WO2001023353A2 - Verfahren zur herstellung von indolderivaten an fester phase - Google Patents
Verfahren zur herstellung von indolderivaten an fester phase Download PDFInfo
- Publication number
- WO2001023353A2 WO2001023353A2 PCT/EP2000/008838 EP0008838W WO0123353A2 WO 2001023353 A2 WO2001023353 A2 WO 2001023353A2 EP 0008838 W EP0008838 W EP 0008838W WO 0123353 A2 WO0123353 A2 WO 0123353A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solid phase
- indole
- ocf
- het
- formula
- Prior art date
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- 0 CC1OCOC1* Chemical compound CC1OCOC1* 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N CC1CCCC1 Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- FBRRMXLSPHLGJM-UHFFFAOYSA-N N#Cc1ccc2[n](C3OC(COCc4ccccc4)CO3)ccc2c1 Chemical compound N#Cc1ccc2[n](C3OC(COCc4ccccc4)CO3)ccc2c1 FBRRMXLSPHLGJM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with 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
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/22—Tin compounds
- C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
Definitions
- the invention relates to a process for the preparation of indole derivatives on a solid phase, the binding to the solid phase on the indole nitrogen being carried out by transacetalization of dialkoxymethyl-protected indoles with a solid phase which carries vicinal diol groups and, according to synthetic chemistry on the solid phase, the Functionalized indole derivative is cleaved "without a trace" from the solid phase.
- Solid phase synthesis has become an established method in the pharmaceutical industry, on the one hand for the production of compound libraries in the sense of combinatorial synthesis, and on the other hand in the highly automated parallel synthesis of individual substances. Compounds with high structural diversity are obtained, which can be mass-screened in test systems. The finding of active ingredient lead structures or crop protection or pharmaceutical active ingredients can be considerably shortened by this procedure.
- the molecules to be built are bound to a polymeric support via a linker during the synthesis.
- Resin resin
- the invention was based on the object, a new simple
- the invention relates to a process for the preparation of indole derivatives on a solid phase, the binding to the solid phase on the indole nitrogen being effected by transacetalization of dialkoxymethyl-protected indoles with a solid phase which carries vicinal diol groups and, according to synthetic chemistry, on the solid phase, the functionalized indole derivative is cleaved "without a trace" from the solid phase.
- the invention further relates to a process for the preparation of indole derivatives on a solid phase, the connection to the vicinal
- Bu butyl o denotes 0, 1, 2 or 3, with the condition that at least one substituent R 1 , R 2 or
- R 3 is not equal to H, takes place.
- A is alkyl, is linear or branched, and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6, carbon atoms.
- A is preferably methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl or tert. Butyl, also n-pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl or n-hexyl.
- A is particularly preferably methyl or ethyl.
- - (CH 2 ) 0 -Hal is F, Cl, Br, I, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, fluoroethyl, chloroethyl, bromoethyl, iodoethyl, fluoropropyl, chloropropyl, bromopropyl or iodopropyl.
- - (CH 2 ) 0 -hal means chloromethyl.
- Shark is preferably F, Cl, Br or I, particularly preferably chlorine.
- R 1 denotes H, A, shark, OA, CF 3 , OCF 3 , CN, NA 2 or N0 2 , where A has one of the meanings given above.
- R 1 can be in position 4, 5, 6 or 7 of the indole skeleton, in particular R is in the 5- or 6-position.
- R 1 is particularly preferably H, CN or N0 2 .
- R 1 H, 5-CN, 6-CN or 5-N0 2 is very particularly preferred.
- R 2 means H, A, - (CH 2 ) 0 -Hal, OA, CF 3 , OCF 3 , CN, N0 2 , COOH, COOA or NA 2 , where A and - (CH 2 ) 0 -Hal are one of the previously has given meanings.
- R 2 H or COOA is particularly preferred.
- the subsequent synthesis chemistry on the solid phase preferably takes place in the 3-position of the indole skeleton, ie on R 2 , or in the 2-position of the indole skeleton, ie on R 3 .
