CS246098B2 - Method of dihydrobenzopyran's derivatives production - Google Patents

Description

It is an object of the present invention to provide novel dihydrobenzopyran derivatives of the formula I

in which

........... 'I

R ¹ represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms,

R ² is hydrogen or halogen,

R ³ , R ⁴ and R ⁵ are each independently hydrogen, C 1 -C 7 alkanoyl, arylcarbonyl, in which "aryl" is phenyl or phenyl substituted with 1 to substituents selected from the group consisting of halogen , trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, nitro, amino, alkylamino of 1 to 7 carbon atoms and dialkylamino of 1 to 7 carbon atoms in the alkyl moieties, or alkyl of 1 to 7 7 carbon atoms, with the proviso that only one of R ³ , R ⁴ and R ⁵ is an alkanoyl or arylcarbonylo246098 group as defined above and either

R ^e and R ⁷ are both hydrogen and

R ⁸ is -COOR ⁹ or

R ⁶ represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms,

R ⁷ is - (CH 2) _n —COOR ⁹ a

R ⁸ represents a hydrogen atom and

R ⁹ represents an alkyl group having 1 to 7 carbon atoms,

X is an alkylene group having 2 to 7 carbon atoms and n is an integer from zero to 4.

These compounds are useful in the treatment of allergic diseases.

C 1 -C 7 alkyl, also referred to hereinafter as "lower alkyl", means a straight or branched saturated hydrocarbon radical having 1 to 7 carbon atoms, preferably up to 4 carbon atoms, such as methyl, ethyl, propyl , isopropyl, butyl, tert-butyl, neopentyl, pentyl, heptyl and the like.

The term "halogen" refers to halogenated bromine, chlorine, fluorine and iodine.

(C 1 -C 7) alkanoyl, hereinafter also referred to as "lower alkanoyl", means a radical derived from an aliphatic carboxylic acid of up to 7 carbon atoms, such as, for example, formyl, acetyl, pripionyl, and the like. Arylcarbonyl is derived from aromatic carboxylic acids such as benzenecarboxylic acid and the like. The alkanoyl group and the arylcarbonyl group may hereinafter be referred to collectively as the "acyl group". A preferred acyl group is an alkanoyl group.

The term "C 3 -C 7 alkylene" refers to a straight or branched chain of 3 to 7 carbon atoms such as propylene, 2-methylpropylene, butylene, pentamethylene, hexamethylene, heptamethylene and the like.

The term "aryl" refers to a phenyl or phenyl group having one to three substituents selected from the group consisting of halogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, nitro, amino, alkylamino C 1 -C 7 dialkylamino having 1 to 7 carbon atoms in the alkyl moieties.

The term "arylalkyl" refers to a straight or branched chain alkyl group having 1 to 7 carbon atoms in which one or more hydrogen atoms are replaced by an aryl group such as a benzyl group and the like. carbon atoms, preferably up to 4 carbon atoms.

Preferred compounds of formula I are those of formula Ia

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^B , R ⁹ , X and n are as defined above.

Another preferred class of compounds of the present invention are those of Formula Ib

.246098 in which

R ⁹ and R ¹¹ represent an alkyl group having 1 to 7 carbon atoms,

R ³¹ represents an acyl group,

X is C 3 -C 7 alkylene and n is an integer from 0 to 4.

Another very preferred group of compounds produced by the process of the present invention are those compounds of formula (Ia) wherein:

R ¹ represents an alkyl group having 1 to 7 carbon atoms,

R ² is hydrogen,

R ³ represents an acyl group,

R ⁴ , R ⁵ and R ^e are hydrogen and

X is C 3 -C 5 alkylene.

More preferred compounds of the present invention are those compounds of formula (Ia) wherein:

R ¹ represents a propyl group,

R ² is hydrogen,

R ³ represents an acetyl radical,

R ⁴ , R ⁵ and R ⁶ are hydrogen and

X is C 3 -C 5 alkylene.

Preferred compounds of formula I are the following:

(rac) -6-Acetyl-7 - [(5- (4-acetyl-3-hydroxy-2-propyleneoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester, (rac) -7- (3- (4-Acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester, ethyl ester (rac j -6- acetyl-7- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3,4-dihydro-2-methyl-8-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester ( rac) -6- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3,4-dihydro-2-methyl-2H-1-benzopyran-2-carboxylic acid ethyl ester (rac) - 7- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid (rac) -6- acetyl-7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H-benzopyran-2-carboxylic acid.

According to the invention, the compounds of the formula I are prepared by treating them with a compound of the formula II

with a compound of formula IV

(f) (v) in which formulas either A is hydrogen and

A ‘represents a group —X — Z, or

A is —X — Z and

A ‘denotes hydrogen,

Z represents a halogen atom, and

R ^1, R ^2, R ^3, R ^4, R ^5, R ^e, R ^7, R ⁸ and X have the above meanings, then optionally obtained rac laugh separated into the optically active isomers.

The reaction of the compounds of formula II with a compound of formula IV to give a compound of formula I can be carried out under anhydrous conditions in an inert solvent such as acetone, methyl ethyl ketone, diethyl ketone, dimethylformamide or the like at reflux. in dimethylformamide, preferably at a temperature in the range of about 70 ° C to about 100 degrees Celsius, and in the presence of an acid binding agent, for example potassium carbonate or the like. A preferred solvent is a mixture of acetone and dimethlyformamide. The resulting compound of Formula I can be obtained using conventional methods, for example, crystallization, chromatography, and the like.

The compounds of formula (II) used as starting materials are known compounds or can be prepared by known methods.

Compounds of formula III which are further used as starting materials can be prepared according to Reaction Schemes I to XIII as follows:

Reaction Scheme I

CCHg ^ CQgR '-------- i. i-y-2

Z-x-Ori

R ³ , R ⁴ , R ⁵ , R ^B , R ^y , X, Z and n have the meanings given above.

Reaction Scheme I illustrates the reaction of a compound of formula VI, which are known compounds or can be prepared by known procedures, with a compound of formula ΙΙΓ to give a compound of formula IV ‘. This reaction may be carried out in an inert organic solvent such as dimethylformamide, acetone, methyl ethyl ketone or the like, preferably dimethylformamide, in the presence of a base, for example (IV ') alkali metal carbonate such as potassium carbonate, sodium carbonate or the like, or hydride an alkali metal such as sodium hydride or the like at a temperature in the range of about 20 ° C to about 150 ° C, preferably at room temperature. The resulting compound of formula IV ‘can be obtained using conventional methods, for example, crystallization, extraction, chromatographic methods or the like.

Reaction Scheme II

 .246098

The general symbols have the following meaning:

R ⁸ , R ^{9 and} n are as defined above,

R ³² , R ⁴² and R ⁵² represent a hydrogen atom or a lower alkyl group and

R is lower alkyl or aryl.

In the process shown in Reaction Scheme 1i, a compound of Formula IIT is reacted with an allyl halide to form a compound of Formula VII in an inert organic solvent such as dimethylformamide, acetone, methyl ethyl ketone and the like, preferably dimethylformamide, in the presence of a base. an alkali metal carbonate such as potassium carbonate, sodium carbonate or the like, or an alkali metal hydride such as sodium hydride or the like at a temperature in the range of about 20 ° C to about 150 ° C, preferably at room temperature. The resulting compound of formula VII can be isolated using conventional methods, for example, crystallization, extraction, chromatography or the like.

The compound of formula (VII) is converted to a compound of formula (VIII) under the conditions typically used for olefin hydroboration. For example, using a hydride of formula (Q) 2BH wherein Q is hydrogen, lower alkyl or lower cycloalkyl, preferably borane (BHz), dicyclohexylborane or borane-dimethylsulfide complex, in an inert ether solvent, preferably tetrahydrofuran, at a temperature in the range of about 0 ° C to about 100 ° C, preferably at room temperature. The resulting organoborane intermediate is oxidized, preferably using alkaline hydrogen peroxide or similar agents. The resulting compound of formula VIII can be isolated by conventional methods.

The compound of formula (VIII) is reacted with a sulfonyl chloride of formula (RSO) Cl in which R is an alkyl or aryl group such as a phenyl group to form a compound of formula (VIIIa) under conditions generally used to convert an alcohol to a sulfonic acid ester. , preferably to the methanesulfonic acid ester. For example, the sulfonation is carried out in an inert solvent such as dichloromethane using a sulfonating agent such as alkylsulfonyl chloride, preferably methanesulfonyl chloride, in the presence of a base such as tri (lower jalkylamine, pyridine or the like, preferably triethylamine) at a temperature ranging from about 0 ° C to about 25 ° C, preferably at 0 ° C. The resulting compound of formula VIIIa can be isolated using conventional methods.

The compound of formula VIIIa is converted to the compound of formula IV ‘and under the conditions usually used to convert sulfonic acid esters to iodides. For example, a compound of formula VIIIa is treated with an alkali metal iodide such as sodium iodide, lithium iodide, potassium iodide and the like, preferably sodium iodide, in a solvent such as a dialkylketone such as ethylmethylketone, acetone and the like, preferably acetone, at in the range between about 20 ° C and about 100 ° C, preferably at 20 ° C. The resulting compound of formula (IVa) can be isolated by conventional methods.

Alternatively, a compound of formula (VII) is converted to a compound of formula (IV ⁾ and under conditions commonly used to convert a terminal olefin into a primary iodide by hydroboration and iodination. For example, the reaction may be carried out using an iodine and a hydride of the formula [Q ₁₂ BH, wherein Q is hydrogen, lower alkyl or lower cycloalkyl, preferably dicyclohexylborane, in the presence of an inert ether solvent such as tetrahydrofuran and a base, e.g. an alkali metal acid, preferably sodium acetate, at a temperature between about 0 ° C and about 20 ° C. The resulting compound of formula IVa 'may be isolated by conventional methods.

Reaction Scheme III

+ - ₆ hJ ₃ p ^ ch co ₂ p ⁰

->

(*)

(Xl)

-½

CH ₂ CO ₂ R ⁹

General symbols have the following meanings:

R ³² , _R 42, _R 52 _{) R} 6 _{and R 11} have the meanings given above and

R‘ represents an arylalkyl group.

Reaction Scheme III illustrates the reaction of a compound of formula IXa with a compound of formula (ΟθΗ5) 3Ρ = CHCO ² R ⁹ wherein R ⁹ is a lower alkyl group, preferably an ethyl group, which are known compounds or can be prepared by known methods to form a compound of formula XI. This reaction may be carried out in an inert aromatic hydrocarbon, preferably toluene, at a temperature in the range of about 20 ° C to about 150 ° C, preferably at about 110 ° C. The resulting compound of formula XI can be isolated by conventional methods.

The compound of formula XI can be converted to a compound of formula IIIb ‘by any of the known methods of catalytic hydrogenolysis. For example, treatment with hydrogen in the presence of a catalyst such as palladium on carbon in a solvent such as an alcohol such as ethanol, preferably at room temperature and at atmospheric pressure. The resulting compound of formula IIIb ‘may be isolated by conventional methods.

whereas

R ³² , R ⁴² , R ⁵² and R ⁹ are as defined above.

According to Reaction Scheme IV, compounds of formula XII which are known compounds or can be prepared by known methods are hydrogenated to give compounds of formula IIIIc ¹ . In particular, the reaction is carried out using a catalyst, for example palladium on carbon, in a solvent such as a lower carboxylic acid, preferably acetic acid, at temperatures between about 20 ° C and about 150 ° C, preferably at 25 ° C, and at elevated pressure, preferably at a pressure of 50 psi. The resulting compounds of formula IIIc 'can be isolated by conventional methods.

Reaction Scheme IV

->

Reaction Scheme V, Q

JI ₉ R '

Λ (xHl) (XLV)

(CH 2) 12

(tlťd.)

R ³² , R ⁴² , R ⁵² , R 6 and R ⁹ are as defined above and n 'is 2, 3 or 4.

According to Reaction Scheme V, compounds of formula XIII, which are known compounds or can be prepared by known methods, are reacted with compounds of formula XIV, which are known compounds or can be prepared by known methods, to form compounds of formula XV. This reaction is carried out in the presence of a catalyst such as a cyclic secondary amine, such as pyrrolidine, and in an inert aromatic hydrocarbon, preferably toluene, at a temperature between about 25 ° C and about 150 ° C, preferably at 110 degrees Celsius. The resulting compound of formula XV can be isolated by conventional methods.

Compounds of formula XV may be reduced to compounds of formula IIId 'using, for example, borane in the presence of a Lewis acid such as boron trifluoride, boron trichloride, aluminum chloride and the like, preferably boron trifluoride etherate, and an inert ether solvent such as tetrahydrofuran at temperatures. between about 0 ° C and about 25 ° C, preferably at 0 ° C. The resulting compounds of formula IIId ‘can be isolated by conventional methods.

Reaction Scheme VI

(Wfj taking

R ⁴² , R ^B , R ^{9 and} n are as defined above, and

R 'represents a hydrogen atom or a lower alkyl group.

Reaction Scheme VI illustrates the reaction of a phenolic compound of formula IIIe 'to its lacylderivative of formula XIX using any suitable acylating agent such as (lower alkanoyl halide or lower alkanoic anhydride, preferably acetic anhydride, in a suitable base such as pyridine, lower alkylamine or the like. , preferably pyridine, at temperatures between about 0 ° C and about 150 ° C, preferably at 25 ° C. The resulting compound of formula (XIX) can be isolated by conventional methods if such isolation is desired.

The compound of formula (XIX) can be converted to a compound of formula (IIIf) using conventional reaction conditions to effect the Fries rearrangement of the phenyl esters. For example, the rearrangement may be carried out in the presence of a Lewis acid catalyst, for example in the presence of aluminum chloride, tin tetrachloride, boron trifluoride, and the like, preferably boron trifluoride etherate, in a solvent such as a halogenated hydrocarbon, lower alkanoic acid and the like. acetic acid, at temperatures between about 20 ° C and about 150 ° C, preferably at 120 ° C. The resulting compound of formula IITf is isolated using conventional methods.

