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WO1998043973A1 - Produits intermediaires et procede pour preparer des derives de pyrimidine - Google Patents

Produits intermediaires et procede pour preparer des derives de pyrimidine Download PDF

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Publication number
WO1998043973A1
WO1998043973A1 PCT/EP1998/001760 EP9801760W WO9843973A1 WO 1998043973 A1 WO1998043973 A1 WO 1998043973A1 EP 9801760 W EP9801760 W EP 9801760W WO 9843973 A1 WO9843973 A1 WO 9843973A1
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formula
compound
salt
meanings given
lower alkyl
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German (de)
English (en)
Inventor
Marian Misun
Reto Fischer
Michael Mutz
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Novartis Pharma GmbH Austria
Novartis AG
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Novartis Erfindungen Verwaltungs GmbH
Novartis AG
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Priority to AU72103/98A priority Critical patent/AU7210398A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/12—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to hydrogen atoms

Definitions

  • the invention relates to a new process for the preparation of pharmaceutically usable pyrrolopyrimidines and salts thereof and new intermediates and salts thereof, provided that a salt-forming group is present; as well as new crystal modifications of the compounds mentioned.
  • European patent application EP 0 682027 (published on November 15, 1995) and international application WO 97/02266 (published on January 23, 1997) describe pyrrolopyrimidine compounds which have specific inhibitory effects, primarily as inhibitors of protein kinases, in particular as protein Tyrosine kinase inhibitors and / or as inhibitors of protein serine / threonine kinases, and so valuable pharmacologically usable properties, for example for the treatment of tumor diseases and / or psoriasis, but also for the treatment of other diseases on which protein -Tyrosine kinases, which are involved in signal transmission by trophic factors.
  • the two patent applications mentioned are incorporated here by reference. Insofar as these two patent applications are mentioned, the corresponding priority documents are always included, which are accessible to the public through inspection of the files.
  • the production process according to the invention has a number of unexpected advantages:
  • the production process is based on new intermediate products and is advantageously suitable for large-scale implementation directly an end product of very high purity and with a high yield and in particular in the preferred embodiments has more.
  • unexpected advantages for example controlled development of carbon dioxide instead of its abrupt release, which thus hinders the large-scale synthesis of release, Possibility of dispensing with protective groups and / or one-pot reactions in the production of certain precursors.
  • the process is therefore excellently suited for the production of pyrrolopyrimidines on an industrial scale and thus for the production of the resulting active ingredients.
  • the invention relates to surprisingly and unexpectedly found new crystal forms of pyrrolopyrimidines and processes for their preparation. These crystal formers have advantageous storage properties and are well suited for pharmaceutical formulations.
  • the invention relates primarily to a process for the preparation of a compound of the formula I,
  • n is 0 to 5; q represents 0 or 1;
  • Ri and R 2 together represent an alkylene chain with 2 to 5 carbon atoms, which is unsubstituted or substituted by lower alkyl; or
  • R 1 and R 2 together denote C -C 10 alkadienylene which is unsubstituted or by amino, lower alkanoylamino, lower alkylamino, di-lower alkylamino, nitro, halogen, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkylcarbamoyl or cyano is substituted; or Ri and R 2 together mean aza-1,4-alkadienylene with up to and including 9 carbon atoms;
  • R 3 represents halogen, lower alkyl, trifluoromethyl, lower alkoxy, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-diniederalkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino or diniederalkylamino; and
  • R 4 represents hydrogen, lower alkyl, lower alkoxycarbonyl, carbamoyl, N-lower alkyl carbamoyl or N, N-di-lower alkyl carbamoyl; or a salt of it.
  • a compound of the formula I, or a salt thereof, is prepared by the process according to the invention, in which an imino compound of the formula II,
  • R 1 and R 2 have the meanings given for compounds of the formula I, with an imino compound of the formula IV,
  • R 3 , FU, n and q have the meanings given for a compound of the formula I, in the presence of a suitable acid with an orthoformate of the formula VI,
  • R 5 is lower alkoxy or substituted lower alkoxy, wherein free functional groups in an amino compound of the formula VI, an orthoformate of the formula VI or both, which are not to take part in the reaction, are in protected form if necessary, and wherein the compound of the formula V, the compound of the formula VI or both can also be in the form of a salt if a salt-forming group is present,
  • reaction C a compound of the formula II, or a salt thereof, in which functional groups which should not participate in the reaction to a compound of the formula I can be present in protected form, is obtained by directly Amino compound of the formula V, in which R 3 , R .., n and q have the meanings given for a compound of the formula I, with an orthoformate of the formula VI, in which R 5 is lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A, as shown above, in which R 3l F, n and q have the meanings given for compounds of the formula I, and with a cyanopyrrole compound of the formula III in which R, and R 2 have the meanings given for compounds of the formula I (one-pot Reaction without isolation of intermediates, for example of the formula IV), functional groups in a cyanopyrrole compound of the formula III, an amino compound of the formula V, in an orthoformic acid ester of the formula
  • This one-pot reaction is also an object of the present invention by itself.
  • reaction B * Also an imino compound of the formula IV, in which R 3 , FU, n and q have the meanings given for compounds of the formula I and R 5 is a radical of the formula IV-A, in which Rs, Ri, n and q are those for compounds of the formula I meanings, in particular the meanings given for compounds of the formula I designated as preferred, are a preferred subject of the present invention.
  • Cyanopyrrole compounds of the formula III are known or can be prepared by processes known per se. For example, they can be produced by or analogously to a process described in European patent application EP 0 682 027 (published on November 15, 1995) or international application WO 97/02266 (published on January 23, 1997).
  • a preferred process for the preparation of a compound of the formula III, or a salt thereof, in which functional groups can be present in free or protected form, and in which R 2 and Ri have one of the meanings given for compounds of the formula I, is based on an amino acid of the formula VII
  • R T and R 2 have the meanings given for a compound of formula I; where in an amino acid of the formula VII functional groups which are not intended to take part in the reaction are, if necessary, in protected form;
  • R 2 ' is lower alkyl in the presence of a carboxylic acid of formula IX, wherein R 2 'is lower alkyl, and a tertiary nitrogen base to a compound of formula X.
