CA1074321A - Process for the preparation of 1-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinolines - Google Patents
Process for the preparation of 1-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinolinesInfo
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- CA1074321A CA1074321A CA243,777A CA243777A CA1074321A CA 1074321 A CA1074321 A CA 1074321A CA 243777 A CA243777 A CA 243777A CA 1074321 A CA1074321 A CA 1074321A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ALKOXY-1,2-DIHYDROQUINOLINES
Abstract of the Disclosure The preparation of 1-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinolines is carried out by the reaction of quinoline with a chloroformate and an aliphatic alcohol at a temperature of from -10°C to 20°C and a pH of 7 to 10 in the presence of an inert organic diluent which is insoluble or only sparingly soluble in water.
Abstract of the Disclosure The preparation of 1-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinolines is carried out by the reaction of quinoline with a chloroformate and an aliphatic alcohol at a temperature of from -10°C to 20°C and a pH of 7 to 10 in the presence of an inert organic diluent which is insoluble or only sparingly soluble in water.
Description
3'~
The invention relates to a new process for the preparation of l-alkoxysarbonyl-2-alkoxy-1,2-dihydroquinoline.
It is known t~ prepare l-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinoline by reacting quinoline with chloro-formates in the presence of an alcohol and o~ a tertiary amine as acld-binding agent, as is described in U.S. Patents No. 3,389,142 and 3,452,140 and in the article by Muren und Weissmann, J. Med. Chem. 14 (1971), 51 and Fieser & Fieser "Reagents for organic syntheses" Volume 2, page 191.
One disadvantage of the known processes is that the maximum yield which can be obtained is only 70 %, according to Muren und Weissmann, which is i~su~ficient for economic utilisation of the process.
It is an object of this invention to provide a process for the preparation of 1-alkoxycarbonyl-2-alkoxy-1,2-dihydro-quinoline from which higher yields can be obtained than in the known processes and which makes it possible for the compounds to be produced on a larger scale.
The invention relates to a process for the preparation of 1-alkoxycarbonyl-2-alkoxy-1,2-dihydro~uinoline of the general formula 1~ -OR2 O-,C-OR
in which Rl represents a primary or secondary alkyl group with 1 to 6 carbon atoms which may be substituted by a nonionic group, for example a methyl, ethyl, n-propyl, isobutyl, n-butyl, A-~ 1308 - 2 - ~
~Q~321 sec. butyl or isobutly group, an alkoxyalkyl group containing 1 to 3 carbon atoms in each alkyl group, e.g. a 2-alkoxymethyl or 2-alkoxyethyl group, a cycloalkyl group containing 3 to 8 carbon atoms, e.g. a cyclo-pentyl or cyclohexyl group or an aralkyl group containing 1 to 4 carbon atoms in the alkyl group, e.g. a benzyl or phenethyl group and R2 may have the same meaning as Rl or may represent a tertiary alkyl group such as a t-butyl or t-amyl group, an alkyl thioethyl group such as a methyl thioethyl or ethyl thioethyl group, an alkane sulphonyl ether or a cyanoalkyl group, in particular a cyanoethyl group, by the reaction of quinoline with an aliphatic chlorocarbonic acid ester (i.e. a chlorofor-mate) and an aliphatic alcohol, in which quinoline is reacted with a one to ten-times excess of an alcohol of the formula H - ~R2 in which R2 has the meaning specified above and with not more than the stoichiometric quantity of a chloroformate of the general formula Cl - C - OR
lo in which Rl has the meaning speciied above at a temperature of from -10C
to 20C and a p~l of 7 to 10 in the presence of an aqueous inorganic neutral-ising agent and if desired in the presence of an inert organic diluent which is insoluble or only sparingly soluble in water.
The aliphatic alcohols used as starting materials for the process according to the invention are all available commercially. Lower aliphatic primary alcohols and the corresponding secondary alcohols, ethylene glycol monoalkyl ether, lower cycloalkanols and lower aryl carbinols are particularly suitable. The process is in principle, also ~ l - 3 -~07~
suitable for higher alcohols but the products obtained from them cannot be puri.fied by ~is~illation ~ithout great difficulty ~nd considerable loss of yield. Alcohols containing prima:ry, secondary or tertiary amino groups are unsuitable for thc process.
The chloroformates used as starting materials are either available commercially or prepared, for examyle, by the reaction of phosgene with a suitable alcohol or as described in E.H. Ro~ Chemistry of Carbon Compounds"
Volume 1, part B "Aliphatic Compounds", pages 833 and 886 to 899, Elsevier Publishing Company, New York, N.Y. (1952) or in Houben-Weyl, Volume 8, pages lOl et. seq. Information about many of these compounds may be found in "Chemical Abstracts" in which they are indexed as esters lmder the heading "Formic acid, chl.oro-".
In contrast to the previous1y known processes for the prcparation of l-alkoxycarbonyl-7-alkoxy-l,2-dihydroquinolines, whlch are all carried out with strict exclusion of water, the reaction according to the inventi.on is carried out in an aqueous organic medium, preferably in a diphasic aqueous organic medium, although in certain cases, the advantageous results of the invention can also be obtained in a monophasic medium with a relatively low water content.
It has been found particularly advantageous to introduce the quinoline into the reaction vessel together with a multiple excess of the alcohol used as its reactant and an inert organic solvent in contact with an aqueous solution or suspension of the inorganic neutralising agent which should have a pH of from 7 to lO, and to add the chlorocarbonic acid ester to this reaction mixture The presence of a large excess of alcohol, in general four to ten times the stoichiometric quantity for the reaction, A-G 1308 _ 4 _ ~7 ~3~i prevents the formation of any significant quantities of
The invention relates to a new process for the preparation of l-alkoxysarbonyl-2-alkoxy-1,2-dihydroquinoline.
