IE43737B1 - 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid esters - Google Patents

Description

This invention relates to novel racemic 3 - hydroxy methylene - 6,7. - dimethoxy - 2 - methyl - 4 - oxo - 1,2, 3,4 - tetrahydro - 1 - quinoline carboxylic acid alkyl, phenyl and benzyl' esters which are useful intermediates in the preparation of analgesics.

Patent Specification Ko. 43736 discloses a compound: wherein R^ taken separately is hydrogen or methyl; R^ taken separately is hydrogen, alkyl of one to five carbon atoms, propargyl, phenyl, naphthyl, phenylalkyl wherein said alkyl has one to four carbon atoms, naphthylalkyl wherein said alkyl has from one to four carbon atoms, dimethylaminoalkyl wherein said alkyl has from two to four carbon atoms where15 in the two nitrogen atoms are separated by at least two carbon atoms or mono-substituted 2-ethyl wherein said substituent is phenoxy or methoxy; R^ and R^ when considered together with the nitrogen atoms to which they are attached form a piperidino, pyrrolidino or morpholino ring; R^ is alkyl of one to five carbon atoms, phenyl, - 3 43737 benzyl or mono-substituted phenyl or benzyl wherein the substituent is fluoro, chloro, methyl, methoxy or trifluoromethyl; and the pharmaceutically acceptable acid addition salts thereof wherein Rg +s sa+d dimethylamino5 alkyl.

These compounds are generally useful as analgesics and tranguilising agents.

The present invention provides a group of compounds of the formula: wherein R^ is alkyl of one to five carbon atoms, phenyl, benzyl or mono-substituted phenyl or benzyl wherein the substituent group is fluoro, chloro, methyl, methoxy or trifluoromethyl.

The compounds of the present invention are useful intermediates in the preparation of the analgesic com pounds disclosed in Patent Specification No. 43736.

As will be recognised by one skilled in the art, the compounds of the present invention possess an asyme20 trie carbon atom at the 2-position, and can exist in two forms. These forms can be distinguished by their ability to rotate the plane of polarized light. One form rotates the plane of polarized light to the right and is known as the dextrorotatory enantiomers or the d( + ) enantiomers, while the other form rotates the plane of 3737 - 4 polarized light to the left and is known as the levorotatory enantiomers ' at .1( ) enantiomers. A mixture of equal amounts of the d. and 1. entantiomers of these compounds does not affect the plane of polarized light, and is known as a racemic mixture of d 1 form. For the purpose of the present invention, when determining whether a compound is dextrorotatory or levorotatory, it is the effect of the compound on light having a wavelength of 5893 Angstroms, the so-called D line of sodium, which is to be considered.

The invention provides the compounds defined above in the form of their d entantiomers, their JL enantiomers, and mixtures, particularly racemic mixtures,of the two. Where a compound is prepared in the form of a racemic mixture the d. and 1 enatiomers can be prepared therefrom by known methods.

Since the absolute configuration of the methyl group at the 2-position is not known the bond of the methyl substituent to the 2-position is depicted as In accordance with the process employed for synthesizing the compounds of the present invention the following scheme is illustrative: $ 3 7 3 7 pto2 (1) NaOH (2) HC1 OCH S7 37 wherein is previously defined, PEA represents polyphosphoric acid and R1 is lower alkyl having 1—3 carbon atoms.

In the first of the above-depicted reaction steps. an alkyl aceto-acetate such as ethyl acetoacetate is condensed with 3,4-dimethoxy-aniline in the presence of a suitable solvent such as benzene and a small amount of an acid catalyst such as acetic acid. Recovery of the resulting alkyl 3 - [(3,4 - dimethoxy) - anilino] 2 - butenoate (JL) upon reaction completion, which may be determined by thin layer chromatography, is possible by solvent removal at reduced pressure. Recrystallization from solvents such as hexane yields the desired butenoate intermediate.

The second step of the aforesaid reaction sequence involves hydrogenation of the butenoate product of the first step utilizing conditions for the reduction of double bonds (M. Freifelder, Practical Catalytic Hydrogenation, Techniques and Applications: Wiley-Interscience. New York 1971), preferably catalytic hydrogenation over palladium, palladium on carbon or platinum oxide under acidic conditions, i.e., at a pH of about 3 up to 7. Acetic acid is a preferred acid for obtaining this pH. The resulting alkyl 3 - [(3,4 - demethoxy)anilino]butanoate (2) may be recovered by filtration of the hydrogenated mixture, concentration under reduced pressure, dissolving resulting product in a solvent such as chloroform, washing with sodium bicarbonate solution and saturated sodium chloride, drying the organic layer using magnesium sulfate and concentration under reduced pressure.