  • R 1 has the meanings given for a compound of the formula I and R 2 'is lower alkyl; where in an amino acid of the formula VII functional groups which are not intended to take part in the reaction are, if necessary, in protected form;
  • reaction D * is also the subject of the present invention.
  • the hitherto unknown, unexpectedly possible addition of a carboxylic acid of the formula IX surprisingly enables the reaction in a very particularly preferred embodiment by continuous or stepwise metering
  • the invention also relates to new crystal forms of compounds of the formula I.
  • new crystal forms of the free base of the compound of the formula I in which Ri. and R 2 each represents methyl; q represents 0 (zero); n represents 1 (one); and R 3 represents chlorine in the meta position of the pheny ring relative to the binding nitrogen on the pyrrolopyrimidine ring.
  • Form II a crystal form, referred to as Form II, of the compound of formula I with the name 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, which is represented by the following main lines
  • the X-ray diagram obtained using copper K ⁇ 1 radiation with a Guinier camera is characterized: 2 ⁇ intensity
  • Form III a crystal form, referred to as Form III, of the compound of formula I with the name 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, which is represented by the following main lines
  • the X-ray diagram obtained using copper K ⁇ 1 radiation with a diffractometer is characterized:
  • Form I is the preferred of these three crystal forms due to its thermodynamic stability.
  • the crystal modifications are obtained by converting a salt of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine into the free base by contact with water; the longer the treatment, the less Form II and IM is obtained, while the longer Form I forms.
  • compounds of the formula I can be in the form of mixtures of enantiomers, for example racemates, or (in the case of 2 or more centers of asymmetry) in the form of mixtures of diastereomers, or wise in the form of an enriched, especially pure enantiomer or diastereomer.
  • n is preferably 0 or 1.
  • Lower alkyl is unbranched or has one or more branches. Preferred is n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or especially ethyl or especially methyl.
  • Halogen is preferably fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine and primarily bromine or especially chlorine.
  • Lower alkoxy is especially methoxy or ethoxy.
  • Lower alkoxycarbonyl is, for example, methoxycarbonyl.
  • Niederalkanoylamino is especially acetylamino.
  • Lower alkylamino is, for example, methylamino.
  • N, N-di-lower alkylamino is, for example, dimethylamino.
  • Lower alkanoyloxy is, for example, acetoxy.
  • N-Lower alkyl-carbamoyl is preferably N-methyl-carbamoyl, furthermore N- (n-butyl) -carbamoyl or N- (3-methyl-but-1-yl) -carbamoyl.
  • N, N-Diniederalkyl-carbamoyl is, for example, N, N-dimethyl-carbamoyl.
  • Substituted phenyl R T or R 2 may carry one or more, preferably not more than 3, substituents which are the same or different; Substituted phenyl preferably carries only one substituent which is bonded in the ortho, meta or preferably para position. Phenyl-substituted phenyl R T or R 2 is, for example, 4-biphenylyl.
  • Pyridyl is, for example, 2-pyridyl.
  • Lower alkanoyl is preferably acetyl.
  • Lower alkenyl is, for example, vinyl, prop-1-enyl or prop-2-enyl (allyl).
  • Lower alkenyloxy is, for example, vinyloxy, prop-1-enyloxy or prop-2-enyloxy (allyloxy).
  • Substituted lower alkyl R 1 or R 2 can carry one or more, preferably not more than three, substituents, which can be identical or different. Substituted lower alkyl R 1 or R 2 preferably has only one substituent.
  • R 1 or R 2 is in particular appropriately substituted methyl, for example anilino-methyl or 4-methoxyanilino-methyl.
  • Alkylene with 2 to 5 carbon atoms formed from R 1 and R 2 is an ethylene, propylene or preferably a pentiene or in particular butylene chain which is substituted or preferably unsubstituted by lower alkyl, in particular methyl or ethyl.
  • C 4 -C 1 -alkadienylene formed from R 1 and R 2 together is a divalent buta-1, 3-diene radical in which the carbon atoms with the numbers 1 and 2 have a free valence and which can be substituted by lower alkyl, where however, the bivalent radical may not have more than 10 carbon atoms in total, preferably buta-1,3-dien-1, 4-ylene.
  • Aza-1,4-alkadienylene with up to and including 9 carbon atoms is C 4 -C 10 -1,4-alkadienylene, as defined above, in which at least one carbon atom of the butadiene chain, in particular a terminal carbon atom of the butadiene chain, is replaced by nitrogen, for example 1-aza-1,4-alkadienylene, in particular 1-aza-buta-1,3-diene-1,4-ylene.
  • Aza-1,4-alkadienylene preferably contains 1 to three carbon atoms, especially one.
  • 1-aza-1,4-alkadienylene with only one nitrogen atom is preferably bonded via this nitrogen atom to carbon atom 6 of the 7H-pyrrolo [2,3-d] pyrimidine ring system.
  • Salts are primarily the pharmaceutically usable salts of compounds of the formula I or intermediates of the formula II, the formula III, the formula IV, the formula V, the formula VI, the formula VII or the formula X (and also other starting compounds or intermediates ) if there is a salt-forming group.
  • Such salts are formed, for example, from the end products of the formula I or the intermediates of the last-mentioned formulas with a basic nitrogen atom as acid addition salts, preferably with organic or inorganic acids, in particular the pharmaceutically usable salts.
  • Suitable inorganic acids are, for example, hydrohalic acids, such as hydrochloric acid; Sulfuric acid; Nitric acid; Carbonic acid; or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfonamic acids, for example acetic acid, trifluoroacetic acid, propionic acid, octanoic acid, pivalic acid, decanoic acid, dodecanoic acid, stearic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucose monocarboxylic acid, fumaric acid, fumaric acid , Adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, acetone dicarboxylic acid, amino acids such as glutamic acid, aspartic acid, N-methylglycine, acetyiaminoacetic acid, N-acetylasparaginic acid, n-acetytraceticinic acid, N-acetytracosinic acid, N-ace
  • salts can also be formed with bases, e.g. Metal or ammonium salts such as alkali metal or alkaline earth metal salts, e.g. Sodium, potassium, magnesium or calcium salts or ammonium salts with ammonia or suitable organic amines such as tertiary monoamines, e.g. Triethylamine or tri- (2-hydroxyethyl) amine, or heterocyclic bases, e.g. N-ethyl-piperidine or N, N'-dimethyl-piperazine.