Alternatively, the compound of formula IIe can be converted to the compound of formula III-f under the conditions commonly used in the Friedel-Craft phenol acylation. For example, such acylation may be carried out using a Lewis acid catalyst such as aluminum chloride, tin tetrachloride, boron trifluoride and the like, preferably using boron trifluoride gas, and an acylating agent such as a lower alkanoyl halide, a lower alkanoic anhydride, a lower alkanoic acid. of an acid or the like, preferably in acetic acid, at temperatures ranging from about 20 ° C to about 150 ° C, preferably at 80 ° C. The resulting compound of formula III-f can be isolated by conventional methods.

Reaction Scheme VII

* 1 - CHO

wherein r32, r42 _and p52 are as defined above,

R 11 represents a hydrogen atom or an aryl (lower) alkyl group, preferably a benzyl group and

R ¹² represents a lower alkyl group.

According to Reaction Scheme VII, compounds of formula XXI, which are known or can be prepared by known methods, can be reacted with acrolein to form compounds of formula XXII, operating in the presence of a catalyst, e.g., a strong mineral acid such as hydrochloric acid, sulfuric acid, arylsulfonic acid or alkanesulfonic acid such as p-toluenesulfonic acid or the like, preferably using sulfuric acid, in a solvent such as a lower alkanol such as ethanol, methanol, or the like, preferably methanol, at a temperature in the range of about 20 ° C to about 200 ° C, preferably at 150 degrees Celsius. The resulting compound of formula XXII can be isolated by conventional methods.

A compound of formula XXII is converted to a compound of formula IX in 246098 using a strong mineral acid, such as dilute hydrochloric acid, sulfuric acid, or arylsulfonic acid, or an alkanesulfonic acid, such as p-toluenesulfonic acid, or a similar acid catalyst, preferably using dilute aqueous hydrochloric acid in a water-miscible organic solvent such as acetone, methanol, ethanol, tetrahydrofuran, acetic acid, or the like, preferably acetone, at a temperature in the range of about 20 ° C to about 150 ° C, preferably at 60 ° C.

Reaction Scheme VIII

P ^{= Cn} · »<*)

(xxvi)

In Reaction Scheme VIII, R ³² , R ^42, R ⁵² , R ^9, and R 'are as defined above. ' ^e S88

According to Reaction Scheme VIII, compounds of formula XXIII, which are known compounds or may be prepared by known methods, may be reacted with compounds of formula X, which are also known compounds or may be prepared by known methods, to form compounds of formula XXIV in inert organic etherlckém solvent or an aromatic hydrocarbon, such as tetrahydrofuran, dioxane, dimethoxyethane, benzene, toluene, xylene, or similar solvents, preferably toluene, at temperatures ranging from about 20 ³ C to about 200 ° C preferably at 110 ° C. The resulting compounds of formula XXIV may be isolated by conventional methods.

A compound of formula XXIV can be hydrogenated to a compound of formula XXV using a hydrogenation catalyst such as palladium on carbon, palladium oxide, nickel, or the like, preferably palladium oxide, in the presence of solvents such as lower alkanoic acids, ethyl acetate and the like, preferably ethyl acetate, at a temperature in the range of about 20 ° C to about 100 ° C, preferably at 20 ^° C, and at atmospheric pressure. The resulting compound of formula XXV can be isolated by conventional methods.

Compounds of formula XXV may be converted to compounds of formula XXVI by saponification and subsequent lactonization. The saponification may be carried out using an alkali metal hydroxide, preferably potassium hydroxide, in a solvent, for example a lower alcohol, preferably methanol, at a temperature in the range of about 20 ° C to about 100 ° C, preferably at 65 ° C. The lactonization can be carried out, for example, by treating a lower alkanoic anhydride such as acetic anhydride, which can also be used as a solvent, at temperatures in the range of about 20 ° C to about 200 ° C, preferably at the boiling point of acetic anhydride. The resulting compounds of formula XXVI may be isolated by conventional methods.

Compounds of formula XXVI may be converted to compounds of formula IXb using conventional reducing agents, for example di (lower) alkylaluminum hydride, preferably diisobutylaluminum hydride, at a temperature in the range of about -50 ° C to about -100 degrees Celsius, preferably at -75 ° C in an inert solvent, for example an aromatic hydrocarbon, a chlorinated alkane or a lower alkane, preferably dichloromethane. The resulting compounds of formula (IXb) can be isolated by conventional methods.

Reaction Scheme IX

Reaction Scheme X wherein

R ³ , R ⁴ , R ⁵ , R ⁹ , X and Z are as defined above.

Scheme IX shows the reaction of a compound of formula VI with a compound of formula III "to form a compound of formula IV". This reaction is carried out in an inert organic solvent such as dimethylformamide, acetone, methyl ethyl ketone or the like, preferably dimethylformamide, in the presence of a base such as an alkali metal carbonate such as potassium carbonate, sodium carbonate or the like, or an alkali metal hydride such as sodium hydride or the like, at a temperature in the range of about 20 degrees Celsius to about 150 ° C, preferably at room temperature. The resulting compound of formula (IV) may be isolated by conventional methods, for example, crystallization, extraction, chromatography, and the like.

.24609 8

In Reaction Scheme X, R ³² , R ⁴² , R ⁵² , R ^9, and R 'are as defined above.

According to Reaction Scheme X, a compound of Formula XXIII can be reacted with acrylonitrile to form a compound of Formula XXVII. This reaction is performed preferably in the presence of a catalyst, for example an amine such as triethylamine, diazabicycloundecene, diazabicyclo (2,2,2) octane, while the latter is the preferred amine catalyst at a temperature ranging from about 20 ° C to about 100 C ^3, preferably at 80 ° C, without solvent. The resulting compound of formula XXVII may be isolated by conventional methods.

A compound of formula XXVII may be converted to a compound of formula XXVIII by saponification, for example by treatment with an alkali metal hydroxide such as potassium hydroxide in a solvent such as a water miscible organic solvent such as tetrahydrofuran, methanol, ethanol, or the like. preferably in ethanol or tetrahydrofuran at a temperature ranging from about 20 ° C to about 100 ° C, preferably at 60 ° C for ³ to 70 DEG C. the resulting compound of formula XXVIII may be isolated by conventional methods.

Conversion of a compound of formula XXVIII to a compound of formula XXIX may be carried out by esterification using a lower alcohol reagent and solvent such as ethanol at temperatures in the range of about 20 ° C to about 100 ^° C, preferably at 78 ° C, at in the presence of a catalyst, for example a strong acid such as sulfuric acid, p-toluenesulfonic acid or the like, preferably p-toluenesulfonic acid. The resulting compound of formula XXIX may be isolated by conventional methods.

A compound of formula XXIX may be converted to a compound of formula III 'by catalytic hydrogenation, for example in the presence of supported palladium, nickel, platinum, preferably palladium on carbon, in the presence of a solvent such as lower alkanol, acetic acid, ethyl acetate or the like. preferably ethanol, at temperatures from about 20 ° C to about 200 ° C, preferably at 20 ° C, at atmospheric pressure. The resulting compound of formula III 'a can be isolated by conventional methods.

Reaction Scheme XI

whereas

R ⁴² , R ⁹ and R 11 have the meanings given above.

Scheme XI illustrates the conversion of a compound of formula II 'b to a compound of formula III' c, which may be carried out directly or via a compound of formula XXXII as described above in Reaction Scheme VI for converting a compound of formula 111'e to the compound of formula III'f.

.24609 8

Reaction Scheme XII

(XXXIV) dialkylaluminum hydride

In the above reaction scheme, R ⁴² , R ⁶ , R ⁹ , R 'and Z are as defined above.

Scheme XII shows the reaction of a compound of formula III-g with a compound of formula (a) to form a compound of formula XXXIII. The reaction is carried out under anhydrous conditions in an inert solvent such as acetone, methyl ethyl ketone, diethyl ketone, dimethylformamide, or the like, at the reflux temperature of the reaction mixture, preferably at a temperature in the range of about 40 ° C to about 100 ° C. , in the presence of an acid binding agent, for example potassium carbonate, or the like. A preferred solvent is acetone. The resulting compound of formula XXXIII can be isolated by conventional methods, for example, crystallization, chromatography, or the like.

The compound of formula XXXIII can be converted to the compound of formula XXXIV by treatment with a conventional reducing agent, for example di (lower) alkylaluminum hydride, preferably diisobutylaluminum hydride, at a temperature in the range of about -50 ° C to about -100 ° C, preferably at -75 ° C in an inert solvent, for example an aromatic hydrocarbon, a chlorinated alkane, or a lower alkane, preferably toluene. The resulting compound of formula XXXIV can be isolated by conventional methods.

.246098

Reaction Scheme XIII

(Ι // 'Μ)

In Reaction Scheme XIII, m is 0 or 1, and R ⁴² , R ⁶ , R ⁹ and R 'are as defined above.

Scheme XIII depicts the reaction of a compound of formula XXXIV with a compound of formula (CeH 5) 3 P = CH (CH = CH) _m CO 2 R ⁹ in which

R ⁹ is lower alkyl, preferably ethyl, and m is 0 or 1, which are known compounds or can be prepared by known methods to give compounds of formula XXXVI. This reaction is carried out in an inert aromatic hydrocarbon solvent, preferably toluene, at temperatures ranging from about 20 ° C to about 150 ° C, preferably at about 150 ° C. The resulting compound of formula XXXVI can be isolated using conventional methods.

The compound of formula XXXVI can be converted to the compound of formula III-h by any known catalytic hydrogenation method. Thus, for example, by treating the ox in the presence of a catalyst such as palladium on carbon in a solvent such as an alkanol such as ethanol or ethyl acetate, preferably at room temperature and at atmospheric pressure. The resulting compound of formula IITh may be isolated by conventional methods.

The novel compounds of formula I have antiallergic activity and are also intermediates in the synthesis of the corresponding free acids, which are used as medicaments in the treatment of allergic diseases.

Thus, the resulting compound of formula I can be converted to the corresponding free acid by hydrolysis, which is preferably carried out by treatment with alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or the like in a mixture of water and a water miscible solvent such as methanol, ethanol, tetrahydrofuran or the like, at a temperature in the range of about room temperature to the reflux temperature. The resulting compound can be isolated using conventional methods, for example, crystallization, chromatography or the like.

The antiallergic activity of the free acids of the compounds of formula I can be demonstrated by in vitro and warm-blooded animal experiments using standard pharmacological methods. Examples of such methods are:

(a) Test for guinea pig ileum (in vitro):

The biological system for examining guinea pig ileum is described by Orange and Austen, Adv. Immunol. 10, 105-144 (1969). The 1.5 cm segment was removed from animals of 300-400 g and suspended in an organ bath containing 10 ml of Tyrode solution with 10 ^-6 M atropine sulfate pyrilamin maleate. The bath is maintained at t. 37 ° C and aerated with 95% oxygen and 5% carbon dioxide. The SRS-A used in these investigations is obtained by treating pulmonary fragments of actively sensitized guinea pigs with egg albumin in vitro. The response curve for the different doses of SRS-A is determined for the ileum. The dose of SRS-A which elicits maximal contraction (50%) at 50% is then used for the following experiments. The concentration of the test compound (IC 50), which inhibited the inhibition of the plague ileus caused by SRS-A by 50%, was then determined. In this biological system, it has a standard compound, i.e. 7- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropoxy] -4-oxo-8-propyl-4H-1-benzopyran-2 -carboxylic acid, acting antagonistically on SRS-A, IC 50 3.5 χ ΙΟ ⁸ M.

(b) Bronchoconstriction test - guinea pig (in vivo experiment; aerosol)

Male guinea pigs (Hartley strain) weighing 300-500 g are anesthetized with urethran (2 grams / kg) intraperitoneally and a polyethylene cannula is inserted into the jugular vein for administration of test substances. Tracheal pressure is recorded using a cannula inserted into the trachea and connected to a pressure transducer (Statham). After surgical preparation of the animals, a period of time is allowed to stabilize the lung function. The test compound is administered according to the following prescription: Propanolol (0.1 mg / kg) is administered intravenously as the animals breathe spontaneously, and 5 minutes later the animals are exposed to 1% aerosol for 5 minutes (g / 100 milliliters). solution of the test compounds (adjusted to an alkaline value. _{characterized} pH which is required for the dissolution test Lab alkyl) or distilled water to the appropriate pH (for control purposes). To administer the test compounds by inhalation, an ultrasonic nebulizer (Monaghan model 750) was used. The ultrasonic frequency of the nebulizer is adjusted to produce particles with a diameter of 1 to 8 <µm (average 3 μΐη). The aqueous solutions are prepared fresh and fed into the spray chamber. At the end of this period, animals are paralyzed with succinylcholine (1.2 milligrams / kg, iv) and mechanically induced respiration (Harvard respirator) is applied to the tracheal cannula. ) at a rate of 40 breaths / min and 2.5 ml tidal volume. The animals are then given the maximum constrictor dose of leukotriene E4 intravenously 30 seconds after succinylcholine administration.

The change in pressure, (cm H 2 O) between initial and peak ventilation pressure, is reported as the mean for 3 control animals and 5 test animals (treated with the active compound of the invention). The percent inhibition is calculated from the following formula:

control animals - treated animals control animals

When compounds of the invention are tested at different concentrations, the percent inhibition corresponding to each concentration is plotted as the logirit of the loading concentration: the bars versus the inhibition percentage: (per ordinate axis) and the IC 50 value is determined from linear analytical regression .

Using the free acids of the compounds of formula I, which are listed in Table I below, the results described in Table I are obtained in the above test.

SRS-A antagonism test compound guinea pig ileum test (in vitro)

IC 50 (M) guinea pig bronchoconstriction test (in vivo; aerosol) IC 50 (%) (rac) -6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4- dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid (rac) -7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3, 4-Dihydro-2-methyl-2H-1-benzopyran-2-propanoic acid (rac) -6- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3,4- dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid χ 10 " ⁷ χ ΙΟ" ⁷ > 1.0 ·.