It is known t~ prepare l-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinoline by reacting quinoline with chloro-formates in the presence of an alcohol and o~ a tertiary amine as acld-binding agent, as is described in U.S. Patents No. 3,389,142 and 3,452,140 and in the article by Muren und Weissmann, J. Med. Chem. 14 (1971), 51 and Fieser & Fieser "Reagents for organic syntheses" Volume 2, page 191.
One disadvantage of the known processes is that the maximum yield which can be obtained is only 70 %, according to Muren und Weissmann, which is i~su~ficient for economic utilisation of the process.
It is an object of this invention to provide a process for the preparation of 1-alkoxycarbonyl-2-alkoxy-1,2-dihydro-quinoline from which higher yields can be obtained than in the known processes and which makes it possible for the compounds to be produced on a larger scale.
The invention relates to a process for the preparation of 1-alkoxycarbonyl-2-alkoxy-1,2-dihydro~uinoline of the general formula 1~ -OR2 O-,C-OR
in which Rl represents a primary or secondary alkyl group with 1 to 6 carbon atoms which may be substituted by a nonionic group, for example a methyl, ethyl, n-propyl, isobutyl, n-butyl, A-~ 1308 - 2 - ~
~Q~321 sec. butyl or isobutly group, an alkoxyalkyl group containing 1 to 3 carbon atoms in each alkyl group, e.g. a 2-alkoxymethyl or 2-alkoxyethyl group, a cycloalkyl group containing 3 to 8 carbon atoms, e.g. a cyclo-pentyl or cyclohexyl group or an aralkyl group containing 1 to 4 carbon atoms in the alkyl group, e.g. a benzyl or phenethyl group and R2 may have the same meaning as Rl or may represent a tertiary alkyl group such as a t-butyl or t-amyl group, an alkyl thioethyl group such as a methyl thioethyl or ethyl thioethyl group, an alkane sulphonyl ether or a cyanoalkyl group, in particular a cyanoethyl group, by the reaction of quinoline with an aliphatic chlorocarbonic acid ester (i.e. a chlorofor-mate) and an aliphatic alcohol, in which quinoline is reacted with a one to ten-times excess of an alcohol of the formula H - ~R2 in which R2 has the meaning specified above and with not more than the stoichiometric quantity of a chloroformate of the general formula Cl - C - OR
lo in which Rl has the meaning speciied above at a temperature of from -10C
to 20C and a p~l of 7 to 10 in the presence of an aqueous inorganic neutral-ising agent and if desired in the presence of an inert organic diluent which is insoluble or only sparingly soluble in water.
The aliphatic alcohols used as starting materials for the process according to the invention are all available commercially. Lower aliphatic primary alcohols and the corresponding secondary alcohols, ethylene glycol monoalkyl ether, lower cycloalkanols and lower aryl carbinols are particularly suitable. The process is in principle, also ~ l - 3 -~07~
suitable for higher alcohols but the products obtained from them cannot be puri.fied by ~is~illation ~ithout great difficulty ~nd considerable loss of yield. Alcohols containing prima:ry, secondary or tertiary amino groups are unsuitable for thc process.
The chloroformates used as starting materials are either available commercially or prepared, for examyle, by the reaction of phosgene with a suitable alcohol or as described in E.H. Ro~ Chemistry of Carbon Compounds"
Volume 1, part B "Aliphatic Compounds", pages 833 and 886 to 899, Elsevier Publishing Company, New York, N.Y. (1952) or in Houben-Weyl, Volume 8, pages lOl et. seq. Information about many of these compounds may be found in "Chemical Abstracts" in which they are indexed as esters lmder the heading "Formic acid, chl.oro-".
In contrast to the previous1y known processes for the prcparation of l-alkoxycarbonyl-7-alkoxy-l,2-dihydroquinolines, whlch are all carried out with strict exclusion of water, the reaction according to the inventi.on is carried out in an aqueous organic medium, preferably in a diphasic aqueous organic medium, although in certain cases, the advantageous results of the invention can also be obtained in a monophasic medium with a relatively low water content.
It has been found particularly advantageous to introduce the quinoline into the reaction vessel together with a multiple excess of the alcohol used as its reactant and an inert organic solvent in contact with an aqueous solution or suspension of the inorganic neutralising agent which should have a pH of from 7 to lO, and to add the chlorocarbonic acid ester to this reaction mixture The presence of a large excess of alcohol, in general four to ten times the stoichiometric quantity for the reaction, A-G 1308 _ 4 _ ~7 ~3~i prevents the formation of any significant quantities of
2-llydroxy-1-alkoxy-carbonyl_1,2-dihydroquinoline which is an unwanted product and extremely sensitive to hydrolysis.
If too large an excess of alcohol is used, however, too much water is introduced into the organic phase where it gives rise to side reactions, particularly if a lower alcohol which is highly water-soluble is used. The optimum ~uantities of alcohol can easily be determined by simple tests.
Organic solvents or diluents are only required if exceptionally highly water-absorbent alcohols such as methanol, methyl glycol or ethyl glycol ~re used.
The solvents or diluents use~ may be inert hydrocarbons, e.g. chlorinated hydrocarbon~such as dichloromethane or 1,2-dichloroethane, ketones or e~ters, or al~o ethers wh~ h have a low water absorption capacity. The b~st result~ are ~ener~lly obtained with dichloromethane.