- R 2 therefore also means - (CH 2 ) n -NH 2 , - (CH 2 ) n -NHA, - (CH 2 ) n -NA 2 , Het or - (CH 2 ) n -Het-Ar.
- Particularly preferred for R 2 after synthetic chemistry is - (CH 2 ) n -NA 2 or - (CH 2 ) ⁇ -Het-Ar, where A has one of the meanings given above, n is 0, 1 or 2 and - (CH 2 ) n -Het-Ar has one of the preferred or very preferred meanings mentioned below.
- n is particularly preferably 1.
- R 3 denotes H, A, - (CH 2 ) 0 -Hal, OA, CF 3 , OCF 3 , CN, NA 2 , N0 2 or SnBu 3 , where A and Hai have one of the meanings given above and o 0.1 , 2 or 3 can be. Particularly preferred for R 3 is H, chlorine, methyl or SnBu. 3
- R 3 also means Ar, particularly preferably phenyl substituted by CN, het or - (CH 2 ) n -Het-Ar, particularly preferably 3,4-dichlorophenyipiperazin-4-yl-methyl, phenylpiperazin-4-yl-methyl or 2-chlorophenylpiperazin-4-yl-methyl.
- Ar means phenyl which is unsubstituted or substituted one, two or three times by A, CN, OH, OA or shark.
- Ar is therefore preferably phenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-isopropylphenyl, 2-, 3- or 4-propylphenyl, 2-, 3 - or 4-tert-butylphenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2 -, 3- or 4-
- Het means a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, 0 and / or S atoms, which is unsubstituted or mono-, di- or triple by shark, A, OH, OA, CF 3 , CN, or N0 2 may be substituted.
- Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-
- Benzisothiazolyl 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3- , 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3- or 4-carbazolyl, 1-, 2-, 3-, 4- or 9-acridinyl, 3-, 4 -, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
- the heterocyclic radicals can also be partially or completely hydrogenated.
- Het can also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or - 5-furyl, tetrahydro -2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or - 3-thienyl, 2,3-dihydro-2-, -3-, -4- or -5-pyrrolyl , 2,5-dihydro-2-, -3-, -4- or -5-pyrrolyl, 2- or 3-pyrrolidinyl, tetrahydro-2- or -3-pyrollyl, tetrahydro-2- or 4-imidazolyl, 2 , 3-dihydro-2-, -3-, -4-, -5-, -6- or -7-1 H-indolyl, 2,3-dihydro-3-, -4- or -5-pyr
- Het, Ar and n have one of the preferred or particularly preferred meanings given above.
- - (CH 2 ) n -Het in - (CH 2 ) n -Het-Ar is piperazin-4-yl-methyl, piperazin-4-yl-ethyl, piperidin-4-yl-methyl or piperidin-4-yl -ethyl and Ar in - (CH 2 ) n -Het-Ar an unsubstituted or mono-, di- or by A, CN, OH, OA or Hai trisubstituted phenyl.
- Suitable solid phases bearing vicinal diol groups are, for example, solid phases of the formula II
- R 4 is H or A, A alkyl having 1 to 6 carbon atoms, m 1, 2, 3 or 4 and
- Y means O, S, NH or NA.
- R 4 denotes H or A, where A has one of the meanings given above.
- R 4 H is particularly preferred.
- Y means O, S, NH or NA, where A has one of the meanings given above.
- Y O is particularly preferred.
- rn means 1, 2, 3 or 4, particularly preferably 1.
- o denotes 0, 1, 2 or 3, particularly preferably 1 or 2, very particularly preferably 1.
- the symbol stands for the polymeric carrier material as well as for all atoms of the anchor group of a solid phase, except for the terminal functional group.
- the anchor groups of a solid phase also called linkers, are necessary for the connection of the connection to be functionalized to the solid phase.
- Phase and the solid phases and / or linkers that can be used for this purpose are given, for example, in Novabiochem - The Combinato al Chemistry Catalog, March 99, pages S1-S72.
- C j means polymeric carrier material
- polymeric carrier material is copolystyrene / 1% divinylbenzene.
