CS241464B2 - Process for the production of new benzo [quinolines] - Google Patents

Abstract

A process for the preparation of novel benzo[c]quinolines of the general formula III in which the general symbols have the meanings given below, is carried out by means of an inorganic base. The compounds produced are useful as starting materials for the preparation of agents acting on the central nervous system.

Description

(54) Process for the production of new benzo[c]quinolines «

Process for the production of new benzo[c]quinolines of general formula III

in which the general symbols have the meanings given below, acts as an inorganic base.

The compounds produced are useful as starting materials for the preparation of agents acting on the central nervous system.

The invention relates to a process for the preparation of novel benzo[c]quinolines, in particular 1-hydroxytetrahydrobenzo[c]quinolin-9(8H)-ones, which are useful as starting materials for the preparation of agents acting on the central nervous system, especially as analgesics and tranquilizers, as hypotensives in mammals (including humans), as agents for the treatment of glaucoma and as diuretics, and as intermediates for the preparation of these compounds.

The above-mentioned intermediates are compounds of the general formula

in which the individual general symbols have the meanings given below, which are converted in accordance with the method according to the invention by the action of a base into compounds of the general formula III

R1 represents a hydrogen atom or an acetyl group,

R4 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms or the residue — ICHajz—C6H5, in which z is a number with a value of 1 or 2,

R 5 represents a hydrogen atom, a methyl or ethyl group,

Z represents an alkylene group or an alkyleneoxy group having 1 to 9 carbon atoms and

W represents a hydrogen atom or a phenyl group.

These resulting products can then be further reduced to pharmacologically active compounds corresponding to the general formulas

or they can be converted to ketals or thioketals in which the ketal moiety contains 2 to 4 carbon atoms.

An alternative nomenclature for the compounds described herein is to replace the base "benzo[c)quinoline" with the base "phenanthridine".

Although a wide variety of analgesic agents are available, the search continues for new and better agents of this type that can be used to relieve pain of the most diverse origin and whose use would be accompanied by minimal side effects. The most commonly used substance, aspirin, is practically worthless for pain relief and is known to cause various side effects. Other, more potent analgesics, such as d-propoxyphene, codeine and morphine, are habit-forming. There is therefore an evident need for better and more potent analgesic agents.

The analgesic properties of 9-nor-9/3-hydroxyhexahydrocannabinol and other substances of cannabinoid structure, such as Δ ⁸ -tetrahydrocannabinol and its primary metabolite, ll-hydroxy-Δ ⁸ -tetrahydrocannabinol, have been described by Wilson and May, Absts. Papers, Am. Chem. Soc., 168 Meet., MEDI 11 (1974), J. Med. Chem. 17, 475—476 (1974) and J. Med. Chem. 18, 700—703 (1975).

U.S. Patent Nos. 3,507,885 and 3,636,058 disclose various 1-hydroxy-3-alkyl-6H-dibenzo[b,d]pyrans bearing substituents at the 9-position such as oxo, hydrocarbyl, hydroxyl, chlorine, hydrocarbylidene, and intermediates thereof.

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U.S. Patent No. 3,649,650 discloses a series of tetrahydro-6,6,9-N-alkyl-6H-dibenzo[b,d]pyran derivatives bearing a <o-dialkylaminoalkoxy group in the 1-position which are effective as psychotherapeutic agents.

DOS No. 2,451,934 describes 1,9-dihydroxyhexahydrodibenzo[b,d]pyrans and certain 1-acyl derivatives of these substances carrying an alkyl or alkylene group in the 3-position, which are effective as hypotensive, psychotropic, sedative and analgesic agents. The starting hexahydro-9H-dibenzo[b,d]pyran-9-ones used for the preparation of the above-mentioned compounds, for which the same utility is stated as for the corresponding 9-hydroxy compounds, are described in DOS No. 2,451,932.

U.S. Patent No. 3,856,821 describes a series of 3-alkoxy-substituted dibenzo[b,d]pyrans exhibiting antiarthritic, anti-inflammatory, and central nervous system activity.

Bergel et al., J. Chem. Soc. 286—287 (1943) investigated the replacement of the pentyl group in the 3-position of 7,.8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [ b,d ] pyran-1-ol with various alkoxy groups (butoxy, pentyloxy, hexyloxy, and octyloxy) and found that this replacement resulted in a loss of biological activity. These authors reported that the hexyloxy derivative showed a slight hashish-like effect at doses of 10 to 20 mg/kg. The remaining ethers were ineffective at doses up to 20 mg/kg.

In a more recent study, Loev et al., J.

Med. Chem., 16, 1200—1206 (1973) comparison of 7,8,'9,10-tetrahydro-3-subst.-6,6,9-trimethyl-6H-dibenzo [ b,d ] pyran-1-ols substituted in position 3 by the group

-OCH(CH3)C5Hu, ’ —C«2CH.(CH3)C5Hll, or — CHi(CH3)C5Hn.

The compound containing the ether side chain had a 50% lower effect on the central nervous system than the corresponding compound in which the alkyl side chain is attached directly to the aromatic nucleus (i.e. not through an oxygen atom) and five times higher potency than the compound in which the oxygen atom is replaced by a methylene group.

Hoops et al., J. Org. Chem., 33, 2995-2996 (1968), reported the preparation of the 5-aza analog A ^{of 6a!(10a,} -.tetrahydrocannabinol, which is described in that work as 7,8,9,10-tetrahydro-1-hydroxy-5,6,6,9-tetramethyl-3-n-pentylphenanthridine, but they do not give any use for this substance. In the book "Psychomimetic Drugs" (ed. Efron, Raven Press, New York, 1970), Beil states on page 336 that this compound is completely inert as far as animal pharmacology is concerned.

Hardman et al., Proc. West. Pharmacol.

Soc., 14, 14—2Θ (1*971) mention some pharmacological activity of 7,8,'9,10-tetrahydTO-1-hyftrHřy-6,'6,9-trimethyl-3-n-pentylphenanthridine (S-aza-A^^-tetrahydrocannabinol ].

In the book “Marijuana” (ed. Mechoulam, Academie Press, New York, 1973), Mechoulam and Edery state on page 127 that major structural changes in the tetrahydrocannabinol molecule probably result in a profound decrease in analgesic efficacy.

Paton in Annual Review of Pharmacology, 15, 192 (1975) presents a generalization of the structure-activity relationships of various cannabinoid-type substances. The presence of geminal dimethyl in the pyran ring is of decisive importance for the activity of a cannabinoid-type substance, while the replacement of nitrogen in the pyran ring by oxygen results in a loss of activity.

It has now been found that certain benzo[c]quinolines, namely 1,9-dihydrooctahydro-6H-benzo(e)quinolines of the general formula I and 1-hydroxyhexahydro-6H-benzo[C']quinolin-9(8H)-ones of the general formula II are useful as central nervous system agents, in particular as analgesics and tranquilizers, as hypotensive agents which are not narcotic in nature and do not pose a risk of addiction, and in particular as agents for the treatment of glaucoma and as diuretics. The invention also describes various derivatives of these compounds, useful as dosage forms, and intermediates for their preparation. The above-mentioned compounds and their derivatives correspond to the general formulas I and II set out below. The compounds of the above-mentioned general formula III are precursors of the compounds of the general formulas II and I.

In these general formulas

R represents a hydroxyl group, an alkanoyloxy group with 1 to 5 carbon atoms or a hydroxymethyl group, R 1 represents a hydrogen atom or an acetyl group,

R1 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms or a residue of the formula —(CH2z—C6H5, where z is a number with a value of 1 to 4,

R 5 represents a hydrogen atom, a methyl or ethyl group,

Rs represents a hydrogen atom, — (CH2) _y -carbalkoxy group, in which y has the value 0 or represents a number with a value of 1 to 4 and the alkoxy group contains 1 to 4 carbon atoms, further a benzyloxycarbonyl group, a formyl group, an alkanoyl group with 2 to 5 carbon atoms, an alkyl group with 1 to 6 carbon atoms, a residue of the formula — ( _CH2 ) _X —C6H5, where x is a number with a value of 1 to 4, or a residue of the formula —CO(CH2)x_i—CsHs, where x has the above meaning,

R _a represents an oxo group, a methylene group or an alkylenedioxy group with 2 to 4 carbon atoms,

Z represents an alkylene group with 1 to 9 carbon atoms or a residue of the formula ' ' ' ’ ' -O-alkyl' where alk represents an alkylene group with 1 to 9 carbon atoms, and

W represents a hydrogen atom or a phenyl group.

The compounds of the above-mentioned general formulas I, II contain centers of asymmetry in positions 6a or/and 10a. Centers of asymmetry can also be located in position 3 of the —Z—W substituent, and in positions 5, 6 and 9. Due to their greater biological effect (quantitatively), diastereomers with configuration 9/3 are generally more preferred than gw-isomers. For the same reason, trans (6a,10a) diastereomers of compounds of general formula I are generally more preferred than the corresponding cis(6a,10a) diastereomers. As regards compounds of general formula II, in which one of the symbols R4 and Rs has a meaning other than a hydrogen atom, the respective cis-diastereomers are more preferred due to their higher biological activity. Of the enantiomers of a given compound, due to its higher activity, one of the enantiomers is usually always more preferred than the other enantiomer and than the racemate. The more preferred enantiomer is determined by the procedures described below. For example, the 1-enantiomer 5,6,6a/i,7,8,9,10,10aa-octah.hydro-1-acetoxy-9/3-hydroxy-6/3-methyl-3-(5-phenyl-2-pentyloxy)benzo[c]quinoline is preferred over the d-enantiomer and over the racemate due to its higher analgesic activity. For convenience and simplicity, the above formulas depict racemic compounds, but include racemic modifications of the compounds corresponding to these formulas, mixtures of diastereomers, as well as pure enantiomers and diastereomers. The utility and applicability of racemic mixtures, diastereomeric mixtures, as well as pure enantiomers and diastereomers is determined by the tests of their biological activity described below.

Various intermediates and starting materials for the preparation of compounds of general formulas I, II and III can be described by general formulas V, VI and VII.

tví 1 o or, ^R SR ₇ (VII I in which

R-1, R5, R6 and Z-W have the meanings given above,

Rz represents a hydrogen atom or a formyl group and

Y 1 represents a hydrogen atom or a protecting group for the hydroxyl function, in particular a methyl, ethyl or benzyl group.

In the starting materials of general formulas V, VI and VII, asymmetric centers may occur in position 2 and in substituents in position 7 (—Z—W), and of course also in other positions, for example in the substituent in position Γ. Positions 2 and 7 in general formulas V,

VI and VII correspond to positions 6 and 3, respectively, of compounds of general formulas I, II and III.

Due to their higher efficacy compared to the other compounds described herein, those compounds of general formulas I and II (which can be prepared from compounds of general formula III) are preferred, in which

Z alkylene group with 5 to 9 carbon atoms alkylene group with 2 to 5 carbon atoms —O—alk—

Particularly preferred are those compounds in which

R represents a hydroxyl group (only compounds of general formula I),

R 1 represents a hydrogen atom or an acetyl group,

Rs represents a hydrogen atom,

R a represents a methyl or especially a propyl group,

Re represents a hydrogen atom, a methyl or an ethyl group, in the case where Z represents an alkylene group with 2 to 5 carbon atoms, W represents a phenyl group, in the case where Z represents a residue of the formula —O—alk—, where alk represents an alkylene group with 4 to 9 carbon atoms, W represents a hydrogen atom or a phenyl group and in the case where Z represents an alkylene group with 5 to 9 carbon atoms, W represents a hydrogen atom.

Furthermore, those compounds of general formulas III, V, VI and VII which serve as starting materials and intermediates for the production of preferred compounds of general formula I or II are preferred.

