CA1066284A - Process for preparing 3 hydroxy methylene 6,7 dimethoxy-2-methyl-4-oxo 1,2,3,4 tetrahydro 1 quinoline carboxylic acid esters - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Novel intermediates of the formula

Description

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This application is a divisional of application No. 263850 filed on October 21, 1976.
This invention relates to the production of novel racemic 3-hydroxy-methylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3~4-tetrahydro-l-quinoline carboxylic acid, alkyl, phenyl and ben~yl esters, and to the resolved enantiomers thereof, which compounds are useful inter-mediates leading to the preparation of novel racemic 3-aminomethylene-6,7-aimethoxy-2-methyl-4-oxo-1,2,3,~4-tetra-hydro-l-quinoline carboxylic acid, alkyl, phenyl and benzyl esters which are analgesic agents.
The said racemic analgesic agents are compounds of the formula: -~3 ~ 2 C~3 ~ H3 ; 2 3 wherein Rl is hydrogen or methyl; R2 is hydrogen, alkyl of I one to five carbon atoms, propargyl, phenyl, naphthyl, phenylalkylene wherein said alkylene has one to four carbon atoms~ naphthyl-alkylene wherein sa~d alkylene has from one to four carbon atoms, dimethylaminoalkylene wherein said alkylene has from two to four carbon atoms or mono-substituted 2~ethyl wherein sald subs~ituent is phenoxy or methoxy; Rl and R2 when considered together with the nitrogen atoms to which they are attached form a piperi~ino, pyrrolidino or morpholino ring; R3 is alkyl of one to five ,,,,, ~

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~06i~;'Z~4 carbon atoms, phenyl, 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 R2 is said 5 dimethylaminoalkylene, and these compounds are described and claimed in Patent Application No. 263850.
The useful intermediates of the present invention are racemic compounds of the formula:

CH3Q ~ ~ 1 HOH

CH3O~/ ~CH3 wherein R3 iS as previously defined.
Accordingly the present invention provides a process for the preparation of a racemic compound of the formula.

C33 ~ H3 6 15 and it.s resolved enatiomers;
wherein R3 is selected from the group consisting of alkyl having from one to five carbon atoms, phenyl, benzyl and mono-substituted benzyl and phenyl wherein said substituent is selected from the group consisting of fluoro, chloro, methyl, methoxy and trifluoromethyl;
comprising treating the appropriate alkyl, phenyl or benzyl 6,7-dimethoxy-2-methyl-4~oxo-1,2,3,4-tetrahydroquinoline-l-carboxylate with an alkyl formate and an alkoxide to form the compound of structure AS will be recognized by one ~killed in the art, the analgesic agents mentioned above and the useful inter--- ,,' .. . . . .

6Z8~
--3~
mediates of the present in~ention possess an asymmetric carbon atom at the 2-position, and may exist in two forms.
These forms may be distinguished by their ability to rotate the plane or polarized lighta One form rotates the plane of polarized light to the right and is known as the dextrorotatory enantiomer or the _(+) enantiomer, while the other form rotates the plane of polarized light to the left and is known as the levorotatory enantiomer or 1(-) enantiomerO A mixture of equal amounts of the d and 1 enantiomers of these compounds does not affect the plane of ~olarized light, and is known as a racemic mixture of dl 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.
Since the absolute configuration of the methyl group at the 2-posltion is not known the bond of the methyl substituent to the 2-position is depicted as:

~N3

2 3 The following reaction scheme illustratès the process employed for the preparation of the intermediate compound 6 of the present invention and also shows the conversion of these intermediate compounds to the analgesic agents of Formula 7. This latter step is more fully described in Patent Application No. 263850.
~H2 ~H3 ~CH2C02R ' . .

~OCN ~- ~ CN3 . . .