The neutralising agent~ used are most suitably aqueous ~olution~ or suspensions of alkali metal carbonates or alkali metal bicarbonates such as sodium or pota~sium carbonate or bicarbonate. Carbonates have the advantage o~
retaining m~re water in the aqueous phase, particularly if they are used at higher concentrations and in excess. On the other hand, i~ bicarbonates are u~ed as neutralising agents, generally in an excess o~ 20 to 100~ by weight, based on the chloroformate, the resulting reaction is easier to control and leads to purer products. Above all, bicarbonates suppress the troublesome formation of 2-hydroxy compoundsO
Since the hydroxy compound is relatively stable under the reaction conditions, it is not removed until the product is isolated, and at that stage it either prevents crystallisation or causes breakdown of the vacuum used for distillation due to A-G 1308 - 5 _ 1C~7~321 thermal decomposition to guinoline, alcohol and carbon dioxide when alkoxy carbonyl-alkoxy dihydroquinolines, which are high-bolling compounds when pure, are purified by distillation The advantages of the process according to the invention, compared with the previously known processes are immediately apparent if no water is added to the reaction mixture or only toward~ the end of the reaction. In that case, neutralisation of the hydrogen chloride liberated proceeds too slowly and traces of hydrogen chloride cause losses in yield when the product is isolated.
The use of an exces~ of quinoline, generally from 2 to 40 oh by weight, compared with the chloroformate is advantageous but not essential. In special cases, a quinoline exce~s may also be replaced by corresponding quantities of a volatile tertiary amine such Q9 triethylamine a~ auxlllary base.
~he reactlon temperature ~hould generally be from -10C to 10C, more preferably from -5C to 5C, but may be higher if less reactive chloroformates are u~ed.
Above 20C, the yields drop drastically. The use of catalysts, e.g. Lewis acid~ ~uch as zinc chloride, boron trliluoride or ferric chloride is not necessary and, in most cases, even harm~ul because it renders the product~ of the process unstable.
It i~ presumed that the reaction gives ri~e to an extremely short-lived l-alko~ycarbonyl quinolinium ion in the organic phase, and that this ion i~ scarenged by the addition of alcohol. The hydrogen chloride liberated is initially taken up by iree quinoline ~nd then ab~orbed by the neutrali~ing agent of the aqueou~ phase.
The proce~s according to the invention is ~uitable ~07~3Z'l among other things for the preparation of certain dihydro-~uinoline derivatives which have been described as tranquillisers in US Patent Specifications No. 3,389,142 and No. 3,452,140.
The process according to the invention may also be used for the preparation of most of the 2-alkoxy-1,2-dihydro-quinoline-l-carboxylic acid esters which have been described . as hardeners for protein-containing layers in Belgian Paten B j Specification No. 816 41V,(U.Y.. nppl. Mo. ~7851/7~ .
The process according to the invention will now be more fully described in the following examples.
If too large an excess of alcohol is used, however, too much water is introduced into the organic phase where it gives rise to side reactions, particularly if a lower alcohol which is highly water-soluble is used. The optimum ~uantities of alcohol can easily be determined by simple tests.
Organic solvents or diluents are only required if exceptionally highly water-absorbent alcohols such as methanol, methyl glycol or ethyl glycol ~re used.
The solvents or diluents use~ may be inert hydrocarbons, e.g. chlorinated hydrocarbon~such as dichloromethane or 1,2-dichloroethane, ketones or e~ters, or al~o ethers wh~ h have a low water absorption capacity. The b~st result~ are ~ener~lly obtained with dichloromethane.
The neutralising agent~ used are most suitably aqueous ~olution~ or suspensions of alkali metal carbonates or alkali metal bicarbonates such as sodium or pota~sium carbonate or bicarbonate. Carbonates have the advantage o~
retaining m~re water in the aqueous phase, particularly if they are used at higher concentrations and in excess. On the other hand, i~ bicarbonates are u~ed as neutralising agents, generally in an excess o~ 20 to 100~ by weight, based on the chloroformate, the resulting reaction is easier to control and leads to purer products. Above all, bicarbonates suppress the troublesome formation of 2-hydroxy compoundsO
Since the hydroxy compound is relatively stable under the reaction conditions, it is not removed until the product is isolated, and at that stage it either prevents crystallisation or causes breakdown of the vacuum used for distillation due to A-G 1308 - 5 _ 1C~7~321 thermal decomposition to guinoline, alcohol and carbon dioxide when alkoxy carbonyl-alkoxy dihydroquinolines, which are high-bolling compounds when pure, are purified by distillation The advantages of the process according to the invention, compared with the previously known processes are immediately apparent if no water is added to the reaction mixture or only toward~ the end of the reaction. In that case, neutralisation of the hydrogen chloride liberated proceeds too slowly and traces of hydrogen chloride cause losses in yield when the product is isolated.
The use of an exces~ of quinoline, generally from 2 to 40 oh by weight, compared with the chloroformate is advantageous but not essential. In special cases, a quinoline exce~s may also be replaced by corresponding quantities of a volatile tertiary amine such Q9 triethylamine a~ auxlllary base.
~he reactlon temperature ~hould generally be from -10C to 10C, more preferably from -5C to 5C, but may be higher if less reactive chloroformates are u~ed.
Above 20C, the yields drop drastically. The use of catalysts, e.g. Lewis acid~ ~uch as zinc chloride, boron trliluoride or ferric chloride is not necessary and, in most cases, even harm~ul because it renders the product~ of the process unstable.