- C j means polymeric carrier material
- polymeric carrier material is copolystyrene / 1% divinylbenzene.
- PJ representsative of the polymeric support material and for all atoms of the anchor group of a solid phase, except for the terminal functional group
- a solid phase without a terminal group means, for example, for 4- (bromomethyl ) phenoxyethyl polystyrene according to formula 3 (Lit. Novabiochem - The Combinatorial Chemistry Catalog, March 99, p. 8)
- polymeric carrier material is copolystyrene / 1% divinylbenzene
- polymeric carrier material is copolystyrene / 1% divinylbenzene.
- Polymeric solid phase support materials are selected in particular from the group of crosslinked polystyrenes, crosslinked polyacrylamides or other resins, natural polymers or silica gels.
- the group of cross-linked polystyrenes, cross-linked polyacrylamides or other resins includes polyacrylamide, polymethacrylamide,
- Polyethylene glycol graft polymers (meth) acrylate copolymers of e.g.
- Crotonic acid, maleic acid or polyurethane foams, epoxy resins or other copolymers are preferred.
- the group of natural polymers includes agarose, cellulose, alginate,
- the group of silica gels includes all technically manufactured as well as natural silica xerogels (in short silica gels), such as diatomaceous earth or
- Carrier materials are preferably used in the range from 1 ⁇ m to 500 ⁇ m.
- the size distribution of the particles can be homogeneous or heterogeneous; homogeneous particle sizes are preferred.
- Solid phases carrying vicinal diol groups can in some cases be purchased (Lit. Novabiochem - The Combinatorial Chemistry Catalog, March 99), but they can also be analogous to Leznoff, CC and Wong, JY, Can. J. Chem. 1973, 51, 3756 by the following method, in which
- A, R 4 and m have a meaning given in formula II and L is Cl, Br or a free, reactive, functionally modified OH group.
- Suitable compounds of the formula IV are, for example, Merrifield resin (chloromethylpolystyrene-divinylbenzene), brominated PPOA resin, brominated Wang resin, bromo- (4-methoxyphenyl) methyl polystyrene, 4- (bromomethyl) phenoxyethyl polystyrene, 4- (bromomethyl) phenoxymethyl polystyrene (Wang Br), 4-Bromo polystyrene, 4-Methyltrityl Chloride resin, 4-Methoxytrityl Chloride resin, NovaSyn ® TG bromo resin, NovaSyn ® Dichlorotrityl alcohol TG resin, Bromoacetamidomethyl NovaGel TM, (Bromomethyl) phenylacetamidomethyl NovaGel TM, (4-Bromophenyl) - diisopropylsilyloxymethyl polystyrene or 2-brom
- a particularly preferred compound of formula V is 2,2-dimethyl-1,3-dioxolane-4-methanol.
- Suitable phases of the formula VI, where Y is 0, are, for example, Wang resin (Lit .: Novabiochem - The Combinatorial Chemistry Catalog, March 99, pp. 30-42) or hydroxymethylpolystyrene.
- Suitable phases of the formula VI, where Y is NH are, for example, N- (2-amino-ethyl) aminomethyl polystyrene, aminomethylated polystyrene, amino- (4-methoxyphenyl) methyl polystyrene, N-benzylaminomethyl polystyrene, MBHA resin (4-methylbenzhydrylamine resin), N-methylaminomethyl polystyrene, NovaSyn ® TG amino resin, Aminomethyl NovaGel TM, NovaSyn ® TGR resin, Rink Amid NovaGel TM, 4-sulfamylbenzoyl NovaSyn ® TG resin, 4 - Sulfamylbenzoyl NovaG
- Functionally modified OH groups are e.g. Tosylates or mesylates.
- the OH groups are converted into a leaving group, which enable nucleophilic substitution.
- R ⁇ R 2 , R 3 and A have the meanings given in claim 2, are preferably prepared by reacting the free indoles substituted by R 1 , R 2 or R 3 with the corresponding orthoformate.
- the reaction with triethyl orthoformate is particularly suitable, giving diethoxymethyl-protected indoles.