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4_ ~H (~HCH2C02R ' ~OC~{3 l~H-CHCH2C02H
2 ~3 ( 2 ) :HC1 ~f oCH3 h' .
H3~

3 ~
CH30~N~H3 H

4 2 ~02R3 : : . , .: . . .
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NaOC2H5 C 3 ~ ~H3 CH30 ~J~H N~ 1 6 HNR R ~ --~ I 1 2 1 ~ l :
CH30 ~/ \ N~ 3 wherein Rl, R2 and R3 are previously defined, PPA represents polyphosphoric acid and R' is lower alkyl.
In the first of the above-depicted reaction steps, an alkyl acetoacetate such as ethyl acetoacetate is con-densed with 3,4-dimethoxyaniline in the presence of a suitable solvent such as benzene and a small amount of an acid catalyst such as ac~tic acid. Recovery of the resulting alkyl 3-[(3, 4-dimethoxy)anilino]-2-butenoate (1) upon reaction completion, which may be ~etermined 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 hydrogenatlon of the butenoate product of the first step utilizing conditions for the reduction of doubls 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 con-ditions, i.e., at a pEI of about 3 up to 7. Acetic acid ~ ~ .

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is a preferred acid for obtaining this p~. The resulting alkyl 3-[t3,4-dimethoxy~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 con-centration 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 water-miscible solvent such as methanol. The resulting 3-~(3,4-dimethoxy)anilino]butanoic acid (3) containing 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 polyphosphoric acid, which not only serves as the agent responsible for causing cyclization but also serves as solvent or 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. ~ Interscience Publishers, New York, 1963. The resulting 6,7-dimethoxy-2~
methyl-4-oxo-1,2,3,4-tetrahydroquinoline (4) reaction con-; 30 taining mixture may then be poured into ice, extracted with chloroform and recovered by concentrating the combined dried organic extracts under reduced pressure.
The product of the fourth reaction step maythen be acylated with an alkyl, phenyl or benzyl chloro-- 35 formates in conventional fashion. The desired alkyl, phenyl or benzyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,~-tetrahydroqulnoline-l-carboxylate (5) is then recovered .
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from the reaction mixture via extraction, drying of the combined extract layers and concentration under reduced pressure.
Transformatlon of 5 into the useful intermediates of the present invention of structure 6 is effected by treatment of ~he appropriate alkyl, phenyl or benzyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-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 6 remains in the water layer as the sodium salt and is liberated by neutralization with acidO The resulting product, which is isolated by extraction or decentation, is ~urther purified by recrystallization from an appropriate solvent.
Synthesi~ for the racemic analgesic agents of structure 7 is ef~ected through the reaction of 6 with the requisite amine as described in Application No. 263850.
Of the racemic 3-hydroxymethylene compounds (6) 20 of the present invention which are useful as intermediates, -those which are particularly preferred for this use are 3-hydroxy-methylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-l-quin~line carboxylic acid, ethyl ester and 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,~-tetrahydro-l-quinolme carboxylic acid, benzyl ester.
The ~ollowing Examples illustrate the preparation of the compounds of this invention.
ExamJ~le 1 3-Hydroxy-methylene-6,7-dimethoxy-2-methyl-4-o~o-30 1,2,3,4-tetrahvdro-1-quinoline carboxvlic acid, ethvl ester A. Ethyl-3-[3,4-Dimethoxv~Anilino]-2-Butenoate 4-Aminoveratrole (62.0 g.), ethyl acetoacetate (63.0 g.), benzene (375 ml.), and acetic acid (2.1 ml.) are combined and re~luxed in a flask equippea 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 ~rom hexane gives 79.0 g.

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of a tan powder, m.p~ 59-60; a second crop a~forded 6.7 g., m.p. 54-56. A sample is recrystallized from ethanol/-water to givean analytical sample, m.p. 57-58.
Anal. Calc'd ~or C14I~lgNO4: C, 63~38; H~ 7.22; Nj 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 l-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 magneslum sulfQte 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 con-~erted to the hydrochloride salt, m.p. 137.5-139. An equivalent sample of the hydrochloride salt 20 (m.p. 138-139.5) ia analyzed~
AnalO Calc'd. for C14H21NO4.HCl: C, 55.35; H, 7.30; N, 4.61 Found: C, 55.73; H, 7.33; N, 4.33 C. 3- E ( 3,4-Dimethoxy~Anilino]-Butanoic Acid A 54 g. sample of the unpurified ester product of Example l-B is combined wi~h 17.5 g. of sodium hydroxide, 550 ml. of methanol and 130 ml. of water, and re~luxed for 1.5 hrs. The reaction mixture is cooled, c~ncentrated 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.
35 D. 6,7-Dimethox~-2-_ethyl-4-Oxo-1,2,3,4-tetrahvdroquinoline The crude acid of Example I-C (48 g.) and 500 g.
of polyphosphoric acid are heated for 1 hr. on a steam bath . . . . :. ' :. :
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g 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- CalcidO for C12H153N C~ 65-14; H~ 6-83; N~ 6-33 Found: C, 65.18; H, 5.86; N, 6~25 E. Ethyl 6,7-Dimethoxy-2-Methyl-4-Oxo-1,2,3,4-tetrahydro-quinoline-l-Carboxvlate ~ . . _ ............... . .
A mixture of 15 g. of the quinoline product of Example I-D, 95 g. of potassium carbonate, and 225 ml. of methyl~ne 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. portions of ethyl chloroformate are added after 24 and 48 hrs. and 47 g. of potassium carbonate is added after 48 hrs. The reaction mixture is ~uenched 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 standingi 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. 11605-18~.
or C15 lgN 5 , 61. 2; H, 6.53; N, 4078 Found: C, 61.37; H, 6.51; N, 4.78.
F. 3-Hydroxymethylens-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,-4-tetrahydro-1-quinoline caboxyllc 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-oxo-1,2,3,4-tetrahydro-quinollne-l-carboxylate and 19.8 ml. of ethyl formate in 150 ml. of benzene over a 45 mln. period. The reaction i , . . . ~ .