It i~ presumed that the reaction gives ri~e to an extremely short-lived l-alko~ycarbonyl quinolinium ion in the organic phase, and that this ion i~ scarenged by the addition of alcohol. The hydrogen chloride liberated is initially taken up by iree quinoline ~nd then ab~orbed by the neutrali~ing agent of the aqueou~ phase.
The proce~s according to the invention is ~uitable ~07~3Z'l among other things for the preparation of certain dihydro-~uinoline derivatives which have been described as tranquillisers in US Patent Specifications No. 3,389,142 and No. 3,452,140.
The process according to the invention may also be used for the preparation of most of the 2-alkoxy-1,2-dihydro-quinoline-l-carboxylic acid esters which have been described . as hardeners for protein-containing layers in Belgian Paten B j Specification No. 816 41V,(U.Y.. nppl. Mo. ~7851/7~ .
The process according to the invention will now be more fully described in the following examples.
3'~
Example 1 l-methoxycarbonyl-2-methoxy-1,2-dihydroquinoline ,H
C=O
~CH3 1.1: 180 g of potassium carbonate (1.3 mol) in 120 ml of water are added to a solution of 160 of quinoline (1.24 mol) in 200 ml of methanol and 400 ml of dichloromethane and cooled to between -2C and 2C. 94.5 g (1 mol) of methyl chloroformate are added dropwise with stirring at 0C and the reaction mixture is warmed to 25C. The organic phase is separated from the pasty sediment of salt, washed twice with 200 ml portions of water, dried over solid sodium carbonate, concentrated by evaporation and distilled under vacuum. After the first runnings consistine of quinoline (b.p. 80 to 90C), the vacuum deteriorates while an intermediate fraction is distilled off. The main product then distils over at a temperature of 140 to 150C and 3 to 4 Torr.
The yield was 146 g of viscous oil which was 67 % of the theory.
1.2: 94.5 g of methyl chloroformate are added dropwise with stirring at 0C to a suspen5ion of 120 g (1.43 mol) of sodium bicarbonate in 300 ml of methanol, 300 ml of dichloro-methane, 132g of quinoline (1.02 mol) and 40 ml of water.
The temperature of the mixture is raised to 25C. 800 ml of water are added and the organic phase is separated, washed twice with 200 ml portions of water and dehydrated over solid potassium carbonate. It is then concentrated by evaporation at reduced pressure and distilled under vacuum. The vacuum A-~ 1308 - 8 -10 ~3~1~
t3 mm) remains constant after the quinoline ~20 g) has be~n distilled off.
The yield was 172 g which was 78 /0 of the theory and the product had a bp3mm ~ 140 to 150C
1.3: The procedure is -the same as in method B but using 160 g fo quinoline (24 /0 excess) instead of 132 g.
First runnings: 45 g of quinoline Main fraction: 176 g (80 o~ of the theory), bp3mm: 138 - 150 C-Example 2l-methoxycarbonyl-2-ethoxy-1,2-dihydroquinoline yl 0=C-OCH3 ~15 94,5 g (1 mol) of methyl chloroformate are added dropwise witll stirrin~ at 0C to a suspension of 120 g of sodium ~icar,l)onate in 300 ml of ethanol, 132 g of quinoline (1.02 mol) and 40 ml of water. The temperature i9 kept at 0C for one hour more and the crystalline product is then precipitated with 600 ml of ice water. The precipitate is suction-filtered, washed with 500 ml of water and dried in a vacuum.
The yield was 19~ g, which was ~5 ~ Or the theory and the melting point after crystallisation from Ligroin was 72 to 74C.
Example 3 l-methoxycarbonyl-2-isopropQxy-1,2-dihydroquinoline 0-CH ~CH
3 b ~ 7 /~ \
~_~ i O OCH3 A-~ 130~ - 9 -10~ 3~1 94.5 g (1 mol) of methyl chloroformate are added dropwise with stirring t~- a ~uspension of 120 g of sodium bicarbonate (1.43 mol) in 30() ml of isopropanc,l, 300 ml of dichloromethane, 132 g of quinoline (1.02 mol) and 40 ml of water. The reaction temperature is kept at O to 10C by cooling. Stirring is continued for one more hour at 5C and tlle mixture is then heated to 25C. 600 ml of water are added and the organic phase is separated llf~ washed twice with 200 ml portions of water, dehydrated over solid pota~sium carbonate, concentrated by evaporation under vacuum and left to crystallise. 50 ml of Ligroin are then added and the product is ~uction-filtered.
The yield was 200 g which was 81 % of the theory, and th0 product had a melting poin1; of 48 to 50c.
Example 4 l-methoxycarbonyl-2-(2-methoxy)ethyl-1,2~dihydroquinoline H
, l O-cH2~H2-ocH3 /~
94.5 g (1 mol) of methyl chloroformate are added dropwise with stirring at n to 5C to a suspension of 120 g (1.43 mol) of sodium bicarbonate in 300 ml of methyl glycol, 300 ml of dichloromethane, 160 g of quinoline (1.24 mol) and 40 ml of water. The temperature is kept at 10C for a further 2 hours and the reaction mixture is then warmed to 25 C, 500 ml of water are added and the organic phase is separated off and washed twice with 200 ml portions of water. After dehydration over solid potassium carbonate, the product is concentrated by evaporation at reduced pressure and distilled under vacuum.