Compounds of general formula V are prepared from appropriately substituted anilines, for example from 3-hydroxy-3-(Z—W-substituted) anilines of general formula VIII below or from their derivatives, in which the hydroxyl group in position 3 is protected by a residue Yi, which can be easily cleaved off with regeneration of the hydroxyl group. Suitable protecting groups are those which do not adversely affect the subsequent reactions of the said 5-substituted anilines carrying a protected hydroxyl group in position 3, and which can be cleaved off under conditions which do not cause undesirable reactions at other sites of the above-mentioned compounds or products prepared therefrom. Representative protecting groups in the meaning of the symbol Yi include methyl, ethyl and benzyl groups.

R 1 represents a hydrogen atom or an alkanoyl group,

Rs represents a hydrogen atom, a methyl or an ethyl group, each of the symbols Ri and Re represents a hydrogen atom or an alkyl group, and

Z and W have the following meanings:

m n W

- — H — — CeHs

1 C6H5 or H nu, a substituted benzyl group, where the substituent is, for example, an alkyl group with 1 to 4 carbon atoms, a halogen atom (chlorine, bromine, fluorine, iodine) and an alkoxy group with 1 to 4 carbon atoms.

The exact chemical structure of the protecting group is not critical in this case, as its importance lies in its ability to perform the above-mentioned functions.

The selection and identification of appropriate protecting groups will not be difficult for those skilled in the art. The suitability and effectiveness of a given group as a hydroxyl protecting group is determined by the utility of such a group in the above-described reaction sequence. It should therefore be a group that can be readily cleaved to regenerate the hydroxyl group. A preferred alkyl protecting group is the methyl group because it can be readily cleaved by the action of pyridine hydrochloride. The benzyl group, which is also a preferred protecting group, is removed by catalytic hydrogenolysis or acidic hydrogenolysis.

When Z represents a radical of the formula —O—alk—, Y1 preferably represents a benzyl or substituted benzyl group, since such a group can then be removed without damaging the radical in the meaning of the symbol Z.

The protected aniline derivative (VIII) is then converted into the compound of the general formula IX below by a known method, as described below.

The following is a reaction scheme illustrating the preparation of representative compounds of general formula V from 3-hydroxy-5-(Z-W-substituted)anilines with a protected hydroxyl group in position 3 (VIII), in which Z-W represents a methoxy group.

in;·

241484

Scheme A

OCH _and

And (Vlit)

NH.

CH^O

ch ₃ o

O

RC-CH ₂ C00R°

--—CH^COOH

CH.O

RlR _with C=CH-C00R ^o “ ° or r^coch ₂ coor

N&CNBH*

OCH ³ COOR°

I R?H )

1) ClC00C ₂ Hs

ΟΙ 1 J/ppa' y^RV*COOCft

X) iV-Bi iv-o

In the above reaction scheme, R° represents an alkyl group with 1 to 6 carbon atoms and PPA represents polyphosphoric acid. In the reaction scheme, in the individual formulas, instead of the symbol Rs, there is a hydrogen atom, but in reactions VIII -► X or VIII -> - V—B, Rs can represent a methyl or ethyl group in addition to a hydrogen atom.

The substituent in position 5 of the compounds of general formula VIII may be the group — Z—W, which is to be contained in the resulting compounds of general formula II or I, or a residue which can be easily converted to this group. If Z in the group —Z—W represents a residue of the formula —O—alk-, it is a substituent in position 5 in the case where W represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group corresponding to the formula —O—Yi, where Yi has the meaning given above.

In accordance with the above scheme, the appropriate 3-hydroxy-5-substituted anilines discussed above are reacted, preferably in the form of derivatives in which the hydroxyl group in position 3 (and the hydroxyl group in position 5, if present) is protected in the manner described above so as to allow satisfactory reaction, with an alkyl /3-keto ester, for example with an alkyl acetoacetate, in the presence of acetic acid, to form the corresponding β-(3-hydroxy-5-subst.anilino) -β-(R4)-acrylate with a protected hydroxyl group in position 3 (IX). The reaction is generally carried out in an inert solvent, such as benzene or toluene, at a temperature of about 50 ° C to the reflux temperature of the solvent, and under conditions that allow removal of the water formed as a by-product. When the reaction is carried out at reflux, benzene and toluene are suitable solvents because allow for azeotropic removal of the water formed during the reaction. Other means for removing the water of reaction can also be used, such as molecular sieves, as well as other solvents that allow for azeotropic removal of water.

Preferred protecting groups for the starting 3-hydroxy-5-substituted anilines are methyl, ethyl and benzyl because such ethers are easy to prepare, give satisfactory yields of compounds of formulae IX and X, and can be conveniently cleaved to remove the ether protecting group.

The alkyl (S-ketoester, preferably one in which the alkyl group contains 1 to 6 carbon atoms, is generally used in excess to ensure maximum conversion of the starting aniline to the corresponding alkyl-^-anilino-ijS-(Rdj-acrylate (IX). A 10% to 20% excess of the alkyl (S-ketoester) is usually sufficient to achieve satisfactory conversions. A catalytic amount of acetic acid is used to facilitate the reaction.

The alkyl-/3-anilino-(3-(R4)-acrylate (IX) is then reduced to the corresponding alkyl-3-(3-hydroxy-5-substituted anilino)-3-(R4)-propionate with a protected hydroxyl group in position 3 (Xj, for example using the sodium borohydride-acetic acid system and catalytic hydrogenation. A preferred catalyst is platinum dioxide, which allows the reaction to be carried out at low pressures, i.e. at pressures below 0.35 MPa. Other catalysts, such as noble metals, for example platinum, palladium or rhodium, whether on a support or without a support, can be used at a hydrogen pressure ranging from approximately atmospheric pressure to superatmospheric pressure, for example 14 MPa. In addition to these catalysts, which are heterogeneous catalysts, this reaction can also be carried out using homogeneous catalysts, such as Wilkinson's catalyst [tris-(triphenylphosphine)rhodium chloride].

If the protecting group(s) is a benzyl or substituted benzyl group, it will of course be removed during catalytic hydrogenation. For this reason, methyl and ethyl groups are preferred protecting groups for the hydroxyl functions in the 3- and/or 5-positions of the starting materials of formula VIII.

Alternatively, compounds of formula X can be prepared directly from compounds of formula VIII by reacting compounds of formula VIII with alkyl-3,3-R1R5-acrylate in acetic acid. This reaction is conveniently carried out by reacting equimolar amounts of alkyl-3,3-R4R5-acrylate and disubstituted aniline (VIII) in 0.1 to 2 equivalents of glacial acetic acid at a temperature of from 0°C to reflux.

Alternatively, compounds of general formula V—B can be prepared directly by condensing equimolar amounts of a compound of formula VIII and an appropriately substituted acrylic acid (R4R3C = CH—COOH) in pyridine hydrochloride at a temperature of 150 to 200°C.

Furthermore, when both R4 and R5 are alkyl groups, the compound of formula VIII and an alkyl-R4,R5-acrylate in an inert solvent, for example tetrahydrofuran, are reacted with mercuric acetate and subsequently reduced with sodium borohydride to give the compound of formula X.

Direct conversion of compounds of formula VIII to compounds of formula X is also conveniently carried out by reacting 3,5-dihydroxyaniline hydrochloride, in which both hydroxyl groups are in protected form, with an excess of alkyl acetoacetate, for example ethyl acetoacetate, in the presence of sodium cyanoborohydride in a solvent such as methanol.

The alkyl 3-anilino-3-(R4)-propionate (X) is then cyclized to the corresponding 2-(R4)-quinolin-4-one (V-A or V-B) by the action of a suitable cyclizing agent such as polyphosphoric acid, hydrogen bromide-acetic acid, sulfuric acid, oleum (fuming sulfuric acid), hydrogen fluoride, trifluoroacetic acid, phosphoric acid-formic acid, and other reagents known in the art. In accordance with a modification of this conversion, the alkyl 3-anilino-3-(R4)-propionate (X) can be converted to the corresponding acid, for example, by saponifying the ester and then acidifying it prior to cyclization.

The ether protecting groups on the hydroxyl groups in the 3- and 5-positions can be removed during the cyclization by using hydrobromic acid in acetic acid as both the cyclizing agent and the deprotecting agent (or groups). Typically, 4% aqueous hydrobromic acid is used, which acts satisfactorily both as the cyclizing agent and as the deprotecting agent for the ether protecting groups. The reaction is carried out at elevated temperature, preferably under reflux. However, if Z is a residue of the formula —O-alk-, the cyclization should be carried out under other conditions, such as using polyphosphoric acid or trifluoroacetic acid, to avoid cleavage of the ether or thioether bond.

Alternatively, the protecting group(s) may be removed after the cyclization reaction. A preferred reagent for removing the protecting group(s) at this stage of the synthesis is also hydrobromic acid in acetic acid. The reaction is carried out as described above.

Other agents such as hydroiodic acid, pyridine hydrochloride or hydrobromide can be used to remove ether protecting groups (such as methyl and ethyl groups). If the protecting groups are benzyl or substituted benzyl groups, they can be removed by catalytic hydrogenolysis. Suitable catalysts in this case are palladium or platinum, especially supported on carbon. Alternatively, these protecting groups can be removed by solvolysis using trifluoroacetic acid.

A preferred method for converting compounds of formula X into compounds of formula V, which provides satisfactory yields and allows the use of relatively mild conditions, is the conversion of compounds of formula X into N-alkoxycarbonyl derivatives, in which the N-alkoxycarbonyl group contains 2 to 5 carbon atoms, by reaction with the appropriate alkyl or benzyl chloroformate. The N-alkoxycarbonyl or benzyloxycarbonyl derivative of compound X is then cyclized by the action of polyphosphoric acid to the corresponding N-alkoxycarbonyl or benzyloxycarbonyl derivative of compound V. N-substituted derivatives of compounds of formula X can optionally be hydrolyzed to the corresponding

3-[(N-subst.)-3-hydroxy-5-subst.anilino]-3-(R4)-propionic acid with a protected hydroxyl group in position 3. Polyphosphoric acid generally provides the best yields in the cyclization and is therefore the preferred cyclizing agent.

Compounds of formula V in which the hydroxyl group or groups are protected and in which the nitrogen atom is substituted by an alkoxycarbonyl group, give compounds of formula V—A upon treatment with hydrobromic acid in acetic acid. If the protecting groups of the hydroxyl function or functions are benzyl or substituted benzyl, the hydroxyl groups are regenerated by catalytic hydrogenolysis. The alkoxycarbonyl group, if present on the nitrogen atom, remains intact in this reaction. If desired, this group can be cleaved off subsequently by treatment with hydrobromic acid in acetic acid or by treatment with any other of a wide variety of acids or bases. When the benzyl protecting group is cleaved off by treatment with trifluoroacetic acid, the N-alkoxycarbonyl group present is also cleaved off.

If the substituent —Z—W in the compounds of the general formula V is the group —OH, and if it is desired that this substituent —Z—W in the compounds of the general formula II or I represents the residue —O-alk-W, the conversion of the group —OH to the group —O-alk-W is carried out expediently and advantageously at that point in the overall reaction sequence. Thus, the group —7-OH in the compound of the above-mentioned general formula V—B is converted by a Williamson reaction with the appropriate bromide Br-alk-W, mesylate or tosylate to the group of the formula —O-alk-W [formula V—C)

For this advantageous protection of the nitrogen atom from protonation, a number of other groups can be used instead of the alkoxycarbonyl or benzyloxycarbonyl group, such as any of the groups falling within the scope of the symbol R6.

The group Re, if not already present in the compounds of the general formula V—A, V—B or V—C, can be introduced before the formation of the hydroxymethylene derivative (VI) by reaction with the appropriate reagent Cl—R6 or Br—Ra, carried out in a manner known per se. However, if in the products of the general formula I or II R6 is to represent an acyl group, for example an acetyl group, this group is generally introduced only after the formation of the compound of the general formula ^V , in which Re represents a hydrogen atom, for example by acylation with the appropriate acyl halide, carried out in a manner known per se.

The conversion of compounds of general formula III, prepared by the process according to the invention, into compounds of the above-mentioned general formulas I and II is described in our related Czechoslovak patent specification No. 241,459.