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. , . ~ , ' - ' ', ' ' .. .. : ' . , : . , , . ' ' : . "

~ ti6'~l~4 ~10-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 lN aqueous sodium hydroxideO 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, resulting in the formation of a yellow oil. Crystallization of the oil from hexane gives 15.4 g. of the desired intermediate, mOp. 98-101C. Further recrystallization from the same solvent raises the melting point to 129-130C.
16 196 C, 9.8; H, 6.0; N, 4.4 Found: C, 59.7; H, 5.9; N, 4.3.
Example 2 3-Hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, meth~l ester A. Methyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-quinoline-l-carboxYlate . . . =
A mixture of 102 g. (5.45 mmol) of the quinoline product of Example l-D, 79~ mg. (10.7 mmol) of dry pyridine and 5O5 ml. of methylene chloride are stirred and cooled by an ice-water ~ath while 758 mg. (8.02 mmol) of methyl chloroformate in 1 mlO of methylene chloride is added over a 10 min. period at a rate to maintain a 10-15CG
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 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 mlO anhydrous ether, filt~red, and washed with minimum ether, then air dried to 1.1 gO of a yellow solid, m.p. 156-158C. This material is dissolved in 10 mlO of hot ethyl acetate, treated with 50 mgO
Darco G60, filtered and crystallized by the addition of hexane to gi~e 727 mg. of an off-white solld, m.p.
159-1~0C. a~ter drying in ~acuum at 100~C. (lmm) for 2~ hrs.

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' ' ' ', ., :. , . ': , ' ' ' : ' ' . ' ' , ',' ~ ' ' ' ~ ' ' ' . ' ~ ~06G284 Anal- Calc'd- for C14H175N C, 60-2; H~ 6-1; N, 5.0 Found: C, 60.3; H, 6.3; N, 5.3 . 3-Hydroxymethylene-6,7 dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrah~dro-l-quinoline carboxvlic acid, methvl ester , . ~ ~ . .
Methyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetra-hydroquinoline-l carboxylate (13.8 g.) in 140 ml. of benzene containing 19 mlO 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 lN
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 ln vacuo to dryness. The residue is employed in subsequent reactions without further purification.
Example 3 3-Hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, butyl ester - A. Butyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-auinoline-l-carboxvlate __ To a cooled mixture of 1~15 g. (5017 mmol3 of the quinoline produc~ of Example l-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 10-15C.
temperature. After the addition is complete the bath is removed, the reaction stirred at room temperature for 45 mln., and poured onto 25 ml. saturated sodium bicarbonate solution. The organic phase is collected and washed with 25 ml. o~ saturated sodium bicarbonate solution, 50 ml.
saturated sodium chlorlde solutlon, dried over magnesium sulfate, then gravity filtered and evaporated to a viscous amber oll. Evaporatlve dlstillation at llO~C. (0.05 mm) .... . . .. . . . . . . . . .

