KR820001353B1 - Process for preparation of benzo(c)quinolines - Google Patents

Abstract

Title compds. (I; R1 = H, benzyl, benzoyl, C1-5 alkanoyl; R4 = H, C1-6 alkyl; R5 = H, methyl, ethyl; R6 = H, carbobenzyloxy, formyl, C2-5 alkanoyl, C1-6 alkyl; Z = C1-9 alkylene; W = H, methyl, pyridyl, piperidyl), useful as analgesics, were prepd. by the reraction of II and metal hydride. Thus, 1.10 g 3-[(3,5-dimethoxy-N-ethoxycarbonyl)anilino -propionic acid and 4 g polyphosphoric acid were reacted at 65≰C for 45 min in N2 gas to give 645 mg 1-carbethoxy-5,7-dimethoxy-4-oxo-1,2,3,4-tetrahydroquinoline.

Description

Method for preparing benzo [C] quinoline

The present invention relates to several benzo [C] quinolines, especially 1,9-dihydroxyoctahydrobenzo [C], which are useful as CNS agents, in particular analgesics and sedatives, mammalian relaxers, glaucoma agents, and diuretics. Quinoline, 1-hydrocyhexahydrobenzo [C] quinolin-9 (8H) -one, and 1-hydroxytetrahydrobenzo [C] quinoline and the like and derivatives and intermediates thereof; It is about.

The above-mentioned active compounds and intermediate products include compounds represented by the following structural formulas.

Also selected from ketal and thioketal containing 2-4 carbon atoms in the ketal group in the compound of A-valent (III ') and pharmacologically acceptable acid addition salts of compounds of A- or (II'), -0-alkylene-0- is alkylenedioxy containing 2-4 carbon atoms, and some of the compounds may be described by the structural formulas (I) to (X) shown below.

Another acceptable nomenclature for compounds represented by the formulas (I)-(IV) is to replace "benzo [C] quinoline" with "phenanthridine". Thus, d, l-trans-5,6,6aβ, 7,8, 9,10,10aα-octahydro-1-acetoxy-9β-hydroxy-6β-methyl-3 (5-phenyl-2-pantyl Roxy) benzo [C] quanoline is d, l-trans-5,6,6aβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9β-6β-methyl-3 (5-phenyl 2-tenthyloxy) phenanthridine.

While there are a number of painkillers available today, the search continues for new and improved drugs, which point to the fact that there are no drugs that are useful for relieving a wide range of pain and have minimal side effects. Aspirin, the most widely used drug, is known to be effective in eliminating extreme pain and to exhibit a number of undesirable side effects. More potent analgesics, d-fgopoxifen, codeine and morphine, are addictive. Thus, the need for improved and strong analgesics is obvious.

테트라하이드로 칸나비놀

및 그 주된 대사 물질인 11-하이드록시-

등의 진통제적 특성은 잘 알려져 있다. 9번 위치에 옥소, 하이드로카아빌, 하이드록시, 클로로, 하이드로카아빌리덴 등의 치환기를 갖는 여러 가지 1-하이드록시-3-알킬-6H-디벤조-[b,d] 피란과 그 중간 생성물도 잘 알려져 있다.There are a variety of painkillers known in the art. 9-nor-9β-hydroxyhexahydro cannabinol and other cannabinoid structure compounds, for example

Tetrahydro cannabinol

And 11-hydroxy-, the main metabolite thereof

Analgesic properties of the back are well known. Various 1-hydroxy-3-alkyl-6H-dibenzo- [b, d] pyrans and intermediates thereof with substituents such as oxo, hydrocarbyl, hydroxy, chloro, hydrocarbylide at position 9; Also well known.

It is also known that various tetrahydro-6,6,9-trialkyl-6H-dibenzo [b, d] pyran derivatives having a ω-dialkyl amino alkoxy group at position 1 are useful as psychotherapeutic agents. 1,9-dihydroxyhexa hydrodibenzo [b, d] pyrans and several 1-acyl derivatives thereof having alkyl or alkylene groups at position 3 are used as relaxants, psychotherapeutics, sedatives and analgesics. It is also known to have the same utility as the hexahydro-9H-dibenzo [b, d] pyran-9-temperature equivalent 9-hydroxy compound, which is a preliminary compound used for the preparation.

It is known that 3-alkoxy substituted dibenzo [b, d] pyrando has antiarthritis, anti-inflammatory and central nervous effects. The pentyl group at position 3 of 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol is alkoxy (butoxy, It is also known that substitution with pentyloxy, hexyloxy, and octyloxy) results in biological inactivation. Hexyloxy derivatives show weak anesthesia at a dose of 10-20 mg / kg, while other ethers do not show any action at 20 mg / kg.

-테트라하이드로 칸나비놀의 5-아자 동족화합물은 동물 약리학에 완전히 불활성이라고 알려져 있다. 7,8,9,10-테트라하이드로-1-하이드록시-6,6,9-트리메틸-3n-펜틸페난트리딘의 5-아자

-테트라하이드로 칸나비놀의 약리적 효과도 알려져 있다. 테트라하이드로 칸나비놀 분자에 주요한 구조적 변화를 일으키면 진통제로서의 효과가 급격히 감소한다는 사실도 알려져 있다 칸나비노이드에서 그 구조와 효과와의 관계가 일반화되어 있다. 피란링에 디메틸기가 존재한다는 것은 칸나비노이드의 효과에 결정적으로 중요하며, 피란링에 있는 O를 N으로 치환하면 효과가 제거된다는 것이 그것이다.7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo [b, d] 3-substituted group of pyran-1-ol-OCH (CH ₃ ) C ₅ Comparing the case of H ₁₁ or —CH (CH ₃ ) C ₅ H ₁₁ , the compound containing the edel side chain is more central than the corresponding compound in which the alkyl side chain is attached directly to the aromatic ring without the oxygen atom in the middle. It is also known that nerve action is 50% less effective and oxygen is five times more effective than methylene substituted compounds. 7,8,9,10-tetrahydro-1-hydroxy-5,6,6,9-tetramethyl-3n-pentylphenanthridine

Tetrahydro cannabinol's 5-aza cognate is known to be completely inactive in animal pharmacology. 5-aza of 7,8,9,10-tetrahydro-1-hydroxy-6,6,9-trimethyl-3n-pentylphenanthridine

The pharmacological effects of tetrahydro cannabinol are also known. It is also known that major structural changes in tetrahydrocannabinol molecules dramatically reduce their effectiveness as analgesics. The relationship between structure and effect is common in cannabinoids. The presence of a dimethyl group in the pyran ring is critical to the effect of the cannabinoids, and the substitution of O in the pyran ring for N eliminates the effect.

Several benzo [C] quinolines, ie 1,9-dihydroxy octahydro-6H-benzo [C] quinoline (I), 1-hydroxy nuxahydro-6H-benzo [C] -quinoline-9 (8H)- ON (II) and 1-hydroxy-tetrahydroquinoline (IV) are found by the present inventors to be effective as CNS agents, especially as analgesics and sedatives, narcotic and non-addictive strainers, glaucoma and diuretics. It became. Also various derivatives and intermediates of these compounds have been identified. The above mentioned compounds and derivatives are represented by the formulas (I), (II) and (IV). Compounds of formulas (III) and (IV) are pre-step products of compounds of formulas (II) and (I).

Wherein R is selected from hydroxy, alkanoyloxy having 1-5 carbon atoms, hydroxymethyl and the like.

R ₁ is selected from hydrogen, benzyl, benzoyl, alkanoyl having 1-5 carbon atoms, -CO- (CH ₂ ) p-NR ₂ R _3, etc., where p takes a number from 0-4, R ₂ and R ₃ are individually selected from hydrogen and alkyl having 1-4 carbon atoms, and R ₂ and R ₃ and the nitrogen to which they are attached together form a ring of 5 or 6 heteroatoms, and Ferridino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having 1-4 carbon atoms in the alkyl group.

R ₄ is selected from hydrogen, alkyl having 1-6 carbon atoms, — (CH ₂ ) zC ₆ H ₅ where z is 1-4 and the like.

R ₅ is selected from hydrogen, methyl and ethyl.

R ₆ is hydrogen,-(CH ₂ ) y-carabalkoxy (where the alkoxy group has 1-4 carbon atoms and y is 0-4), carbobenzyloxy, formyl, alkanoyl having 2-5 carbon atoms , Alkyl having 1-6 carbon atoms,-(CH ₂ ) xC ₆ H ₅ , wherein x is 1-4, -CO (CH ₂ ) x _-1 -C ₆ H ₅ , and the like.

Ro is selected from oxo, methylene and alkylene dioxy having 2-4 carbon atoms.

R 'is selected from R and Ro.

z is alkylene having 1-9 carbon atoms and-(a1k ₁ ) mxx (a1k ₂ ) n- (where a1k ₁ and a1k ₂ are each alkylene having 1-9 carbon atoms, and a1k ₁ and a1k ₂ The sum of the carbon atoms included is not more than nine, m and n are each 0 or 1, and x is selected from O, S, SO and SO ₂ ).

(여기서 W₂는 수소 및

으로 부터 선택되고,a는 1-5 이며 b는 0-5이고, a와 b의 합은 5가 넘지 않음) 등으로 부터 선택된다.W is hydrogen, methyl, pyridyl, piperidyl, (Wherein W ₁ is selected from hydrogen, fluoro and chloro, etc.), and

Where W ₂ is hydrogen and

A is 1-5, b is 0-5, and the sum of a and b does not exceed 5).

Ketals of the compounds of formulas (II), (III) and (IV) have 2-4 carbon atoms in the ketal group.

The present invention also includes pharmacologically acceptable acid addition salts of the formulas (I) and (II). These representative salts include mineral salts such as hydrochloride, bromate, sulfate, nitrate and phosphate, citrate, acetate, sulfosalicylate, tartarate, glycolate, malonate, maleate, fumarate and 2-hydroxy-3- Organic acid salts such as naphthoates, pamolates, salicylates, stearates, phthalates, succinates, gluconates, mandelates, lactates, and methanesulfonates.

Compounds of formulas (I), (II) and (III) have asymmetric centers at the 6a and / or 10a positions. There may be other asymmetric centers at the 3-position substituent (-ZW) and at the 5, 6 and 6 positions. 9β-shaped diastereomeric isomers are better than 9α-type isomers because of their greater biological activity. For the same reason, the trans (6a, 10a) diastereoisomer of the compound of formula (I) is better than the cis (6a, 10a) diastereoisomer. In the compound of formula (II), when one of R ₄ and R ₅ is other than hydrogen, the cis-diastereomeric isomer has a greater biological activity and is therefore better. In the compound of formula IV, an asymmetric center is present in the substituents at the 9 and 3 positions.

Among the enantiomeric isomers of a given compound, the isomers are usually better in activity than the other isomers and racemates, and the better enantiomeric isomers are determined as follows. For example, 5,6,6aβ-7,8,9,10,10aα-octahydro-1-acetoxy-9β-hydroxy-6β-methyl-3-C5-phenyl-2-pentyloxy) benzo [C The l-enantiomers of quinoline have better analgesic effects than d-enantiomers and racemates.

For convenience, the structural formulas represent racemic compounds. However, the above structural formulas should be considered to include all racemic modifiers, diastereomeric isomeric mixtures, pure enantiomer isomers and diastereomeric isomers thereof of the compounds of the present invention. Effects of racemic mixtures, diastereomer mixtures, pure enantiomers, diastereomers thereof, and the like are determined by the following biological evaluation.

In addition, various intermediate products useful for preparing the compounds of the formulas (I), (II), (III) and (IV) have the following structure.

Wherein R ₄ , R ₅ , R ₆ and ZW are as described above, R ₇ is selected from hydrogen and formyl and Y ₁ is selected from hydrogen and hydroxy protecting groups, in particular methyl, ethyl, benzyl and the like.

In intermediates (V), (VI) and (iii), an asymmetric center may be present in the substituents at positions 2 and 7 (-Z-W) and may also be present in other positions such as substituents at 1 position. Positions 2 and 7 of the formulas (V)-(iii) correspond to positions 6 and 3 of the compounds of formulas (I), (II), (III) and (IV).

Compounds of structural formulas (I) and (II) which have a greater biological activity than other compounds are as follows.

R and Ro are as described above.

R ₁ is hydrogen or alkanoyl.

R ₅ is hydrogen, methyl or ethyl.

R ₄ and R ₆ are each hydrogen or alkyl.

Z and W are as follows.

Even better as the compound of formula (I) is that R is hydroxy and trans in the compound. As a better compound of formula (II), Ro is oxo.

Particularly preferred as compounds of the structural formulas (I) and (II) are the following cases.

R is hydroxy (only for formula (I))

R ₁ is hydrogen or acetyl.

R ₅ is hydrogen.

R ₄ methyl or propyl.

R ₆ is hydrogen, methyl or ethyl.

W is phenyl 4- or pyridyl when Z is an alkylene of 2-5 carbon atoms.

If Z is-(a1K ₁ ) mO- (a1k ₂ ) n-, where m is 0 and n is 1 and (a1k ₂ ) n is alkylene of 4-9 carbon atoms, W is hydrogen or phenyl.

If Z is an alkylene of 5-9 carbon atoms, W is hydrogen.

Or a preferred kind of intermediates of the formulas (III), (IV), (V), (VI) and (iii) is an intermediate product used to prepare the preferred compounds of formulas (I) and (II).

Compounds in which R ₆ is other than hydrogen, alkyl and-(CH ₂ ) x-C ₆ H ₅ as compounds of formulas (I) and (II) are R ₆ valent hydrogen as compounds of formulas (I) and (II). , Alkyl, or an intermediate product for producing-(CH ₂ ) xC ₆ H ₅ .

The compound of the present invention of formula (V) can be easily removed by appropriately substituted aniline, for example, 3-hydroxy-5- (ZW-substituted) -aniline or a derivative thereof to remove the 3-hydroxy group. It is produced from being protected by a group (Y ₁ ). Suitable protecting groups are those which can be removed under conditions that do not interfere with the next reaction of the 3- (protected hydroxy) -5-substituted aniline and do not cause undesirable reactions at other positions of the compound or the product prepared therefrom. . Representative protecting groups (Y ₁ ) include methyl, aryl, benzyl, substituted benzyl (where the substituent is alkyl of 1-4 carbon atoms), halo (C1, Br, F, 1) and alkoxy of 1-4 carbon atoms, etc. .

The importance of the protecting group can serve the function as described above, so the exact chemical structure of the protecting group is not critical to the invention.

Selecting and confirming suitable protectors is readily available to those skilled in the art. The suitability and effect of any group as a hydroxy protecting group is determined by using such groups in the reaction sequence described above. Therefore, such groups should be easily removable to regenerate hydroxyl groups. Methyl groups are good as protective alkyl groups because they are easily removed by treatment with pyridine hydrochloride. Benzyl groups are also good protecting groups, which are removed by catalytic hydrogenolysis or acid hydrolysis.

When Z is-(a1k ₁ ) mX- (a1k ₂ ) n-, it is preferred that Y ₁ is a benzyl or substituted benzyl group, which can be removed later without damaging the Z group.

The protective aniline derivative is converted into a compound of formula (VII) by a known method described later.

The summarized reaction sequence for preparing the representative compound of formula (V) from 5- (protected hydroxy) -5- (ZW-substituted) aniline in which -ZW is OCH ₃ is shown in the following flowchart A It is.

In process A above, Ro is an alkyl of 1-6 carbon atoms. R ₅ is represented by hydrogen for purposes of illustration in the overall process diagram. However, R ₅ may be hydrogen, methyl, or ethyl in the course of (i) → (i) or (i) → (V-B).

The 5-substituted group of formula (VII) can be the desired -ZW group in the compound of formula (II) or (I) or a group which can be easily converted to this group. If Z in the -ZW group is-(a1k ₁ ) mX- (a1k ₂ ) n-, where X is O or S and m and n are each 0, then the 5-substituent is -XH ( For example OH or SH) or a protective-XH group of the formula -XY ₁ (Y ₁ is as described above). When -ZW is-(a1k ₁ ) mX- (a1k ₂ ) nW, where m is 1, n is 0 and W is hydrogen, the 5-substituent is-(a1k ₁ ) mXH. The -XH group is advantageously protected in the manner described above.

