyran-2-carb 
oxylate 
An aqueous solution of sodium bicarbonate (0.35 g) and the product of step 
(a) (1.35 g) was filtered, evaporated to near dryness then diluted with 
acetone. Crystallisation occurred and the crystals were filtered off and 
the desired sodium salt recovered as a cream powder (1.2 g). 
EXAMPLE 25 
Sodium 
8,9-dihydro-5-methoxy-8,8-dimethyl-4-oxo-4H,10H-benzo[1,2-b:3,4-b']dipyran 
-2-carboxylate 
(a) 5-Hydroxy-7-methoxy-2,2-dimethylchroman was prepared according to 
literature procedures 
(b) 
8,9-Dihydro-5-methoxy-8,8-dimethyl-4-oxo-4H,10H-benzo[1,2-b:3,4-b']dipyran 
-2-carboxylic acid 
To a solution of dimethylacetylenedicarboxylate (7.5 g) in dioxan (100 ml) 
containing `Triton 8` (10 drops) was added 
5-hydroxy-7-methoxy-2,2-dimethylchroman (10.0 g) and the resulting mixture 
was warmed on a steam bath for 2 hours. A solution of sodium hydroxide 
(4.0 g) in water (20 ml) was added and heating was continued for 2 hours 
more. The organic solvent was removed and water (50 ml) was added to the 
residue and the mixture was acidified to give an oil which was extracted 
into ethylacetate. This solution was dried over MgSO.sub.4, filtered and 
the filtrate was evaporated to dryness. The oil so obtained was dissolved 
in concentrated H.sub.2 SO.sub.4 (50 ml) and the solution was stirred at 
room temperature for 30 minutes, poured into ice and extracted with ethyl 
acetate. This solution was washed with water, dried (MgSO.sub.4), filtered 
and evaporated to dryness. The oil so produced was triturated with ethyl 
acetate, cooled to 0.degree., and the solid produced was filtered and 
dried. The solid was crystallised from ethanol to give 
8,9-dihydro-5-methoxy-8,8-dimethyl-4-oxo-4H,10H-benzo[1,2-b:3,4-b']dipyran 
-2-carboxylic acid as a white solid (3.4 g, 23%) mp 225.degree.-6.degree.. 
(c) Sodium 
8,9-dihydro-5-methoxy-8,8-dimethyl-4-oxo-4H,10H-benzo[1,2-b:3,4-b']dipyran 
-2-carboxylate 
The acidic product of step (b) (1.4 g) was converted into its sodium salt 
(1.3 g: 87%), by the method of Example 4(d). 
EXAMPLE 26 
(a) Ethyl 
2,3,6,7,8,9-hexahydro-2-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-c 
arboxylate 
A solution of the product of Example 1(c) (5.75 g) and diethyl oxalate (7.3 
g) in petroleum ether (60.degree.-80.degree.) (50 ml), was treated with a 
50% w/w dispersion of sodium hydride in oil (2.5 g). The mixture was 
stirred and gently heated until all of the hydride had reacted. To the 
mixture was then added ethanol (25 ml) and concentrated hydrochloric acid 
(5 ml). This mixture was heated under reflux for 5 minutes, cooled and 
evaporated. The residue was treated with a water/chloroform mixture and 
the chloroform layer was isolated, washed with water and evaporated. This 
residue was crystallised from an ethyl acetate/petroleum ether 
(60.degree.-80.degree.) mixture to give ethyl 
2,3,6,7,8,9-hexahydro-2-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-c 
arboxylate as white crystals, (4.3 g), mp 126.degree.-8.degree.. (The 
structure was confirmed by NMR spectroscopy). 
(b) Ethyl 
6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
The product of step (a) (1 g) in ethanol (50 ml) containing concentrated 
HCl (1 ml) was heated under reflux for 4 hours. Evaporation of the 
resulting solution to a volume of 20 mls caused the chromone ester, 
identical to that of Example 1(d) to crystallise. 