Quinolines of the above general formula V are converted into hydroxymethylene derivatives of the general formula VI

(VIJ in which the individual general symbols have the meanings given above, by reaction with formic ethyl and sodium hydride. This formylation reaction produces the bis-formylated derivative of formula VI in excellent yield. The action of methyl vinyl ketone on this bis-formylated derivative produces a mixture of the corresponding mono-N-formylated Michael adduct of general formula VII and the 1,3-bis-formylated Michael adduct. These two products are conveniently separated by column chromatography on silica gel.

The conversion of compounds of general formula VII to compounds of general ^formula III is carried out by aldol condensation of the mono-N-formyl derivative of general formula VII. The 1,3-bis-formylated Michael adduct provides, upon aldol condensation, compounds of formula III—A with spiro-fused rings as the main product, according to the following scheme:

Η ( lil A I

However, the compound of formula VII-A can also be converted by treatment with an equivalent amount of potassium carbonate in methanol to the compound of formula VII.

In addition to the product with spiro-annelated rings, small amounts of the desired enone (formula III] and compounds of formula V are also formed.

The actual subject of the invention is a process for the production of new benzo[c]quinolines of the above-mentioned general formula III, characterized in that the compound of the general formula

in which

R1, R2, R3, Z and W have the same meaning as in general formula III and

R7 represents a hydrogen atom or a formyl group, acting as a base.

3-Hydroxy-5-(Z-W-substituted) anilines are prepared from the corresponding 5-(Z-W-substituted) resorcinols by the Bucherer reaction, which consists in reacting the appropriate 5-(Z-W-substituted) resorcinol with aqueous ammonium sulfite or bisulfite. The reaction is carried out in an autoclave at elevated temperatures, for example from 150 to 230° Celsius. The aniline product is isolated by acidifying the cooled reaction mixture and extracting the acidic mixture, for example with ethyl acetate. The acidic solution is neutralized and extracted with a suitable solvent, for example chloroform, to isolate the aniline product. Alternatively, the aniline product can be isolated by extracting the cooled reaction mixture with a suitable solvent and separating the crude product by column chromatography.

5-(Z-W-substituted] resorcinols, if not known, are prepared from 3,5-dihydroxybenzoic acid. The method of preparation consists either in esterification of 3,5-dihydroxybenzoic acid in which the hydroxy groups are protected (for example as methyl, ethyl or benzyl ethers), or alternatively in conversion of 3,5-dihydroxybenzoic acid, with protected hydroxyl groups; into an amide.

The overall sequence of reactions is illustrated by the following reaction scheme:

The starting 3,5-dihydroxybenzoic acid (XI) is converted into a compound of formula (XIII) in which Y2 represents an alkoxy group (methoxy or ethoxy group or amino group) and Y1 is a protecting group for the hydroxyl function, according to a procedure described in the literature.

The benzoic acid derivative (XII), containing two protected hydroxyl groups, is then converted into a compound of formula XIV in a known manner. According to one of these methods, the substance of formula XII is subjected to hydrolysis to form the corresponding acid (Y2 = OH) or lithium salt, which is reacted with a suitable alkyl lithium to form a dialkyl-substituted phenyl ketone (Y2 = alkyl). When methyl lithium is used, the resulting acetophenone derivative is reacted with a Grignard reagent (W—Z'—MgBr). The intermediate is hydrolyzed to the corresponding alcohol, in which the hydroxyl group is then replaced by hydrogen by hydrogenolysis. This method of preparation is particularly suitable for those substances in which Z is an alkylene group.

Ether protecting groups are removed by a suitable method, such as reaction with pyridine hydrochloride (Yi = methyl) or catalytic hydrogenolysis (Yi = benzyl) or by reaction with an acid such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid or sulfuric acid.

Another method for converting compounds of formula XII to compounds of formula XIV consists in the reaction of a ketone of formula XII (Y2 = alkyl) with a suitable triphenylphosphonium bromide derivative [(C&H5)3P ⁺ —Z—W]Br~ in the presence of a base (e.g. sodium hydride). The reaction proceeds via an alkene, which is converted to an alkane by catalytic hydrogenation, and removal of the protecting groups to give the dihydroxy compound (XIV). However, if Z is a residue of the formula —O-alk- and Yi is benzyl, the catalytic hydrogenation also cleaves the benzyl ethers.

The conversion of compounds of structure XII to compounds of structure XIV can also be achieved by the reaction sequence XII -> XII - XIV. In this reaction sequence, the benzamide (XII, Y2 = = NH2J, bearing two protected hydroxyl groups on the benzene ring, is converted to the ketone (XII, Z' = Z without one CH2 group), and (Br—Mg—Z'—W). This reaction is then followed by a reaction with a Grignard reagent with methyl or ethyl magnesium halide, in which the corresponding carbinol is formed. Dehydration of the carbinol, for example with p-toluenesulfonic acid, gives the corresponding alkene, whose catalytic hydrogenation (Pd/C) gives the alkane (XIV). The ether groups are converted to free hydroxyl groups as described above.

When Z is alkylene, it is preferred that Yi represents alkyl of 1 to 4 carbon atoms or benzyl. The function of the group Yi is to protect the hydroxy groups during the reaction process. Its ability to perform this specific function, that is, to protect the hydroxy groups, is more important than its structure. The selection and determination of suitable protecting groups can be easily carried out by anyone skilled in the art. The suitability of the group for protecting the hydroxyl function is determined by the utility of such a group in the reaction sequence described above. It should be a group which is readily removable by reaction.

241484 generation of hydroxyl group. Methyl is suitable as an alkyl protecting group because it is easily removed by the action of pyridine hydrochloride. If a benzyl group is used as a protecting group, it is removed by catalytic hydrogenolysis or acid hydrolysis.

When Z represents a radical of the formula —O-alk-, Y1 preferably represents a benzyl or substituted benzyl group, since this can be removed without damaging the Z group.

Compounds of formula VIII—A can also be prepared from 3-amino-5-hydroxybenzoic acids by the method described in the following reaction scheme D.

Compounds of formula VIII—A, in which —Z—W is —alkylene-W or —O-alk-W, are obtained according to the following reaction scheme D:

Scheme D (Ac = acetyl)

The first step in the above reaction sequence (Wittig reaction) allows, by selecting the appropriate reagent, to prepare compounds containing straight or branched alkylene groups. The amino group is protected by acetylation, which is carried out in a standard manner. In the above scheme, R" represents a methyl group or an ethyl group, allowing the formation of a compound in which the alkyl chain is substituted by an alkyl group on a carbon atom (also attached to the phenyl group). Substitution of the methyl or ethyl group to another position, for example the /3-carbon atom in the alkylene group, is achieved by selecting the appropriate carbalkoxyalkylidenetriphenylphosphorane, for example (C6H5)3P=C(R")_COOC2H5 .

The unsaturated ester thus obtained is reduced to the corresponding saturated alcohol by reaction with lithium aluminium hydride. This reaction is sometimes accelerated by a small amount of aluminium chloride. In the case where Yi is a substituent other than benzyl (e.g. methyl), the alcohol can alternatively be obtained by catalytic reduction of the unsaturated ester using palladium on carbon, and by treatment of the saturated ester thus obtained with lithium aluminium hydride. Conversion of the alcohol to the corresponding tosylate or mesylate, followed by alkylation of these with a suitable alkali metal salt of HO-alk-W. Removal of the protecting groups Yi then gives the desired compound (VIII—A).

A variation of the above reaction sequence consists in bromination of the alcohol instead of converting it to the tosylate or mesylate. A suitable brominating agent is phosphorous bromide. The bromide derivative is then reacted with a suitable reagent

HX'-(alk ₂ ) _n -W in the presence of a suitable base (Williamson reaction J.

In the above reaction sequence, bromine derivatives serve as convenient intermediates for chain extension of the alkylene moiety to form compounds in which Z is -alkylene-W. This procedure involves reacting the bromine derivative with triphenylphosphine to form the corresponding triphenylphosphonium bromide. Reaction of triphenylphosphonium bromide with a suitable aldehyde or ketone in the presence of a base such as sodium hydride or n-butyllithium produces the unsaturated derivative, which is then catalytically hydrogenated to the corresponding saturated compound.

In this variation, the choice of protecting group Yi depends on which of the possible reaction procedures is chosen. If the reaction sequence shown in the reaction scheme on the right is chosen, the benzyl group is the preferred protecting group due to the inclusion of catalytic hydrogenation in this sequence. If the reaction sequence shown in the reaction scheme on the left is carried out, the methyl group is the preferred protecting group, since it can be conveniently cleaved by reaction with an acid, as described herein.

Esters of compounds of formulae II and III, in which R1 is acetyl, are readily prepared by reacting compounds of formulae II and III with acetic acid in the presence of a condensing agent such as dicyclohexylcarbodiimide. In addition, these substances can be prepared by reacting compounds of formulae II or III with acetic acid chloride or anhydride in the presence of a base such as pyridine.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way.

In the examples, abbreviations with the following meanings are used for NMR spectra:

s = singlet d ·= doublet t = triplet q = quartet m = multiplet š = broad signal TMS = tetramethylsilane Et = ethyl.

Example

Ethyl ester of d,l-3-(3,5-dimethoxyanilinobutyric acid)

A mixture of 95.7 g of 3,5-dimethoxyaniline (0.624 mol), 87.2 ml of ethyl acetoacetate (0.670 mol), 535 ml of benzene and 3.3 ml of glacial acetic acid is refluxed for 15 hours under nitrogen and the water formed is removed using a Dean-Stark trap. The reaction mixture is cooled to room temperature, decolorized with activated carbon, filtered and then concentrated under reduced pressure. 168.7 g of ethyl esters of 3-(3,5-dimethoxyaniline-2-butenoic acid) are obtained in the form of an oil.

A mixture of 5.0 g of ethyl esters of 3-(3,5-dimethoxyanilino)-2-butenoic acid (18.7 mmol) in 42 ml of glacial acetic acid and 250 mg of platinum dioxide is hydrogenated for 1.5 hours in a Paar shaker at a pressure of 0.35 MPa. The reaction mixture is filtered, 50 ml of benzene is added and the solution is concentrated under reduced pressure to an oil. This oil is extracted with chloroform and the solution is shaken successively with saturated sodium hydrogen carbonate solution (2x50 ml) and saturated sodium chloride solution, then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 5.1 g of the product in the form of an oil.

In the same manner, using 168.7 g of ethyl esters of 3-(3,5-dimethoxyaniline-2-butenoic acid, 320 ml of glacial acetic acid and 2.15 g of platinum dioxide, 160.8 g of product are obtained.

Example 2

d,1-3-(3,5-dimethoxyanilino)butyric acid ethyl ester

To a solution of 370 g of 3,5-dimethoxyaniline hydrochloride (1.45 mol) in 4.5 liters of methanol and 286.3 g of ethyl acetoacetate (2.64 mol), presented in a twelve-liter three-necked round-bottomed flask equipped with a mechanical stirrer and a reflux condenser, 54 g of sodium cyanoborohydride (0.73 mol) are added in a single portion. After the reflux has subsided (10 minutes), the mixture is heated on a steam bath for a further 20 minutes. To the cooled reaction mixture is added again

5.4 g of sodium cyanoborohydride (0.07 mol) and 28.6 g of ethyl acetoacetate (0.26 mol) and the mixture are refluxed for 30 minutes. This last operation is repeated once more.

The reaction mixture is worked up in 500 ml portions, which are poured into a mixture of 1 liter of water and 500 ml of methylene chloride, the layers are separated and the aqueous phase is washed with 100 ml of methylene chloride. This procedure is repeated until all the reaction mixture is worked up.

The methylene chloride layers were combined, dried over magnesium sulfate, decolorized with activated charcoal, filtered, and evaporated to a yellow oil.

