WO2012127472A1 - Procédé et intermédiaires pour la préparation du préladenant et composés associés - Google Patents

Procédé et intermédiaires pour la préparation du préladenant et composés associés Download PDF

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WO2012127472A1
WO2012127472A1 PCT/IL2012/050100 IL2012050100W WO2012127472A1 WO 2012127472 A1 WO2012127472 A1 WO 2012127472A1 IL 2012050100 W IL2012050100 W IL 2012050100W WO 2012127472 A1 WO2012127472 A1 WO 2012127472A1
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formula
compound
preladenant
process according
sulfonate
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Ehud Marom
Michael Mizhiritskii
Shai Rubnov
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Mapi Pharma Ltd
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Mapi Pharma Ltd
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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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to processes for the preparation of substituted 5-amino- pyrazolo[4,3-e]-l,2,4-triazolo[l,5-c]-pyrimidines, in particular Preladenant and its analogs, and their solvates (e.g., hydrates) and salts with physiologically acceptable acids.
  • the present invention further relates to certain intermediates formed in such processes. BACKGROUND OF THE INVENTION
  • Preladenant (also known as SCH-420814) is an adenosine A 2A antagonist under development for the treatment of Parkinson's Disease (PD) (Neustadt et al, Bioorganic & Medicinal Chemistry Letters, 2007, 17, 1376-1380). Preladenant has high selectivity towards A 2A receptor as compared to Ai, A 2B , and A 3 receptors, and excellent in vivo activity against PD symptoms.
  • PD Parkinson's Disease
  • WO 2005/044819 describes yet another method for the preparation of Preladenant by reacting alkyl N-4-cyano- 1 -(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin- 1 -yl)ethyl)- 1 H- pyrazol-5-yl formimidate with 2-furoic hydrazide in isobutyric acid at reflux conditions, followed by acid hydrolysis to form 4-(3-(furan-2-yl)-lH-l,2,4-triazol-5-yl)-l-(2-(4-(4-(2- methoxyethoxy)phenyl)piperazin-l-yl)-ethyl)-lH-pyrazol-5-amine, which is subsequently cyclized to Preladenant via a reaction with a cyanating reagent (cyanates or cyanogens halides - the use of which is industrially problematic as these are considered highly toxic, corrosive and hazardous materials).
  • the present invention describes processes for the synthesis of 2-(furan-2-yl)-7-[2-[4- [4-(2-methoxyethoxy)phenyl]piperazin- 1 -yl] ethyl] -7H-pyrazolo [4, 3 -e] [ 1 ,2,4] - triazolo [1,5- c]pyrimidin-5-amine (Preladenant) represented by the structure of formula (1), and solvates and salts thereof, especially salts with pharmaceutically acceptable acids.
  • the present invention further relates to certain intermediates in such processes.
  • the process of the present invention comprises the following steps:
  • Z is OH, halogen (Hal) or O-sulfonate and Y is H, and the process comprises the step of:
  • Cyclization of compound (3b) to compound (15) may be carried out directly or by oxidative cyclization/bromination and reduction of an intermediate compound of formula
  • the step of converting the hydrazine moiety of compound (2) to Schiff base (3) can be performed by any manner known in the art.
  • the step of cyclization of the Schiff base to form the pyrazolopyrimidine moiety is preferably conducted in the presence of an acid or base catalyst which is preferably selected from the group consisting of sodium acetate, acetic anhydride/pyridine, pyridine/pyridinium chloride, bromine in acetic acid and iodobenzenediacetate. Bromine (Br 2 ) in acetic acid and iodobenzenediacetate are currently preferred reagents for this step.
  • an acid or base catalyst which is preferably selected from the group consisting of sodium acetate, acetic anhydride/pyridine, pyridine/pyridinium chloride, bromine in acetic acid and iodobenzenediacetate.
  • Bromine (Br 2 ) in acetic acid and iodobenzenediacetate are currently preferred reagents for this step
  • the process of the present invention is useful not only for Preladenant production, but also for the preparation of other biologically active compounds of general formula (17), such as A2a receptor antagonists used for the treatment of central nervous system diseases, among others.