χ ΙΟ “ ⁷

1.0 bronchoconstriction test - - guinea pig (in vivo; aerosol)

IC 50 (θ / o) test compound guinea pig ileum test (in vitro)

IC 50 (M) (rac) -7- (3- (4-Acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3,4-dihydro-2-methyl-8-propyl-3H-1-benzopyran- 2-acetic acid 5 χ 10 ^-7 (rac) -6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2-methyl-2H-1-benzopyran- 2-carboxylic acid 1 χ 10 ^-7 (rac) -6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2-methyl-2H-1- benzopyran-2-propanoic acid 5 χ 10 ^-7 (rac) -6-acetyl-7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -2-methyl-8-propyl-2H- 1-Benzopyran-2-propanoic acid 8 x 10 ^-8 (rac) -6- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3,4-dihydro-5,7,8- trimethyl-2H-1-benzopyran-2-carboxylic acid 1 χ 10 ^-7 (rac) -7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H- 1-benzopyran-2-acetic acid 1 χ 10 ^-7 (rac) -6- (3- (4-acetyl-3-dihydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H-1-benzopyran- 2-acetic acid 4 χ 10 ^-7 (rac) -6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H-1-benz opyran-2-carboxylic acid 5 χ 10 ^-7 (rac) -7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-8-propyl-2H-benzopyran -2-carboxylic acid-1 χ 10 ^-7 na (rac) -7- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3,4-dihydro-2H-1-benzopyran -2-carboxylic acid 6 χ 10 ^-8 (rac) -7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H-1-benzopyran-3- 10 ^-7 (rac) -e-acetyl-7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H-1-benzopyran-2- carboxylic acid carboxylic acid X x IQ ^-7

0.71

0.20> 1.0

0.12

1.0

0.67

1.0

0.50

0.20

0.14

1.0

0.20 test compound .246098 guinea pig ileum test (in vitro)

IC50 (M) bronchoconstriction test bronchoconstriction test

IC 50 (%) (rac) -6-acetyl-7- [3- (4-acetyl-3-hydroxy-2-propyl jpro _t) oxy] -3,4-dihydro-8-propyl-2H-benzopyran-2 carboxylic acid of 1 x 10 ⁷ • Λ? ·· (rac) -7-acetyl-6- [3- (4-acetyl • 3-hydroxy-2-propyl jpropoxy] -3,4-dihydro-2H- -benzopyran-2-carboxylic acid 2 x 10 ^-7

N '- (rac) -6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 6 x 10 ⁸ (rac) -6-Acetyl-7 - [(7- / 4-acetyl-4-hydroxy-2-propylphenoxy / heptyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 1 χ 10 ^-6 (rac) -8-acetyl-7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid acid 3 10 ⁷ χ * iB (rac) -7-acetyl-6- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy j propoxy] -3,4-dihydro-2-methyl-2H- 1-Benzopyran-2-carboxylic acid 5 χ 10 ' ⁷ (rac) -7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran -2-carboxylic acid 2 x 10 (rac) -6-acetyl-7- [5- (4-acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran -2-carboxylic acid, 1 x 10 ⁶ (rac) -6-acetyl-7- [5- (4-acetyl-3-hydroxyphenoxy jpentyloxy] -3,4-dihydro-2H-benzopyran-2-carboxylic acid 3 χ 10 ^-6 (rac) -6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propyl) Phenoxy] pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid 5 χ 10 ^-7 (rac) -6- [5- (4-acetyl-3-hydroxy-2)] -propylphenoxy) pentyloxy] -3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid

0.38

0.34

0.052

1.0

0,59 x ΙΟ ⁷ .246098 bronchoconstriction test - - guinea pig (in vivo; aerosol)

IC50 (%) test compound guinea pig ileum test (in vitro)

IC 50 (M) (rac) -7- [5- (4-Acetyl-3-hydroxyphenoxy) pentyloxy) -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 5x10- ^e (rac) -6-acetyl-7- [6- (4-acetyl-3-hydroxy-2-propyl) hexyloxyJ-3 4-dihydro-2H-l-benzopyran-2-carboxylic acid, 3 x 10 ⁶ (rac) -6 -acetyl-7- [4- (4-acetyl-3-hydroxy-2-propyl-phenoxy) butoxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 2 x 10 ^-6 (rac ) -7- (5- (4-acetyl-3-hydroxyphenoxy) pentyloxy) -3,4-diidro-8-propyl-2H-1-benzopyran-2-carboxylic acid 6 x 10 ^-6 (rac) -7- (5- (4-acetyl-3-liydroxy-2-propyl Jpentyloxy] -3,4-dihydro-8-propyl-2H-benzopyran-2-carboxylic acid 8 χ 10 ^"7 (+) - (R) -6 - [5- (4-Acetyl-3-hydroxy-2-propylphenoxy) pentoxy] -3,4-diliydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid 10 ^-7 (-) - (S) -6- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentylcyl] -3,4-dihydro-2,5,7,8-tetramethyl-2H-1 -benzopyran-2-carboxylic acid 8 χ 10 ^-7 (S) -6-acetyl-7-15- (4-acetyl-3-hydroxy-2-pr opylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 6 χ 10 ^-8 (R 1 -6-acetyl-7- [5- (4-acetyl-3-hydroxy-2- propylphenoxy) pentyloxy] -3,4-dibydro-2H-1-benzopyran-2-carboxylic acid x 10 ' ⁷

246093

If, in the above biological experiment, leukotriene E4 is replaced by leukotriene D4, that is, (rac) -6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propyleneoxy) pentyloxy] -3,4- dihydro-2H-1-benzopyran-2-carboxylic acid, then an IC 50 inhibition value of 0.0056% is determined;

for (R) - (-) -6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid acid, was found to inhibit bronchoconstriction IC 50 of 0.018% and for (S - (+) - 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro -2H-1-benzopyran-2-carboxylic acid was found to inhibit bronchoconstriction IC 50 value of 0.0018%.

cj Leukotriene antagonist test (oral)

Male guinea pigs (Hartley strain, Charles River) weighing 400-600 g are intraperitoneally anesthetized with urethane (2 g / kg) and a polyethylene cannula is inserted into the jugular vein for administration of test compounds. Tracheal pressure is recorded from a pressure transducer (Stathamj. A certain period of time has elapsed after surgical preparation of the animals to stabilize spontaneous respiration. If previous studies have shown a potent effect of propranolol (0.1 mg / kg, iv) on synthetic leukotriene propranolol 5 minutes prior to leukotriene administration Two minutes later, spontaneous breathing is paralyzed with succinylcholine chloride (1.2 milligrams / kg, even in animals, artificial respiration (Harvard respirator) at 40 breaths / min and a tidal volume of 4.0 ml The animals are then dosed with the maximum constrictor dose of either leukotriene C4 or leukotriene D4 or leukotriene E4 (25 µg / kg, iv) within 5 minutes Two hours prior to leukotriene administration as a vehicle control or test substance at a dose 10 mg / kg orally (if necessary to dissolve the test substances Furthermore, the ID50 value for the test compound is determined by changing its dose from 10 mg / kg p.o. to 100, 50, 30, 20, 5, 3 and 1 mg / kg p.o.

To determine the duration of action by oral administration, the time between administration of the test substance and administration of leukotriene varies.

In test c), when the test compounds were administered orally, it was found that racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H- 1-Benzopyran-2-pentanoic acid, when administered orally at a dose of 10 mg / kg, shows 46% + + 14% inhibition of bronchoconstriction induced by leukotriene D4.

A compound of formula I or a composition comprising a therapeutically effective amount of a compound of formula I may be administered by methods well known in the art. The compounds of the present invention may be administered either singly or together with other pharmaceutical formulations, for example antihistamines, mediator release inhibitors, methylxanthines, κ-agonists or antiasthmatic steroids such as prednisone and prednisolone, either orally, parenterally, rectally or by inhalation , for example in the form of an aerosol, in the form of powders containing microparticles, or in the form of a solution applicable in the form of a mist. For oral administration, tablets, capsules, for example in admixture with talc, starch, milk sugar or other inert ingredients, i.e. pharmaceutically acceptable carriers, or aqueous solutions, suspensions, elixirs or aqueous or alcoholic solutions, for example in admixture with sugar or other sweetening, flavoring, coloring, thickening and other conventional pharmaceutical auxiliaries. For parenteral administration, the compounds of the invention may be administered in the form of solutions or suspensions, for example, as an aqueous solution or as a solution in peanut oil or an aqueous suspension in peanut oil using the excipients and carriers customarily used for this method of administration. When administered in the form of aerosols, the compounds of the invention may be dissolved in a suitable solvent that is pharmaceutically acceptable, for example, in ethanol or miscible solvent mixtures, and then mixed with a pharmaceutically acceptable propellant. Such aerosol formulations are filled prior to use into a pressurized container having a valve adapted to release the appropriate dose of the pressurized formulation. Preferably, the valve is a metering valve, i.e., a valve that upon actuation releases a predetermined effective dose of the aerosol formulation.

At present, the most preferred method of administering the compounds of formula I is by inhalation, for example in the form of an aerosol, and in particular for use of the compounds of the invention as antiasthmatic agents.

The dose of the compound of formula I to be administered and the frequency of application depend on the intensity and duration of action of the applied product as well as the route of administration as well as the severity of the disease, the age of the warm-blooded animal treated. the use according to the invention is in the range of about 25 to 1000 mg / day, preferably in the range of about 25 to about 250 mg, either as a single dose or in several divided doses over the day.

If the compounds of formula I produced by the process of the present invention contain an asymmetric carbon atom, they are usually obtained as a racemic mixture. The resolution of such racemates into optically active isomers can be accomplished by known methods.

Cleavage can be carried out by treating the acid corresponding to the acid component of the ester of formula IV with an optically active amine as a resolving agent, such as (R) - or (S) -α-methylbenzylamine, (Rj- or (S) -α-naphthylethylamine, quinine, quinidine). , ephedrine and the like, preferably by treatment with (R 1 - or (S) -? - methylbenzylamine) After separation of the diastereomeric salts as described above, the optically active acid is recovered by treatment with an acid and converted to the corresponding optically active compound of formula I as described above for the preparation of racemic mixtures,

In the following examples, all reactions are carried out under an inert gas (argon) atmosphere. The term "conventional process" or "conventional process" includes a triple extraction with the specified solvent. The organic extracts were combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in a water pump vacuum. The residue is dried to constant weight under high vacuum at 40-50 ° C. Column chromatography is performed using silica gel with a particle size of 0.063-0.2 mm.

The following examples describe and illustrate the invention in a broader context, but do not limit the scope thereof.

Example 1

Mixture of 30,4 g of 2 ‘, 4‘-dihydroxyacetophenone,

28.8 g of levulic acid ethyl ester, 21.3 g of pyrrolidine and 400 ml of toluene are stirred and the reaction mixture is heated under reflux for 3 hours while removing water using a Dean-Stark trap. The mixture was cooled in an ice bath and 300 mL of a 1.2N aqueous hydrochloric acid solution was added. The mixture was stirred for 45 minutes at room temperature, then ether was added and the aqueous layer was separated. The organic solution was washed with a 1.2N hydrochloric acid solution. The aqueous acidic solutions were combined and extracted twice with ether. The organic solutions were combined, washed with water, saturated aqueous sodium bicarbonate solution and brine, then dried (magnesium sulfate), filtered, and the filtered solution was concentrated under reduced pressure. The residual red oil (42 g) was chromatographed on 400 g of silica gel. A 9: 1 mixture of toluene and ethyl acetate is used as the blowing agent. 32.3 g (58.1%) of racemic 3,4-dihydric 7-hydroxy-2-methyl-4-oxo-2H-1- benzopyran-2-propanoic acid as an orange viscous oil.

Example 2

To a stirred solution of 1.5 g of racemic 3,4-dihydro-7-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid ethyl ester in 8 ml of absolute tetrahydrofuran cooled in an ice bath was added 1.4 ml of boron trifluoride etherate over 2 minutes. The reaction mixture was stirred at 0-5 ° C for 5 minutes, during which time 5.4 ml of 1M borane in tetrahydrofuran solution was added. Stirring was continued at 0-5 ° C for 2.5 hours and then quenched by the addition of glacial acetic acid. The solvents were removed in vacuo and the residue was dissolved in methylene chloride. The resulting solution was washed with sodium bicarbonate solution and brine, then dried, filtered, and concentrated under reduced pressure. The residual orange oil (1.4 g) was chromatographed on 50 g of silica gel. Elution with hexane / ethyl acetate 4: 1 gave 0.9 g (63.1%) of racemic 3,4-dihydro-7-hydroxy-2-methyl-2H-1-benzopyran-2- ethyl ester propanoic acid as a colorless oil.

Analysis for:

C15H20O4 calculated:

% C, 68.16;% H, 7.63;

found:

% C, 67.86;% H, 7.60.

Example 3

To a stirred suspension of 120 mg of 50% sodium hydride dispersed in mineral oil in 0.5 ml of absolute N, N-dimethylformamide was added a solution of 292 mg of racemic 3,4-dihydro-7-hydroxy-2-methyl-2H-1-benzopyran ethyl ester. Of 2-propanoic acid in 3 ml of absolute N, N-dimethylformamide. The reaction mixture was stirred at room temperature for 25 minutes and then a solution of 364 mg of 4- (3-bromopropoxy) -2'-hydroxy-3‘-n-propyl acetophenone in 3 ml of absolute N, N-dimethylformamide was added. The reaction mixture was then stirred at room temperature for 21 hours. Ether and dilute hydrochloric acid were added thereto, and after working up in the usual manner using ether, 523 mg of an orange oil was obtained. This product is chromatographed on 50 g of silica gel. Toluene / ethyl acetate (19: 1) was used as the eluent. 257 mg (46.5%) of racemic 7- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) propoxy] -3 racemic ethyl ester was obtained. 4-Dihydro-2-methyl-2H-1-benzopyran-2-propanoic acid as a pale yellow oil.

.246093

Analysis for:

C29H38O7 calculated:

% C, 69.86;% H, 7.68; found:

69.65% C, 7.73 θ / o H.

Example 4

To a mixture of 1.55 g of the ester of Example 3 and 35 ml of a 1: 1 mixture of tetrahydrofuran and water was added 2.3 g of lithium hydroxide monohydrate while stirring. The mixture was then stirred for 22 hours at room temperature and diluted with water, then extracted three times with ether (the ethereal extracts were discarded J. The aqueous solution was acidified to pH 1 by addition of a saturated aqueous solution of oxalic acid and then worked up in conventional manner using ether. with 1.4 g (95.8%) of racemic 7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2-methyl-2H-1-benzopyran -2-propanoic acid in the form of a viscous yellow oil.

Analysis for:

C27H34O7 calculated:

% C, 68.92;% H, 7.28;

found:

% C, 68.62;% H, 7.23.