  • bases e.g. Metal or ammonium salts such as alkali metal or alkaline earth metal salts, e.g. Sodium, potassium, magnesium or calcium salts or ammonium salts with ammonia or suitable organic amines such as tertiary monoamines, e.g. Triethylamine or tri- (2-hydroxyethyl) amine, or heterocyclic bases, e.g. N-ethyl-pipe
  • a compound of the formula I or one of the intermediates mentioned can also form internal salts.
  • Lower alkoxy R 5 or R 5 ' is preferably ethoxy.
  • Substituted lower alkoxy R 5 or R 5 ' is preferably methyl or ethyl substituted by aryl, such as phenyl, by lower alkoxy, such as methoxy, or further by any other substituent.
  • the invention preferably relates to the preparation of a compound of the formula I in which
  • R 2 is lower alkyl, especially methyl, or hydrogen; especially methyl;
  • R 3 is halogen, in particular halogen bonded in the meta position to the phenyl ring, especially chlorine, or hydrogen;
  • R 4 is lower alkyl, especially methyl; or a salt of it.
  • Ri is lower alkyl, especially methyl
  • R 2 is lower alkyl, especially methyl
  • R 3 in the meta position on the phenyl ring is halogen, especially chlorine
  • R 4 is lower alkyl, especially methyl; or a salt thereof.
  • a preferred intermediate of formula II according to the invention is a compound of formula II, wherein n represents 0 or 1; q represents 0 or 1;
  • R T denotes lower alkyl, in particular methyl, hydroxyphenyl, in particular 4-hydroxyphenyl, lower alkanoylaminophenyl, in particular 4-acetylaminophenyl, or N-lower alkylcarbamoyl, in particular N-methylcarbamoyl; especially methyl;
  • R 2 is lower alkyl, especially methyl, or hydrogen; especially methyl;
  • R 3 is halogen, in particular halogen bonded in the meta position to the phenyl ring, especially chlorine, or hydrogen;
  • R 4 is lower alkyl, especially methyl; or a salt of it.
  • i is lower alkyl, especially methyl
  • R 2 is lower alkyl, especially methyl
  • R 3 in the meta position on the phenyl ring is halogen, especially chlorine
  • R 4 is lower alkyl, especially methyl; or a salt of it.
  • R 1 is lower alkoxy, substituted lower alkoxy or a radical of formula IV-A as defined above, preferably methoxy or a radical of formula IV-A, wherein n, y, R 3 and R 4 are those for compounds of the formula I have meanings, preferably the meanings mentioned above and below as preferred.
  • R 5 'in a compound of formula VI is lower alkoxy or substituted lower alkoxy, especially methoxy.
  • R 2 'in a compound of the formulas VIII, IX or X is lower alkyl, in particular methyl, and corresponds to the corresponding radical R 2 in a compound of the formula I.
  • Starting materials and intermediates can be used in pure form, for example after working up, in partially purified form or, for example, directly as a crude product.
  • the free compounds or their salts are also to be understood as meaningful and expediently the corresponding salts or free compounds if the compounds contain salt-forming groups.
  • the compounds, including their salts, can also be obtained in the form of hydrates, or their crystals can e.g. include a solvent used for crystallization (solvates).
  • Functional groups that should not participate in a reaction are present in protected form in the starting and intermediate products. If one or more further functional groups, for example carboxy, hydroxy, amino or mercapto, are or must be in protected form because they should not be involved in the reaction, they are those which are customarily used in the synthesis of peptide compounds, but can also be used by cephalosporins and penicillins as well as nucleic acid derivatives and sugars. These protective groups can already be present in the precursors and are intended to protect the functional groups in question against undesired side reactions such as acylations, etherifications, esterifications, oxidations, solvolysis and the like.
  • the protective groups can also bring about a selective, for example stereoselective, course of reactions. It is characteristic of protective groups that they can be easily split off, ie without undesired side reactions, for example solvolytically, photolytically or also enzymatically, for. B. also under physiological conditions; or also reductively, functional groups then having to be reintroduced for further reactions after one of the reductions and / or hydrogenations mentioned above.
  • the person skilled in the art knows or can easily find out which protective groups are suitable in the reactions mentioned above and below.
  • protective groups that they are easy, i. H. can be split off without undesired side reactions, for example solvolytically, reductively, photolytically or also enzymatically, e.g. B. also under physiological conditions analogous conditions, and that they are not present in the end products.
  • a carboxy group is e.g. B. protected as an ester group that is selectively cleavable under mild conditions.
  • a carboxy group protected in esterified form is primarily esterified by a lower alkyl group which is preferably branched in the 1-position of the lower alkyl group or substituted in the 1 - or 2-position of the lower alkyl group by suitable substituents.
  • a protected carboxy group which is esterified by a lower alkyl group is, for example, methoxycarbonyl or ethoxycarbonyl.
  • a protected amino group is protected by an amino protecting group, e.g. B. in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group or as an azido group.
  • an amino protecting group e.g. B. in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group or as an azido group.
  • acyl is preferably lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl.
  • the protecting groups which are not part of the desired end product of the formula I or of intermediate compounds, are split off in a manner known per se, e.g. B. by means of solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by means of reduction, in particular hydrogenolysis or by means of other reducing agents, and photolysis, if appropriate stepwise or simultaneously, it being also possible to use enzymatic methods.
  • the splitting off of the protective groups is described, for example, in the standard works mentioned earlier in the section on "Protective Groups".
  • salts of compounds of the formula I or starting compounds or intermediates with a salt-forming group can be prepared in a manner known per se. For example, their acid addition salts can be obtained by treatment with an acid or a suitable anion exchange reagent. In particular, the acids mentioned in the definition of salts are used as acids. Salts of a compound of formula I, a starting compound or an intermediate with an acidic group, e.g. a carboxy group, can be treated, for example, by treatment with a metal compound, e.g.