The third step of the process involves alkaline hydrolysis of the product of the second step, employing aqueous sodium or potassium hydroxide together with a watermiscible solvent such as methanol. The resulting 3[(3,4 - dimethoxy)anilino]butanoic acid (3.) containing 37 3? - 8 reaction mixture may then be cooled, concentrated under reduced pressure, diluted with water, neutralized with acid and extracted with an agent such as chloroform.

The combined organic extracts are then dried, for example using anhydrous magnesium sulfate, and concentrated under reduced pressure to give a product suitable for use in the next step of the process without further purification.

The product of the third reaction step is then cyclized by heating in the presence of excess polyphos · phoric acid, which not only serves as the agent responsible for causing cyclization but also serves as solvent for the reaction, or by other Friedel-Crafts type catalysts and non-aqueous solvents as suggested by G. A.

Olah, Friedel Crafts and Related Reactions, Vol. 1, Interscience Publishers, Hew York, 1963. The resulting 6,7 - dimethoxy - 2 - methyl - 4 - oxo - 1,2,3,4 - tetra hydroquinoline (4) containing reaction mixture may then be poured into ice, extracted with chloroform and recove red by concentrating the combined dried organic extracts under reduced pressure.

The product of the fourth reaction step may then be acylated with an alkyl, phenyl or benzyl chloroformate in conventional fashion. The desired alkyl, phenyl or benzyl 6,7 - dimethoxy - 2 - methyl - 4 - oxo - 1,2, 3,4 - tetrahydroquinoline - 1 - carboxylate (5) is then recovered from the reaction mixture via extraction, drying of the combined extract layers and concentration under reduced pressure.

Transformation of 5_ into the useful compounds of the present invention of structure 6 is effected by treatment of the appropriate alkyl, phenyl or benzyl 6, 7 - dimethoxy - 2 - methyl 4 - oxo - 1,2,3,4 tetrahydro - quinoline - 1 - carboxylate with ethyl formate and sodium ethoxide in a solvent such as benzene. On completion of the reaction, which requires 2—6 hours at room temperature, the mixture is quenched in water. The product £ remains in the water layer as the sodium salt and is liberated by neutralization with acid. The resulting product, which is isolated by extraction or decantation, is further purified by recrystallization from an appropriate solvent.

All the starting reagents for these aforementioned synthetic reactions are either commercial reagents, or can be synthesised by literature procedures familiar to one skilled in the art Of the racemic 3-hydroxymethylene compounds of the present invention which are particularly useful as intermediates are 3 - hydroxymethylene - 6,7 - dimethoxy2 - methyl - 4 - oxo - 1,2,3,4 - tetrahydro - 1 - quinoline carboxylic acid, ethyl ester and 3 - hydroxymethy lene - 6,7 - dimethoxy - 2 - methyl - 4 - oxo - 1,2,3,4tetrahydro - 1 - quinoline carboxylic acid, benzyl ester.

The following examples are provided solely for the purpose of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the spirit or scope thereof.

EXAMPLE 1.

- Hydroxymethylene - 6,7 - dimethoxy - 2 - methyl4 - oxo - 1,2,3,4 -· tetrahydro - 1 - quinoline carboxylic acid, ethyl ester.

A. Ethyl - 3 [(3,4 - Dimethoxy)Anilino] - 2 - Butenoate. 73 7 - 10 4-Aminoveratrole (62.0 g.), ethyl acetoacetate (63.0 g ), benzene (375 ml.), and acetic acid (2.1 ml.) are combined and refluxed in a flask equipped with a Dean-Stark trap to remove water until thin layer chromatography indicated the reaction is complete. The solvent is removed under reduced pressure to give a dark oil which crystallized upon standing. Recrystallization from hexane gives 79.0 g. of a tan powder, m.p. 59—60°; a second crop afforded 6.7 g., m.p. 54—56°. A sample is recrystallized from ethanol/water to give an analytical sample, m.p. 57—58°C.

Anal. Calc'd. for c14H19N04: C, 63.35; H, 7.22; N, 5.28 Found: C, 63.45; H, 7.06; N, 5.33 B. Ethyl - 3 - [(3,4 - Dimethoxy)Anilino] Butanoate.