The aforementioned 3-hydroxy-5-substituted aniline is a 3-hydroxy group (and, if present, a 5-hydroxy) group, in the form of a derivative protected by the method described above, in the presence of acetic acid alkyl β-ketoester such as alkyl It is preferable to react with acetoacetate, thereby producing a satisfactory reaction to prepare a corresponding β-[(3-protected hydroxy) -5-substituted anilino] -β- (R ₄ ) -acrylate. do.

This reaction is usually carried out in a reaction inert solvent such as benzene or toluene, between 50 ° C. and the reflux temperature of the solvent, under conditions in which the byproduct moisture can be removed. Benzene and toluene can be used to remove a byproduct of water azeotropically, making it a useful solvent when the reaction is carried out at reflux. Other solvents capable of azeotropically removing water may be used, or other water removal methods such as molecular sieves may also be used.

Good protecting groups for the 3-hydroxy-5-substituted aniline reactants include methyl, ethyl and benzyl groups, and these ethers are readily prepared and the yields of the compounds of formulas (VII) and (VII) are satisfactory and convenient. Is removed.

In particular, alkyl β-ketoesters having alkyl groups of 1-6 carbon atoms are usually used in excess so that the aniline reactant is converted to the corresponding alkyl β-anilino-β- (R ₄ ) -acrylate in maximum. 10-20% excess alkyl β-ketoester is usually sufficient to achieve a satisfactory conversion. The use of acetic acid in catalytic amounts facilitates the reaction.

Ilky-β-anilino-β- (R ₄ ) -acrylates are for example sodium borohydride-acetic acid and the corresponding alkyl-3-[(3-protected hydroxy) -5 by catalytic hydrogenation. -Substituted anilino] -3- (R ₄ ) -propionate. Platinum dioxide is a preferred catalyst because it allows this reaction to be carried out at low pressures, for example at pressures below 50 p.si. When the hydrogen pressure is in the range of atmospheric pressure to superatmospheric pressure, such as 2000 p.si, noble metals such as platinum, palladium rhodium and the like can be used as catalysts in the indicated or unsupported state. In addition to these heterogeneous catalysts, it is also possible to use homogeneous catalysts such as Wilkinson's catalyst, ie tris (triphenyl phosphine) chlorodium (I).

Of course, if the protecting group is benzyl or substituted benzyl, these groups are removed by catalytic hydrogenation. For this reason, methyl or ethyl groups are preferred as protecting groups for the 3- and / or 5-hydroxy groups of the reactants of formula (VII).

The compound of formula _IV can also be prepared directly by reacting the compound of formula _IV with alkyl 3,3-R ₄ R ₅ -acrylate in acetic acid. This reaction can be carried out by reacting an equimolar amount of alkyl 3,3-R ₄ R ₅ -acrylate and di-substituted hanilline in 0.1-2 equivalents of glacial acetic acid at a temperature of 0 ° C reflux temperature.

The compound of formula (V-B) can be prepared directly by condensing the compound of formula (VII) with equimolar flavor and a suitable substituted acrylic acid (R ₄ R ₅ C = CH-COOH) in pyridine hydrochloride at 150 ° -200 ° C. have.

When both R ₄ and R ₅ are alkyl groups, the compound of formula (III) and alkyl R ₄ R ₅ acrylate are treated with mercury acetate in a reaction inert solvent such as tetrahydrofuran, followed by sodium borohydride. When reduced, it becomes a compound of the structural formula (VII).

By treating 3,5- (unprotected hydroxy) -aniline hydrochloride with excess alkyl acetoacetate, such as ethyl acetoacetate, in the presence of sodium cyanoborohydride in a solvent such as methanol, the compound of formula Direct conversion to the compound of iii).

Alkyl 3-anilino-3- (R4) -propionate is a suitable cyclizing agent such as polyphosphoric acid (PPA), hydrogen bromide-acetic acid, sulfuric acid, fuming sulfuric acid, hydrogen fluoride, trifluoroacetic acid, phosphoric acid- Corresponding ring-shaped compounds 2- (R ₄ ) -quinoline-4- are made of the structural formulas (V-A) and (V-B) using formic acid and other known cyclizing agents.

In one modification of this conversion, the alkyl 3-anilino-3- (R ₄ ) propionate can be converted to the corresponding acid, for example by saponification of the ester, and then acidified.

The ether protecting or blocking group of 3- (and 5-) hydroxy can be removed when cyclization occurs by using bromic acid in acetic acid as the cyclizing agent and blocking agent. 48% aqueous solution of methacrylic acid is commonly used because it satisfies cyclization and blocking breakage. This reaction is carried out at high temperature, preferably at reflux temperature. However, when Z is-(a1k ₁ ) mX- (a1k ₂ ) n-, a cyclizing agent such as polyphosphoric acid or trifluoroacetic acid should be used to avoid cleavage of the bonds of ether or thioether.

The protecting group can also be removed after the cyclization reaction. Bromic acid-acetic acid is also good as a blocking agent at this stage. This reaction is carried out as described above.

Other reagents such as iodide, pyridine hydrochloride or bromate can be used to remove protective ether groups such as methyl and ethyl groups. If the protecting group is a benzyl or benzyl group, it can be removed by catalytic hydrogenolysis. Suitable catalysts include palladium or platinum, especially those coated with carbon. In addition, these protecting groups can also be removed by solvolysis using trifluoroacetic acid. If -Z-W contains sulfur, of course, benzyl removal by acid rather than catalytic benzyl removal is used.

The method of converting the compound of formula (VII) to the compound of formula (IV), which satisfies the yield and can be carried out under relatively mild conditions, reacts the compound of formula (IV) with a suitable alkyl or benzyl chloroformate. In this case, the N-carabalkoxy group is converted into an N-carabalkoxy derivative having 2-5 carbon atoms. The N-carabalkoxy or carbobenzyloxy derivatives of formula (VIII) are then cyclized to polyphosphoric acid to form N-carabalkoxy or carbobenzyloxy derivatives of the corresponding compound of formula (V). The N-substituted derivatives of the compounds of the formula (V) are hydrolyzed as desired, corresponding to 3-[(N-substituted) -3- (protected hydroxy) -5-substituted alinino) -3 prior to cyclization. It can be made from-(R4) -propionic acid. Polyphosphoric acid generally results in maximum cyclization and is therefore a preferred cyclizing agent.

The compound of formula (V) wherein the hydroxy group is protected and the nitrogen atom is substituted with carbalkoxy becomes a compound of formula (V-A) when treated with bromic acid-acetic acid. If the hydroxy protecting group is benzyl or substituted benzyl, the hydroxy group is regenerated by catalytic hydrogenolysis. If a carb alkoxy group is present at the nitrogen atom it is not changed by this reaction. This can be removed later by treatment with bromic acid-acetic acid or any of a variety of acids or bases as desired. Treatment of the benzyl protecting group with trifluoroacetic acid also removes any N-carab alkoxy groups present.

The -ZW substituent of the compound of formula (V) is -XH (X = O or S) and -X- (a ₁ k ₂ ) nW where X is a -ZW substituent in the compound of formula (II) or (I) Is O, S, SO or SO ₂ , and W is as described above), at this point in the overall reaction sequence, the -XH group is conveniently and advantageously converted to -X- (a ₁ k ₂ ) nW. You can. Thus, the 7-XH group of formula (V-B), such as -OH, is Williamson reacted with a suitable bromate [Br (a ₁ k ₂ ) nW], mesylate, or tosylate to -O- (a ₁ k ₂ ) nW Convert to Structural Formula (V-C).

Similarly, even when the -ZW group in the formula (V) is-(a1k ₁ ) -XH, this is-(a1k ₁ ) -X- (a1k ₂ ) nW, where n is 0 or 1 and W is other than hydrogen. Conversion may be effected by the Williamson reaction at this stage of the reaction process.

In this good way of preventing nitrogen from quantizing, it is possible to use various groups, such as those belonging to the definition of R ₆ , in place of carabalkoxy or carbobenzyloxy.

If there is no R ₆ group already present in the formulas (V-A), (V-B) or (V-C), the hydroxymethylene derivative (form C1- R ₆ or Br-R ₆ reactant and reaction by, it is possible to introduce a group R _6. of course, if desired the product acyl group R _6, such as an acetyl group in the formula (ⅰ) or (ⅱ), in the reaction sequence (Figure B) The acyl group R ₆ can be introduced by forming a compound of formula (II) wherein R ₆ is hydrogen and then acylating it with a suitable acyl halide by known methods.

Structure (Ⅴ) and also the structural formula (Ⅴ-A), compounds of (Ⅴ-B) and (Ⅴ-C) has structural formula (Ⅱ) by the following reaction sequence (Figure B) and (Ⅰ) (wherein R ₅ is Hydrogen).

The quinoline of formula (V) is converted to the hydroxy methylene derivative of formula (VI) by reaction with ethyl formate and sodium hydride. This reaction is a formylation reaction, in which bis-formylated derivative (VI) is produced in good yield. Treatment of bis-formylated derivatives with methyl vinyl ketone results in a mixture of the corresponding pseudo-N-formylated Michael adducts and 1,3-bis-formylated Michael adducts. These two products are conveniently separated by column chromatography on silica gel.

The conversion of the compound of formula (VII) to the compound of formula (III) is carried out by aldol condensation of the mono-N-formyl compound of formula (VII). Aldol condensation of the 1,3-bis-formylated Michael adduct produces a spiro-annealed product (III-A) as a main product. However, the compound of formula (VII-A) can be converted to the compound of formula (VII) by treatment with 1 equivalent of potassium carbonate in methanol.

In addition to the spiro-annealing products, small amounts of the desired compounds of the formulas (III) and (V) are also produced.

Enones of formula (III) are converted to compounds of formula (II) by Birch reduction. Both cis- and trans-isomers are produced. This reduction is conveniently carried out by using lithium as the metal. Sodium or potassium can also be used. This reaction is carried out at temperatures from about -35 ° C to about -80 ° C. The reason why birch reduction is good is that the desired trans-ketone of formula (II) is produced as the main product because of its stereoselective power. If a cis-diastereomer is desired as the main product, catalytic reduction on a noble metal is preferred.

The hydroxyketones of formula (II) (R ₀ is oxo and R ₁ is hydrogen) and the dihydroxy compounds of formula (I) (R = OR ₁ -OH) appear rather unstable. If left untreated, these compounds oxidize to become purple or red. These colored by-products are also formed when the hydroxyketone undergoes sodium borohydride reduction. To prevent the formation of colored byproducts, the 1-hydroxyl group (OR ₁ ) is acylated, in particular acetylated, with acetic anhydride in pyridine and also forms acid addition salts such as hydrochloride. Acetyl derivatives are stable even in the next reaction even if left unchecked.

The colored by-products have a quinoidoid structure, and it is thought that the 1-hydroxy group (OR ₁ ) is oxidized to oxo, and a second oxo group is introduced at the 2-or 4-position. This by-product itself is also effective as a CNS agent, in particular analgesics, sedatives and relaxants, and therefore is used at the same dosage level in the same way as the compounds of formulas (I) and (II).

When the 9-oxo group of the compound of formula (II) and the acetyl wave derivative of formula (II) are reduced by the metal hydride reduction method for the reasons of the above-mentioned stability, a structural formula in which the hydroxyl group is present as an acetylated derivative in the 1-position Obtain the compound of (I). At this stage, sodium borohydride is preferred as the reducing agent, which not only gives the desired product a satisfactory yield, but also maintains the acetoxy group in the 1-position and also hydroxyl solvents (methol, ethanol, mol). This is because they react slowly enough so that they can be used as a solvent. A temperature of about 0 ° C-30 ° C is usually used. In order to increase the selectivity of the reduction, it can be used at low temperatures, such as about -70 ° C. High temperatures cause sodium borohydride to react with hydroxyl solvents and also cause deacetylation. If high temperatures are desired or required for a given reduction, use isopropyl alcohol or dimethyl ether of diethylene glycol as solvent. Preferred reducing agent is potassium tri-sec-butyl borohydride, which assists in stereo selective formation of 9α-hydroxy groups. This reduction is carried out in anhydrous tetrahydrofuran at a temperature of about −50 ° C. or less using equimolar amounts of 9-oxo compounds and reducing agents.

Lithium borohydride Reducing agents such as lithium aluminum hydride also require anhydrous conditions and hydroxyl solvents such as 1,2-dimethoxyethane, tetrahydrofuran, ether, dimethyl ether of ethylene glycol, and the like.

More preferably, the compound of formula (III), in particular when 1-hydroxy is protected with ester or benzyl ether, is converted to the compound of formula (I) by catalytic hydrogenation. A convenient way is to catalytically hydrogenate on palladium, such as palladium on carbon or other supported or unsupported precious metal.

The acetylated derivative of formula (I) thus produced is converted to the corresponding hydroxy derivative by cleaving the acetyl group in a conventional manner.

Isomers of structural formula (I), 9-α- and 9-β-hydroxy compounds, are produced in the reduction step. In the presence of a dehydrating agent such as p-toluenesulfonic acid or other acids such as oxalic acid or adipic acid, keto compounds of the formulas (II)-(IV) are suitable alkylene glycols or alkyls of 2-4 carbon atoms Treatment with lene dithiol yields the corresponding ketal or thiogtal.

The compound of formula (I) wherein R is hydroxy methyl is prepared by reacting the corresponding 9-oxo compound of formula (II) with methylenetriphenylphosphorane or other suitable methylide. This reaction is carried out under relatively mild conditions to yield the corresponding 9-methylene compound. Hydrogen boronation-oxidation of the 9-methylene compound then yields a hydroxy methyl derivative. Borane in tetrahydrofuran is preferred in this hydrogen boration step because borane is commercially available and gives the desired hydroxy methyl compound in satisfactory yield. This reaction is usually carried out in tetrahydrofuran or diethylene glycol dimethylether. The borane product is oxidized directly with alkaline hydrogen peroxide without separation to form a hydroxymethyl compound.

Compounds of formulas (I) and (II) include those wherein each of R ₄ and R ₅ is alkyl, and the following process is also made in the order of C.

The first step of the sequence is the above-mentioned enone (flow chart B) in the presence of an equivalent amount of p-toluenesulfonic acid or other acid commonly used to azeotropically remove water in benzene to form a ketal as described above. Is reacted with a suitable alkylene glycol (eg ethylene glycol) to convert to the corresponding ketal.

A mixture of two ketals is obtained. That is, formula (II-A) is in reduced form and formula (II-B) is in oxidized form. To assist in the formation of Structural Formula (IV-A), additives such as air, Pd / C, sulfur or 2,3-dichloro-5,6-dicyanobenzoquinone are added to the reaction mixture. Removal of the oxidant from the reaction mixture or addition of a reducing agent to the reaction mixture aids in the formation of formula (II-A).

Deketalization of the compounds of formulas (II-A) and (IV-A) affords the compounds of formulas (II) and (IV). These latter compounds are converted to the compounds of the formulas (I) and (IV) by the method of Process B.

The reduced compounds of formula (II-A) are oxidized (dehydrogenated) with various oxidants, including iodine, to obtain compounds of formula (IV-A).

Heterogeneous aromatic compounds of formula IV-A are readily added to organometallic reagents to form azomethine bonds. Organolithium reagents, such as methyl and ethyl lithium, react with formula (IV-A) to produce an additive of formula (III-B). The additive thus formed is oxidized, for example, with an oxidizing agent such as air to give an aromatic compound, which is substituted at the 6-position in the formula (IV-B). Further reaction of the compound of formula (IV-B) substituted with the 6-position with an organic lithium reagent yields the 6,6-disubstituted product of the formula (II-B).

The addition of the second group (R ₅ ) to the 6-position is readily carried out by quaternizing and activating the azomethine bond, especially when R ₅ is greater than methyl. This activation causes the compounds of formula (III-B) to undergo alkyl halides (such as methyl iodide or ethyl) or aralkyl halides, preferably aralkyl bromide such as benzyl bromide [C ₆ H ₅ (CH ₂ ) x B ] To obtain a compound of formula (III-C) with the 5-position substituted. This activated compound readily reacts with excess organolithium or Grignard reagents to yield a trisubstituted compound of formula II-B. Hydrolysis of the ketals of Structural Formulas (II-B) and (III-C) yields the corresponding enones, which are converted to the compounds of Structural Formulas (II) and (I) in the manner described above. Of course, when R ₆ of the compound of formula (III) or (III-C) is benzyl, the benzyl group is cleaved even if the enone is reduced to lithium-ammonia.

The process for further introducing an alkyl group at the 6-position in the final production of the compounds of formulas (I) and (II) is shown in process diagram D.

