HU180917B - Process for preparing 5,6,6a,7-tetrahydro-benzo/c/quinolin -9/8h/-one derivatives - Google Patents

Description

The present invention relates to a novel process for the preparation of 5,6,6a, 7tetrahydrobenzo [c] quinolin-9 (8H) -one derivatives of general formula I, which are valuable intermediates in particular.

In the manufacture of 1,9-dihydroxyoctahydrobenzofluoroquinolines, 1-hydroxyhexahydrobenzo, c] quinolin-9 (8H) -one, and 1-hydroxytetrahydrobenzo [c] quinoline, which are central nervous system agents, and are analgesics, antihypertensives, and as active ingredients in diuretics.

Despite the large number of analgesics available, research is under way to produce new and effective agents to achieve a broader analgesic effect and minimize side effects. The most commonly used drug, aspirin, is not suitable for the relief of certain pains and is known to have various undesirable side effects. Other, more potent analgesic agents, such as d-propoxyphene, codeine, and morpholine, show narcotic effects. Thus, it is self-evident that good and effective analgesic agents are needed.

9-nor-9β-hydroxyhexahydrocannabinol and other compounds having a cannabinoid structure, such as α-tetrahydrocannabinol (Δ 1 -THC) and its primary metabolite, 11-hydroxy-Δ ⁸ 180917

The analgesic effect of THC is described by Wilson and May in Absts. Papers, Am. Chem. Soc., 168 Meet., MEDI 11 (1974), J. Med. Chem 17, 475-476 (1974) and J. Med. Chem., 18, 700-

703 (1975).

United States Nos. 3,507,885 and 3,636,058

U.S. Patents disclose various 1-hydroxy-3-alkyl-6H-dibenzo [b, d] pyrans having various substituents at position 9, such as oxo, hydrocarbyl, hydroxy, chlorine or hydrocarbylidene. contain substitutes and also mention their intermediates.

U.S. Patent 3,649,650 discloses a series of tetrahydro-6,6,9-trialkyl-6H-dibenzofb, djpyran derivatives which contain a 1-position dialkylaminoalkoxy group. These compounds may be active as psi20 chotherapeutic agents.

German Patent Publication No. 2,451,934 discloses 1,9-dihydroxyhexahydrodibenzo [b, d] pyrans and refers to certain 1-acyl moieties thereof which have an alkyl or alkylene group at the 3-position. They contain. These compounds are active as antihypertensive, psychotherapeutic, sedative and analgesic agents. Hexahydro-9H-dibenzo [b, d] -pyran-9-1130917 ones are intermediates in the preparation of these compounds and are used for the same purposes as 9-hydroxy compounds as disclosed in Federal Patent No. 2,451,932. disclosed in the disclosure document.

U.S. Pat. No. 3,858,821 mentions a series of dibenzo [b, d] pyran substituted by 3-alkoxy groups. These compounds may be active ingredients in anti-inflammatory, anti-inflammatory and central nervous system (CNS) agents.

Berger et al. - J. Chem. Soc., 286-287 (1943) - found that if 7,8,9,

In the 3-position of 10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol, the pentyl group is replaced by an alkoxy group (butoxy-pentyloxy, hexyloxy or octyloxy). , receive biologically inactive substances. The hexyloxy derivative has been found to have a mild hashish effect at 10-20 mg / kg. The other ethers show no effect up to 20 mg / kg.

In a recent work, Loev et al., J. Med. Chem. 16, 1200-1206 (1973), 7,8,9,10-tetrahydro-3-substituted -6,6,9-trimethyl-6H-dibenzo [b, d) Pyran-1-ol was compared in autumn with the 3-substituent -OCH / ClL'CsIII, -CH 1 CH ₂ -CH aJCgHn and -CH (CH ₃ ) C ₅ H _h . The effect of the ether side chain compound on the central nervous system was 50% less than that of the corresponding compound in which the alkyl side chain is directly attached to the aromatic ring. In the case of the ether side chain, the coupling is via an oxygen atom. Said compound is 5 times more active than the compound in which the oxygen is replaced by a methylene group.

Hoops et al. J. Org. Chem., 33, 2995-2996 (1968), discloses the 5-aza analog of 6a (ic, '-tetrahydrocannabinol, where 7,8,9,10-tetrahydro-1-hydroxy-5,6,6,9 reference was made to a compound of tetramethyl-3-n-pentylphenanthridine, but no further use of the compound was mentioned, Beil in "Psychomimetic Drugs" (Efron, Raven Press ¹ , New York, 1970, p. 336) states that the compound is "completely inert in veterinary medicine ”.

Hardmann et al. [Proc. West. Pharmacol. Soc., 14, 14-20 (1971)], some pharmacological activity is mentioned in the case of 7,8,9,10-tetrahydro-1-hydroxy-6,6,9-trimethyl-3-n-pentylphenanthridine, a 5-α-tetrahydrocarbonyl. compound.

Mechoulam and Edery, in "Marijuana" (Mechoulam, Academic Press, New York, 1977, p. 127), argue that larger structural changes in the tetrahydrocannabinol molecule are accompanied by a drastic reduction in the analgesic effect.

Pa. In General Review of the Annual Review of Pharmacology, 15, 192 (1975), generalizations are made with respect to structure-effect relationships for cannabinoids. The presence of the gemimethyl dimethyl group in the pyran ring is crucial for cannabinoid activity and ceases to be active when the N atom is replaced by an O atom.

In the compounds of the formula I

Bi is hydrogen or C 2-4 alkanoyl,

R 1 is hydrogen, C 1-6 alkyl, or phenyl (C 1-4) alkyl,

R 1, H, methyl or ethyl, and Z is C 2 -C 9 alkoxy or C 2 -C 9 alkyl optionally substituted by phenyl or naphthyl.

The compounds of formula (I) contain asymmetric centers in the 6α and / or 10α positions. There may be additional asymmetric centers in the 3-position (—Z) substituent and in the 5-position. In situations 6 and 9. The diastereoisomers of the 9/7 configuration are generally preferred over the 9α-isomer vessels because of their (quantitative) higher biological activity. For this reason, the trans (6a, 10a) diastereomers of the compounds of formula I are generally preferred over the cis (6a, 10a) diastereomers.

The following formulas represent racemic compounds. These formulas are general in nature and include racemic modifications of the compounds of the present invention, diastereomers, pure enantiomers and diastereomers. The utility of racemic mixtures, diastereomeric mixtures, and pure enantiomers and diastereomers can be determined by the biological assay described below.

(I) The compounds of formula I prepared by reaction of (II) compound, wherein R, R ₅ and Z are each as defined above, and R; hydrogen or formyl; and R1 is hydrogen, methyl, ethyl or benzyl, with a base.

Asymmetric centers may exist in the 2-position of the intermediates of formula (II) and the (-Z) substituent in the 7-position, but may also have asymmetric centers in substituents at other positions, such as the 1-position. The 2 and 7 positions of the compounds of formula II are the 6 and 6 positions of the compounds of formula I

They correspond to position 3.

Compounds of formula II may be prepared by converting quinolines of formula III into hydroxymethylene derivatives of formula IV using ethyl formate and sodium hydride. This reaction, which is a formylation reaction, affords the bis-formylated derivative (IV) in excellent yield. Treatment of the bis-formylated derivative with methylvin-2180917 nylketone results in a mixture of the corresponding monor-N-formylated Michael adduct of formula II and the 1,3-bis-formylated Michael adduct. The two products are easily separated by column chromatography on silica gel.

Conversion of these compounds to compounds of formula I is accomplished by aldol condensation of the mono-N-formyl compound of formula II.

Alternatively, the compounds of formula (I), in particular those derivatives in which the 1-hydroxy group is protected as an ester, may also be converted to the compounds of formula (I) by catalytic hydrogenation. According to a suitable method, the catalytic hydrogenation is carried out over palladium such as palladium on carbon or other precious metal which may be supported on a support,

The invention is further illustrated by the following examples.

Example 1

Ethyl dl-3- (3,5-dimethoxyanilino) butyrate

A mixture of 95.7 g (0.624 mol) of 3,5-dimethoxyaniline, 87.2 ml (0.670 mol) of ethyl acetate, 535 ml of benzene and 3.3 ml of glacial acetic acid was refluxed for 15 hours under a nitrogen atmosphere and water in a Dean-Stark trap. collected. The reaction mixture was then cooled to room temperature, decolorized with charcoal, filtered and then concentrated under reduced pressure. This gave 168.7 g of ethyl 3- [3,4- (dimethoxy) anilino] -2-butenoate as an oil.