The excess ethyl acetoacetate was distilled off on an oil bath at 130°C under a pressure of 133 to 667 .Pa, yielding 376 g (72 percent) of crude 3-(3,51-dimethoxyanilino)butyric acid ethyl ester as an amber-colored viscous oil, which was used without further purification.

This substance has the following spectral characteristics:

1H NMR (60 MHz) δ ™ ^with l5 (PPm): <·

5.82 to 6.0 (m, 3H, aromatic hydrogens),

4.20 (q, 2H, ester methylene),

3.80 to 4.00 (m, 2H, —NH and —N—CH—CHs),

3.78 (s, 6H, —OCHs),

2.40 to 2.55 (m, 2H, -CH2COOEt),

1.78 (d, 3H, -CH3),

1.29 (t, 3H, -CH3).

Example 3

Ethyl ester of d,l-3-(3,5-dimethoxyanilino-)hexanoic acid

By a procedure analogous to that in Example 2, the condensation of 3,5-dimethoxyaniline hydrochloride with ethyl butanoyl octanoate yields ethyl d,1-3-(3,5-dimethoxyaniline)hexanoic acid, which is converted to hydrogen by passing hydrogen chloride into its solution in methylene chloride. The hydrochloride melts at 126 to 129.5 °C. Recrystallization from a mixture of cyclohexane and benzene (5:1) yields an analytical sample melting at 126 to 128.5 ^° C.

Analysis: for CisHžsOiN . HC1 calculated:

57.91% C, 7.90% H, 4.22% N, found ·

57.89 O/o C, 7.74 O/o H, 4.40 O/o N. m/e: 295 (m ⁺ ) ⁴ H NMR (60 MHz) δ (ppm):

10.76 to 11.48 (w, 2H, Νζ+),

6.77 (d, J = 2 Hz, 2H, hydrogens in m-position),

6.49, 6.45 (double d, J = 2 Hz, 1H, m-H),

4.08 (q, 2H, OCH2),

3.77 [s, 6H, (OCH3)2], ca. 3.5 to 4.8 (m, 1H, CH—NJ,

2.90 (t, 2H, CHz—C=O), ca. 1.4 to 2.2 [m, 4H, (CHzJzj,

1.21 (t, 3H, O—C—CH3),

0.84 (t, 3H, —C—CH3).

Example 4

Ethyl ester of d,l-3-[(3,5-dimethoxy-N-ethoxycarbonyl)aniline] butyric acid Preparation method A:

To a mixture of 159.8 g of ethyl 3-(3,5-dimethoxyanilino)butyric acid ester (0.598 mol), 100 ml of methylene chloride and 100 ml of pyridine (1.24 mol) under a nitrogen atmosphere at 0 ^° C was added dropwise over 45 minutes:

71.4 ml of ethyl chloroformate (0.75 mol). After addition of ethyl chloroformate, the mixture is stirred for 40 minutes, then poured into a mixture of 750 ml of chloroform and 500 ml of ice-water. The chloroform layer is separated, washed with 10% hydrochloric acid (3 x 500 ml), saturated aqueous sodium hydrogen carbonate solution (1 x x 300 ml) and saturated aqueous sodium chloride solution (1 x 400 ml), then dried over magnesium sulfate and decolorized with activated carbon. Concentration under reduced pressure gives 215 g of an oily product, which is used as such further.

Preparation method B:

A mixture of 376 g of ethyl 3-(3,5-dimethoxyanilino)butyric acid ester (1.4 mol), 1.4 liters of methylene chloride and 388.8 g of anhydrous sodium carbonate (2.81 mol) was cooled to 0 to $ ’C under nitrogen with stirring and 153 g of ethyl chloroformate (1.41 mol) was added in a single portion. The mixture was allowed to warm to room temperature over 1 hour, 153 g of ethyl chloroformate (1.41 mol) was added again and the resulting mixture was refluxed on a steam bath for 1 hour. The reaction mixture was allowed to cool to room temperature and the sodium carbonate was filtered off. The red-coloured filtrate is washed with water (2 x 1000 ml) and brine (1 x 500 ml), dried over magnesium sulphate, decolourised and evaporated under reduced pressure. 439 g of crude product is obtained, which is used without further purification.

1H NMR (60 MHz] δ (PPm):

6.2 to 6.42 (m, 3H, aromatic hydrogens),

4.65 (sextet, 1H, —N—CH—, CH3),

4.10 to 4.15 (2q, 4H, ester methylenes),

3.70 (s, 6H, — OCH 3 ),

2.30 to 2.60 (m, 2H, —CH2COOEt),

1.00 to 1.40 (m, 9H, 3 x CH 3 ).

Example 5

d,l-3 ( (3,5-dimethoxy-N-ethoxycarbonyl) anilino] butyric acid Preparation method A:

A mixture of 202 g of ethyl 3-((3,5-dimethoxy-N-ethoxycarbonyl)anilino]-butyric acid ester, 595 ml of 1N aqueous sodium hydroxide and 595 ml of ethanol is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure to a volume of about 600 ml, the concentrate is diluted with water to a volume of 1,200 ml and extracted three times with 750 ml of ethyl acetate each time. The aqueous layer is acidified with 10% hydrochloric acid to pH 2 and the mixture is extracted three times with 750 ml of ethyl acetate each time. These last extracts are combined, washed with sodium chloride solution, dried with magnesium sulfate and, after filtration, concentrated in vacuo. 163.5 g (88.2%) of the title compound is obtained as an oil.

Preparation method B:

A solution of 439 g (1.41 mol) of ethyl 3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid ester in 2 liters of ethanol is placed in a 5-liter three-necked round-bottomed flask equipped with a mechanical stirrer and a reflux condenser. 2 liters of 1 N sodium hydroxide are added and the mixture is heated under reflux on a steam bath for 3 hours. The reaction mixture is poured into 5 liters of ice-water and extracted in 1-liter portions with 500 ml of diethyl ether. The aqueous layer is cooled by adding about 1 liter of ice and then acidified by adding 1.75 ml (2.1 mol) of concentrated hydrochloric acid. The resulting mixture is extracted in 1-liter portions with 250 ml of methylene chloride. The methylene chloride layers are combined, dried over sulfate. magnesium, decolorized with activated carbon and evaporated. The viscous yellow oily residue gives, after crystallization from a mixture of ether and cyclohexane (1:2), 224 g (55.3%) of crystalline product with a melting point of 78-80 °C. This material is used without further purification in the next reaction step.

1H NMR (60 MHz) δ (ppm):

6.24 to 6.53 (m, 3H, aromatic hydrogens),

4.65 (sextet, 1H, —N(COOC2H5)CH(CH3)CH2COOC2H5),

4.10 (quartet, 2H, ester methylene),

3.78 (s, 6H, —OCH3],

2.40 to 2.60 (m, 2H, —CH2COOH], _:

1.18 (t),

1.28 (d, 6H, methyls),

10.8 (s, 1H, COOH).

Mass spectrum (molecular ion m/e = 311.

✓

The analytical sample obtained after recrystallization from a mixture of ethyl acetate and hexane (1: : 5) melts at 89 to 91 °C.

Analysis: for C15H21O6N calculated:

57.86% C, 6.80% H, 4.50% N, found:

58.08% C, 6.65% H, 4.46% N.

Example of d- and 1-3-((3,5-dimethoxy-4-N-ethoxy-. . . 'carbonyl)anilino]butyric acid

A mixture of 136.6 g (0.44 mol) of d,1-3-((3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid and 72.5 g (0.44 mol) of 1-ephedrine was dissolved in 500 ml of methylene chloride, after which the methylene chloride was evaporated in vacuo to give the salt of d,1-3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid with 1-ephedrine as an oil having a temperature of ²⁵ °C <= -20.0° (c = 1.0, chloroform). After addition of 1,500 ml of ether, a white solid crystallized out, which was filtered off and dried. 102 g of material melting at 114-116°C was obtained, which, after recrystallization from a mixture of ethyl acetate and hexane (1:1), gave 71.1 g (34 percent) salt of 1-3-[3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid with 1-ephedrine, melting at 126 to 127 °C. Analysis: for C25H36O7N2 calculated:

63.00% C, 7.61% H, 5.88% N, found:

62.87% C, 7.64% H, 5.88% N.

[a]o ²⁵ = -43.5% (c = 1.0, chloroform).

The salt of the 1-isomer of the above acid with 1-ephedrine is stirred for 10 minutes in a mixture

1000 ml of ethyl acetate and 400 ml of 10% hydrochloric acid. The organic phase is separated, washed twice with 400 ml of 10% hydrochloric acid, dried and concentrated under reduced pressure. The oily residue gives, after crystallization from 400 ml of a mixture of ethyl acetate and hexane (1:1), 34.6 g of 1-3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid with a melting point of 96 to 97 ^C C. Analysis: for C15H21O6N calculated:

57.86% C, 6.80% H, 4.50% N, found ·

57.90 °/o C, 6.66% H, 4.45% N.

The mother liquors from the crystallization of the 1-isomer salt with 1-ephedrine are treated with hydrochloric acid as described above to give crude d-3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid. Reaction of this crude acid with d-ephedrine, after crystallization from ether, gives the d-isomer salt with d-ephedrine, melting at 124-125°C.

Analysis: for C25H3SO7N2 calculated:

63.00% C, 7.61% H, 5.88% N, found:

62.82% C, 7.47% H, 5.97% N.

[a] _D ²⁵ ₌ 4-44.0 ⁰ (c = 1.0, chloroform).

By the above-described procedure for converting the 1-ephedrine salt to the free acid, the d-ephedrine salt is converted to d-3-((3,5-dimethoxy-N-ethoxycarbonyl)anilino]butyric acid melting at 96-97°C after recrystallization from ethyl acetate and hexane (3:5).

Analysis: for C15H21O&N calculated:

57.86% C, 6.80% H, 4.50% N, found:

57.95% C, 6.57% H, 4.35% N.

[α ²⁵ = +25.3° (c = 1.0, chloroform).

Example 7

3-(3,5-Dimethoxyanilino)propionic acid methyl ester

A mixture of 114.9 g (0.75 mol) of 3,5-dimethoxyaniline, 69.73 g (0.81 mol) of methyl acrylic acid ester and 2 ml of glacial acetic acid was heated to reflux for 20 hours. The reflux was then stopped, the reaction mixture was concentrated and the residue was distilled in vacuo. 106.8 g (73.9%) of the title product were obtained, boiling at 174-179 ^° C/93 Pa, *H NMR (60 MHz) 5 j™ ³ , ' (PPm):

5.62 to 5.95 (m, 3H, aromatic protons),

4.1 (ss, 1H, —NH),

3.74 (s, 6H, —OCH 3 ),

3.68 (s, 3H, COOCH3),

3.41 and 2.59 (two triplets for 2H, —NCH2CH2CO2).

Example

d, 1-3-{[ 3-Hydroxy-5-(5-phenyl-2-pentyl)-janilin-propionic acid methyl ester

A mixture of 1.0 g of 3-hydroxy-5-(5-phenyl-2-pentyl)aniline, 345 mg of methyl acrylic acid ester and 0.1 ml of acetic acid is heated overnight at 106-110 °C. The cooled residue is dissolved in 100 ml of ethyl acetate and the solution is washed twice with 100 ml of saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and evaporated to a crude residue, which is chromatographed on 130 g of silica gel using a benzene/ether mixture (2:1) as eluent. After washing out the less polar impurities, 540 mg (40%) of methyl d .,1-3-( [ 3-hydroxy-5-(5-phenyl-2-pentyl) ] anilinopropionic acid ester is obtained, which has the following spectral characteristics:

⁴ H NMR .(60 MHz) δ (ppm):

7.14 (s, 5H, aromatic protons),

5.83 to 6.13 (m, 3H, aromatic protons),

3.66 (s, 3H, —COOCHs),

3.37 (t, 2H, —NCH2),

2.16 to 2.78 (m, 5H, —CH2COO and benzyl protons),

1.28 to 1.69 [m, 4H, — (CH ₂ ) 2 —],

1.11 (d, 3H, \-CH 3 ),

4.4 to 5.2 and 1.28 to 2.78 (1H, NH, OH), m/e = 341 (m ⁺ ).