The 6-oxohexahydrobenzo [C] quinoline of the formulas (IV-C) and (IV-E) is purified with sodium hydroxide or potassium hydroxide at a fine level, such as at about 200 ° C.-300 ° C. It is made by reaction. By quaternizing the nitrogen of formula (IV-A) by reacting formula (IV-A) with methyl or ethyl iodide, benzyl bromide, or other aralkyl halides, the reaction with sodium hydroxide or potassium is further enhanced. It can be carried out under mild conditions. The resultant intermediate is easily oxidized with a mild oxidizing agent containing air to form an oxo compound of formula IV-E, which is substituted with a substituent (methyl, ethyl, aralkyl) on the nitrogen atom as a result of quaternization. ).

Another method is formula (IV-A), which is treated with peracids such as m-chloro perbenzoic acid and peracetic acid to form the corresponding N-oxides, which are then reacted with acetic anhydride to rearrange. To obtain the structural formula (IV-C). Other known methods may be used to convert the N-oxide to lactam.

Treatment of a compound of formula (IV-C) or (IV-E) with an excess of suitable Grignard reagent, such as methyl or ethyl magnesium bromide, results in the corresponding 6,6-dialkyl of formula (II-B) Obtain the compound.

3-hydroxy-5- (ZW-substituted) aniline is prepared by the Bucherer reaction of the corresponding 5- (ZW-substituted) resorcinol, i.e. by reaction with aqueous ammonium sulfite or bisulfite. . This reaction is carried out in a pressure vessel at high temperature, such as about 150 ° C-230 ° C. The aniline product is separated by acidifying the cooled reaction mixture and extracting the acid mixture, for example with ethyl acetate. The acid solution is neutralized and extracted with a suitable solvent such as chloroform to recover the aniline product. The aniline product may also be separated by column chromatography of the crude product after extraction of the cooling reaction mixture.

5- (Z-W-substituted) resorcinol is prepared from 3,5-dihydroxybenzoin acid. In this process, 3,5-dihydroxybenzoic acid is esterified with a protected hydroxy group (such as methyl, ethyl or benzyl edel), or 3,5-[di (protected hydroxy)]-benzoic acid is amide. Make it angry.

The overall reaction sequence is summarized in process diagram E.

The starting material of 3,5-dihydroxy benzoic acid of formula (XI) is a compound of formula (XII), wherein Y ₂ is an alkoxy group-preferably a methoxy or ethoxy or amino group and Y ₁ is a hydroxy protecting group Switch).

The diprotected benzoic acid of formula (XII) is converted to the compound of formula (XIV) by a known method. One method hydrolyzes the structural formula (XII) to the corresponding acid (Y ₂ = OH) or lithium salt, which is reacted with a suitable alkyllithium to produce an alkyl disubstituted phenylcatone (Y ₂ = alkyl). If methyl lithium is used, the resulting acetopanone derivatives are treated with Grignard reagent (W-Z'-MgBr). The intermediate product is hydrolyzed to the corresponding alcohol, which is then hydrogenated again to replace the hydroxy group with hydrogen. This method is particularly effective for compounds where Z is alkylene.

The ether group is destroyed in an appropriate manner. Ie, pyridine hydrogen chloride (Y ₁ = methyl) or catalytic hydrolysis (Y ₁ -benzyl) or an acid such as trifluoroacetic acid, hydrochloric acid, bromic acid or sulfuric acid. If ZW contains sulfur, it is, of course, decanted benzylation.

In another method of converting a compound of formula (XII) to a compound of formula (XV), the ketone (Y ₂ = alkyl) of formula (XII) is converted to a suitable triphenylphosphonium bromide in the presence of a base (such as sodium hydride). derivative _{[(C 6 H 5) 3} P + -ZW] - it is reacted with Br. The reaction proceeds through alkenes, which are then catalytically hydrogenated to the corresponding alkanes (ZW) and destroyed again to convert to dihydroxy compounds of formula IV. Of course, when -Z- is (a1k ₁ ) mX- (a1k ₂ ) n and Y ₁ is benzyl, the benzyl edel cleaves as a result of catalytic hydrogenation.

The conversion of the compound of formula (XII) to the compound of formula (XIV) may be carried out in the order of XII → XIII → XV. In this case, diprotective benzamide (XII) (Y ₂ = NH ₂ ) is reacted with a suitable Grignard reagent (BrMg-Z'-W) to give ketone (Z) (Z '-= Z minus 1 CH ₂ group). ), Which is then reacted with methyl- or ethyl-magnesium halide to form the corresponding carbinol. Dehydration of the carbinol with, for example, P-toluenesulfonic acid yields the corresponding alkene, which is catalytically hydrogenated to give (Pd / C) alkanes (XIV). The ether group is blocked (converted to hydroxy) as described above.

When Z is alkylene, it is preferable that Y ₁ is alkyl or benzyl of 1-4 carbon atoms. The function of the Y ₁ group is to protect the hydroxyl period during the next reaction. The significance of the Y ₁ group is not its structure, but rather its specific function, ie the protection of the hydroxyl group. Selection and identification of suitable protecting groups can be performed by any person skilled in the art. The suitability and effects of certain groups as hydroxy protecting groups are determined by using such groups in the reaction sequences described above. Therefore, such a protecting group should be one that can be easily removed to recover the hydroxyl group. Methyl is easily removed by treatment with pyridine hydrogen chloride and is thus a protective alkyl group. When the benzyl group is used as a protecting group, it is removed by catalytic hydrogenolysis or acid hydrolysis.

When Z is-(a1k ₁ ) mX- (a1k ₂ ) n-, it is preferable that Y ₁ is a benzyl or substituted benzyl group, since these groups can be removed later without damaging the Z group.

Compounds of formula (VIII-A) can also be prepared from 3-amino-5-hydroxy benzoic acid by the method of Process F.

-ZW is -alkylene-W or-(a1k ₁ ) -X '-(a1k ₂ (() nW), wherein (a1k ₁ ), (a1k ₂ ), W and n are as described above and X' The compound of formula (VIII-A), which is O or S, can be obtained by the procedure F.

The first step in the sequence (Wittig reaction) is to select the appropriate reactants to give the opportunity to produce compounds with straight or branched alkylene groups. Amino groups are protected by acetylation in conventional manner. In the above example, when R ¹¹ is methyl or ethyl, it causes to form a compound having alkyl substitution at the carbon atom α adjacent to the phenyl group. Substitution of the methyl or ethyl group at another position, such as the β carbon atom of the alkylene group, is carried out by selecting the appropriate carboalkoxy alkylidene triphenylphosphorane, ie, (C6H5) 3P = C (R ¹¹ ) -COOC ₂ H ₅ . do. The unsaturated ester thus produced is reacted with lithium aluminum hydride and reduced to the corresponding saturated alcohol.

The presence of small amounts of aluminum chloride can promote this reaction.

If Y ₁ is other than benzyl (eg methyl), alcohols are produced by catalytic reduction of unsaturated esters with palladium-carbon and treatment of the saturated esters thus produced with lithium aluminum hydride. The alcohol is converted to the corresponding tosylate or mesylate, the tosylate or mesylate is alkylated with an alkali metal salt of the appropriate HX '-(a1k ₂ ) nW reactant, and finally the protecting group (Y ₁ ) is removed. The desired compound of (VIII-A) is obtained. When X 'is sulfur, the protecting group Y ₁ is methyl.

One variation of the above sequence is to bromide the alcohol instead of converting it to tosylate or mesylate. Tribrominated phosphoric acid is a convenient brominating agent. The bromo derivative is reacted with the appropriate HX '-(a1k ₂ ) nW in the presence of a suitable base (Williamson reaction).

Bromo compounds are also important intermediate products which act in this order to increase the length of the chain of the alkylene group, thus obtaining compounds in which Z is -alkylene-W. In this method the bromo derivative is treated with triphenyl phosphine to make the corresponding triphenyl bromide.

Reaction of triphenyl phosphorus bromide with a suitable aldehyde or ketone in the presence of a base such as sodium hydride or n-butyllithium yields an unsaturated derivative which is then catalytically hydrogenated to the corresponding saturated compound.

In the above modification, the protecting group Y ₁ to be selected differs depending on the specific order to be performed. When using the vertical sequence on the right, benzyl is the preferred protecting group for reasons in the catalytic hydrogen involvement step. When using the left vertical sequence, methyl is the preferred protecting group because methyl is conveniently removed by treatment with acid.

Compounds of formula (II) wherein -ZW is-(a1k ₁ ) mX- (a1k ₂ ) nW and X is -SO- or -SO ₂ -are obtained by oxidizing the corresponding compound where X is -S-. Hydrogen peroxide is a convenient oxidant for oxidizing thioethers to sulfoxides. Oxidation of thioedel with the corresponding sulfone is conveniently carried out using peracids such as perbenzoic acid, perphthalic acid or m-chloroperbenzophosphoric acid. In particular, m-chloro perbenzoic acid is a very useful peracid because it can easily remove the by-product m-chlorobenzo phosphoric acid.

Esters of the compounds of the formula (II)-(IV) wherein R 1 is alkanoyl or -CO- (CH ₂ ) p-NR ₂ R _{3 represent} dicyclonuclearcarbodiimide of the compounds of the formula (II)-(IV). Easily prepared by reacting with a suitable alkanophosphoric acid or acid of the structural formula HOOC- (CH ₂ ) p-NR ₂ R ₃ in the presence of a condensing agent such as: These esters may also be prepared by reacting the compounds of formulas (II)-(IV) with a suitable alkanophosphate chloride or anhydride such as acetyl chloride or acetic anhydride in the presence of a base such as pyridine.

Esters of the compounds of formula (I) in which each of the R and R ₁ groups are esterified are prepared by acylating in the manner described above. Compounds acylated only with 9-hydroxy groups are prepared by gentle hydrolysis of the corresponding 1,9-diacyl derivatives, in which case the hydrolysis of the acyl groups of phenol is very easy. The compound of formula (I) in which only 1-hydroxy group is esterified is obtained by borohydride reduction of the ketone of the corresponding formula (II) in which 1-position is esterified. The compound of formula (I) thus produced has a 1-acyl-9-hydroxy substitution or 1-hydroxy-9-acyl substitution, which is further acylated with another acylating agent to yield esters in 1-position and 9-position The diesterated compound of structural formula (I) from which a group differs is obtained.

The presence of a base in the ester group (OR ₁ ) of the compound of the present invention makes it possible to form an acid addition salt containing the base. When a basic ester is prepared by condensing a suitable amino acid hydrogen chloride (or other acid addition salt) with a compound of the appropriate structural formulas (I)-(IV) in the presence of a condensing agent, the hydrogen chloride salt of the basic ester is produced. Careful neutralization gives free bases. This free base can be converted into other acid addition salts by known methods.

As can be appreciated by those skilled in the art, acid addition salts can form with nitrogen in the benzo [C] quinoline system. Such salts are prepared by conventional methods. Basic esters can form mono- or di-acid addition salts because of their basicity.

The analgesic properties of the compounds of the present invention are characterized by the ability of the compounds to inhibit thermal stimulation (e.g., touching the tail of a mouse with a hot object) or chemical stimulation (e.g., stimulating the mouse from stimulation of phenylbenzoquinone). Method of measurement).

The above and other tests are described below.

[Test using thermal stimulation]

[a) Analgesic test of mice on hot plate]

A controlled thermal stimulus is applied to the paws of mice on an aluminum dish 1/8 inch thick. Place an infrared heat lamp with a 250-watt reflector under the bottom of the aluminum plate. A thermostat connected to the thermometer on the dish surface maintains the temperature of the heat lamp at a constant temperature of 57 ° C.

Each mouse is dropped into a glass cylinder (6.5 inches in diameter) placed on this hot plate and timed from when the mouse's foot touches the plate. At 0.5 and 2 hours after treatment with the test compound, the mice are first shaken by one or both of the hind paws. 10 seconds did not wobble. MPE ₅₀ = 4-5.6 mg./kg of morphine. (sc).

[b) Analgesic Testing of the Mouse's Tails]

High intensity controlled heat is applied to the tail of the mouse. Place each mouse in a cozy metal cylinder with its tail at one end. The arrangement of this cylinder is such that the tail of the mouse rests flat on the hidden heat lamp. At the beginning of the test, peel off the aluminum plate covering the lamp so that the light is focused through the gap at the tip of the mouse tail. At the same time time is measured. Observe sudden clashes of tails. Untreated drugs typically respond within 3-4 seconds after exposure to the lamp. Treated mice respond in 10 seconds. Each mouse is tested 0.5 and 2 hours after treatment with morphine and test compounds.

MPE ₅₀ = 3.2-5.6 mg./kg. (Sc) of morphine.

[Test using chemical sensitive stimulus]

[Suppresses wobble from stimulation of phenylbenzoquinone]

Groups of 5 mice were pretreated subcutaneously or orally with saline, morphine, codeine or test compound. After 20 minutes for subcutaneous treatment or 50 minutes after oral treatment, phenylbenzoquinone is injected into each group internally. This injection is known to cause abdominal contractions. Start 5 minutes after the injection and watch for 5 minutes to see if the mouse is wobbled. Check MPE ₅₀ for pretreatment drugs to avoid wriggling.

The results of the test are reported as the maximum possible effect (% MPE) expressed as a percentage. The% MPE for each group is controlled compared to the% MPE for standard and pretreatment drug controls. % MPE is calculated as

The table below shows the analgesic effects as MPE ₅₀ , which is the dosage observed in a test given half of the maximum possible analgesic effects.

The compounds of the present invention are effective analgesics in oral and topical administration and are conveniently administered in the form of compositions. Such compositions include a pharmacological carrier selected based on the route of administration and standard medical practice. For example, it may be administered in the form of tablets, pills, powders, or particles containing ingredients such as starch, milk sugar, clay in certain forms, and the like. It may be administered in capsules with the same or equivalent ingredients. It may also be administered in the form of oral suspensions, solutions, emulsions, syrups and elixirs, including sweeteners and pigments. When orally administering a therapeutic agent of the invention, tablets or capsules containing about 0.01-100 mg are suitable for most applications.

The dosage that is best for an individual patient will be determined by the doctor, and the dosage will vary depending on age, weight, individual patient's response, and route of administration. In general, however, the first dose used as an analgesic for adults is 0.01-500 mg per day, which can be taken once or in portions. In many cases, it is not necessary to exceed 100 mg per day. A good oral dosage unit is 0.01 mg-300 mg per day, with a more preferred range of 0.10-50 mg per day. Good local dosages range from about 0.01-100 mg per day and more preferred units are about 0.01-20 mg per day.

In the same manner as described above, the analgesic effects of the various compounds of the invention and several conventional compounds are determined. The following abbreviations are used in the table below.

Wobble due to PBQ = phenylbenzoquinone

TF = Touching Tail

HP = hot plate

TABLE 1

TABLE 2

Analgesic effect (MPE ₅₀ = mg / kg., Sc)

[* = Hydrochloride salt]

The effect of the compound as a relaxant is determined by the ability to lower the blood pressure of the nervous mice and dogs when the compound is administered orally to rats and dogs by the above-described dosages.

The effect of the compound as a sedative is manifested in a decrease in autonomic nervous system when orally administered to rats at a dosage of about 0.01-50 mg / kg.

It is believed that the use of these compounds as glaucoma agents is due to their ability to reduce intraocular pressure. Their effect on intraocular pressure is determined by testing in dogs. Test drugs are injected into the dog's eye in the form of a solution or administered systematically over several periods of time. The eyes are then catastrophized with 2 drops of 1/2% tetracaine hydrogen chloride. After such local anesthesia, after several minutes, the pressure of the guide was measured with Shiotsu's mechanical tension meter, the fluorescein dye was dosed, and the intraocular pressure was measured with Holberg's manual tension meter. Test drugs are conveniently used in the following solutions. : Test solution (1 mg.), Ethanol (0.05 mg.), Splatter 80 (polyoxyalkylene derivative of sorbitan mono-urate, (50 mg.), And brine (amount that makes the whole 1 ml): More concentrated solutions present in the proportions of 10 mg., 0.10 ml., 100 mg. And 1 ml., Respectively, when used in humans, drug concentrations of 0.01 mg./kg-10 mg./kg are effective.

The effect of these compounds as diuretics is determined by testing in mice. The dosage range for this use is the same as described above for the effect as an analgesic.

The present invention also provides pharmacological compositions comprising unit dosage forms, which compositions are important for analgesics and other uses. Dosage forms can be made one or several times to achieve an effective daily dosage for a particular application.