A mixture of 5.0 g (18.7 mmol) of ethyl 3- (3,5-dimethoxyanilino) 2-buteonate, 42 mL of glacial acetic acid and 250 mg of platinum oxide was hydrogenated in a Parr shaker at 3.5 atmospheric pressure for 1.5 hours. The reaction mixture was filtered through a filter, 50 ml of benzene were added to the filtrate and the solution was concentrated under reduced pressure to an oil. The oil was taken up in chloroform and the solution was washed first (2x50 mL) with saturated sodium bicarbonate solution, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 5.1 g of an oil are thus obtained.

The procedure described above was repeated, but using 168.7 g of ethyl 3- (3,5-dimethoxyanilino) -2-butenoate, 320 ml of glacial acetic acid and 2.15 g of platinum oxide. 160.8 g of product are obtained.

Example 2

Ethyl dl-3- (3,5-dimethoxyanilino) butyrate

To a solution of 370 g (1.45 mol) of 3.5 dimethoxyaniline hydrochloride in 4.5 liters of methanol and 286.3 g (2.64 mol) of ethyl acetate were placed in a 12 liter round-bottom flask and the flask was a 3-necked mechanical flask. with a stirrer and a reflux condenser, 54 g (0.73 mol) of sodium cyanoborohydride are added in one portion. After refluxing for about ten minutes, the mixture was heated in a water bath for an additional 20 minutes and then cooled. 5.4 g (0.07 mol) of sodium cyanoborohydride and 28.6 g (0.26 mol) of ethylacetoacetate are added to the cooled mixture and the mixture is refluxed for 30 minutes. This latter process is repeated once more.

The reaction mixture was separated in portions by pouring about 500 mL into 1 L of ice water / 500 mL of methylene chloride, separating the layers and washing the aqueous phase with 100 mL of methylene chloride. This process was repeated with another 500 mL reaction and the isolation continued until the entire reaction mixture was worked up.

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

The excess ethyl acetate was distilled off in a 130 ° C oil bath and 1-5 mm Hg to give 376 g of crude ethyl 3- (3,5-dimethoxyanilino) butyrate as an amber viscous oil which could be used without further purification. Yield: 72%.

The product has the following spectral characteristics: TMS

Ή NMR (60 MHz) δ _{CD {?]} (Ppm): 5.82—

6.0 (m, 3H, aromatic), 4.20 (q, 2H, ésetermetilén), 3.80-4.00 (m, 2H, -NH and -N-CH-CH _3), 3.78 ( s, 6H, _-OCH3), 2.40-2.55 (m, 2H, _-CH2 COOEt), 1.78 (d, 3H, methyl), and 1.29 (t, 3H, methyl).

Example 3 dl-Ethyl-3- (3,5-dimethoxyanilino) hexanoate

In the same manner as in Example 2, 3,5-dimethoxyaniline hydrochloride and ethyl butyryl acetate were condensed. This gives d, 1-3- (3,5-dimethoxyanilino) hexanoate. This compound is converted to the hydrochloride by adding hydrogen chloride to a methylene chloride solution of the compound.

127-129.5 ° C. The product was recrystallized from cyclohexane / benzene (5: 1), m.p. 126-128,5 ° C. Analysis calculated for C 16 H 25 O 4 N-HCl: C, 57.91; H, 7.90; N, 4.22%; Found: C, 57.89; H, 7.74; N, 4.40%.

m / e - 295 (m +)

TMS

Ή NMR (60 MHz) δ (ppm): 10.76—

11.48 (b, variable, 2H, _NH2 +), 6.77 (d, J = 2Hz, 2H, meta-HK), 6.49, 6.45 (d-d, J = 2 Hz, 1H, methane H), 4.08 (q, 2H, OCH _2), 3.77 (s, 6H, [OCH ₃ I _2), approx. 3.5-4.8 (m. 1H, CH-N), 2.90 (t, 2H, CH> -C = O), ca. 1.4-2.2 (m, 4H, _{[CH2] 2),} 1.21 (t, 3H, O = _C-CH3), 0.84 (t, 3H, _C-CH3).

-3180917

Example 4 dl-Ethyl 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) -anilino-butyrate

The method

Ethyl 3- (3,5-dimethoxyanilino) butyrate (159.8 g, 0.598 mol), methylene chloride (100 ml) and 100 ml (1.24 mol) were added dropwise over 7 minutes (71.4 ml, 0.75 mol) in chloroformate. pyridine mixture at 0 ° C under a nitrogen atmosphere. The mixture was stirred for 40 minutes, after the addition of the chloroformate and poured into 750 ml of chloroform and 500 ml of ice-water. The chloroform layer was separated, washed with 10% hydrochloric acid (3x500 mL), saturated aqueous sodium bicarbonate solution (1x300 mL) and brine (1x400 mL), and dried over anhydrous magnesium sulfate. then decolorize with activated charcoal and concentrate under reduced pressure. This gives 215 g of an oil which can be used as such.

Method B.

A mixture of 376 g (1.4 mol) of ethyl 3- (3,5-dimethoxyanilino) butyrate, 1.4 L of methylene chloride and 388.8 g (2.81 mol) of anhydrous potassium carbonate was stirred under a nitrogen atmosphere and in an ice bath 0-5 Cool to C °. To the mixture was then added 153 g (1.41 mole) of ethyl chloroformate per portion. The mixture is allowed to warm to room temperature over one hour, then 153 g (1.41 mol) of chloroformic acid ester are added all at once and the whole is heated at reflux for 1 hour. The mixture was then allowed to cool to room temperature and the potassium carbonate was filtered off. The red filtrate was first washed with water (2 x 1000 mL), brine (1 x 500 mL), dried over anhydrous magnesium sulfate, decolorized and evaporated under reduced pressure. 439 g of crude product are obtained which can be used without further purification.

Ή NMR (60 MHz) δ ^ ποΐ ₃ (PP ^m ) ^: 6.2-

6.42 (m, 3H, aromatic), 4.65 (sec., 1H, -NCH-, CH3), 4.10-4.15 (2 quartet, 4H, ester methylene), 3.70 (s, 6H, -OCH ₃ ), 2.30-2.60 (m, 2H, -CH ₂ COOEt), 1.00-1.40 (m, 9H, 3 methyl).

and stir overnight at room temperature. The reaction mixture was then concentrated under reduced pressure to about 600 mL volumes, the concentrate was diluted with 1200 mL water and extracted with ethyl acetate (3 x 750 mL). The aqueous layer was then treated with 10% hydrochloric acid.

It was acidified to pH 2 and extracted again with ethyl acetate (3x750 mL). The latter extracts were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. This gave 163.5 g of the title compound as an oil. Yield 88.2%.

Method B.

Into a 5 L 3-necked round-bottomed flask equipped with mechanical stirrer and reflux condenser add 439 g (1.41 mol) of ethyl 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] butyrate in 2 L of ethanol. . To the solution was added 2 L of 1N sodium hydroxide solution and the mixture was heated under reflux for 3 hours on a water bath. The reaction mixture was poured into ice water and extracted with 500 ml of diethyl ether in 1 liter portions. The aqueous layer was cooled by adding about 1 liter of ice and then acidified with 1.75 ml (2.1 mol) concentrated hydrochloric acid and extracted with 250 ml to 250 ml / ml methylene chloride in 1 liter portions. The methylene chloride layers were combined, dried over magnesium sulfate, decolorized with activated carbon and evaporated to dryness. This gave a yellow viscous oil which was crystallized from ether / cyclohexane (1: 2) to give 224 g of crystalline product. M.p. 78-80 ° C. Yield 55.3%.

The resulting material can be used in the next step without further purification.

Ή NMR (60 MHz) δ δ qqq- (ppm): 6.24—

6.53 (m, 3H, aromatic), 4.65 (sequenced, 1H, -N (COOC ₂ H ₅ ) CH ₃ (CH ₂ COOC ₂ H ₅ ), 4.10 (quartet, 2H, ester methylene) 3.78 (s, 6H, _-OCH3). 2,40- 2.60 (m, 2H, _-CH2 COOH), 1.18 (t), 1.28 (d, 6H, methyl); 10.8 (bs, variable, 1H, COOH) Mass spectrum (mole ion) m: 311.

For analysis, a sample was recrystallized from ethyl acetate / hexane (1: 5), m.p. 89-91 ° C.

Analysis calculated for Οι-ΗνιΟ, -Ν: C, 57.86; H, 6.80; N, 4.50%; Found: C, 58.08; H, 6.65; N, 4.46%.

Example 5 dl-3- [3,5-Dimethoxy-N-ethoxycarbonyl) anilino] butyric acid

The method

202 g (0.595 mol) of ethyl 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] butyrate, 595 ml of 1N aqueous sodium hydroxide solution and 995 ml of ethanol were combined.