Example 9

3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino]propionic acid methyl ester

To a mixture of 1.0 ml (10.5 mmol) of methyl 3-(3,5-dimethoxyanilino)propionic acid, 5 ml of methylene chloride and 5 ml of pyridine, 2.0 g (8.4 mmol) of ethyl chloroformate were added dropwise over 10 minutes under nitrogen at 0 °C. After the addition of ethyl chloroformate, the mixture was stirred first for 20 minutes at 0 ^° C and then for a further 20 minutes at room temperature, after which it was poured into a mixture of 75 ml of methylene chloride and 50 ml of ice-water. The methylene chloride layer is separated, washed successively twice with 50 ml of 10% hydrochloric acid, once with 30 ml of saturated aqueous ^sodium bicarbonate solution and once with 40 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, decolorized with activated carbon and concentrated under reduced pressure to an oily residue weighing 2.72 g. The product is used without any further treatment.

Example 10

3-[(3,5-dimethoxy-N-ethoxycarbonylaniline jpropionic acid

A mixture of 2.72 g (8.36 mmol) of 3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino]propionic acid methyl ester, 8.4 ml of 1N aqueous sodium hydroxide and 8.4 ml of ethanol is stirred overnight under nitrogen at room temperature. The reaction mixture is concentrated under reduced pressure to half volume, diluted with 35 ml of water and extracted with ethyl acetate. The aqueous phase is acidified to pH 2 with 10% hydrochloric acid and extracted three times with 50 ml of methylene chloride each time. The combined extracts are washed with sodium chloride solution, dried over magnesium sulfate and concentrated. 2.47 g of an oily product is obtained, which is used without any further treatment.

Example 11 1-Ethoxycarbonyl-5,7-dimethoxy-4-oxo-1,2,3,4-tetrahydroquinoline

A mixture of 1.10 g (3.7 mmol) of 3-[(3,5-dimethoxy-N-ethoxycarbonyl]anilino]propionic acid and 4 g of polyphosphoric acid is heated at 65°C for 45 minutes under a nitrogen atmosphere, then cooled to 0°C and 200 ml of a mixture of equal parts of methylene chloride and water are taken. The organic layer is separated and the aqueous phase is extracted twice with 100 ml of methylene chloride each time. The combined extracts are washed three times with 100 ml of saturated sodium hydrogen carbonate solution, once with 100 ml of sodium chloride solution, dried over magnesium sulfate and evaporated. An oily product is obtained, crystallising from benzene. The crystalline product melts at 109-111°C. The yield is 645 mg.

Analysis: for CmHvOjN calculated:

60.21% C, 6.14% H, 5.02% N, found:

60.11% C, 6.14% H, 4.80% N.

Example 12

5,7-dihydro-4-oxo-1,2,3,4-tetrahydroquinoline

A mixture of 60 ml of glacial acetic acid, 60 ml of 48% hydrobromic acid and 4.0 g (14.3 mmol) of 1-ethoxycarbonyl-5,7-dimethoxy-4-oxo-1,2,3,4-tetrahydroquinoline is refluxed overnight and then concentrated in vacuo to a dark oily residue which is dissolved in 50 ml of water. The aqueous solution is neutralized with 1N sodium hydroxide to pH 6-7, after which 50 ml of saturated sodium chloride solution in water is added and the resulting mixture is extracted three times with 150 ml of ethyl acetate each time. The extracts are combined, dried over magnesium sulphate and concentrated under reduced pressure to an oily residue. This oily material is dissolved in a mixture of equal parts of benzene and ethyl acetate, and the solution is applied to a silica gel column. The column is first eluted with an equal volume of benzene as The column volume is then eluted with 250 ml of a mixture of benzene and ethyl acetate (4:1) and 250 ml of a mixture of benzene and ethyl acetate (1:1), while 75 ml fractions are collected. Fractions 4 to 9 are combined and evaporated under reduced pressure. The oily residue gives, after crystallization from a mixture of ethanol and hexane (1:10), 1.86 g of the desired product, melting at 166-169 °C.

Upon further recrystallization, the melting point increases to 171-172.5° C. m/e = 179 (m ⁺ ).

Analysis for C9H9O3N calculated:

60.33% C, 5.06% H, 7.82% N, found:

60.25% C, 4.94% H, 7.55% N.

Example 13 d,1-1-Ethoxycarbonyl-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline

To 5.0 g of polyphosphoric acid, heated on a steam bath to 60 °C, a solution of 4.0 g (12.8 mmol) of 3-[(3,5-dimethoxy-N-ethoxycarbonyl] anilinobutyric acid in 2 ml of chloroform is added dropwise with stirring. The reaction mixture is heated for another 2 hours at 60 to 65 °C, after which it is poured into a mixture of 100 g of ice and 100 ml of ethyl acetate. The aqueous layer is extracted twice more with 100 ml of ethyl acetate each time and the combined organic extracts are washed successively three times with 100 ml of saturated sodium hydrogen carbonate solution and once with 100 ml of sodium chloride solution. After drying with anhydrous magnesium sulfate, the extract is evaporated under reduced pressure, thereby obtaining 2.6 g of crude product.

Purification is carried out by chromatography of a benzene solution of 2.5 g of crude product on a 95 g silica gel column. The column is first taken out with a volume of benzene corresponding to half the volume of the column and then eluted with a mixture of equal parts of benzene and ethyl acetate. Fractions of 40 ml are collected. Fractions 9 to 18 are combined and evaporated in vacuo to give 1.55 g of product, which after further purification by recrystallization from petroleum ether gives 1.33 g of product melting at 92.5 to 94 °C.

After recrystallization of this product from a hot mixture of equal parts ethyl acetate and hexane, an analytical sample with a melting point of 94-95°C is obtained.

Analysis: for C15H19O5N calculated:

61.42% C, 6.53% H, 4.78% N, found:

61.54% C, 6.55% H, 4.94% N. m/e = 293 (m ⁺ ).

IR (KBr): 5.85, 5.95 μ ( > =0).

Example 14 d,1-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline

Preparation method A:

A mixture of 240 ml of glacial acetic acid, 240 ml of 48% hydrobromic acid and 16.0 g (55 mmol) of 1-ethoxycarbonyl-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline is refluxed overnight and then concentrated in vacuo. The dark oily residue is dissolved in 200 ml of water, the aqueous solution is neutralized with 1 N sodium hydroxide to pH 6-7, 200 ml of saturated aqueous sodium chloride solution is added and the resulting mixture is extracted three times with 500 ml of ethyl acetate each time. The extracts are combined, dried over magnesium sulfate and concentrated under reduced pressure. 12.8 g of a dark oily residue is obtained, to which a mixture of hexane and ethyl acetate (10:1) is added. Filtration of the precipitated crystals gave 3.8 g of material melting at 158-165°C, from which trituration with ethyl acetate gave 1.65 g of product melting at 165-169°C.

From the mother liquors, a further 2.9 g of material with a melting point of 168 to 170 °C is separated by standing. Chromatography of the filtrate on a silica gel column using a mixture of benzene and ether (1:11) gives a further 4.6 g of product with a melting point of 167 to 169 °C.

After further purification by recrystallization from ethyl acetate, a product with a melting point of 173-174°C is obtained.

Analysis: for CroHnOjN calculated:

02.16% C, 5.74% H, 7.25% N, found:

62.00% C, 5.83% H, 7.14% N. m/e = 193 (m ⁺ ).

Preparation method B:

A mixture of 100 g (0.32 mol) of d,l-3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino-1-butyric acid and 500 ml of 48% hydrobromic acid in 300 ml of glacial acetic acid is heated in an oil bath at 110 °C for 2 hours, after which the temperature of the oil bath is increased to 145 °C and heating is continued for another 2 hours. During this latter heating, about 200 to 300 milliliters of an azeotropic mixture boiling at 42 to 110 °C are distilled off. The resulting, deep red-colored homogeneous solution is allowed to cool to room temperature, added to 3 liters of ice-water and 2 liters of ether, the layers are separated and the aqueous layer is washed twice with 1,000 milliliters of ether each time. The ether layers are combined, washed successively twice with 1000 ml of water, once with 500 ml of sodium chloride solution, four times with 250 ml of saturated sodium bicarbonate solution and finally once with 500 ml of sodium chloride solution, dried over magnesium sulfate, decolorized with activated carbon and the ether is evaporated. The yellow oily residue gives, after crystallization from about 300 ml of methylene chloride, 31.3 g (50.4%) of pure 5,7-dihydroxy-2-methyl-4-oxo-1,2,3.4 tetrahydroquinoline. A further portion of the product can be isolated from the mother liquor by chromatography on silica gel.

H1 NMR (60 MHz) <S™ ^S (100 mg sample/ /0.3 ml. CDCW0.2 ml CDsSOCDs) (ppm):

12.40 (8, 1H, C1-OH),

5.72 (d, 2H, meta-hydrogen),

5.38 to 5.60 (ss, 1H, Cz—OH),

3.50 to 4.00 (m, 1H, C2—H),

2.38 to 2.60 Jm, 2H, Cs—Hž),

1J2 (d, 3H, methyl).

m/e = 193 (m ⁺ ).

Analysis: for CioHuOsN calculated:

' 62.16% C, 5.74% H, 7.25% N, found:

62.01% C, 5.85% H, 7.02% N.

In an analogous manner, methyl ester of d,1-3-{ í 3-hydroxy-5-'( 5-phenyl-2-pentyl) ] anilinoylpropionic acid is converted into d,1-5-hydroxy-7~ (5-phenyl-2-pentyl)-4-oxo-1,2,3,4-tetrahydroquinoline, which is purified by column chromatography on silica gel using a mixture of benzene and ether (5:1) as eluent.

m/e = 309 (m ⁺ ).

*H NMR (60 MHz) О ™® _l3 (PPm):

12.22 (s, 1H, 5—OH),

7.14 (s, 5H, C 5 H 5 ),

6.04 (d, J = 2.5 Hz, 1H, meta-hydrogen),

5.87 (d, J = 2.5 Hz, meta-hydrogen),

4.19 to 4.60 (s, 1H, NH),

3.48 (t, 2H, CH2N),

2.18 to 2.89 (rn, 5H, ArCH, ArCHz, CHz—C=O),

1.38 to 1.86 [m, 4H, — (CH2H2— ]),

1.13 (d, 3H, CH3), ethyl ester of d,1-3-(3,5-dimethoxyanilino)hexanoic acid hydrochloride to d,1-5,7-dihydroxy-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline melting after crystallization from methylene chloride at 117 to 119 °C, m/e = 221 (m ⁺ ), 135 (basic signal, m + -propyl),

1-3- [ (3,5-dimethoxy- (N-ethoxycarbonyl) anilinobutyric acid to d-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline with melting point 167-168 °C, [α] _D ²⁵ = +167.8° (c = 1.0, methanolj. m/e = 193 (m+j.

Analysis: for CioHnOjN calculated:

62.16% C, 5.74% H, 7.25% N, found:

61.87 0/o C„ 5.62 ’% H, 6.96% N.

and d-3-[3,5-dimethoxy-(N-ethoxycarbonyl)anilinobutyric acid to 1-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline, melting point 166-168°C, [ort] _D ²⁵ = —168.5° (c = 1.0, methanolj. m/e = 193 (m+j.

Analysis: for· C10H11O3N calculated:

62.16% C, 5.74% H, 7.25% N, found:

61.82% C, 5.83% H, 7.22% N.

Example 15 d,1-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline

A mixture of 230 g (1.5 mol) of 3,5-dimethoxyaniline, 150 g (1.5 mol) of crotonic acid methyl ester and 90 g (1.5 mol) of glacial acetic acid is heated to reflux for 6 hours, after which another g (1.5 mol) of glacial acetic acid is added and the mixture is heated to reflux overnight. After adding 1000 ml of 48% hydrobromic acid and 850 ml of glacial acetic acid, the reaction mixture is heated to reflux for 4.5 hours. The title product is isolated and purified by the procedure described in Example 12. 36 g of product with a melting point of 166-170 ° C are obtained.