- the transacetalization i.e. the reaction of the dialkoxymethyl-protected indole derivatives with solid phases bearing vicinal diols takes place under mildly acidic conditions, the indole derivatives bound to the solid phase forming a cyclic acetal.
- the transacetalization is usually carried out in an inert solvent, in the presence of a catalytic amount of an acid, for example p-toluenesulfonic acid, camphorsulfonic acid, hydrochloric acid or in the presence of an acidic ion exchanger, in particular a catalytic amount of p-toluenesulfonic acid.
- a catalytic amount of an acid for example p-toluenesulfonic acid, camphorsulfonic acid, hydrochloric acid
- an acidic ion exchanger in particular a catalytic amount of p-toluenesulfonic acid.
- the reaction time is between a few minutes and several days
- the reaction temperature is between about 0 ° and 150 ° C., normally between 20 ° and 100 ° C., preferably between 20 ° and 40 °.
- Suitable inert solvents are e.g. Hydrocarbons such as benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or 1,4-dioxane; Ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone;
- Hydrocarbons such as benzene, toluene or xylene
- chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane
- Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or 1,4-
- Amides such as acetamide, N-methyl-pyrrolidone (NMP), dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulphide; Nitro compounds such as nitromethane or nitrobenzene or mixtures of the solvents mentioned. 1,4-dioxane is particularly suitable for transacetalization.
- Bu butyl o denotes 0, 1, 2 or 3, with the condition that at least one substituent R 1 , R 2 or R 3 is not H, with a vicinal diol group-bearing solid phase of the formula II
- R 4 is H or A, A alkyl having 1 to 6 carbon atoms, m is 1, 2, 3 or 4 and YO, S, NH or NA the indoles of formula III bound to the solid phase are initially formed
- YO, S, NH or NA means, on the condition that at least one substituent R 1 , R 2 or R 3 is not H, which are further functionalized by the subsequent synthetic chemistry.
- R 2 - (CH 2 ) n -NH 2 , - (CH 2 ) n -NHA, - (CH 2 ) n -NA 2 , Het or - (CH 2 ) n -Het-Ar and R 3 can mean Ar, Het or - (CH 2 ) n -Het-Ar, where
- Ar is unsubstituted or mono-, di- or trisubstituted by A, CN, OH, OA or shark and Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or one, two or three times by shark, A, OH,
- OA, CF 3 , CN, or N0 2 may be substituted.
- the invention also relates to the solid phase-bound indole derivatives of the formula III
- R 3 H A, - (CH 2 ) 0 -Hal, OA, CF 3 , OCF 3 , CN, NA 2 , N0 2 , Ar, Het, - (CH 2 ) n - Het-Ar or SnBu 3 ,
- Ar is phenyl which is unsubstituted or mono-, di- or trisubstituted by A, CN, OH, OA or shark, Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by shark,
- A, OH, OA, CF 3 , CN, or N0 2 can be substituted, Bu butyl, n 0, 1 or 2, m 1, 2, 3 or 4, o 0, 1, 2 or 3 and
- YO, S, NH or NA means, with the condition that at least one substituent R 1 , R 2 or R 3 is not equal to H.
- IR spectroscopy offers itself as an analytical detection method for the solid phase-bound indole derivatives of the formula III, provided the substituents R 1 , R 2 , R 3 and / or R 4 are IR-active and generate a specific signal.
- the loading of the solid phase is generally between 0.3 and 1.5 mmol / g, in particular between 0.3 and 0.8 mmol / g.
- Suitable for the subsequent synthetic chemistry are all reactions which have already been described for syntheses in solution for the functionalization of indole derivatives and which are known to the person skilled in the art, although the reaction conditions must not lead to acetal cleavage and thus to cleavage from the solid phase , Reactions which functionalize the indole starting materials in the 2- or 3-position are particularly suitable.
- nucleophilic substitutions in particular the Mannich reaction, oxidations, reductions, Pd-catalyzed aryl couplings, for example according to Suzuki, Negishi, or the Stille coupling, in particular the Stille coupling, iodonolysis Stannans and subsequent Pd-catalyzed coupling according to Heck or Sonogashira or Pd-catalyzed formylations are suitable.