  • an alkali metal salt of a suitable organic carboxylic acid such as an alkali metal salt of 2-ethyl-hexanoic acid, an alkali - or alkaline earth metal salt of an inorganic acid, such as a hydroxide, carbonate or hydrogen carbonate, for example sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate or with ammonia or a suitable organic amine, preferably the stoichiometric amount or an excess of salt-forming agent can be used.
  • Salts can be converted into the free compounds in a conventional manner, for example by treatment with a suitable basic agent, for example with alkali metal carbonates, bicarbonates or hydroxides, for example potassium carbonate or sodium hydroxide.
  • the free compounds of formula I can also be obtained from a salt of a compound of formula I as an alternative to conversion with a metal salt, ammonia or an organic amine by contact with water without treatment with a basic agent.
  • the conversion of a salt of a compound of the formula I to a free compound of the formula I then preferably takes place at a temperature between -5 ° C. and the reflux temperature of the reaction mixture.
  • a salt of a compound of the formula I (solid, as a suspension or as a solution in a suitable solvent or solvent mixture) is admixed with water or a water-containing solvent in such a way that the free compounds of the formula I can form in various crystal modifications.
  • Suitable solvents for this process are: water, aqueous acids, such as aqueous inorganic acids, for example hydrochloric acid, aqueous buffers, for example phosphate buffers, ketones, such as acetone, methyl isopropyl ketone or methyl isobutyl ketone, nitriles, such as acetonitrile, alcohols, for example C1-C10 Alkanols, such as methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, amyl alcohol or octanol, diols, such as ethylene glycol, unsubstituted or substituted by lower alkyl, hydroxy or oxo-cyclic hydrocarbons, such as cyclohexane, methylcylohexane, Cyclohexanoi and cyclohexanone, Ethers, such as die
  • Crystal modifications of the free base of a compound of the formula I can be achieved, for example, by adding a salt of a compound of the formula I, in particular 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine, converted to the free base by contact with water.
  • a salt of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, in particular the methanesulfonate salt is preferably added a temperature between room temperature and the reflux temperature of the reaction mixture.
  • a salt of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, especially the methanesulfonate salt preferably at a temperature between 20 and 30 ° C, in particular at about 25 ° C, preferably suspended in a water-containing solvent for about 20 or less than 20 hours, are converted into the corresponding free base as crystal modification II and IM.
  • the appropriate solvents can be found in the previous section.
  • Mixtures of stereoisomers e.g. B. mixtures of diastereomers can be separated into the corresponding isomers in a manner known per se by suitable separation processes. Diastereomer mixtures can thus be separated into the individual diastereomers by fractional crystallization, chromatography, solvent distribution and the like. This separation can take place both at the stage of one of the starting products and in the compounds of the formula I itself.
  • Enantiomers in mixtures of enantiomers can be separated by formation of diastereomeric salts, for example by salt formation with an enantiomerically pure chiral acid, or by chromatographic means, for example by chromatography, for example HPLC, using chromatographic support materials with chiral ligands.
  • the rearrangement of a compound of formula II into a compound of formula I is preferably carried out at elevated temperature, in particular at temperatures between 40 ° C. and the reflux temperature of the reaction mixture, in a suitable solvent or solvent mixture, in particular in water, an aqueous alkali, for example an aqueous one Alkali metal or ammonium hydroxide solution, such as aqueous sodium hydroxide, potassium hydroxide or ammonia, an aqueous acid, such as an aqueous inorganic acid, for example hydrochloric acid, a ketone, such as acetone, methyl isopropyl ketone or methyl isobutyl ketone, a nitrile, such as acetonitrile, an alcohol, for example ad-C 10 -alkanol, such as methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, amyl alcohol or
  • a cyanopyrrole compound of the formula III takes place at a preferred temperature between 0 and 200 ° C, in particular between 20 and 60 ° C, for example between room temperature and approximately 40 ° C; with the addition of an acid, in particular to adjust a pH between 3 and 10, especially between 5 and 8, the acid preferably being a carboxylic acid, for example a lower alkanoic acid, such as formic or acetic acid, or a pyridinecarboxylic acid, such as nico- tic acid, a suifonic acid, for example a lower alkanesulfonic acid, such as methane or ethanesulfonic acid, or an arylsulfonic acid, such as toluene-4-sulfonic acid, or further one of the other acids mentioned in the definition of salts; or a salt of such an acid with a nitrogen base, in particular a tertiary or quaternary nitrogen base, such as a
  • the reaction of an amino compound of the formula V with an orthoformic acid ester of the formula VI is preferably carried out at elevated temperature, in particular a temperature between 50 ° C. and the boiling point of the corresponding reaction mixture, in particular an existing solvent being distilled off while continuously or gradually increasing the temperature in the range given ; in the presence of a suitable acid, in particular a carboxylic acid, for example a lower alkanoic acid, such as formic or acetic acid, or a pyridinecarboxylic acid, such as nicotinic acid, a suifonic acid, for example a lower alkanesulfonic acid, such as methane or ethanesulfonic acid, or an arylsulfonic acid, such as toluene-4-sulfonic acid , or one of the other acids mentioned in the definition of salts; or a salt of such an acid with a nitrogen base, in particular a tertiary or quaternary nitrogen base, such as an unsubstituted
  • reaction serves to prepare a substituted formimidate of the formula IV, in which R 5 is lower alkoxy or substituted lower alkoxy and the other radicals have the meanings given for formula IV
  • one of the salts mentioned in a nitrogen base, in particular pyridinium is preferably used for the reaction -4- sulfonate.