Example 16 d,1-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline

A mixture of 4.6 g (0.03 mol) of 3,5-dimethoxyaniline, 2.54 g (0.03 mol) of crotonic acid and 3.0 g (1.26 mol) of pyridine hydrochloride was heated at 185-200 °C for 45 min. The cooled reaction mixture was suspended in 500 ml of water (pH ca. 3), the pH was adjusted to 7 and the resulting mixture was stirred for 10 min. The organic layer was separated, dried over magnesium sulfate and concentrated to give 3.2 g of a yellow oily material.

A mixture of 110 ml of glacial acetic acid, 110 ml of 48% hydrobromic acid and the yellow oily material prepared above was heated to reflux for 1 hour and then concentrated in vacuo. The dark oily residue was dissolved in water and the aqueous solution was neutralized with 1N sodium hydroxide to pH 6-7. Saturated aqueous sodium chloride was added and the resulting mixture was extracted with ethyl acetate. The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. 2.8 g of a dark oily residue was obtained. Column chromatography of the crude residue on silica gel using a benzene-ether (4:1) mixture as eluent gave 510 mg of product melting at 168-170° Celsius.

After further purification by recrystallization from ethyl acetate, the product melts at 173-174°C.

Analysis: for C10H11O3N calculated:

62.16% C, 5.74% H, 7.25% N, found:

62.00% C, 5.83% H, 7.14% N.

m/e = 193 (m+j, 178 (m+-methyl, basic signal).

In an analogous manner, from 3,3-dimethylacrylic acid and 3,5-dimethoxyaniline, after purification by column chromatography on silica gel using a mixture of equal parts of benzene and ether as eluent, is obtained

5,7-dihydroxy-2,2-dimethyl-4 oxo-1,2,3,4-tetrahydroquinoline in the form of a yellow oil.

Mass spectrum:

mol. signal 'm ⁺ j:

for CiiHt30sN calculated: 207.0 895 found: 207.0 895, basic signal (m ⁺ -l5) for CicHioOsN calculated: 192.0 681 found: 192.0 655.

In an analogous manner, the reaction of styrylacetic acid with 3,5-dimethyloxyaniline yields oily d,1-5,7-dihydroxy-2-benzyl-4-oxo-1,2,3,4-tetrahydroquinoline for chromatographic purification using a mixture of benzene and ether (3:1) as eluent.

m/e = 269 (m ⁺ ), 178 (m ⁺ -benzyl, basic signal),

NMR (CDCl3, δ values in ppmj:

8.76 (s, 1H, 5-OH),

7.18 to 7.6 (m, 5H, Celte),

5.84 (d, J = 3 Hz, ÍH), . 5.62 (d, J = 3 Hz, ÍH) for m-bonded aromatic protons,

2.14 to 4.82 (4m, 7H) for the remaining protons (7-OH, CH—N, CH2—C-O, —CPH-CeH5 and N—H).

Example 17 d,1-hydroxy-2-methyl-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline

To a solution of 1.0 g (52 mmol) of d,l-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline in 10 ml of N,N-dimethylformamide is added 325 mg (52 mmol) of potassium hydroxide in pellets. The mixture is slowly heated to 100 ^C( C and to the resulting solution is added 1.08 g (60 mmol) of d,l-2-bromoheptane in a single portion with vigorous stirring. After 10 minutes, first another 160 mg of potassium hydroxide and then another 500 mg of d,l-2-bromoheptane are added. This additional addition of potassium hydroxide and d,l-2-bromoheptane is repeated twice more, each time using 80 mg of potassium hydroxide and 250 mg of d,l-2-bromoheptane. The reaction mixture is further The mixture is stirred for 10 minutes, then cooled, 50 ml of chloroform and 25 ml of 1N aqueous sodium hydroxide are added, the resulting mixture is stirred for 10 minutes, and the layers are separated. After repeated extraction with chloroform, the extracts are combined, dried over magnesium sulfate and concentrated under reduced pressure. The dark oily residue is chromatographed on 120 g of silica gel using benzene as eluent. Fractions of 30 ml are collected. The twelfth to eighteenth fractions are combined and concentrated under reduced pressure. 850 mg of a yellowish oily material is obtained, which crystallizes on standing. After filtration and recrystallization from hot hexane, the desired product is obtained with a melting point of 76-77 °C.

The above procedure is repeated using twenty times the amount of reactants and using a mixture of benzene and ethyl acetate (9:1) as the solvent in the chromatography, in which fractions of 750 ml are collected. From the combined fractions 1 to 6, 32 g of an oily product are obtained, which is partially crystallized from hexane after cooling and standing to give 18.2 g of the desired product. A further 3.2 g of product is obtained by concentrating the mother liquors and crystallization of the concentrate by standing in the cold. The total yield is 21.4 g.

Analysis: for Cí.zHsvOjN.

calculated:

70.07% C, 8.65% H, 4.81% N, found:

69.82% C, 8.67% H, 4.93% N.

m/e = 291 (m ⁺ j.

IR (KBrj: 6.01 μ. (=O).

In an analogous manner, 5,7-dihydro-4-oxo-1,2,3,4-tetrahydroquinoline is converted into oily d,1-5-hydroxy-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline.

*H NMR (60 MHz) O (PPmj: ,

13.3 (s, ÍH, phenolic hydrogen),

5.5 to 5.7 (d, 2H, J = 2 Hz, aromatic hydrogens),

4.6 (ss, 1H, —NH),

4.1 to 4.6 (m, ÍH, —O—CH—j,

3.3 (t, 2H, J = 7 Hz, —CHz—),

2.6 (t, 2H, J = 7 Hz, —CHž—j,

2.0 to 0.7 (m, remaining protons).

Example 18 d,1-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline

A mixture of 16.4 g (100 mmol) of 5-phenyl-2-(R,S)-pentanol, 28 ml (200 mmol) of triethylamine and 80 ml of dry tetrahydrofuran is cooled under nitrogen in a cooling bath consisting of ice water, after which 8.5 ml (110 mmol) of methanesulfonyl chloride in 20 ml of dry tetrahydrofuran are added dropwise at such a rate that the temperature is kept practically constant. The resulting mixture is allowed to warm to room temperature, triethylamine hydrochloride is removed by filtration, the filter cake is washed with dry tetrahydrofuran, the filtrate is combined with the washing liquid and evaporated under reduced pressure. The oily residue is dissolved in 100 ml of chloroform and the solution is washed first with 100 ml of water and then once with 20 ml of saturated sodium chloride solution. After evaporation of the solvent, the

21.7 g (89.7 θ/ο) of d,l-5-phenyl-2-pentanol mesylate, which is used without further purification in the next reaction step.

A mixture of 1.0 g (5.2 mmol) of d,1-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline,

14.35 g (0.104 mol) of potassium carbonate, 60 ml of N,N-dimethylformamide and 13.68 g (57 mmol) of d,l-5-phenyl-2-pentanol mesylate are heated in an oil bath at 80 to 82 ?C for 1.75 hours under a nitrogen atmosphere. The resulting mixture is cooled to room temperature and poured into 300 ml of ice-water. The aqueous solution is extracted twice with 50 ml of ethyl acetate each time, the combined extracts are washed successively three times with 50 ml of water each time and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and, after decolorization with activated carbon, evaporated to give the desired product.

m/e = 339 (m ⁺ ).

The above procedure is repeated using 114.8 g (0.594 mol) of d,1-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline, 612 ml of N,N-dimethylformamide, 174.8 g (1.265 mol) of potassium carbonate and 165.5 g (0.638 mol) of d,1-5-phenyl-2-pentanol mesylate. After cooling, the reaction mixture is poured into 4 liters of ice-water and the aqueous solution is extracted twice with 4 liters of ethyl acetate each time. The combined extracts are washed four times with 2 liters of water each time and once with 2 liters of sodium chloride solution, dried over magnesium sulfate and evaporated. 196 g of the title compound are obtained, which is used without further purification.

*H NMR (60 MHz) <S ™? _l3 (PPm):

12.73 (s, 1H, OH),

7.22 (s, 5I-I, aromatic hydrogens),

5.80 (d, J = 3 Hz, 1H, meta-hydrogen),

5.58 (d, J _z = 3 Hz, 1H, meta-hydrogen),

1.25 (d, 6H, CHs—CH—N and CHs—CH—O—),

1.41 to 4.81 (m, 11H, remaining protons).

Example 19 d,1-5-hydroxy-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline

The procedure described in Example 18 is repeated, except that instead of 5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline,

5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline. An oily d,1-5-hydroxy-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline is obtained in a yield of 74%.

m/e - 325 (m ⁺ ).

Analysis: for C20H23NO3 calculated:

73.70 1% C, 7.12 Ψο H, 4.31 % N, found:

73.69% c, 7.15% H, 4.08 θ/ο N.

Ή NMR (60 MHz) Ó ™| _ls (PPm):

12.6 (ss, 1H, phenolic hydrogen),

7.3 (s, 5H, aromatic hydrogens),

5.8 (d, 1H, aromatic hydrogen, J = 2 Hz),

5.6 (d, 1H, aromatic hydrogen, J = 2 Hz),

4.7 to 4.1 (m, 2H, NH and O—CH),

3.5 (t, 2H, CH2, I = 7 Hz),

3.1 to 2.1 (m, 4H, 2-CHa—),

2.1 to 1.5 (m, 4H, 2-CH2—),

1.3 (d, 3H, —CH—CH3, J = 6 Hz).

In an analogous manner, 27 g (0.14 mol) of d,1-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline were alkylated with 35.2 g (0.154 mol) of 4-phenylbutyl methanesulfonate to give 41.1 g (90%) of the desired d,1,-5-hydroxy-2-methyl-7-(4-phenylbutoxy)-4-oxo-1,2,3,4-tetrahydroquinoline with a melting point of 88 to 90 °C. After recrystallization from a mixture of ethyl acetate and hexane (1:2), an analytical sample with a melting point of 90 to 91 °C was obtained. Analysis: for C20H23O3N calculated:

73.82% C, 7.12% H, 4.30% N, found:

73.60% C, 7.09% H, 4.26% N. m/e = 325 (m ⁺ ).

⁴ H NMR (60 MHz) δ ™£ _]3 (Ppm):

12.58 (s, 1H, —OH),

7.21 (s, 5H, C6H5),

5.74 (d, J = 2.5 Hz, 1H, meta-hydrogen),

5.5 (d, J = 2.5 Hz, 1H, meta-hydrogen),

4.36 (ss, 1H, NH),

3.33 to 4.08 (m, 3H, —O—CH2, —CH—N),

2.29 to 2.83 (m, 4H, — CH2— C=,

CeHs—CHz),

1.51 to 1.92 (m, 4H, — (CH2)z,

1.23 (d, 3H, CH3).

In an analogous manner, alkylation of d-5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline with d-2-octyl methanesulfonate yields d-5-hydroxy-2-methyl-7-[2-(R)-octyloxy]-4-oxo-1,2,3,4-tetrahydroquinoline with a melting point of 64 to 68 °C.

[«Id ²⁵ = +110.2° (c = 1.0, chloroform), and by alkylation of d,l-5,7-dihydroxy-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline with d,l-5-phenyl-2-pentanol mesylate d,l-4-hydroxy-7-(5241464

-phenyl-2-pentyloxy)-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline, m/e == 367 (m ⁺ ).