  • the present invention provides a process for the preparation of a compound represented by the structure of formula (17):
  • A is H, Ci-C 6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or a Ci-C 6 alkylene-R a wherein R a is selected from the group consisting of cycloalkyl, aryl, heterocyclyl and heteroaryl, each of which may optionally be substituted;
  • R is an unsubstituted or substituted alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, preferably furanyl, thienyl, pyridyl, pyridyl N-oxide, oxazolyl, phenyl or pyrrolyl; and
  • Q is H, an unsubstituted or substituted alkyl, an unsubstituted or subsituted aryl or a nitrogen protecting group;
  • step (c) optionally, when Z is OH, halogen or O-sulfonate and Y is H, further converting the product of step (b) to the compound of formula (17).
  • the present invention further relates to certain intermediates formed in the aforementioned processes.
  • One novel intermediate is 4-Chloro-l-(2-(4-(4-(2- methoxyethoxy)phenyl)piperazin-l-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-6-amine, a compound of formula (6).
  • P is a nitrogen protecting group, preferably Boc
  • Z is OH, Hal or O-sulfonate and
  • Y is H is or CHO.
  • Another novel intermediate is 5-amino-7-chloro-2-(furan-2-yl)-[l,2,4]triazolo[l,5- c]pyrimidine-8-carbaldehyde, a compound of formula (10).
  • Another novel intermediate is 4-(2-(furan-2-ylmethylene)hydrazinyl)-l-(2-(4-(4-(2- methoxyethoxy)phenyl) piperazin-l-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-6-amine, a compound of formula (3 a).
  • the present invention relates to a Preladenant or a solvate, or salt thereof, wherein the Preladenant is prepared in accordance with the process of the present invention.
  • the present invention further relates to a method of treating a neurodegenerative disease, especially Parkinson's Disease (PD), comprising administering to a subject in need thereof a therapeutically acceptable amount of Preladenant or a solvate, or salt thereof, wherein the Preladenant is prepared in accordance with the process of the present invention.
  • a neurodegenerative disease especially Parkinson's Disease (PD)
  • PD Parkinson's Disease
  • the present invention further relates to the use of Preladenant, or a solvate, or salt thereof, prepared in accordance with the process of the present invention for treating a neurodegenerative disease, especially Parkinson's Disease (PD).
  • PD Parkinson's Disease
  • the present invention relates to processes for the synthesis and isolation of 2-(furan-
  • the production method relates to a process for manufacturing compound (1) by coupling compound (2) with furfural and cyclizing the resulting compound (3) to (1) directly or through an intermediate of formula ( ⁇ ) (Scheme 1).
  • Schemes 2 and 3 Two alternative embodiments of this process are set forth in Schemes 2 and 3.
  • a compound of formula (2a) is reacted with furfural and the resulting compound of formula (3a) is cyclized to (1) directly.
  • Scheme 3 A a compound of formula (2b) is reacted with furfural and the resulting compound of formula (3b) is cyclized to compound (15), which is then formylated to produce a compound of formula (10), which in turn is coupled with a compound of formula (5) to result in (1).
  • Cyclization of compound (3b) to compound (15) may be carried out directly or by oxidative cyclization/bromination and reduction of an intermediate compound of formula (16) (Scheme 3B).
  • the compound of formula (2) such as compounds (2a) and (2b)
  • furfural are preferably used in about an equimolar amount or in an excessive amount for either of the compounds and the mixture is stirred in an inert solvent under suitable reaction conditions, which can be determined by a person of skill in the art, in the absence or in the presence of an acid or base catalyst, preferably at about room temperature (e.g., about 20°C to 25°C) to about reflux (which temperature will depend on the nature of the solvent), generally for about 0.1 hour to about 1 day, or any period of time there between.
  • room temperature e.g., about 20°C to 25°C
  • reflux which temperature will depend on the nature of the solvent
  • the nature of the solvent is not particularly limiting. Some examples include, but are not limited to aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, MTBE, diisopropyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane, and 1,2- diethoxy ethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; N,N- dimethylformamide (DMF), N-methylpyrrolidone ( MP), dimethyl sulfoxide (DMSO), and any mixtures thereof. Each possibility represents a separate embodiment of the present invention. Alcohol (e.g., ethanol) is a currently preferred solvent.