  • the preferred one-pot reaction involving the reaction of an amino compound of the formula V, as defined above, with an orthoformate of the formula VI, as defined above, and with a cyanopyrrole compound of the formula IM, as defined above, to give a corresponding compound of the formula II is carried out in particular at a temperature between 0 and 100 ° C, especially between 20 and 60 ° C, in particular at about 40 ° C, in the presence of a suitable acid, in particular a carboxylic acid, for example a lower alkanoic acid, such as formic or acetic acid, or a pyridinecarboxylic acid, such as nicotinic acid, a suifonic acid, for example a lower alkanesulfonic acid, such as methane or ethanesulfonic acid, or an arylsulfonic acid fonic acid, such as toluene-4-sulfonic acid, or one of the other acids mentioned in the definition of salts; or a salt of such an
  • the particularly preferred one-pot reaction also forming an object of the present invention, of a cyanopyrrole compound of the formula IM, in which R 1 and R 2 have the meanings given for compounds of the formula I, with an imino compound of the formula IV, in which R 3 , P H , n and q have the meanings given for compounds of the formula I and R 5 denotes a radical of the formula IV-A, in which R 3 , R- ⁇ , n and q have the meanings given for compounds of the formula I, to give a compound of the formula II is preferably carried out at a preferred temperature between 0 and 200 ° C, in particular between 20 and 60 ° C, for example between room temperature and approximately 40 ° C; with the addition of an acid, in particular to adjust a pH between 3 and 10, especially between 5 and 8, the acid preferably a carboxylic acid, for example a lower alkanoic acid, such as formic or acetic acid, or a pyridinecarboxylic acid, such as nico
  • halogen is preferably fluorine or chlorine; activated aryloxy preferably means a conventional radical for activated esters, for example nitrophenyl, such as 4-nitrophenyl or 2,4-dinitrophenyl.
  • activated aryloxy preferably means a conventional radical for activated esters, for example nitrophenyl, such as 4-nitrophenyl or 2,4-dinitrophenyl.
  • the amino acid of the formula VIII * can be in the D, L or (preferably) D, L form.
  • the tertiary nitrogen base used is preferably an unsubstituted or mono- or bicyclic heterocycle having 3 to 14, in particular 4 to 10 ring nitrogen atoms and at least one ring nitrogen atom, for example substituted by lower alkyl or di-lower alkylamino, preferably a corresponding monocycle with at least one ring nitrogen atom, preferably 1 to 3 nitrogen atoms , for example pyridine, picoline, such as 2-, 3- or 4-picoline, di-lower alkylaminopyridine, such as 2,6-lutidine, 4- (N, N-dimethylamino) pyridine; or a tri-lower alkylamine such as triethylamine; or a mixture of these nitrogen bases, for example of triethylamine
  • the amino acid of the formula VIII * can be in the D, L or (preferably) D, L form.
  • the reaction can be carried out according to variant (i) or (ii).
  • the metering is metered in evenly or in portions over a longer period (which depends in particular on the total amount of the reaction mixture), for example over one or more hours, e.g. with a size of the batch after adding all components of about 0.5 liters over an hour.
  • Mixtures of the reagents can be present as solutions or suspensions.
  • the reaction of a compound of formula X, in particular X *, in which the radicals have the meanings given under formula X or X *, with malononitrile in the presence of a base is preferably carried out at a temperature between above the melting temperature of the reaction mixture and 100 ° C., in particular between about 0 and 30 ° C, in a suitable solvent or solvent mixture, for example water, a ketone, such as acetone, methyl isopropyl ketone or methyl isobutyl ketone, a nitrile, such as acetonitrile, an alcohol, for example a CrCno-alkanol, such as methanol, Ethanol, propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, amyl alcohol or octanol, a diol such as ethylene glycol, an unsubstituted or substituted by lower alkyl,
  • reaction conditions are preferably replaced by the conditions mentioned above for the corresponding specific reaction conditions.
  • reaction A rearranging a compound of the formula II obtained into a compound of the formula I in a suitable solvent or solvent mixture at elevated temperature
  • starting and intermediate compounds which may also be in the form of salts, provided that at least one salt-forming group is present, functional groups which are not intended to take part in the reaction are, if necessary, in protected form and protective groups which are no longer required are eliminated at a suitable reaction stage, and, if desired, intermediates obtainable as a free compound are also converted into the corresponding salts, intermediates obtainable as salts can be converted into the free compound or another salt, and / or, in the case of a mixture of isomers of an intermediate which is obtainable, carries out a separation into isomers;
  • R T and R 2 have the meanings given for compounds of the formula I, with an imino compound of the formula IV obtainable by the previous reaction,
  • R, R 4 , n and q have the meanings given for compounds of the formula I and R 5 is lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A
  • reaction A rearranging a compound of the formula II obtained into a compound of the formula I in a suitable solvent or solvent mixture at elevated temperature
  • starting and intermediate compounds which may also be in the form of salts, provided that at least one salt-forming group is present, functional groups which are not intended to take part in the reaction are, if necessary, in protected form and protective groups which are no longer required are eliminated at a suitable reaction stage, and, if desired, intermediates obtainable as a free compound are also converted into the corresponding salts, intermediates obtainable as salts can be converted into the free compound or another salt, and / or, in the case of a mixture of isomers of an intermediate which is obtainable, carries out a separation into isomers;
  • starting and intermediate compounds which may also be in the form of salts, provided that at least one salt-forming group is present, functional groups which are not intended to participate in the reaction are, if necessary, in protected form and protective groups which are no longer required are eliminated at a suitable reaction stage, and, if desired, intermediates obtainable as a free compound are also converted into the corresponding salts, intermediates obtainable as salts can be converted into the free compound or another salt, and / or, in the case of a mixture of isomers of an intermediate which is obtainable, carries out a separation into isomers;
  • reaction D reacted (reaction D), wherein R T and R 2 have the meanings given for a compound of the formula I;
  • R 3 , R, n and q have the meanings given for compounds of the formula I and R 5 is lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A
  • reaction A rearranging a compound of the formula II obtained into a compound of the formula I in a suitable solvent or solvent mixture at elevated temperature (reaction A), wherein an imino compound of formula IV is prepared by using an amino compound of formula V,
  • DSC melting points are determined with a PERKIN-ELMER DSC7 using a DSC thermogram.
  • DSC is the technique of dynamic differential calorimetry. With this technique it is possible to measure the melting temperature by heating the sample only until a thermal event, i.e. an endothermic or exothermic sensation.
  • the DSC melting points specified in this text are measured on a PERKIN-ELMER DSC7, with approximately 1.5 to 2.5 mg of the respective sample being weighed into an aluminum crucible under an ambient air atmosphere and measured at a heating rate of 10 K / min (start at 30 ° C.) become.
  • Crystal modifications can be distinguished by their X-ray diagrams.
  • X-ray diagrams recorded with a diffractometer or a Guinier camera in transmission geometry and using Cu-K ⁇ 1 radiation, are preferably used to characterize solids of organic substances.