Example 20 d,1-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline

To sodium hydride (72 g, 3.0 mol, obtained by washing 144 g of 50% sodium hydride three times with 500 ml of hexane) was added dropwise, with vigorous stirring, a solution of 195 g (ca. 0.58 mol) of d,1-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline in 1140 g (14.6 mol) of ethyl formate. After approximately 1.5 hours, when 2/3 of the ethyl formate solution had been added, the addition was stopped to allow the strong foaming to subside. 600 ml of diethyl ether was added and the mixture was stirred for 15 minutes before the remaining ethyl formate solution was added. After the addition is complete, 600 ml of diethyl ether are added, the reaction mixture is stirred for a further 10 minutes and then poured into 2 litres of ice-water. After acidification with 10% hydrochloric acid to pH 1, the phases are separated and the aqueous phase is extracted twice with 2 litres of ethyl acetate. The organic solutions are combined, washed successively, first twice with 2 litres of water and then once with 1 litre of sodium chloride solution, and dried over magnesium sulphate. After evaporation, 231 g of a reddish-brown oily product are obtained, which is used without ^further purification.

R _f = 0.1 to 0.5 (thin layer silica gel plates, mixture of equal parts benzene and ether as solvent system).

In an analogous manner, d,1-5-hydroxy-7-[5-phenyl-2-pentyloxy)-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline is converted to d,1-formyl-5-hydroxy-3-hydroxymethylene-7-(5-phenyl-2-pentyloxy]-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline, which is used in the following examples without any further work-up.

Example 21 d,1-1-Formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline

To 18.2 (0.38 mol) of sodium hydride (obtained by washing a 50% dispersion of sodium hydride in mineral oil with pentane) was added dropwise a solution of 11.1 g (0.038 mol) of d,1-5-hydroxy-2-methyl-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline in 110 g (1.48 mol) of ethyl formate over a period of 0.5 hour, resulting in an exothermic reaction accompanied by violent evolution of hydrogen and the formation of a yellow precipitate. The reaction mixture was cooled, 750 ml of ether was added, the resulting mixture was heated to reflux with stirring for 3 hours, then cooled to 0°C and neutralized by adding 400 ml of 1 N hydrochloric acid. The ether layer was separated and the aqueous phase was extracted twice. each with 150 ml of ether. The ethereal extracts are combined, washed successively with twice 100 ml of saturated sodium bicarbonate solution and once with 150 ml of sodium chloride solution, dried over magnesium sulfate and evaporated to give 10.8 g of an orange foamy product. A further 2.3 g of product is obtained by acidifying the sodium bicarbonate solutions from the washings with concentrated hydrochloric acid and subsequently extracting the acidic solution with twice 100 ml of ether. The ethereal extracts are then combined, dried and concentrated to give 2.3 g of product. The total yield is

13.1 g. The product is used for the next reaction without any further work-up.

1H NMR (60 MHz) β (ppm):

12.27 (br, 1H, ArOH),

8.8 to 11.9 (m, 1H, -COH),

8.73 (s, 1H, N—CHO),

7.41 (s, 1H, =CH),

6.32 (s, 2H, aromatic hydrogens),

5.52 (q, 1H, —CH—N),

4.18 to 4.77 (rn, 1H, —O—CH),

0.6 to 2.08 (m, 17H, CHs—C—CsHii and

CH3—C—N).

In an analogous manner, d,1-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline is converted to d,1-1-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline, 1H NMR (60 MHz) $ (PPm):

12.22 (br, 1H, ArOH),

8.8 to 11.6 (1H, =COH),

8.64 (s, 1H, —CHO),

7.21 (ss, shoulder at 7.30, 6H, aromatic hydrogens and =CH),

6.23 and 6.17 (two doublets of 1H, J = 2 Hz, meta-hydrogens),

5.42 (mq, 1H, N—CH1,

4.18 to 4.70 (m, 1H, —OCH),

2.4 to 3.0 (m, 2H, Ar—CHs.),

1.53 to 2.0 [m, 4H, — (CH2) ₂ —),

1.29 (overlapping doublets, 6H,

CHs—C—N and CHs—C—Q.

In an analogous manner, d,1-5-hydroxy-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline is converted into d,1-1-formyl-5-hydroxy-3-hydroxymethyl-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline in the form of an oil,

1H NMR (60 MHz) S (PPm):

12.1 (ss, 1H, phenolic hydrogen),

8.8 (s, 1H, -N-CHO),

8.1 (s, 1H),

7.3 (s, 1H),

6.1 (s, 2H, aromatic hydrogens),

4.5 (ss, 2H, — CH2—),

4.2 to 4.8 (m, —O—CH2—),

2.0 to 0.7 (remaining protons).

In an analogous manner, d,l-5-hydroxy-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline is converted to d,l-1-formyl-5-hydroxy-3-hydroxymethylene-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline, *H NMR (60 MHz) δ (PPm):

12.4 (ss, 1H, phenolic hydrogen),

8.5 (s, 1H, CHO),

7.2 (m, 6H, aromatic hydrogens and =CH—),

6.2 (m, 2H, aromatic hydrogens),

4.5 (s, 2H, —CH2—),

4.4 (m, 1H, —CH—CH3),

2.6 (Sh, 2H, —CHa—),

1.7 (m, 5H, remaining protons),

1.3 (d, 3H, — CH—CH?, J = 6 Hz).

In an analogous manner, d,1-5-hydroxy-2-methyl-7-(4-phenylbutyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline is also converted into d,1-1-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7-(4-phenylbutyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline melting after crystallization from hexane at 132 to 135 °C. After recrystallization from hot methanol, an analytical sample melting at 131 to 132 °C is obtained.

Analysis: for < C22H23O5N calculated:

69.27% C, 6.08% H, 3.67% N, found:

69.25% C, 5.88% H, 3.88% N. m/e = 381 (m ⁺ ), % NMR (60 MHz) δ ™ _c ^s l3 (PPm):

OH

FROM

12.4 to 13.6 (m, 1H, = ),

12.26 (s, 1H, 5-OH),

8.62 [s, 1H, — C(=O) —H],

H

From about 7.18 to 7.48 (m, 1H, = ),

7.27 (s, 5H, CsHs),

6.26 (ss, 2H, meta-hydrogens),

5.46 (q, 1H, CH—N),

3.82 to 4.23 (m, 3H, —CH2—OJ,

2.49 to 2.80 (m, 3H, ArCH2),

1.67 to 2.02 [m, 4H, — (CH 2 ) 2 ),

1.27 (d, 3H, CH3).

Example 22 d, 1-1-formyl-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline

To a solution of 229 g (ca. 0.58 mol) of d,1-1-formyl-3-hydroxymethylene-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline in 880 ml of methanol, 27.2 ml of triethylamine were added under nitrogen atmosphere with stirring, then 97.0 ml of methyl vinyl ketone were added and the mixture was stirred overnight at room temperature.

After this time, the reaction is complete and the reaction mixture is formed by a mixture of the title compound and d,l-l,3-diformyl-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline. The following actions are performed to convert the diformyl derivative to the title compound:

The reaction mixture is diluted with 6 liters of water, washed successively four times with 1700 ml of 10% aqueous sodium carbonate solution and once with 2 liters of sodium chloride solution, and dried over magnesium sulfate. The solution is concentrated to give 238 g of a reddish-brown oily residue, which is dissolved in 1920 ml of methanol. The solution is cooled to 0°C, 21.2 g of potassium carbonate are added, the mixture is stirred at 0°C for 3 hours, after which 18.7 g of acetic acid are added. The methanol is evaporated under reduced pressure and the oily residue is stirred with 2 liters of water and 2 liters of ethyl acetate for 10 minutes. The aqueous phase is separated, extracted once with 2 liters of ethyl acetate, the combined ethyl acetate solutions are washed twice with 2 liters of water and once with 2 liters of sodium chloride solution, and dried over magnesium sulfate. Concentration under reduced pressure and chromatography of the concentrate on 1.8 kilograms of silica gel give 15.9 g of the title compound.

m/e = 437 (m ⁺ ), % NMR (60 MHz] 5 CDCl 3 (Ppm):

12.7 (s, 1H, OH),

8.78 (ss, 1H, —CHO),

7.22 (s, 5H, aromatic hydrogens),

6.22 (ss, 2H, meta-hydrogens),

2.12, 2.07 (s, 3H, —CHs—CO—),

1.31 (d, 3H, — CHs—C—O—),

1.57 to 5.23 (m, 13H, remaining protons).

By analogous treatment of 35 g (0.09 mol) of d,1-1-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7-(4-phenylbutyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline, 22.7 g (60%) of d,1-1-formyl-5-hydroxy-2-methyl-7-(4-phenylbutyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline with a melting point of 101 to 103 °C is obtained. After recrystallization from methanol, an analytical sample melting at 104 to 105 °C is obtained.

Analysis: for CžsHžsOsN calculated:

70.90% C, 6.90% H, 3.31% N, found:

70, 77% C, 6.81% H, 3.46% N.

H1 NMR (60 MHz) δ™®, ₃ (PPm):

12.88 (s, 1H, —OH),

9.08 (ss, 1H, —CHO),

7.29 (s, 5H, C 5 H 5 ),

6.25 (ss, 2H, meta-hydrogens),

4.88 to 5.43 (m, 1H, -CHN),

3.86 to 4.21 (m, 2H, — CHs—O—), ca. 2.49 to 3.02 [m, 7H, ArCHz, _(CH2)2-Cp=O)-, - CH—C(=O) ],

2.18 [s, 3H, CH3—C(=O)],

1.68 to 2.03 [m, 4H, —(CH2J2— ],

1.13 (d, 3H, CHs). m/e = 423 (m+).

Similarly, from d,1-1-formyl-5-hydroxy-3-hydroxymethylene-7-(5-phenyl-2-pentyloxy)-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline, d,1-1-formyl-5-hydroxy-7-(5-phenyl-2-pentyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline is obtained, which is used as such.

Example 23 d-,1-1-formyl-5-hydroxy-2-methyl-7-(2-heptyloxy)-4-oxo'-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline and d,1-1,3-diformyl-5-hydroxy-2-methyl-7-(2-heptyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline • To a solution of 13.1 g (37.7 mmol) of d,1-5-hydroxy-3-hydroxymethylene-2-methyl-7-(2-heptyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline in 56 ml of methanol and 5.52 mg (68 mmol) of methyl vinyl ketone was added 1.3 ml (9.3 mmol) of triethylamine. The mixture was stirred for 18 hours at under nitrogen atmosphere at room temperature, then diluted with 550 ml of ether. The solution is washed first four times with 60 ml of 10% aqueous sodium hydrogen carbonate solution and then once with 100 ml of sodium chloride solution, dried with magnesium sulfate and the ether is evaporated. 16 g of a dark oily residue are obtained, which is dissolved in a minimum volume of benzene and the solution is applied to a 500 g silica gel column. The column is washed with the same volume of benzene as the volume of the column, then elution is carried out with 15% ether in benzene. As soon as the first colored band begins to elute from the column, 100 ml fractions are taken. Fractions 5 to 13 are combined and concentrated under reduced pressure to give 8.7 g of a yellow oily product. d,1-1,3-diformyl-5-hydroxy-2-methyl-7-(2-heptyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline.

The column is further eluted with 15% ether in benzene. Fractions 19 to 37 are combined and concentrated under reduced pressure to give

4.6 g of oily d,1-1-formyl-5-hydroxy-2-methyl-7-(2-heptyloxy)-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline. Another monoformylated product is obtained as follows:

g of the diformylated derivative is stirred with 200 mg of potassium carbonate in 25 ml of methanol for 2 hours at 0 °C, after which the solvent is evaporated in vacuo and the residue is suspended in ether. The suspension is filtered, the filtrate is concentrated and the residue is partitioned between ether and water. The organic layer is separated, the aqueous phase is acidified with 10% hydrochloric acid and extracted with ether. The combined ether extracts are washed successively with saturated sodium bicarbonate solution and sodium chloride solution, dried over magnesium sulfate and evaporated after filtration to give another monoformyl derivative.

The monoformyl derivative has the following NMR spectrum:

^J H NMR (60 MHz) á ™ _c ^s l3 (ppm):

12.73 (s, 1H, ArOH),

8.87 (s, 1H, N—CHO),

6.12 (s, 2H, aromatic hydrogens),

4.78 to 5.50 (m, 1H, N—CH),

4.11 to 4.72 (m. 1H, —O—CH),

2.21 [s, 3H, CH3—C(=O)—],

0.63 to 3.12 (m, 22H, remaining hydrogens).