A mixture of 30.0 g. of the product of Example 1—A (m.p<. 59—60°), and 2.0 g. of platinum oxide in 250 ml. of acetic acid is hydrogenated in a Paar shaker at 50 p.s.i.; reduction is complete in 1 hr. The mixture is filtered and concentrated under reduced pressure to give an amber oil which is dissolved in chloroform and washed with sodium bicarbonate solution and saturated sodium chloride. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure to give 30.0 g. of an amber oil which is used in the next step without further purification. A sample of oil is converted to the hydrochloride salt, m.p. 137.5—139°. An equivalent sample of the hydrochloride salt (m.p. 138—139.5°) is analyzed. - 11 Anal. Calc'd. for C H^HO^Cl: C, 55.35; H, 7.30; N, 4.61.

Pound: C, 55.73; Ά, 7.33; N, 4.33.

C. 3 - [(3,4 - Dimethoxy)Anilino] - Butanoic Acid. A 54 g. sample of the unpurified ester product of Example 1—B is combined with 17.5 g. of sodium hydroxide, 550 ml. of methanol and 130 ml. of water, and refluxed for 1.5 hrs. The reaction mixture is cooled, concentrated under reduced pressure, diluted with water and neutralized with 6N hydrochloric acid to give an oily mixture which is extracted with chloroform. The combined organic extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 48 g. of an oily product. This material is used in the next step without further purification.

D. 6,7 - Dimethoxy - 2 ~ Methyl - 4 - Oxo - 1,2, 3,4 - tetrahydroquinoline.

The crude acid of Example 1—C (48 g.) and 500 g. of polyphosphonic acid are heated for 1 hr. on a steam bath with vigorous stirring, then poured onto 700 g. of ice and extracted with chloroform. The organic extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 26.4 g. of a yellow solid, m.p. 145—48°. A small sample is sublimed at 110° ('.05 mm) to give a pale yellow solid, m.p. 150—151°.

Anal. Calc'd for Ο1Γ,Η1Ε.Ο N: C, 65.14; H, 6.83; N, 6.33 Pound: C, 65.18; H, 6.86; H, 6.25 ϊ Γί ο *7 Ε. Ethyl 6,7 - Dimethoxy - 2 - Methyl - 4Oxo - 1,2,3,4 - tetrahydroquinoline - 1Carboxylate.

A mixture of 15 g. the quinoline product of 5 Example 1—D, 95 g. of potassium carbonate, and 225 ml. of methylene chloride are stirred for 1 hr., then 14.7 g of ethyl chloroformate in 20 ml. of methylene chloride is added dropwise and the suspension is allowed to stir for 72 hrs. at room temperature. Additional 7.3 g. por~ tions of ethyl formate are added after 24 and 48 hrs and 47 g. of potassium carbonate is added after 48 hrs. The reaction mixture is quenched with water and extracted several times with methylene chloride. The combined organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an oil which solidifies upon standing; trituration with 5% ethyl acetate in hexane gives 17 g. of a solid, m.p, 112—116°. This solid is chromatographed on silica gel, eluting with 1:1 ethyl acetate/hexane, and recrystallized from 1:1 ethyl acetate/hexane to give 13.9 g. of white crystals, m.p. 116.5—18°.

Anal. Calc d for C.JH, NO,.: 19 5 C, 61.42; H, 6.53; N, 4.78 Pound: C, 61.37; II, 6.51; N, 4.78.

P. 3 - Hydroxymethylene - 6,7 - dimethoxy - 2methyl - 4 - oxo - 1,2,3,4 - tetrahvdro1 - quinoline carboxylic acid, ethyl ester.

To sodium ethoxide freshly prepared from 4.8 g. of sodium hydride and 6.0 ml, of ethanol is added 14.7 g. of ethyl 6,7 - dimethoxy - 2 - methyl - 4 - oxo1,2,3,4 - tetrahydroquinoline - 1 - carboxylate and 19.8 ml. of ethyl formate to 150 ml. of benzene over a 3 7 3 7 - 13 45 min. period. The reaction mixture, after stirring at room temperature for 3 hrs., is poured onto 250 ml. of ice water. The aqueous layer is retained and the organic layer extracted with IN aqueous sodium hydroxide. The basic extract is combined with the separated aqueous layer and backwashed with benzene. The aqueous layer is then added to 250 ml. of 12N hydrochloric acid, resulting in the formation of a yellow oil. crystallization of the oil from hexane gives 15.4 g, of the desired intermediate, m.p. 98—101°C. Further recrystallization from the same solvent raises the melting point to 129— 130°C.