Example 6 d- and 1- [3- (3,5-Dimethoxy-4-N-ethoxycarbonyl) anilino] butyric acid

A mixture of 136, 6 g (0.44 mol) of dl-3- [3,5-dimethoxy-N-ethoxycarbonyl) anilino-butyric acid and 72.5 g (0.44 mol) of 1ephedrine is dissolved in 500 ml of methylene chloride. The methylene chloride is then removed in vacuo to give 1-ephedrine salt of dl-3 - [(3,5-dimethoxy-N-ethoxy-4180917 carbonyl) -anilino] -butyric acid as an oil.

Mg = -50 0 (c = 1.0, CHCl 3)

To the resulting salt was added 1500 ml of ether to give a white crystalline solid which was isolated by filtration and dried. The amount of precipitated and dried material is 102 g and the melting point is 114-116 ° C. The resulting crystalline material was recrystallized from a 1: 1 mixture of ethyl acetate and hexane to give 71.1 g (34%) of 13 - [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] butyric acid 1-ephedrine salt. mp 126-127 ° C.

Analysis calculated for C 25 H ₃₆ O ₇ N ₂ : C, 63.00; H, 7.61; N, 5.88%; Found: C, 62.87; H, 7.64; N, 5.88%

Mg = -43.5 ° (c = 1.0, CHCl ₃ ).

The 1-ephedrine salt of the 1-isomer was stirred in 1000 ml of ethyl acetate and 400 ml of 10% hydrochloric acid solution for 10 minutes. The organic layer was separated (2x400 mL), washed with 10% hydrochloric acid solution, dried and concentrated under reduced pressure to an oil. The residue was crystallized from 400 ml (1: 1) ethyl acetate / hexane to give 34.6 g of 1-3 - ((3,5-dimethoxy-N-ethoxycarbonyl) aniloylbutyric acid).

96-97 ° C.

Analysis for C ₅ H ₂ IO {N Calcd: C, 57.86; H, 6.80; N, 4.50%; Found: C, 57.90; H, 6.66; N, 4.45%.

[α] D = -25.4 ° (c = 1.0, CHCl 3).

The mother liquor from the recrystallization of the 1-ephedrine salt of the 1-isomer is treated with hydrogen chloride as described above to give crude d-3 - [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] butyric acid. The raw acid would be d-ephedrine! and recrystallization from ether to give the d-isomer-d-ephedrine salt.

124-125 ° C.

Analysis calculated for C 25 H 36 O 7 N 2: C, 63.00; H, 7.61; N, 5.88%; Found: C, 62.82; H, 7.47; N, 5.97%.

Mg + 44.0 ° (c = 1.0, CHCl 3).

The d-ephedrine salt is converted to d-3 - [(3,5-dimethoxy-N-ethoxycarbonyl) aniline butyric acid as described for the conversion of the i-ephedrine salt. 96-97 ° C (3: 3) after recrystallization from ethyl acetate / hexane.

Analysis calculated for C 15 H 20 O 3 N: C, 57.86; H, 6.80; N, 4.50%; Found: C, 57.95; H, 6.57; N, 4.35%.

Mg + 25.3 ° (c = 1.0, CHCl 3).

Example 7 Phenyl 3- (3,5-dimethoxyanilino) propionate

A mixture of 114.9 g (0.75 mole) of 3,5-dimethoxyaniline, 69.73 g (0.81 mole) of methyl acrylate and 2 ml of glacial acetic acid was heated at reflux for 20 hours. The heating was then stopped and the reaction mixture was concentrated and the residue was distilled under vacuum. 106.8 g of the expected product are obtained, m.p. 174-179 ° C (0.7 mmHg).

TMS ⁴ H NMR (60 MHz) δ _CDC] (ppm): 5.62—

5.95 (m, 3H, aromatic), 4.1 (variable, bs, 1H, -NH), 3.74 (s, 6H, -OCH3), 3.68 (s, 3H, COOCH3), 3, 41 and 2.59 (two 2H triplets, -NCH ₂ CH ₂ CO ₂ ).

Example 8 dl-Methyl-3 - ([3-hydroxy-5- (5-phenyl-2-pentyl)] anino) propionate

A mixture of 1.0 g of 3-hydroxy-5- (5-phenyl-2-pentyl) aniline, 345 mg of methyl acrylate and 0.1 ml of acetic acid was heated at 106-110 ° C overnight. The cooled residue was dissolved in 100 mL of ethyl acetate and washed twice with 100 mL of 100 mL of saturated sodium bicarbonate. The organic layer was then dried over anhydrous magnesium sulfate and evaporated to give a crude residue which was chromatographed on silica gel (130 g) using benzene / ether (2: 1) as eluent. Elution of the low polar impurity gave 540 mg (40%) of d.l-methyl-3 - [(3-hydroxy-5- (5-phenyl-2-pentyl)] anilino) propionate. The spectral characteristics of this product are as follows:

TMS

Ή NMR (60 MHz) δ _CDC] (ppm): 7.14 (s,

SH, aromatic), 5.83 -6.13 '(m, 3H, aromatic), 3.66 (s, 3H, COOCH3), 3.37 (t, 2H, -NCH _2), 2,16- 2.78 (m, 5H, -CÍHCOO and benzyl), 1.28-1,69 (m, 4H, - (CH ₂₎ 2), 1.11 (d, 3H,>_{CH; s),} 4, 4-5.2 and 1.28-2.78 (variable, 1H, NH, OH), m / e = 341 (m +).

Example 9

Methyl 3- [3,5-dimethoxy-N-ethoxycarbonyl) propionate fluoroanilino

Chloroformate (2.0 g, 8.4 mmol) was added dropwise over 10 minutes to a mixture of 3- (3,5-dimethoxyanilino) propionate (1.0 mL, 10.5 mmol) in methylene chloride (5 mL) and pyridine (5 mL) at 0 ° C. on nitrogen atmosphere. After the addition of the chloroformic acid ethyl ester, the mixture was stirred at 0 ° C for 20 minutes and at room temperature for an additional 20 minutes and then poured into 75 ml of methylene chloride and 50 ml of ice water. The methylene chloride layer was separated, washed with 10% hydrochloric acid (2 x 50 mL), saturated aqueous sodium bicarbonate (1 x 30 mL) and brine (1 x 40 mL) and dried over anhydrous magnesium sulfate. The layer is then decolorized with activated carbon and concentrated under reduced pressure to an oil. This gives 2.72 g of material which can then be used.

Example 10

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

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Methyl 3 - [(3-, 5-dimethoxy-netoxycarbonyl) -anilino] -propionate (2.72 g, 8.36 mmol), 1N aqueous sodium hydroxide solution (8.4 ml) and ethanol (8.4 ml) were combined. and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The reaction mixture was then concentrated under reduced pressure to half volume, diluted with water (35 mL) and then extracted with ethyl acetate. The aqueous phase was acidified with 10% r. Hydrochloric acid to lead 2 and extracted with methylene chloride (3 x 50 mL). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated. This gave 2.47 g of an oil which was used as ameCy.

Example 11 l-carbethoxy-5,7-dimethoxy-4-oxo-l, _2,3> 4tetrahidrokinolin

A mixture of 1.10 g (3.7 mmol) of 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] propionic acid and 4 g of polyphosphoric acid was heated at 65 ° C for 45 minutes under nitrogen atmosphere and then at 0 ° C. cool. The mixture was then taken up in 200 ml of 1: 1 methylene chloride / water. The organic layer was separated and the aqueous layer (2x100 mL) was extracted again with methylene chloride. The combined extracts (3 x 100 mL) were washed with saturated sodium bicarbonate solution (1 x 100 mL), brine and dried over anhydrous magnesium sulfate. The dry extract is concentrated to give an oily product which is crystallized from benzene.

Yield: 645 mg. Mp 109-111 ° C.

Analysis calculated for C11 H20 O8 N: 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 in glacial acetic acid, 60 ml in 48% hydrobromic acid and 4.0 g (14.3 mmol) of 1-carbethoxy-5,7-dimethoxy The mixture of 4-oxo-1,2,3,4-tetrahydroquinoline was refluxed overnight and then concentrated in vacuo to a dark oil. The oil was dissolved in water (50 mL) and the aqueous solution was neutralized to pH 6-7 with 1N sodium hydroxide solution. A saturated aqueous solution of sodium chloride (50 mL) was then added to the neutralized solution and the resulting mixture (3 x 150 mL) was extracted with ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate and concentrated to an oil under reduced pressure. The oil was taken up in U: 1 benzene-ethyl acetate and the solution was applied to a silica gel column. The column was eluted with an equal volume of benzene, 250 mL (4: 1) benzene-ethyl acetate, and then 250 mL (1: 1) benzene-ethyl acetate. Fractions of 75 ml were collected. 4, -9. The 6 fractions were combined and concentrated under reduced pressure. To obtain a crystalline product, the oily residue is crystallized from ethanol-hexane (1:10).

