DE2120443A1 - Chromone-2-carboxylic acid compounds and processes for their preparation, and pharmaceutical compositions containing them - Google Patents

Description

2 1 7 O UL 3

PATENTANWÄLTE * I * V f · »ν

dr. W.Schalk dipl.-ing. P. Wirth dipl.-ing. C. Dannenberc DR.V. SCHMIED-KOWARZIK · DR. P. WEINHOLD · DR. D. GUDEL

6 FRANKFURT AM MAIN

01. CtCHINHIlMfR «TRASS! »♦

BA 20002/70
Wd / CW-500

FISONS LIMITED
Harvest House,
Felixstowe, Suffolk, England

Chromone-S-carboxylic acid compounds and processes for their preparation, and pharmaceutical compositions containing them

The present invention relates to chromone-2-carboxylic acids, their manufacture and compositions containing them.

The invention relates to compounds of the formula I

where P, Q, T, P, Q and T. can be the same or different and each group can be hydrogen or some other substituent can,

R is hydrogen or an optionally substituted alkyl or alkoxy group having about 1 to 10 carbon atoms or an optionally substituted aryl group,

1? 1

R "is hydrogen, a -COCHpR - group, an alkyl group or

an alkyl-substituted allyl group of up to 6 carbon atoms is,

X is a carbon-carbon bond or a single atom

109846/1954

OR) GtNAL

wofe @ l the single atom can carry substituents that are not part of the chain itself between the two benzene nuclei and

W is a hydrogen atom or a -COCHoR - group and pharmaceutically acceptable derivatives thereof.

The invention also relates to processes for production a compound of the formula I and pharmaceutically usable Derivatives thereof, which include:

a) The preparation of a compound of formula Ia

p P 'ρ ¹

UWl

Λ Λ Jt Λ Jt *)

where P, Q, T, P, Q, T, E, R and ¥ have the meaning given above comes to

X represents a sulfur or oxygen atom, by reacting a compound of the formula II O

KOOC

1
where P, Q, R and T are as defined above,

L a good leaving group or a -XY - group, where Y is hydrogen or an alkali metal means and

R is hydrogen or forms an ester group together with the 00C group

109846/1954

with a compound of the formula III,

P ¹

III

) R ¹² V

where P _f Q, T, R and V have the meaning given above

2 11

and L is easily cleavable if L is a -X Y group

1 1

and a -X Y group, provided that L can be easily split off,

b) Production of a compound with the formula I by ring formation of the groups A ι
with the term VI,

1 2
Formation of groups A and A in a corresponding connection

VI

111 12
where P, Q _f T, P, Q _f T, ¥, R and X have the meaning given above and

1 2

A and A represent the group pairs

i) -COCHR ¹ COGOr ⁶ and -OM
or ii) -H and -0-C (COOM) = CR ¹ -COOM

wherein R is an -OM group or a group convertible therein,

M is hydrogen or an alkali metal and R is as defined above,

c) Preparation of a compound of the formula Ic

109846/1954

OOCH "R

OH

Ic

1111 wherein P, Q, T, P , Q , T, R and X are as defined above

i) performing a Fries rearrangement to a corresponding compound of formula Id, ₄

QQ ¹ 'T ¹

OCOCH ₂ R ¹

Id

1111 wherein P, Q, T, P, Q., T, R, R and X is as defined above, or

ii) opening of the pyrone ring of an individual chromone nucleus in a corresponding compound with the formula VIII,

VIII

1 1 1 1
wherein P, Q, T, P, Q, T, R, R and X are as defined above, under alkaline conditions.

d) Production of a compound of the formula I by hydrolysis or oxidation of a corresponding compound with the formula IX,

109846/1954

BATH ORIGINAL

OR

IX

1 1 1 12 1

wherein P, Q, T, P, Q, T, X, V, R and R are as defined above and

D represents a group which can be hydrolyzed to a -COOH group or is oxidizable,

e) Preparation of a compound of the formula I by dehydrogenation a corresponding compound with the formula X,

Q Q

A A A A 12

wherein P, Q, T, P, Q, T, X, W, R \ R and R are as defined above comes to

f) preparation of a compound with the formula If,

If

112
wherein R, X, W, R and R have the meaning given above and

Pf, Qf, Tf, PT ¹ , Qf ¹ and Tf ^{1 have the} same meaning as P, Q, T, P ¹ , Q ¹ and T above, with the proviso that at least one of the

11 1

Groups Pf, Of, Tf, Pf, Qf and Tf an alkyl group with at least

109846/1954

represents two carbon atoms,

by creating a corresponding compound of the formula XI

XI

1 12
where R, X, W, R and R are as defined above and Pg, Qg, Tg,

111 11

Pg, Qg and Tg. Have the same meanings as P, Q ₉ T, P, Q and T above, provided that at least one of the groups

• 111

pen Pg, Qg, Tg, Pg, Qg and Tg represent an alkenyl group, is selectively hydrogenated, g) preparation of a compound with the formula Ig ₉

1 11

wherein P, Q, T, R, X, W and R. are as defined above and Pq, Qq

1 111 "

and Tq have the same meaning as P, Q and T above, with

11 1

with the exception that at least one of the groups Pq, Qq and Tq represents an allyl group or an alkyl-substituted allyl group with up to 6 carbon atoms,

by heating a compound with the formula

PP *

T ^ Q QrI tv ¹

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1 1

wherein P, Q, T, R, X, W and R are as defined above and Pr,

11 111

Qr and Tr have the same meaning as P, Q and T above, below

1 1 the requirement that at least one of the groups Pr, Qr

and Tr represents hydrogen and

11
R is an alkyl group or an alkyl-substituted allyl

group with up to 6 carbon atoms,
to increased temperatures,

h) Preparation of a compound of the formula Id, wherein a compound of the formula Ih

You

where P, Q, T _f P, Q, T _t X, W, R and R are as defined above,

is reacted with a compound of the formula R CH ₂ COOH or an anhydride or a halide thereof, or

i) Preparation of a compound with the formula Ik 0 PP ¹ . 4th

RDX

111 1 11

wherein Ρ, Ο, 'Τ, Ρ, Q, T, W, R, R, X and R are as defined above, by reacting a compound of the formula Im

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BAD OfUGtNAL

wherein P, Q, T, P, Q, T, V ₁ X ₁ R and R are as defined above,

11 11

with a compound of the formula R Hai, wherein R is as above is defined and Hai represents an active halogen atom,

optionally or necessarily converting the compound of the formula I into a pharmaceutically acceptable derivative thereof is converted or vice versa.

In process a) the active halogen atom, for example iodine, or a correspondingly active anion-forming group, for example a p-toluenesulfonate or a methylsulfonate group, can be. An alkali metal atom is preferred for Y. The reaction can, if appropriate, be carried out in the presence of a catalyst, such as, for example, copper-I-iodide. It can be carried out in a solvent which is inert under the reaction conditions, such as, for example, 2: 4: 6-trimethylpyridine, and preferably at an elevated temperature, for example between about 100 and 170 ^° C.

The cyclization of process b) i) can be carried out by heating or under basic or neutral conditions. However, it is preferred to carry out the cyclization in the presence of an acid, for example hydrochloric acid, and in a solvent which is inert under the reaction conditions. The reaction may be carried out at about 20 to 150 ⁰ C. The -COR group is preferably a group which can be hydrolyzed to a -COOH group, for example an ester group.

The cycling of process b) ii) is carried out by e.g. the compound of formula VI with a cyclizing agent, e.g.

1 09846/1954

"■: / ■ -, - ■;: .- ■■ BAD ORIGINAL

-9 - 2120W3

a dehydrating agent such as polyphosphoric, chlorosulfonic or sulfuric acid. The reaction will preferably carried out under anhydrous conditions. The cyclization can also be carried out by converting the free carboxyl groups of the compound of formula VI to acyl halide, for example acyl chloride groups, are achieved, the resulting Acyl halide is subjected to an intramolecular Friedel-Crafts reaction.

Process c) i) can be carried out under conditions which are customary for a Fries rearrangement, for example by Treatment of the compound of the formula Id with aluminum chloride or titanium chloride in a solvent under the reaction conditions is inert, e.g. nitrobenzene, at an elevated temperature.

Process c) ii) can be carried out using just as much alkali as is sufficient, one of the compounds in the compound of the formula VIII present chromon nucleus to hydrolyze. So the reaction can be carried out by adding 1 equivalent of an acid of formula VIII with one equivalent of an alkali metal allhydroxyds, e.g. sodium hydroxide. Y / ird an ester of the formula VIII is used or the compound of ' If formula I in the form of a salt is desired, a larger amount of alkali should be used.

In process d) the group D can be an ester, amide or nitrile group each of which hydrolyzes to a -COOH - group can be. The hydrolysis can be carried out using conventional methods, e.g. hydrolyzing an ester using a base such as sodium hydroxide, carbonate or bicarbonate in an aqueous alcohol medium will. The amide can be hydrolyzed under acidic conditions, e.g., by refluxing into a hydrogen bromide solution in acetic acid. The nitrile can, also under acidic Conditions are hydrolyzed, e.g., by reflux in a

1098-48 / 1954

Hydrogen chloride solution in dioxane. Optionally, group D can be a Alkyl such as methyl, aralkenyl such as styryl, acyl such as acetyl, or an aldehyde such as a formyl group. The oxidation can be carried out using conventional methods, for example an alkyl group can be carried out using Selenium dioxide are oxidized, for example under reflux in aqueous dioxane, or chromic acid, for example under reflux in aqueous acetic acid. Aralkenyl groups can be oxidized by adding, for example, neutral or alkaline potassium permanganate in aqueous ethanol is used, and acyl groups can be oxidized by, for example, chromic acid or an aqueous hypochlorite such as sodium hypochlorite "is used. Aldehyde groups can be oxidized by for example chromic acid or silver oxide is used.