- Chloroalkyldialkylamine preferably implemented in DMF.
- the solid-phase-bound indole derivatives according to the invention are likewise stable under the reaction conditions glacial acetic acid / dichloromethane in a ratio of 1: 4 to 4: 1 for Mannich reactions.
- a ratio of glacial acetic acid / dichloromethane of 1: 4, 1: 1 and 4: 1 is particularly suitable; glacial acetic acid / dichloromethane in a ratio of 4: 1 is very particularly preferably used.
- a compound of the formula III where R 3 is H is also preferably reacted with formaldehyde and an arylpiperazine, where aryl in arylpiperazine is an unsubstituted or mono- or disubstituted by A, CN, OH, OA or Shark-substituted phenyl, in particular an unsubstituted or mono- or disubstituted phenyl by phenyl, can mean.
- the Mannich reaction is an example of synthetic chemistry at the 3-position of the indole skeleton, but this nucleophilic substitution is not limited to the 3-position of the indole skeleton.
- the reaction takes place in an inert solvent, especially in DMF.
- the reaction time is between a few minutes and several days, the reaction temperature is between about 0 ° and 150 ° C., normally between 20 ° and 100 ° C., preferably between 20 ° and 40 °.
- the process according to the invention is particularly suitable for the synthesis of solid-phase-bound indole derivatives of the formula III in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
- Some preferred groups of solid-phase-bound indole compounds can be expressed by the following sub-formulas lilac to Ulf, which correspond to the formula III and in which the radicals not specified have the meaning given for the formula III, but in which
- R 4 denotes H, m 1, o 1 and YO with the condition that at least one substituent R 1 , R 2 or R 3 is not H;
- YO means; with the condition that at least one substituent R 1 , R 2 or R 3 is not H;
- R 2 COOA, - (CH 2 ) n -NA 2 or - (CH 2 ) n -Het-Ar,
- Y represents 0; in all R 1 H or CN,
- R 2 COOA, - (CH 2 ) n -NA 2 or arylpiperazin-4-yl-methyl,
- Aryl in arylpiperazin-4-yl-methyl is phenyl which is unsubstituted or mono- or disubstituted by A, CN, OH, OA or shark;
- Aryl in arylpiperazin-4-yl-methyl is phenyl which is unsubstituted or mono- or disubstituted by A, CN, OH, OA or shark.
- the process according to the invention is particularly suitable for the synthesis of 2- or 3-substituted D4 receptor ligands of the formula 5
- the functionalized indole derivative is cleaved after synthetic chemistry on the solid phase by acidic hydrolysis, as is known to those skilled in the art, or by acid-catalyzed transacetalization.
- the functionalized indole derivative is preferably reacted with a mixture of 1,4-dioxane and hydrochloric acid in a ratio of 1: 1.
- the acid-catalyzed transacetalization preferably takes place in the presence of an alcohol, in particular methanol or ethanol, and a catalytic amount of p-toluenesulfonic acid, camphorsulfonic acid or in the presence of an acidic ion exchanger.
- the invention therefore also relates to a process for the preparation of indole derivatives on a solid phase, characterized in that
- Bu butyl and o denotes 0, 1, 2 or 3, with the condition that at least one substituent R 1 , R 2 or
- R 3 is not equal to H, with a solid phase II carrying vicinal diol groups
- Group means R 4 H or A
- Y denotes 0, S, NH or NA
- both the attachment and the cleavage take place under mildly acidic conditions.
- customary work-up means: if necessary, water is added and, if necessary, the pH is adjusted to between 2 and 10, depending on the constitution of the end product, extracted with ethyl acetate or dichloromethane, separated, dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
- Cpj - CH 2 - Merrifield Resin means without the terminal functional group.
- the loading of the solid-phase-bound compound of the formula X is calculated to be 0.76 mmol / g.