Yield 1, .86 g. Mp 166-169 ° C.

After further recrystallization, the melting point

171-172 ° C.

m / e = 179 (m +).

Analysis calculated for C 8 H 8 O 9 N: C, 60.33; H, 5.06; N, 7.82%; Found: C, 60.25; H, 4.94; N, 7.55%.

Example 13 dl-1-Carbetoxy-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline

4. A solution of 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) -anilino] -butyric acid (0 g, 12.8 mmol) in chloroform (2 ml) was added dropwise to 5.0 g of polyphosphoric acid in a water bath at 60 ° C. warmed up. After 2 hours at 60-65 ° C, the reaction mixture was poured into 100 g of ice and 100 ml of ethyl acetate. The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined organic extracts were washed first with brine (3 x 100 mL), brine (1 x 100 mL) and dried over anhydrous magnesium sulfate. The dry extract was concentrated under reduced pressure to give 2.6 g of crude product.

The benzene solution of the crude product (2.5 g) was purified by column chromatography over 95 g of silica gel. The column was eluted with half the volume of benzene and then further eluted with benzene / ethyl acetate (1: 1). We take fractions. 9-18. fractions were combined and concentrated in vacuo. This gives 1.55 g of product which is further purified by recrystallization from petroleum ether to give 1.33 g of product, m.p. 92.5-94 ° C.

For analytical purposes, a sample of this product was recrystallized from a 1: 1 mixture of ethyl acetate and hexane, m.p. 94-95 ° C. Analysis for C45H19O5N: C, 61.42; H, 6.53; N, 4.78%; Found: C, 61.54; H, 6.55; N, 4.94%.

m / e = 293 (m +).

IR (KBr) - 5.85 _fl (> = O).

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

The method

A mixture of glacial acetic acid (240 mL), 48% hydrobromic acid (240 mL) and l-carbethoxy-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquimoline (16.0 g, 55 mmol) was added overnight. heat to reflux and then evaporate in vacuo to a dark oil. The oil was dissolved in 200 mL of water and a

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180 947

Neutralize Χ4 aqueous solution with 1N sodium hydroxide solution to pH 6-7. Saturated brine was added to the neutral solution (200 mL) and the resulting mixture (3 x 500 mL) was extracted with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. 12.8 g of a dark oil are obtained, to which a mixture of hexane-ethyl acetate (10: 1) is added and the resulting crystalline material is isolated by filtration. 3.8 g of product are isolated, m.p. 158-165 ° C. The crystalline material was treated with ethyl acetate to give 1.65 g of product, m.p. 165-168 ° C.

A further 2.9 g of product is precipitated from the mother liquor, m.p. 168-170 ° C. The filtrate was subjected to column chromatography eluting with benzene-ether (1: 1) to give an additional 4.6 g of product.

M.p. 167-169 ° C.

The product is further purified by recrystallization from ethyl acetate. The melting point will then be 173-174 ° C.

Analysis for C _{(OH (03N} per ₁ O: C 62.16; H 5.74; N 7.25% Found: H, 62,00; H, 5.83; N, 7.14%.

m / e = 193 (m +).

Method B.

A mixture of 100 g (0.32 mol) of d, 1 - 3 - [(3,5-dimethoxy-N-ethoxycarbonyl) anilino] butyric acid, 500 ml of 48% hydrogen bromide solution and 300 ml of glacial acetic acid at 110 ° C was added. heat in an oil bath for 2 hours. The oil bath temperature was then raised to 145 ° C and heating continued for a further 2 hours. During this latter heating period, the azeotropic mixture distils at about 200-300 ml at a boiling range of 42 ° C to 110 ° C. The resulting dark red homogeneous solution was allowed to cool to room temperature, poured into a mixture of 3 L of ice water and 2 L of ether, the layers were separated and the aqueous solution (2 x 1000 mL) was washed with ether. The ether layers were combined and washed successively with water (2 x 1000 mL), brine (1 x 500 mL), saturated sodium bicarbonate (4 x 250 mL) and brine (1 x 500 mL), dried over anhydrous magnesium sulfate, decolorized with charcoal and evaporated. This gave a yellow foam which was crystallized from about 300 mL of methylene chloride. 31.3 g (50.4%) of pure 5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline are obtained. Further product can be isolated from the mother liquor by chromatography on silica gel.

TMS

Ή NMR (60 MHz) δ (100 mg sample /

0.3 ml CDCl ₃ / 0.2 ml CD ₃ SOCD ₃ ) (ppm): 12.40 (s, 1H, C ₅ -OH), 5.72 (d, 2H, m-H), 5.38-5 60 (bs, 1H, C7-S), 3.50-4.00 (m, 1H, C2H), 2,38- 2.60 (m, 2H, C ₃ -H _2), 1.12 ( d, 3H, methyl). m / e = 193 (m +).

Analysis: Calculated for C ?? H ?? ClN: C, 62.16; H, 5.74; N, 7.25%; Found: C, 62.01; H, 5.85; N, 7.02%.

In a similar manner, methyl dl-3 - ([3-hydroxy-5- (5-phenyl) -2-pentyl] anilino) propionate was converted to dl-5-hydroxy-7- (5-phenyl-2-pentyl) -4 -oxo -1,2,3,4-tetrahydroquinoline, which was purified by column chromatography on silica gel using a 5: 1 mixture of benzene and ether. m / e = 309 (m +).

TMS

Ή NMR (60 MHz) _CDCl? (Ppm): 12.22 (s,

1 H, 50 H), 7.14 (s, 5 H, C 1 H ₅ ), 6.04 (d, J = 2.5 Hz, 1H H 2 H), 5.87 d, J = 2.5 Hz, 1 H methyl H), 4.19-4.60 (b, 1H, NH), 3.48 (t, 2H, CH ₂ N), 24.8-2.89 (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 dl-3- (3,5-dimethoxyanilino) hexanoate hydrochloride dl -5,7-dihydroxy-2-propyl-4, -O-1,2,3,4-tetrahydroquinoline. 117-119 ° C '(from methyl enichloride).

m'e-221 (m +), 135 (base peak, m + propyl), and 1- 3 - [(3,5-dimethoxy) - (N-ethoxycarbonyl) anilino] butyric acid d-5,7- dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline.

Mp: 167-168 ° C.

+] + = 167.8 ° (c = 1.0, CH 3 OH).

m / e = 193 (m +).

Analysis calculated for C CHHqONN: C, 62.16; H, 5.74; N, 7.25%; Found: C, 61.87; H, 5.62; N, 6.96%, and d-3f (3,5-dimethoxy-N-ethoxycarbonyl) anilino] -butyric acid into 1-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline.

m.p .; 166-168 ° C.

[α] D = -168.5 ° (c = 1.0, CH 3 OH).

m / e = 193 (m +).

Analysis calculated for C 10 H 11 O 3 N: C, 62.16; H, 5.74; N, 7.25%; Found: C, 61.82; H, 5.83; N, 7.22%.

Example 15 dl-5,7-Bihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline

A mixture of 230 g (1.5 moles) of 3,5-dimethoxyaniline, 150 g (1.5 moles) of methyl cronate and 90 g (1.5 moles) of glacial acetic acid was heated at reflux for 6 hours. Glacial acetic acid (90 g, 1.5 mol) was then added and the mixture was heated overnight at room temperature. Subsequently, 1000 µl of 48% hydrobromic acid solution and 850 ml of glacial acetic acid were added, which was heated under reflux for 4.5 hours. The title product was isolated and purified as described in Example 12.

Yield: 36 g Mp: 166-170 ° C.

Example 16 dl-5,7-Dihyroxy-2-methyl-4-oxp-1,2,3,4-tetrahydroquinoline

-7180917

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

A mixture of glacial acetic acid (110 ml), 48% hydrobromic acid (110 ml) and yellow oil was heated to reflux and then concentrated in vacuo to a dark oil. The oil was dissolved in water and the aqueous solution was neutralized with 1 N sodium hydroxide solution to pH δ-7, then saturated brine was added and the mixture was extracted with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. This gives a dark oil which is purified by column chromatography on silica gel. Elution was carried out with benzene-ether (4: 1). The eluent provided an additional 510 mg of product. Mp 168-170 ° C.