Anal. Calc'd for 16 19 6 C, 59.8; H, 6.0; N, 4.4. Found: C, 59.7; H, 5.9,- N, 4.3. EXAMPLE 2.

- Hydroxymethylene - 6,7 - dimethoxy - 2 - methyl4 — oxo - 1,2,3,4 - tetrahydro - 1 - quinoline carboxylic acid, methyl ester.

A. Methyl 6,7 - dimethoxy - 4 - oxo - 1,2,3,4tetrahydroquinoline - 1 - carboxylate.

A mixture of 1.2 g. (5.45 mmol) of the quinoline product of Example 1—D, 792 mg. (10.7 mmol) of dry pyridine and 5.5 ml. of methylene chloride are stirred and cooled by an ice-water bath while 753 mg, (3.02 mmol) of methyl chloroformate in 1 ml. of methylene chloride is added over a 10 min. period at a rate to maintain a 10—15°C temperature. The ice bath is removed and the reaction allowed to stir at room temperature for 45 min., then poured onto 25 ml. of saturated sodium bicarbonate solution. The methylene chloride layer is separated and washed with 25 ml. saturated sodium bicarbonate 37 37 -. 14 solution and saturated sodium chloride solution, then dried over magnesium sulfate, and gravity filtered and evaporated to a yellow solid. The solid is triturated with 5 ml. anhydrous ether, filtered, and washed with minimum ether, then air dried to 1.1 g. of a yellow solid, m.p. 156—158°C. This material is dissolved in 10 ml. of hot ethyl acetate, treated with 50 mg.

Darco G60 ( Trade Mark) ,, filtered and crystallized by the addition of hexane to give 727 mg. of an off-white solid, m.p. 159—160°C. after drying in vacuum at 100°C. (1 mm) for 24 hrs.

Anal. Calc'd for C^^H^^O^N: C, 60.2; H, 6.2; N, 5.0.

Found: C, 60.3; H, 6.3,- N, 5.3.

B. 3 - Hydroxymethylene - 6,7 - dimethoxy - 2methyl - 4 - oxo - 1,2,3,4 - tetrahydro - 1quinoline carboxylic acid, methyl ester.

Methyl 6,7 - dimethoxy - 2 - methyl - 4 - oxo20 1,2,3,4 - tetrahydro - quinoline - 1 - carboxylate (13.8 g.) in 140 ml. of benzene containing 19 ml. of ethyl formate is added to sodium ethoxide freshly prepared from 4.8 g. of sodium hydride and 6 ml. of ethanol over a period of 45 min. After stirring at room temperature for 4 hrs. the reaction mixture is poured onto 250 ml. of ice-water. The aqueous layer is retained and the organic layer washed with IN aqueous sodium hydroxide. The washings are combined with the aqueous extracts and backwashed with benzene. The aqueous layer is then made acid with 12N hydrochloric acid and extracted with chloroform. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is employed in subsequent reactions without further purification. 3 7 3 7 - 15 EXAMPLE 3.

- Hydroxymethylene - 6,7 - dimethoxy - 2 - methyl4 - oxo - 1,2,3,4 - tetrahydro - 1 - quinoline carboxylic acid, butyl ester.

A. Butyl 6,7 - dimethoxy - 2 - methyl - 4 - oxo1,2,3,4 tetrahydro - quinoline - 1carboxylate.

To a cooled mixture of 1.15 g. (5.17 mmol) of the quinoline product of Example 1—D, 751 mg. (10.15 mmol) of dry pyridine and 5.5 ml. of methylene chloride stirred, under a nitrogen atmosphere is added dropwise 1.03 g. (7.60 mmol) of butyl chloroformate in 1 ml. methylene chloride over 10 min. at a rate to maintain a 10—15°C. temperature. After the addition is complete the bath is removed, the reaction stirred at room temperature for 45 min., and poured onto 25 ml. saturated sodium bicarbonate solution. The organic phase is collected and washed with 25 ml. of saturated sodium bicarbonate solution, 50 ml. saturated sodium chloride solution, dried over magnesium sulfate, then gravity filtered and evaporated to a viscous amber oil. Evaporative distillation at 110°C. (0.05 mm) gave 1.4 g. of a very viscous amber oil.

Anal. Calc'd for C27H23°5N: C, 63.5; H,7.2; N, 4.4.

Pound; C, 63.7; H, 7 2; N, 4.1.