After a first runnings of about 50 g of quinoline and a short 3'~
intermediate fraction, 196 g (74.5 ~ of the theory) distil over at 175 to 195C and 3 to 4 Torr without breakdown of the vacuum.
Example 5 l-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline ~EEDQ~
1~ C2H5 //c 5.1: 300 ml of ethanol and 132 g of quinoline (1.02 mol) are added to 110 g of potassium carbonate (0.8 mol) in 90 ml of water. 10~.6 g ¦1 mol) of ethyl chlorocarbonate are added dropwise at 0 to 3C with vigorous stirring. The temperature is then kept at 0 to 5C for 1 hour more before the product is prscipitated by the addition of 500 ml of ice water.
The precipitate i9 suction-filtered and recrystallieed from 00 ml of methanol.
The yield was 210 g which was 85 ~ of the theory and the product had a melting point of 62 to 64C.
5.2: Method A is repeated except that instead of potassium carbonate, ~ suspension of 120 g of sodium bicarbonate in 60 ml of water is used as neutralising agent.
The yield was 227 g which was 92 ~ of the theory melting and the product had a melting point o~ 62 to 64C.
5.3: (comparison experiment) The procedure is the same as in method A except that instead of potassium carbonate, 50 g (1.25 mol) of sodium hydroxide in 40 ml of water is used as neutralising agent. An oily product which consists for the most part of quinoline and does notcrystalliee is obtained.
5.~: (comparison e~periment) The procedure is the same as in method A except that the reaction is carried out without ~7~
water. 190 g of a semi-solid product are obtained, irom which 90 to 120 g of solid sub~tance can be isolated by cry~talli~ation from ligroin.
5.5: (comparison experiment):
2-ethoxy-1-(2H)-quinoline carboxylic acid ethyl ester:
10.8 g (0.10 mol) o~ ethyl chloroformate are added dropwi~e to 12.9 g (0.1~ mol) oi quinoline under nitrogen. The mixture iB stirred for 1 hour at O to 7C. A white precipitate forms, which di~solves when a ~olution of 12.9 g (0.10 mol) of dii~opropyl ethylamine in 5(~ ml of absolute alcohol i~
added. The ~olution is then warmed up to room temperaturé and evaporated to drynes~ under vacuum. 200 ml of cyclohexane are added to the re~idue, followed b~ 200 ml oi ice water, and the organic pha~e iB dehydrated over magnesium ~ulphate.
22.5 g oi a pale yellow oil are obtained aiter evaporation of the solvent. Vacuum di~tillation yield~ 16.9 g of colourle 8~ compound with a boiling point of 115 to 118C
(0,1 mm). The oily liquid ~olldliie~ when left to ~tand.
The melting polnt was 64 to 68C (irom llgroin) 5.6: (comparl~on experlment):
A. Preparation oi 2-hydroxy-N-carbethoxy-1,2-dlhydroquinollne and di-(N-curbethoxy-1,2-dihydro-2-quinolyl)-ether ~ -OH
o=c-o-cH2cH3 and ~_o ~3 CH3CH2-o-C=o ~=C-O-CH~CH~
3o A solution o~ 240 g Or pota~ium hydroxide in 400 ml oi water a~d 1600 g o~ ice i~ added over a period o~ 5 minute~
~V~
with vigorous stirring to a solution, which has been cooled to 15C~ of 220 g (2.0 mol) of ethyl chloroformate, 260 g (2.0 mol) of quinoline and 600 ml of dimethyl formamide.
When the mixture has been stirred for a further 10 minutes, it is extracted with 1 litr0 of methylene chloride and the organic phase is washed with water, dehydrated over anhydrous magnesium sulphate, filtered and evaporated. 400 g of a pale-brown liquid containing 2-hydroxy-N-carbethoxy-1,2-dihydroquinoline, di-(N-carbethoxy-1,2-dihydro-2-quinolyl) ether and quinoline are obtained (product A).
200 g of the oil are concentrated by distillation at a bath temperature below 100C to remove unreacted quinoline.
125 g of a residue containing 2-hydroxy-N-carbethoxy-1,2-dihydroquinoline and di-(N-carbothoxy-1,2-dihydro-2-quinolyl)-ether are obtained (product B).B. Preparation of N-carbethoxy-2-ethoxy-1,2-dihydroquinoline O=J-O-CH2CH3 A solution oi 120 g of product B, 100 ml of absolute alcohol, 500 ml of anhydrou~ diethyl ether and 10 drop~ of borotrifluoride etherate i9 stirred for 5 hours at 20 C.
80dium The ethereal ~olution i~ wa~hed with saturated ~icarbonate ~5 solution and water, dehydrated over magnesium sulphate, filtered and concentrated. An oil is obtained ~rom which 47 g of the colourle~s compound N-carbethoxy-2-ethoxy-1,2-dihydro-quinoline are obtained by distillation. The product had a boiling point of 125 to 128C at 0.1 mm. The product ~olidifies when le~t to stand and had a melting point of 56 to 57C.
~-~ 1308
Example 1 l-methoxycarbonyl-2-methoxy-1,2-dihydroquinoline ,H
C=O
~CH3 1.1: 180 g of potassium carbonate (1.3 mol) in 120 ml of water are added to a solution of 160 of quinoline (1.24 mol) in 200 ml of methanol and 400 ml of dichloromethane and cooled to between -2C and 2C. 94.5 g (1 mol) of methyl chloroformate are added dropwise with stirring at 0C and the reaction mixture is warmed to 25C. The organic phase is separated from the pasty sediment of salt, washed twice with 200 ml portions of water, dried over solid sodium carbonate, concentrated by evaporation and distilled under vacuum. After the first runnings consistine of quinoline (b.p. 80 to 90C), the vacuum deteriorates while an intermediate fraction is distilled off. The main product then distils over at a temperature of 140 to 150C and 3 to 4 Torr.