EXAMPLE 27 
Methyl 
7,8,9,10-tetrahydro-5-methoxy-4-oxo-6-propyl-4H-naphtho[1,2-b]pyran-2-carb 
oxylate 
(a) Methyl 
7,8,9,10-tetrahydro-5-hydroxy-4-oxo-6-propyl-4H-naphtho[1,2-b]pyran-2-carb 
oxylate 
The product of Example 18(a) (1.0 g) was converted into the corresponding 
methyl ester (0.8 g), mp 153.degree.-154.degree. by the method of Example 
20(a). 
(b) Methyl 
7,8,9,10-tetrahydro-5-methoxy-4-oxo-6-propyl-4H-naphtho[1,2-b]pyran-2-carb 
oxylate 
The product of step (a) (0.5 g) was converted into the title compound (0.2 
g) mp 124.degree., by the method of Example 20(b). The product of step (b) 
may be hydrolysed to the free acid. 
EXAMPLE 28 
5-Hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
(a) Ethyl 5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
The product of Example 9(a) (10 g) and sulphur (1.5 g) were ground together 
to form an intimate mixture. This was heated at 250.degree. under an 
atmosphere of nitrogen for one and a half hours. After cooling to room 
temperature the reaction mixture was extracted with acetone, removal of 
the acetone in vacuo yielded a dark brown amorphous material. This was 
crystallised from acetone/ethyl acetate with charcoaling, to yield the 
desired product as dark orange needles, mp 148.degree.-150.degree., 3.4 g 
(35%). 
(b) Sodium 5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
The product of step (a) (6 g) was heated at 100.degree. with sodium 
bicarbonate (1.55 g) in a mixture of water (50 ml) and ethanol (5 ml), for 
4 hours. The ethanol was removed, in vacuo, and the remaining aqueous 
solution was filtered and cooled. The sodium salt (1.8 g) crystallised 
from this solution as orange needles. 
(c) 5-Hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
The product of step (b) (0.2 g) was dissolved in hot water (20 ml) and 
acidified with hydrochloric acid. The title acid precipitated as an orange 
solid (0.18 g) mp 283.degree. (decomp). 
EXAMPLE 29 
10-Formyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
(a) 5,6,7,8-Tetrahydro-3-acetyl-1-formyl-2-naphthol 
To a solution of 5,6,7,8-tetrahydro-3-acetyl-2-naphthol (9.5 g) in dry 
dichloromethane (50 ml), cooled in an ice bath, was added titanium 
tetrachloride (38 g) over a period of three minutes. After fifteen minutes 
stirring dichloromethyl methyl ether (8.05 g) was added over a period of 
five minutes. The mixture was retained in the ice bath for a further ten 
minutes, then stirred without cooling for thirty minutes, and finally 
warmed to 35.degree. for twenty minutes. 
The reaction mixture was thrown into ice-water (250 ml), stirred for five 
minutes, and the organic phase was separated. The aqueous phase was 
extracted into dichloromethane (3.times.75 ml). After drying, the combined 
organic phases were evaporated to yield a red-orange solid (10.5 gm, 95%) 
which was pure enough for subsequent reactions. 
Crystallisation of a small sample from ethanol gave the title product as 
red-orange needles, mp 77.5.degree.-78.5.degree.. 
(b) Ethyl 
10-formyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylate 
The product of step (a) (5.5 g) was treated with sodium (1.45 g) and 
diethyl oxalate (18.25 g), under the conditions described in Example 1(d), 
to give the title ester (7.7 g), mp 134.degree.-135.degree., as yellow 
needles. 
(c) 10-Formyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylic 
acid 
The product of step (b) (6.0 g) was hyrolysed to the corresponding acid 
using the conditions of Example 5(b)m.p. 200.degree.(decomp). 
(d) Sodium 
10-Formyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylate 
The product of step (c) (3.0 g) was converted into its sodium salt (2.9 g), 
by the method of Example 4(d). 