  • the acid catalyst can be an inorganic or organic acid such as hydrochloric, hydrobromic, phosphoric, sulfuric, para-toluenesulfonic, methanesulfonic or tungstic acid. Also, polymeric acid resins and the like can be used.
  • the reaction can also be catalyzed by bases, such as piperidine or a phosphate salt (e.g., sodium and potassium phosphate, hydrogen phosphate or dihydrogen phosphate). Microwave irradiation can facilitate this reaction. In such case the reaction proceeds without solvent, using excess of furfural.
  • bases such as piperidine or a phosphate salt (e.g., sodium and potassium phosphate, hydrogen phosphate or dihydrogen phosphate).
  • alkyl group refers to any saturated aliphatic hydrocarbon, including straight-chain, branched-chain and cyclic alkyl groups (cycloalkyl).
  • the alkyl group has 1- 12 carbons, designated herein as Ci-Ci 2 -alkyl.
  • the alkyl group has 1-6 carbons, designated herein as Ci-C6-alkyl.
  • the alkyl group has 1-4, carbons designated herein as Ci-C 4 -alkyl.
  • alkyl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio thioalkyl, and the like.
  • alkylene denotes a bivalent radical.
  • Ci to C 12 alkylene denotes a bivalent radical of 1 to 12 carbons.
  • a "cycloalkyl” group refers to a non-aromatic mono- or multicyclic ring system. In one embodiment, the cycloalkyl group has 3-10 carbon atoms. In another embodiment, the cycloalkyl group has 5-10 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and the like. The cycloalkyl group can be unsubstituted or substituted with any one or more of the substituents defined above for alkyl.
  • a cycloalkenyl is a cycloalkyl group containing one or more double bonds within the ring.
  • aryl refers to an aromatic ring system containing from 6-14 ring carbon atoms.
  • the aryl ring can be monocyclic, bicyclic, tricyclic and the like.
  • Non-limiting examples of aryl groups are phenyl, naphthyl including 1-naphthyl and 2-naphthyl, and the like.
  • the aryl group can be unsubstituted or substituted with any one or more of the substituents defined above for alkyl.
  • alkynyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond including straight-chain and branched-chain.
  • the alkynyl group has 2-8 carbon atoms in the chain, designated herein as C 2 -C8-alkynyl.
  • the alkynyl group has 2-6 carbon atoms in the chain, designated herein as C 2 -C 6 - alkynyl.
  • alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl, n- pentynyl, heptynyl, octynyl, nonanyl and decynyl.
  • the alkynyl group can be unsubstituted or substituted through available carbon atoms with one or more groups defined hereinabove for alkyl.
  • heteroaryl used herein alone or as part of another group refers to a heteroaromatic system containing at least one heteroatom ring wherein the atom is selected from nitrogen, sulfur and oxygen.
  • the heteroaryl contains 5 or more ring atoms.
  • the heteroaryl group can be monocyclic, bicyclic, tricyclic and the like. Also included in this definition are the benzoheterocyclic rings. If nitrogen is a ring atom, the present invention also contemplates the N-oxides of the nitrogen containing heteroaryls.
  • heteroaryls include thienyl, benzothienyl, 1-naphthothienyl, thianthrenyl, furanyl, benzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, purinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbolinyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl and the like.
  • a preferred heteroaryl group is furanyl.
  • the heteroaryl group can be unsubstituted or substituted through available atoms with one or more groups defined hereinabove for al
  • heterocyclic ring or “heterocyclyl” used herein alone or as part of another group refers to a five-membered to eight-membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.
  • heteroatoms such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.
  • These five-membered to eight-membered rings can be saturated, fully unsaturated or partially unsaturated, with fully saturated rings being preferred.
  • Preferred heterocyclic rings include piperidinyl, pyrrolidinyl pyrrolinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl, indolinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, dihydropyranyl, tetrahydropyranyl, dihydrothiazolyl, and the like.
  • a preferred heterocyclyl group is piperazinyl, which may be substituted.
  • the heterocyclyl group can be unsubstituted or substituted through available atoms with one or more groups defined hereinabove for alkyl.
  • O-sulfonate refers to a group of formula -OS0 2 - ' where R' is an alkyl or aryl as defined hereinabove.
  • solvate means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
  • Solvate encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is water.
  • nitrogen protecting group refers to a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction.