Further purification is achieved by recrystallization of the product from ethyl acetate. 173-174 ° C.

Analysis calculated for C 10 H 11 O 8 N: C, 62.16; H, 5.74; N, 7.25%; Found: C, 62.00; H, 5.83; N, 7.14%.

m / e = 193 (mM), 178 (m + -methyl, base peak).

Condensation of 3,3-dimethylacrylic acid and 3,5-dimethoxyaniline after purification by chromatography on silica gel (eluent: 1: 1 benzene / ether) 5,7-dihydroxy-2,2-dimethyl-4-oxo-1,2,3 , Gives 4-tetrahydroquinoline in the form of a yellow oil.

Analysis (MS) for C 11 H 13 O 3 N: Calcd

Five peaks (m '). Calculated: 207.0895 Found: 207.0895

Base Peak (m + -15) Calcd for C ₁₀ H ₁₀ O; sN: 192.0661 Found: 192.0665.

Similar condensation of styrylacetic acid and 3,5-dimethoxyaniline affords dl-5,7-dihydroxy-2-benzyl-4-oxo-1,2,3,4-tetrahydroquinoline in the form of an oil after purification. The eluent in this case is a 3: 1 benzene / ether mixture. m / e = 269 (m +) and (m 1 + benzyl, base peak).

NMR (CDCl 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) and

5.62 (d, J = 3Hz, 1H) for the aromatics attached in the meta-position and 2.14-4.82 (4m, 7H) for the remaining protons (7-OH, CH-N, CH ₂ -C = O, -CH 2 COOH and NH).

Example 17 dl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline

Potassium hydroxide (325 mg, 52 mmol) was added in granular form to 1.0 g (52 mmol) of d, 1-8.

5,7-Dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline. 10 ml of a solution of Ν, Ν-dimethylformamide. The mixture was heated slowly to 10 ° C and 1.08 g (60 mmol) of d, l-2-bromoheptane was added all at once while stirring vigorously. After 10 minutes, 160 g of potassium hydroxide and another 500 mg of d / -2-bromoheptane are added. The addition of potassium hydroxide and d, l-2-bromoheptane was repeated twice, each time using 80 mg of potassium hydroxide and 250 mg of d, l-2-bromoheptane. The reaction mixture was stirred for an additional 10 minutes and then cooled, then chloroform (50 ml) and 1N aqueous sodium hydroxide solution (25 ml) were added. The mixture was stirred for 10 minutes and the layers were separated. The chloroform extracts were repeated, the extracts were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This gave a dark oil which was chromatographed on 120 g silica gel using benzene as solvent. Fractions were collected at 30 ml. 12-18. fractions were combined and concentrated under reduced pressure. This gives 850 mg of a light yellow oil which crystallizes on standing. The desired product is isolated by filtration and recrystallized from hot hexane. M.p. 76-77 ° C.

The above procedure was repeated 20 times, but using benzene-ethyl acetate (9: 1) as a solution for chromatography A total of 750 ml of different fractions was collected. 2-6. fractions were combined to give 32 g of an oil which partially crystallized on standing and cooling. This way

18.2 g of product are obtained. An additional 3.2 g of product is obtained after concentrating the mother liquor by allowing the concentrate to stand under cooling. Total yield = 21.4 g.

Analysis calculated for C 17 H 23 O 3 N: C, 70.07; H, 8.65; N, 4.81%; Found: C, 69.82; H, 8.67; N, 4.93%.

m / e = 291 (m +).

IR (KBr): 6.01 μ (= O).

In a similar manner, 5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline is converted to d, 1-5-hydroxy-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline. which is oil-shaped.

TMS

Ή NMR (60 MHz) δ-nQp, (PP ^m ): 13.3 (s,

1H, phenolic), 5.5 and 5.7 (d, 2H, J = 2Hz, aromatic),

4.6 (bs, 1H, -NH), 4.1-4.6 (m, 1H, -O-VH-), 3.3 (t, 2H, J = 7Hz, -CH2-), 2, 6 (t, 2H, J = 7Hz, CH _2), 2.0-0.7 (m, remaining protons).

Example 18 dl-5-Hydroxy-2-melyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline

A mixture of 16.4 g (100 mmol) of 5-phenyl-2- (R, S) -pentanol, 28 mL (200 mmol) of triethylamine and 80 mL of dry tetrahydrofuran was cooled under an atmosphere of nitrogen in an ice / water bath. To the mixture drop by drop

Add -8180917 (8.5 mL, 110 mmol) of methanesulfonyl chloride in 20 mL of dry tetrahydrofuran at a rate such that the temperature is substantially constant. The mixture was then allowed to warm to room temperature and then filtered to remove triethylamine hydrochloride. The filter cake was washed with dry tetrahydrofuran and the combined washings and filtrates were evaporated under reduced pressure. The product was obtained as an oil, which was dissolved in chloroform (100 ml) and washed with water (2x100 ml) and brine (1x20 ml), and the solvent was evaporated. This gives 21.7 g (89.7%) of d, 1-5-phenyl-2-pentanol mesylate which can be used in the next step without further purification.

1.0 g (5.2 mmol) of dl-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline, 14.35 g (0.104 mol) of potassium carbonate, 60 ml of Ν, Ν- iformamide and

A mixture of 13.68 g (57 mmol) of dl-5-phenyl-2-pentanol mesylate was heated at 80-82 ° C in an oil bath for 1.75 hours under nitrogen. The mixture was cooled to room temperature and then poured into 300 ml of ice / water. The aqueous solution was extracted with ethyl acetate (2 x 50 mL), and the combined extracts were washed with water (3 x 50 mL) and brine (1 x 50 mL). The extracts were dried over anhydrous magnesium sulfate, decolorized with charcoal and evaporated. In this way, the desired product is obtained.

m / e = 339 (m +).

The above procedure was repeated, but 114.8 g (0.594 mol) of dl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline, m.p. of N, N-dimethylformamide, 174.8 g (1.265 moles) of potassium carbonate and 165.5 g (0.638 moles) of dj-5-phenyl-2-pentanol mesylate were used. The reaction mixture was cooled and poured into 4 L of ice water. The aqueous solution was extracted with ethyl acetate (2 x 4 L). The combined extracts were washed first with water (4x2 liters), then with brine (1x2 liters) and then dried over anhydrous magnesium sulfate. Concentration of the solution afforded 196 g of the title compound which was used without further purification.

TMS

Ή NMR (60 MHz) δ _DC1 (ppm): 12.73 (s,

1 H, OH), 7.22 (s, 5 H, aromatic), 5.80 (d, J = 3 H ₃ , 1H, m-H), 5.58 (d, J = 3 H, 1H, m-H). , 1.25 (d, 6H, CH 3 -CH-N and CH 3 -CH-O-), 1.41-4.81 (m, UH, residual protons).

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

The procedure described in Example 18 was followed except that 5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline was used in 5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline. instead of ^one and gives dl-5-hydroxy-7- {2-We5Hl péntiIöxi) -4-oxo-l, 2,3,4 -tetrahidrokinolint as an oil in 74% yield.

m / e = 325 (m +).

Analysis calculated for C20 H23 NO3: C, 73.70; H, 7.12; N, 4.31%. Found: C, 73.69; H, 7.15; N, 4.08%.

TMS 1 H NMR (60 MHz) δ _CDCl (ppm): 12.6 (bs, 1H, phenolic), 7.3 (s, 5H, aromatic), 5.8 (d, 1H, aromatic J = 2Hz), 5.6 (d, 1H, aromatic, J = 2Hz),

4.7-4.1 (m, 2H, NH and -O-CH), 3.5 (t, 2H, CH, J = 7Hz), 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, 27 g (0.14 mol) of dl-5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline is alkylated with 35.2 g (0.154 mol) of 4-phenylbutyl methanesulfonate to give 41.1 g (90%) of the desired dl-5-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline are obtained, m.p. are good. The product was recrystallized from ethyl acetate-hexane (1: 2) to give a melting point of 90-91 ° C.

Analysis calculated for C ₂ oH ₂ ;; 0.jN O: C 73.82; H, 7.12; N, 4.30%; Found: C, 73.60; H, 7.09; N, 4.26%.

m / e = 325 (m +).

TMS 1 H NMR (60NHz)? _R (ppm): 12.58 (s, 1H, -OH), 7.21 (s, 5H, C ₆ H _G ), 5.74 (d, J = 2, 5 Hz, 1H, Meta H), 5.5 (d, J = 2.5 Hz, 1H, metaH), 4.36 (bs, 1H, NH), 3.53-4.08 (m, -O -CH ₂ , -CHN), 2.29-2.83 (m, 4H, -CH ₂ -C = D, C ₆ H ₅ CH ₂ ). 1.51-1.92 (m, 4H, - [CH-,] ₂ ), 1.23 (d, 3H, .CH: -).