The yield was 146 g of viscous oil which was 67 % of the theory.
1.2: 94.5 g of methyl chloroformate are added dropwise with stirring at 0C to a suspen5ion of 120 g (1.43 mol) of sodium bicarbonate in 300 ml of methanol, 300 ml of dichloro-methane, 132g of quinoline (1.02 mol) and 40 ml of water.
The temperature of the mixture is raised to 25C. 800 ml of water are added and the organic phase is separated, washed twice with 200 ml portions of water and dehydrated over solid potassium carbonate. It is then concentrated by evaporation at reduced pressure and distilled under vacuum. The vacuum A-~ 1308 - 8 -10 ~3~1~
t3 mm) remains constant after the quinoline ~20 g) has be~n distilled off.
The yield was 172 g which was 78 /0 of the theory and the product had a bp3mm ~ 140 to 150C
1.3: The procedure is -the same as in method B but using 160 g fo quinoline (24 /0 excess) instead of 132 g.
First runnings: 45 g of quinoline Main fraction: 176 g (80 o~ of the theory), bp3mm: 138 - 150 C-Example 2l-methoxycarbonyl-2-ethoxy-1,2-dihydroquinoline yl 0=C-OCH3 ~15 94,5 g (1 mol) of methyl chloroformate are added dropwise witll stirrin~ at 0C to a suspension of 120 g of sodium ~icar,l)onate in 300 ml of ethanol, 132 g of quinoline (1.02 mol) and 40 ml of water. The temperature i9 kept at 0C for one hour more and the crystalline product is then precipitated with 600 ml of ice water. The precipitate is suction-filtered, washed with 500 ml of water and dried in a vacuum.
The yield was 19~ g, which was ~5 ~ Or the theory and the melting point after crystallisation from Ligroin was 72 to 74C.
Example 3 l-methoxycarbonyl-2-isopropQxy-1,2-dihydroquinoline 0-CH ~CH
3 b ~ 7 /~ \
~_~ i O OCH3 A-~ 130~ - 9 -10~ 3~1 94.5 g (1 mol) of methyl chloroformate are added dropwise with stirring t~- a ~uspension of 120 g of sodium bicarbonate (1.43 mol) in 30() ml of isopropanc,l, 300 ml of dichloromethane, 132 g of quinoline (1.02 mol) and 40 ml of water. The reaction temperature is kept at O to 10C by cooling. Stirring is continued for one more hour at 5C and tlle mixture is then heated to 25C. 600 ml of water are added and the organic phase is separated llf~ washed twice with 200 ml portions of water, dehydrated over solid pota~sium carbonate, concentrated by evaporation under vacuum and left to crystallise. 50 ml of Ligroin are then added and the product is ~uction-filtered.
The yield was 200 g which was 81 % of the theory, and th0 product had a melting poin1; of 48 to 50c.
Example 4 l-methoxycarbonyl-2-(2-methoxy)ethyl-1,2~dihydroquinoline H
, l O-cH2~H2-ocH3 /~
94.5 g (1 mol) of methyl chloroformate are added dropwise with stirring at n to 5C to a suspension of 120 g (1.43 mol) of sodium bicarbonate in 300 ml of methyl glycol, 300 ml of dichloromethane, 160 g of quinoline (1.24 mol) and 40 ml of water. The temperature is kept at 10C for a further 2 hours and the reaction mixture is then warmed to 25 C, 500 ml of water are added and the organic phase is separated off and washed twice with 200 ml portions of water. After dehydration over solid potassium carbonate, the product is concentrated by evaporation at reduced pressure and distilled under vacuum.
After a first runnings of about 50 g of quinoline and a short 3'~
intermediate fraction, 196 g (74.5 ~ of the theory) distil over at 175 to 195C and 3 to 4 Torr without breakdown of the vacuum.
Example 5 l-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline ~EEDQ~
1~ C2H5 //c 5.1: 300 ml of ethanol and 132 g of quinoline (1.02 mol) are added to 110 g of potassium carbonate (0.8 mol) in 90 ml of water. 10~.6 g ¦1 mol) of ethyl chlorocarbonate are added dropwise at 0 to 3C with vigorous stirring. The temperature is then kept at 0 to 5C for 1 hour more before the product is prscipitated by the addition of 500 ml of ice water.
The precipitate i9 suction-filtered and recrystallieed from 00 ml of methanol.
The yield was 210 g which was 85 ~ of the theory and the product had a melting point of 62 to 64C.
5.2: Method A is repeated except that instead of potassium carbonate, ~ suspension of 120 g of sodium bicarbonate in 60 ml of water is used as neutralising agent.
The yield was 227 g which was 92 ~ of the theory melting and the product had a melting point o~ 62 to 64C.
5.3: (comparison experiment) The procedure is the same as in method A except that instead of potassium carbonate, 50 g (1.25 mol) of sodium hydroxide in 40 ml of water is used as neutralising agent. An oily product which consists for the most part of quinoline and does notcrystalliee is obtained.
5.~: (comparison e~periment) The procedure is the same as in method A except that the reaction is carried out without ~7~
water. 190 g of a semi-solid product are obtained, irom which 90 to 120 g of solid sub~tance can be isolated by cry~talli~ation from ligroin.