In an analogous manner, the following compounds are prepared from the appropriate reactants:

d,l-l-formyl-5-hydroxy-7 (2-heptyloxy) -4-ΟΧΟ-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline in the form of an oil,

Ή NMR (60 MHz) (PPm):

12.8 (s, 1H, phenolic hydrogen),

8.7 (s, 1H, N-CHO),

6.1 (s, 2H, aromatic hydrogens),

4.1 to 4.6 (m, 1H, —O—CH),

4.1 (d, 2H, J = 5 Hz, —CHž—j,

2.3 to 3.0 [m, 3H, CH2 and CH—(=C)J,

2.2 [s, 3H, —C(=O)—CH3],

2.3 to 0.7 (remaining protons), d,ll-formyl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy j ~4-oxo-3- (3-oxobutyl j -1,2,3,4'tetrahydroquinoline, ^X H NMR (60 MHz) δ ™j _l3 (ppm):

12.68 (s, 1H, —OH),

8.82 [ss, 1H, — C(O)H),

7.20 (Ss, 5H, CsHs,

6.18 (ss, 2H, aromatic hydrogens),

4.78 to 5.34 (m, 1H, —N—CH),

4.18 to 4.68 (m, 1H, —O—CH),

2.17 [s, 3H, -C(O)CH ₃ ],

1.30 (d, 3H, —O—C—CH 3 ),

1.12 (d, 3H, — N—C—CHs),

1.4 to 3.1 (m, 11H, remaining hydrogens), d,11formyl-5-hydroxy-7-(5-phenyl-2-pentyloxy-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline, m/e = 423 (m ⁺ ).

In all these preparations, the corresponding 1,3-diformyl derivative is always obtained as a by-product.

Example 24 d, 1-5,6,6a,7-tetrahydro-1-hydroxy-6 H -methyl-3-(5-phenyl-2-pentyloxy)benzo[c]quinolin-9(8H)-one

A solution of 174 g (0.398 mol) of d,1-1-formyl-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline in 5.9 liters of .2 N methanolic potassium hydroxide and 5.9 liters of methanol was heated to reflux under nitrogen overnight with stirring, the resulting solution was then cooled and 708 g of acetic acid was added dropwise to it over 15 minutes with stirring. The solution obtained was concentrated on a rotary evaporator under water pump vacuum to a semi-solid residue, which was filtered and washed first with water to remove potassium acetate and then with ethyl acetate until all traces of black tarry material were removed. 68 g (44%) of a yellow solid with a melting point of 188-190° C. are obtained. Recrystallization from hot ethyl acetate gives the pure product with a melting point of 194-195° C.

m/e = 391 (m ⁺ ).

Analysis: for C25H29O3N calculated:

76.09% C, 7.47% H, 3.58% N, found:

76.43% C, 7.48% H, 3.58% N.

¹ H NMR (60 MHz] <$™ ^with [100 mg dissolved in 0.3 ml CD3OD and 0.3 ml CD3S(O)CD3] (PPm):

7.21 (s, 5H, aromatic hydrogens),

5.80 (s, 2H, meta-hydrogens),

1.20 (d, 6H, CH3—CHO and CH3—CH—N).

After evaporation of the mother liquors, a small amount of the corresponding axial methyl derivative is obtained, which is purified by chromatography on a silica gel column using a mixture of equal parts of benzene and ether as eluent. After evaporation of the aluate and recrystallization of the residue from a mixture of ether and hexane (1:1), an analytically pure product is obtained, melting at 225-228 °C.

The Rf value of this material by thin layer chromatography on silica gel using 2.5% methanol in ether as the solvent system (detection by permanent blue) is 0.34. The θβ-methyl derivative has _Rf = 0.41. m/e = 391 (m ⁺ ).

¹ H NMR (60 MHz) ó ^TMS [100 mg dissolved in 0.3 ml CD3OD and 0.3 ml CD5S(Ó)CD3] (PPm):

7.19 (s, 5H, aromatic hydrogens),

5.75 (s, 2H, meta-hydrogens),

1.21 (d, 3H, CH 3 -CHO -),

0.95 (d, 3H, CH3—CH—N).

By analogous treatment of 22 g of d,1-1-formyl-5-hydroxy-2-methyl-7-(4-phenylbutoxy)-4-OXO-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline, 17.1 g (87%) of d,1-5,6,6a,7-tetrahydro-1-hydroxy-6jS-methyl-3-(4-phenylbutyloxy)benzo[c]quinolin-9(8H)-one with a melting point of 222 to 224°C was obtained. An analytical sample of the product was obtained by recrystallization from methanol and melted at 224 to 225°C. Analysis: for C214H27Q3N calculated:

76.36% C, 7.21% H, 3.71% N, found:

76.03 1% C, 7.08 0/0 H, 3.68% N.

^X H NMR (60 MHz) [mixture (CD3SO and CD3OD in a ratio of 1:1) (ppm):

1.24 (d, 3H, 6,/3-CH ₃ ), m/e = 377 (m ⁺ ).

Evaporation of the mother liquors yields 2.8 grams of product melting at 185 to 195 °C, which, according to NMR spectroscopy, consists of a mixture of 6/3-methyl derivative (approx. 40%) and d,l-5,6,6a,7-tetrahydro-1-hydroxy-6a-ethyl-3-(4-phenylbutyloxy)benzo[c]quinolin-9(8H)-one, *H NMR (60 MHz) [mixture of (CD3)2SO and CĎ3OD in a ratio of 1:1] (ppm):

1.24 (d, 1.2H, 6/3-CH 5 ),

0.95 (d, 1.8H, 6af-CH3).

Example 25 d,1-5,6,6a,7-tetrahydro-1-hydroxy-6/3-methyl-3-(2-heptyloxy)benzo[c]quinolin-9[8H)-one To a solution of 4.5 g (11.5 mmol) d,1-1-formyl-5-hydroxy-2-methyl-7-(2-heptyloxy)-4-oxo-3-(3-oxobutyl)-1,2,3,4-tetrahydroquinoline in 150 ml. of methanol was added 150 ml. of 2 N methanolic potassium hydroxide solution. The mixture was stirred for 1 hour at room temperature, then heated to reflux under nitrogen for 20 hours. The dark red reaction mixture was allowed to cool to room temperature, neutralized with acetic acid and concentrated under reduced pressure to a volume of about 100 ml. The concentrate is diluted with 400 ml of water, the separated brownish-red solid material is filtered off and, after washing with water, dried. 6 g of crude product are obtained, which are triturated first with ether and then with methanol. After filtration and drying, 1.96 g of product with a melting point of 223-229 °C are obtained, which, after recrystallization from hot methanol, gives a crystalline product melting at 235-237 °C.

Analysis: for C21H29O3N calculated:

73.43% C, 8.5.1% H, 4.08% N, found:

73.22% C, 8.30% B> 4.11 ψο N,

Additional material was obtained by evaporating all the mother liquors and the aqueous solution from which the brownish-red crude product was isolated was extracted with chloroform and the extract was evaporated. The two residues were combined and purified by column chromatography on silica gel using ether as eluent.

In an analogous manner, the following compounds are obtained from the appropriate reactants:

d-1-5,6,6a,7-tetrahydro-1-hydroxy-3-(5-phenyl-2-pentyloxy)benzo[c]quinolin-9(8H)-one melting after recrystallization from chloroform at 170-173 °C, m/e = 377 (m ⁺ ).

Analysis: for C24H27O3N calculated:

76.36% C, 7.21% H, 3.71 θ/ο N, found:

76.38% C, 7.21% H, 3.85% N.

d,1-5,6,6a,7-tetrahydro-1-hydroxy-3-(2-heptyloxy)benzo[c1quinolin-9(8H)-one, melting point 208-209°C, m/e = 329 (m+j.

‘Analysis: for C20H27O3N calculated:

72.92% C, 8.26% H, 4.25% N, found: ’

72.92% C, 8.31% H, 4.42% N.

d,1-5,6,6a,7-tetrahydro-1-hydroxy-3-(5-phenyl-2-pentyloxy)-6,6-propylbenzo[c]quinolin-9(8H)-one with a melting point of 164 to 166° Celsius,

Analysis: for C27H33O5N calculated:

77.29% C, 7.93% H, 3.34% N, found:

76.97% C, 7.98% H, 3.41% N.

1-5,6,6a,7-tetrahydro-1-hydroxy-3-(5-phenyl-2-pentyloxy)-6/2-methylbenzo[cymolin-9(8H)-one, melting point 176-178° Celsius, [α] _D ²⁵ = -416.0° (c = 0.33, methanol), m/e = 391 (m+).

Analysis: for C25-H29O3N calculated:

76.69 θ/ο C, 7.47 O/o H, 3.58 θ/ο N, found:

76.32% C, 7.36% H, 3.33 θ/ο N.

d-5,6,6a,7-tetrahydro-1-hydroxy-3-(5-phenyl-2-pentyloxy)-6^-methylbenzo[c]quinolin-9(8H)-one with melting point 172 to 174° Celsius, [qs]d ²⁵ = +412.9° (c = 1.0, methanol), m/e = 391 (m+).

Analysis: for C25H23O3N vvRead:

76.69 C, _7.47 H, 3.58% N, found:

76.40% C, 7.39% H, 3.51% N.

In an analogous manner, the compounds summarized in the following overview are prepared:

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b) d-enantiomer; [a]o ²⁵ = +412.9° (c = 1.0, methanol)

Entry 1 and d 26 d,1-5,6,6a,7-tetrahydro-1-acetoxy-6i/3-methyl-3-(5-phenyl-2-pentyloxy)benzo[c]quinolin-9-(8H)-one

To a solution of 4.5 g (0.0115 mol) of d,1-5,6,6a,7-tetrahydro-1-hydroxy- _6-1 -methyl-3-(5-phenyl-2-pentyloxy)benzo[c]quinolin-9(8H)-one in 45 ml of pyridine at room temperature with stirring was added 45 ml of acetic anhydride, the resulting solution was stirred for 3.5 hours and then poured into 250 ml of ice-water. The mixture was extracted twice with 250 ml of diisopropyl ether, the combined extracts were washed three times with 200 ml of water, dried over magnesium sulfate and evaporated under reduced pressure to a yellow-brown oily residue, which solidified upon scratching the walls of the container with a glass rod. Trituration of the solid material with n-heptane gave 2.0 g (40% yield) of the 1-acetoxy derivative, which, after purification by recrystallization from a mixture of hot chloroform and n-hexane (1:4), gave the pure ester with a melting point of 138-140 ^° C. m/e = 433 (m+j.

^X H NMR (60 MHz) S ™* ₃ (ppm):

7.21 (broad s, 5H, aromatic protons],

6.62 (d, J = 1.5 Hz, IH, C=C—H],

5.97 (d, J=3 Hz, 1H, meta-H,

5.86 (d, J=3 Hz, 1H, meta-H),

2.27 [s, 3H, CH 3 —C(=O) j,

1.21 (d, J = 7 Hz, 6Ή, CH3—C—N, —CHs—C—O),

1.49—4.51 (m, 14H, remaining protons).

Claims (1)

Process for the preparation of the novel benzo [c] quinolines of the general formula III R 1 represents a hydrogen atom or an acetyl group, R1 represents a hydrogen atom, a (C1-C6) alkyl group or a - (CH2) _Z- C6H5 radical in which z is a number of 1 or 2, R 5 represents a hydrogen atom, a methyl or ethyl group of the invention Z represents an alkylene group or an alkyleneoxy group having 1 to 9 carbon atoms and W represents a hydrogen atom or a phenyl group, characterized in that it is a compound of the general formula in which R 1, R 1, R 5, Z and W are as defined in formula III and R 7 represents a hydrogen atom or a formyl group, acting with an inorganic base.