Similarly, d-5,7-dihydroxy-4-oxo-1,2,3,4-tetrahydroquinoline is alkylated with d-2-octylmethanesulfonate to give d-5-hydroxy-2-methyl-7- [2- (R) -octyloxy] - 4-oxo-1,2,3,4-tetrahydroquinoline is obtained. M.p. 64-68 ° C.

_[A] 25 * = + 110.2 ° (c = 0, CHCl3).

Similarly, dl-5,7-dihydroxy-2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline is alkylated with dl-5-phenyl-2-perethanol mesylate to give dl-5-hydroxy-7- (5-phenyl-2-pentyloxy) ) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline is obtained.

m / e = 367 (m +).

Example 20 dl-1-Photomethyl-hydroxy-5-hydroxymethylene-methyl-7 - (- 5-phenyl-2-pentyloxy) -4-axo-1,2,3,4-tetrahydroquinoline

195 g (about 0.58 mol) of dl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline 1140 g (14.6 g). of a solution of ethyl monomer in ethylmyrmate was added dropwise to a solution of sodium hydride (72 g, 3.0 mol) under vigorous stirring, which was obtained by washing 144 g of 50% sodium hydride with 3 x 500 ml of exane. After about one and a half hours, when 2/3 of the ethyl formate was added, the addition was discontinued and wait until

-9180917 Strong foaming subsides. Diethyl ether (600 ml) was then added and the mixture was stirred for 15 minutes before addition of the remaining ctilformate. After the addition was complete, 600 ml of diethyl ether were added and the reaction mixture was stirred for an additional 10 minutes and then poured into 2 liters of ice water. The pH of the mixture was adjusted to 1 with 10% hydrochloric acid solution, and the phase was separated and extracted with ethyl acetate (2 x 2 L). The combined organic solutions were washed with water (2 x 2 L), brine (1 x 1 L), dried over anhydrous magnesium sulfate, and concentrated. This gives 231 g of a tan oil which can be used without further purification,

_Rf = 0.1 to 0.5 (provided) by thin layer chromatography, silica plates (1: 1 alkylbenzene mixture).

In a similar manner, dl-5-hydroxy-7- (5-phenyl-2-pentyloxy) 2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline is transformed into dl-1-formyl-5-hydroxy-3-hydroxymethylene. -7- (5-phenyl-2-pentyloxy) -2-propyl-4-oxo-1,2,3,4-tetrahydroquinoline. This compound is used in the following example.

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

To 18.2 g (0.38 mole) of sodium hydride obtained by washing 50% sodium hydride in an oil dispersion with pentane, 11.1 g (0.038 mole) of dl-5-hydroxy-2-methyl- is added dropwise over half an hour. A solution of 7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline in 110 g (1.48 mol) of ethyl formate. At this point, an exothermic reaction begins with strong hydrogen evolution and a yellow precipitate forms. The reaction mixture was cooled, ether (750 mL) was added and the resulting mixture was heated to reflux and stirred for 3 hours. The reaction mixture was then cooled to 0 ° C and neutralized with 400 ml of IN hydrochloric acid. The ether layer was separated and the aqueous layer was extracted with ether (2 x 150 mL). The ethereal extracts were combined, washed with saturated aqueous sodium bicarbonate (2 x 100 mL), brine (1 x 150 mL), and dried over anhydrous magnesium sulfate, and then concentrated the dry extract. This gave 10.8 g of an orange foam. An additional 2.3 g was obtained by acidifying the sodium bicarbonate washings with concentrated hydrochloric acid and extracting the acidic solution with ether (2 x 100 mL). The ether extracts were concentrated after drying to give 2.3 g of product (total product 13.1 g). The material is used in this manner.

TMS

Ή NMR (60 MHz) δ Qryn. (PP ^m ) ^; 12.27 (bs,

1H, ArOH), 8.8 - 11.9 (m, 1H, variable, = COH),

8.73 (s, 1H, N-CHO), 7.41 (s, 1H, -CH), 6.32 (s, 2H, aromatic), 5.52 (q, 1H, -CH-N), 4.18 - 4.77 (m,

1H, O-CH), 0.6 to 2.08 (m, 17H, CHA-C-Cs), and _CH3 CN).

We redesign it in a similar way:

dl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline dl-1-formyl-5-hydroxy-3-hydroxymethylone-2-methyl -7- (5-phenyl-2-pentyloxy-4-oxo-1,2,3,4-tetrahydroquinoline).

TMS

Ή NMR (60 MHz) δ (ppm): 12.22 (bs,

1H, ArOH), 8.8 - 11.6 (variable), 1H, = COH), 8.64 (s, 1H, -CHO), 7.21 (bs, shoulder at 7.30, 6H, aromatic and = CH), 6.23 and 6.17 (two 1H doublets, J = 2Hz, meth), 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 (overlapping doublets, 6H, CH3-CN and CH ₃ -C-O).

dl-5-hydroxy-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline d, 11-formyl-5-hydroxy-3-hydroxymethylene-7- (2-heptyloxy) -4 oxo-1,2,3,4-tetrahydroquinoline which is an oil.

TMS

Ή NMR (60 MHz), 1 pp, -η (PP ^m ) ^: 12.1 (bs, phenol), 8.8 (s, 1H. -N-CHO), 8.1 (s, 1H), δ. , 3 (s. 1H), 6.1 (s, 2H, aromatic), 4.5 (bs, 2H, -CH ₃ -), 4.2-4.8 (m, -O-CH ·) - ), 2.0-0.7 (residual protons).

dl-5-hydroxy-7- (5-pentyl-2-pentyloxy) -4-oxo-1

2.3.4-Tetrahydroquinoline to d, l-1-formyl-5-hydroxy-3-hydroxymethylene-7- (5-phenyl-2-pentyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline.

TMS 1 H NMR (60 MHz) fp / i. (ppm): 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, -CHCH _3, J = 6Hz).

dl-5-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline dl-1-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (4-phenylbutyloxy) -4-first 2,3,4-tetrahydroquinoline.

132-135 ° C (from hexane). After recrystallization from hot methanol, m.p. 131-132 ° C.

Analysis calculated for C C RH ^ ^NNN: C, 69.27; H, 6.08; N, 3.67 Found: C, 69.25; H, 5.88; N, 3.88%.

m / e - 381 (m +)

TMS

Ή NMR (60 MHz) δ ppm: (ppm): 12.4—

13.6 (m, H, -OH), 12.26 (s, 1H, 5-OH), 8.62 (s, 1H, -C (= O) -H), about 7.18-7 , 48 (m, = - II), 7.27 (s, 5H, CeH5). 6.26 (bs, 2H, meta-H), 5.46 (q, 1H, CH-N), 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 dl-1-Formyl-5-hydroxy-2-m, ethyl-7- (5-phenyl-2-pentoxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline

229 g (about 0.58 mol) of dl-1-formyl-3-hydroxymethylene-5-hydroxy-2-methyl-7- (5-phenyl-2-pen-1021-yloxy) -4-exo-1, To a solution of 2,3,4-tetrahydroquinoline in 880 ml of methanol was added 27.2 ml of triethylamine under nitrogen, followed by 97.0 ml of methyl vinyl ketone, and the mixture was stirred overnight at room temperature.

The reaction is complete and the title compound and dl-1,3-diformyl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-3- (3-oxobutyl) are obtained. a mixture of -1,2,3,4-tetrahydroquinoline. In the following steps, the diformyl compound is converted to the desired product.

The reaction mixture was diluted with ether (6 L) and washed with 10% aqueous sodium carbonate solution (4 x 1700 mL) and brine (1 x 2 L) and dried over anhydrous magnesium sulfate. The solution was concentrated to give 238 g of a red-brown oil. The oil was dissolved in methanol (1920 mL) and the solution was cooled to 0 ° C and 21.2 g of potassium carbonate was added. The mixture was stirred for 3 hours at 0 ° C and then

18.7 g of acetic acid are treated. The methanol was removed under reduced pressure and the resulting oil was stirred with 2 L of water and 2 L of ethyl acetate for 10 minutes. The aqueous phase was separated, extracted with ethyl acetate (1 x 2 L), and the ethyl acetate solutions were washed with water (2 x 2 L) and brine (1 x 2 L), and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure and the concentrate was chromatographed on 1.8 kg of silica gel to give 159 g of the title compound.

m / e = 437 (m +).