5.5: (comparison experiment):
2-ethoxy-1-(2H)-quinoline carboxylic acid ethyl ester:
10.8 g (0.10 mol) o~ ethyl chloroformate are added dropwi~e to 12.9 g (0.1~ mol) oi quinoline under nitrogen. The mixture iB stirred for 1 hour at O to 7C. A white precipitate forms, which di~solves when a ~olution of 12.9 g (0.10 mol) of dii~opropyl ethylamine in 5(~ ml of absolute alcohol i~
added. The ~olution is then warmed up to room temperaturé and evaporated to drynes~ under vacuum. 200 ml of cyclohexane are added to the re~idue, followed b~ 200 ml oi ice water, and the organic pha~e iB dehydrated over magnesium ~ulphate.
22.5 g oi a pale yellow oil are obtained aiter evaporation of the solvent. Vacuum di~tillation yield~ 16.9 g of colourle 8~ compound with a boiling point of 115 to 118C
(0,1 mm). The oily liquid ~olldliie~ when left to ~tand.
The melting polnt was 64 to 68C (irom llgroin) 5.6: (comparl~on experlment):
A. Preparation oi 2-hydroxy-N-carbethoxy-1,2-dlhydroquinollne and di-(N-curbethoxy-1,2-dihydro-2-quinolyl)-ether ~ -OH
o=c-o-cH2cH3 and ~_o ~3 CH3CH2-o-C=o ~=C-O-CH~CH~
3o A solution o~ 240 g Or pota~ium hydroxide in 400 ml oi water a~d 1600 g o~ ice i~ added over a period o~ 5 minute~
~V~
with vigorous stirring to a solution, which has been cooled to 15C~ of 220 g (2.0 mol) of ethyl chloroformate, 260 g (2.0 mol) of quinoline and 600 ml of dimethyl formamide.
When the mixture has been stirred for a further 10 minutes, it is extracted with 1 litr0 of methylene chloride and the organic phase is washed with water, dehydrated over anhydrous magnesium sulphate, filtered and evaporated. 400 g of a pale-brown liquid containing 2-hydroxy-N-carbethoxy-1,2-dihydroquinoline, di-(N-carbethoxy-1,2-dihydro-2-quinolyl) ether and quinoline are obtained (product A).
200 g of the oil are concentrated by distillation at a bath temperature below 100C to remove unreacted quinoline.
125 g of a residue containing 2-hydroxy-N-carbethoxy-1,2-dihydroquinoline and di-(N-carbothoxy-1,2-dihydro-2-quinolyl)-ether are obtained (product B).B. Preparation of N-carbethoxy-2-ethoxy-1,2-dihydroquinoline O=J-O-CH2CH3 A solution oi 120 g of product B, 100 ml of absolute alcohol, 500 ml of anhydrou~ diethyl ether and 10 drop~ of borotrifluoride etherate i9 stirred for 5 hours at 20 C.
80dium The ethereal ~olution i~ wa~hed with saturated ~icarbonate ~5 solution and water, dehydrated over magnesium sulphate, filtered and concentrated. An oil is obtained ~rom which 47 g of the colourle~s compound N-carbethoxy-2-ethoxy-1,2-dihydro-quinoline are obtained by distillation. The product had a boiling point of 125 to 128C at 0.1 mm. The product ~olidifies when le~t to stand and had a melting point of 56 to 57C.
~-~ 1308
Claims (34)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a 1-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinoline of the formula in which R1 represents a primary or secondary alkyl group containing 1 to 6 carbon atoms; an alkoxy alkyl group containing 1 to 3 carbon atoms in each alkyl group, a cycoalkyl group containing 3 to 8 carbon atoms or an aralkyl group containing 1 to 4 carbon atoms in the alkyl group and R2 has the same meaning as R1 or represents a tertiary alkyl group; an alkyl thioethyl group; an alkane sulphonyl ether or a cyanoalkyl group, by the reaction of quinoline with an aliphatic chloroformate and an aliphatic alcohol, in which quinoline is reacted with a one- to ten-times excess of an alcohol of the formula in which R2 has the meaning specified above, and with not more than the stoichiometric quantity of a chloroformate of the general formula in which R1 has the meaning specified above, at a temperature of from -10 to 20°C and a pH of 7 to 10 in the presence of an aqueous inorganic neutralising agent.
2. A process as claimed in claim 1 in which R1 and/or R2 represents an alkyl group with 1 to 6 carbon atoms.
3. A process as claimed in claim 2 in which R1 and/or R2 represents a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. butyl or iso-butyl group.
4. A process as claimed in claim 1 in which R1 and/or R2 represents a 2-alkoxymethyl or 2-alkoxyethyl group.
5. A process as claimed in claim 1 in which R1 and/or R2 represents a cyclopentyl or cyclohexyl group.
6. A process as claimed in claim 1 in which R1 and/or R2 represents a benzyl or phenethyl group.
7. A process as claimed in claim 1 in which R2 represents a tertiary-butyl or tertiary-amyl group.
8. A process as claimed in claim 1 in which R2 represents a methyl thioethyl or ethyl thioethyl group.
9. A process as claimed in claim 1 in which the alcohol of formula H-OR2 is an aliphatic primary or secondary alcohol containing 1 to 6 carbon atoms; ethylene glycol monoalkyl ether containing 1 to 3 carbon atoms in the alkyl group; a cycloalkanol containing 3 to 8 carbon atoms or an aryl carbinol containing 1 to 4 carbon atoms in the chain.