  • X-ray diffraction diagrams are successfully used to determine the crystal modification of a substance.
  • the measurements in the angular range (2 ⁇ ) of 2 ° and 35 ° are carried out with substance samples which were kept at room temperature.
  • Variant 2 A mixture of 250 ml (2.64 mol) of acetic anhydride, 420 ml (3.0 mol) of triethylamine, 35 ml (0.6 mol) of acetic acid and 1.47 g (12 mmol) of 4-dimethylaminopyridine is added at 45-50 ° within 6 hours C 108 g (1.2 mol) alanine metered in, which is accompanied by a continuous gas evolution. When the addition is complete, stirring is continued at 45 ° C. for 12 h. The solvent mixture is then distilled off in vacuo and crude 3-acetylamino-2-butanone is obtained in the form of a reddish-brown oil. It can be used in the next stage without further cleaning.
  • the crude 3-acetylamino-2-butanone from Example 1 is dissolved in 250 ml of water and 33 g (0.5 mol) of malononitrile are added at RT.
  • the brown solution is cooled to 0 ° C. and, with vigorous stirring, 157 ml (3.0 mol) of a 50% strength aqueous sodium hydroxide solution are added for 20-30 min, which is accompanied by heating.
  • the resulting suspension is stirred for 15 min at 0 ° C and then poured onto 600 ml of ice water. After stirring at 0 ° C. for 1 h, the mixture is filtered off and washed with water.
  • Example 4 3-f3-chlorophenyl) -5,6-dimethyl-4H-pyrrolor2.3-dlpyrimidin-4-imine
  • Ethanol is added to 71.5 g (0.4 mol) of the crude ethyl N- (3-chlorophenyl) formimidate from Example 3/1.
  • the pH is adjusted to 8.0 by adding a 10% solution of pyridinium (toluene-4-sulfonate) in ethanol.
  • the suspension is stirred at RT for 24 h, after which 60 ml of water are added.
  • Variant 2 A suspension of 3.0 g (22.19 mmol) of 2-amino-3-cyano-4,5-dimethylpyrrole in 50 ml of ethanol is mixed with 6.5 g (24.51 mmol) of N, N'- Bis- (3-chlorophenyl) formamidine (Example 3/2) and 0.10 ml (1.6 mmol) acetic acid were added and the mixture was stirred at RT for 5 h. 5 ml of water are then added, the mixture is cooled to 0 ° C. and filtered off. The filtrate is washed with ethanol / water (4: 1).
  • Variant 3 A suspension of 25 g (0.2 mol) of 2-amino-3-cyano-4,5-dimethylpyrrole in 75 ml abs. Ethanol, 47 ml (0.3 mol) of triethyl orthoformate and 23 ml (0.2 mol) of 3-chloroaniline are mixed with 0.81 ml (12.86 mmol) of anhydrous acetic acid and heated to 40.degree. After 4 hours of stirring at 40 ° C., the mixture is cooled in an ice bath and then filtered off.
  • Example 5 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo r 2,3-d] pyrimidine 300 g (1.1 mol) 3- (3-chlorophenyl) -5,6-dimethyl -4H-pyrrolo [2,3-d] pyrimidin-4-imine are suspended in 750 ml of water, 750 ml of ethanol and 1500 ml of ethylene glycol and heated to reflux (95 ° C.) within about 2 hours. The suspension is boiled at 95 ° C. for 3 hours and then cooled to 25 ° C. within 90 minutes. The mixture is stirred for 1 h, the product is filtered off and washed with water.
  • Crystal modification of the 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine obtained in the following, called Form I melts at a heating rate in the DSC of 10 ° C./min Interval of 240 ° C and 255 ° C with a melting point range from and with 244 ° C to and with 250 ° C.
  • the crystal modifications referred to below as Form II and Form IM are less stable and are converted into the crystal modification Form I when heated.
  • Tables 1, 2 and 3 show the X-ray diffraction diagrams of the crystal modifications Form I, Form II and Form IM.
  • Table 1 X-ray diffraction diagram (reflection lines and intensities of the most important lines) of the crystal modification Form I of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolor2.3-dlpyrimidine (recorded with a X-ray diffractometer).
  • Variant 2 20 g (0.054 mol) of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine methanesulfonate (Example 6) are suspended in 400 ml of water and for 10 h stirred at 25 ° C. The product is filtered and washed with water. After drying under high vacuum, 12.6 g (0.046 mol, 85%) of 4- (3-chlorophenylamino) - 5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine are obtained in the form of white crystals. (NMR data as above). The crystal modification of the product is characterized by the X-ray diffraction pattern of Form I. The same compound can be obtained in two further crystal modifications as follows:
  • Variant 3 75 mg (0.0002 mol) of 4- (3-chlorophenyiamino) -5,6-dimethyl-7H-pyrrolo [2,3-djpyrimidine methanesulfonate (Example 6) are suspended in 20 ml of water and for 20 h stirred at 25 ° C. The product is filtered and dried in room air. 4- (3-Chlorophenylamino) -5,6-dimethyl-7H-pyrroio [2,3-d] pyrimidine methanesulfonate is obtained in the form of white crystals (NMR data as above). It is found that the product obtained in this way is present in a further crystal form in addition to the crystal forms Form I and Form IM.
  • Form II is characterized by the X-ray diffraction pattern shown in Table 2 below.
  • Table 2 X-ray diffraction diagram (reflection lines and intensities of the most important lines, recorded with a Guinier camera) of the crystal modification Form II of 4- (3-chlorophenylamino) -5.6-dimethyl-7H-pyrrolof2.3-dlpyrimidine.
  • Variant 4 20 g (0.054 mol) of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-djpyrimidine methanesulfonate (Example 6) are suspended in 400 ml of water and while Stirred at 25 ° C for 2 h. The product is filtered and washed with water. After drying under high vacuum, 12.6 g (0.046 mol, 85%) of 4- (3-chlorophenylamino) - 5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine are obtained in the form of white crystals. (NMR data as above). It was found that the product obtained in this way is in a crystal modification which is different from Form I and Form, namely Form III. .. Form III is characterized by the following X-ray diffraction pattern (Table 3):
  • Table 3 X-ray diffraction diagram (reflection lines and intensities of the most important lines) of the crystal modification Form IM of 4- (3-chlorophenylamino) -5.6-dimethyl-7H-pyrrolo [2.3-dlpyrimidine.