TMS

Ή NMR (60 MHz) δ _CDCl (ppm): 12.7 (s,

1H, OH), 8.78 (bs, 1H, -7.22 (s, 5H, aromatic), 6.22 (bs, 2H, m-H), 2.12, 2.07 (s, 3H, -CH3-CO-), 1.31 (d, 3H, -CH2-CO) and 1.57-5.23 (m, 13H, residual protons).

g (0.09 mol) of dl-1-formyl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (4-phenylbutyloxy) -4-oxo-1,2,3,4-tetrahydrochlorin

22.7 g (60%) of dl-1-formyl-5-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydro-choline are obtained, m.p. mp 101-103 ° C. After recrystallization from methanol, the melting point is 104-105 ° C. Analysis calculated for C 25 H 29 O 5 N: C, 70.90; H, 6.90; N, 3.31%; Found: C, 70.77; H, 6.81; N, 3.46%.

TMS ⁽¹ H NMR (60 MHz) δ (PP ^m ) ^: 12.88 (s,

1 H, -OH), 9.08 (bs, 1H, -CHO), 7.29 (s, 5H, C ₆ H ₅ ), 6.25 (bs, 2H, meth H), 4.88-5. 43 (m, 1H, CHN), 3.86 to 4, Bl (m, 2H, _-CH2 -O-), 2,49- about 3.02 [m, 7H, _ArCH2, - _(CH2 ) ₂ -C (= O) -, -CH-C (= O)], 2.18 [s, 3H, CH ₃ -C (= O)], 1.68-2.03 [m, 4H, - (CH ₂ ) ₂ ], 1.13 (d, 3H, CH ₃ ).

m / e = 423 (m +).

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

Example 23 dl-1-Formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) 4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline and d, 11 3-Diformyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline

13.1 g (37.7 mmol) of d, 1-5-hydroxy-3-hydroxymethylene-2-methyl-7- (2-heptyloxy) -4-oxo-1,2,3,4-tetrahydroquinoline in 56 ml of methanol. To this solution of triethylamine (1.3 mL, 9.3 mmol) was added. The mixture was stirred at room temperature under nitrogen for 18 hours and then diluted with ether (550 mL). The solution was washed with 4 x 60 mL 10% aqueous sodium bicarbonate, then with 1 x 100 mL brine, and dried over anhydrous magnesium sulfate. The ether was evaporated to give 16 g of a dark oil. The oil was dissolved in as small a volume of benzene as possible and applied to a column packed with 500 g of silica gel. The column was eluted with an equal volume of benzene. The eluting solvent was then changed to 15% ether-benzene and 100 mL fractions were collected. The elution is stopped when the first color bar appears. 5-13. fractions were combined and concentrated under reduced pressure to give 8.7 gd, 11, 3-diformyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2, 3,4-Tetrahydroquinoline was obtained as a yellow oil.

The column was further eluted with 15% ether in zol. 19-37. fractions were combined and concentrated under reduced pressure. 4.6 g of d, 1-formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline are obtained in the form of an oil. Further monoformyl product is obtained as follows:

g of the diformyl product is mixed with 200 mg of potassium carbonate in 25 ml of methanol for two hours at 0 ° C. The solvent was then evaporated in vacuo and the residue was slurried in ether and filtered. The filtrate was concentrated and the residue was partitioned between ether and water. The organic layer was separated and the aqueous layer was acidified with 10% hydrochloric acid and extracted with ether. The combined extracts were washed first with saturated sodium bicarbonate solution, then with brine, dried over anhydrous magnesium sulfate, then filtered and concentrated. This gives an additional monoformyl product.

The monoformyl derivative has the following NMR spectrum:

TMS 1 H NMR (60 MH ₂ ) δ (δ DCI (PP ^m ) ^: 12.73 (S,

1H, ArOH), 8.87 (s, 1H, N-CHO), 6.12 (S, 2H, aromatic), 4.78-5.50 (Μ, 1H, N-CH), 4.11- 4.72 (Μ, 1H, -O-CH), 2.21 (S, 3H, CH ₃ -C (= O) -), 0.63-3.12 (Μ, 22H, remaining hydrogen).

In a similar manner, the following compounds were prepared from the appropriate starting materials: dl-1-formyl-5-hydroxy-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline, oil.

TMS

Ή NMR. (60 MH ₂ ) δ qqqj., (PP ^m ): 1,2,8 (S,

-1 123

1Η, phenolic), 8.7 (S, 1H, N-CHO), 6.1 (S, 2H, aromatic), 4.1-4.6 (m, 1H, -O-CH), 4.1 (d, 2H, J = 5H ₂ , -CH ₂ -), 2.3-3.0 (m, 3H, CH ₂ and CH-C (= O)), 2.2 (S, 3H, -C (= O) -CH ₃ ), 2.3-0.7 (residual protons).

dl-1-formyl-5-hydroxy-2-methyl-7- (5-phenylpentyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline.

TMS 1 H NMR (60 MH ₂ ) t) _; , (ppm): 12.68) S,

1 H, -OH), 8.82 (b, s, 1H, -C (O) H), 7.20 (b, s, 5H, C ₆ H ₅ ), 6.18 (b, s, 2K, aromatic, 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, -N C-CH ₃ ), 1.4-3.1 (m, 11H, residual H ).

dl-1-formyl-5-hydroxy-7- (5-phenyl-2-pentyloxy) 4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline. m / e = 423 (m +).

The corresponding 1,3-diformyl derivative is also formed as a by-product in the preparation of chemical compounds.

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

174 g (0.398 mol) of d, 11-formyl-5-hydroxy-2-methyl-7- (5-phenyl-2-pentyloxy) -4-oxo-3- (3-oxobutyl-1,2,3,4-tetrahydroquinoline) A solution of 5.9 L of 2N methanolic potassium hydroxide in 5.9 L of methanol was stirred and refluxed under nitrogen overnight, then cooled and 708 g of acetic acid was added dropwise over 15 minutes with stirring. vacuum (water pump), concentrated to a semi-solid, filtered and washed with water first to remove potassium acetate followed by ethyl acetate wash to remove black tar to give 68 g (44%) of a yellow solid, m.p. 190 DEG C. The product was recrystallized from warm ethyl acetate, m.p. 194-195 ° C.

m / e = 391 (m +).

Analysis calculated for C25 H20 O3 N: C, 76.09; H, 4.47; N, 3.58%; Found: C, 76.43; H, 7.48; N, 3.58%.

TMS 1 H NMR (60 MHz) δ (100 mg dissolved)

0.3 ml CD3 OD and 0.3 ml _CD3 (O) _CD3) O (ppm): 7.21 (s, 5H, aromatic), 5.80 (s, 2H, meta-H), 1.20 (d, 6H, CH ₃ -CHO and CH ₃ -CH-N).

The mother liquors afford a small amount of axial methyl derivative which is purified by column chromatography on silica gel using a 1: 1 mixture of benzene and ether. After evaporation of the eluate and recrystallization of the residue from ether-hexane (1: 1), the pure material melted at 225-228 ° C.

TLC on silica gel using 2.5% ether in methanol 12 as eluant, Rf = 0.34. 6 / - methyl derivative _Rf 0.41.

m / e = 391 (m +).

^m MS

Ή NMR (60 MHz) Λ ^X (100 mg dissolved in 0.3 ml and 3.0 ml CD.sOD CD ₃ S (O) _CD3) O (ppm): 7.19 (s, 5H, aromatic), 5 , 75 (s, 2H, m H), 1.21 (d, 3H, CH ₃ -CHO-) and 0.95 (d, 3H CH ₃ -CH-N).

22 g of dl-1-formyl-5-hydroxy-2-methyl-7- (4-phenylbutyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3,4-tetrahydroquinoline were treated in a similar manner to give 17.1 g. (87%) of dl-5,6,6a, 7-tetrahydro-1-hydroxy-6 N-methyl-3- (4-phenylbutyloxy) -benzo [c] quinolin-9 (8H) -one is obtained.

Mp 222-224 ° C. After recrystallization from methanol, the melting point is 224-225 ° C.

Analysis calculated for C 24 H 7 O ₃ N ₂ O: 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 CD 3 OD]: 1.24 (d, 3H, 6? - CH ₃ ). m / e = 377 (m +).

After evaporation of the mother liquor, 2.8 g of product are obtained, m.p. 185-195 ° C. The NMR spectrum shows that the 6? a mixture of -1-hydroxy-6a-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, δ-CH ₃ ) and 0.95 (d, 1.8H) , 6a-CH ₃ ).