The dehydrogenation of process e) can be carried out by oxidation, using, for example, selenium dioxide, palladium black or chloranil in a solvent which is inert under the reaction conditions, such as, for example, amyl alcohol; the reaction is preferably carried out at an elevated temperature, for example under reflux. The dehydrogenation can also be carried out indirectly by halogenation and then by dehydrohalogenation, for example by treatment with N-bromosuccinimide or pyridinium bromide perbro mLd in a solvent that is inert under the reaction conditions, which is then followed by the dehydrobromination of the 3-bromine compound formed. '-

The hydrogenation of process f) can be carried out in a solvent be carried out which is inert under the reaction conditions, such as ethyl acetate, and in the presence of a hydrogenation catalyst, such as palladium or platinum on charcoal. The reaction is conveniently carried out at room temperature under atmospheric or something greater than atmospheric pressure.

109846/1954

In process g), the reaction can take place for a Claisen rearrangement usual conditions are carried out.

In process h), the reaction can be carried out under the conditions customary for carrying out acylation reactions for example in a solvent which is inert under the reaction conditions, e.g. dry pyridine,

In method i) the atom shark can be a bromine clay and the The reaction can be carried out in a solvent which is inert under the reaction conditions, such as acetone, in Presence of an acid binder such as potassium carbonate and optionally in the presence of a catalyst such as potassium iodine.

In all of the methods mentioned above, the group R can be a lower alkyl group such as ethyl group.

Compounds of the formulas II and III are either known or can be used in analogous ways that are used in the preparation of similar known compounds are known.

1 2 'Compounds of the formula VI in which A and A represent the group pair -COCHR COCOR and -OM can be prepared by adding a compound of formula VIa

Via

111 12
wherein Ρ, Ο, Τ, Ρ, Q _t T, X, R and W are as defined above and

1 1

W is a -COCH ₂ R - group,

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with a sufficient amount of a compound of the formula R COCOR to convert ¥ to a -COCHR COCOR - group.

1 2 Compounds of the formula VI, in which A and A are the group pairs -H and -0-C (COOM) = CH-COOM can be obtained by reacting a compound of the formula VIb

VIb

p ¹² n ^ L ^ ^ ₁ VJL _nH

111 12

where P, Q, T, P, Q, T, X, R and ¥ are as defined above,

with enough dialkyl, for example dimethylacetylene dicarboxylate, to convert only the -OH group on the ring that does not carry the -V group to the -0-C (COO-alkyl) = CH-COO-alkyl group, and hydrolysis of the product, the desired -0-C (COOM) = CH-COOM group being obtained.

Compounds of formula VIII can be prepared by treating a compound of formula Villa.

R ⁵ OCOCCHR ¹ OC ^ _ ^^ CV "^ COCHR ¹ COCOr ⁶

villa

where P, Q, T, P, Q, T, M, X, R and R are as defined above, be made with acid.

Compounds of the formula Villa can be made by

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for example a compound of formula VIIIb

HO

VIIIb

wherein P, Q, T, P ¹ , Q 1, T ¹ , R and X are as defined above, with a compound of the formula R COCOR, for example with diethyloxalate.

Compounds of the formula Via, VIb and VIIIb can be prepared by the corresponding monobenzoid compounds by processes analogous to process a) given above are or using other known methods or, if X is a carbon-carbon bond, by a Ullmann reaction, or if X is a -CHp- group, through Implementation of a corresponding activated dihydroxybenzene compound with diiodomethane under alkaline conditions in Presence of an inert solvent, condensation of a corresponding phenol with formaldehyde or under. use of a benzyl halide (or a benzoyl halide with subsequent reduction) in a Friedel-Craft reaction will.

Compounds of the formula IX can be prepared by methods analogous to those given above for the preparation of compounds of the formula I. or, in certain cases, are formed from compounds of the formula I.

Compounds of the formula X can be prepared by selective hydrogenation of the corresponding compound of the formula I or by cyclization, for example by treating a compound of the formula XII-109846/1954

. R ¹
I.

ROOC-CH = CCO

XII

with a base in a solvent that is inert under the reaction conditions,

where P, Q, T, P, Q, T, W, X, R and .. R are as defined above.

Compounds of the formula XII can be prepared by reacting a compound of the formula VIa with glyoxalic acid or an ester thereof or a compound of the formula VIb with maleic anhydride in a suitable solvent and in the presence of a Lewis acid, for example aluminum chloride.

The compounds of the formula I are valuable as intermediates in the preparation of the compounds of the formula VIII, wherein the compounds of Formula VIII are themselves for use in the treatment of allergic asthma at one dosage from about 0.1 to 50 mg can be applied. The compounds of the formula I can be analogous to compounds of the formula VIII .Process for the above for the preparation of compounds of the formula VIII, and for the preparation of compounds of the formula I, starting from compounds of the formula VI described processes are converted.

The compounds of the formula I and their pharmaceutically usable ones Derivatives, e.g. their pharmaceutically acceptable salts, esters and amides, e.g. their sodium salts and lower alkylamine, e.g., ethylamine salts ^ and their amides with Amino acids, such as glycine, are also valuable as they possess pharmacological properties. In particular, these compounds act against the slowly acting anaphylaxis

109846/1954

BAp ORIGINAL

substances or their pathological effects as antagonists, e.g. from their effectiveness in the following Try shows:

1. SRS-A (obtained by collecting lung perfusate from ovalbumin sensitized guinea pigs during a time of 1.5-10 minutes after the antigen attack) is used to achieve reproducible subraaximal continuous contractions of an isolated guinea pig Ileum preparation in the presence of an antihistamine (to prevent a disturbing influence due to the histamine, which is also present in SRS-A preparations). The anti-SRS-A effectiveness of the compound will be as the dose (added to the ileum 30 seconds before the SRS-A) determined to reduce the 50 # contractions caused by SRS-A are necessary is. '.

2. SRS-A (as obtained in 1.) was taken at 10-minute intervals anesthetized guinea pigs that were pretreated with an antihistamine were injected intravenously during the resistance against inflation during artificial respiration was recorded. Corresponding effects on the bronchoconstictor of similar strength are obtained with an appropriate dose of SRS-A. The anti-SRS-A effect in vivo of the intravenously administered compound is given as the smallest dose that the bronchoconstrictor effect, which was caused by SRS-A was prevented significantly (P <0.05). The effectiveness of the Compound was also studied after aerosol inhalation or oesophageal administration.

The compounds can be applied in the same way as those of Dutch patent application 6811740.

Thus, the compounds can be used in the treatment of disorders,

109846/1954

in which SRS-A plays a role, e.g. skin disorders, hay fever or respiratory diseases, such as asthma, be used.

For the purposes indicated above, the administration dose varies of course, depending on the compound used, the mode of administration and the one desired Treatment. In general, however, a daily administration dose of about 1 to 10 mg per kg of body weight is obtained of the animal, which is preferably administered in divided doses 2 to 4 times daily or as permanent release preparations, satisfactory Results. For larger mammals, the total daily dose is between about 50 and 700 mg, and that for Doses suitable for oral administration include about 12 to 350 mg that with a solid or liquid pharmaceutical Carrier or diluent mixed compound. The compounds can be used during or before the attack of illness to be treated administered.

The compounds can be used as a sterile mixture with a pharmaceutical usable diluents or carriers can be administered, the composition used being of many factors «! including the disease to be treated. The invention thus creates such a mixture, as well as a method for the preparation thereof which comprises admixing the active ingredient with the carrier or diluent Compounds can be administered parenterally, orally, by inhalation, or topically.

The invention also relates to a process for the preparation of a pharmaceutically acceptable salt of a compound of the formula I directed, a process comprising treating a compound of the formula, an ester or other salt thereof with a suitable base such as sodium base.

Other pharmaceutically acceptable derivatives of the compounds of formula I, e.g. esters and amides (simple or of a

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2120U3

Amino acid such as e.g. Glycine, derived amides) can be made from the compounds of Formula I can be prepared using conventional methods.

The -X atom can be an oxygen or sulfur atom, a substituted one Sulfur or nitrogen atom, or a methylene group or a substituted methylene group. Specific Examples of such substituted atoms are the group

2 2

-SO-, -SO ₂ -, -CO-,> NH and) NR - groups, where R is an alkyl, alkenyl, alkoxy, aralkyl, aryl, acyl, hydroxy, carboxy radical or a carbocyclic or is heterocyclic ring, and the groups or rings preferably contain less than 10 carbon atoms or such groups or rings carry a hydroxy, halogen, lower alkyl, lower alkoxy or phenyl substituent. Examples of the latter groups are the ^ NCH-2 or ^ NC ₃ H ₇ - group.

