WO2003062202A2 - Verfahren zur herstellung von substituierten 1,2,3,4-tetrahydrochinolin-2-carbonsäuren - Google Patents
Verfahren zur herstellung von substituierten 1,2,3,4-tetrahydrochinolin-2-carbonsäuren Download PDFInfo
- Publication number
- WO2003062202A2 WO2003062202A2 PCT/EP2003/000082 EP0300082W WO03062202A2 WO 2003062202 A2 WO2003062202 A2 WO 2003062202A2 EP 0300082 W EP0300082 W EP 0300082W WO 03062202 A2 WO03062202 A2 WO 03062202A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- radical
- saturated
- aryl
- formula
- branched
- Prior art date
Links
- 0 *C1C(C(O)=O)Nc2ccccc2C1* Chemical compound *C1C(C(O)=O)Nc2ccccc2C1* 0.000 description 1
Classifications
-
- 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
Definitions
- the present invention relates to a process for the preparation of substituted 1, 2,3,4-tetrahydroquinoline-2-carboxylic acids, such as 7,9-dichloro-3a, 4,5,9b-tetrahydro-3H-cyclopenta [c] quinoline-4 carboxylic acid.
- NMDA Antagonists that selectively bind to the glycine B binding site of the NMDA ion channel.
- the compounds are analgesic and are suitable for the treatment of pain, in particular chronic or neuropathic pain (WO 01/58875).
- substituted 1,3,3,4-tetrahydroquinoline-2-carboxylic acids are obtained by the Grieco three-component synthesis.
- aromatic amines, glyoxylic acid alkyl esters and olefins are converted with acid catalysis with trifluoroacetic acid to substituted 1, 2,3,4-tetrahydoquinoline-2-carboxylic acid esters, from which the carboxylic acids must be obtained by saponification.
- the object of the present invention was therefore to provide a process for the preparation of substituted 1, 2,3,4-tetrahydroquinoline-2-carboxylic acids, such as 7,9-dichloro-3a, 4, ⁇ 5.9b-tetrahydro-3H-cyclopenta [ c] quinoline-4-carboxylic acid, which is characterized by a one-step procedure, short reaction times, ie less than an hour, and a high yield.
- the present invention therefore relates to a process for the preparation of a substituted 1, 2,3,4-tetrahydroquinoline-2-carboxylic acids of the general formula I,
- R 1 and R 2 identical or different, represent hydrogen, a halogen, a trifluoromethyl group, an optionally bonded via oxygen, linear or branched, saturated or unsaturated aliphatic C- ⁇ -6 radical or together form a C 3 to 5 chain under Forming a condensed ring,
- R 3 and R 4 together form a saturated or unsaturated aliphatic C 3-5 chain to form a cycloaliphatic ring or
- R 3 represents a linear or branched, saturated or unsaturated aliphatic C- ⁇ - 6 radical, a cycloaliphatic C 3-6 radical, an aryl radical or a heteroaryl radical, the aryl or heteroaryl radical optionally with halogen, a linear or branched, saturated or unsaturated C 1-6 alkyl radical and / or a linear or branched, saturated or unsaturated C 1 - 6 - alkoxy group may be substituted, and
- R 4 represents a linear or branched, saturated or unsaturated aliphatic C 6 radical, an aryl or heteroaryl radical, where the radicals mentioned above may optionally be bonded via a hetero atom and / or the aryl or heteroaryl radical with halogen, one linear or branched, saturated or unsaturated C 6 alkyl radical, an aryl radical, a heteroaryl radical, a cyano group, an aldehyde group, a radical of the formula -C n F2n + ⁇ , in which n stands for an integer from 1-6, and / or a radical of the formula -C (OR 5 ) 2 , -C (O) -NR 5 2 or -YR 5 and / or the aryl or heteroaryl radical which is not bonded via a hetero atom can optionally be part of a polycyclic system, where
- R 5 represents a linear or branched, saturated or unsaturated aliphatic C ⁇ - 6 radical, an aryl or heteroaryl radical and
- Y represents a hetero atom or a bridge of the formula -C (O) -0- or-C (0) -S,
- R 1 and R 2 represent hydrogen, chlorine, a methyl group, a
- R 3 and R 4 together form a saturated or unsaturated aliphatic C 3-4 chain
- R 3 represents a linear or branched, saturated or unsaturated aliphatic C -3 radical, a cycloaliphatic C 5-6 radical, an aryl radical or a heteroaryl radical, the aryl or heteroaryl radical optionally having a linear or branched, saturated or unsaturated C -3 alkoxy may be substituted, and
- R 4 represents a linear or branched, saturated or unsaturated aliphatic C 1-3 radical, an aryl or heteroaryl radical, where the radicals mentioned above can optionally be bonded via oxygen or sulfur and / or the aryl or heteroaryl radical with halogen , a linear or branched, saturated or unsaturated C -3 alkyl group, an aryl group, a heteroaryl group, a cyano group, an aldehyde group, a group of the formula -C n F 2n + ⁇ , where n is an integer from 1-3, and / or a residue of the formula -C (OR 5 ) 2 , -C (O) -NR 5 2 or -YR 5 substituted and / or the aryl or heteroaryl radical not bonded via oxygen or sulfur can optionally be part of a polycyclic system, where
- R 5 represents a linear or branched, saturated or unsaturated aliphatic C ⁇ _ radical, an aryl or heteroaryl radical and
- Y represents oxygen, sulfur or a bridge of the formula -C (0) -O- or -C (0) -S-.