The compounds of the present invention can be formulated for oral or topical administration in solid or liquid form. A capsule comprising a drug of the present invention, such as a compound of formula (I) or (II), is prepared by mixing 1 part by weight of a drug with 9 parts by weight of dim, i.e. starch or milk sugar, and 100 parts by weight of this mixture in each capsule. Prepared by placing in gelatin capsules.

Tablets comprising Structural Formulas (I) or (II) are prepared by appropriately mixing the drug with the usual ingredients used in the manufacture of the tablets, such as starch binders and lubricants, so that each tablet contains 0.01-100 mg of the drug.

These drugs, in particular suspensions and solutions of compounds in which R ₁ is hydroxy in the formulas (I) and (II), are usually prepared immediately before use, because of problems with the stability of the drug (eg oxidation) and of the suspension or solution. This is to avoid storage problems (sedimentation). Compositions suitable for this use are usually in the form of a dry solid which is reconstituted to be administered by injection.

Example 1

[Ethyl d, 1-3- (3,5-dimethoxyanilino) butyrate]

A mixture of 3,5-dimethoxyaniline 95.7 g, 0.624 mol), ethyl acetoacetate (87.2 ml, 0.670 mol), benzene (535 ml) and glacial acetic acid (3.3 ml) was refluxed for 15 hours under an atmosphere of nitrogen and mol. .

The reaction mixture was cooled to room temperature, bleached with activated carbon, filtered and concentrated under reduced pressure to afford the product ethyl 3- [3,5-dimethoxy) anilino] -2-butenoate as an oil (168.7 g). .

A mixture of ethyl 3- (3,5-dimethoxyanilino) -2-butenoate (5.0 g, 18.7 mmol) and platinum oxide (250 mg) in glacial acetic acid (42 ml) is hydrogenated at 50 psi for 1.5 hours. The reaction mixture is filtered, benzene (50 ml) is added and the solution is concentrated under reduced pressure to an oil. The oil is taken up in chloroform and the solution is washed sequentially with saturated sodium bicarbonate solution (2 x 50 ml) and saturated sodium chloride solution.

Then drying (MgSO ₄ ), filtration and concentration under reduced pressure yields the product as an oil (5.1 g).

Repeating the process with 168.7 g of ethyl 3- (3.5-dimethoxyanilino) -2-butenoate, glacial acetic acid (320 ml) alc platinum oxide (2,15 g) yielded 160.8 g of product.

Example 2

[Ethyl d, 1-3- (3.5-dimethoxyanilino) butyrate]

Twelve-liter, three-neck, round-bottom, three-necked plastic stirrer with reflux condenser, 3,5-dimethoxy aniline hydrogen chloride (370 g, 1.45 moles), reagent grade methanol (4.5 l and ethyl acetoacetate (286.3 g, 2.64 moles) Add a solution of sodium cyano borohydride (54 g, 0.73 mol) at once, and reflux for 10 minutes, then heat the mixture again in a steam bath for 20 minutes. To the mixture (additional amount of sodium cyanoborohydride (5.4 g, 0.26 mol) is added and the mixture is refluxed for 30 minutes. The latter procedure is repeated once more.

Pour about 500 ml of the reaction mixture into 1 L of ice water / 500 ml of methylene chloride and separate the liquid layer and wash the aqueous phase in reverse with additional methylene chloride (100 ml). do.)

The methylene chloride layers are combined, dried, decolorized with (MgSO ₄ ) carbon, filtered and evaporated to yield a yellow oil.

Excess ethylacetoacetate was distilled off (at an oil bath temperature of 130 ° C. and a pressure of 1-5 mm) to prepare 376 g (72%) of ethyl 3- (3,5-dimethoxyanilino) butyrate (amber viscous oil). Yield), which is used without further purification.

It has the following spectral characteristics.

: 5.82-6.0(m,3H,방향성), 4.20(g,2H, 에스테르메틸렌),3.80-4.00(m,2H,-NH 및 -N-CH-CH₃), 3.78(s,6H,-OCH₃),2.40-2.55(m,2H,-CH2COOEt) 1.78(d,3H,메틸) 미 1.29(t,3H, 메틸).'H NMR (60 MHz)

: 5.82-6.0 (m, 3H, aromatic), 4.20 (g, 2H, estermethylene), 3.80-4.00 (m, 2H, -NH and -N-CH-CH ₃ ), 3.78 (s, 6H, -OCH ₃ ), 2.40-2.55 (m, 2H, -CH 2 COOEt) 1.78 (d, 3H, methyl) Mi 1.29 (t, 3H, methyl).

Example 3

[d, 1-ethyl-3- (3,5-dimethoxyanilino) hexanoate]

Condensation of 3,5-dimethoxyaniline hydrogen chloride and ethylbutyryl acetate in accordance with the method of Example 2 affords ethyl d, 1-3- (3,5-dimethoxyanilino) hexanoate. Hydrogen chloride is added to the methylene chloride solution of this compound to convert to hydrogen chloride. Melting point 127 ° -129.5 ° C. Recrystallization from cyclohexane / benzene (5: 1) yields analytical specimens with melting points of 126 ° -128.5 ° C.

Assay: for C ₁₆ 1H ₂₅ O ₄ N · HC1

Calculated Value: C 57.911, H 7.90, N 4.22%

Measured value: C 57.89, H 7.74, N 4.40%

m / e-295 (m ⁺ )

: 10.76-11.48(b, 가변성, 2H, NH₂ ⁺), 6.77(d,j=2H, 메타H'S), 6.49, 6.49(d,fd,J=2Hz,1H, 메타H), 4.08(q,2H,OCH₂),3.77(s,6H,[OCH₃]₂), 약 3.5-4.8(m,1H, CH-N), 2.90(t,2H, CH₂-C=O), 약 11.4-2.2(m,4H,[CH₂]₂), 1.21(t, 3H,O-C-CH₃), 0.84(t,3H,-C-CH₃)'H NMR (60 MHz)

: 10.76-11.48 (b, ^{_{variable, 2H, NH 2 +),}} 6.77 (d, j = 2H, meta H'S), 6.49, 6.49 ( d, fd, J = 2Hz, 1H, meta H), 4.08 (q, 2H, OCH ₂ ), 3.77 (s, 6H, [OCH ₃ ] ₂ ), about 3.5-4.8 (m, 1H, CH-N), 2.90 (t, 2H, CH ₂ -C = O), about 11.4- 2.2 (m, 4H, [CH ₂ ] ₂ ), 1.21 (t, 3H, OC-CH ₃ ), 0.84 (t, 3H, -C-CH ₃ )

Example 4

[d, 1-ethyl-3-[(3,5-dimethoxy-N-ethoxycarboyl) anilino] butyrate]

[Method A]

To a mixture of ethyl 3- (3,5-dimethoxyanilino) butyrate (159.8 g, 0.598 mol), methylene chloride (100 ml) and pyridine (100 ml, 1.24 mol), ethylchloroformate 71.4 ml, 0.75) is added dropwise over 45 minutes. After the addition of ethyl chloroformate, the mixture is stirred for 40 minutes and then poured into a mixture of chloroform (750 ml) and ice water (500 ml). The chloroform layer is separated, washed sequentially with 10% hydrochloric acid (3 x 500 ml), saturated aqueous sodium bicarbonate solution (1 x 300 ml), saturated sodium chloride solution (1 x 400 ml), and dried (MgSO ₄ ). Then decolorized with activated carbon and concentrated under reduced pressure to give oil (215 g). This product is used as is.

[Method B]

Under a nitrogen atmosphere, a mixture of ethyl 3- (3,5-dimethoxyanilino) butyrate (376 g, 1.4 mol), methylene chloride (1.4 L) and anhydrous potassium carbonate (388.8 g, 2.81 mol) was stirred and in an ice bath Cool to 0 ° C-5 ° C. Ethyl chloroformate (153 g, 1.41 mol) is added in one portion.

The mixture is left for one hour to warm to room temperature, ethylchloroformate (153 g, 1.41 moles) is added again and the mixture is refluxed in a steam bath for one hour. It is then allowed to cool to room temperature and potassium carbonate is removed by filtration. The red filtrate is washed sequentially with mole (2 × 1000 ml) and the like, dried (MgSO ₄ ), decolorized and evaporated under reduced pressure to give 493 g of a crude product. This product is used without further purification.

: 6.2-6.42(m,3H,방향성), 4.65(조, 1H,-N-CH-CH₃), 4.10-4.15(2개의 4조, 4H, 에스테르메틸렌),3.70(s, 6H,-OCH₃), 2.30-2.60(m,2H,-CH₂COOEt), 1.00-1.40(m,9H,3메틸)1 H NMF (60 MHz

: 6.2-6.42 (m, 3H, aromatic), 4.65 (crude, 1H, -N-CH-CH ₃ ), 4.10-4.15 (two quaternary, 4H, estermethylene), 3.70 (s, 6H, -OCH ₃ ), 2.30-2.60 (m, 2H, -CH ₂ COOEt), 1.00-1.40 (m, 9H, 3 methyl)

Example 5

[d, 1-3-[(3,5-dimethoxy-N-ethoxycarboyl) anilino] butyric acid]

[Method A]

Ethyl 3-[(3,5-dimethoxy-N-ethoxycarbonanyl) anilino] butyrate (202 g, 0.595 mol), aqueous sodium hydroxide solution (595 ml with 1N concentration), ethanol (595 ml), etc. Stir overnight at room temperature. The reaction mixture is concentrated under reduced pressure to a capacity of about 600 ml, and the concentrate is diluted with water to a volume of 1200 ml and extracted with ethyl acetate (3 x 750 ml). The aqueous layer is then acidified with 10% hydrochloric acid to pH 2 and exported again to ethyl acetate (3 x 750 ml). These later extracts were combined, washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to yield the title product as oil (163,5 g, 88.2%).

[Method B]

In a 5-liter flask with round bottom and three widths, equipped with a mechanical stirrer and reflux condenser, ethyl 3-[(3,5-dimethoxy-N-ethoxycarbonanyl) anilino] -butyrate (439 g, 1.41 mol) ) Add ethanol (2 L) solution. Sodium hydroxide (2 L of 1 N) is added and the mixture is refluxed for 3 h in a steam bath. The reaction mixture is poured into 5 L of ice water, 1 L each is extracted with diethyl ether (500 ml each time).

About 1L of ice is added to the aqueous layer, cooled, and acidified with concentrated hydrochloric acid (1.75ml, 2.1 mol). Take 1 L each and extract with methylene chloride (250 ml each time). The methylene chloride layers are combined, dried over magnesium sulfate, decolorized with carbon and evaporated to dryness to produce a yellow viscous oil. Crystallization from ether / cyclohexane (1: 2) yields 224 g (55.3%) of crystal product. Melting point is 78 ° -80 ° C. This material is used in the next step without further purification.

: 6.24-6.53-(m,3H,방향성),4.65(6조, 1H,-N(COOC₂H₅) CH(CH₃) CH₂COO₂H₅), 4.10(4조, 2H,에스테르케틸렌), 3.78(s, 6H,-OCH₃), 2.40-2.60(m,2H,-CH₂COOH),1.18(t),1.28(d,6H,메틸), 10.8(bs,가변성,1H,COOH).'H NMR (60 MHz)

: 6.24-6.53- (m, 3H, aromatic), 4.65 (6 trillion, 1H, -N (COOC ₂ H ₅ ) CH (CH ₃ ) CH ₂ COO ₂ H ₅ ), 4.10 (4 trillion, 2H, ester) Styrene), 3.78 (s, 6H, -OCH ₃ ), 2.40-2.60 (m, 2H, -CH ₂ COOH), 1.18 (t), 1.28 (d, 6H, methyl), 10.8 (bs, variable, 1H, COOH).

MS (water ion) m / e-311.

The melting point of the analytical sample obtained by recrystallizing the burner with ethyl acetate / hexane (11: 5) was 89 ° -91 ° C.

Assay: for C ₁₅ H ₂₁ O ₆ N

Calculated Value: C 57.86, H 6.80, N 4.50%

Measured value: C 58.08, H 6.65, N 4.46%

Example 6

['d- and 1-3 [(3,5-dimethoxy-4-N-ethoxycarboyl) anilino] butyric acid]

A mixture of d, 1-3 [(3,5-dimethoxy-N-ethoxycarboyl) anilino] butyric acid (136.6 g, 0.44 mole) and 1-ephedrine (72.5 g, 0.44 mole) was added to methylene chloride ( In 500 ml). The methylene chloride is then removed in vacuo to give 1-ephedrine salt of d, 1-3 [(3,5-dimethoxy-N-ethoxycarbonanyl) anilino] butyric acid as oil.

=-20.0°(C=1.0,CHC1₃)에델(1500ml)을 가하면 백색고체물질의 결정이 생기며 이것을 여과로 분리하여 건조하면 1102g의 생성물을 얻는다. 융점=114°-116℃

= -20.0 ° (C = 1.0, CHC1 ₃ ) Edel (1500ml) gives white solid crystals which are separated by filtration and dried to give 1102g of product. Melting point = 114 ° -116 ° C

Recrystallization from ethyl acetate / hexane (1: 1) yielded 71.1 g (34%) of 1-ephedrine salt of 1-3-[(3,5-dimethoxy-N-ethoxycarbonanyl) anilino] butyric acid Get Melting point: 126 ° -127 ° C.

Assay: for C ₂₄ H ₃₆ O ₇ N ₂

Calculated Value: C 63.00, H 7.61, N 5.88%

Found: C 62.87, H 7.64, N 5.88%

=-43.5°(C=1.0, CHC1₃)

= -43.5 ° (C = 1.0, CHC1 ₃ )

The 1-isomer of 1-ephedrine salt in a mixture of ethyl acetate (1000 ml) and 10% hydrochloric acid (400 ml) is stirred for 10 minutes. The organic phase is separated, washed with 10% hydrochloric acid (2 x 400 ml), dried and concentrated under reduced pressure to form oil. Crystallization of this oil from ethyl acetate / hexane (400 ml of 1: 1) yields 34.6 g of 1-30 [(3,5-dimethoxy-N-ethoxycarbonanyl) anilino] butyric acid. Melting Point: 96 ° -97 ℃

Assay: for C ₁₅ H ₂₁ O ₆ N

Calculated Value: C 57.86, H 6.80, N 4.50%

Found: C 57.90, H 6.66, N 4.45%

= -25.4°(C=1.0,CHC1₃)

= -25.4 ° (C = 1.0, CHC1 ₃ )

Treatment of the mother liquor from the recrystallization of the 1-isomer 1-ephedrine salt with hydrochloric acid as described above yields the crude d-3-[(3,5-dimethoxy-N-ethoxycarboyl) anilino] butyric acid. I. Treatment of this crude acid with d-ephedrine and crystallization from ether gives the d-ephedrine salt of the d-isomer. Melting point = 124 ° -125 ° C

Assay: for C ₂₅ H ₃₆ O ₇ N ₂

Calculated Value: C 63.00, H 7.61, N 5.88%

Found C 62.82, H 7.47, N 5.97%

=+40.0°(C=1.0, CHC1₃)

= + 40.0 ° (C = 1.0, CHC1 ₃ )

The d-ephedrine salt is converted into the free acid in the same manner as described above to be d-3-[(3,5-dimethoxy-N-ethoxycarboyl) anilino] butyric acid. Melting point after recrystallization from ethyl acetate / hexane (3: 5) = 96 ° -97 ° C

For C ₁₅ H ₂₁ O ₆ N

Calculated Value: C 57.86, H 6.80, N 4.50%

Found: C 57.95, H 6.57, N 4.35%

=+25.3(C=1.0,CHC1₃)

= + 25.3 (C = 1.0, CHC1 ₃ )

Example 7

[Methyl-3 (3,5-dimethoxyanilino) propionate]

A mixture of 3,5-dimethoxyaniline (114.9 g, 0.75 mol), methyl acrylate (69.73 g, 0.80 ml), glacial acetic acid (2 ml) and the like was refluxed for 20 hours. After reflux, the reaction mixture was concentrated and distilled in vacuo yielding 106.8 g (73.9%) of the title product. Melting point = 174 ° -179 ° C. (0.7 mm).