Example 5

Mixture 3.88 g 2 ^: 4 ^! -dihydroxy-3'-n-propyl acetophenone, 3.17 g of levulic acid ethyl ester, 0.83 ml of pyrrolidine and 20 ml of toluene are stirred at room temperature for 1 hour and then heated at reflux for 3 hours while removing water with Dean -Stark separators. The resulting dark red mixture was cooled, treated with 25 ml of 1N hydrochloric acid solution and stirred at room temperature for 30 minutes, then water was added and the reaction mixture was worked up using ether in the usual manner. 5.1 g of a dark-red oil are obtained. This material is chromatographed on 100 g of silica gel. A 9: 1 and 4: 1 mixture of toluene and ethyl acetate is used as eluent. 2.9 g (45.3%) of racemic 3,4-dihydro-7-hydroxy-2-methyl-4-oxo-3-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester is obtained in the form of of yellow oil.

Analysis for:

C18H24O5 calculated:

% C, 67.48;% H, 7.55;

found:

% C, 67.31;

Example 6

The procedure is as described in Example 2, with 257 mg of racemic 3,4-dihydro-7-hydroxy-2-methyl-4-oxo-8-n-propyl-2H-1-benzopyran-2-propanoate ethyl ester of the acid is reduced using borane and tetrahydrofuran and boron trifluoride etherate. 195 mg of racemic 3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester is obtained in the form of a pale yellow oil. (After chromatographic purification on silica gel). Analysis for:

C18H26O4 calculated:

% C, 70.56;% H, 8.55; found:

% C, 70.01;% H, 8.28.

Example 7

To a stirred suspension of 108 mg of 50% sodium hydride dispersed in mineral oil (previously washed with hexane) in 1 ml of anhydrous Ν, Ν-dimethylformamide was added a solution of 268 mg of racemic 3,4-dihydro-7-hydroxy-2-methyl-3- ethyl ester. n-propyl-2H-1-benzopyran-2-propanoic acid in 3 ml of absolute Ν, Ν-dimethylformamide at room temperature for 1 minute. The reaction mixture was stirred at room temperature for 30 minutes and then a solution of 313 mg of 4- (3-bromopropoxy) -2‘-hydroxy-3‘-n-propyl acetophenone in 3 ml of absolute Ν, Ν-dimethylformamide was added dropwise. Sodium iodide (0.3 g) was then added and the mixture was stirred at room temperature

After 2.5 hours, 1 ml of water was added. After 30 minutes, 0.3 g of lithium hydroxide monohydrate and 1 ml of water are added and stirring is continued for 3 hours. The reaction mixture is acidified to pH 1 with 1N hydrochloric acid solution and worked up in the usual manner using ether. The orange oil (0.7 g) was chromatographed on 50 g of silica gel. Using toluene / ethyl acetate as eluent (4:

: 1) 310 mg (69.1%) of racemic 7- (3- (4-acetyl-3-hydroxy-2-n-propylphenoxy) propoxy) -3,4-dihydro-2-methyl-8-n are obtained. propyl-2H-1-benzopyran-2-propanoic acid as a viscous yellow oil (after drying at 60 ° C under high vacuum).

Analysis for:

C30H40O7 η 4; »fj η g calculated:

70, 29% C, 7.87% H; nelezeno:

% C, 70.19;% H, 7.99.

Example 8

Using the procedure described in Example 1, 15 g of 2‘, 5‘-diliydroxyacetophenone are reacted, which is condensed with 14.2 g of levulic acid ethyl ester and 12.3 ml of pyrrolidine in 200 ml of toluene. The crude product (20.5 g) was purified by high pressure liquid chromatography (silica gel, solvent system: hexane / ethyl acetate 2: 1) to give 17.6 g (64.1%) of racemic 3,4-dihydro-ethyl ester. 6-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid as a yellow oil.

Analysis for:

C 18 H 18 O 5 calculated:

% C, 64.74;% H, 6.52;

found:

% C, 64.28;% H, 6.64.

Example 9

To a solution of 8.25 g of racemic 3,4dihydro-6-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid ethyl ester in 50 ml of ethylene glycol absolute diethyl ether is added 7.29 ml of boron trifluoride etherate after drops while stirring and cooling in an ice bath. After stirring at 0-5 ° C for 10 minutes, 1.75 g of the borane-dimethylamine complex compound was added to the mixture. Stirring is continued for 1 hour at room temperature and then 5 ml of glacial acetic acid are added to the mixture and the solution is poured into cold water and worked up in the usual manner using ether (the combined organic extracts are additionally washed with sodium bicarbonate solution). Thus, 8.1 g of a yellow oil are obtained which is purified by preparative HPLC (silica gel, solvent system: hexane / ethyl acetate). in a ratio of 2: 1 to give 5.8 g (74.1%) of racemic 3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a yellow oil .

Example 10

Using the procedure described in Example 7, 0.695 g of racemic 3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acid ethyl ether is alkylated with

0.939 g of 4‘- (3-bromopropoxy) -2‘-hydroxy-3‘-n-propyl acetophenone using sodium hydride in absolute Ν, Ν-dimethylformamide. After saponification (1.25 g of lithium hydroxide monohydrate), 1.4 g of crude acid is obtained. Column chromatography on silica gel (50 grams) afforded 0.837 g (67%) of racemic 6- (3 '- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2-methyl-2H-1. benzopyran-2-propanoic acid as a colorless oil, eluting with toluene / ethyl acetate (9: 1 and 4: 1).

Analysis for:

C27H34O7 calculated:

% C, 68.92;% H, 7.28; found:

% C, 68.36;% H, 7.20.

Example 11

Using the procedure described in Example 7, 0.9 g of racemic 3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylic acid ethyl ester was alkylated using 1.5 g of 4 '- (3 bromopropoxy) -2'-hydroxy-3'-n-propyl acetophenone and 12.16 mmol of sodium hydride and 10 mmol of sodium iodide in Ν, Ν-dimethylformamide. After saponification using 1.5 g of lithium hydroxide monohydrate, the crude acid is purified by chromatography on silica. 1.16 g (68.9%) of racemic 6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2-methyl-2H-1- benzopyran-2-carboxylic acid as a white solid, m.p. 108-110.5 ° C.

Analysis for:

C2SH30O7 calculated:

% C, 67.86;% H, 8.83;

found:

67.92% C, 6.97% H.

Example ¹ 2

385 ml of a 50% dispersion of sodium hydride in mineral oil was washed with hexane and suspended in 32 ml of anhydrous N, N-dimethylformamide. To the stirred suspension was added 1 g of racemic 3,4-dihydro-2,5,7,8-tetramethyl-6-hydroxy-2H-1-benzopyran-2-carboxylic acid methyl ester. The reaction mixture was stirred at room temperature for 45 minutes and then 3.2 ml (4.47 g) of allyl bromide was added dropwise. Stirring is continued for 90 hours at room temperature and then 3 ml of methanol are added. The mixture was poured into water and then worked up in the usual manner using ether to give 1.8 g of an amber-colored alley. This product was purified by 246098 silica gel column chromatography followed by preparative high pressure liquid chromatography (silica gel, solvent system: hexane / ethyl acetate 19: 1). There was thus obtained 3,4-dihydro-2,5,7,8-totramethyl-6- (2-propenyloxy) -2H-1-benzopyran-2-carboxylic acid racemic methyl ester 772 mg (67%) as a pale yellow oil. . This material was distilled to give an oil which crystallized on standing at a bath temperature of 105-107 ° C and a pressure of 2.6 Pa. The solid obtained melts at 68-70 ° C.

Analysis for:

C18H24O4 calculated:

C, 71.03; H, 7.95;

found:

% C, 71.37;% H, 7.90.

Example 13

To a solution of 1.8 g of racemic 3,4-dihydro-2,5,7,8-tetramethyl-6- (2-propenyloxy) -2H-1-benzopyran-2-carboxylic acid methyl ester in 36 ml of anhydrous tetrahydrofuran is added 1.98 ml of borane / dimethylsulphide mixture with stirring and cooling on an ice bath. The reaction mixture was stirred at 0-5 ° C for 1.5 hours and then quenched by the dropwise addition of 9 mL of water. After stirring at 0-5 ° C for 10 minutes, 6.84 ml of 3N sodium hydroxide solution was added dropwise, followed by 2.2 ml of 30% hydrogen peroxide. The mixture was stirred at 5-10 ° C for 1 hour and then acidified with 7 mL of 3N hydrochloric acid. Thereafter, the reaction mixture was worked up in the usual manner using ether to give 2 g of an oil which was purified by preparative HPLC (silica gel, solvent system: 1: 1 hexane / ethyl acetate). In this way, 1.22 g (64%) of racemic 3,4-dihydro-2,5,7,8-tetramethyl-6- (3-hydroxypropoxy) -2H-1-benzopyran-2-carboxylic acid methyl ester is obtained in the form of colorless oil.

Analysis for:

C18H26O5 in / unread:

67.06% C, 8.13% II;

n Nezeno:

% C, 67.39;% H, 8.19.

Example 14

X a solution of 0,3 g of racemic 3,4-dlhydro-2,5,7,8-tetramethyl-6- (3-hydroxypropoxy) -2H-1-benzopyran-2-carboxylic acid methyl ester in 5 ml of anhydrous methylene chloride and 0, 33 ml of triethylamine are added with 0.17 ml of methylsulfonyl chloride. The reaction mixture was stirred at room temperature for 45 minutes, then an IN sulfuric acid solution was added thereto, and then worked up in the usual manner using methylene chloride. There was obtained 0.461 g of racemic 3,4-dihydro-2,5,7,8-tetramethyl-6- (3-methanesulfonyloxypropoxy) -2H-1-benzopyran-2-carboxylic acid methyl ester as an oil used for subsequent reaction without further purification.

Example 15

A mixture of the crude methanesulfonate of Example 14 (about 0.932 mmol), 595 mg of sodium iodide and 5 ml of acetone was stirred at room temperature for 43.5 hours and then worked up in the usual manner after addition of water using ether (additional ether extracts were washed with dilute bisulfite solution). The oily product (390 mg) was chromatographed on 20 g of silica gel, eluting with hexane / ethyl acetate (19: 1 and 9: 1) to give 306 mg (76.0 percent) of racemic 3,4-dihydro-2-methyl ester. 5,7,8-tetramethyl-6- (3-iodopropoxy) -2H-1-benzopyran-2-carboxylic acid as a colorless oil The iodide prepared by this method in another process crystallizes to a solid, m.p. 5 degrees Celsius.

Example 16

A mixture of 0.1 g g of 2hyd, 4‘-dihydroxy-3lacet-n-propyl acetophenone, 0.195 g of anhydrous potassium carbonate and 3 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 1 hour. A solution of the iodide of Example 15 (0.306 g) in 5 ml of N, N-dimethylformamide was then added and the mixture was stirred at room temperature for 30 minutes and at 60 degrees Celsius for 31 hours. After cooling, a 1N hydrochloric acid solution was added to the reaction mixture, and the reaction mixture was worked up in the usual manner using ether. The oily product (0.406 g) was chromatographed on 20 g of silica gel. Elution with 4: 1 hexane: ethyl acetate gave 0.291 g (82.5 percent) of racemic 6- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3,4-dihydro- 2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid as a pale yellow oil. The product prepared in this way in another example crystallizes and affords a colorless solid, mp 121-123 ° C (from ethanol).

Analysis for:

C29H38O7 calculated:

% C, 69.86;% H, 7.68;

found:

% C, 69.31;% H, 7.67.

Example 17

A solution of 0.246 g of the methyl ester of Example 16, and 0.227 g of sodium hydroxide in 8 ml of methanol and 2 ml of water was stirred at room temperature for 1.5 hours, followed by the addition of 1N hydrochloric acid solution and working up in the usual manner using ether. The crude product was redissolved in ether and the solution washed with dilute sodium bicarbonate solution. The aqueous alkaline phase was acidified with 2N hydrochloric acid solution and worked up in the usual manner using ether. 0.161 g (67.3%) of the acid is obtained in the form of a yellow oil which crystallizes on standing. Recrystallization from benzene / hexane gave racemic 6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2,5,7,8-tetramethyl-2H-1- benzopyran-2-carboxylic acid as a colorless solid, mp 137-139 ° C.

Analysis for:

C26H36O7 calculated:

% C, 69.40;% H, 7.49; found:

69.28% C, 7.58 θ / ο H.

Example 18

Using the procedure described in Example 12, 1.42 grams of 3,4-dihydro-2,5,7,8-tetramethyl-6-hydroxy-2H-1-benzopyran-2-acetic acid racemic methyl ester is 2.79 g allyl bromide and 5.58 mmol sodium hydride in anhydrous N, N-dimethylformamide. 1.35 g of racemic 3,4-dihydro-2,5,7,8-tetramethyl-6- (2-propenyloxy) -2H-1-benzopyran-2-acetic acid methyl ester (83.1% of theory) are obtained. as a yellow oil (after chromatography on a silica gel column eluting with hexane / ethyl acetate 9: 1).

Analysis for:

C19H26O4 calculated:

% C, 71.67;% H, 8.23; found:

% C, 71.54;% N, 8.25.

Example 19

To a stirred, ice-cooled 1M solution of borane in 10 mL of tetrahydrofuran was added dropwise a solution of 2 mL (1.64 g) of cyclohexene in 6 mL of absolute tetrahydrofuran. The reaction mixture was then stirred at 0-5 ° C for 1.5 hours. To the resulting dicyclohexylborane suspension was added dropwise a solution of 1.59 g of the allyl ether of Example 18 in 4 mL of tetrahydrofuran. The reaction mixture was stirred at 0-5 ^° C for 1 hour and at room temperature for 18 hours. 20 ml of 1M methanolic sodium acetate solution are then added dropwise, followed by 23.8 ml of 0.4M methanolic iodine solution. The resulting reaction mixture was stirred at room temperature for 4 hours, then 3.1 mL of aqueous sodium thiosulfate was added. The reaction mixture was then poured into water and worked up in the usual manner using ether. Chromatography of the crude product (4.4 g) per 100 g of silica gel gives 1.71 g (76.7% of theory) of the racemic 3,4-dihydro-6- (3-iodopropoxy) -2,5,7-racemic methyl ether, 8-tetramethyl-2H-1-benzopyran-2-acetic acid as an oil, eluting with hexane / ethyl acetate (19: 1 and 9: 1).

