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1. WO2000040555 - METHOD FOR PRODUCING (2S,4R,9S)-OCTAHYDRO-1H-INDOLE-2-CARBOXYLIC ACID AND INTERMEDIATE PRODUCTS THEREFOR

Publication Number WO/2000/040555
Publication Date 13.07.2000
International Application No. PCT/EP1999/010159
International Filing Date 21.12.1999
Chapter 2 Demand Filed 29.05.2000
IPC
C07D 209/42 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
209Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
02condensed with one carbocyclic ring
04Indoles; Hydrogenated indoles
30with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
42Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
CPC
C07D 209/42
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
209Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
02condensed with one carbocyclic ring
04Indoles; Hydrogenated indoles
30with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
42Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Applicants
  • BASF AKTIENGESELLSCHAFT [DE/DE]; D-67056 Ludwigshafen, DE (AllExceptUS)
  • EBEL, Klaus [DE/DE]; DE (UsOnly)
  • OHLBACH, Frank [DE/DE]; DE (UsOnly)
  • NÜBLING, Christoph [DE/DE]; DE (UsOnly)
Inventors
  • EBEL, Klaus; DE
  • OHLBACH, Frank; DE
  • NÜBLING, Christoph; DE
Common Representative
  • BASF AKTIENGESELLSCHAFT; D-67056 Ludwigshafen, DE
Priority Data
199 00 205.307.01.1999DE
Publication Language German (DE)
Filing Language German (DE)
Designated States
Title
(DE) VERFAHREN ZUR HERSTELLUNG VON (2S,4R,9S)-OCTAHYDRO-1H-INDOL-2-CARBONSÄURE UND ZWISCHENPRODUKTE DAFÜR
(EN) METHOD FOR PRODUCING (2S,4R,9S)-OCTAHYDRO-1H-INDOLE-2-CARBOXYLIC ACID AND INTERMEDIATE PRODUCTS THEREFOR
(FR) PROCEDE DE PREPARATION D'ACIDE (2S,4R,9S)-OCTAHYDRO-1H-INDOL-2-CARBOXYLIQUE ET PRODUITS INTERMEDIAIRES APPROPRIES
Abstract
(DE)
Es wird ein Verfahren zur Herstellung von (2S,4R,9S)-Octahydro-1H-indol-2-carbonsäure beschrieben, welches darin besteht, daß man: a. eine Verbindung der Formel (I) (R1O)2CH-CH2-CH(OR2)2, worin R1 und R2 gleich oder verschieden sind und C1-4-Alkyl-gruppen darstellen, mit Wasser in Gegenwart eines sauren Katalysators umsetzt; b. die so erhaltenen 3,3-Dialkoxypropionaldehyde der Formel (II) (R1O)2CH-CH2-CHO einer Henry-Reaktion mit Nitromethan unterwirft; c. das so erhaltene 4,4-Dialkoxy-1-nitro-2-butanol der Formel (III) (R1O)2CH-CH2-CHOH-CH2-NO2 dehydratisiert; d. das so erhaltene Nitroolefin IV mit Hilfe einer Diels-Alder-Reaktion in das entsprechende trans-4-(2,2-Dialkoxyethyl)-5-nitro-1-cyclohexen V überführt; e. die so erhaltene Substanz V zum entsprechenden trans-4-(2,2-Dialkoxyethyl)-5-amino-1-cyclohexan VI hydriert; f. die Verbindung VI einer Racematspaltung unterwirft und das (1S,2R)-1-Amino-2-(2,2-dialkoxyethyl)-cyclohexan VII durch enzymatische Racematspaltung in enantiomerenreiner Form gewinnt; g. die so erhaltene Verbindung VII zum entsprechenden Acetal VIII hydrolysiert; h. den so erhaltenen Aldehyd in das entsprechende Nitril VIII überführt und; i. Dieses Nitril zur (2S,4R,9S)-Octahydro-1H-indol-2-carbonsäure cyclisiert.
(EN)
The invention relates to a method for producing (2S,4R,9S)-octahydro-1H-indole-2-carboxylic acid. The invention is characterised in that a. a compound of the formula (I) (R1O)2CH-CH2-CH(OR2)2, wherein R1 and R2 are equal or different and represent C1-4-alkylgroups, is converted with water in the presence of an acid catalyst; b. the 3,3-dialkoxypropionaldehydes of the formula (II) (R1O)2CH-CH2-CHO thus obtained are subjected to a Henry reaction with nitromethane; c. the 4,4-dialkoxy-1-nitro-2-butanol of the formula (III) (R1O)2CH-CH2-CHOH-CH2-NO2 thus obtained is dehydrated; d. the nitroolefin IV thus obtained is converted into the corresponding trans-4-(2,2-dialkoxyethyl)-5-nitro-1-cyclohexene V by means of a Diels-Alder reaction; e. the substance V thus obtained is hydrated to form corresponding trans-4-(2,2-dialkoxyethyl)-5-amino-1-cyclohexane VI; f. the compound VI is subjected to a racemic division and the (1S,2R)-1-amino-2-(2,2-dialkoxyethyl)-cyclohexane VII is obtained in the enantiomerically pure form by enzymatic racemic division; g. the compound VII obtained thereby is hydrolised to form the corresponding acetal VIII; h. the aldehyde obtained thereby is converted into the corresponding nitrile VIII and i. said nitrile is cyclised to form the (2S,4R,9S)-octahydro-1H-indole-2-carboxylic acid.
(FR)
L'invention concerne un procédé permettant de préparer de l'acide (2S,4R,9S)-octahydro-1H-indol-2-carboxylique, selon lequel: a) un composé de la formule (I) (R1O)2CH-CH2-CH(OR2)2 dans laquelle R1 et R2 sont identiques ou différents et désignent des groupes alkyle C1-C4, est mis à réagir avec de l'eau en présence d'un catalyseur acide; b) les 3,3-dialcoxypropionaldéhydes ainsi obtenus de la formule (II) (R1O)2CH-CH2-CHO sont soumis à une réaction d'Henry avec du nitrométhane; c) le 4,4-dialcoxy-1-nitro-2-butanol ainsi obtenu de la formule (III) (R1O)2CH-CH2-CHOH-CH2-NO2 est déshydraté; d) la nitro-oléfine IV ainsi obtenue est transformée par réaction de Diels-Alder en trans-4-(2,2-dialcoxyéthyle)-5-nitro-1-cyclohexène V correspondant; e) la substance V ainsi obtenue est hydrogénée pour former le trans-4-(2,2-dialcoxyéthyle)-5-amino-1-cyclohexane VI correspondant; f) le composé VI est soumis à une séparation racémique et le (1S,2R)-1-amino-2-(2,2-dialkyléthyle)cyclohexane VII est obtenu par séparation racémique enzymatique sous sa forme exempte d'énantiomère; g) le composé VII ainsi obtenu est hydrolysé pour former l'acétal VIII correspondant; h) l'aldéhyde ainsi obtenu est transformé en nitrile VIII correspondant et i) ce nitrile est cyclisé pour former de l'acide (2S,4R,9S)-octahydro-1H-indol-2-carboxylique.
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