EXAMPLE 30 
Ethyl 
6,7,8,9-tetrahydro-10-ethoxymethyl-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxyl 
ate 
(a) 7-Acetyl-1,2,3,4-tetrahydro-6-hydroxy-5-chloromethylnaphthalene 
To a solution of 7-acetyl-1,2,3,4-tetrahydro-6-hydroxynaphthalene (100 g) 
in acetic acid (350 ml) was added paraformaldehyde (29 g), concentrated 
hydrochloric acid (500 ml) and orthophosphoric acid (150 ml). The 
resulting solution was heated on a steam bath for 2 hours, poured into 
water (3 l) and the oil which separated was extracted into ethyl acetate. 
This solution was washed with water, dried over MgSO.sub.4, filtered and 
evaporated to dryness leaving an oil. This was triturated with a small 
amount of ether and the yellow solid was filtered off and dried to give 
7-acetyl-1,2,3,4-tetrahydro-6-hydroxy-5-chloromethylnaphthalene, 98 g 
(78%) mp 88.degree.-90.degree.. 
(b) 7-Acetyl-1,2,3,4-tetrahydro-6-hydroxy-5-hydroxymethylnaphthalene 
To a solution of the product of step (a) (23.8 g) in ethanol (500 ml) was 
added a solution of potassium hydroxide (11.2 g) in ethanol (250 ml) and 
water (100 ml). The resulting mixture was heated on a steam bath for 30 
minutes, poured into water (2 l) and the mixture was made acid with 
concentrated hydrochloric acid. It was then extracted with ethyl acetate 
and the extracts were dried (MgSO.sub.4), filtered and the filtrate was 
evaporated to dryness leaving 
7-acetyl-1,2,3,4-tetrahydro-6-hydroxy-5-hydroxymethylnaphthalene as an 
oil, 21 g (95%). 
(c) Ethyl 
10-ethoxymethyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxyl 
ate 
A solution of the product of step (b) (15.4 g) in ethanol (50 ml) was added 
to one of sodium (4.0 g) in ethanol (50 ml). To this mixture was added 
diethyl oxalate (50 g) and the whole mixture was heated at-reflux for 2 
hours, then poured into a mixture of chloroform (500 ml) and concentrated 
HCl (100 ml). The organic layer was separated, evaporated to dryness and 
the residue was heated at reflux in ethanol (200 ml) containing 
concentrated hydrochloric acid (5 ml) for 2 hours. The solution was 
evaporated to dryness and the residue was taken up in ethyl acetate. This 
solution (was washed well with water, dried (MgSO.sub.4), filtered and the 
filtrate was evaporated to dryness leaving an oil. This was dissolved in a 
small amount of ethyl acetate and the solution was allowed to crystallise 
to give the title ester 6.3 g (30%), mp 115.degree.-6.degree.. It should 
be noted that under these reaction conditions the hydroxymethyl group of 
the starting naphthol has been converted into an ethoxymethyl grouping. 
(d) 
10-Ethoxymethyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxyl 
ic acid 
The product of step (c) (3.0 g) was hydrolysed to the corresponding acid mp 
239.degree. using the conditions of Example 5(b). 
(e) Sodium 
10-ethoxymethyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxyl 
ate 
The product of step (d) (2.1 g) was converted into its sodium salt-(2.0 g) 
by the method of Example 4(d). 
EXAMPLE 31 
6,7,8,9-Tetrahydro-10-(2,3-dihydroxyprop-1-yl)-4-oxo-4H-naphtho[2,3-b]pyran 
-2-carboxylic acid 
(a) Ethyl 
10-(2,3-epoxyprop-1-yl)-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2- 
carboxylate 
A solution of the allyl compound of Example 3(a) (10 g) in dichloromethane 
(150 ml) was stirred at 0.degree. while m-chloroperbenzoic acid (7.15 g) 
was added. The mixture was allowed to warm slowly to room temperature at 
which it was stirred for 2 days. The solution was washed with aqueous 
sodium metabisulphite, aqueous sodium bicarbonate and water and was dried 
(MgSO.sub.4). The drying agent was removed by filtration and the filtrate 
was evaporated to dryness leaving a white solid which was crystallised 
from ethanol to give the required epoxide, 3.0 g (29%), mp 
138.degree.-140.degree.. 