  • the nitrogen protecting group can be an acid labile protecting group, a base labile protecting group, or a protecting group that is removable under neutral conditions.
  • Non-limiting examples of nitrogen-protecting groups are silyl protecting groups (Si(R") 3 wherein R" is alkyl, aryl, aralkyl etc.), acyl groups such as acetyl (COCH 3 ), benzoyl, 2-bromoacetyl, 4-bromobenzoyl, tert-butylacetyl, carboxaldehyde, 2-chloroacetyl, 4-chlorobenzoyl, a-chlorobutyryl, 4-nitrobenzoyl, o-nitrophenoxyacetyl, phthalyl, pivaloyl, propionyl, trichloroacetyl, and trifluoroacetyl; amide groups such as acetamide and the like; sulfonyl groups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate groups of the formula -C(0)0-R"' wherein R"
  • nitrogen protecting group include, but are not limited to: benzyl, formyl, phenylsulfonyl, (Fmoc), p-nitrobenzenesulfoethoxycarbonyl propargyloxycarbonyl, picolinyl, prenyl, o-nitrobenzyloxy methyl, 4-methyoxyphenoxymethyl, guaiacolmethyl, siloxymethyl, such as tnisopropylsiloxymethyl, 2-cyanoethyoxymethyl, 2-quinolinylmethyl, dichloroacetyl, trichloroacetyl, 2-[4-nitrophenyl]ethylsulfonate, p-methoxy benzyl and trityl.
  • Boc Boc
  • nitrogen-protecting groups are described by C. B. Reese and E. Haslam, "Protective Groups in Organic Chemistry, “J.G. W. McOmie, Ed. , Plenum Press, New York, NY, 1973, Chapters 3 and 4, respectively, and T. W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis,” 2nd ed. , John Wiley and Sons, New York, NY, 1991, Chapters 2 and 3, each of which is incorporated herein by reference.
  • Preladenant of formula (1) is prepared by coupling a compound of formula (2a) with furfural to form a hydrazone (Schiff base) of formula (3a), which is subsequently cyclized to Preladenant of formula (1).
  • X is a halogen (e.g., F, CI, Br or I, preferably CI) or O-sulfonate
  • P is a nitrogen protecting group as defined herein.
  • Preladenant (1) While any of the aforementioned methods can be applied to the synthesis of Preladenant (1), it has now been surprisingly found that this reaction proceeds with good yield of the desired compound (1) by bromine assistance, which plays a role of oxidant and catalyst for rearrangement.
  • the reaction may be carried out in, e.g., glacial acetic acid preferably at about room temperature (e.g., about 20°C to 25°C) to about reflux, generally for about 0.1 hour to about 24 hours, or any period of time there between.
  • Sodium or potassium acetate can be added as facilitating additives.
  • Another preferred reagent for the oxidation reaction is iodobenzenediacetate.
  • Compound (1) can be separated from the reaction mixture as a free base or in the form of a salt with physiologically acceptable acids.
  • This method is economically advantageous on an industrial scale over the methods in the prior art, due to the fewer number of stages and the simplicity of execution.
  • Preladenant of formula (1) is prepared by coupling a compound of formula (2b) with furfural to form a hydrazone (Schiff base) of formula (3b), which is subsequently cyclized to form compound (15), formylated to form compound (10) and coupled with compound (5) to form Preladenant of formula (1).
  • Transformation of compound (2b) to compound of formula (10) may be achieved by two alternative methods, hereinafter designated Method A and B, shown generally in Scheme 5, and in further detail in Schemes 6 (Method A) and 7 (Method B).
  • Method A comprises the following steps (Scheme 6):
  • compound (11) cyclization of compound (11) to form compound (8) directly (for example by reaction with iodobenzenediacetate (IBA)), or by oxidative cyclization/ bromination (e.g., with Br 2 /AcOH) and reduction (e.g., with H 2 , Pd/C) of intermediate compound (12); and c) halogenation/O-sulfonylation and formylation of compound (8) to form compound (10).
  • compound (8) may be converted to the corresponding compound (10) by reaction with POCI 3 /DMF.