¥ 0 -X- is a substituted methylene group, it can have the formula / C (R) ₂ , in which each group R independently of one another is hydrogen, hydroxy, halogen; Alkyl, alkenyl or alkynyl, where in the last 3 groups a carbon atom can be replaced by a / 'sulfur or nitrogen atom or a carbonyl group or an amide or ester chain, the alkyl, alkenyl or alkynyl groups being a halogen, hydroxy - Can carry carboxy or alkoxy substituents; a carboxylic acid group (including salts, esters and amides thereof); an aryl, aralkyl, aryloxy or aralkoxy group which can carry any of the substituents listed above; or a heterocyclic one

can be _t

or carbocyclic ring / which can carry any of the substituents indicated above. The methylene group may also have substituents, these are connected by double bonds jt _m, as is the case with the Group II) c = 0, ^ C = O ') C = S or) C = ^. The substituted methylene group preferably contains less than 10 carbon atoms.

Preferred forms of -X- are those in which the --X- Abom or substituted atom> CH ₂ ,) CHpH,) C (R ⁴ ) ₂ ,) C = 0, ^ CHCOOK,

109846/195 4

OBIGlNAL

> CHC00R ⁴ , ^ C = CCi ₂ , iCHni ^ J,> NH, -S-, -SO-, -SO ₂ - and -0-, where R is a lower alkyl group, ζ. 'Β. Ethyl, propyl or pentyl group.

The term "lower" is used here in the sense of about 1 to 6 Group containing carbon atoms- used.

11 1

The P, Q, T, P, Q and T substituents can carry straight or branched straight or branched chain alkyl groups with, for example, about 1 to 8 carbon atoms (for example methyl, ethyl or isopropyl groups) which _{carry one or more hydroxy T} , lower alkoxy or halogen substituents can, like · ζ.Β. a hydroxymethyl, hydroxypropyl, ethoxyethyl or chloromethyl group; alkoxy corresponding to the above alkyl groups, such as, for example, an isopropoxy, a hydropropoxy or an ethoxyethoxy group; Alkenyl or alksnyloxy which corresponds to such alkyl or alkoxy groups; Amino, which may have a substituent such as a lower mono- or dialkylamino group; Amino-lower alkoxy which can carry a substituent, such as, for example, a di-lower-alkyl-amino-lower-alkoxy group; a nitro group; a hydroxy group; or a halogen atom. Specific examples of the

111
Groups P, Q, T, P, Q and T are chlorine, bromine, "iodine, hydroxy,.

Acetoxy, nitro, methyl, ethyl, propyl, butyl, tert-butyl, Allyl, 1-methyl-allyl, prop-1-enyl, methoxy, ethoxy, propoxy, Butoxy, allyloxy, but-3-enoxy, acetyl, hydroxymethyl, ethoxymethyl, Chloromethyl, 2-chloroethoxy, 2-iodoethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 2-hydroxybutoxy, 3-methylbutoxy, 2-ethoxyethoxy, 3-methoxy-2-hydroxypropoxy, 3-butoxy-2-hydroxypropoxy, diethylaminoethoxy, aminoethylamino, acetylamino or hydrogen.

1
R can be lower alkyl, for example methyl, ethyl, propyl or pentyl, lower alkoxy or phenyl.

Preferred compounds of the formula I are those in which the -X- group is attached to the 6- or 7-position of the chromonic nucleus

109846/1954

BAD ORiGlNAt

is bound. It is also preferred that the -X- group in

1 Para position either to the -OH - group or the -COCH ₂ R group.

Preferred connecting groups are those in which the group X is a sulfur or oxygen atom or a -CH ₉ - group, where P to T is hydrogen, or one of them is lower alkyl or lower alkenyl and in which both R groups are hydrogen.

The following examples serve to illustrate the invention without restricting it. The temperatures are given in ⁰ C and the parts are based on weight.

Example 1 .

6- (3-Acetyl-4-hydroxyphenylthio) -4-OXO-4H-1-benzopyran-2-carboxylic acid

a) 4-iodophenoxy-fumaric dimethyl ester

A solution of p-iodophenol (119 g), acetylenedicarboxylic acid dimethyl ester (71 g) and benzyltrimethylammonium hydroxide solution (40% w / v in water) (1 ml) in ethanol (250 ml) was refluxed for 10 minutes, cooled, filtered and washed with ethanol, whereby

4-Jodphenoxyf umardimethylester, F.ρ »95-8 ° C, received.

The recrystallization increased the melting point to 101-2 C.

Analysis:

Found: C 40.1% H 2.95% M.G. (Mass spec.) 362 ber .:

C 39.8% H 3.04% M.G. 363

b) 4-iodophenoxyfumaric acid

A solution of 4-iodophenoxy-fumaric dimethyl ester (72.4 g)

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and sodium hydroxide (16.5 g) in 5 6 w / v. aqueous ethanol was refluxed for -2 hours. The solution was acidified and ethanol was evaporated. The yellow solid which precipitated on cooling was filtered off, washed with water §er and recrystallized from water to give 4 = £ odphenoxyfiimarsäure having a melting point of 229-34 ⁰ C. Recrystallization from water raised the melting gunkt to 237 ^ -8 ° C _t

Analysis: | 5. 196 H 1.9696 996 H 2.1 % fcer ,?

2 ^ carboxy-6-4odchromon

A mixture of 4 = iodophenpxyfumaric acid (33 »4 g) and concentrated sulfuric acid (66 ml) was heated on a water bath for 10 minutes. The resulting solution was added dropwise to stirred ice water (11). The precipitated solid was äbfiltriert, washed with water and recrystallized from ethanol to give 2-carboxy-6-jodchromon having a melting point 258-61 yon received ⁰ C.

Recrystallization from ethanol raised the melting point

to 262-63 ⁰ C 38 , 0% H 1 .53% Analysis: 38 H 1 .58% found: C ber .: C

M.Q. (Mass spec) 316 M.G. '316

d) 2-ethoxycarbonyl-6-iodochromone

2-carboxy-6-iodochromone (15.8 g) was dissolved in ethanol (100 ml) suspended and heated to reflux. A slow stream of gaseous hydrogen chloride was passed through the refluxing suspension for 90 minutes. The suspension was then cooled, filtered and treated with ethanol

109846 / 19S4

wash, taking 2-Xthoxycarbonyl with a melting point of 147-9 ° C.

Analysis:

found: C 41.8% H 2.48% J 36.4% M.G. (mass spec) calc .: C 41.87% H 2.62% J 36.9% M.G.

C ₁₂ H ₉ JO ₄

The structure was confirmed by nuclear magnetic resonance.

e) 2-hydroxy-5-mercaptoacetophenone

To a stirred solution of 5-amino-2-hydroxyacetophenone hydrochloride (93.8 g) in aqueous hydrochloric acid (62.5 ml concentrated hydrochloric acid, made up to 300 ml) a solution of sodium nitrite - (35 g) in water (75 ml) was added dropwise. The temperature The mixture was kept between 15 and 20 ° C. during the entire addition. Stirring was continued for one hour and then add the resulting solution to a solution of potassium xanthate (112g) in water (250ml) for one hour slowly added at a temperature of 70-75 ° C. After the temperature increased to 90 ° C for a further 30 minutes a slow stream of nitrogen was passed through it the mixture and sodium hydroxide (80 g) were added. The resulting solution was left under nitrogen for 16 hours Heated to reflux, cooled and acidified with 50% sulfuric acid (250 ml). The product was dissolved in benzene (2x 125 ml) and a solid that separated between the two layers was filtered off and saved. The combined extracts were washed with water, dried over sodium sulfate and evaporated, whereby an oil was obtained. This oil was distilled under reduced pressure using a nitrogen stream. 2-Hydroxy-5-mercaptoacetophenone with a boiling point (0.3 mm) of 100 ° C. was obtained. The connection froze when he stood and had a melting point of 58-60 C.

109846/19 54

The solid that separates out during the benzene extraction

1 1

te, was 4,4-dihydroxy-3,3-diacetyldiphenyl disulfide (33 g) This solid was concentrated with St anno chloride (82.5 g) Hydrochloric acid (300 ml) heated to reflux for 5 hours. The solution was concentrated in chlorinated water acid (300 ml) and mixed with chloroform (2x250 ml) extracted. The chloroform extracts were combined, dried over sodium sulfate and evaporated, leaving an oil which then extracted with petroleum ether (boiling point 40-60 ° C), further 2-hydroxy-5-mercaptoacetophenone with a melting point of 58-60 ° C. was obtained.

Analysis:

gei: C. .57, 55% H 4, 69% S. 18 75% M. .G. 168 ber .: C. 57, 16% • H 4, 76% S. 19 05% M. .G. 168 C ₈ H ₈ O ₂ S -

f) ethyl 6- (3-acetyl-4-hydroxyphenolthio) -4-oxo-4H-1-benzopyran-2-carboxylate

A solution of 2-hydroxy-5-mercaptoacetophenone (16.8 g) and sodium bicarbonate (8.4 g) in 66% v / v. watery Ethanol (300 ml) was refluxed for 30 minutes. The solution was evaporated to dryness, whereby a yellow solid was obtained. The solid was partially dried by evaporation of acetone (5x) and Finally left to stand in a vacuum desiccator over sodium hydroxide. . .