  • Example 6 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2.3-d] pyrimidine methanesulfonate 50 g (0.18 mol) 4- (3-chlorophenylamino) -5,6-dimethyl- 7H-pyrrolo [2,3-d] pyrimidine are suspended in 650 ml of 97% ethanol, and 18.6 g (0.19 mol) of methanesulfonic acid are added at RT. The yellow suspension is heated to reflux, a clear light yellow solution being formed. The solution is filtered, boiled briefly again and then cooled to 0 ° C. within 2 h.
  • the suspension formed is stirred for 2 h at 0 ° C., filtered off and washed with cold abs. Washed ethanol. After drying the product, 61.9 g (0.17 mol, 92%) of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine methanesulfonate are obtained in the form of colorless crystals.
  • the product melts at a DSC heating rate of 10 ° C / min in an interval of 207 ° C and 225 ° C with a melting point range from and with 215 ° C to and with 222 ° C.
  • the 4- (3-chlorophenylamino) -5.6-dimethvl-7H-pvrrolof2,3-dlpyrimidine methanesulfonate can be recrystallized according to the following procedure: 16 g (0.04 mol) of crude 4- (3-chloro-henylamino) -5,6 -dimethyl-7H-pyrrolo [2,3-d] pyrimidine methane sulfonate are suspended in 580 ml acetone / water 95: 5 and heated to reflux. The solution formed is filtered, boiled briefly and then crystallized by cooling to 2 ° C. within 3 h. It is filtered off, washed with cold acetone and dried in a high vacuum.
  • Example 8 3- (2-Chlorophenvh-5.6-dimethyl-4H-pyrrolof2.3-dlpyrimidin-4-imine 19.2 g (0.14 mol) of 2-amino-3-cyano-4,5-dimethylpyrrole from Example 2 is suspended in 120 ml of absolute ethanol and heated to 50 ° C. 31 g (0.17 mol) of N- (2-chlorophenyl) formimidic acid ethyl ester from Example 7 are added and the solution is allowed to slowly cool to RT.
  • Example 9 4- (2-chlorophenylamino) -5,6-dimethyl-7H-pyrrolof2.3-c ⁇ pyrimidine 15 g (55 mmol) 3- (2-chlorophenyl) -5,6-dimethyl-4H-pyrrolo [2,3- d] pyrimidin-4-imine are suspended in 135 ml of ethylene glycol and 15 ml of water and heated to 100 ° C. within 1 h. The suspension is stirred at 100 ° C. for 40 min and then cooled to RT within 3 h. It is cooled in an ice bath, filtered off and washed with water.
  • Example 10 4- (2-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2.3-d] pyrimidine methanesulfonate 6 g (22 mmol) 4- (2-chlorophenylamino) -5,6-dimethyl-7H- pyrrolo [2,3-d] pyrimidine are suspended in 67 ml of 97% ethanol, and 2.33 g (24 mmol) of methanesulfonic acid are added at RT. The solution is heated to reflux, filtered hot and, after boiling again briefly, slowly cooled to 0 ° C. within 2 h.
  • Example 12 3- (4-Chlorophenv ⁇ -5.6-dimethyl-4H-pyrrolof2.3-dlpyrimidin-4-imine 113.5 g (0.8 mol) of 2-amino-3-cyano-4,5-dimethylpyrrole from Example 2 are suspended in 730 ml of absolute ethanol and heated to 50 ° C. 184 g (1.0 mol) of the crude ethyl N- (4-chlorophenyl) formimidate from Example 11 are added to the suspension Heated to 55 ° C. and cooled to RT within 4 h and then stirred for 16 h at 25 ° C.
  • the pH is adjusted to 8.0 by adding a 10% solution of pyridinium (toluene-4-sulfonate) in ethanol
  • the mixture is stirred at RT for a further 24 h, 420 ml of ethanol / water (1: 1) are added and the mixture is cooled to -10 ° C.
  • the mixture is then stirred for 1 h at -10 ° C. and the product is filtered off / Water (4: 1), dried and obtained as yellow crystals (216 g, 94%) (0.8 mol), mp. 185-193 ° C.
  • Example 13 4- (4-chlorophenylamino) -5,6-dimethyl-7H-pyrrolor2.3-dlpyrimidine 15 g (55 mmol) 3- (4-chlorophenyl) -5,6-dimethyl-4H-pyrrolo [2,3- d] pyrimidin-4-imine are suspended in 135 ml of ethylene glycol and 15 ml of water and heated to 110 ° C. within 30 minutes. The suspension is stirred at 110 ° C. for 17 h, cooled to 5 ° C. and then filtered off. The product is washed with water and dried.
  • the 4- (4-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine obtained can be recrystallized according to the following procedure: 104 g of 4- (4-chloropheny! Amino) -5,6- dimethyl-7H-pyrrolo [2,3-d] pyrimidine are suspended together with 5.2 g of activated carbon in a mixture of 4300 ml of tetrahydrofuran and 2500 ml of water and heated to reflux. The suspension is filtered, boiled briefly and then crystallized by cooling to 2 ° C. within 3 h. After filtration of the product, cold abs. Washed ethanol and dried in a high vacuum.
  • Example 14 4- (4-chlorophenylamino) -5,6-dimethyl-7H-pyrrolof2.3-dlpyrimidine methanesulfonate 6 g (22 mmol) 4- (4-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2, 3-d] pyrimidine are suspended in 130 ml of ethanol 97% and mixed with 2.33 g (24 mmol) of methanesulfonic acid. The mixture is heated to reflux, the solution is filtered, briefly heated to reflux and cooled to RT within 2 h. After cooling in an ice bath, the mixture is filtered off with abs. Washed and dried ethanol.

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  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un nouveau procédé permettant de préparer un composé de la formule (I) ou un de ses sels. Dans cette formule, les restes ont les significations mentionnées dans la description. Ce procédé concerne un nouveau composé intermédiaire de la formule (II) dans laquelle les restes ont les significations mentionnées dans la description. Ledit composé intermédiaire peut également figurer sous forme de sel ou sous une forme protégée. L'invention concerne également de nouvelles formes cristallines de la formule (I) et leur préparation. Les composés de la formule (I) sont efficaces sur le plan pharmacologique, par exemple pour lutter contre des maladies à évolution chronique.