- a method is particularly preferred in which a compound of the formula II is used as optionally substituted aniline, in which
- R 1 and R 2 represent hydrogen and chlorine or a methyl group in the 6 or 7 position, each represent chlorine or a methyl group in the 6 and 7 position or in the 5 and 7 position, and
- R 3 and R 4 together form a saturated or unsaturated aliphatic C 3-4 chain
- R 3 represents a phenyl radical optionally substituted with an alkoxy group, preferably a methoxy group, and
- R 4 represents a methyl group, a methoxy group or a phenyl radical optionally substituted with halogen and / or a methyl group.
- Acetonitrile is preferably used as the solvent. Sufficient solvent is used to dissolve the starting compounds at 25 ° C.
- the reaction is preferably carried out at a temperature of 40-80 ° C., particularly preferably at 50-60 ° C.
- the reaction is preferably isothermal.
- the reaction according to the invention takes place in less than one hour, preferably in less than 30 minutes, particularly preferably in 5-15 minutes.
- An apparatus with an output of 100-1200 watts, preferably 600-1000 watts, is used for the irradiation with microwaves. Irradiation with microwaves is preferably carried out during the entire reaction time.
- the reaction can be carried out batchwise or continuously, preferably batchwise.
- the reaction is preferably carried out in a closed, pressure-stable, inert vessel. In the production process it is possible to use flow reactors or microreactor technology.
- the solvent is preferably removed or the poorly soluble compound of general formula I is filtered off.
- a compound of the general formula I which is pure for analysis is usually already obtained.
- the isolated compound of the general formula I can be purified, preferably with a suitable solvent, particularly preferably with a non-polar organic solvent, very particularly preferably hexane or acetonitrile, and / or the compound can be recrystallized.
- the compound of formula I can also be converted into its salts or solvates.
- the corresponding salt can be formed by adding a base, such as sodium hydroxide, or the corresponding hydrochloride can be formed by adding hydrochloric acid.
- the starting compounds of the synthesis are available on the market or can be obtained by simple reactions known to the person skilled in the art.
- Substituted 1, 2,3,4-tetrahydroquinoline-2-carboxylic acids of the general formula I such as 7,9-dichloro-3a, 4,5,9b-tetrahydro-3H-cyclopenta [c] quinoline-4-carboxylic acid, are considered as Medicines, preferably used to treat pain, especially chronic or neuropathic pain.
- the reactions under microwave radiation were carried out in a laboratory microwave of the make MLS ETHOS 600 from the company MLS-GmbH (D-88299 Leutkirch, Auenweg 37, Germany).
- the thin layer chromatography was carried out on RP-8-DC plates with fluorescent indicator (Merck, Darmstadt) with the following solvent mixture: methanol / water / NaCl; 12: 5: 3rd Detection was carried out by staining in the iodine chamber.
- the ESI-MS spectra were measured using a device (device name Finnigan LCQ) from Thermoquest, Analystische Systeme GmbH, Boschring 12, D-63329 Egelsbach.
- the GC analysis was carried out on the HP 6890 gas chromatograph (with PTV injector) and a coupled mass detector 5973 (mass selective detector) from Hewlett-Packard.
- the aqueous phase was adjusted to pH 1 with 1 M hydrochloric acid and extracted five times with dichloromethane.
- the combined organic phase was washed with water, dried over magnesium sulfate and concentrated. A colorless crystal mass was obtained.