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gave 1.4 gO of a very viscous amber ~
Anal Calc'd- for C17~235N C, 63.5; H~ 7-2; N~ 4-4 Found: C, 63.7; H, 7.2; N, 401 B o 3-Hydroxymethylene-6,~-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro~ uinoline 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-dimethoxy-2-methyl-4-oxo-1~2,3,4-tetrahydro-quinoline-l-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 temperature for 4 hrs., is poured onto 250 ml. of ice-waterO The aqueous layer is retained and the organic layer extracted with lN 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 chloroform layer dried over magnesium sulfate.
The solvent is removed under reduced pressure and the regidual product used in subse~uent reactions without further purification.
Example 4 3-Hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo- ~-1,2,3,4-tetrahvdro-1-auinoline carboxylic acid, benzYl ester ~ . ~ .
A. Benzyl 6,7~dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro- -quinoline-l-carboxylate To a solution o 10.0 g~ (45.3 mmol) of the quinoline product of Example l-D in 75 mlO of pyridine cooled to 0C. is added over a 30 min. period 55 ml. of benzyl chloroformateO 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 5S0 ml. chloroform/300 ml. water. Thechloroform layer is separated, waqhed successively with 10% hydro-chloric acid (3 x 300 ml.), saturated aqueous sodium bicarbonate ~1 x 200 ml.) and brine (1 x 200 ml.), and . .. .. . . .. . . . . . . ... . . . . . . . . . . .

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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 system gave 11.4 g. of the desired product, m.p. 127.5-129.5DC.
B~ 3-Hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-l-quinoline carboxylic acid, benzyl ester Following the procedure of Examples l-E, 2-B and 3-B, 9.5 g. o~ benzyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-l-carboxylate, 10.95 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 afforaed 6.0 g. of crude product, m.p. 106-110C. The analytical same is recrystallized several times from methanol, m.p. 116-118~C.
Anal. Calc'd. for C21H21O6N: 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-methyl-4-oxo-1,2,3,4-quinoline and employing the procedure of Example 4-A and B, the following 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, phenyl and benzyl esters are synthesized:

CH8 ~ HOH

3 ~ ~ ~ 3 o~C~O (C112) n~

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' 66~

n X

0 4~F
0 3-Cl 0 4-Cl 0 4-OCH3 :
3 : ~ :

1 3-F .:
- 1 4-F ::
1 2-Cl 1 4-Cl : 1 3-CH3 1 4-CH3 - ::

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Claims (11)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a racemic compound of the formula:

and its resolved enantiomers;
wherein R3 is selected from the group consisting of alkyl having from one to five carbon atoms, phenyl, benzyl and mono-substituted benzyl and phenyl wherein said substituent is selected from the group consisting of fluoro, chloro, methyl, methoxy and trifluoromethyl;
comprising treating the appropriate alkyl, phenyl or benzyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-quinoline-1-carboxylate with an alkyl formate and an alkoxide to form the compound of structure 6.

2. A process according to claim 1, comprising acylating 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-quinoline to form the desired alkyl, phenyl or benzyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate.

3. A process according to claim 2, comprising cyclizing 3-[(3,4-dimethoxy)anilino] butanoic acid to form 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-quinoline.

4. A process according to claim 3, comprising subjecting an alkyl-3-[(3,4-dimethoxy)anilino] butanoate to alkaline hydrolysis to form 3-[(3,4-dimethoxy)anilino]-butanoic acid.

5. A process according to claim 4, comprising hydrogenating an alkyl 3-[(3,4-dimethoxy)anilino]-2-butenoate to form a butanoate.

6. A process according to claim 5, comprising condensing an alkyl acetoacetate with 3,4-dimethoxyaniline to form an alkyl 3-[(3,4-dimethoxy)anilino]-2-butenoate.

7. A process according to claim 1, wherein there is employed as starting material ethyl 6,7-dimethoxy -2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate.

8. A process according to claim 1, wherein there is employed as starting material benzyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate.

9. A racemic compound of the formula:
and its resolved enantiomers wherein R3 is selected from the group consisting of alkyl having from one to five carbon atoms, phenyl, benzyl and mono-substituted benzyl and phenyl wherein said substituent is selected from the group consisting of fluoro, chloro, methyl, methoxy and trifluoromethyl whenever obtained by the process of claim 1 or any obvious equivalent thereof.

10. The compound of claim 9, wherein R3 is ethyl whenever obtained by the process of claim 7, or an obvious equivalent thereof.

11. The compound of claim 9, wherein R3 is benzyl whenever obtained by the process of claim 8, or an obvious equivalent thereof.