Example 20

As described in Example 16, 328 mg of 2 ', 4'-dihydroxy-3'-n-propyl acetophenone was alkylated with 756 mg of the iodide described in Example 19 and 467 mg of anhydrous potassium carbonate in anhydrous N, N-dimethylformamide. Thus, 0.789 g (91.1% of theory) of racemic 6- (3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy) -3,4-dihydro-2,5,7,8,8-racemic methyl ester is obtained ^. tetramethyl-2H-1-benzopyran-2-acetic acid as a yellow oil (after column chromatography on silica gel with hexane / ether 4: 1).

Example 21

The methyl ester of Example 20 (0.639) is saponified with sodium hydroxide as described in Example 17. The product, i.e. the crude acid, is chromatographed on 30 g of silica gel. Elution with hexane / ethyl acetate (2: 1) gave 0.336 g (59.6% of theory) of racemic 6- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3, 4-Dihydr 0-2,5,7,8-tetramethyl-2H-1-benzopyranacetic acid as a yellow glassy product.

Analysis for:

C29H38O7 calculated:

% C, 69.86;% H, 7.68;

found:

% C, 69.63;% H, 7.89.

Example 22

To a stirred solution of 0.8 g of racemic 3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester in 8 mL of pyridine is added 0.37 mL of acetic anhydride . The reaction solution was stirred at room temperature for 5 hours, then poured into ice-water and the mixture was worked up in the usual manner using ether (the combined ether extracts were additionally washed with 1N hydrochloric acid solution and saturated sodium bicarbonate solution). 1.0 g of the oily product is chromatographed on 50 g of silica gel. Elution with toluene / ethyl acetate (19: 1) gave 0.575 g (63.3% of theory) of racemic 7-acetoxy-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2 ethyl ester. -propanoic acid in the form of a pale yellow oil.

Analysis for:

C20H28O5 calculated:

% C, 68.94;% H, 8.10;

found:

68.75% C, 8.06% H.

Example 23

To a stirred solution of 276 mg of 7-acetoxy-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid racemic ethyl ester in 2 mL glacial acetic acid was added at room temperature. 21 ml of boron trifluoride etherate. The reaction mixture was stirred for 24 hours at 105 ° C and then cooled and diluted with ether. The ethereal solution was washed with water and brine, and worked up in the usual manner to give 298 mg of a yellow-brown oil. This product is chromatographed on 30 g of silica gel. Elution with toluene / ethyl acetate (4: 1) gave 183 mg (72.1% of theory) of racemic 6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-n-propyl-1H-benzopyran-2. -propanoic acid as a white solid. M.p. 154-156 ° C.

Analysis for:

C18H24O5 calculated:

% C, 67.48;% H, 7.55;

found:

% C, 67.17;% H, 7.72.

Example 24

A solution of 692 mg of racemic 6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid and 100 mg of p-toluenesulfonic acid monohydrate in 10 ml of absolute of ethanol was stirred for 17 hours while heating to reflux. The resulting solution was cooled, a small amount of saturated sodium bicarbonate solution was added, and the solution was concentrated in vacuo to remove ethanol. The residue is treated with ether and the ether solution is worked up in the usual manner. 752 mg of a yellow oil are obtained. This material is chromatographed on 50 g of silica gel. Elution with toluene / ethyl acetate (4: 1) afforded 706 mg (93.9% of theory) of racemic 6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H ethyl ester. -1-benzopyran-2-propanoic acid as a yellow oil.

Analysis for:

C20H28O5 calculated:

% C, 68.94;% H, 8.10;

found:

% C, 68.86;% H, 7.85.

Example 25

A mixture of 263 mg of 6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid racemic ethyl ester, 222 mg of anhydrous potassium carbonate, 0.39 ml 1,3-dibromopropane, 6 ml of anhydrous acetone and 3 ml of anhydrous Ν, Ν-dimethylformamide are stirred for 16 hours at reflux. 0.25 g of anhydrous potassium carbonate was then added and the reaction mixture was further stirred at reflux for 25 hours. The reaction mixture was cooled and the volatiles were removed first under water pump vacuum and then under high vacuum. The residue was treated with ether and acetone and the solids were removed by filtration. Concentration of the filtrate in vacuo afforded 359 mg of racemic 6-acetyl-7- (3-bromopropoxy) -3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a form. orange oil.

Example 26

A mixture of 335 mg of 6-acetyl-7- (3-bromopropoxy) -3,4-dlhydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid racemic ethyl ester, 143 g of 2 ', 4 1-dihydroxy-3'-n-propyl acetophenone, 217 mg of anhydrous potassium carbonate, 6 ml of anhydrous acetone and 3 ml of anhydrous Ν, Ν-dimethylformamide were stirred and refluxed for 17 hours. Then an additional 100 milligrams of potassium carbonate is added and stirring and refluxing is continued for 4 hours. The reaction mixture was then cooled to room temperature and 1N hydrochloric acid solution was carefully added to acidify the reaction mixture to pH 1. Water was then added and the mixture was worked up in the usual manner using ether. The residue is chromatographed on 24609 δ on 50 g of silica gel. Elution with 9: 1 toluene / ethyl acetate gave 219 mg (52.6% of theory) of racemic 6-acetyl-7- [3- (4-acetyl-3-hydroxy-2-n-propylphenoxy) propoxy] racemic ethyl ester - 3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid as a yellow oil.

Example 27

191 mg of the product of Example 26 are saponified with lithium hydroxide monohydrate (273 mg) in 5 mL of a 3: 2 mixture of tetrahydrofuran and water using the procedure described in Example 4. After silica gel column chromatography, racemic 6-acetyl is obtained. -7- (3- (4-acetyl-3-hydroxy-2-n-propylphenoxy) propoxy] -3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid in the form of yellow viscous oil.

Analysis for:

C32H42O8 calculated:

% C, 69.29;% H, 7.63;

found:

% C, 69.07;% H, 7.79.

Example 28

809 mg of racemic 3,4-dihydro-6-hydroxy-5,7,8-trimethyl-2H-1-benzopyran-2-carboxylic acid ethyl ester is alkylated by treatment with 1.2 g of 4 '- (3-bromopropoxy) -2' hydroxy-3'-n-propyl acetophenone, 448 mg of a 50% dispersion of sodium hydride in mineral oil and 1.2 g of sodium iodide in anhydrous dimethylformamide as described in Example 7. After saponification (1.2 g of lithium hydroxide monohydrate J), This was chromatographed on 50 g of silica gel, eluting with toluene / ethyl acetate (4: 1, then 2: 1 and finally 1: 1) to give 1.2 g (83.2 g). % of theory] racemic 6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy] propoxy] -3,4-dihydro-5,7,8-trimethyl-2H-1-benzopyran-2-carboxylic acid 144-147 ° C.

Analysis for:

C27H34O7 calculated:

% C, 68.92;% H, 7.28;

found:

% C, 68.68;% H, 7.02.

Example 29

A mixture of 25 g of p-benzyloxyphenol, 20 ml of freshly distilled acrolein, 70 ml of methanol and 0.5 ml of concentrated sulfuric acid was heated to 150 ° C in a pressure vessel with stirring for 2 hours. The reaction mixture was cooled and diluted with ether. The ether solution was washed with water and saturated sodium bicarbonate solution and then worked up in the usual manner 47.9 g of a brown oily residue was chromatographed on 250 g of silica gel. Elution with toluene gave 23.1 g of an orange oil which was re-chromatographed on 300 g of silica gel. Elution with 9: 1 hexane: ethyl acetate gave 12.8 g (37.9 percent of theory) of racemic 3,4-dihydro-2-methoxy-6- (phenylmethoxy) -2PI-1-benzopyran as a yellow oil. This material was dissolved in 200 ml of acetone and 120 ml of 2N aqueous hydrochloric acid was added and the reaction mixture was stirred at reflux for 2 hours, then kept at room temperature overnight and then heated again. After cooling, the reaction mixture was concentrated in a fume hood to remove most of the acetone, and the aqueous residue was worked up in the usual manner using ether (the combined ether extracts were additionally washed with saturated sodium bicarbonate solution) to give 12 g. This was chromatographed on 250 g of silica gel, eluting with 9: 1 and 4: 1 toluene: ethyl acetate to give 9.8 g ( 80.7% of theory] of racemic 3,4-dihydro-6- (phenylmethoxy) -2H-1-benzopyran-2-ol as a pale yellow solid. Melting point 92.5-95 ° C.

Analysis for:

C16H16O3 calculated:

74.98% C, 6.29% H;

found:

74.78% G, 6.41% H.

Example 30

A solution of 1.8 g of racemic 3,4-dihydro-6- (phenylmethoxy) -2H-1-benzopyran-2-ol and 2.6 g of (camphomethoxymethylene) triphenylphosphorane in 20 ml of toluene is stirred and heated to reflux. condenser for 22 hours. The solution was cooled and transferred to a column of 50 g silica gel in toluene. Elution with 19: 1 toluene: ethyl acetate gave 1.7 g (74.2% of theory) of racemic 3,4-dihydro-6- (phenylmethoxy) -2H-1-benzopyran-2-acetic acid ethyl ester as light of yellow oil. This oil was dissolved in 25 mL absolute ethanol and stirred in the presence of 0.2 g of 10% palladium on carbon at room temperature under a hydrogen atmosphere. After 1.5 hours the uptake of hydrogen ceased and the catalyst was removed from the 246098 by filtration. The filtrate was concentrated in vacuo to give 1.2 g (97.6%) of racemic 3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester as a pale yellow oil.

Example 31

A mixture of 1.2 g of racemic 3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester, 1.8 g of 4 ^; - (3-Bromopropoxy) -2'-hydroxy-3'-n-propyl acetophenone, 1.6 g of anhydrous potassium carbonate, 30 ml of absolute acetone and 15 ml of absolute dimethylformamide are stirred under reflux for 23 hours. An additional 1.6 g of potassium carbonate is then added and the mixture is stirred under reflux for a further 2.5 hours. After cooling, the mixture was carefully poured into a 1N aqueous hydrochloric acid solution. The mixture was then worked up in the usual manner using ether (the combined ether extracts were additionally washed with a saturated aqueous sodium bicarbonate solution). 3.7 g of a brown oil are obtained which is chromatographed on 50 g of silica gel. Elution with toluene / ethyl acetate (19: 1) gave 1.6 g of a pale yellow oil. A solution of this ester and 3.0 g of lithium hydroxide monohydrate in 40 ml of a 1: 1 mixture of tetrahydrofuran and water was stirred at room temperature for 23 hours. The resulting solution was diluted with water and acidified to pH 1 with 2N hydrochloric acid solution. Working up the mixture in the usual manner using ether gives an oil which is chromatographed on 50 g of silica gel. Elution with toluene / ethyl acetate (4: 1, 2: 1 and 1: 1) gave 831 mg (37% of theory) of racemic 6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3 4-dihydro-2H-1-benzopyran-2-acetic acid as a pale yellow solid. 102.5-105 ° C.

Analysis for:

C25H30O7 calculated:

% C, 67.86;% H, 6.83;

found:

68.03% C, 6.75% H.

Example 32

A mixture of 17.5 g of (ethoxycarbonylmethylene) triphenylphosphorane and 11.4 g of 4-benzyloxy-2-hydroxybenzaldehyde in 200 ml of toluene is stirred and heated to reflux for 1 hour. This residue was dissolved in 300 mL of ethyl acetate and the solution was hydrogenated at atmospheric pressure at room temperature in the presence of 0.35 g of platinum oxide, then the catalyst was filtered off and the filtrate The mixture was concentrated in vacuo to give 28.1 g of the product containing (4'-benzyloxy-2'-hydroxy) -benzenepropanoic acid ethyl ester, to which was added 100 mL of 5% methanolic potassium hydroxide solution and the mixture was heated to reflux for The bulk of the methanol was removed by concentration in vacuo and the residue was partitioned between ether and water. The aqueous phase is acidified with 2N hydrochloric acid solution and worked up in a conventional manner using a 1: 1 mixture of ether and tetrahydrofuran. It is obtained

9.8 g of (4‘-benzyloxy-2-hydroxy) benzenepropanoic acid. This acid was dissolved in 98 ml of acetic anhydride and the solution was heated at reflux for 2 hours. After cooling, 100 ml of methanol are added to the solution and the solvent is removed by concentration in vacuo. The methanol addition and subsequent evaporation were repeated two more times and the residue was purified by high pressure liquid chromatography on silica gel using 4: 1 hexane / ethyl acetate as eluent. 6.2 g (48.8% of theory) of 3,4-dihydro-7- (phenylmethoxy) -1-benzopyran-2-one are obtained in the form of a solid.

Example 33

To a stirred solution of 6.2 g of 3,4-dihydro-7- (phenylmethoxy) -1-benzopyran-2-one in 80 ml of dichloromethane was added dropwise 20 ml of diisobutylaluminum hydride dissolved in toluene (25% solution) at -76 ° C. The reaction mixture is stirred at this temperature for 1 hour, 5 ml of methanol are then carefully added to the reaction mixture, then the solution is poured into 25 ml of 1N sulfuric acid solution and the mixture is worked up in the usual manner using ether. The residue (5.9 g) was purified by high pressure liquid chromatography on silica gel (3: 1 hexane / ethyl acetate) to give 4.8 g (76.8%). theory) of racemic 3,4-dihydro-7- (phenylmethoxy) -2H-1-benzopyran-2-ol as a colorless solid, mp 64-65.5 ° C.

Analysis for:

C16H16O3 calculated:

74.98% C, 6.29% H;

found:

% C, 74.44;% H, 6.38.

Example 34

2.2 g of racemic 3,4-dihydro-7- (phenylmethoxy) -2H-1-benzopyran-2-ol were condensed with 3.2 g of (ethoxycarbonylmethylene) triphenylphosphorane as described in Example 30. 2.6 g (92 g) of the title compound were obtained. , 8% of theory) racemic 3,4-dihydro-7- (phenylmethoxy) -2H-1-benzopyran-2-acetic acid ethyl ester as a yellow oil (after column chromatography for purification), which is hydrogenolyzed in the presence of 0.2 g of 10% palladium on carbon as described in Example 30. 1.9 g of racemic 3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester are obtained in the form of a pale yellow oil.

