WO2013163892A1 - Nouveaux composés de triazolopyrimidine et leur procédé de préparation - Google Patents

Nouveaux composés de triazolopyrimidine et leur procédé de préparation Download PDF

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WO2013163892A1
WO2013163892A1 PCT/CN2013/000495 CN2013000495W WO2013163892A1 WO 2013163892 A1 WO2013163892 A1 WO 2013163892A1 CN 2013000495 W CN2013000495 W CN 2013000495W WO 2013163892 A1 WO2013163892 A1 WO 2013163892A1
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compound
formula
solvent
amino
acid
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Hailong Wang
Zhongqing Wang
Jing Shi
Kailai KONG
Zhigang Wang
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Sunshine Lake Pharma Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/54—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions
    • C07C209/58—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions from or via amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/08—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a pyrimidine compound useful as a pharmaceutical intermediate, to a process for preparing said pyrimidine compound, to intermediates used in said process, and to the use of said pyrimidine compound in the preparation of pharmaceuticals.
  • a series of triazolo (4,5-D) pyrimidine compounds have been disclosed in CN 99815926.3, wherein, Ticagrelor, chemically is (I S, 2S, 3R, 5S)-3-[7-[(lR, 2S)-2-(3,4- difluorophenyl)-cyclopropylamino]-5-(thio-propyl)-3H-[ 1 ,2,3] triazolo [4,5-d] pyrimidine-3-yl] -5-(2-hydroxyethoxy) cyclopentane-l ,2-diol, has a following formula (A), is an activity P2T (ADP) receptor antagonist and is used for the treatment and prevention of acute coronary syndrome in patients with cardiovascular.
  • ADP activity P2T
  • R is selected from the following groups: — C(R R ),— C(-O),— BR , thereinto R , R 2 are C 2 - 6 alkyl (preferably ethyl), benzyl, (C]. 6 alkyl) 3 Si (preferably t-butyldimethylsilyl), and
  • Ci-6 alkyl group such as acetyl
  • the two groups R and R together with the atoms to which they are attached form an alkylidene ring such as a methylidene or isopropylidene ring
  • R 1 and R 2 can form an alkoxymethyliene ring such as ethoxymethylidene
  • R 3 are Ci_6 alkyl (preferably methyl).
  • a process for preparing the Ticagrelor of formula (A) comprising: a) cyclization a compound of formula (I) with alkali metal nitrite (e.g.sodium nitrite) or an organic nitrite (e.g. isopentyl sulfoxide nitrate) in the presence of a suitable acid and a solvent at the suitable temperature to obtain a compound of formula (VII),
  • alkali metal nitrite e.g.sodium nitrite
  • organic nitrite e.g. isopentyl sulfoxide nitrate
  • a process for preparing the compound of formula (II), comprising chlondizing a compound of formula (IV) with a chlorinating agent in the presence of a catalyst and a base,
  • R 4 is hydrogen or an amino protecting group.
  • R 4 is defined in the formula (IV),
  • a process for preparing Trans-(1R, 2S)-2-(3,4- difluoro-substituted phenyl) cyclopropylamine comprising: a) Condensation a compound of formula (X) with a hydroxylamine or an acid addition salt of the hydroxylamine or in the presence of a catalyst and a base and a first solvent to produce compound of formula IX),
  • R 5 is selected from OH, F, CI, Br, I or alkoxy; b) Converting the compound of formula (IX) into a compound of formula (VIII) in the presence of an activator and a second solvent.
  • room temperature refers to a temperature from about 18 °C to about 35 °C or a temperature from about 20 °C to about 24 °C or a temperature at about 22 °C.
  • R R L +k*(Ru-R L ), wherein k is a variable ranging from 1 % to 100% with a 1% increment, i.e., k is 1 %, 2%, 3%, 4%, 5%,..., 50%, 51%, 52%,..., 95%, 96%. 97%, 98%, 99%, or 100%.
  • k is a variable ranging from 1 % to 100% with a 1% increment, i.e., k is 1 %, 2%, 3%, 4%, 5%,..., 50%, 51%, 52%,..., 95%, 96%. 97%, 98%, 99%, or 100%.
  • any numerical range defined by two R numbers as defined above is also specifically disclosed.
  • R 1 , R 2 are C 2-6 alkyl (preferably ethyl), benzyl, (C ) -6 alkyl) 3 Si (preferably t-butyldimethylsilyl), and a C(O) Ci -6 alkyl group such as acetyl.
  • the two groups R 1 and R 2 together with the atoms to which they are attached form an alkylidene ring such as a methylidene or isopropylidene ring.
  • R 1 and R 2 can form an alkoxymethyliene ring such as ethoxymethylidene.
  • R 3 is C] -6 alkyl (preferably methyl).