(b) Ethyl 
6,7,8,9-tetrahydro-10-(2,3-dihydroxyprop-1-yl)-4-oxo-4H-naphtho[2,3-b]pyra 
n-2-carboxylate 
To a solution of the epoxide from step (a) (5.0 g) in dioxan (100 ml) was 
added water (20 ml) and concentrated sulphuric acid (0.5 ml). The 
resulting solution was heated on a steam bath for 30 minutes then poured 
into a large volume of water (1 l) and the mixture extracted with ethyl 
acetate. The extracts were washed well with water, dried (MgSO.sub.4) and 
evaporated to small bulk. The title compound crystallised to give a yield 
of 2.7 g (78%), mp 142.degree.-4.degree.. 
(c) 
6,7,8,9-Tetrahydro-10-(2,3-dihydroxyprop-1-yl)-4-oxo-4H-naphtho[2,3-b]pyra 
n-2-carboxylic acid 
The ester product of step (b) (2.3 g) was hydrolysed to the title acid by 
the method of Example 5(b), mp 217.degree.-218.degree.. 
(d) Sodium 
6,7,8,9-tetrahydro-10-(2,3-dihydroxyprop-1-yl)-4-oxo-4H-naphtho[2,3-b]pyra 
n-2-carboxylate 
The product of step (c) (1.6 g) was converted into its sodium salt (1.6 g), 
by the method of Example 4(d). 
EXAMPLE 32 
10-(3-Chloro-2-hydroxyprop-1-yl)-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b] 
pyran-2-carboxylic acid 
(a) 
10-(3-Chloro-2-hydroxyprop-1-yl)-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b 
]pyran-2-carboxylic acid 
To a solution of the ester of Example 31(a) (10.0 g) in glacial acetic acid 
(150 ml) was added concentrated hydrochloric acid (75 ml) and the mixture 
was heated on a steam bath for 5 hours. This solution was diluted with a 
large volume of water (1 l) and the resulting solid was filtered and 
dried. The solid was crystallised from ethyl acetate to give the title 
acid, 3.3 g (30%), mp 242.degree.-4.degree. (decomp). 
(b) Sodium 
10-(3-chloro-2-hydroxyprop-1-yl)-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b 
]pyran-2-carboxylate 
To a suspension of the acid from step (a) (1.474 g) in water (30 ml) was 
added sodium bicarbonate (0.368 g) and the resulting solution was 
freeze-dried. The solid obtained was dried in vacuo to give the required 
salt, 1.4 g (89%). 
EXAMPLE 33 
4-Oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
2-Methyl-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho [2,3-b]pyran (0.06 
g) and selenium dioxide (0.44 g) were dissolved in 20% aqueous dioxan (30 
ml) and the resulting solution heated under reflux for 4 days. The 
reaction mixture was filtered and evaporated to dryness in vacuo. The 
residue was dissolved in ethyl acetate (200 ml). The resulting solution 
was filtered and extracted with saturated aqueous sodium bicarbonate 
(2.times.100 ml). The bicarbonate extracts were bulked acidified with 2 N 
aqueous hydrochloric acid and the resulting precipitate extracted into 
ethyl acetate (2.times.100 ml). The ethyl acetate extracts were bulked, 
dried (Na.sub.2 SO.sub.4) and evaporated leaving the title compound as a 
bright-yellow solid (0.18 g), mp 245.degree.-8.degree.. 