B. 3 - Hydroxymethylene 6,7 - dimethoxy - 2methyl - 4 - oxo - 1,2,3,4 - tetrahydro1 - quinoline carboxylic acid, butyl ester.

To sodium ethoxide freshly prepared from 4.8 g. of sodium hydride and 6.0 ml of ethanol is added 16.0 g. of butyl 6,7 - dimethyl ·- 2 - methyl -4-- oxo - 1,2,3,4tetrahydro - quinoline - 1 - carboxylate and 19.8 ml. of ethyl formate in 150 ml. of benzene over a 30 min. period. The reaction mixture, after stirring at room 2 7 3 7 temperature for 4 hrs., is poured onto 250 ml. of icewater. The aqueous layer is retained and the organic layer extracted with IN aqueous sodium hydroxide. The. base extracted is combined with the separated aqueous and backwashed with benzene.. The aqueous layer is then added to 250 ml. of 12N hydrochloric acid The resulting yellow oil is extracted with chloroform and the chloro form layer dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title product.

IO EXAMPLE 4.

- Hydroxymethylene - 6,7 - dimethoxy - 2 - methyl - 4oxo - 1,2,3,4 - tetrahydro - 1 - quinoline carboxylic acid, benzyl ester.

A. Benzyl 6,7 - dimethoxy - 2 - methyl - 4 - oxo15 1,2,3,4 - tetrahydroquinoline - 1 - carboxyla te.

To a solution of 10.0 g (45.3 mmol) of the quinoline product of Example 1—D in 75 ml. of pyridine cooled to 0°C. is added over a 30 min. period 55 ml. of benzyl chloroformate. After 20 min. the reaction mixture was warmed on a steam bath during which time the reaction became exothermic. Heating at steam bath temperatures is continued for 30 min., and the mixture allowed to cool to room temperature.' The resulting suspension is added to a mixture of 550 ml. chloroform/300 ml. water The chloroform layer is separated, washed successively with 10% hydrochloric acid (3 x 300 ml.), saturated aqueous sodium bicarbonate (1 x 200 ml.) and brine (1 x 200 ml.), and dried over magnesium sulfate. The chloroform layer is concentrated to dryness and the residue crystallized from ethyl acetate-hexane, 14.0 g. Recrystallization from the same solvent gave 11.4 g. of the desired product, m.p. 127.5—129.5°C. 4-S7 37 Β. 3 - Hydromethylene -6,7 dimethoxy - 2methyl - 4 - oxo - 1,2,3,4 - tetrahydro 1 - quinoline carboxylic acid, benzyl ester.

Following the procedure of Examples 1—F, 2—B and 3—B, 9.5 g. of benzyl 6,7 - dimethoxy - 2 - methyl - 4oxo - 1,2,3,4 - tetrahydroquinoline - 1 - carboxylate, .95 ml. of ethyl formate and sodium ethoxide prepared from 2.57 g. of sodium hydride and 3.23 ml. of ethanol in 120 ml. of benzene gave on work up a yellow oil which on crystallization afforded 6.0 g. of crude product, m.p. 106—110°C. The analytical sample is prepared by recryo stallizing several times from methanol, m.p. 116—118 C.

Anal. Calc dfOr C21H21°6N C, 65.8; H, 5.6; N, 3.7. Found: C, 65.4; H, 5.6; N, 3.7. EXAMPLE 5.

Starting with the appropriately substituted phenyl or benzyl chloroformate and 6,7— dimethoxy - 2 - methyl4 - oxo - 1,2,3,4 - quinoline and employing the procedure of Example 4—A and B, the following 3 - hydroxymethylene6,7 - dimethoxy - 2 - methyl - 4 - oxo - 1,2,3,4 - tetrahydro - 1 - quinoline carboxylic acid, phenyl and benzyl esters are synthesized: X ¢3737 Ο Ο Ο Ο ο ο ο ο ο 2-F 4—F 3— C1 4— C1 2CH3 3— CH.

J 4— CH. a 3— 0CH3 4— OCH. 3—CF 2— F 3— F 4— F 2— Cl 4—Cl 3— CH3 4— ^H3 2—0CH3 4—OCH3 2—CF 437 37

Claims (3)

1. A compound of the formula: wherein P, I s alkyl having from one to five carbcn atoms, phenyl, benzyl or mono-substituted benzyl or phenyl wherein said substituent is fluoro, chloro, methyl, methoxy or trifluoromethyl.

2. The compound as claimed in claim 1 wherein R^ is ethyl.

3. The compound as claimed in claim 1 wherein R^ is benzyl.