Example 25 dl-5,6,6a, 7-tetrahydro-1-hydroxy-6-methyl-3- (2-heptyloxy) -benzo [c] quinolin-9 (8H) -one

4.5 g (11.5 mmol) of dl-1-formyl-5-hydroxy-2-methyl-7- (2-heptyloxy) -4-oxo-3- (3-oxobutyl) -1,2,3, A solution of 4-tetrahydroquinoline in 150 ml of methanol is treated with 150 ml of 2N methanolic potassium hydroxide solution. The mixture was stirred at room temperature for 1 hour and then heated under reflux for 20 hours under a nitrogen atmosphere. The dark red mixture was allowed to cool to room temperature, neutralized with acetic acid and concentrated to about 100 ml under reduced pressure. The concentrate was diluted with water (400 mL), the tan-red solid was collected by filtration, washed with water and dried to give about 6 g of product. The product was first treated with ether then methanol, filtered off and dried. 1.96 g, m.p. 223-229 ° C. After recrystallization from hot methanol, the product has a melting point of 235-237 ° C. Analysis: Calculated for C ₂₁ H ₂ gO ₃ N: C, 73.43; H, 8.51; N, 4.08%; Found: C, 73.22; H, 8.30; N, 4.11%.

Further material was obtained by evaporation of the mother liquor and extraction of the aqueous solution with chloroform, of which a brownish-red color was obtained.

The product was extracted and the extract was evaporated. The combined residues were chromatographed on silica gel eluting with ether.

In a similar manner, the following compounds can be prepared from the appropriate materials:

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

m / e = 377 (m +).

Analysis calculated for C24 H27 O3 N: C, 76.36; H, 7.21; N, 3.71%; Found: C, 76.38; H, 7.21; N, 3.85%;

dl-5,6,6a, 7-tetrahydro-1-hydroxy-3- (2-heptyloxy) -benzo [c] quinolin-9 (8H) -one. M.p. 208-209 ° C.

m / e = 329 (m +).

Anal. Calcd for C20H27O3N: C, 72.92; H, 8.26; N, 4.25%; Found: C, 72.92; H, 8.31; N, 4.42%.

dl-5,6,6a, 7-tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyloxy) -6H-propylbenzo [c] quinolin-9 (8H) -one.

164-166 ° C.

Analysis: Calculated for C27H33O3N: C, 77.29; H, 7.93; N, 3.34%; Found: C, 76.97; H, 7.98; N, 3.41%.

1-5,6,6a, 7-Tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyloxy) -6H-methylbenzo [c] quinolin-9 (8H) -one. 176-178 ° C.

[α] ²¹ D = 416.0 ° (c = 0.33, CH ₃ OH) m / e = 391 (m +).

Analysis calculated for C 25 H 29 O 3 N: C, 76.69; H, 7.47; N, 3.85%; Found: C, 76.32; H, 7.36; N, 3.33%.

d-5,6,6a, 7-Tetrahydro-1-hydroxy-3- (5-phenyl-2-pentyloxy) -6H-methylbenzo [c] quinolin-9 (8H) -one. Mp: 172-174 ° C.

Md = + ^{412 '9} ° (c = 0, CH ₃ OH). m / e = 391 (m +).

Analysis calculated for C 9 O ₂ gH ₂ N ₃ O: C 76.69; H, 7.47; N, 3.58%; Found: C, 76.40; H, 7.39; N, 3.51%.

Example 26

By the methods given in the previous examples, compounds of formula I are prepared.

where R | and R5 is in the a, Rz, and / or N-position. Z m / e R ⁴ R ₃ (m +) op. (° C) formula Analysis calculated because the) -O-CH (CH ₃ ) (CH ₂ ) _{3 C 6} H 5 C ₂ Hg H 405 155-6 C, jH _3j O ₃ N C, 77.00; H, 7.71; N, 3.45 C, 76.86; H, 7.62; N, 3.45 b) -O-CH (CH ₃ ) (ΟΗ ₂ ) ₃ ΟβΗ ₃ CfiHi ₃ H 46i 139-141 C 30 H 31 _{N 3} O ₃ N C, 78.05; H, 8.52; N, 3.03 C 78.16 H, 8.53; N, 3.09 c) -O-CH (CH ₃ ) (CH ₂ ) ₃ C ₆ H ₅ CgH, H 477 150-3 c ₂₉ h ₃₇ o ₃ n C, 77.81; H, 8.33; N, 3.13 C, 77.73; H, 8.19; N, 3.13 d) -O-CH (CH ₃ ) (CH ₂ ) ₃ C ₆ H 5 CgHn H 433 160-2 c ₂₈ h ₃₅ o ₃ n C, 77.56; H, 8.14; N, 3.23 C, 77.28; H, 7.92; N, 3.18 e) -O-CH (CH ₃ ) (CH ₂ ) ₃ C ₆ H ₅ HC ₄ H «, 433 95-98 C ₂₆ H ₃₅ O ₃ N C, 77.56 H, 8.14; N, 3.23 C, 77.86; H, 8.37; N, 3.17 f) -O-CH (CH ₃ ) (CH ₂ ) ₃ C ₆ H ₅ - (CH ₂ ), - C ₆ H ₅ η 481 200-201 C ₃₂ H ₃₅ O ₃ N C, 79.80; H, 7.33; N, 2.91 C, 79.64; H, 7.34; N, 2.93 g) -O-CH (CH ₃ ) (CH ₂ ) ₃ C ₆ H ₅ CH.! H, 363 246-7 C23H25O3N C, 76.00; H, 6.83; N, 3.85 C, 76.19; H, 7.14; N, 3.89 h) -C (CH ₃ ) 2 -CeH ₁₃ CH.s H 355 261-2 C2 ₃ H ₃₃ O ₂ N C, 77.70; H, 9.36; N, 3.94 C, 77.94; H, 9.21; N, 3.99 i) -O (CH ₂ ) _{2 C 6} H 5 CH ₃ H 349 248-250 C _{2 2} H ₂₃ O ₃ N C, 75.62; H, 6.63; N, 4.01 C, 75.26; H, 6.66; N, 3.93

-13180917

Example 27

As described in the previous examples, for the preparation of compounds of the general formula (I) wherein R 1 is an acetyl group and R 1, a, R ₄ are at an op position m / e.

r ₄ rr, (° C) (M +) formula calculated because the) -C (CH ₃ ) ₂ -C ₆ H | ₃ ch ₃ H 108-112 397 C ₂ ! H _{3 5} NO ₃ C, 75.53; H, 8.37; N, 3.52 C, 75.62; H, 8.73; N, 3.52 b) -O-CH (CH ₃ ) (CH ₂ ) ₃ C ₆ H ₅ [6R, 6aR] H CH ₃ 125-130 433 c ₂₇ h ₃ , and ₄ n C, 74.80; H, 7.21; N, 3.23 C, 74.96; H, 7.11; N, 3.19 c) -OCH (CH i) (CH _{2) 3} C (íH5 [6S, 6aR] ;, CH H 145-146 433 C ₂₇ H ₃₁ O ₄ N C, 74.80; H, 7.21; N, 3.23 C, 74.91; H, 7.20; N, 3.24 d) -OCH (CH ₃ ) (CH ₂ ) ₃ C ₁₅ H, -, [2'S, 6S, 6aR] ch ₃ H 167-168 433 C ₂₇ H _3i O ₄ N C, 74.80; H, 7.21; N, 3.23 C, 74.66; H, 7.20; N, 3.33 e) -OCH (CH ₃ ) (CH ₂ ) ₃ C ₆ H ₅ [2'R, 6S, 6aR] ch ₃ H 120-121 433 C ₂₇ H _3t O ₄ N C, 74.80; H, 7.21; N, 3.23 C, 74.58; H, 7.19; N, 3,2 '; f) -OCH ₂ CH ₂ C ₆ H ₅ ch ₃ H 159-60 391 C ₂₄ H ₂₅ O ₄ N C, 73.63; H, 6.44; N, 3.58 C, 73.33; H, 6.41; N, 3/9

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Claims (2)

2 is a C 2 -C 9 alE 1 group optionally substituted with phenyl or naphthyl, or a C 2 -C 9 alkyl group, which is prepared by the use of vala R 1 hydrogen or C 2 -C 4 alkanoyl group. a compound of Formula II wherein P 1, R 1 is hydrogen, benzyl, methyl or ethyl; hydrogen, C 1-6 alkyl groups, a phenyl group or a (1-4C) the alkyl R / 'R ₃ and Z are as defined above and port R; hydrogen or formyl - bázisR ₅ is hydrogen, methyl or ethyl, and reacted with 10 scarf. 2 sheets with formulas Λ responsible for publishing: Director of Economic and Legal Publishing House Zalai Nyomda 84 613 - Chief Executive Officer: József Gállá Director