: 5.62-5.95(m,3H, 방향성), 4.1(가변성, bs, 1H,-NH), 3.74(s,6H,-OCH₃), 3.68(s,3H,COOCH₃), 3.41 및 2.59(2개의 2H 3조,-NCH₂CH₂CO₂)'H NMR (60 MHz)

: 5.62-5.95 (m, 3H, aromatic), 4.1 (variable, bs, 1H, -NH), 3.74 (s, 6H, -OCH ₃ ), 3.68 (s, 3H, COCH ₃ ), 3.41 and 2.59 (2) 2H 3 trillion-NCH ₂ CH ₂ CO ₂ )

Example 8

[d, 1-methyl 3-[(3-hydroxy-5- (5-phenyl-2-pentyl)] anilino} propionate]

A mixture of 3-hydroxy-5- (5-phenyl-2-pentyl) -aniline (1.0 g), menylacrylate (345 mg), acetic acid (0.1 ml), etc., was stirred overnight at a temperature of 106 ° -110 ° C. Heat. The cooled residue is dissolved in 100 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution. Drying of the organic phase (MgSO ₄ ) and evaporation gave a crude residue which was chromatographed on 130 g of silica gel using benzene-ether (2: 1) as eluent.

After eluting the less polar impurities, 540 mg (40%) of d, l-methyl 3-{[3-hydroxy-5-) 5phenyl-2-pentyl)] anilino} propionate are collected. This has the following spectral characteristics.

: 7.14(s,5H, 방향성, 5.83-6.13(m,3H, 방향성), 3.66(s, 3H, -COOH₃), 3.37(t,2H, -NCH₂), 2.16-2.78(m,5H, -CH₂COO 및 벤질성), 1.28-1.69(m,4H, -(CH₂)₂-), 1.11(d, 3H, ＞-CH3), 4.4-5.2 및 1.28-2.78(가변성, 1H,NH,OH)me/e-341(m⁺) ₁ H NMR (60 MHz)

: 7.14 (s, 5H, directional, 5.83-6.13 (m, 3H, directional), 3.66 (s, 3H, -COOH ₃ ), 3.37 (t, 2H, -NCH ₂ ), 2.16-2.78 (m, 5H, -CH ₂ COO and benzyl), 1.28-1.69 (m, 4H,-(CH ₂ ) _2- ), 1.11 (d, 3H,> -CH3), 4.4-5.2 and 1.28-2.78 (variable, 1H, NH) , OH) me / e-341 (m ⁺ )

Example 9

[Methyl3-[(3,5-dimethoxy-N-ethoxycarbonanyl) anilino] propionate]

To a mixture of methyl 3- (3,5-dimethoxyanilino) pyropiionate (1.0 ml, 10.5 mmol), methylene chloride (5 ml) and pyridine (5 ml), ethylchloroformate (2.0) under nitrogen atmosphere at 0 ° C. g, 8.4 mmol) was added dropwise over 10 minutes. After addition of ethylchloroformate, the mixture was stirred at 0 ° C. for 20 minutes and then left at room temperature for 20 minutes and then poured into a mixture of methylene chloride (75 ml) and ice water (50 ml). The methylene chloride layer is separated, washed sequentially with 10% hydrochloric acid (2 x 50 ml), saturated sodium bicarbonate solution (1 x 30 ml), saturated aqueous sodium chloride solution (1 x 40 ml), and dried. (MgSO ₄ ) Then decolorized with activated carbon and concentrated under reduced pressure to give oil (2.72 g).

This product is used as is.

Example 10

[3-[(3,5-Dimethoxy-N-ethoxycarbonanyl) anilino] propionic acid]

Methyl 3-[(3,5-dimethoxy-N-ethoxycarbonanyl) anilino] propionate (2.7 2 g, 8.36 mmol), aqueous sodium pure oxide solution (1 N of 8.4 ml) and ethanol (8.4 ml) Combine and stir overnight at room temperature under nitrogen. The reaction mixture is concentrated under reduced pressure to reduce the volume in half, diluted with water (35 ml) and extracted with ethyl acetate. The aqueous phase is acidified with 10% hydrochloric acid to pH 2 and extracted with methyl chloride (3 x 50 ml). The combined extracts are washed with brine, dried (MgSO ₄ ) and concentrated to give the product as an oil (2.47 g). This product is used as is.

Example 11

[1-Carbethoxy-5,7-dimethoxy-4-oxo-1,2,3,4-detrahydroquinoline]

A mixture of 3-[(3,5-dimethoxy-N-ethoxycarboyl) anilino] propionic acid (1.10 g, 3.7 mmol) and polyphosphoric acid (4 g) was heated at 65 ° C. for 45 minutes under a nitrogen atmosphere, and then 0 Cool to ° C. The reaction mixture is taken up in a methylene chloride-water mixture (200 ml of 1: 1).

The organic layer is separated and the aqueous phase is extracted again with methylene chloride (2 x 100 ml). The combined extracts were washed with saturated sodium bicarbonate solution (3 × 100 ml) and brine (1 × 100 ml) and dried (MgSO ₄ ). The dried extract was concentrated to give the product oil, which was crystallized from benzene. Yield = 645 mg, Melting Point = 109 ° -111 ° C

Analysis: for C14H17O5N

Calculated Value: C 60.21, H 6.14, N 5.02%

Found: C 60.11, H 6.14, N 4.80%

Example 12

[5,7-Dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline]

Glacial acetic acid (60 ml), 40% hydrochloric acid (60 ml) and 1-Caboethoxy-5,7-dimethoxy-4-oxo-1,2,3,4-tetrahydro-rokinoline (4.0 g, 1413 mmol) The mixture of was refluxed overnight and then concentrated in vacuo to give a thick oil. This oil is dissolved in water (50 ml) and the aqueous solution is neutralized with 1 N sodium hydroxide to pH6-7.

Saturated solution of brine (50 ml) is added and the resulting mixture is extracted with ethyl acetate (3 x 150 ml) fh. The combined extracts are dried (MgSO ₂ ) and concentrated under reduced pressure to yield an oil. This oil is taken up in benzene-ethyl acetate (1: 1) and the solution is placed in a silica gel column. Elution with the same volume of benzene as this column, and also with benzene-ethyl acetate (250 ml of 4: 1) and benzene-ethyl acetate (250 ml of 1: 1). Collect the fractions (75 ml). Combine fractions 4-9 and evaporate under reduced pressure. The oily residue is crystallized from ethanol-hexane (1: 10). Yield 1.86 g, fusion 166 °-169 ° C

Recrystallization again raises the melting point to 171 ° -172.5 ° C. m / e-179 (m ⁺ )

Assay: for C ₉ H ₉ O ₃ N

Calculated Value: C 60.33, H 5.06, N 7.82%

Found: C 60.25, H 4.94, N 7.55%

Example 13

[d, 1-1-carabethoxy-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline]

A solution of 3-[(3,5-dimethoxy-N-ethoxycarboyl) anilino] butyric acid (4.0 g, 12.8 mmol) in chloroform (2 ml) was heated in a steam bath at 60 ° C. in polyphosphoric acid (5.0 Add dropwise to g) with stirring. The reaction mixture is kept at 60 ° -65 ° C. for 2 hours and then poured onto a mixture of ice (100 g) and ethyl acetate (100 ml). The aqueous layer is further extracted with ethyl acetate (2 x 100 ml) and these organic extracts are combined, washed with saturated sodium bicarbonate solution (3 x 100 ml) and brine (1 x 100 ml) fh ckf {, and dried over anhydrous magnesium sulfate. The dried extract was concentrated under reduced pressure to yield 2.6 g of crude product.

The benzene solution of the preparation (2.5 g) is further purified by column chromatography on silica gel (95 g). The column is eluted with benzene at an amount equal to half its volume, followed by elution again with benzene / ethyl acetate (1: 1). Collect fractions (40 ml). Vacuum distillation of fractions 9-18 yielded 1.55 g of product which was further purified by recrystallization from petroleum ether. Yield = 1.33 g, Melting point = 92.5 ° -94 ° C

The product is recrystallized from hot ethyl acetate hexane (1: 1) to obtain a sample for analysis. Melting point 94 ° -95 ℃

Assay: for C ₁₅ H ₁₉ O ₅ N

Calculated Value: C 61.42, H 6.53, N 4.78%

Found: C 61.54, H 6.55, N 4.94%

m / e-293 (m ⁺ )

1R (KBr) -5.85, 5.95μ (> = 0)

Example 14

[d, 1-5,7-Dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline]

[Method A]

Glacial acetic acid (240 ml), 48% bromic acid (240 ml) and 1-carabethoxy-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (16.0 g, 55 mmol) is refluxed overnight and then concentrated in vacuo to give a thick oil. This oil is neutralized with 1N sodium hydroxide in water (200ml) to pH 6-7. Saturated solution of brine (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (3 x 500 ml). The combined extracts are dried (MgSO ₄ ) and concentrated under reduced pressure to give a thick oil (12.8 g). Hexane-ethyl acetate (10: 1) is added to this oil, and the produced crystal | crystallization is collect | recovered by filtration. Yield = 3.8 g, melting point = 158 ° -165 ° C. When this crystal is ground in ethyl acetate, 1.65 g of product is obtained. Melting point 165 ° -168 ° C The mother liquor is allowed to settle further. Yield 2.9 g, boiling point = 168 ° -170 ° C. Using benzene-ether (1: 1) as a solvent, the filtrate was column chromatographed on silica gel to give 4.6 g more product. Melting Point: 167 ° -169 ℃

The product is further purified by recrystallization from ethyl acetate. Melting point = 173 ° -174 ° C

Assay: C 62.16, H 5.74, N 7.25%

7.25%Calculated Value: C 62.16, H 5.74,

7.25%

7.14%Found: C 62.00, H 5.83,

7.14%

m / e-193 (m ⁺ )

[Method B]

A mixture of d, 1-30 [(3,5-dimethoxy-N-ethoxycarboyl) anilino] butyric acid (100 g, 0.32 mol), 48% bromic acid (500 ml) alc glacial acetic acid (300 ml) was added to the oil bath. Heat to 100 ° C. for 2 hours. The temperature of the oil bath is raised to 145 ° C and heated again for 2 hours. During this later heating, the azeotrope is distilled off (melting point 42 ° -110C, 200-300 ml) and the deep red fungal solution is allowed to cool to room temperature. The mixture is poured into ice water (3 L) and ether (2 L), the liquid layer is separated and the aqueous solution is washed with ether (2 x 1000 ml). The ether layers are combined, washed sequentially with water (2 x 1000 ml), brine (1 x 500 ml), saturated NaHCO ₃ solution and brine (1 x 500 ml), and dried. (MgSO ₄ ). Decolorization with carbon and evaporation of ether give yellow bubbles, which are crystallized from about 300 ml of methylene chloride and 31.3 g (50.4%) of pure 5,7-dihydroxy-2-methyl-4-oxo-1,2 Obtain 3,4-tetrahydroquinoline. The mother liquor can be chromatographed on silica gel to further separate the product.

¹ H NMR (60 MHz) δ TMS (100 mg sample / 0.3 ml / 0.2 ml CD ₃ SOCD ₃ ) (ppm): 12.40 (s, 1H, C ₅ -OH), 5.72 (d, 2H, metaH) 5.38-5.60 _{(bs, 1H, C 7,} -OH), 3.50-4.00 (m, 1H, C 2 H), 2.38-2.60 (m, 2H, C 5 -H 2), 1.12 (d, 3H, methyl) m / e-193 (m ⁺ )

Assay: for C ₁₀ H ₁₁ O ₃ N

Calculated Value: C 62.16, H 5.74, N 7.25%

Found: C 62.01, H 5.85, N 7.02%

Similarly methyl d, 1-30 {[(3-hydroxy-5- (5-phenyl-2-pentyl)] anilino} propionate is converted to d, 1-5-hydroxy-7- (5-phenyl- 2-pentyl) -4-oxo-1,2,3,4-tetrahydroquinoline was converted and purified again by column chromatography on silica gel using benzene / ethyl (5: 1) as eluent.

m / e-309 (m ⁺ )

: 12.22(s,1H, 50H), 7.14(s, 5H, C₆H₅), 6.04(d,J=2.5Hz,1H 메타 H),5.87(d,J=2.5Hz, 1H 메타 H), 4.19-4.60(b,1H, NH), 3.48(t,2H,CH₂N), 2.18-2.89(m,5H,ArCH,ArCH₂, CH₂-C=O),1.38-1.86(m,4H, -[CH₂]₂-), 1.13(d,3H,CH₃). ¹ H NMR (60 MHz)

: 12.22 (s, 1H, 50H), 7.14 (s, 5H, C ₆ H ₅ ), 6.04 (d, J = 2.5 Hz, 1H meta H), 5.87 (d, J = 2.5 Hz, 1H meta H), 4.19-4.60 (b, 1H, NH), 3.48 (t, 2H, CH ₂ N), 2.18-2.89 (m, 5H, ArCH, ArCH ₂ , CH ₂ -C = O), 1.38-1.86 (m, 4H ,-[CH ₂ ] _2- ), 1.13 (d, 3H, CH ₃ ).

And ethyl d, 1-3- (3,5-dimethoxyanilino) hexanoate hydrogen chloride as d, 1-5,7-dihydroxy-2-propyl-4-oxo-1,2,3,4 Convert to tetrahydroquinoline. Melting point = 117 ° -119 ° C

(From methylene chloride)

m / e-221 (m ⁺ ), 135 (base maximal, m ⁺ -propyl).

In addition, 1-3-[(3,5-dimethoxy- (N-ethoxycarboyl) anilino] butyric acid was added to d-5,7-dihydroxy-2-methyl-4-oxo-1,2,3 Convert to 4-tetrahydroquinoline Melting Point = 167 ° -168 ° C

[a] a ²⁵ = + 167.8 (CH ₃ OH

m / e-193 (m ⁺ )

Assay: for C ₁₀ H ₁₁ O ₃ N

Calculated Value: C 62.16, H 5.74, N 7.25%

Found: C 61.87, H 5.62, N 6.96%

D-3- [3,5-dimethoxy-N-ethoxycarboyl) anilino] butyric acid was added to 1-5,7-dihydroxy-2methyl.-4-oxo-1,2,3,4 Convert to tetrahydroquinoline. Melting point = 166 ° -168 ° C

=-168.5°(C=1.0,CH3OH)

= -168.5 ° (C = 1.0, CH3OH)

m / e-193 (m ⁺ )

Assay: for C ₁₀ H ₁₁ O ₃ N

Calculated Value: C 62.16, H 5.74, N 7.25%

Found: C 61.82, H 5.83, N 7.22%

Example 15

[d, 1-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline]

A mixture of 3,5-dimethoxyaniline (230 g 1.5 mol), methyl chloronate (150 g, 1.5 mol), glacial acetic acid (90 g 1.5 mol) and the like is heated under reflux for 6 hours. Additional glacial acetic acid (90 g, 1.5 moles) is added and the mixture is refluxed overnight. Bromic acid (100 ml of 48% solution) and glacial acetic acid (850 ml) are added to the reaction mixture and heated at reflux for 4.5 hours. The title product is isolated and purified by the method of Example 12. Yield: 36 g, Melting point = 166 ° -170 ° C]

Example 16

[d, 1-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline]

A mixture of 3,5-dimethoxyaniline (4.6 g 0.03 mol), crotonic acid (2.54 g, 0.03 mol) and pyridine hydrogen chloride (3.0 g, 1.26 mol) and the like is heated at 185 ° -200 ° C. for 45 minutes. The reaction mixture is cooled, suspended in water (500 ml) (pH-3) and adjusted to pH 7 and the resulting mixture is stirred for 10 minutes. The organic layer is separated, dried (MgSO ₄ ) and concentrated to give 3.2 g of yellow oil.

The mixture of glacial acetic acid (110 ml), 48% bromic acid (110 ml) and the yellow oil is refluxed for 1 hour and concentrated in vacuo to give a thick oil. This oil is dissolved in water and the aqueous solution is neutralized with 1N sodium hydroxide to pH6-7. A saturated solution of brine is added and the resulting mixture is extracted with ethyl acetate. The combined extracts were dried (MgSO ₄ ) and concentrated under reduced pressure to give a thick oil (2.8 g). The crude residue was subjected to column chromatography on silica gel using benzene-ether (4: 1) as the eluent to yield further 510 mg of product. Melting Point: 168 ° -170 ℃

The product is further purified by recrystallization from ethyl acetate. Melting Point: 173 ° -174 ° C

Assay: for C ₁₀ H ₁₁ O ₃ N

Calculated Value: C 62.16, H 5.74, N 7.25%

Found: C 62.00, H 5.83, N 7.14%

m / e-193 (m ⁺ ), 178 (m ⁺ -methyl, chlorinated maximum)

Similarly, 3,3-dimethylacrylic acid and 3,5-dimethoxyaniline were subjected to silica gel chromatography (benzene / ether 1: 1 as eluent) to 5,7-dihydroxy-2,2-dimethyl-4- Oxo-1,2,3,4-tetrahydroquinoline is produced under yellow name.