- the yield of the crude product was 96% of theory.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03701493A EP1470110A2 (de) | 2002-01-24 | 2003-01-08 | Verfahren zur herstellung von substituierten 1,2,3,4-tetrahydrochinolin-2-carbonsäuren |
AU2003202547A AU2003202547A1 (en) | 2002-01-24 | 2003-01-08 | Method for the production of substituted 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acids |
US10/896,728 US7145011B2 (en) | 2002-01-24 | 2004-07-22 | Method for the production of substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acids |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10202864A DE10202864A1 (de) | 2002-01-24 | 2002-01-24 | Verfahren zur Herstellung von substituierten 1,2.3,4-Tetrahydrochinolin 2-carbonsäuren |
DE10202864.8 | 2002-01-24 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/896,728 Continuation US7145011B2 (en) | 2002-01-24 | 2004-07-22 | Method for the production of substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acids |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003062202A2 true WO2003062202A2 (de) | 2003-07-31 |
WO2003062202A3 WO2003062202A3 (de) | 2004-01-22 |
Family
ID=7713051
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2003/000082 WO2003062202A2 (de) | 2002-01-24 | 2003-01-08 | Verfahren zur herstellung von substituierten 1,2,3,4-tetrahydrochinolin-2-carbonsäuren |
Country Status (5)
Country | Link |
---|---|
US (1) | US7145011B2 (de) |
EP (1) | EP1470110A2 (de) |
AU (1) | AU2003202547A1 (de) |
DE (1) | DE10202864A1 (de) |
WO (1) | WO2003062202A2 (de) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001058875A2 (de) * | 2000-02-07 | 2001-08-16 | Grünenthal GmbH | Substituierte 1,2,3,4-tetrahydrochinolin-2-carbonsäurederivate |
-
2002
- 2002-01-24 DE DE10202864A patent/DE10202864A1/de not_active Withdrawn
-
2003
- 2003-01-08 EP EP03701493A patent/EP1470110A2/de not_active Withdrawn
- 2003-01-08 WO PCT/EP2003/000082 patent/WO2003062202A2/de not_active Application Discontinuation
- 2003-01-08 AU AU2003202547A patent/AU2003202547A1/en not_active Abandoned
-
2004
- 2004-07-22 US US10/896,728 patent/US7145011B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001058875A2 (de) * | 2000-02-07 | 2001-08-16 | Grünenthal GmbH | Substituierte 1,2,3,4-tetrahydrochinolin-2-carbonsäurederivate |
Also Published As
Publication number | Publication date |
---|---|
US20050004366A1 (en) | 2005-01-06 |
WO2003062202A3 (de) | 2004-01-22 |
AU2003202547A1 (en) | 2003-09-02 |
DE10202864A1 (de) | 2003-07-31 |
EP1470110A2 (de) | 2004-10-27 |
US7145011B2 (en) | 2006-12-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CH494730A (de) | Verfahren zur Herstellung von Dibenzocyclopentenen | |
CH640224A5 (de) | 2-pyrrolidonderivate, verfahren zu ihrer herstellung und ihre verwendung zur herstellung von 4-aminohex-5-ensaeure. | |
EP0496238A1 (de) | Substituierte Benzoxazepine und Benzthiazepine, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln | |
DE1770161A1 (de) | Heterocyclische Verbindungen und Verfahren zu ihrer Herstellung | |
CH626615A5 (de) | ||
WO2003062202A2 (de) | Verfahren zur herstellung von substituierten 1,2,3,4-tetrahydrochinolin-2-carbonsäuren | |
DE3028369A1 (de) | Verfahren zur herstellung von 7-alkoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1-phthalazon und die dabei auftretenden zwischenprodukte | |
DE2806909C2 (de) | ||
CH653996A5 (de) | Tryptaminderivate und verfahren zu deren herstellung. | |
EP0102318B1 (de) | Herstellung von beta-Amino-alpha,beta-ungesättigten Carbonsäureestern | |
DE69821483T2 (de) | Verfahren zur gewinnung von chinaprylhydrochlorid und solvaten, die bei der isolierung und reinigung von chinaprylhydrochlorid nützlich sind | |
AT202152B (de) | Verfahren zur Herstellung von neuen Dimethylaminopropylidenthiaxanthenen. | |
DE2409675A1 (de) | Alpha-alkyl(oder -aryl)-thio-5-hydroxytryptophan-derivat und verfahren zu seiner herstellung | |
JP3088561B2 (ja) | 2,3−ジアミノピリジン類の製造方法 | |
DE1693032B1 (de) | Verfahren zur Herstellung von 1,2-disubstituierten Adamantanverbindungen | |
DE19853558A1 (de) | Verfahren zur Herstellung von 2,3-Dihydroindolen (Indolinen), neuartige 2,3-Dihydroindole sowie deren Verwendung | |
DE2521088B2 (de) | Dihydro- und Tetrahydroabietinsaureanilide und Verfahren zu ihrer Herstellung | |
DE2746762C3 (de) | Verfahren zur Umwandlung von trans- in cis-N,N-Dimethyl-9- [3-(4-methyl-1 -piperazinyD-propyliden] -thioxanthen-2-sulfonamid | |
DE2020762A1 (de) | Azainden-3-niedrigaliphatische-Saeuren und Verfahren zu deren Herstellung | |
DE69728703T2 (de) | Verfahren zur Herstellung von 1,1-disubstituierten-1H-Benz[e]indol Derivaten und Hydroxyl-substituierte 1,1-disubstituierte-1H-Benz[e]indol Derivate | |
DE2618721C2 (de) | Benzo(b)-bicyclo[3,3,1]nonene, Verfahren zu deren Herstellung und pharmazeutische Mittel, die diese Verbindungen enthalten | |
CH623574A5 (de) | ||
EP0539330B1 (de) | Verfahren zur Herstellung substituierter Indole | |
DE2644789A1 (de) | Alkylen-di-phenylalk(en)ylcarbonsaeuren und ihre herstellung und verwendung | |
DE1545759C3 (de) | Vincaleukoblastin-derivate und ein Verfahren zu ihrer Herstellung |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2003701493 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10896728 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 2003701493 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 165895 Country of ref document: IL |
|
NENP | Non-entry into the national phase |
Ref country code: JP |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2003701493 Country of ref document: EP |