10. A process as claimed in claim 1 in which the quinoline is reacted with a four to ten times excess of alcohol.
11. A process as claimed in claim 1 which is carried out in the presence of an inert organic solvent which is insoluble or only sparingly soluble in water.
12. A process as claimed in claim 11 in which the solvent is an inert hydrocarbon, ketone, ester or ether.
13. A process as claimed in claim 12 in which the solvent is a chlorinated hydrocarbon.
14. A process as claimed in claim 13 in which the solvent is dichloromethane or 1,2-dichloroethane.
15. A process as claimed in claim 1 in which the neturalising agent is an aqueous solution or suspension of an alkali metal carbonate or bicarbonate.
16. A process as claimed in claim 15 in which the neutralising agent is an aqueous solution or suspension of sodium or potassium carbonate or bicarbonate.
17. A process as claimed in claim 1 in which the reaction is carried out at a temperature of from -10 to 10°C.
18. A process as claimed in claim 17 in which the reaction is carried out at a temperature of from -5 to +5°C.
19. A process as claimed in either of claims 2, 3 or 4 in which the quinoline is reacted with a four to ten times excess of alcohol.
20. A process as claimed in either of claims 2, 3 or 4 which is carried out in the presence of an inert organic solvent which is insoluble or only sparingly soluble in water.
21. A process as claimed in either of claims 2, 3 or 4 which is carried out in the presence of an inert organic solvent which is insoluble or only sparingly soluble in water, said solvent being chosen from the group consisting of an inert hydrocarbon, a ketone, an ester or an ether.
22. A process as claimed in either of claims 2, 3 or 4 which is carried out in the presence of an inert organic solvent which is insoluble or only sparingly soluble in water, said solvent being a chlorinated hydrocarbon.
23. A process as claimed in either of claims 2, 3 or 4 which is carried out in the presence of a solvent selected from the group consisting of dichloromethane and 1,2 dichloroethane.
24. A process as claimed in either of claims 2, 3 or 4 in which the neutralising agent is an aqueous solution or suspension of an alkali metal carbonate or bicarbonate.
25. A process as claimed in either of claims 2, 3 or 4 in which the neutralizing agent is an aqueous solution or suspension of sodium or potassium carbonate or bicarbonate.
26. A process as claimed in either of claims 2, 3 or 4 in which the reaction is carried out at a temperature of from -10° to 10°C.
27. A process as claimed in either of claims 5, 6 or 7 in which the quinoline is reacted with a four to ten times excess of alcohol.
28. A process as claimed in either of claims 5, 6 or 7 which is carried out in the presence of an inert organic solvent which is insoluble or only sparingly soluble in water.
29. A process as claimed in either of claims 5, 6 or 7 which is carried out in the presence of an inert organic solvent which is insoluble or only sparingly soluble in water, said solvent being chosen from the group consisting of an inert hydrocarbon, a ketone, an ester or an ether.
30. A process as claimed in either of claims 5, 6 or 7 which is carried out in the presence of an inert organic solvent which is insoluble or only sparingly soluble in water, said solvent being a chlorinated hydrocarbon.
31. A process as claimed in either of claims 5, 6 or 7 which is carried out in the presence of a solvent selected from the group consisting of dichloromethane and 1,2 dichloroethane.
32. A process as claimed in either of claims 5, 6 or 7 in which the neutralising agent is an aqueous solution or suspension of an alkali metal carbonate or bicarbonate.
33. A process as claimed in either of claims 5, 6 or 7 in which the neutralizing agent is an aqueous solution or suspension of sodium or potassium carbonate or bicarbonate.
34. A process as claimed in either of claims 5, 6 or 7 in which the reaction is carried out at a temperature of from -10° to 10°C.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19752502201 DE2502201A1 (en) | 1975-01-21 | 1975-01-21 | PROCESS FOR THE PRODUCTION OF L-ALKOXYCARBONYL-2-ALKOXY-L, 2-DIHYDROCHINOLINES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1074321A true CA1074321A (en) | 1980-03-25 |
Family
ID=5936886
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA243,777A Expired CA1074321A (en) | 1975-01-21 | 1976-01-19 | Process for the preparation of 1-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinolines |
Country Status (7)
| Country | Link |
|---|---|
| BE (1) | BE836005A (en) |
| CA (1) | CA1074321A (en) |
| CH (1) | CH619214A5 (en) |
| DE (1) | DE2502201A1 (en) |
| FR (1) | FR2298541A1 (en) |
| GB (1) | GB1520032A (en) |
| IT (1) | IT1052947B (en) |
-
1975
- 1975-01-21 DE DE19752502201 patent/DE2502201A1/en not_active Withdrawn
- 1975-11-27 BE BE1007038A patent/BE836005A/en unknown
-
1976
- 1976-01-19 IT IT4767976A patent/IT1052947B/en active
- 1976-01-19 CA CA243,777A patent/CA1074321A/en not_active Expired
- 1976-01-20 FR FR7601426A patent/FR2298541A1/en active Granted
- 1976-01-20 GB GB213476A patent/GB1520032A/en not_active Expired
- 1976-01-20 CH CH66576A patent/CH619214A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IT1052947B (en) | 1981-08-31 |
| BE836005A (en) | 1976-05-28 |
| CH619214A5 (en) | 1980-09-15 |
| FR2298541B1 (en) | 1979-08-10 |
| DE2502201A1 (en) | 1976-07-22 |
| FR2298541A1 (en) | 1976-08-20 |
| GB1520032A (en) | 1978-08-02 |
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