EXAMPLE 34 
Methyl 
5-methoxy-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carb 
oxylate 
A mixture of methyl 
2,3-dihydro-5-methoxy-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b] 
pyran-2-carboxylate (3.4 g) and N-bromosuccinimide (1.78 g) was heated at 
reflux in carbon tetrachloride (150 ml) for 6 hours. The solution was 
cooled, washed with water, dried (Na.sub.2 SO.sub.4) and evaporated. The 
residue was crystallised from petroleum ether (60.degree.-80.degree.) 
giving the title compound as a fawn solid, mp 92.degree.-3.degree.. 
EXAMPLE 35 
5-Hydroxy-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carbo 
xylic acid 
5-Hydroxy-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho 
[2,3-b]pyran-2-carbonitrile (1.0 g) was dissolved in a mixture of dioxan 
(20 ml) and dilute hydrochloric acid (20 ml) and heated under reflux for 
24 hours. The dioxan was evaporated in vacuo and the residue extracted 
with chloroform (100 ml). The chloroform solution was extracted with 
saturated aqueous sodium bicarbonate (50 ml) and then the bicarbonate 
extract acidified with dilute hydrochloric acid. The resulting precipitate 
was filtered off, washed with water and dried giving the title compound as 
a light-yellow solid, mp 260.degree.-2.degree.. 
EXAMPLE 36 
5-Hydroxy-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carbo 
xylic acid 
A suspension of 
5-methoxy-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carb 
oxylic acid (5 g) in 48% aqueous hydrobromic acid (130 ml) was heated under 
reflux for 7 hours. The reaction mixture was cooled and excess saturated 
aqueous sodium bicarbonate added. The resulting solution was filtered, the 
filtrate acidified with concentrated hydrochloric acid and then extracted 
with chloroform (100 ml). The chloroform solution was dried (Na.sub.2 
SO.sub.4) and evaporated leaving a residue which, when crystallised from 
acetone, gave the title compound as an orange crystalline solid mp 
259.degree.-260.degree.. 
EXAMPLE 37 
10-(2-Hydroxypropyl)-4-oxo-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carb 
oxylic acid 
To a stirred solution of sodium borohydride (0.4 g) in 0.02 N aqueous 
sodium hydroxide (30 ml) was added dropwise a solution of 
4-oxo-10-(2-oxopropyl)-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2carboxyl 
ic acid (2.3 g) in 0.02N aqueous sodium hydroxide (100 ml). The resulting 
solution was stirred at ambient temperature for 20 hours, then cooled in 
ice and acidified with dilute hydrochloric acid. The precipitate was 
filtered washed with water and dried giving the title compound as a white 
solid, mp 235.degree.. 
EXAMPLE 38 
4-Oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
A mixture of 
10-propyl-6,7,8,9-tetrahydro-4-thioxo-4H-naphtho[2,3-b]pyran-2-carboxylic 
acid (0.025 g), methyl iodide (3 drops), acetone (10 ml) and water (4 
drops) was stirred in the dark at ambient temperature for 2 days. 
Concentration of the reaction mixture in vacuo gave a brown solid which on 
crystallisation from acetone gave the title compound as a light-yellow 
solid, mp 245.degree.-8.degree.. 
EXAMPLE 39 
5-Methoxy-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carbo 
xylic acid 
A solution of 
5-methoxy-10-propyl-4-spiro-2'-(1',3'-dithiane)-6,7,8,9-tetrahydro-4H-naph 
tho[2,3-b]pyran-2-carboxylic acid (0.1 g) and periodic acid (0.1 g) in a 
mixture of acetone (15 ml) and water (5 ml) was stirred at ambient 
temperature for 2 hours. Removal of the acetone in vacuo produced a solid 
which was extracted into chloroform (100 ml). The chloroform was washed 
with water, dried (Na.sub.2 SO.sub.4) and evaporated leaving a solid 
which, when crystallised from acetone, gave the title compound as a 
bright-yellow solid, mp 228.degree.-9.degree.. 