To the dried product in 2: 4: 6 trimethylpyridine (200 ml) became copper iodide (9.5 g) and 2-ethoxycarbonyl-6-iodochromone (27.8 g) given. The mixture was heated to 145-7 ° C for one hour under a stream of nitrogen. cooled and acidified with concentrated hydrochloric acid. The solid was filtered off, washed with water and dissolved in chloroform. (At this point it was some disulfide filtered off) Ethanol was added * This expression is used in the following to denote the corresponding copper I salts

109846/1954

and the chloroform is distilled off. 6- (3-Ac ethyl- 4-hydroxyphenylthio) - 4- oxo- 4H-1 -b enz opyr an- 2- carboxylic acid ethyl ester the end. After aluminum oxide filtration and crystallization as above, a product was obtained with a melting point of 172-173 ° C.

Analysis:.

found: C 62.2% H 4.0996 S 8.14% MG (mass spec)

Calc .: C 62.596 H 4, Ϊ7 # S 8.3496

^C 2O ^H 16 ° 6 ^S

g) 6- (3-Acetyl-4-hydroxyphenylthio) -4-oxo-4H-1 -benzopyran-2 ~ carboxylic acid and sodium salt

A suspension of 2.-ethoxycarbonyl-6- (3-acetyl-4-hydroxyphenylthio) chromone (3.84 g) and sodium bicarbonate (0.84 g) in aqueous ethanol (100 ml, 50%) was added for 4 hours heated to reflux.

50 ml of the resulting solution was treated with ethanol (50 ml) and allowed to crystallize. The resulting Solid was recrystallized from water, 6- (3-acetyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt received.

The remaining solution was made with concentrated chlorinated water acidic acid, using 6- (3-acetyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid with a melting point of 282-284 ° C.

Example 2

6- (4-Hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

a) monothiohydroquinone sodium salt

A mixture of 20.25 parts of monothiohydroquinone and 13.5

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Parts of sodium hydrogen carbonate were dissolved in a mixture of 300 parts of water / water and 150 parts of ethyl alcohol for one hour. heated to reflux. The solution was evaporated to half volume and then freeze-dried, leaving 23.7 parts Monothiohydroquinone sodium salt was obtained as a pale yellow solid.

b) Ethyl 6- (4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate

A mixture of 23.7 parts of monothiohydroquinone sodium salt, 55 parts of ethyl-6- ^ od-4-oxo-4H-1-benzopyran-2-car-

f boxylat, 15 parts of copper iodine and 300 parts of pyridine were refluxed for 3 hours with stirring under a nitrogen atmosphere. After cooling, the mixture was acidified with concentrated hydrochloric acid, the precipitate was filtered off, washed with water, dried, and then 500 parts by volume of chloroform was added. After the insoluble material was filtered off, the filtrate was evaporated to dryness and chromatographed on a column of 750 parts of silica gel in chloroform. The solid obtained by evaporation of the corresponding chromatography fractions was recrystallized from 300 parts of ethyl alcohol, 19.1 parts of ethyl 6- (4-hydroxyphenyl-

t thio) -4-oxo-4H-1-benzopyran-2-carboxylate as pale yellow crystals with a melting point between about 190 and 191 ° C.

Analysis:

Found: C 63.6 H 4.0 S 9.6 calcd. i C 63.2 H 4.1 S 9.35 C ₁₈ H ₁₄ O ₅ S

c) 6- (4-Hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid

A mixture of 10.9 parts of ethyl 6- (4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate and β parts of sodium hydrogen carbonate in 200 parts of ethyl alcohol was 2 hours

109846/1954

cooked for a long time, and the volume would be kept constant by adding water. The solution was concentrated with Hydrochloric acid acidified, the precipitate filtered off, washed with water and then dried. She became a Recrystallized mixture of 150 parts of ethyl alcohol and 150 parts of dioxane, 7.4 parts of 6 ~ (4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid as yellow crystals with a melting point of 281 ° C (decomposition).

Analysis: C. 60, 8th H 3 , 3 S. 10, 3 found: C. 61, 15th •H 3 , 2 S. 10, 2 ber .: ^C 16 ^H 10 ° 5 ^S

d) 6- (4-Hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carbonic acid sodium salt

1.65 parts of sodium hydrogen carbonate were added to a suspension of 6.4 parts of 6- (4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid in 150 parts of water, and the reaction temperature was increased to 50% ^{Maintained 0} C until the surge stopped. After hot filtration, the solution was freeze-dried, 6.6 parts of 6- (4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt being obtained as a pale yellow microcrystalline solid.

Example 3 . ·

6- (4-Acetyl-3-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt

a) 4-acetyl-3-hydroxythiophenol

To a solution of 23.3 parts of 4-acetyl-3-hydroxyaniline in 53 parts by volume of concentrated hydrochloric acid at 0 ⁰ C a solution of 11.8 parts of sodium nitrite in 20 parts of water was added in an amount sufficient, the temperature below 3 C. This mixture was then stirred for 5 minutes to a solution of 6.2 parts

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len copper chloride dihydrate and 5 parts of water in 100 parts by volume of acetic acid saturated with sulfur dioxide. The precipitate was filtered off, dried and then distilled under reduced pressure, 13.8 parts of crude 4-acetyl-3-hydroxybenzenesulfonyl chloride being obtained as a pale yellow crystalline solid with e
at 0.8 mm Hg.

linen solids with a boiling point between 148 and 150 C

Dry hydrochloric acid was bubbled into a stirred suspension of 80 parts of stannous chloride dihydrate in 300 parts of acetic acid • bubbled to obtain an almost clear solution and to this 13.8 parts of crude 4-acetyl-3-hydroxy-benzyl W zolsulfonylchlorid given. After stirring for 20 minutes, the mixture was dropped into 300 parts of concentrated hydrochloric acid, 600 parts of water was added, the precipitate was extracted with 300 parts by volume of chloroform, and then it was dried with magnesium sulfate. Evaporation of the solvent and distillation of the residue under reduced pressure gave 8.8 parts of 4-acetyl-3-hydroxythiophenol as a yellow solid with a boiling point between 100 and

102 ⁰ C at 0, 5 mm Ed. 8th H 4, 7th S. 19th ,1 Analysis: 1 H 4, 8th S. 19th , 0 found: C. 56, ber .: 'C 57, C ₈ H ₈ O ₂ S

b) 4-acetyl-3-hydroxythiophenol sodium salt

By following the procedure of Example 2a) there was obtained 8.5 parts of 4-acetyl-3-hydroxythiophenol reacted with sodium hydrogen carbonate, 9.6 parts of 4-acetyl-3-hydroxythiophenol sodium salt obtained as a pale yellow microcrystalline solid. :

c) Ethyl 6- (4-acetyl-3-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate .

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21204A3

By following the procedure of Example 2b), 9.6 parts of 4-acetyl-3-hydroxythiophenol sodium salt were obtained with ethyl 6-jbd-4-oxo-4H-1-benzopyran-2-carboxylate and copper-I-iodide reacted in pyridine, giving 9.5 parts of ethyl (4-acetyl-3-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate as almost white crystals with a melting point between 183 and 184 ° C.

Analysis: C. 62 , 4 • H 4, 25th S. 8.6 found: C. 62 , 5 H 4, 2 S. 8 ', 3 ber .: ^C 20 ^H 16 ° 6 ^S

d) 6- (4-Acetyl-3-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt

A mixture of 7.2 parts of ethyl 6- (4-acetyl-3-hydroxy- • phenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate and 1.56 parts Sodium hydrogen carbonate in 150 parts of ethyl alcohol was boiled for 2 hours and the volume was increased by the Addition of water kept constant. The precipitated material was filtered off, discarded and the filtrate 3 times with Washed 100 parts of chloroform. The aqueous phase was freeze-dried, 4.6 parts of 6- (4-acetyl'-3-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt as an almost white powdery solid.

Example 4

6- (5-Acetyl-4-hydroxy-2-methoxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt

a) 5-Acetyl-4-hydroxy-2-methoxybenzenesulfonic acid

To a stirred solution of 100 parts of 2-hydroxy-4-methoxyacetophenone in 350 parts by volume of chloroform, which at 0 C * 140 parts of chlorosulfonic acid were added at a rate sufficient to keep the temperature below

1 09846/195 4

2120A43

Hold C. After warming to room temperature, the yellow solution was allowed to flow onto 1000 parts of crushed ice, the precipitate was filtered off and washed with diethyl ether. This was recrystallized from a mixture of 350 parts of diethyl ether and 350 parts of ethyl alcohol to give 104.8 parts of S-Acetyl ^ -hydroxy ^ -methoxybenzolsulfonsäure as pink crystals having a melting point between 129 and 13O ⁰ C was given.