  • Method B comprises the following steps (Scheme 7):
  • compound (13) can be prepared from commercially available 4,6-dichloropyrimidin-2-amine or a similar compound wherein X is a halogen or O-sulfonate, by sequential reactions with hydrazine and furfural, c) cyclization of compound (13) to form compound (9) (for example by reaction with iodobenzenediacetate (IBA)), or by oxidative cyclization/bromination (e.g., with Br 2 /AcOH) and reduction (e.g., with H 2 , Pd/C) of intermediate compound (14); and d) formylation of compound (9) to form compound (10).
  • compound (9) may be converted to the corresponding compound (10) by reaction with POCI 3 /DMF.
  • Reaction of compound (2b) with furfural followed by cyclization and Dimroth-type rearrangement of compounds (11) or (13) may be performed in accordance with the conditions set forth for conversion of compound (2a) to (3a) to (1) as described hereinabove.
  • the process of the present invention may further comprise the conversion of Preladenant to a salt, preferably with pharmaceutically or physiologically acceptable acids.
  • salt encompasses both basic and acid addition salts, including but not acid addition salts with salts with amine nitrogens.
  • the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids.
  • Such acids include, but are not limited to, hydrochloric, hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
  • the process of the invention is unexpectedly advantageous over the processes described in the prior art (e.g. WO 01/092264, WO 2005/054245 and WO 2005/044819).
  • the high overall yield, mild reaction conditions and available reagents make this approach industrially useful not only for Preladenant production, but also for the preparation of other biologically active compounds of general formula (17), such as A2a receptor antagonists used for the treatment of central nervous system diseases, among others.
  • A is H, Ci-C 6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or a Ci-C 6 alkylene-R a wherein R a is selected from the group consisting of cycloalkyl, aryl, heterocyclyl and heteroaryl, each of which may optionally be substituted, or A is any substituent as described, for example, in WO 01/092264, WO 2005/054245 and WO 2005/044819, the contents of each of which are incorporated by reference herein;
  • R is an unsubstituted or substituted alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, for example furanyl, thienyl, pyridyl, pyridyl N-oxide, oxazolyl, phenyl, pyrrolyl etc.; and
  • Q is H, an unsubstituted or substituted alkyl, an unsubstituted or subsituted aryl, a nitrogen protecting group, etc.
  • SCH-58261 (5-Amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo(4,3-e)- l,2,4-triazolo(l,5-c)pyrimidine), SCH-442,416 (2-(2-furyl)-7-[3-(4-methoxyphenyl)propyl]- 7H-pyrazolo[4,3-e][l,2,4]triazolo[l,5-c]pyrimidin-5-amine), and the compounds described in Miiller et al. Recent Pat CNS Drug Discov. 2007 Jan;2( 1 ) : 1 -21 , the contents of each of which are incorporated by reference herein. The process is described in Scheme 8:
  • the process comprises the steps of:
  • step (c) optionally, when Z is OH, halogen or O-sulfonate and Y is H, further converting the product of step (b) to the compound of formula (17).
  • Reaction of compound (18) with the aldehyde R-CHO followed by cyclization and Dimroth-type rearrangement of compound (19) may be performed in accordance with the conditions set forth for conversion of compound (2a) to (3 a) to (1), or of compound (2b) to (3b) to (1), or any variations thereof, as set forth in Schemes 1-7 above.
  • 2-amino-4,6-dihydroxypyrimidine is commercially available or can be prepared starting from diethyl malonate and guanidine hydrochloride or nitrate (both commercially available) by condensation in basic conditions (sodium methylate)
  • Diethyl malonate and guanidine hydrochloride or nitrate both commercially available
  • condensation in basic conditions sodium methylate
  • 2-amino-4, 6-dichloropyrimidine-5-carboxaldehyde can be prepared from 2-amino-
  • Tert-butyl carbazate (mono Boc-hydrazine) is commercially available or can be prepared, according to JACS, 1957, 79, 98-101; Helvetica Chimica Acta, 1950, 44, 2151-3; Organic Syntheses, 1964, 44, 20-5; Zhurnal Organicheskoi Khimii, 13(12), 1977, 2531-5; Tetrahedron Letters, 1991, 32(26), 3079-82; WO 01/040163; CN1580040; Bioorganic & Medicinal Chemistry Letters, 2006, 16(4), 978-983; AND CN101823986.