EXAMPLE 40 
4-Oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
To a refluxing solution of 
4-oxo-10-(2-oxopropyl)-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxy 
lic acid (3.1 g) in water (100 ml) containing sodium hydroxide (0.12 g) was 
added portion-wise sodium borohydride (3.04 g). The resulting mixture was 
heated under reflux for 2 hours. After cooling the solution was acidified 
with concentrated hydrochloric acid and the precipitate filtered off, 
washed with water and dried giving the title compound as a white solid, mp 
235.degree.. 
EXAMPLE 41 
Ethyl 
5-fluoro-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylate 
A solution of ethyl 
5-chloro-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylate (9 g) and desiccated potassium fluoride (2.32 g) in DMF (50 ml) was 
heated at 160.degree. for 3.5 hours. After cooling, the reaction mixture 
was poured into water (250 ml) and the precipitate filtered off, washed 
with water and dried. Recrystallisation from cyclohexane gave the title 
compound as a pale-yellow solid, mp 126.degree.-9.degree.. 
EXAMPLE 42 
Ethyl 
6,7,8,9-tetrahydro-4-oxo-10-(2-styryl)-4H-naphtho[2,3-b]pyran-2-carboxylat 
e 
N-Butyl lithium (0.23 g) was added to a stirred suspension of benzyl 
triphenyl phosphonium chloride (1.34 g) in dry ether (75 mls) under 
nitrogen. After 25 minutes the product compound of Example 29(b) (1 g), 
suspended in dry ether (50 mls) was added. The reaction was allowed to 
stir for 65 hours and then poured into water (250 mls). The resulting 
mixture was extracted into methylene chloride (3.times.100 mls), which was 
then dried and evaporated to give a yellow solid (2.15 g). Chromatography 
on a silica column with ether as eluant produced the title compound as a 
crystalline yellow solid (1.25 g, 100%) mp 168-169. The ester may be 
hydrolysed to the free acid. 
EXAMPLE 43 
Ethyl 
6,7,8,9-tetrahydro-4-oxo-10-(2-phenylethyl)-4H-naphtho[2,3-b]pyran-2-carbo 
xylate 
The product of Example 42 (0.6 g) in ethanol (150 mls) was hydrogenated 
over a 5% Pd/C catalyst (0.2 g) at atmospheric pressure. When the 
theoretical amount of hydrogen had been absorbed the catalyst was removed 
and the solvent evaporated to afford the title compound as a yellow solid 
(0.6 g, 100%) mp 156-158. The ester may be hydrolysed to the free acid. 
EXAMPLE 44 
5-Methoxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
(a) Ethyl 5-methoxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
The product of Example 28(a) (4.5 g) and potassium carbonate (2.0 g) were 
stirred together in dimethylformamide (150 ml), containing methyl iodide 
(6 ml), at room temperature for 24 hours. Further quantities of methyl 
iodide were added in portions of 2 ml, over the next 10 hours, until the 
total volume of the reagent used was 20 ml. Finally the mixture was heated 
on a steam bath for 1 hour, then cooled and poured into water. The 
resulting mixture was extracted into ethyl acetate and the organic layer 
was dried (MgSO.sub.4) and evaporated, in vacuo, to yield the title ester 
(4.0 g) as a red oil. 
(b) 5-Methoxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid 
The ester from step (a) (4.0 g) was hydrolysed to the corresponding acid 
(3.5 g) mp 245.degree.-247.degree., using the method of Example 5(b). 
(c) Sodium 5-methoxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate 
The product of step (b) (3.4 g) was converted into its sodium salt (3.3 g) 
by the method of Example 4(d). 