The structure of this compound was confirmed by its nuclear magnetic resonance ^ 7.50 (3H, S); 6.20 (3H, S); 4.55 (2H, t diffuse); 3.54 (1H, S); 1.87 (1H ₁ S)].

b) 5-acetyl-4-hydroxy-2-methoxythiophenol

A mixture of 100 parts of 5-acetyl-4-hydroxy-2-methoxybenzenesulfonic acid and 28.1 parts of potassium carbonate in 400 • parts of water were stirred until the evolution of carbon dioxide stopped. The precipitate was filtered off, 93.5 parts of S-acetyl ^ -hydroxy ^ -methoxy-benzenesulfonic acid potassium salt received as a pink amophene solid. This was done with 300 YoI. Parts for 1 hour Phosphoryl chloride heated to reflux and, after cooling, the mixture was carefully "crushed" to 1,000 parts . Given ice. The resulting brown suspension was filtered off, whereby 54 parts of crude 5-acetyl-4-hydroxy-2-methoxybenzenesulfonyl chloride were obtained. '-

Dry hydrochloric acid was poured into a stirred suspension blown from 265 parts of stannous chloride dihydrate in 1,000 parts of acetic acid until an almost clear solution is obtained and added thereto were 54 parts of crude 5-acetyl-4-hydroxy-2-methoxybenzenesulfonyl chloride given. After stirring for 30 minutes, the mixture was concentrated into 1,000 parts Hydrochloric acid is allowed to flow, 1,000 parts of water are added, the precipitate is 500 parts by volume Chloroform and extracted with magnesium sulfate

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dried. Evaporation of the solvent, sublimation of the residue in vacuo and recrystallization from carbon tetrachloride gave 29.7 parts of 5-acetyl-4-hydroxy-2-methoxythiophenol as colorless crystals with a melting point between 127 and 128 ° C.

Due to rapid oxidation, one could not find a satisfactory one Element araialyse preserved, but the structure was confirmed by nuclear magnetic resonance. [^ 7.5I (3H, S); 6.50 (1H, S); 6.13 (3H, S); 3.61 (1H, S); 2.39 (1H, S); -2.56

c) ethyl 6- (5-acetyl-4-hydroxy-2-methoxyphenylthio) -4-oxo-4H-1 benzopyran-2-carboxylate

By following the procedure of Example 2a), 23.4 parts of 5-acetyl-4-hydroxy-2-methoxythiophenol were made with sodium hydrogen carbonate implemented, 5-acetyl-4-hydroxy ~ 2-methoxythiophenol sodium salt received as a yellow amophene solid. This was carried out using the procedure of Example 2 b) Ethyl 6-iodo-4-oxo-4H-1-benzopyran-2-carboxylate and copper-I-iodide reacted in pyridine, after recrystallization from dioxane 28.7 parts of ethyl 6- (5-acetyl-4-hydroxy-2-methoxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate as yellow crystals with a melting point between 218 and 219 ° C.

Analysis: C. 60, 7th H 4, 5 S. 7, 6th found: C. 60, 9 H 4, 4th S. 7, 7th ber .: C ₂₁ H ₁₈ O ₇ S

d) 6- (5-Acetyl-4-hydroxy-2-methylphenylthio) -4-oxo ~ 4H-1-'benzopyran-2-carboxylic acid, sodium salt

A suspension of 8.24 parts of ethyl 6- (5-acetyl-4-hydroxy-2-methoxy-phenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate in 82.5 parts by volume of a 0.242N sodium hydroxide solution in

1 0 9 8 A 6/1 9 5 4

Methanol and 100 parts of methanol were stirred for 3 hours, heated to reflux and then cooled. The solid became filtered off, washed with 100 parts of methanol and then triturated with parts of hot methanol, 3.2 parts 6_ (5-Acetyl-4-hydroxy-2-methoxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt as pale yellow: · obtained flaky crystals.

Example 5 ■ ·

• 6- (3-Acetyl-4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt

a) 2-Hydroxy-5- (4-hydroxyphenoxy) acetophenone

A mixture of 15 parts of 4- (4-hydroxyphenoxy) phenyl acetate, 25.5 parts of anhydrous aluminum chloride and 90 parts of chlorobenzene was stirred and refluxed for 20 minutes and then decomposed with ice to give a yellow solid which was extracted with chloroform . The chloroform layer was washed successively with sodium hydrogen carbonate solution, whereby the 4.4 ^! -Dihydroxyphenylether removed, then with sodium carbonate solution (10%) and with sodium hydroxide solution (0.2 ^). The sodium carbonate and sodium hydroxide layers were combined, acidified and extracted with chloroform, which was evaporated to give a yellow solid. The solid was recrystallized from a mixture of benzene and light petroleum (bp 60-80) to give 2-hydroxy-5- received 3 parts of (4-hydroxyphenoxy) acetophenone having a melting point of ¹ 14O-141 ° C.

Analysis: C. 69 , 6 H 4, 85 found: C. 68 .8th. H 4, 95 ber .: C ₁₄ H ₁₂ O ₄

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" ³¹ " 212QU3

b) 6- (3-Acetyl-4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid

10 parts of 2-hydroxy-5 - (- hydroxyphenoxy) acetophenone and 7 parts of dimethylacetylene dicarboxylate were mixed in 20 parts of dioxane and 6 drops of Triton B were added. The mixture was heated on a steam bath for 20 minutes and then evaporated under reduced pressure to a dark oil which was washed with water and sodium hydroxide (0.5%), dried and evaporated. The residue was heated on a steam bath with 50 parts of sodium hydroxide solution (3050) for 20 min and acidified to give a gummy solid which was taken up in sodium hydrogen carbonate solution, filtered off, washed with ethyl acetate and then acidified to give 5 _f 5 Received parts of a green solid. Nuclear magnetic resonance showed that the solid consisted of a mixture of approximately 60% (3-acetyl-4-hydroxyphenoxy) -fumaric acid and 40% (3-acetyl-4-hydroxyphenoxy) -maleic acid. The solid was pulverized, dissolved in 10 parts of concentrated sulfuric acid and allowed to flow in water after 3 minutes, giving 5 parts of a brown solid which crystallized from aqueous dimethylformamide, 3 parts of a green solid having a melting point of 282-283 ⁰ C (decomposition) was obtained. The solid was dissolved in a small excess of hot sodium hydrogen carbonate solution, filtered off, cooled and acidified, giving 2 parts of a cream-colored powder.

The powder was 6- (3-acetyl-4-hydrophenoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid.

c) Sodium 6- (3-acetyl-4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylate

Sodium 6- (3-acetyl-4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylate was made from 6- (3-acetyl-4-hydroxyphenoxy) -4-oxo-. 4H-1-benzopyran-2-carboxylic acid by neutralization with a Equivalent of sodium hydrogen carbonate in distilled water

1 09846/1954

produced and the resulting solution freeze-dried.

Example 6

6- (4-Hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

a) Ethyl 6- (4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylate

To one made from 7.5 parts of sodium and 240 parts of ethanol Sodium ethoxide solution became a slurry of 45 parts of diethyl oxalate, -15 parts of 2-hydroxy-5- (4-hydroxyphenoxy) acetophenone and 50 parts of dry ether and the mixture was refluxed for 5 hours, cooled, allowed to flow in ether with Washed with water and then with sodium hydroxide solution (5%). The combined aqueous layers were acidified and

- extracted with chloroform which was washed with water, dried and evaporated to give a red oil. The oil was dissolved in dry ethanol and saturated with hydrogen chloride. The solution refluxed for 20 minutes heated, evaporated to a small volume and treated with ethyl acetate, then with water, sodium hydrogen carbonate solution and water, dried and evaporated to give a buff solid which is composed of aqueous Ethanol crystallized out, giving 10 parts of ethyl 6- (4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylate as

- Received needles with a melting point of 159-16O ° C.

Analysis: C. 66 6th H 4, 25th found: C. 66 3 H 4, 3 ber .: • ^C 18 ^H 14 ° 6

b) 6- (4-Hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid

A solution of 9.5 parts of ethyl 6- (4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylate in 1,000 parts of ethyl acetate

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was repeatedly washed with sodium hydroxide (0.3%) (almost 4,000 parts, total). The combined aqueous washing solutions were acidified to give a solid which was recrystallized from an ethanol / acetone mixture, 5.3 parts of 6- (4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2- carboxylic acid with a melting point of 280-281 ⁰ C (decomposition)

received. C " 64, 5 H 3, 3 Analysis: C. 64, 6th -H 3, 4th found: ber .: ^C 16 ^H 10 ° 6

c) Sodium 6- (4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylate

The sodium salt was prepared by the procedure of Example 5c) from 6- (4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid manufactured.

Example 7

6- (3-Acetyl-4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboric acid, sodium salt

a) 4-Acetoxy-4 ^l ~ hydroxydiphenylmethane

A solution of 5.6 parts of potassium hydroxide in 70 parts by volume Water became a solution of 20.0 parts of 4,4 · -dihydroxydiphenylmethane in 250 parts by volume of water and 140 parts by volume of acetone are added dropwise with stirring. The resulting The solution was cooled to 5 ° C. and 10.5 parts of acetic anhydride were slowly added with stirring. The mixture was further stirred for one hour. The products were extracted from the reaction mixture by extraction with j5 χ Parts by volume of diethyl ether removed. The combined essential extracts were washed with water and over anhydrous Dried magnesium sulfate. Evaporation of the essential solution gave a red oil that was absorbed with chloroform

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and chromatographed on a silica gel column with chloroform as the eluent, 3.7 parts of 4,4'-diacetoxydiphenylraethane, 13.0 parts of 4-acetoxy-4'-hydroxydiphenylmethane and 4.4 parts of 4,4'- Dihydroxydiphenylmethane received. 4-Acetoxy-4 ^l -hydroxydiphenylmethane crystallized from benzene as colorless plates with a melting point between 129 and 130 ° C.