Example 35

0.9 g of racemic 3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester is alkylated with 3 g of 4 '- (3-bromopropoxy) -2'-hydroxy-3'-n-propyl acetophenone The crude product was chromatographed on 50 g of silica gel using toluene / ethyl acetate (19: 1) to give 1.2 g of the desired ester as a pale yellow oil. This material is saponified by treatment with 2.0 g of lithium hydroxide monohydrate as described in Example 31. 1.1 g of the crude acid is chromatographed on 50 g of silica gel. Elution with 2: 1 and 1: 1 toluene / ethyl acetate gave 682 mg (40.5% of theory) of racemic 7- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propoxy] -3,4- dihydro-2H-1-benzopyran-2-acetic acid as a pale yellow solid. Melting point 107 to 107 ° C

109.5 ° C.

Analysis for:

C25H30O7 calculated:

% C, 67.86;% H, 83.83;

found:

C, 68.07; H, 6.87.

Example 36

A solution of 8.75 g of ethyl 6-hydroxychromone-2-carboxylate in 200 ml of acetic acid is hydrogenated in the presence of 2 g of 10% palladium on activated carbon at 50 psi at room temperature with shaking of the suspension for 17 hours. The catalyst is then filtered off and the filtrate is evaporated under reduced pressure. 7.85 g of crude product is obtained. Purification of the compound by high performance liquid chromatography (solvent system: 3: 1 hexane: ethyl acetate) yielded 4.9 g (59%) of pure crystalline racemic 3,4-dihydri-6-hydroxy-2H-1-benzopyran- Recrystallization from ethyl acetate / hexane gave a colorless solid, mp 72-74 ° C.

Analysis for:

C12H14O4 calculated:

% C, 64.85;% H, 6.35;

found:

% C, 64.57;% H, 6.45.

Example 37

As a solution of 2.23 g of racemic ethyl 6-hydroxychroman-2-carboxylate in 30 ml of acetic acid, a stream of boron trifluoride gas is introduced at a temperature of 20 to 25 ^° C. uses cold water baths to control the temperature of the exothermic reaction. Then, the cold water bath is removed and the reaction mixture was heated to 80 ^N for 5 hours. The reaction mixture was cooled and poured carefully into a saturated solution of sodium bicarbonate and ice and the product was extracted with a 1: 1 mixture of tetrahydrofuran and ether. The crude product obtained after evaporation of the solvent was chromatographed on a silica gel column. 1.6 g (60% of theory) of racemic 7-acetyl-6-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester as a viscous oil.

Example 38

Using the procedure described in Example 32, 1.0 g of racemic ethyl 6-hydroxychroman-2-carboxylate was converted to racemic 6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H 1-benzopyran-2-carboxylic acid is obtained, yielding 27.3% of the theoretical yield of a white crystalline product, m.p. 125-127 ° C.

Analysis for:

C24H28O7 calculated:

% C, 67.28;% H, 6.59;

found:

% C, 67.27;% H, 6.67.

Example 39

A mixture of racemic 7-acetyl-6-hydroxychroman-2-carboxylic acid ethyl ester (1.6 g), potassium carbonate (3.0 g), 1,3-dibromopropane (5 ml), absolute acetone (60 ml) and absolute dimethylformamide (30 ml) was stirred for 20 hours. under reflux. After removing most of the solvent in vacuo, the residue was diluted with ether and a 1N hydrochloric acid solution was carefully added. The organic phase was separated, washed with saturated sodium bicarbonate solution and water, dried and concentrated in vacuo. 2.1 g of the crude bromopropyl derivative are dissolved in 30 ml of acetone and this solution is added to a mixture of 1.2 g of 2 ', 4'-dihydro-3'-propylacetophenone, 2.5 g of anhydrous potassium carbonate, 30 ml of absolute acetone and 30 ml of acetone. ml of dimethylformamide. The reaction mixture is gently refluxed for 25 hours. After removal of most of the solvent, the product is extracted with ether, the ether extracts are washed with brine and dried. 3.1 g of the crude product obtained after evaporation of the solvent are chromatographed on silica gel to give 1.3 g (43% of theory) of the desired ester. This product was hydrolyzed by reacting the ester (1.3 g in 18 mL tetrahydrofuran) with aqueous lithium hydroxide solution (2.2 g lithium hydroxide monohydrate in 18 mL water). The cloudy reaction mixture was stirred at room temperature for 21 hours, then poured into 1N hydrochloric acid solution and the product was extracted with ether. The organic phase was washed with brine, dried and evaporated. 1.2 g of a viscous yellow oil are obtained. Purification by silica gel column chromatography afforded 0.778 g (27.3 percent of theory) of racemic 7-acetyl-6- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H 1-benzopyran-2-carboxylic acid as a yellow crystalline product, m.p. 140.5-142.5 ° C (from ethyl acetate).

Analysis for:

C26H30O8 calculated:

% C, 66.37;% H, 6.43;

found:

% C, 66.44;% H, 6.51.

Example 40

Under the hydrogenation conditions described in Example 36, 1.09 g of ethyl 7-hydroxychroman-2-carboxylate was converted to racemic ethyl 7-hydroxychroman-2-carboxylate in 53% yield. The product is obtained as a crystalline solid, m.p. 81-82.5 ° C. (from ethyl acetate / hexane).

Analysis for:

C12H14O4 calculated:

% C, 64.85;% H, 6.35; found:

% C, 64.60;% H, 6.26.

Example 41

To 1.1 g of racemic ethyl 7-hydroxychromo-2-carboxylate was added 10 ml of a 1: 1 mixture of acetic anhydride and pyridine and the reaction mixture was stirred at room temperature for 17 hours. After removal of the solvents, the remaining product (1.2 g) was dissolved in 12 ml of glacial acetic acid and 1.26 ml of boron trifluoride etherate was added. The reaction mixture was heated to gentle reflux for 17 hours, then cooled, poured carefully into a mixture of sodium bicarbonate and ice, and then the product was extracted with a 1: 1 mixture of tetrahydrofuran and ether. Evaporation of the solvent gave 1.1 g of crude racemic 7-hydroxy-6-acetylchroman-2-carboxylic acid. The conversion to the corresponding ethyl ester was achieved by heating 1.1 g of the crude acid in absolute ethanol in the presence of 10 mg of p-toluenesulfonic acid for 17 hours under reflux. After removal of most of the solvent, the product was extracted with 1: 1 tetrahydrofuran / ether, washed with saturated sodium bicarbonate solution and water, dried and concentrated to give 1.2 g of crude ethyl ester as a 6-acetyl- and 8- mixture. The title compound was purified by column chromatography on silica gel to give 0.7 g (53.5% of theory) of racemic 6-acetyl-3,4-dihydro-7-hydroxy-2H-1 ethyl ester. benzopyran-2-carboxylic acid as a colorless crystalline solid, m.p. 93.5-95.5 ° C (from ethyl acetate / hexane).

Example 42

A mixture of 1 g of racemic ethyl 7-hydroxychroman-2-carboxylate, 1.6 g of 4 '- (3-bromopropoxy) -2'-hydroxy-3'-propylacetophenone, 1.6 g of anhydrous potassium carbonate, 25 ml of acetone and 12 g of ethyl acetate. ml of dimethylformamide is heated under reflux for 23 hours with stirring. After cooling the reaction mixture was carefully added. 1N hydrochloric acid solution and the product was extracted with ether. The ether layer was washed with brine, dried and evaporated in vacuo. 3.6 g of an orange oil are obtained. Chromatographic purification on silica gel gave 1.4 g of alkylated ethyl ester. This material was dissolved in 20 mL of tetrahydrofuran, aqueous lithium hydroxide solution (2.6 g of lithium hydroxide monohydrate in 20 mL of water) was added, and the reaction mixture was stirred at room temperature for 23 hours. Then the reaction mixture was acidified and the product was extracted with ether, washed with brine and dried. Removal of the solvent gave 1.3 g of a pale yellow acid which was purified by silica gel column chromatography to obtain 0.554 g (28.7% of theory) of racemic 7- [3- (4-acetyl-3-hydroxy-2-). propylphenoxy) propoxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid as a white crystalline solid, m.p. 142.5-145 ° C.

Aualysis for:

C24H28O7

4 Β O 9 3 calculated:

% C, 67.28;% H, 6.59;

found:

% C, 67.34;% H, 6.62.

Example 43

Following the procedure described in Example 39, 0.840 g of racemic ethyl 6-acetyl-7-hydroxychroman-2-carboxylate was reacted to racemic 6-acetyl-7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyl]. opoxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid; yield 49.5% of theory. The product is obtained as a colorless solid, m.p. 176-178.5 ° C (dec.) (From ethyl acetate).

Analysis for:

C2SH30O8 calculated:

66, 37% C, 6.43% H; found:

% C, 66.27;% H, 6.39.

Example 44

Under hydrogenation conditions as described in Example 36, 5.52 g of ethyl ^1-7- hydroxy-8-propylchromon-2-carboxylate was converted into racemic-ethyl 7-hydroxy-8-propylchroman-2-carboxylate. Yield: 43.5%. Obtained as a viscous yellow oil.

Example 45

Following the procedure described in Example 41, 1.3 g of racemic 3,4-dihydro-7-hydroxy-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester was converted to the corresponding 6-acetyl derivative. Yield 79.5% of theory. The substance is obtained in the form of a viscous oil.

Example 46

Using the procedure described in Example 42, 1.0 g of racemic 7-hydroxy-8-propylchroman-2 carboxylic acid ethyl ester was converted to racemic 7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3, 4-Dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid as a pale yellow solid, mp 105-107 ° C.

Analysis for:

C27H34O7 calculated:

% C, 68.92;% H, 7.28;

found:

% C, 69.06;% H, 7.29.

Example 47

A mixture of 0.85 g of racemic ethyl 6-acetyl-7-hydroxy-8-propylchroman-2-carboxylate,

1.2 g of anhydrous potassium carbonate, 2.3 ml of 1,3-dibromopropane, 0.1 g of 18-crown-6-ether and 20 ml of acetonitrile are heated at reflux for 23 hours. After cooling, the reaction mixture was diluted with ether. Then, the organic phase is washed with brine, dried and evaporated. It is obtained

1.2 g of bromopropyl derivative as a yellow oil. Under the conditions described in Example 39, this bromide is converted by alkylation of 2 ', 4'-dihydroxy-3'-propylacetophenone followed by saponification to racemic 6-acetyl-7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) Propoxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid in a yield of about 40% based on all reaction steps. The acid is obtained as a colorless solid, m.p. 108-110.5 ° C (from ethyl acetate / hexane).

Analysis for:

C29H36O8 calculated:

% C, 67.95;% H, 7.08;

found:

% C, 68.16;% H, 7.20.

Example 48

Proceeding as in Example 39 except that instead of 1,3-dibromopropane using l, 5-di rompentanu ^b, the ethyl ester of racemic 6-acetyl-7-hydroxy-3,4-dihydro-2H-benzopyran-2 The carboxylic acid is converted to racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid. Yield 32.8% of a colorless solid. Mp 113-115 ° C (from ethyl acetate / hexane).

Analysis for:

C28H34O8 calculated:

% C, 67.45;% H, 6.87; found:

% C, 67.61;% H, 6.80.

Example 49

Using the procedure described in Example 39 except that 1,7-dibromoheptane was used instead of 1,3-dibromopropane, racemic 6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester was used. converting the acid into racemic 6-acetyl-7- (7- (4-acetyl-3-hydroxy-2-propylphenoxy) heptyloxy] -3,4-di-246098 hydro-2H-1-benzopyran-2-carboxylic acid as a colorless solid. Melting point 133 DEG-135 DEG C. (from ethyl acetate / hexane), yield 39.1% of theory.

Analysis for:

G30H58O8 vynočteno:

% C, 68.42;% H, 7.27; nnlezeno:

% C, 68.22;% H, 7.18.

Example 50

Using the procedure described in Example 39, 0.62 g of racemic 8-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester is converted to racemic 8-acetyl 1-7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in a total yield of 27.7%. 146.5-148.5 ° C (from ethyl acetate / hexane).

Analysis for:

C26H30O8 calculated:

% C, 66.37;% H, 6.43;

found:

% C, 66.51;% H, 6.47.

Example 51

0.125 g of racemic 3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylic acid ethyl ester was converted to racemic 3,4-dihydro-7-acetyl-6-hydroxy-2-methyl ethyl ester -2H-1-benzopyran-2-carboxylic acid. Yield 65.5 θ / o. The product was obtained as a viscous oil (using the procedure described in Example 37).

Example 52

96.5 mg of racemic 3,4-dihydro-7-acetyl-6-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylic acid ethyl ester is converted to racemic 7-acetyl-6- [3- (4- acetyl-3-hydroxy-2-propylphenoxypropoxy] -3,4-dihydro-2-methyl-2H-1-benzopyran-2-carboxylic acid in a yield of 65.7%. Example 39 j.

Example 53

A mixture of 1.14 g of 4-benzyloxy-2-hydroxybenzildehyde, 0.125 g, 4-diazabicyclo [2.2.2] octane and 0.65 g of acrylonitrile is stirred under heating at 80-85 ° C under argon for 54 hours. 2 hours. After removal of the solvent, the remaining product was dissolved in a 1: 1 mixture of tetrahydrofuran and ether, the solution was washed with 1 N sodium hydroxide solution, water, dried and the solvent was evaporated in vacuo. The crude product (1.10 g) was purified by silica gel column chromatography to give 0.6 g (45.7 percent of theory) of 7- (phenylmethoxy) -2H-1-benzopyran-3-carbonitrile as a colorless solid, m.p. mp 95-98 ° C (from ethyl acetate / hexane).

Analysis for:

C17H13NO2 calculated:

% C, 77.55;% H, 4.98;% N, 5.32;

found:

% C, 77.41;% H, 5.00;% N, 4.80.