EXAMPLE 45 
7,8-Dihydro-6-methyl-4-oxo-4H,6H-benzo[1,2-b, 5,4-b']dipyran-2-carboxylic 
acid 
(a) 2,3-Dihydro-4-hydroxy-7-methoxy-4-methyl-4H-1-benzopyran 
Methyl iodide (145 g; 64.2 ml) in dry ether (50 ml) was added dropwise with 
stirring to magnesium turnings (22 g) in dry ether (730 ml). After the 
initial reaction had ceased the reaction mixture was refluxed for 1/2 
hour, cooled and 2,3-dihydro-7-methoxy-4-oxo-4H-1-benzopyran, (77.9 g) in 
dry ether (440 ml) was added dropwise with stirring. After addition the 
reaction mixture was refluxed for 1 hour, cooled and the complex was 
decomposed by the addition of ammonium chloride solution. The ethereal 
layer was separated, washed with water and dried. Evaporation of the 
solvent left 76 g of the title compound as an oil (89%). MS and NMR 
analysis were correct for the required compound. 
(b) 7-Methoxy-4-methyl-2H-1-benzopyran 
The carbinol of step (a) (73.3 g) was stirred with phosphorus oxychloride 
(19.3 g; 11.6 ml) in dry pyridine (380 ml) for 20 hours under nitrogen. 
The reaction mixture was poured into water, extracted with ether and the 
ethereal extracts were washed with dilute acid, then sodium bicarbonate 
solution, then water and dried. Evaporation of the solvent left 58 g of 
residue (87.2%). MS evidence was correct for the required compound. NMR 
suggested that the product was in fact a mixture of isomeric alkenes. 
(c) 2,3-Dihydro-7-methoxy-4-methyl-4H-1-benzopyran 
The alkene mixture of step (b) (29 g) was dissolved in ethanol (300 ml) and 
hydrogenated in the presence of 5% palladium on charcoal (1.0 g) at 45 
psi; until hydrogen uptake had ceased. The catalyst was filtered off 
through a supercel filter aid and the filtrate was evaporated to give the 
desired compound 29.2 g (99.4%). NMR and MS analysis were correct for the 
required compound. 
(d) 6-Acetyl-2,3,-dihydro-7-methoxy-4-methyl-4H-1-benzopyran 
The methyl ether of step (c) (58.0 g) was dissolved in dry benzene (1 l) 
and glacial acetic acid (22.3 ml) was added. Boron trifluoride gas was 
bubbled through the reaction mixture for 1 hour and then stirring was 
continued overnight. The reaction mixture was poured into water, the 
organic layer was separated and the aqueous phase was extracted with more 
ether. The organic extracts were washed with sodium bicarbonate solution, 
then water, and dried. Evaporation gave 67.8 g of the desired product 
(95%). MS and NMR analysis were correct for the required compound. 
(e) 6-Acetyl-2,3,-dihydro-7-hydroxy-4-methyl-4H-1-benzopyran 
The product of step (d) (57.4 g) in dry methylene chloride (500 ml) was 
treated with boron trichloride (61 g) in dry methylene chloride (150 ml) 
at -70.degree. C. The cooling bath was removed and the reaction mixture 
was allowed to warm to room temperature during 1 hour. The reaction 
mixture was poured into water and the methylene chloride layer was 
separated, washed with water and dried. Evaporation of the solvent left 
55.7 g of crude product; this was dissolved in ether and extracted several 
times with a sodium hydroxide solution. The basic extracts were acidified 
and the precipitated product extracted with ether, which was washed with 
water and dried. Evaporation of the solvent gave 36.4 g of product mp 
91.degree.-96.degree.. A recrystallisation from ethanol gave the title 
compound, mp 104.degree.-105.degree.. 
(f) Ethyl 7,8-dihydro-6-methyl-4-oxo-4H,6H-benzo[1,2-b, 
5,4-b']dipyran-2-carboxylate 
The product of step (e) (17.7 g) was treated with sodium (9.9 g) and 
diethyl oxalate (31.4 g) under the conditions of Example 1(d), to give the 
title compound (23.5 g), mp 114.degree.-115.degree.. 
(g) 7,8-Dihydro-6-methyl-4-oxo-4H,6H-benzo[1,2-b: 
5,4-b']dipyran-2-carboxylic acid 
The ester of step (f) (21.5 g) was hydrolysed to the corresponding acid 
(13.9 g, mp 293.degree. (decomp), by the method of Example 5(b). 