Analysis: C. 74, 5 H 5, 76% found: C. 74, 34 H 5, 83% ber .: ^C 15 ^H 14 ° 3

b) 3-acetyl-4,4'-dihydroxydiphenylmethane

87.5 parts of titanium tetrachloride were slowly added with stirring to a solution of 37.2 parts of 4-acetoxy-4'-hydroxydiphenylmethane in 350 parts by volume of dry repeated destil- "liertem nitrobenzene, which was maintained at 0 ⁰ C was added. The mixture was then stirred at 50 ⁰ C for 14 hours. the mixture was cooled and 6N with 300 parts by volume hydrochloric acid and extracted with diethyl ether. the ethereal solution was extracted with 3 x 100 parts by volume of 2N sodium hydroxide solution and the alkaline The extract was acidified with concentrated hydrochloric acid to give a suspension of a red oil which was extracted with diethyl ether, the ethereal solution was dried over anhydrous magnesium sulphate, evaporated and the remaining oil was chromatographed on a column of silica gel with chloroform as the eluent to give 18, 3 parts of 3-acetyl-4,4'-dihydroxydiphenylmethane, TLC analysis showed that the product had a small amount ge of 3,3 '-diacetyl-4-4 ¹ -dihydroxydiphenylmethane was contaminated. The product was not cleaned any further. Nuclear magnetic resonance (CDCl, solution, 10%, TMS)

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COCH ₃

HO

7.51 T (3p singlet) -C0CH ₃ i6.2iT (2p singlet) -CH ₂ ; 4.15ftiCHp broad)

// Yv -2.07 (1 CHpSingletl / 7 VV- OH

Singlet HO.

Aromatic signals: AA ¹ , BB * Quartet center at about 3.12'T; H ₁ (meta coupled) 2.54T; H ₂ (Ortho and Meta coupled) about 2.78 f.
H ₃ (ortho coupled) about 2.9.

c) Ethyl 6- (3-acetyl-4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylate

A solution of 8 parts of 3-acetyl-4,4'-dihydroxydiphenylmethane, 5.2 parts of dimethyl acetylenedicarboxylate and 3 drops of benzyltrimethylammonium hydroxide in 30 parts by volume Dioxane was heated on a steam bath for 20 minutes. 7 parts by volume of sodium hydroxide solution (25%) were added, and the mixture was further heated for 30 minutes. Dilution with water and acidification of the solution with concentrated Hydrochloric acid gave a brown oil which was extracted with diethyl ether. The essential solution was washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solution gave a resin that was partial was added to 50 parts by volume of concentrated sulfuric acid at room temperature. After 15 minutes left the acid solution was poured into water and a buff-colored solid precipitated out. This was collected, dried and overnight in 40 parts by volume of dry ethanol in the presence of 3 drops of concentrated sulfuric acid refluxing

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212QU3

heats. The ethanol solution was evaporated in vacuo and the residue was taken up in 100 parts by volume of chloroform. ■ The chloroform solution was washed with an aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. The concentrated chloroform solution was chromatographed in batches on preparative silica gel HF ₂ c4 layered plates measuring 20 cm × 100 cm, using chloroform as the developing solvent for two "passes" per plate. The main bands were collected and eluted with ethyl acetate.

.. Evaporation under vacuum gave a residue of ethyl 6- (3-acetyl-4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylate, which crystallized from ethanol as a platelet (0.958 parts) with a melting point of 159 ° C.

Analysis: C. 68, 89 H 4, 89% found: C. 68, 84 H 4, 95% ber .: ^C 21 ^H 18 ° 6

d) 6- (3-Acetyl ~ 4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylic acid

A solution of 1.68 parts of sodium bicarbonate in 10 parts by volume Water was added to a solution of 0.56 parts of ethyl 6- (3-acetyl-4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylate given in 50 parts by volume of ethanol ·. The mixture was heated on a steam bath. While advancing Further amounts of water were added to hydrolysis. When the ethanol had evaporated, the solution was made with water diluted and washed 3 times with diethyl ether. Acidification of the aqueous solution with concentrated hydrochloric acid precipitated the product as a pale yellow solid, which was obtained from ethanol as fine needles (0.40 parts) with a melting point between 274 and 275 ° C crystallized with decomposition.

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2120A43

e) 6 ~ (3-Acetyl-4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt

0.070 part of sodium bicarbonate was made into a suspension of 0.284 parts of 6- (3-acetyl-4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylic acid in 50 parts by volume of water. When the dissolution of the acid was complete, the solution filtered off and freeze-dried, whereby 0.305 parts of sodium salt were obtained.

Example 8

6- (4-Hydroxybenzyl) -4-OXO-4H-1-benzopyran-2-carboxylic acid, natriura salt

a) 6- (4-Hydroxybenzyl) -4-oxo-4H-1-benzopyran-2- carboxylic acid aryl ester

1.94 parts of sodium were in 50 parts by volume of dry etha- • nol solved. A solution of 4.84 parts of weakly impure 3-acetyl-4,4'-dihydroxydiphenylmethane was added to this solution and 9.3 parts of diethyl oxalate in 25 parts by volume of dry diethyl ether slowly added with stirring. the Mixture was refluxed for 4 hours with exclusion of atmospheric moisture and then heated in 200 parts by volume of 2N hydrochloric acid allowed to flow, -The mixture was extracted 3 times with diethyl ester and the combined extracts evaporated. The remaining oil was dissolved in 20 parts by volume of ethanol and 2 parts by volume. Centered hydrochloric acid refluxed for 1 hour. Evaporation under vacuum gave an oil, which was taken up in ethyl acetate and washed with aqueous sodium bicarbonate solution and water / water. The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated in vacuo to give an oily Solid residue received. Half of this residue was dissolved in 500 parts by volume of chloroform, and the solution was extracted with 50 parts by volume of sodium hydroxide solution (1%). Acidification of the alkaline extract gave 6- (4-

109846/1954

Hydroxybenzyl) -4 ~ oxo-4H-1-benzopyran-2-carboxylic acid as yellow Solid which recrystallizes twice as fine yellow needles (0.93 parts) with a melting point between 266 and 268 ° C from ethanol became.

Analysis; C. 69 , 16. H 4, 25% found: C. 68 , 95 H 4, 05% ber .: C ₁₇ H ₁₂ O ₅

The remainder of the oily residue was batchwise purified by preparative layer chromatography (silica gel HF ₂₅ ^) with dimensions of 20 cm × 100 cm with chloroform as the developing solvent and 3 "passes" per plate. Elution of the main bands with ethyl acetate, removal of the solvent under vacuum and crystallization of the residue from ethanol gave 1.0 part of ethyl 6- (4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylate as colorless crystals a melting point between 176 and 177 C.

Analysis: C. 70.56 H 5, 08% found .; C. 70.36 H 4, 94% ber .:

b) 6- (4-Hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

A solution of 0.130 parts of sodium bicarbonate in 10 parts by volume Water was added to a suspension of 0.494 parts of 6- (4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylic acid given in 20 parts by volume of water. The mixture was heated briefly and filtered while it was hot. After cooling down crystallized / the 6- (4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt as colorless needles (0.360 parts).

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Example 9

6- (3-Acetyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid

a) Ethyl 6- O-acetyl ^ -hydroxyphenylthio) -4-oxo-4H-1 -benzopyran-2-carboxylate

A solution of 1.1 parts of 6,6'-th'iobis (2-carboxy-4-oxo-4H-1-benzopyran) and 0.33 parts of sodium hydroxide in 50 parts of water were refluxed for 6 hours. After cooling, the solution was acidified with dilute hydrochloric acid and the yellow precipitate became filtered off, washed with water and dried. This solid (1.0 part) became 60 parts dry Ethanol, 20 parts of benzene and 1.0 part of concentrated sulfuric acid were added. The mixture was for 30 hours heated back flowing. The volume of the resulting solution was reduced by evaporation and then reduced to serene. The suspension was filtered off and the residue washed with water and recrystallized from ethanol, 0.6 parts of yellow plates were obtained. Nuclear magnetic resonance spectroscopy showed that this material is a Mixture of ethyl 6- (3-acetyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate and 6,6'-thiobis (2-carboxy-4-oxo-4H-1-benzopyran) diethyl ester was. 0.6 part of the above mixture was subjected to preparative thin layer chromatography using silicon oxide as adsorbent and chloroform as eluent. 2 bands were separated and the one with the larger Rf value was extracted from the silicon oxide with chloroform. Evaporation of the Solution gave 0.13 part of ethyl 6- (3-acetyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate as a yellow solid with a melting point of 171-3 ° C.

Example 10

6- (4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid

A solution of 0.268 parts of 6- (4-hydroxyphenoxy) -2-methyl-4-oxo-4H-1-benzopyran and 0.445 parts of selenium dioxide in one

109846/1954

A mixture of 6 parts of water and 24 parts by volume of dioxane was gently refluxed for 12 hours. After cooling, the solution was filtered off and the solvents were evaporated from the filtrate. The residue thus produced was dissolved in 100 parts by volume of chloroform, and the resulting solution was extracted with 30 parts portions of a solution containing 5 parts of sodium bicarbonate in 100 parts of water. The combinatorial. th aqueous washing solutions were acidified with concentrated hydrochloric acid, whereby a solid was obtained which was recrystallized from an ethanol-acetone mixture to 6- (4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid with to obtain a melting point of 280-281 ⁰ C (decomposition).