Example 54

2.2 g of 7- (phenylmethoxy) -2H-1-benzopyran-3-carbonitrile are dissolved in 40 ml of a 1: 1 mixture of tetrahydrofuran and ethyl alcohol, 20 ml of 2N potassium hydroxide solution are added and the reaction mixture is heated to reflux under argon for 21 hours. A further 10 ml of 2N potassium hydroxide solution was added and the mixture was stirred at reflux for a further 27 hours. The reaction mixture was acidified with 1N hydrochloric acid solution, extracted with ethyl acetate, the ethyl acetate extract was washed with brine, dried and the solvent was evaporated in vacuo. It is obtained

2.2 g of orange solid. This material was dissolved in 30 ml of ethanol containing 0.3 g of p-toluenesulfonic acid monohydrate and then heated under reflux for 18 hours under argon. After removal of most of the solvent, the remaining product was extracted with ether, the ether extract was washed with saturated sodium bicarbonate solution, water, dried and the solvent was evaporated. It is obtained

2.3 g of crude ethyl esters. Chromatography by silica gel column chromatography is obtained

1.4 g of 7- (phenylmethoxy) -2H-1-benzopyran-3-carboxylic acid ethyl ester as a crystalline solid.

Example 55

The ester of Example 54 (1.4 g) was dissolved in 25 ml of absolute alcohol and the solution was hydrogenated at atmospheric pressure in the presence of 0.2 g of 10% palladium on carbon. The catalyst was filtered through diatomaceous earth and the solvent was removed from the filtrate. 0.9 g of racemic 3,4-dihydro-7-hydroxy-2H-1-benzopyran-3-carboxylic acid ethyl ester is obtained in the form of a white solid.

.246088

Example 56

The ethyl ester of Example 55 is converted to racemic 7-) 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -3,4-dihydro-2H-1-benzopyran-3-carboxylic acid in a total yield of 17, 7% as described in Example 42. The acid obtained is a colorless solid, m.p. 153.5-155.5 ° C (from ethyl acetate / ether / hexane).

Analysis for:

C24H28O7 calculated:

% C, 67.28;% H, 6.59; found:

% C, 67.46;% H, 6.66.

Example 57

Racemic 7-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester (0.9 g) was dissolved in pyridine (5 ml) and acetic anhydride (1.2 ml) was added. The reaction mixture was stirred at room temperature for 3 hours and then diluted with ether. The organic layer was washed with 2N hydrochloric acid solution, sodium bicarbonate, brine, dried and the solvent was evaporated. 1.2 g of crude acetate are thus obtained, which is dissolved in 10 ml of glacial acetic acid and 1 ml of boron trifluoride etherate is added. The reaction mixture was heated at 100 ° C under argon for 6 hours. After cooling, ether was added. The organic layer was washed several times with water, dried and the solvent was evaporated in vacuo. 1.0 g of an orange oil is obtained. Esterification of this material with ethanol as described in Example 41 affords racemic 6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester.

Example 58

Racemic 6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester is converted to racemic 6-acetyl-7- [3- (4-acetyl-3-hydroxy-2- propylphenoxy) propoxy] -3,4-dihydro-2H-1-benzopyran-3-carboxylic acid as described in Example 39. This is a colorless solid, mp 127-129 degrees C (dec.) (from ethyl acetate / hexane) ).

Analysis for:

C26H50O8 calculated:

% C, 66.37;% H, 6.43;

found:

% C, 66.45;% H, 6.43.

Example 59

A mixture of 1 g (4.5 mmol) of racemic 3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester, 3.7 ml (27.2 mmol) of 1,5-dibromopentane, 2 g Anhydrous potassium carbonate (14.5 mmol), acetone (30 ml) and Ν, Ν-dimethylformamide (15 ml) were stirred and heated to reflux for 20 hours. The reaction mixture was then cooled and diluted with ether. The ethereal solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 7.2 g of a yellow liquid. This liquid is chromatographed on 50 g of silica gel. Elution with toluene / ethyl acetate (19: 1 and 9: 1) gave 1.2 g (72%) of racemic 7 - [(5-bromopentyl) oxy] -3,4-dihydro-2H-1-benzopyran- 2-carboxylic acids in the form of a pale yellow oil.

Example 60

Following the procedure described in Example 59 using molar amounts of the following compounds as starting materials, the following compounds were obtained. All compounds were purified by silica gel chromatography and isolated as pale yellow oils.

from racemic 6-acetyl-7-hydroxy-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester and 1,5-dibromopentane to give racemic 6-acetyl-7- ( -bromopentyl) oxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid;

from racemic 6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester and 1,5-dibromopentane to give racemic 6-acetyl-7 - [(5-bromopentyl) ethyl ester oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

from racemic 6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester and 1,6-dibromohexane to give racemic 6-acetyl-7 - [(6-bromohexyl) oxy ethyl ester -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

from racemic 6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester and 1,4-dibromobutane to give racemic 6-acetyl-7 - [(4-bromobutyl) oxy] ethyl ester -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

from racemic 3,4-dihydro-7-hydro57,224,6098 xy-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester and 1,5-dibrompentane ethyl ester of racemic 7 - [(5-bromopentyl) oxy] ethyl ester -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid;

starting from methyl esters of racemic 8-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid and 1,5-dibromopentane gives methyl esters of racemic 8-acetyl-7 - [(5-bromopentyl) oxy -3,4-Dihydro-2H-1-benzopyran-2-carboxylic acid.

Example 61

A mixture of 1.2 g (3.23 mol) of racemic 7-f (5-bromopentyl) oxy) -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester,

1.0 g (5.15 mmol) of 2 ', ^4! of dihydroxy-3'-propylacetophenone, 1.8 g (13.0 mmol) of anhydrous potassium carbonate, 30 ml of acetone and 15 ml of Ν, Ν-dimethylformamide are heated under reflux for 6 hours. After cooling, the reaction mixture was diluted with ether. The ether phase was then washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue (2.1 g) is chromatographed on 50 g of silica gel. Elution with toluene / ethyl acetate (19: 1) yielded 1.3 g (83%) of racemic 7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentoxy] -3,4-dihydro- 2H-1-benzopyran-2-carboxylic acid as a yellow oil.

Example 62

Following the procedure described in Example 61, the following compounds were obtained using molar amounts of the following starting materials. All compounds were purified by silica gel chromatography and isolated as a pale yellow oil.

from racemic 6-acetyl-7-f (5-bromopontyl) oxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester and 2 ', 4'-dihydroxyacetophenone to give racemic ethyl ester 6-acetyl-7- [5- (4-acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid;

from racemic 6-acetyl-7 - [(5-bromopentyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester of 2 ', 4'-dihydroxyacetophenone from racemic 6-acetyl ethyl ester -7- [(5-bromopentyl) oxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid and 2 ', 4'-dihydroxy-3'-propylacetophenone yields racemic ethyl ester 6 -acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid;

from racemic 7-f (5-bromopentyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester and 2 ', 4'-dihydroxyacetophenone to give racemic 7- [5- (4- acetyl-3-hydroxyphenoxypentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

from ethyl racemic 6-acetyl-7 - [(6-bromohexyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 2 ', 4'-dihydroxy-3'-propylacetophenone to give the ethyl ester Racemic 6-acetyl-7- [6- (4-acetyl-3-hydroxy-2-propylphenoxy) hexyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

from ethyl racemic 6-acetyl-7 - [(4-bromobutyl) oxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 2 ', 4'-dihydroxy-3'-propylacetophenone to give the ethyl ester Racemic 6-acetyl-7- (4- (4-acetyl-3-hydroxy-2-propylphenoxy) butoxy) -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid;

from racemic 7 - [(5-bromopentyl) oxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid ethyl ester and 2 ', 4'-dihydroxyacetophenone to give racemic 7-η 5 - (4-Acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid;

from ethyl racemic 7 - [(5-bromopentyl) oxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid and 2 ', 4'-dihydroxy-3'-propylacetophenone to give the ethyl ester Racemic 7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy) -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid racemic 8- acetyl-7- ((5-bromopentyl) oxy) -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 2 ', 4'-dihydroxy-3'-propylacetophenone to give racemic 8-acetyl ethyl ester -7- [5- (4-acetyl-3-hydroxy-2-propyleneoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid.

Example 63

A mixture of 1.3 g (2.68 mmol) of the ester from Example

4 S 5Ί

61, 60 ml of a 1: 1 mixture of tetrahydrofuran and water. 2.4 g (57.1 mmol) of lithium hydroxide monohydrate were stirred at room temperature for 5 hours. The reaction mixture was then diluted with water and extracted three times with ether. The aqueous phase was acidified to pH 1 with 2N hydrochloric acid solution and extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 0.725 g of racemic 7- (5- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -phenyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in as a colorless solid. mp 124 DEG-126.5 ^R G.

SQ

Analysis for:

C26H32O7 calculated:

% C, 68.40;% H, 7.07;

found:

% C, 68.34;% H, 7.29.

Example 64

Using the procedure and molar amounts of the compounds of Example 63, saponification of the corresponding ester of Example 62 gave the acids listed in the following table:

Table

merging- on melting point (° C) after recrystallization AND 105-107 from a mixture of ethyl acetate hexane (B) 183-185.5 ethyl acetate C oil - D 146.5 - 149 of hexane ethyl acetate E 138.5 - 142 of hexane ethyl acetate F 137-140 of hexane ethyl acetate G 120 - 123 of hexane ethyl acetate H oil - AND 134-136 acetonitrile

ί z formula microanalysis calculated% found% C H C H : u and C28H31O8 67.45 6.87 67.24 6.91 C25H28O8 65.78 6.18 65.80 6.08 C31H40O8 68.87 7.46 68.76 7.70 and Οδ3Η26θ7 66.65 6.32 66.51 6.29 and C29H36O8 67.95 7.08 67.99 7.14 and C27H32O8 66.93 6.66 67.21 6.77 and C26H32Q7 68.40 7.07 68.70 7.44 C29H38O7 69.86 7.63 70.02 7.80 C28H34O8 67.45 6.87 67.20 6.84

Explanatory notes:

A Racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxyphenoxy) pententyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid

B Racemic 6-acetyl-7- (5- (4-acetyl-3-hydroxyphenoxy) pentyloxy) -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

C Racemic 6-acetyl-7- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid

D Racemic 7- (5- (4-acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

E Racemic 6-acetyl-7- [6- (4-acetyl-3-hydroxy-2-propylphenoxy) hexyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

F Racemic 6-acetyl-7- [4- (4-acetyl-3-hydroxy-2-propylphenoxy) butoxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

G Racemic 7- (5- (4-acetyl-3-hydroxyphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid

H Racemic 7- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid

Racemic 8-acetyl-7- [5- (4-acetyl-3-hydroxy) -4- (9-methoxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid.

Example 65

(R) - (+) - 6-Hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester (6.5 g, 24.6 mmol) 10.37 g (75.1 mmol) of anhydrous potassium carbonate, 1.12 g of 18-crown-6-ether, 39.3 ml (0.2 mol) of 1,5-dibromopentane and 150 ml of acetonitrile are heated with stirring to reflux for 21 hours. Then the reaction mixture was cooled and ether and water were added. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified first by silica gel column chromatography (400 g, using a 49: 1 mixture of toluene and ethyl acetate) and then by preparative HPLC on silica gel using a 9: 1 mixture of hexane and ethyl acetate as the mobile phase. 9.71 g (95.6% of theory) of (R) - (+) - 6 - [(5-bromo-pentyl) -oxy] -3,4-dihydro-2,5,7,8-tetramethyl-2H-methyl ester is obtained. -l-benzopyran-2-carboxylic acid as a solid. Recrystallization from ethanol gave a colorless solid melting at 64 DEG ^C. 65.5 C. [alpha] _D ²⁵ = ^C +36,37 (c = 2, CHCI3).

Analysis for:

G20H29BrO4 calculated:

% C, 58.12;% H, 7.07;% Br; found:

% H, 7.07;% Br, 19.20. Example 66

Using the procedure described in Example 65 and employing molar amounts of the reactants, the (S) - (-) -6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-methyl ester was alkylated. -carboxylic acid with 1,5-dibromopentane to give (S) - (-) - 6 - ((5-bromopentyl) oxy) -3,4-dihydro-2,5,7,8-tetramethylliyl-2H-, methyl ester 1-benzopyran-2-carboxylic acid. [α] _D ²⁵ = 34.60 degrees Celsius (c - 2, CHCl 3) in 88.15% yield.

Analysis for:

C 20 H 29 BrO 4 calculated:

58.12% C, 7.07% H, 19.33% Br; found:

H, 7.19; Br, 19.33.

Example 67

Following the procedure described in Example 65 and using molar amounts of the ingredients of Example 65, 1 g of racemic 6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester is alkylated with 1,5-dibromopentane to give racemic 6 - ((5-bromopentyl) oxy] -3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester 72.5-74.5 ° C in 90% yield after silica gel chromatography purification.

Analysis for:

C 20 H 29 BrO 4 calculated:

% C, 58.12;% H, 7.07;% Br;

found:

% C, 58.13;% H, 7.15;% Br, 19.30.

Example 68

A mixture of 7.35 g (17.8 mmol) of (R) - (+) - bromo ester 2 of Example 65, 3 _; 85 g (19.8 mmol) of 2 *, 4'-dihydroxy-3'-propylacetophenone, 8.93 g (64.7 mmol) of anhydrous potassium carbonate, 154 ml of absolute acetone and 77 ml of absolute Ν, Ν-dimethylformamide are heated with stirring at reflux for 5.5 hours. The reaction mixture was then cooled and diluted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 10.8 g of an oil are obtained. This material was purified by preparative high performance liquid chromatography on silica gel using hexane / ethyl acetate (2: 1) as the mobile phase. 9.1 g (97% of theory) of (R) - (+) -6- [5- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -pentyloxy] -3,4-dihydr 0-2 methyl ester are obtained, m.p. 5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid as a yellow oil. [α] _D ²⁵ = +26.62 ° C (c = 2, CHCl 3).

Analysis for:

C31H42O7 calculated:

% C, 70.70;% H, 8.04;

found:

% C, 70.06;% H, 8.18.

Example 69

Following the procedure described in Example 68, the (S) - (-) - bromo ester of Example 66 (8.4 g) was converted by alkylation with 4.4 g of 2 ', 4'-dihydroxy-3'-propylacetophenone to the methyl ester (Sj, 2- 3309

G3

- (-) - 6- (5- (4-Acetyl-3-hydroxy-2-propylphenoxy) -3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid The product was obtained as a yellow oil.

Analysis for:

C31H42O7 calculated:

% C, 70.70;% H, 8.04; found:

% C, 70.13;% H, 7.73.