  • l-(4-(2-methoxyethoxy)phenyl)piperazine is commercially available or can be prepared according to Bioorganic & Medicinal Chemistry Letters, 2007, 17, 1659-1662.
  • 2-(4-(4-(2-Methoxyethoxy)phenyl)piperazin-l-yl)ethanol and l-(2-chloroethyl)-4-(4- (2-methoxyethoxy)phenyl)piperazine can be prepared from l-(4-(2-methoxyethoxy)phenyl)- piperazine, according to Bioorganic & Medicinal Chemistry Letters, 2009, 19, 967-971.
  • l-(2-hydrazinylethyl)-4-(4-(2-methoxyethoxy)phenyl)piperazine (5) can be prepared from l-(2-chloroethyl)-4-(4-(2-methoxyethoxy)phenyl)piperazine by reaction with tert-butyl carbazate, following by acidic removal of Boc-protecting group and separation of the desired compound (5) as a hydrochloride salt.
  • l-(2-hydrazinylethyl)-4-(4-(2-methoxyethoxy)phenyl)piperazine (5) can be prepared from 2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-l-yl)ethanol by mesylation or tosylation, reaction of the formed sulfonate with tert-butyl carbazate, following by acidic removal of the Boc-protecting group and separation of the desired compound (5) as an hydrochloride salt.
  • preladenant 400 mg was mixed with solution of MTBE: ethanol (9: 1) (10 ml) and stirred for 1 h, filtered and washed with MTBE to afford 350 mg of pure preladenant with HPLC purity >98%.
  • 2-Amino-6-hydrazinylpyrimidin-4-ol (2b) can be prepared from commercially available 2-amino-6-chloropyrimidin-4-ol, according to WO 2010/006032 or, preferably, via formation of tert-butyl 2-(2-amino-6-hydroxypyrimidin-4-yl)hydrazinecarboxylate.

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Abstract

La présente invention concerne des procédés de synthèse de 2-(furan-2-yl)-7-[2-[4-[4-(2-méthoxyéthoxy)phényl]pipérazin-l-yl] éthyl]-7H-pyrazolo[ 4,3-e][1,2,4]-triazolo[1,5c]pyrimidin-5-amine (préladenant) représenté par la structure de formule (1 ), ainsi que des solvates et sels dudit composé, notamment des sels présentant des acides pharmaceutiquement acceptables. Le procédé de l'invention est utile non seulement pour la production de préladenant, mais également pour la préparation d'autres composés biologiquement actifs de formule générale (17), tels que les antagonistes des récepteurs A2a utilisés pour le traitement de maladies du système nerveux central, entre autres. L'invention concerne en outre certains intermédiaires préparés selon lesdits procédés.
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CN106167469A (zh) * 2016-07-15 2016-11-30 南通天泽化工有限公司 一种合成2‑氨基‑4,6‑二羟基嘧啶的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020099061A1 (en) * 2000-05-26 2002-07-25 Neustadt Bernard R. Adenosine A2a receptor antagonists
US20030212080A1 (en) * 2001-11-30 2003-11-13 Schering Corporation Adenosine A2a receptor antagonists
US20060009504A1 (en) * 2003-12-19 2006-01-12 Schering Corporation Pharmaceutical compositions
US20060149060A1 (en) * 2003-12-01 2006-07-06 Schering Corporation Process for preparing substituted 5-amino-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines
US20070238726A1 (en) * 2006-03-07 2007-10-11 Blake James F Heterobicyclic pyrazole compounds and methods of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020099061A1 (en) * 2000-05-26 2002-07-25 Neustadt Bernard R. Adenosine A2a receptor antagonists
US20030212080A1 (en) * 2001-11-30 2003-11-13 Schering Corporation Adenosine A2a receptor antagonists
US20060149060A1 (en) * 2003-12-01 2006-07-06 Schering Corporation Process for preparing substituted 5-amino-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines
US20060009504A1 (en) * 2003-12-19 2006-01-12 Schering Corporation Pharmaceutical compositions
US20070238726A1 (en) * 2006-03-07 2007-10-11 Blake James F Heterobicyclic pyrazole compounds and methods of use

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106167469A (zh) * 2016-07-15 2016-11-30 南通天泽化工有限公司 一种合成2‑氨基‑4,6‑二羟基嘧啶的方法

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