PCT/EP1998/001760 1997-03-27 1998-03-25 Produits intermediaires et procede pour preparer des derives de pyrimidine Ceased WO1998043973A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6927219B2 (en) 2001-11-12 2005-08-09 Pfizer Inc. N-alkyl-adamantyl triazinyl benzamide derivatives
US6943174B2 (en) 2000-06-14 2005-09-13 Warner-Lambert Company 6,5-Fused bicyclic heterocycles
US7176202B2 (en) 2002-12-31 2007-02-13 Pfizer Inc. Benzamide inhibitors of the P2X7 receptor
US7186742B2 (en) 2003-05-12 2007-03-06 Pfizer Inc Benzamide inhibitors of the P2X7 receptor
US7214677B2 (en) 2001-11-12 2007-05-08 Pfizer Inc. Benzamide, heteroarylamide and reverse amides
US7244729B2 (en) 2001-08-07 2007-07-17 Novartis Ag 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives
US7323469B2 (en) 2001-08-07 2008-01-29 Novartis Ag 7H-pyrrolo[2,3-d]pyrimidine derivatives
US7465726B2 (en) 2004-08-02 2008-12-16 Osi Pharmaceuticals, Inc. Substituted pyrrolo[2.3-B]pyridines
CN106008305A (zh) * 2016-06-06 2016-10-12 陕西师范大学 一种五取代2-氨基吡咯衍生物的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5980470A (ja) * 1982-10-29 1984-05-09 Konishiroku Photo Ind Co Ltd オキソノ−ル染料の製造方法
WO1997002266A1 (fr) * 1995-07-06 1997-01-23 Novartis Ag Pyrrolopyrimidines et leurs procedes de preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5980470A (ja) * 1982-10-29 1984-05-09 Konishiroku Photo Ind Co Ltd オキソノ−ル染料の製造方法
WO1997002266A1 (fr) * 1995-07-06 1997-01-23 Novartis Ag Pyrrolopyrimidines et leurs procedes de preparation

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
A.JORGENSEN ET AL.: "PHOSPHOROUS PENTOXIDE IN ORGANIC SYNTHESIS.VIII.", CHIMICA SCRIPTA, vol. 23, no. 2, 1984, SWEDEN, pages 73 - 79, XP002075952 *
A.JORGENSEN ET AL.: "PHOSPHOROUS PENTOXIDE IN ORGANIC SYNTHESIS.XX.", JOURNAL OF HETEROCYCLIC CHEMISTRY., vol. 85, no. 22, May 1985 (1985-05-01), PROVO US, pages 859 - 863, XP002075951 *
BOLL. CHIM. FARM., vol. 107, no. 7, 1968, ITALY, pages 401 - 410 *
CHEMICAL ABSTRACTS, vol. 101, no. 20, 1984, Columbus, Ohio, US; abstract no. 173040v, page 92; column 2; XP002075956 *
CHEMICAL ABSTRACTS, vol. 69, no. 23, 1968, Columbus, Ohio, US; abstract no. 96637m, M.RIDI ET AL.: "SYNTHESIS AND BIOLOGICAL ACTIVITY OF AMIDINES" page 9048; XP002075958 *
CHEMICAL ABSTRACTS, vol. 98, no. 17, 1983, Columbus, Ohio, US; abstract no. 143141f, page 552; column 2; XP002075955 *
CL.TAUBER ET AL.: "EIN BETRAG ZUR CHEMIE DES 2,3-DIH.-3-OXO-BENZO(B)THIOPHEN-1,1-DIOXIDS", MONATSHEFTE FUR CHEMIE., vol. 121, no. 4, 1990, WIEN AT, pages 299 - 308, XP002075953 *
J.OSEK ET AL.: "GAS CHROMATOGRAPHIC ANALYSIS OF TAUTOMERIZING AMIDINES", JOURNAL OF CHROMATOGRAPHY., vol. 369, no. 2, 1986, AMSTERDAM NL, pages 398 - 402, XP002075954 *
V.VSETECKA ET AL.: "CONFIGURATION AND CONFORMATION OF N,N' DIARYLAMIDINES.", COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS., vol. 58, no. 1, 1993, PRAGUE CS, pages 105 - 112, XP002076662 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6943174B2 (en) 2000-06-14 2005-09-13 Warner-Lambert Company 6,5-Fused bicyclic heterocycles
US7323469B2 (en) 2001-08-07 2008-01-29 Novartis Ag 7H-pyrrolo[2,3-d]pyrimidine derivatives
US7390805B2 (en) 2001-08-07 2008-06-24 Novartis Ag 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives
US7244729B2 (en) 2001-08-07 2007-07-17 Novartis Ag 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives
US6927219B2 (en) 2001-11-12 2005-08-09 Pfizer Inc. N-alkyl-adamantyl triazinyl benzamide derivatives
US7214677B2 (en) 2001-11-12 2007-05-08 Pfizer Inc. Benzamide, heteroarylamide and reverse amides
US7235549B2 (en) 2001-11-12 2007-06-26 Pfizer Inc. Benzamide, heteroarylamide and reverse amides
US7407956B2 (en) 2002-12-31 2008-08-05 Pfizer, Inc. Benzamide inhibitors of the P2X7 receptor
US7176202B2 (en) 2002-12-31 2007-02-13 Pfizer Inc. Benzamide inhibitors of the P2X7 receptor
US7186742B2 (en) 2003-05-12 2007-03-06 Pfizer Inc Benzamide inhibitors of the P2X7 receptor
US7553972B2 (en) 2003-05-12 2009-06-30 Pfizer, Inc. Benzamide inhibitors of the P2X7 receptor
US7465726B2 (en) 2004-08-02 2008-12-16 Osi Pharmaceuticals, Inc. Substituted pyrrolo[2.3-B]pyridines
CN106008305A (zh) * 2016-06-06 2016-10-12 陕西师范大学 一种五取代2-氨基吡咯衍生物的合成方法

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