(h) Sodium 7,8-dihydro-6-methyl-4-oxo-4H,6H-benzo[1,2-b: 
5,4-b']dipyran-2-carboxylate 
The acidic product from step (g) (5.0 g) was converted into its sodium salt 
(4.8 g), using the conditions of Example 4(d). 
EXAMPLE 46 
The following compounds may be made according to the processes described 
above:- 
(i) 
6-Ethyl-6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbox 
ylic acid. 
(ii) 6,7,8,9-Tetrahydro-7-methyl-4-oxo-10-propyl-4H-naphtho 
[2,3-b]pyran-2-carboxylic acid. 
(iii) 
6,7,8,9-Tetrahydro-4-oxo-3,10-dipropyl-4H-naphtho[2,3-b]pyran-2-carboxylic 
acid. 
(iv) 7,8-Dihydro-6-methyl-4-oxo-10-propyl-4H,6H-benzo[1,2-b: 
5,4-b']dipyran-2-carboxylic acid. 
(v) 6-Ethyl-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylic 
acid. 
(vi) 6,7,8,9-Tetrahydro-7-methyl-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylic 
acid. 
(vii) 7,8-Dihydro-4-oxo-10-(2-styryl)-4H,6H-benzo[1,2-b 
5,4-b']dipyran-2-carboxylic acid. 
(viii) 7,8-Dihydro-4-oxo-10-(2-phenylethyl)-4H,6H-benzo[1,2-b: 
5,4-b']dipyran-2-carboxylic acid. 
(ix) 10-(2-Chloropropyl)-6,7,8,9-tetrahydro-4-oxo-4H-naphtho 
[2,3-b]pyran-2-carboxylic acid. 
(x) 
10-(Cyclohexylmethyl)-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-ca 
rboxylic acid. 
(xi) 
10-(n-Hexyl)-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxylic 
acid. 
(xii) 6,7,8,9-Tetrahydro-4-oxo-10-(3-oxobutyl)-4H-naphtho 
[2,3-b]pyran-2-carboxylic acid. 
(xiii) 
10-(Hex-1-enyl)-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2-carboxyl 
ic acid. 
(xiv) 
10-(2-Cyclopentylethyl)-6,7,8,9-tetrahydro-4-oxo-4H-naphtho[2,3-b]pyran-2- 
carboxylic acid. 
(xv) 10-(Cyclohexylmethyl)-7,8-dihydro-4-oxo-4H,6H-benzo[1,2-b: 
5,4-b']dipyran-2-carboxylic acid. 
(xvi) 
6,7,8,9-Tetrahydro-5-methyl-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carbo 
xylic acid. 
EXAMPLE A 
______________________________________ 
mg/ % by 
Tablet formulation tablet weight 
______________________________________ 
1. Compound of formula I, e.g. of Example 8(a) 
15 9.3 
2. Mannitol BP 90 55.5 
3. Maize Starch BP 15 9.3 
4. Microcrystalline cellulose BPC 
30 18.5 
5. Polyvinylpyrrolidone 10 6.2 
6. Magnesium stearate BP 2 1.2 
______________________________________ 
Items 1-4 are dry mixed, then moistened with an aqueous solution of item 5, 
passed through an 8 mesh screen and dried for 3 hours at 60.degree. C. The 
dry product is passed through a 16 mesh screen and blended with item 6. 
The final mixture is compressed to a Monsanto hardness of 3 to 5 kg. 
______________________________________ 
mg/ % by 
Capsule formulation tablet weight 
______________________________________ 
1. Compound of formula I, e.g. of Example 1(f) 
15 9.6 
2. Lactose BP 90 57.3 
3. Maize starch BP 50 31.8 
4. Magnesium stearate BP 2 1.3 
______________________________________ 
All of the ingredients are blended and filled into empty hard gelatin 
capsule shells on a capsule filling machine.