Example 11
6- (4-Hyiroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylic acid

A mixture of 1.0 part 6- (4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxamide, 20 parts glacial acetic acid and 20 parts of a solution of hydrogen bromide (45% w / v) in Glacial acetic acid was refluxed for 3 hours, then added to 200 parts of water and the resulting aqueous solution with. "Chloroform extracted. The chloroform wash solution was extracted with saturated aqueous sodium bicarbonate solution, followed by acidification of the aqueous layer, a yellow solid which was recrystallized from ethanol to give 6" (4-hydroxybenzyl) -4-oxo- Obtain 4H-1-benzopyran-2-carboxylic acid with a melting point of 266-268 ⁰ C. ■

Example 12

6- (3-acetyl-4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carbon-

A mixture of 1.0 part 6- (3-acetyl-4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carbonitrile, '20 Parts of dioxane and 20 parts of dilute hydrochloric acid were added over 12 hours slightly refluxing heated. The dioxane was evaporated and the reaction mixture extracted with chloroform. The chloroform layer was made with saturated sodium bicarbonate solution

109048/1954

extracted, wherein one) enzopyran-2-carboxylic acid having a melting point of 287 ⁰ C (decomposition) were obtained after acidification 6 ~ (3-acetyl-4-hydroxyphenoxy) -4-oxo-4H-1-t.

Example 13
Ethyl 6- (4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylate

A mixture of 0.315 parts of ethyl 6- (4-hydroxyphenoxy) -2, 3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylate and 0.184 parts of N-bromosuccinimide in 15 parts by volume of carbon tetrachloride was used during 6 Heated to reflux for hours. The resulting solution was washed with water and the organic layer was dried over sodium sulfate. Evaporation of the carbon tetrachloride gave a buff solid which was crystallized from aqueous ethanol to to give ethyl 6- (4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylate having a melting point of 159-160 ⁰ C. received.

Example 14

6- (3-Allyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt

a) Ethyl 6- (4-allyloxyphenylthio) -4-oxo-4H-1-benzopyran-2-. carboxylate '-

A mixture of 19.1 parts of ethyl 6- (4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate (Example 2b), 8 parts of allyl bromide, 60 parts of dry potassium carbonate, 1 part _; Potassium iodide and 600 parts of dry acetone were refluxed for 24 hours. After cooling, the solids were filtered off, the filtrate was evaporated to an orange oil and this was chromatographed in chloroform on a column of 500 parts of silica gel. The solid from the evaporation of the corresponding chromatographic reactions was recrystallized from ethanol, leaving 17.5 parts of ethyl 6- (4-allyloxyphenylthio) -4 ~ oxo-4H-1-benzopyran-2r carboxylate as pale yellow needles with a melting point received 69-69.5 ⁰ C.

109846/1954

Analysis: C. 65, 8th H 4th , 9 S. 8th, 6th found: C. 66 O H 4th , 75 S. 6, 4th ber .:

b) Ethyl 6- (3-allyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate

14 parts of ethyl 6- (4-allyloxyphenylthi ©) -4-oxo-4Li-1-benzopyran-2-carboxylate were heated back flowing during 8 hours under a nitrogen stream at 210 ⁰ C. The brown residue was then chromatographed in chloroform on a column of 300 parts of silica gel. Evaporation of the appropriate fractions gave a solid, which mirde recrystallized from ethanol, leaving 9 parts of ethyl 6- (3-allyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate as yellow crystals with a Melting point between 170.5 and

• Received 171.5C. C. 65, 8th H 4, 9 S. 8th , 5 Analysis: C. 66 O H 4, 75 S. 8th , 4 found: ber .: C ₂₁ H ₁₈ O ₅ S

c) 6- (3-Allyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid

By the method of Example 2c), 5 parts of ethyl 6- (3-allyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate were reacted with sodium hydrogen carbonate, after acidification and recrystallization from ethyl acetate 2 , 6- (3-allyl-4-hydroxyphenylthio) -4-oxo-R4h-1-benzopyran-2-carboxylic acid as yellow crystals with a melting point of 242-244 ⁰ C (decomposition) was 8 parts.

Analysis: C. 64.5 H 4th , 2 S. 9, 0 found: C. 64.4 H 4th , 0 S. 9, 05 ber .: 1 09846 / 195 4th C19H14Q5S

d) 6- (3-Allyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt

By the method of Example 2d), 2.15 parts of 6- (3-allyl-A-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid were reacted with aqueous sodium hydrogen carbonate, 2 parts of 6- (3-Allyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt was obtained as a pale yellow solid.

Example 15

Ethyl 6- (3-acetyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate

a) Ethyl 6- (4-acetoxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate

A mixture of 5 »8 parts of ethyl 6- (4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate, 5 parts of acetic anhydride and 25 parts of dry pyridine were kept at 20 ° C. for 1 hour. The solution was diluted with Acidified with hydrochloric acid and then extracted twice with 200 parts of chloroform. The extract was diluted with Hydrochloric acid and water and then washed dried with magnesium sulfate. The residue was recrystallized twice from ethanol after evaporation of the solvent, 2.15 parts of ethyl 6- (4-acetoxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate as flaky white crystals with a melting point between 83 and 84 ° C.

b) Ethyl 6- (3-acetyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate

A mixture of 6.2 parts of ethyl 6- (4-acetoxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate and 100 parts of nitrobenzene were ^{stirred at 0} ° C., and 6.9 vol. Parts of titanium chloride given for 1 minute. The mixture was then ^{heated to 50 °} C. for 3 hours and, after cooling, the dark red complex was decomposed by the addition of dilute hydrochloric acid. The organic layer was

109846 / 19BA

washed with water and steam distilled, nitrobenzene was eliminated. The residue was extracted into chloroform, dried with magnesium sulfate, evaporated to dryness and chromatographed in chloroform through a column of 250 parts silica gel. The resulting product was recrystallized from ethanol, 1.9 parts of ethyl 6- (3-acetyl-4-hydroxyphenylthio) -3-oxo ~ 4H-1-benzopyran-2-carboxylate as pale yellow crystals with a melting point between 172 and 173 ° C ".

Example 16

6- (4-Hydroxy-3-n-propylphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt

a) Ethyl 6- (4-hydroxy-3-n-propylphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate

A mixture of 5 parts of ethyl 6- (3-allyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylate, 0.1 part of palladium-charcoal catalyst (5%) and 100 parts Ethyl acetate was hydrogenated for one hour at 20 ° C and 1 atm with constant agitation. The catalyst was filtered off, the solvent was removed by evaporation and the remaining oil was recrystallized from ethanol, 4.1 parts of ethyl 6- (4-hydroxy-3-n-propylphenylthio) -4-oxo-4H-1- benzopyran-2-carboxylate was obtained as pale yellow crystals with a melting point between 151 and 152 ^° C.

b) 6- (4-Hydroxy-3-n-propylphenylthip) -4-oxo-4H-1-benzopyran-2-carboxylic acid, sodium salt

A mixture of 2 parts of ethyl 6- (4-hydroxy-3-n-propylphenylthio) -4-oxo-4H ~ 1-benzopyran-2-carboxylate, 0.42 parts of sodium hydrogen carbonate, 30 parts of ethanol and 30 parts of water were kept at 60 ° C. for 2 hours. Ethanol was made removed by evaporation in vacuo, and the solution was extracted with ethyl acetate, leaving unreacted starting material was eliminated. The aqueous layer was freeze-dried to give 6- (4-hydroxy-3-n-propylphenylthio) -4-oxo-4H-1-benzopyran-2-carbo-acid sodium salt received.

BATH ORIGINAL

Claims (1)