Analyzes (MS): Maternal maximum (m ⁺ ) Calcd for C ₁₁ H ₁₃ O ₃ N: 207.0895,

Found: 207.0895

Base maximum (m ⁺ -15) Calcd for C ₁₀ H ₁₀ O ₃ N: 192.0661

Found: 192.0655

Likewise, styryl acetic acid and 3.5-dimethoxyaniline are condensed and purified using benzene / ether (3: 1) as eluent to give yellow d, 1-5,7-dihydroxy-2-benzyl-4- Oxo-1,2,3,4-tetrahydroquinoline is produced.

m / e = 269 (m ⁺ ) and 178 (m ⁺ -benzyl, base maximum)

MNR (CDCI ³ ) δ (ppm): 8.76 (s, 1H, 5-OH), 7.18-7.6 (m, 5H, C ₆ H ₅ ), 5.84 (d, J = 3Hz, 1H) for meta-bonded aromatics And 5.62 (d, J = 3 Hz, 1H), and 2.14-4.82 (4 m, 4) for the remaining protons (7-OH, CH-N, CH ₂ -C = 0, -CH ₂ -C ₆ H ₅ and NH). 7H).

Example 17

[d, 1-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline]

D, l-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (1.0 g, 52 mmol) solution in N, N-dimethylformamide (10 ml) To potassium hydroxide operation (325 mg, 52 mmol) is added. The mixture is slowly heated to 100 ° C. and d, l-2-bromoheptane (1.08 g, 60 mmol) is added in one portion while stirring the resulting solution well.

After 10 minutes, further potassium hydroxide (160 mg) is added and then d, .- 2-bromohetan (500 mg) is added again. Add another potassium hydroxide and d, l-2-bromoheptane two more times using 80 mg potassium hydroxide and 250 mg d, l-2-bromo-heptane each time.

The reaction mixture is stirred for another 10 minutes and then lowered. Chloroform (50 ml) and aqueous sodium hydroxide solution (1 ml of 25 ml) are added, the reaction mixture is stirred for 10 minutes and the liquid layer is separated. Chloroform extraction is repeated, the extracts are combined, dried (MgSO ₄ ) and concentrated under reduced pressure to give a thick oil. This oil is chromatographed on silica gel (120 g) using benzene as solvent. Collect 30 ml of each fraction. The 12-18th fractions were combined and concentrated under reduced pressure to yield a pale yellow oil (850 mg), which was then crystallized. The desired product is separated by filtration and recrystallized from hot hexanes. Melting Point: 76 ° -77 ℃

The process is repeated on a 20-fold scale of the above example using benzene-ethyl acetate (9: 1) as the chromatography solution. Collect 750 ml of each fraction. The 2-6th fractions combined add 32 g of oil, which is left to hexane to partially crystallize and then cooled to give 18.2 g of product. The mother liquor is concentrated and left to cool to crystallize to give 3.2 g more product. Total yield: 21.4g

Assay: for C ₁₇ H ₂₅ O ₃ N

Calculated Value: C 70.07, H 8.65, N 4.81%

Found: C 69.82, H 8.67, N 4.93%

m / e-29 (m ⁺ ) 1R (KBr): 6.01μ = 0)

Similarly, 5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline was converted into d, 1-5-hydroxy-7- (2-heptyloxy) -4-oxo-1, Conversion to 2,3,4-tetrahydroquinoline gives oil.

: 13.3(s,1H, 페놀성), 5.5 및 5.7(d, 2H,J=2Hz, 방향성), 4.6(bs, 1H, -NH), 4.1-4.6(m,1H,-0-CH-),3.3(t, 2H,J=7Hz, -CH₂-2.6(t,2H,J=7Hz,-CH₂-),2.0-0.7(m, 나머지 프로톤)1 H NMR (60 MHz) δ

: 13.3 (s, 1H, phenolic), 5.5 and 5.7 (d, 2H, J = 2 Hz, aromatic), 4.6 (bs, 1H, -NH), 4.1-4.6 (m, 1H, -0-CH-) , 3.3 (t, 2H, J = 7Hz, -CH ₂ -2.6 (t, 2H, J = 7Hz, -CH _2- ), 2.0-0.7 (m, rest proton)

Example 18

A mixture of 5-phenyl-2- (R, S) -pentanol (16.4 g, 100 mmol), triethylamine (28 ml, 200 mmol) and anhydrous tetrahydrofuran (80 ml) is cooled in an ice bath under nitrogen atmosphere. . Methanesulfonyl chloride (8.5 ml, 110 mmol) in anhydrous tetrahydrofuran (20 ml) is added dropwise to keep the temperature constant. The mixture is allowed to warm to room temperature and then filtered to remove triethylamine hydrogen chloride.

The filter residue is washed with anhydrous tetrahydrofuran, and the washing solution and the filtrate are combined and evaporated under reduced pressure to obtain a product oil. The oil is dissolved in chloroform (100 ml), the solution is washed with water (2 x 100 ml) and again with saturated brine (1 x 20 ml). Evaporation of the solvent yields 21.7 g (89.7% of mesylate salt of d, l-5-phenyl-2-pentanol, which is used in the next step without further purification) d, l-5,7-dihydroxy 2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (1.0 g, 52 mmol), potassium carbonate (14.35 g, 0.104 mol), N, N-dimethylformamide (60 ml) and k A mixture of l-5-phenyl-2-pentanol mesylate (13.68 g, 57 mmol) and the like is heated to 80'-82'C for 1.75 hours in an oil bath under nitrogen atmosphere.

The mixture is cooled to room temperature and then poured into ice water (300 ml). The aqueous solution is extracted with ethyl acetate (2 x 500 ml) and the extracts are combined and washed sequentially with water (3 x 50 ml) and saturated brine (1 x 50 ml). The extract is dried (MgSO ₄ ) decolorized with carbon and evaporated to give product. m./e-339 ⁽ m ⁺ )

114.8 g (0.594 mole) of 612 ml of N, N-dimethylformamide, 174,8 g (1.265 mole) of potassium carbonate and 165.5 g (0.638 mole) of d, l-5-phenyl-2-pentanol mesylate Repeat the method using. The reaction mixture is cooled, poured into iced water (4 L) and the aqueous solution is extracted with ethyl acetate (2 x 4 L). The combined extracts are washed with water (4 × 2 L) and brine (1 × 2 L) and dried. (MgSO ₄ ). Evaporation gives 196 g of the title product. This is used without further purification.

: 12.73(s,1H,OH), 7.22(s,5H, 방향성)5.80(d,J=3H₃,1H,메타H) H5.58(d,J=3H₃,1H,메타H),1.25(d,6H,CH₃-CH-N 및 CH₃-CH-0-1.41-4.81(m,11H, 나머지 프로톤.)1 H NMR (60 MHz) δ

: 12.73 (s, 1H, OH), 7.22 (s, 5H, directional) 5.80 (d, J = 3H ₃ , 1H, Meta H) H5.58 (d, J = 3H ₃ , 1H, Meta H), 1.25 (d, 6H, CH ₃ -CH-N and CH ₃ -CH-0-1.41-4.81 (m, 11H, remaining protons.)

Example 19

[d, l-5-hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydro] roquinoline 5,7-dihydroxy-2- The method of Example 18 using 5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline instead of methyl-4-oxo-1,2,3,4-tetrahydroquinoline Repeating to give d, l-5-hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline as oil. Yield = 74%

m / e-335 (m ⁺ )

Assay: for C ₂₀ H ₂₃ NO ₃

Calculated Value: C 73.70, H 7.12, N 4.31%

Found: C 73.69, H 7.15, N 4.08%

: 12.6(bs, 1H, 페놀성), 7.3(s,5H, 방향성, 5.8(d,1H, 방향성, J=2Hz), 5.6(d,1H, 방향성, J=2Hz), 4.7-4.1(m,2H,NH 및 0-CH),3.5(t,2h, CH₂,J=7Hz), 3.1-2.1(m,4H, 2-CH₂-) 2.1-1.5(m,4H,2-CH₂), 1.3(d,3H, -CH-CH₃,J=6Hz)1 H NMR (MHz) δ

: 12.6 (bs, 1H, Phenolic), 7.3 (s, 5H, Directivity, 5.8 (d, 1H, Directivity, J = 2Hz), 5.6 (d, 1H, Directivity, J = 2Hz), 4.7-4.1 (m , 2H, NH and 0-CH), 3.5 (t, 2h, CH ₂ , J = 7 Hz), 3.1-2.1 (m, 4H, 2-CH _2- ) 2.1-1.5 (m, 4H, 2-CH ₂ ), 1.3 (d, 3H, -CH-CH ₃ , J = 6Hz)

Similarly, d, l-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (27 g, 0.14 mole) was added to 4-phenylbutylmethanesulfonate (35.2 g , 0.154 mole) of 41.1 g (90%) of the desired d, l-5,7-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-1,2,3 To obtain 4-tetrahydrokinolyne. Melting point 88 ° -90 ° C. Recrystallized from ethyl acetate-hexane- (1: 2) to obtain an analysis table. Melting Point: 90 ° -91 ℃

For C ₂₁ H ₂₃ O ₃ N

Calculation: C 73.82, H 7.12, N 4.30%

Found: C 73.60, H 7.09, N 4.26%

m / e-325 (m ⁺ )

: 12.58(s,1H,OH), 7.12(s,5h,c6h5),5.74(d,J=2.5Hz,1H,메타H), 5.5(d,J=2.5Hz, 1H, 메타H), 4.36(bs, 1H,NH), 3.33-4.08(m,3H,-0-CH₂,-CH-N),2.29-2.83(m,4H,-CH₂-C=0,C₆H₅-CH₂),1.51-1.92(m,4H,-[CH₂]₂), 1.23(d,3H,CH₃-)1 H NMR (60 MHz) δ

: 12.58 (s, 1H, OH), 7.12 (s, 5h, c6h5), 5.74 (d, J = 2.5Hz, 1H, Meta H), 5.5 (d, J = 2.5Hz, 1H, MetaH), 4.36 (bs, 1H, NH), 3.33-4.08 (m, 3H, -0-CH ₂ , -CH-N), 2.29-2.83 (m, 4H, -CH ₂ -C = 0, C ₆ H ₅ -CH ₂ ), 1.51-1.92 (m, 4H,-[CH ₂ ] ₂ ), 1.23 (d, 3H, CH _3- )

In a similar manner, d, -5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline is alkylated with d, -2-octylmethanesulfonate to give d-5-hydroxy-2 Obtain -methyl-7- (2- (R) -octyloxy-4-oxo-1,2,3,4-tetrahydroquinoline Melting point: 64 ° -68 ° C

= +110.2°(C=1.0,CHCl₃)

= + 110.2 ° (C = 1.0, CHCl ₃ )

D, l-5,7-dihydroxy-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline is also alkylated with d, l-5-phenyl-2-pentanol mesylate d, l-5,7-hydroxy-7- (5-phenyl-2-pentyloxy) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline is obtained. m / e-367 (m ⁺ )

Example 20

[d, l-5,7-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3, 4-tetrahydroquinoline]

Sodium hydride (72 g, 3.0 moles) obtained by washing 50% sodium hydride (114 g) with hexane (3 x 500 ml) was stirred well, while about one drop of a solution of about 0.58 mole in etherformate (1140 g, 14.6 moles). Squeeze After about 1.5 hours, when two-thirds of ethyl formate solution is added, the solution stops adding and the resulting bubbles disappear. Diethyl ether (600 ml) is added and the mixture is stirred for 15 minutes before adding the remaining ethyl formate solution. The mixture is stirred for 15 minutes before adding the ethyl formate solution. After the ethyl formate solution was added, diethyl ether (60 ml) was added, and the reaction mixture was stirred for another 10 minutes, and then poured into ice water (2 L). It is acidified with 10% HCl to pH1, phase separated and extracted with ethyl acetate (2 × 2 l).

The organic solutions are combined, washed successively with water (2 x 2 l), brine (1 x 1 l), and dried. (MgSO ₄ ). Concentration produces 213 g of reddish brown oil, which is used without further purification.

Rf = 0.1-0.5 (expanded in pesticide chromatography, silica gel plate, benzene / ether (1: 1))

Likewise d, l-5-hydroxy-7- (5-phenyl-2-pentyloxy) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline d, l-5,7 -Formyl-5-hydroxy-3-hydroxymethylene-7- (5-phenyl-2-pentyloxy-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline. This is used in the following example as it is.

Example 21

d, l-1-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline

Sodium hydride (18.2 g, 0.38 mole) obtained by washing 50% sodium hydride in mineral oil dispersion with pentane, d, l-5-hydroxy-2-methyl in ethyl formate (110 g, 1.48 mole) A solution of -7- (2-heptyloxy) -4-oxo1,2,3,4-tetrahydroquinoline (11.1 g, 0.038 mol) is added dropwise over half an hour. An exothermic reaction results in the active release of hydrogen and the formation of a yellow precipitate. After cooling the reaction mixture and adding ether (750 ml), the resulting mixture is heated to reflux and stirred for 3 hours.

It is cooled to 0 DEG C and neutralized by addition of 1N hydrochloric acid (400 ml). The ether layer is separated and the aqueous layer is extracted with ether (2 x 150 ml). The combined ether extracts are washed sequentially with saturated sodium bicarbonate solution (2 x 100 ml) and brine (1 x 150 ml) and dried. (MgSO ₄ ). Concentration of the dry extract produces orange foam (10.8 g). The sodium bicarbonate washing solution is acidified with concentrated hydrochloric acid, acidified, and the acidic solution is extracted with ether (2 x 100 ml) to obtain 2.3 g of further product.

The combined ether extracts are dried and concentrated to yield 2.3 g of product. (Total yield = 13.1 g). This product is used as is.

: 12.27(ds,1H,ArOH),8.8-11.9(m,1H, 가변성=COH),8.73(s,1HN -CHO),7.41(s,1H,=CH), 6.32(s,2H,방향성),5.52(q, 1H,-CH-N), 4.18-4.77(m,1H,-0-CH),0.6-2.08(m,17H,CH₃-C-C₅H₁₁및 CH₃-C-N).1 H NMR (60 MHz) δ

: 12.27 (ds, 1H, ArOH), 8.8-11.9 (m, 1H, variable = COH), 8.73 (s, 1HN-CHO), 7.41 (s, 1H, = CH), 6.32 (s, 2H, aromatic) , 5.52 (q, 1H, -CH-N), 4.18-4.77 (m, 1H, -0-CH), 0.6-2.08 (m, 17H, CH ₃ -CC ₅ H ₁₁ and CH ₃ -CN).

In a similar manner, d, l-5--hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline is added to d, l -1-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline Switch.

(60MHz)δ

: 12.22(bs,1H,ArOH), 8.8-11.6(가변성,1H,=COH),8.64(s, 1H,CHO),7.21(bs,7.30에서 쇼올더, 6H,방향성 및 =CH), 6.23 및 6.17(2개의 1H,2조, J=2Hz, 메타), 5.42(bq,1H,N-CH), 4.18-4.70(m,1H,-OCH), 2.4-3.0(m,2H,Ar-CH₂),1.53-2.0(m,4H,-(CH₂)₂-),1.29(중첨 2조,6H,CH₃-C-N 및 CH₃-C-0)1 H NMR (60 MHz) δ

(60 MHz) δ

: 12.22 (bs, 1H, ArOH), 8.8-11.6 (variable, 1H, = COH), 8.64 (s, 1H, CHO), 7.21 (showers at 6, bs, 7.30, 6H, aromatic and = CH), 6.23 and 6.17 (two 1H, two sets, J = 2Hz, meta), 5.42 (bq, 1H, N-CH), 4.18-4.70 (m, 1H, -OCH), 2.4-3.0 (m, 2H, Ar-CH ₂ ), 1.53-2.0 (m, 4H,-(CH ₂ ) _2- ), 1.29 (duplex 2,6H, CH ₃ -CN and CH ₃ -C-0)

d, l-5-hydroxy-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline is d, l-1-formyl-5-hydroxy-3- Convert to the oil of hydroxymethylene-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline.