Example 70

Using the procedure and molar amounts of the reactants described in Example 68, 1.2 g of the racemic bromo ester derivative of Example 67 was converted by alkylation with 0.834 g of 2 ', 4‘-dihydroxy-3'-propyl acetophenone. to racemic 6- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2- methyl ester of carboxylic acid in 72% yield The product was obtained as a pale yellow oil.

Analysis for:

C31H42O7 calculated:

% C, 70.70;% H, 8.04; found:

% C, 70.44;% H, 7.97.

Example 71

A mixture of 7.55 g (14.3 mmol) of the (R) - (+) - ester derivative of Example 68, 140 ml of tetrahydrofuran, 90 ml of water and 12.6 g (0.21 mol) of lithium hydroxide monohydrate was stirred for 7 hours. The reaction mixture was then poured into a cooled 3N hydrochloric acid solution, the organic portion was extracted three times with ethyl acetate, and the ethyl acetate extracts were combined, washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, filtering and concentrating the filtrate under reduced pressure, 7.3 g of the residual yellow glassy product are chromatographed over 350 g of silica gel, eluting with toluene / ethyl acetate (4: 1, 2: 1). There was obtained 5 g of the desired acid which was recrystallized from acetonitrile to give 2.49 g (34% of theory) of (R, - (+) - 6- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyloxy) -3,4-Dihydro-2,5,7,8-tetramethyl-2H-1b enzopyran-2-carboxylic acid as a colorless solid, m.p. 92.5-95 ° C. (aj, / = +37,86 ⁵ ° C (c - = 2, CHC13).

Analysis for:

C30H14O7 calculated:

% C, 70.29;% H, 7.87; found:

% C, 70.25;% H, 7.92.

Example 72

Following the procedure described in Example 71, 9.35 grams (17.8 mmol) of (S) - (β-ester derivative of Example 69) were saponified to give (S) - (-) -6- 5- (4-). acetyl-3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid as a colorless solid, m.p. 93.5 ° C, [α] _D ²⁵ = -38.18 ^° C (c = 2, CHCl 3), after recrystallization from acetonitrile.

Analysis for:

C50H40O7 calculated:

% C, 70.29;% H, 7.87; found:

% C, 70.50;% H, 8.11.

Example 73

Following the procedure described in Example 71, 5.8 g (11 mmol) of the racemic ester of Example 70 were saponified. 2.77 g (49% of theory) of racemic 6- (5- (4-acetyl-3-hydroxy-2-propylphenoxy) were obtained. (pentyloxy) -3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid as a colorless solid, mp 92.5-95 ° C.

Analysis for:

C30H40O7 calculated:

70, 29% C, 7.87% H; found:

% C, 70.28;% H, 7.98.

Example 74

6 g (27 mmol) of racemic 3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester, 6.8 g (54 mmol) of benzyl chloride, 7.5 g (54 mmol) of anhydrous carbonate Potassium iodide and 4.5 g (27 mmol) of potassium iodide in 100 ml of acetone are stirred and heated to reflux for 7 hours. Most of the acetone was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 17.4 g of a yellow oil. This oil is chromatographed on 246 098 silica gel, eluting with toluene: ethyl acetate (19: 1) to give the title compound as a colorless oil.

6.9 g (78% of theory) of racemic 3,4-dihydro-7- (phenylmethoxy) -2H-1-benzopyran-2-carboxylic acid ethyl ester as a yellow oil.

Example 75

6.9 g (22 mmol) of the ethyl ester of Example 74 were dissolved in 70 mL of toluene and the toluene solution was cooled to -78 ° C (on a bath containing a mixture of solid carbon dioxide and acetone). 15.6 ml of a 25% solution of diisobutylaluminum hydride in toluene are then added dropwise with stirring. The reaction mixture was stirred at -78 ° C for 2 hours, then 2.5 mL of methanol was carefully added, followed by a mixture of 2N hydrochloric acid and ice. The reaction mixture was extracted with ethyl acetate and the organic extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue (7.6 g) is chromatographed on silica gel. Elution with a 9: 1 mixture of ethyl acetate and toluene gave 5.6 g (70% of theory) of racemic 3,4-dihydro-7- (phenylmethoxy) -2H-1-benzopyran-2-carboxaldehyde as a pale yellow oil.

Example 76

Following the procedure described in Example 30, 2.7 g (10 mmol) of the aldehyde of Example 75 was condensed with 3.7 g (10.6 mmol) of (ethoxycarbonylmethylene) triphenylphosphorane in 30 ml of toluene (1.5 hours at 100 ° C). Chromatographic purification of the crude product on 50 g of silica gel (using toluene as eluent) gave 3.0 g (88.8 percent of theory) of racemic 3,4-dlhydro-7- (phenylmethoxy-2H-1-benzopyran-2-propene) ethyl ester. acid (mixture of E- and Z-isomer) as a pale yellow oil.

Example 77

The propenoic acid ester of Example 76 (3 g, 8.9 mmol) was hydrogenated at atmospheric pressure and at room temperature. at room temperature in the presence of 0.3 g of 10% palladium on carbon in 35 ml of ethyl acetate. 2.4 g of racemic 3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-propanoic acid ethyl ester are obtained in the form of a viscous oil (after filtering off the catalyst and evaporating off the solvent).

Example 78

Following the procedure described in Example 41, the propanoic ester of Example 77 was converted to 1.4 g (54% of theory) of racemic 6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-propanoic acid ethyl ester. After chromatographic purification on silica gel using toluene / ethyl acetate (19: 1).

The eluent gave a yellow oil which crystallized on standing.

Example 79

Following the procedure described in Example 59, the acetylpropanoic ester of Example 78 (1.4 g, i.e. 4.79 mmol) was converted to racemic 6-acetyl-7 - [(5-bromopentyl) oxy] -3,4-dihydro-2H ethyl ester. -1-benzopyran-2 propanoic acid. Yield 1.6 g (76%). Purification by chromatography on silica gel (toluene / ethyl acetate 19: 1) gives the product as a yellow oil which crystallizes on standing.

Example 80

Following the procedure described in Example 61, the bromo ester of Example 79 (1.6 g, i.e. 3.63 mmol) was converted to racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) ethyl ester. pentyloxy] -3,4-dihhydro-2H-1-benzopyran-2-propanoic acid by alkylation of 2 ', 4'-dihydroxy-3'-propyl acetophenone. Chromatography on silica gel using toluene / ethyl acetate 9: 1 and 4: 1 as eluent gave the ester in 79% yield (1.6 g) as a pale yellow oil.

Example 81

Following the procedure described in Example 63, the ester of Example 80 (1.6 g, i.e. 2.89 mmol) was saponified to give 1 g (66%) of racemic 6-acetyl-7- [5- (4-acetyl-). 3-hydroxy-2-propylphenoxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-propanoic acid as a colorless solid, m.p.

126.5-129 ° C (after recrystallization from ethyl acetate / hexane and then acetonitrile).

Analysis for:

C30H38O8 calculated:

% C, 68.42;% H, 7.27;

found:

68.42% C, 7.49% H.

Example 82

Following the procedure described in Example 30, 2.7 g (10 mmol) of the aldehyde of Example 75 were condensed with 4.4 g (12 mmol) of ethyl 4- (triphenylphosphoranylidene) -2-butenoate in 30 ml of toluene (3.5 hours at 100 ° C) After chromatography of the crude product on 100 g of silica gel, 1.1 g (30%) of racemic 5- [3,4-dihydro-7- (phenylmethoxy) -2H-1-benzopyran-2-yl] ethyl ester is obtained. -2,4-pentadienoic acid (E- and Z-isomer mixture) in a67 yellow oil, eluting with toluene / ethyl acetate (19: 1).

Example 83

The dienoic acid ester of Example 82 (1.1 g, 3.02 mmol) was hydrogenated at atmospheric pressure and at room temperature in 15 mL of ethyl acetate in the presence of 0.95 g of 10% palladium on carbon. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. 0.9 g (100% of theory) of racemic 3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-pentanoic acid ethyl ester is obtained in the form of a pale yellow oil.

Example 84

Following the procedure described in Example 41, the pentanoic acid ester of Example 83 was converted to racemic 6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-pentanoic acid ethyl ester (0.4 g, 41%). in the form of a yellow oil which crystallizes on standing.

Example 85

Following the procedure described in Example 59, the acetylpentanoic acid ester of Example 84 (0.4 grams, 1.25 mmol) was converted to the racemic 6-acetyl-7- ((5-bromo-pentyl) oxy] -3,4-dihydro-2H-1-ethyl ester. of benzopyran-2-pentanoic acid in the form of a yellow oil obtained after column chromatography on silica gel (toluene / ethyl acetate 19: 1), yield 0.3 g (51%).

Example 86

Proceeding as in Example 61 with the bromo ester of Example 85 (0.3 g, i.e. 0.64 mmol) was converted to the ethyl ester of racemic 6-acetyl-7- _L of 5- (4-acetyl-3-hydroxy-2-propylphenoxy pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-pentanoic acid by alkylation with 2 ', 4'-dihydroxy-3'-propylacetophenone. Purification by chromatography on silica gel (toluene / ethyl acetate 19: 1) gave 0.3 g (80% of theory) of the desired ester as a yellow oil.

Example 87

Following the procedure described in Example 63, the ester of Example 86 (0.3 g, 0.51 mmol) was saponified to give 0.137 g (48% of theory) of racemic 6-ac ethyl-7- [5- (4-acetyl-3-)]. hydroxy-2-propylthioxy) pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-pentanoic acid as a colorless solid. 116 DEG-120.5 DEG C. (after recrystallization from acetonitrile).

Analysis for:

C32H42O8 calculated:

% C, 69.29;% H, 7.63;

found:

% C, 69.35;% H, 7.66.

Claims (13)

A process for the preparation of dihydrobenzopa derivatives OF THE INVENTION ann general formula I (I) wherein R ¹ represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms, R ² is hydrogen or halogen, R ³ , R ⁴ and R ⁵ are each independently hydrogen, C 1 -C 7 alkanoyl, arylcarbonyl, in which "aryl" is phenyl or phenyl substituted with 1 to 2 substituents selected from the group consisting of halogen, trifluoromethyl, C1-C7alkyl, C1-C7alkoxy, nitro, amino, C1-C7alkylamino and C1-C7alkylamino or alkyl; With 1 to 7 carbon atoms, with the proviso that only one of substituents 246096 and R ³ , R ⁴ and R ⁵ is an alkanoyl or arylcarbonyl group as defined above, and either R ^B and R ⁷ are both hydrogen and R ⁸ represents a group -COOR ^9, or ^R is hydrogen or alkyl having 1-7 carbon atoms; R ⁷ is - (CH 2) _n -COOR ⁹ R ⁸ represents a hydrogen atom and R ⁹ represents an alkyl group having 1 to 7 carbon atoms, X represents an alkylene group having 3 to 7 carbon atoms and n represents an integer from 0 to 4, characterized in that the compound of formula II (II) in which: R ¹ and R ^z have the above mentioned meanings and A is defined below, with a compound of formula IV / And - (iv) in which R ³ , R ⁴ , R ⁵ , R ^B , R ⁷ and R ⁸ are as defined above, and wherein either A represents a hydrogen atom and A ‘represents a group —X — Z in which X is as defined above and a Z represents a halogen atom, or it represents a group —X — Z, wherein X and Z are as defined above, and A ‘represents a hydrogen atom, whereupon any racemate obtained is separated into optically active isomers. 2. A process as claimed in claim 1, wherein the corresponding compounds of the formulas II and IV are used as starting materials to give compounds of the formula I in which R @ ⁸ represents a hydrogen atom or an alkyl group having from 1 to 7 carbon atoms; ⁷ represents a group of formula - (CH 2) _n —COOR ⁹ R ⁸ represents a hydrogen atom and the other substituents have the meaning given in 1. 3. A process according to claim 1, wherein the corresponding compounds of formulas II and IV are used as starting materials to produce compounds of formula Ib O I, R. CW- / in which R ⁹ and R ¹¹ are C 1 -C 7 alkanoyl, R ³¹ represents an alkanoyl or arylcarbonyl group as defined in point 1, X is C 3 -C 7 alkylene and n is an integer from 0 to 4. 4. A method according to claim 2, characterized in that starting from a corresponding compound of formula II and IV to form a compound of formula I wherein R ¹ represents an alkyl group having 1-7 carbon atoms, R is hydrogen , R ³ represents an alkanoyl or arylcarbonyl group as defined in point 1, R ⁴ , R ⁵ and R ^B are hydrogen and the other substituents are as defined in 2. 5. A process according to claim 4, wherein the corresponding compounds of formula II and IV are used as starting materials to give compounds of formula I wherein X is C3 -C5 alkylene and the other substituents are as defined above. in point 4. 6. A method according to claim 5, characterized in that starting from a corresponding compound of formula II and IV, to give compounds of formula I wherein R ³ represents an acetyl group and the other substituents are defined as in point 5. 7. The method according to point S, characterized in that starting from a corresponding compound of formula II and IV, to give compounds of formula I wherein R ¹ is a propyl group and the other substituents are as defined in point 6. 8. A process according to claim 1, wherein the corresponding compounds of formulas II and IV are used as starting materials to give racemic 6-acetyl-7- [5- (4-acetyl-3-hydroxy-2-propylphenoxy) ethyl ester. pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid. 9. A process according to claim 1, wherein the corresponding compounds of formulas II and IV are used as starting materials to form racemic 7- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) -5-ethyl ester. 4-dihydro-2H-1-benzopyran-2-carboxylic acid. 10. A process according to claim 1 wherein the corresponding compounds of formulas II and IV are used as starting materials to form racemic 6-acetyl 1-7- [3- (4-acetyl-3-hydroxy-2-) ethyl ester. propylphenoxy] propoxy] -2-methyl-8-propyl-2H-1-benzopyran-2-propanoic acid. 11. A process according to claim 1, wherein the corresponding compounds of formulas II and IV are used as starting materials to give racemic 6- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3-ethyl ester, 4-Dihydro-2-methyl-2H-1-benzopyran-2-carboxylic acid. 12. A process according to claim 1, wherein the corresponding compounds of the formulas II and IV are used as starting materials to give racemic 7- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy) -3-ethyl ester. 4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid. 13. A process according to claim 1, wherein the corresponding compounds of the formulas II and IV are used as starting materials to give racemic 6-acetyl-7- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) ethyl ester). propoxy] -3,4-dihydro-2H-benzopyran-2-carboxylic acid.