Claims 1. Process for the preparation of a compound with the Pormol I. (See claim 2) or pharmaceutically usable derivatives thereof, characterized in that one of the following Implementations: a) Preparation of a compound of the formula Ia Yes 1 1 1 1 1 ?
wherein P, Q, T, P, Q, T, R, R and W are those given above Is important X represents a sulfur or oxygen atom, by reacting a compound of the formula II 0 II wherein P, Q, R and T are as defined above, -L is a group which can be easily split off ("good leaving") or an -X YG group, where Y is hydrogen or an alkali metal and R is hydrogen or, together with the OOO group, is one Forms ester group 109846/1954 BATHROOM OBlOLNAL a compound of the formula III, P ¹ 1 1 1 12
wherein P, Q, T, R and W have the meaning given above 2 11 and L is easily cleavable if L is a -X Y group 1 1 and a -X Y group, provided that L can be easily split off, ι b) Production of a compound of the formula I by ring w '12 formation of groups A and A in a corresponding compound with the formula VI, VI 1 1 1 12
wherein P, Q, T, P, Q, T _f W, R and X o "ben meaning indicated and 1 2 A and A represent the group pairs i) -COCHR ¹ COCOr ⁶ and -OM
or ii) -H and -0-C (COOM) = CR ¹ -C0OK wherein R is an -OM group or a group convertible therein, M is hydrogen or an alkali metal and R is as defined above, c) Preparation of a compound of the formula Ic 10984S / 1954 -P- 17th 2120A43 Ic 1111
wherein P, Q, T, P, Q, T, R and X have the meanings given above comes through '. i) Carrying out a Fries rearrangement with a corresponding Connection with the formula Id, » fcOOC OCOGH. Id 1111
wherein P ₁ Q, T, P, Q ₁ , T, R, R and X are as defined above or ii) opening of the pyrone ring of a single chromone nucleus in a corresponding compound with the formula VIII, VIII COOR 1111
wherein P, Q, T, P, Q, T, R, R and X have the meaning given above comes under alkaline conditions. d) Production of a compound of the formula I by hydrolysis or oxidation of a corresponding compound with the formula IX, 109846/1954 BATH ORIGINAL 111 12 1
where P, Q, T, P _t Q, T, X, W, R and R have the above . announcement and. D represents a group which can be hydrolyzed to a -COOH group • or is oxidizable, e) Production of a compound of the formula I by dehydrogenation of a corresponding compound of the formula J, 111 * 12 wherein Ρ, Ο, Τ, Ρ, Q _r T, X, W, R, R and R are as defined above,. . f) preparation of a compound with the formula If, If Qf ¹ ΤΓ 112
wherein R ₉ X, V /, R and R has the meaning given above and Pf _f Qf, Tf ₁ Pf ¹ , Qf ¹ and Tf ^{1 have the} same meaning as P, Q, T, P ¹ , Q ¹ and 1 * T have above, provided that at least one of the Groups Pf, Qf, Tf, Pf ¹ , Qf ¹ and Tf ^{1 have} an alkyl group with at least 109846/1954 BATH ORIGINAL H* represents two carbon atoms, by creating a corresponding compound of the formula XI Qg Qg XI 1 12
where R, X, W, R and R are as defined above and Pg, Qg, Tg, 111 ■ 11 Pg, Qg and Tg have the same meanings as P _f Q, T, P, Q and T above, provided that at least one of the groups 11 1 pen Pg, Qg, Tg, Pg, Qg and Tg represent an alkenyl group, is selectively hydrogenated,
g) preparation of a compound of the formula Ig, Ig 1 11 wherein P, Q, T, R, X, W and R are as defined above and Pq, Qq 1 111 and Tq have the same meaning as P, Q and T above, with 11 with the exception that at least one of the groups Pq, Qq and Tq an allyl group or an alkyl-substituted allyl group with represents up to 6 carbon atoms, by heating a compound with the formula ROOC Ϊ ¥ Γ 'OR T ^ Or ¹ 'for ¹ 109846/1954 T '2120U3 '1 "1 where P, Q, T, R, X _t W and R are as defined above and Pr, Qr and Tr have the same meaning as p \ q ¹ and T ¹ above, provided that at least one of the groups Pr, Qr and Tr is hydrogen and 11
R is an alkyl group or an alkyl-substituted allyl group with up to 6 carbon atoms, to elevated temperatures, h) Preparation of a compound of the formula Id, where a compound of the formula Ih * 4 ^ FOOC where P, O ₉ T ₅ P ¹ ^ ¹ , T ¹ ^ »W, R ¹ and R are defined as obea, 1
with a compound of the formula R CH ^ COGH or an anhydride or a halide thereof is reacted, or · i), preparation of a compound with the formula Ik booc where P ₁ Q ₁ T ₁ P ¹ , Q ¹ , T ¹ , W,?. ¹ , R ₁ X and R ^{11 are} as defined above, by implementing eiaer -Verbli3 <1urig & ®: ~ Formula Im - ■ 10SS48 / 1854 - · -'Λ 2120A43 ,1 wherein P, Q, T ₁ P, Q, T, W, X, R and R are as defined above, 11 11 with a compound of the formula R Hai, wherein R is as above is defined and Hai represents an active halogen atom, optionally or necessarily converting the compound of the formula I into a pharmaceutically acceptable derivative is converted by this or vice versa. 2. Compounds of general formula I where P, Q, T, P, Q and T can be the same or different and each group can be hydrogen or another substituent, R is hydrogen or an optionally substituted one Alkyl or alkoxy group of about 1 to 10 carbon atoms or is an optionally substituted aryl group, 12 1 R is hydrogen, a «COC ^ R group, an alkyl group or an alkyl substituted allyl group of up to 6 Carbon atoms 1st, X is a carbon-carbon bond or a single atom, it being possible for the single atom to carry substituents that are not part of the chain itself between the two bensene nuclei and
W is a hydrogen atom or a COCHpR group and pharmaceutically acceptable derivatives thereof. 109846/1954 BATH Compounds according to claim 2, characterized in that X is an oxygen or sulfur atom, ·. a substituted one Sulfur or nitrogen atom, an optionally substituted methylene group or a carbon-carbon Bond means and P, Q, T, P, Q and T alkyl, alkoxy, alkenyl, Alkenyloxy, these groups optionally being replaced by a hydroxy, lower alkoxy or halogen substituent may be substituted, optionally substituted amino, amino-lower alkoxy, which is optionally substituted can be nitro, hydroxy or halogen. Compounds according to claim 2-3, characterized in that X is a carbon-carbon bond, a sulfur or oxygen atom, a methylene group, the group -SO-, - ₂ -CO -, - NH-, NR ² , C (R ³ ) ₂ or) C = S; R ^{2 is} alkyl, alkenyl, alkoxy, aralkyl, aryl, acyl, hydroxy, carboxy, or a carbocyclic or heterocyclic ring, it being possible for these groups or rings to carry a hydroxy, halogen, lower alkyl, lower alkoxy or phenyl substituent, and each group R, which can be identical or different, represents hydrogen, hydroxy, halogen, an alkyl, alkenyl or alkynyl group, these groups being an oxygen, sulfur or nitrogen atom or a carbonyl group instead of a carbon atom , an amide chain or ester chain and may carry a halogen, hydroxy, carboxy or alkoxy substituent, a carboxyl group (including salts, esters and amides of these), an aryl, aralkyl, aryloxy or aralkoxy group, whichever of the above May carry substituents, or a heterocyclic or carbocyclic ring, which may optionally be substituted by one of the abovementioned substituents. 5 · Connections according to claim 4, characterized in that the group R .. has the meaning given above and less than about 10 carbon atoms, each group R . has the meaning given above and less than about 1098Λ6 / 1954 "f" Has carbon atoms and the groups P, Q, T, P, Q. And T have the meaning given above and have about 1 to 8 carbon atoms 6. Compounds according to claim 2-5 »characterized in that 11 1
the groups P, Q, T, P, Q and T chlorine, bromine, iodine, hydroxy, acetoxy, nitro, methyl, ethyl, propyl, butyl, tert-butyl, allyl, 1-methylallyl, prop-1-enyl, Methoxy, ethoxy, propoxy, butoxy, allyloxy, but-3-enoxy, acetyl, hydroxymethyl, ethoxymethyl, chloromethyl, 2-chloroethoxy, 2-iodoethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 2-hydroxybutoxy, 3-methylbutoxy, 2-ethoxyethoxy, 3-methoxy-2-hydroxypropoxy, 3-butoxy-2-hydroxypropoxy, diethylaminoethoxy, aminoethylamino, acetylamino or hydrogen mean. 7. Compounds according to claim 2-6, characterized in that the group R ^{1 represents} hydrogen, lower-alkyl, lower-alkoxy or phenyl. 8. Compounds according to claim 2-7, characterized in that 1
all groups R are hydrogen. 9. Compounds according to claim 2-8, characterized in that the group X is a sulfur or oxygen atom or a -j is methylene group and the groups R are hydrogen and of the groups P, Q, T, P, Q and T only one low Is alkoxy, lower alkyl or lower alkenyl and the remainder are hydrogen. 10. 6- (3-Acetyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid 11. 6- (4-Hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid 12. 6- (4-Acetyl-3-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid 109846/1954 2120U3 51 13 x 6- (5-Acetyl-4-hydroxy-2-methoxyphenylthio) -4-oxo-4H-1 benzopyran-2-carboxylic acid 14. 6- (3-Acetyl-4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid 15. 6- (3-Acetyl-4-hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylic acid 16. 6- (4-Hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxylic acid - 17- 6- (3-Allyl-4-hydroxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid 18. 6- (4-Hydroxy-3-n-propylphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid 19 x 6- (4-hydroxyphenoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid 20. 6- (4-Allyloxyphenylthio) -4-oxo-4H-1-benzopyran-2-carboxylic acid 21. 6- (4-Acetoxyphenylthio) -4-oxo-4H-1 -benzopyran-2-carboxylic acid 22. Compounds of the general formula 1 1 1. · 1? wherein Ρ, Ο, Τ, Ρ, Q, T, W ₁ R and X have the meaning given above and the group pairs A ¹ and A ^. i) -COCHR ¹ COCOr ⁶ and -OM or
ii) -H and -0-C (COOM) = CR ¹ -COOM represent. 109846/1954 23. Compounds of the general formula wherein P, Q, T, P, Q _f T, X, W, R and R have the meaning given above and D represents a group which can be hydrolyzed or oxidized to a -COOH group. 24. Compounds of the general formula 111 1 12
wherein P, Q, T, P, Q, T, X, W, R, R and R are as defined above. 25 · Pharmaceutically usable salts of the compounds according to claim 10-21. 26. 6- (4-Hydroxybenzyl) -4-oxo-4H-1-benzopyran-2-carboxamide. 27 · Pharmaceutical preparation, characterized in that it is a compound according to claim 2 as an active ingredient, optionally in combination with a customary pharmaceutical Contains lanyard or carrier. 109846/1954