: 12.1(bs,1H, 페놀성, 8.8(s,1H,-N-CHO), 8.1(s,1H),7.3(s,1H),6.1(s,2H,방향성)4.5(bs,2H,-CH₂),4.2-4.8(m,-0-CH₂-),2.C-0.7(나머지 프로톤).1 H NMR (60 MHz) δ

: 12.1 (bs, 1H, Phenolic, 8.8 (s, 1H, -N-CHO), 8.1 (s, 1H), 7.3 (s, 1H), 6.1 (s, 2H, Aromatic) 4.5 (bs, 2H, -CH ₂ ), 4.2-4.8 (m, -0-CH _2- ), 2.C-0.7 (rest protons).

d, l-5-hydroxy-7- (5-pentyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline is converted to quinoline.

: 12.4(bs,1H,페놀성),8.5(s,1H,CHO),7.2(m,6H,방향성 및=CH-),6.2(m,2H, 방향성),4.5(s,2H,-CH₂-),4.4(m,1H,-CH-CH₃), 2.6(bt, 2H,-CH₂, 1.7(m,5H,나머지 프로톤),1.3(d,3H,-CH-CH₃,J=6Hz)1 H NMR (60 MHz) δ

: 12.4 (bs, 1H, Phenolic), 8.5 (s, 1H, CHO), 7.2 (m, 6H, aromatic and = CH-), 6.2 (m, 2H, aromatic), 4.5 (s, 2H, -CH _2- ), 4.4 (m, 1H, -CH-CH ₃ ), 2.6 (bt, 2H, -CH ₂ , 1.7 (m, 5H, remaining protons), 1.3 (d, 3H, -CH-CH ₃ , J = 6 Hz)

And d, l-5-hydroxy-2-methyl-7- (4-phenylbutyroxine) -4-oxo-1,2,3,4-tetrahydroquinoline is d, l-1-formyl- Convert to 5-hydroxy-3-hydroxymethylene-2-methyl-7- (4-phenylphenylbutythoxy) -oxo-4-1,2,3,4-terahydroquinoline. Melting point = 132 ° -135 ° C. (from hexane), recrystallized from hot methanol, to obtain analytical specimens. Melting point = 131 ° -132 ° C

For C ₂₂ H ₂₃ O ₅ N

Calculated Value: C 69.27, H 6.08, N 3.67

Found: C 69.25, H 5.88 N 3.88

m / e -381 (m ⁺ )

: 12.4-13.6(m,H,

),12.26(s,1H,5-OH),8.62(s,1H,-C(=0)-H),약 7.18-7.48(m,1H,

), 7.27(s,5H,C₆H₅),6.26(bs,2H,H'S),5.46(q,1H,CH-(H, 3.82-4.23( m,3H,-CH₂-O),2.49-2.80(m,3H,ArCH₂),1.67-2.02(m,4H,-[CH₂]₂-),1.27(D,3H,CH₃)1 N NMR (60 MHz) δ

: 12.4-13.6 (m, H,

), 12.26 (s, 1H, 5-OH), 8.62 (s, 1H, -C (= 0) -H), about 7.18-7.48 (m, 1H,

), 7.27 (s, 5H, C ₆ H ₅ ), 6.26 (bs, 2H, H'S), 5.46 (q, 1H, CH- (H, 3.82-4.23 (m, 3H, -CH ₂ -O), 2.49 -2.80 (m, 3H, ArCH ₂ ), 1.67-2.02 (m, 4H,-[CH ₂ ] _2- ), 1.27 (D, 3H, CH ₃ )

Example 22

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

Methanol (880ml) inside and outside d, l-1-formyl-3-hydroxymethylene-5-hydroxy-2-methyl-7-15-phenyl-2-pentyloxy) -4-oxo-1,2,3 Triethylamine (27.2 ml) is added while stirring the, 4-tetrahydro chinoline (22 gg, about 0.58) solution under nitrogen atmosphere. Methyl vinyl ketone (97.0 ml) is then added and the mixture is stirred overnight at room temperature.

Here the reaction is complete and the product is d, l-1,3-diformyl-5-hydroxy-2-methyl-7- (5-phenyl-2-phenyloxy) -4-oxo-3 -(3-oxobutyl) -1,2,3,4-tetrahydroxyquanoline. The following steps are necessary to convert the diformyl compound to the title compound.

The reaction mixture is diluted with edel (6 L), washed sequentially with aqueous 10-sodium carbonate solution (4 × 1700 ml) and brine (1 × 2 l), followed by drying (MgSO ₄ ). Concentration of the solution yields 238 g of reddish brown oil. The oil is dissolved in methanol (1920 ml) and the solution is cooled to 0 ° C. Potassium carbonate (21.2 g) is added and the mixture is stirred at 0 ° C. for 3 hours and then treated with acetic acid (18.7 g). The methanol is removed under reduced pressure, and the resulting oil is stirred for 10 minutes with water (2 L), ethyl acetate (2 L) and the like. The aqueous phase is separated and extracted with ethyl acetate (1 × 2 L), then the combined ethyl acetate solutions are washed with water (2 × 2 L) and brine (1 × 2 L) and dried (MgSO ₄ ). Concentration under reduced pressure and chromatography of the concentrate on silica gel (1.8 kg) gave 159 g of the title product.

m / e -437 (m ⁺ )

: 12.7(s,1H,OH),8.78(bs,1H,-CHO),7.22(s, 5H,방향성),6.22( bs,2H,메타 H'S),2.12,2.07(s,3H,-CH₃-CO),1.31(d, 3H, -CH₃-C-O-), 및 1.57-5.23(m,13H,나머지 프로톤).1 H NMR (60 MHz) δ

: 12.7 (s, 1H, OH), 8.78 (bs, 1H, -CHO), 7.22 (s, 5H, directional), 6.22 (bs, 2H, meta H'S), 2.12,2.07 (s, 3H, -CH ₃ -CO), 1.31 (d, 3H, -CH ₃ -CO-), and 1.57-5.23 (m, 13H, remaining protons).

22.7 g (60%) of 35 g (0.09 mol) of d, l-1-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7) (4-phenylbutyloxy) quinoline similarly treated D, l-1-formyl-5-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4- Tetrahydroxyginoline is produced. Melting point = 101 ° -103 ° C. Recrystallized from ethanol to obtain analytical sample. Melting point = 104 ° -105 ° C

For C ₂₅ H ₂₉ O ₅ N

Calculated Value: C 70.90, H 6.90, N 3.31

Found: C 70.77, H 6.81, N 3.46

: 12.88(s,1H,OH), 9.08(bs,1H,-CHO), 7.29(s,5H, C₆H₅), 6.25(bs,2H, 메타 H'S),4.88-5.43(m,1H,-CHN), 3.86-4.21(m,2H,-CH₂-O-), 약 2.49-3.02(m,7H, ArCH2,-(CH₂)₂-C(=O)-,-CH-C(=0)], 2.18[s,3H,CH₃-C(=0)], 1.68-2.03[m,4H,-(CH₂)₂-],1.13(d,3H,CH₃).1 H NMR (60 MHz) δ

: 12.88 (s, 1H, OH), 9.08 (bs, 1H, -CHO), 7.29 (s, 5H, C ₆ H ₅ ), 6.25 (bs, 2H, meta H'S), 4.88-5.43 (m, 1H, -CHN), 3.86-4.21 (m, 2H, -CH ₂ -O-), about 2.49-3.02 (m, 7H, ArCH ₂ ,-(CH ₂ ) ₂ -C (= 0)-, -CH-C ( = 0)], 2.18 [s, 3H, CH ₃ -C (= 0)], 1.68-2.03 [m, 4H,-(CH ₂ ) _2- ], 1.13 (d, 3H, CH ₃ ).

m / e -423 (m ⁺ )

It also generates, which is used as is.

Example 23

d, l-1-formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydro Chinoline and d, l-1,3-diformyl-5-hydroxy-2-methyl-7- (2-haptyloxy) -4-oxo-3- (3-octabutyl) -1,2, 3,4-tetrahydroquinoline

D, l-5-hydroxy-3-hydroxymethylene-2-methyl-7- (2-heptylhydroxy) -4-oxo-1, in methanol (56 ml) and methylvinylkenone (5.25 mg, 68 mmol) Triethylamine (1.3 ml, 9.3 mmol) is added to a 2,3,4-tetrahydrokinoline (13.1 g, 37.7 mmol) solution. The mixture is stirred for 18 h at room temperature under a nitrogen atmosphere and diluted with ether (550 ml). The solution is washed gradually with 10% aqueous sodium bicarbonate solution (4 x 60 ml) and brine (1 x 100 ml) and dried (MgSO ₄ ). The ether is evaporated off to produce thick oil (16 g).

The oil is dissolved in the minimum volume of benzene and the solution is placed in a column of silica gel (500 g). Eluting with benzene in the same volume as this column. Change the eluting solvent to 15% ether-benzene and collect 100 ml fractions when the first color band begins to elute in the column. When the fractions 5-13- are combined and concentrated under reduced pressure, the yellow oil is d, l-1,3-diformyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroxyquinoline (8.7 g) is produced.

The column is further eluted with 15% ether-benzene. Combination of the fractions 19-37 and concentration under reduced pressure yields d, l-1,3-diformyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3 Oxobutyl) -1,2,3,4-tetrahydroxyquinoline (4.6 g) is produced. Further monoformyl products are obtained in the following manner.

1 g of diformyl product is stirred with 200 mg of potassium carbonate in methanol (25 ml) at 0 ° C. for 2 hours. The solvent is evaporated in vacuo, the residue is suspended in ether and 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 ether extracts are combined, washed successively with saturated sodium bicarbonate solution and brine, dried (MgSO ₄ ), filtered and concentrated to afford additional monoformyl product.

Monoformyl derivatives have the following NMR spectrum:

: 12.73(s,1H,ArOH), 8.87(s,1H,N-CHO),6.12(s,2H, 방향성),4.78-5.50(m,1H,N-CH), 4.11-4.72(m,1H,O-CH),2.21( s,3H,-CH3C(=O)-),0.63-3.12(m,22H,나머지 수소).1 H NMR (60 MHz) δ

: 12.73 (s, 1H, ArOH), 8.87 (s, 1H, N-CHO), 6.12 (s, 2H, directional), 4.78-5.50 (m, 1H, N-CH), 4.11-4.72 (m, 1H , O-CH), 2.21 (s, 3H, -CH3C (= 0)-), 0.63-3.12 (m, 22H, remaining hydrogen).

Likewise, the following compounds are prepared from suitable reactants.

d, l-1-formyl-5-hydroxy-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline, oil

:₂-),2.3-3.0(m,3H,CH2및 CH-C(=O)),2.2(s ,3H,-C(=O)-CH3),2.3-0.7(나머지 프로톤).1 H NMR (60 MHz) δ

: _2- ), 2.3-3.0 (m, 3H, CH 2 and CH-C (= 0)), 2.2 (s, 3H, -C (= 0) -CH 3), 2.3-0.7 (rest proton).

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

: 12.68(s,1H,-OH),8.82(b,s,1H,-C(O)H),7.20 (b,s,5H,-C₆H₅), 6.18(b,s,2H, 방향성),4.78-5.34(m,1H-N-CH),4.18-4.68(m,1H,-O-CH),2.17(s,3H,C(O)CH₃),1.30(d,3H,-O-C-CH₃),1.12(d,3H,-N-C-CH₃),1.4-3.1(m,1H,나머지 H'S).1 H NMR (60 MHzδ)

: 12.68 (s, 1H, -OH), 8.82 (b, s, 1H, -C (O) H), 7.20 (b, s, 5H, -C ₆ H ₅ ), 6.18 (b, s, 2H, Directional), 4.78-5.34 (m, 1H-N-CH), 4.18-4.68 (m, 1H, -O-CH), 2.17 (s, 3H, C (O) CH ₃ ), 1.30 (d, 3H, -OC-CH ₃ ), 1.12 (d, 3H, -NC-CH ₃ ), 1.4-3.1 (m, 1H, remaining H'S).

d, l-1-formyl-5-hydroxy-7- (5-phenyl-2-pentyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydro Quinoline

m / e -423 (m ⁺ )

In addition, in each of the above-mentioned manufacturing methods, a corresponding 1,3-diformyl derivative additive product is produced.

Example 24

d, l-5,6,6a, 7-tetrahydro-1-hydroxy-6β-methyl-3- (5-phenyl-2-pentyloxy) benzo [C] quinoline-9 (8H) -silver

D, l-1-formyl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo- in methinolic 2N KOH (5.9l) and methanol (5.9l) The 3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline (174 g, 0.398 mol) solution is stirred and heated to reflux overnight under a nitrogen atmosphere. After cooling the solution, acetic acid (708 g) is added dropwise with stirring over 15 minutes. The resulting solution is concentrated by rotary vacuum evaporation to produce a semi-solid material that is filtered and washed first with water to remove potassium acetate and then with ethyl acetate to remove all black tar. Yield = 68 g (44%) of yellow solid. Melting point = 188 ° -190 ° C. Recrystallized from hot ethyl acetate to obtain pure product. Melting point = 194 ° -195 ° C.

m / e -391 (m ⁺ )

Assay: for C ₂₅ H ₂₉ O ₃ N

Calculated Value: C 76.09, H 7.47, N 3.58

Found: C 76.43, H 7.48, N 3.58

(0.3ml의 CD₃OD 및 0.3ml의 CD₃S(O)CD₃에 용해된 100mg)(ppm) :7.21(s,5H,방향성),5.80(s,2H, 메타 H'S),1.20(d,6H,CH₃-CHO 및 CH₃-CH-N).1 H NMR (60 MHz)

(100 mg dissolved in 0.3 ml of CD ₃ OD and 0.3 ml of CD ₃ S (O) CD ₃ ) (ppm): 7.21 (s, 5H, aromatic), 5.80 (s, 2H, Meta H'S), 1.20 (d , 6H, CH ₃ -CHO and CH ₃ -CH-N).

Evaporation from the mother liquor yields a small amount of the corresponding trans methyl derivative. This was purified by column chromatography on silica gel using benzene ether (1: 1) as eluent. Eluent is evaporated and the residue is recrystallized from ether / hexane (1: 1) to give analytical pure material. Melting point = 225 ° -228 ° C

The thin layer chromatography on silica gel, using 2.5% ethanol in ether, as eluent, and the Rf value of the material when blue was observed was 0.34. 6β-methyl derivative has Rf = 0.41

m / e -391 (m ⁺ )

(0.3ml의 CD₃OD 및 0.3ml의 CD₃S(O)CD₃내에 용해된 100mg)(ppm) : 7.19(s,5H,방향성),5.75(s,2H,메타 H'S),1.21(d,3H,CH₃-CHO), 및 -0.95(d,3H,CH₃-CH-N).1 H NMR (60 MHz)

(100 mg dissolved in 0.3 ml of CD ₃ OD and 0.3 ml of CD ₃ S (O) CD ₃ ) (ppm): 7.19 (s, 5H, aromatic), 5.75 (s, 2H, meta H ′S), 1.21 (d , 3H, CH ₃ -CHO), and -0.95 (d, 3H, CH ₃ -CH-N).

d, l-1-formyl-5-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetra Similar treatment of hydroquinoline resulted in 17.1 g (87%) of d, l-5,6,6a, 7-tetrahydro-1-hydroxy-6β-methyl-3- (4-phenylbutyloxy) benzo [C] Quinolin-9 (8H) -one is produced.

Melting point = 222 ° -224 ° C. Recrystallized from methanol to obtain analytical sample. Melting point = 224 ° -225 ° C

For C ₂₄ H ₂₇ O ₃ N

Calculated Value: C 76.36, H 7.21, N 3.71

Found: C 76.03, H 7.08, N 3.68

1 H NMR (60 MHz) [1: 1 mixture of (CD ₃ ) ₂ SO and DC ₃ OD]: 1.24 (d, 3H, 6β-CH ₃ )

m / e-377 (m ⁺ )

Evaporation of the mother liquor gave 2.8 g of product (melting point = 185 ° -195 ° C.), which was determined by NMR to give 6β-methyl derivative (about 40%) and d, l-5,6,6a, 7-tetrahydro It is shown that it is a mixture of 1-hydroxy-6α-methyl-3- (4-phenylbutyloxy) -benzo [C] quinolin-9 (8H) -one.