- Loading of the solid phase of the formula XIV is calculated to be 0.33 mmol / g for the reaction product.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001526507A JP2003510307A (ja) | 1999-09-30 | 2000-09-11 | 固相上でのインドール誘導体の製造法 |
CA002386074A CA2386074A1 (en) | 1999-09-30 | 2000-09-11 | Method for producing indole derivatives on a solid phase |
EP00960641A EP1222167A2 (de) | 1999-09-30 | 2000-09-11 | Verfahren zur herstellung von indolderivaten an fester phase |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US15719799P | 1999-09-30 | 1999-09-30 | |
US60/157,197 | 1999-09-30 | ||
DE19955087A DE19955087A1 (de) | 1999-09-30 | 1999-11-17 | Verfahren zur Herstellung von Indolderivaten an fester Phase |
DE19955087.5 | 1999-11-17 |
Publications (2)
Publication Number | Publication Date |
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WO2001023353A2 true WO2001023353A2 (de) | 2001-04-05 |
WO2001023353A3 WO2001023353A3 (de) | 2002-05-02 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/EP2000/008838 WO2001023353A2 (de) | 1999-09-30 | 2000-09-11 | Verfahren zur herstellung von indolderivaten an fester phase |
Country Status (4)
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EP (1) | EP1222167A2 (de) |
JP (1) | JP2003510307A (de) |
CA (1) | CA2386074A1 (de) |
WO (1) | WO2001023353A2 (de) |
Cited By (6)
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US7973069B2 (en) | 2004-07-14 | 2011-07-05 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
US8039122B2 (en) | 2005-03-28 | 2011-10-18 | Semiconductor Energy Laboratory Co., Ltd. | Anthracene derivative, material for light emitting element, light emitting element, light emitting device, and electronic device |
US8134147B2 (en) | 2007-03-23 | 2012-03-13 | Semiconductor Energy Laboratory Co., Ltd. | Organic compound, anthracene derivative, and light-emitting element, light-emitting device, and electronic device using anthracene derivative |
US8183793B2 (en) | 2006-08-30 | 2012-05-22 | Semiconductor Energy Laboratory Co., Ltd. | Method for synthesizing anthracene derivative and anthracene derivative, light emitting element, light emitting device, electronic device |
US8669373B2 (en) | 2008-09-19 | 2014-03-11 | Semiconductor Energy Laboratory Co., Ltd. | Carbazole derivative and method for producing the same |
US10636976B2 (en) | 2016-02-26 | 2020-04-28 | Semiconductor Energy Laboratory Co., Ltd. | Organic compound, light-emitting element, light-emitting device, electronic device, and lighting device |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0801083A2 (de) * | 1996-04-08 | 1997-10-15 | Pfizer Inc. | Funktionalisiertes Harz für die chemische Synthese |
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2000
- 2000-09-11 EP EP00960641A patent/EP1222167A2/de not_active Withdrawn
- 2000-09-11 WO PCT/EP2000/008838 patent/WO2001023353A2/de not_active Application Discontinuation
- 2000-09-11 CA CA002386074A patent/CA2386074A1/en not_active Abandoned
- 2000-09-11 JP JP2001526507A patent/JP2003510307A/ja active Pending
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KRAXNER, JOHANNES ET AL: "Traceless linking of indoles. General methodology and application to solid phase supported Mannich and Stille reactions" SYNLETT (2000), (1), 125-127 , XP002171484 * |
SMITH A L ET AL: "Traceless Solid Phase Synthesis of 2,3-Disubstituted Indoles" TETRAHEDRON LETTERS,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, Bd. 39, Nr. 45, 5. November 1998 (1998-11-05), Seiten 8317-8320, XP004139405 ISSN: 0040-4039 in der Anmeldung erw{hnt * |
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US10636976B2 (en) | 2016-02-26 | 2020-04-28 | Semiconductor Energy Laboratory Co., Ltd. | Organic compound, light-emitting element, light-emitting device, electronic device, and lighting device |
Also Published As
Publication number | Publication date |
---|---|
JP2003510307A (ja) | 2003-03-18 |
EP1222167A2 (de) | 2002-07-17 |
CA2386074A1 (en) | 2001-04-05 |
WO2001023353A3 (de) | 2002-05-02 |
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