1 H NMR (60 MHz) [1: 1 mixture of (CD ₃ ) ₂ SO and CD ₃ OD]: 1.24 (d, 1.2H, 6β-CH ₃ ) and 0.95 (d, 1.8H, 6α-CH ₃ )

Example 25

d, l-5,6,6a, 7-tetrahydro-1-hydroxy-6β-methyl-3- (2-heptyloxy) benzo [C] quinolin-9 (8H) -one

D, l-1-formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3 in methanol (150 ml) A, 4-tetrahydroquinoline (4.5 g, 11.5 mmol) solution is treated with 2N potassium hydroxide methinolone solution (150 ml). The mixture is stirred at room temperature for 1 hour and then heated to reflux for 20 hours under a nitrogen atmosphere.

The dark red mixture is allowed to cool to room temperature, neutralized with acetic acid and concentrated to about 100 ml.

The concentrate is diluted with water (400 ml) and the reddish brown solid is separated by filtration, washed with water and dried. It is first triturated in ethanol and then in methanol, filtered and dried (1.96 g). Melting point = 223 ° -229 ° C.

Recrystallization from hot ethanol gives a crystal having a melting point of 225 ° -227 ° C.

For C ₂₁ H ₂₉ O ₃ N

Calculated Value: C 73.43, H 8.51, N 4.08%

Found: C 73.22, H 8.30, N 4.11%

All the mother liquor is evaporated and further material is recovered by chloroform extraction of the aqueous solution from which the reddish brownish preparation is obtained, followed by evaporation of the extract. The remaining mules are combined and purified by silica gel chromatography using ether as eluent.

In the same manner, the following compounds are prepared from suitable reactants.

d, l-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyloxy) benzo [C] quinolin-9 (8H) -one, melting point 170 ° -173 ° C (recrystallized from chloroform)

m / e -337 (m ⁺ )

Assay: for C ₂₄ H ₂₇ O ₃ N

Calculated Value: C 76.36, H 7.21, N 3.71%

Found: C 76.38, H 7.21, N 3,85%

d, l-5,6,6a, 7-tetrahydro-1-hydroxy-3- (2-heptyloxy) benzo [C] quinoline-9 (8H) -silver, melting point = 208 ° -209 ° C

m / e -329 (m ⁺ )

Assay: for C ₂₀ H ₂₇ O ₃ N

Calculated Value: C 77.29, H 7.93, N 3.34%

Found: C 76.97, H 7.98, N 3.41%

d, l-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyloxy) -6β-methyl benzo [C] quinolin-9 (8H) -one, melting point = 176 ° -178 ° C

=-416.0°(C=0.33, CH3OH)

= -416.0 ° (C = 0.33, CH3OH)

m / e -391 (m ⁺ )

Assay: for C ₂₅ H ₂₉ O ₃ N

Calculated Value: C 76.69, H 7.47, N 3.58%

Found: C 76.32, H 7.36, N 3.33%

d, l-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyloxy) -6β-methyl benzo [C] quinolin-9 (8H) -one, melting point = 172 ° -174 ° C

=+412.9°(C=1.0,CH3OH)

= + 412.9 ° (C = 1.0, CH3OH)

m / e -391 (m ⁺ )

Assay: for C ₂₅ H ₂₉ O ₃ N

Calculated Value: C 76.69, H 7.47, N 3.58%

Found: C 76.40, H 7.39, N 3.51%

Example 26

d, l-trans-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9-hydroxy-6β-methyl-3- (2-heptyloxy) benzo [C ] Quinoline.

A suspension of 150 (0.39 mmol) quinoline-9 (8H) -one in ethanol (10 ml) is added 40 mg of sodium borohydride with stirring at 0 ° C. After 0.5 h the reaction mixture is poured into ice-cold 5% acetic acid (50 ml) and ether (75 ml). After separating the ether layer, the aqueous layer is further extracted with ether (2 x 500 ml). The combined ether extracts were washed sequentially with water (2 × 500ml), saturated sodium bicarbonate solution (1 × 50ml), brine (1 × 75ml), dried MgSO ₄ ), filtered and concentrated under reduced pressure to give 156mg of white foam. This bubble is d, l-trans-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9-hydroxy-6β-methyl-3- (2-heptyloxy ) Is a mixture of trans alcohol (large) and cis alcohol (large) of benzo [C] quinoline.

m / e -389 (m ⁺ )

1R (CHCl ₃ ) 5.72μ (Carbonyl ester)

초산메틸에 대한 2.28ppm에서 특색있는 단일선을 보임.NMR (60MHZ,

Characteristic singlet at 2.28 ppm for methyl acetate.

The isomers are separated in the following manner.

d, l-trans-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9-hydroxy-6β-methyl-3- (2-heptyloxy) -benzoquinoline 180 mg of alcohol is added to a column containing 15 g of silica gel and eluted with a mixed solvent of benzene / ether (3: 1). Collect 15 ml aliquots. The fractions 6-8 were combined and concentrated under reduced pressure to give 13 mg of d, l-trans-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9α-hydroxy-6β- Methyl-3- (2-heptyloxy) benzo [C] quinoline is produced.

Combine and concentrate fractions 11-16 to 83 mg of d, l-trans-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9β-hydroxy-6β-methyl- 3- (2-heptyloxy) benzo [C] quinoline is produced.

Other compounds prepared from the appropriate reactants by the methods described above include the following.

d, l-trans-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9-hydroxy-6β-methyl-3- (5-phenyl-2-heptyloxy ) Benzo [C] quinoline.

m / e -437 (m ⁺ )

IR (CHCl ₃ ) -5.70μ (carbonyl ester)

Conversion to hydrogen chloride produces a solid (melting point 188 ° -190 ° C.). Recrystallization from acetone / methanol / ether (25: 1: 100) gives analytical samples of 9β-alcohol. Melting point = 193 ° -194 ° C

Assay: C ₂₇ H ₃₅ O ₄ N. for HCl

Calculated Value: C, 68.42, H, 7.70, N, 2.89%

Found: C, 68.48, H, 7.70, N, 2.89%

Conversion to methanesulfonic acid (to methanesulfonic acid in dichloromethane) produces a solid, which is recrystallized from ethyl acetate to give white crystals. Melting point = 110 ° -114 ° C

IR (CHCl ₃ ): 2.95, 3.70, 3.95, 5.60, 6.06, 6.19 and 6.27μ

Assay: for C ₂₇ H ₃₅ O ₄ N. CH ₄ O ₃ S

Calculated Value: C, 63.02, H, 7.37, N, 2.63%

Found: C, 62.90, H, 7.31, N, 2.74%

d, l-cis-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9-hydroxy-6β-methyl-3- (5--phenyl-2-pentyl Oxy) benzo [C] quinoline.

m / e -437 (m ⁺ )

IR (CHCl ₃ ) 5.71μ (Carbonyl ester)

d, l-trans-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9β-hydroxy-6β-methyl-3- (5--phenyl-2-pentyl Roxy) benzo [C] quinoline, melting point = 120 ° -125 ° C (obtained from hydrogen chloride)

=-98.57°(C=0.351,CH₃OH).

= -98.57 ° (C = 0.351, CH ₃ OH).

m / e -437 (m ⁺ )

Assay: for C ₂₇ H ₃₅ O ₄ N · HCl

Calculated Value: C, 68.42, H, 7.66, N, 2.96%

Found: C, 68.24, H, 7.68, N, 3.00%

d, l-trans-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9β-hydroxy-6β-methyl-3- (5-phenyl-2-pentyloxy ) Benzo [C] quinoline, melting point = 120 ° -125 ° C (obtained from hydrogen chloride)

=+99.33°(C=0.30,CH₃OH)

= + 99.33 ° (C = 0.30, CH ₃ OH)

m / e -437 (m ⁺ )

Assay: for C ₂₇ H ₃₅ O ₄ N · HCl

Calculated Value: C, 68.42, H, 7.66, N, 2.96%

Found: C, 68.41, H, 7.54, N, 2.95%

In a similar manner, the compounds in the table below are prepared from suitable reactants.

* Prepared by adding HCl gas to ether ether solution

Example 27

d, l-trans-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9β-hydroxy-6β-methyl-3- (5--phenyl-2-pentyl Roxy) benzo [C] quinoline

Sodium borohydride (7.57 g, 0.20 mol) is added to methanol (200 ml) under a nitrogen atmosphere and cooled to about -75 ° C in an acetone / dry ice bath. The mixture is stirred for about 20 minutes to dissolve most (but not all) sodium borohydride. D, l-trans-5,6,6αβ, 7,8,9,10,10aα-hexahydro-1-acetoxy-6β-methyl-3- (5--phenyl-2 in tetrahydroputane (88 ml) Cool a solution of -pentyloxy) benzo [C] quinolin-9 (8H) -one (8.71 g, 0.02 mol) to approximately -50 ° C and add dropwise to the sodium borohydride solution over 5-10 minutes. do. After stirring the reaction mixture at about -70 [deg.] C. for 30 minutes, a mixture of water (1000 ml) including ammonium chloride (45 g, 0.80 mol), crushed ice (250 ml), ethyl acetate (250 ml) and the like is poured. The liquid layer is separated and the aqueous phase is washed with ethyl acetate (3 x 200 ml) and dried (MgSO ₄ ). The dried extract is cooled to about 5 ° C. Next, a solution of ethyl acetate (15 ml) /1.5 NHCl (0.025 mol) was added dropwise over 15 minutes. Stirring the mixture at 0 ° -5 ° C. precipitates the hydrogen chloride of the title product. The mixture is stirred for half an hour and filtered to yield 6.378 g (67.3%) of product when the salt is dried at 25 ° C./0.055 mm. Melting point = 195 ° -198 ° C

The title product is also prepared by the following method.

d, l-trans-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9β-hydroxy-6β-methyl-3- (5--phenyl-2-pentyl Roxy) benzo [C] quinoline

D, l-5,6,6a, 7-tetrahydro-1-acetoxy-6β-methyl-3- (5-phenyl-2-pentyloxy) benzo [C] quinoline-9 (8H) in methanol (30 ml) The heterogeneous mixture of) -one (3.0 g, 7 mmol) and palladium on carbon (5% 3.0 g) is hydrogenated with 50 psi of hydrogen at room temperature for 3 hours. The catalyst is filtered off and the methanol glycol filtrate is evaporated under reduced pressure to give the title product.

The product is taken up in ethyl acetate (300 ml) and the solution is cooled to 0 ° C. Excess addition of saturated hydrogen chloride solution in ethyl acetate precipitates the hydrogen chloride of the title product into a white solid. It is filtered, washed with ethyl acetate and dried.

d, l-5,6,6a, 7-tetrahydro-1-acetoxy-6β-methyl-3- (5-phenyl-2-pentyloxy) benzo [C] quinolin-9 (8H) -one is It is prepared as follows.

D, l-5,6,6a, 7-tetrahydro-1-hydroxy-6β-methyl-3- (5-phenyl-2-pentyloxy) benzo [C] quinoline-9 (8H) in pyridine (45 ml) A solution of) -one (4.5 g, 0.0115 mole) is added with acetic anhydride (45 ml) with stirring at room temperature. The solution is stirred for 3.5 hours and then poured into ice water (250 ml) and the mixture is extracted with diisopropyl ether (2 x 250 ml). The combined extracts are washed with water (3 × 200 ml), dried (MgSO ₄ ) and evaporated under reduced pressure to give a tan oil. When the wall of the flask containing this oil is scratched, the oil becomes solid. Trituration of this solid with n-heptane yielded 2.0 g of 1-hacetoxy derivative (yield 40%). Purification by recrystallization from hot chloroform-n-hexane (1: 4) gives pure ester. Melting point = 136 ° -140 ° C

m / e -433 (m ⁺ )

: 7.21(bs, 5H, 방향성), 6.62(d,J=1.5Hz, 1H, C=C-H), 5.97(d,J=3Hz, 1H,메타H) 5.86(d, J=3Hz,1H,메타H),2.27[S,3H,CH3-C(=O)], 1.21(d,H=7Hz,6H, CH3-C-N,CH3-C-O),1.49-4.51m,14H,나머지 프로톤).1H NMR (60MHZ)

7.21 (bs, 5H, Directional), 6.62 (d, J = 1.5 Hz, 1H, C = CH), 5.97 (d, J = 3 Hz, 1H, Meta H) 5.86 (d, J = 3 Hz, 1H, Meta H), 2.27 [S, 3H, CH3-C (= 0)], 1.21 (d, H = 7 Hz, 6H, CH3-CN, CH3-CO), 1.49-4.51 m, 14H, remaining protons.

Example 38

d, l-cis-5,6,6αβ, 7,8,9,10,10aα-octahydro-1-acetoxy-9α-hydroxy-6β-methyl-3- (5--phenyl-2-pentyl Roxy) benzo [C] quinoline

D, l-cis-5,6,6αβ, 7,8,9,10,10aα-hexahydro-1-acetoxy-6β-methyl-3- (5--phenyl- in anhydrous tetrahydrobutane (100 ml) Sodium tri-sec-butyl borohydride (0.5M concentration) over 5 minutes while stirring a solution of 2-pentyloxy) benzo [C] quinolin-9 (8H) -one (1.0 g, 2.296 mmol) at -78 ° C 4.6 ml, 2.296 mmol) of was added dropwise. The reaction mixture is further stirred at −78 ° C. for 30 minutes and then poured into a solution of 5% acetic acid (250 ml) and ether (500 ml) previously cooled to 0 ° C. The liquid layer is separated and the aqueous layer is extracted with additional ether (250 ml). The ether extracts were combined, washed with water (2 × 250ml), saturated sodium bicarbonate solution (1 × 250ml), brine (1 × 250ml), dried over MgSO ₄ and concentrated in vacuo to give a yellow oil (1.4g). ) Is generated. The crude oil is chromatographed on silica gel (100 g) using benzene-ether (3: 1) as eluent. After eluting the less polar impurities, the title compound is separated into a clear oil (700 mg). This oil was dissolved in ethane (35 mg), treated with ethane saturated with HCl gas and recrystallized from ether / chloroform to give the hydrogen chloride of the title compound (448 mg). Melting Point = 115 ° -124 ° C MS (Mole Ion) = 437

IR (KBr): 5.58 μ (ester> C = O)

Assay: C ₂₇ H ₃₅ O ₄ N. for HCl

Calculated Value: C, 68.41, H, 7.66, N, 2.96%

Found: C, 68.52, H, 7.91, N, 2.73%

In the same manner, the following compounds are prepared from suitable reactants.

* HCl salt

Assay: for C ₂₇ H ₃₅ O ₄ N · HCl

Calculated Value: C, 68.41, H, 7.66, N, 2.96%

Found: C, 68.48, H, 7.57, N, 2.93%

Claims (1)

Reacting a compound of the formula with a metal hydride

How to prepare a compound of the following structural formula

Wherein R ₁ is hydrogen, benzyl, benzoyl, alkanoyl of 1-5 carbon atoms or -CO- (CH ₂ ) p-NR ₂ R ₃ , wherein p is an integer of 0 or 1-4: R ₂ and R ₃ is hydrogen or alkyl having 1-4 carbon atoms: or R ₂ and R ₃ together with the nitrogen to which they are attached form a 5-membered or 6-membered heterocycle ring wherein the ring is chiridino pyrrole, R-ldino, morpholino or N-alkylpiperazino having 1-4 carbon atoms in an alkyl group: R ₄ is hydrogen, alkyl having 1-6 carbon atoms or-(CH ₂ ) zC ₆ H ₅ , wherein Z is Is an integer from 1-4: R ₅ is hydrogen, methyl or ethyl; R ₆ is hydrogen, an alkoxy group having 1-4 carbon atoms and-(CH ₂ ) y-carboalkoxy, where y is 0 or 1-4 Carbobenzyloxy, formyl, alkanoyl of 2-5 carbon atoms, alkyl of 1-6 carbon atoms,-(CH ₂ ) x C ₆ H ₅ , where x is an integer of 1-4, or- CO (CH ₂ ) x_ ₁ C ₆ H ₅ and: Z is an alkylene having 1-9 carbon atoms or-(alk ₁ ) mx- (a1k ₂ ) n-, where the sum of carbon atoms in (a1k ₁ ) and (a1k ₂ ) is 9 or less and m and n are or 1 xO, S, SO or SO ₂ and: W is hydrogen, methyl, pyridyl, piperidyl,

or

Wherein W ₁ is hydrogen, fluoro or chloro and W ₂ is hydrogen or

A is an integer of 1-5, b is 0 or an integer of 1-5, but the sum of a and b is 5 or less.