  • Q is — C(R 1 R2 ), particularly preferred compound is 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-diethyltetra hydro-3aH-cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol, represented by the compound of formula (la):
  • preferred compound is (3aS,4R,6S,6aR)-4-((5-amino-6-chloro-2- (propylthio)pyrimidin-4-yl)amino)-6-(2-hydroxyethoxy)tetrahydro-3aH-cyclopenta[d] [ 1 ,3]diox ol-2-one, represented by the compound of formula (lb):
  • Q is — BR
  • preferred compound is 2-(((3aS,4S,6R,6aS)-6- ((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2-methyltetrahydro-3aH-cyclopenta[d] [ 1.3.2]dioxaborol-4-yl)oxy)ethanol. represented by the compound of formula (Ic):
  • reaction in the presence of a suitable solvent and a catalyst and a base at a temperature from 70 °C to 150 °C. or if the temperature exceeded the boiling point of the solvent, the reaction should be carried out in a sealed system with the autogenous pressure.
  • the base is alkali metal hydroxide or organic amine, in some embodiments, the alkali is hydroxide sodium; in some embodiments, the alkali is triethylamine.
  • the suitable solvent is alcohol solvent, nitrile solvent, water or combinations thereof; in some embodiments, the solvent is C1 -C6 fatty alcohol; in some embodiments, the solvent is glycol; in some embodiments, the solvent is ethanol.
  • the suitable salt of compound of formula (III) are inorganic acid salts or organic acid salts, In some embodiments, the inorganic acid salt is hydrochloric, hydrobromic, hydroiodic, nitric or sulfuric acid; In some embodiments, the organic acid salt is acetic acid, tnfluoroacetic acid, oxalic acid or p-toluenesulfonic acid, L-tartaric acid, dibenzoyl-L-tartaric acid, or toluoyl L-tartaric acid.
  • Protecting groups Q can typically be added and removed using conventional protecting group methodology, for example, as described in "Protective Groups in Organic Chemistry,” edited by J W F McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis", 2nd edition, T W Greene & P G M Wutz. Wiley-Interscience ( 1991 ). 20 [0032]
  • the compound of formula (Ilia) can be prepared by the method disclosed in WO 01/192263.
  • the compound of formula (III) can be prepared through the starting material compound of formula (XII) disclosed in WO 01/192263. otude ,o
  • Compound of formula (XII) can be prepared with the process disclosed in WO 201 1/017108.
  • a process for preparing the Ticagrelor of formula (A) comprising: a) cyclization a compound of formula (I) with alkali metal nitrite (e.g.sodium nitrite) or an organic nitrite (e.g. isopentyl sulfoxide nitrate) in the presence of a suitable acid and a solvent at the suitable temperature to obtain a compound of formula (VII),
  • alkali metal nitrite e.g.sodium nitrite
  • organic nitrite e.g. isopentyl sulfoxide nitrate
  • R . R ⁇ R J are as defined in formula (I); b) Reacting the compound of formula (VII) with a compound of formula (VIII) at the suitable temperature in the presence of a certain solvent and a catalyst and a base to obtain a compound of formula (Villi),
  • the suitable acid in step a) is an organic acid, such as acetic acid, propionic acid, oxalic acid, benzoic acid, sorbic acid, citric acid or malic acid; in some embodiments, the acid is acetic acid; in other embodiments, the acid is benzoic acid.
  • the suitable solvent in step a) is aromatic hydrocarbon solvent, or water, or combinations thereof.
  • the reaction temperature is from about -10 °C to about 100 °C, preferable from 10 °C to 50 °C.
  • the solvent in step b) is aromatic hydrocarbon solvent (such as toluene, xylene), alcohol solvent (such as methanol, ethanol or isopropanol), nitrile solvent (such as acetonitrile or propionitrile), water or combinations thereof; in some embodiments, the solvent is one or more of toluene, xylene or water; in other embodiments, the solvent is the mixture of toluene and water.
  • the base in step b) is potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydroxide or triethylamine or combinations thereof; in some embodiments, the base is potassium carbonate; in other embodiments, the solvent is triethylamine.
  • a process for preparing the compound of formula (II), comprising, chloridizing a compound of formula (IV) with a chlorinating agent in the presence of a catalyst and a base, wherein R 4 is hydrogen or an amino protecting group, in some embodiments, the amino protecting group is tert-butoxycarbonyl (t-Boc), fmoc acyl (Fmoc), benzyloxycarbonyl (Cbz), or allyloxycarbonyl (Alloc), phenylsulfonyl, o-acyl-benzenesulfonyl, -NBn benzylamino in some embodiments, the protecting group is tert-butoxycarbonyl (t-Boc).
  • the chlorinating agent refers to any agent that could convert the hydroxy group into chloro group, such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride or a combination thereof; in some embodiments, the chlorinating agent is phosphorus oxychloride; wherein the molar ratio of chlorinating agent to the compound of formula (IV) is from about 1 : 1 to about 1 :10; in some embodiments, the molar ratio is 1 : 10; in some embodiments, the molar ratio is 1 :5.
  • the chlorination reaction described could be carried out in the presence of excess chlorinating agent, in which, the chlorinating agent acted as both a reactant and a solvent. After the reaction was complete, the excess chlorination agent could be removed by distillation or hydrolysis.
  • the base can be aliphatic organic bases; in some embodiments, the base is triethylamine, trimethylamine, N, N-diisopropylethylamine, N-methyl morpholine or N-methyl piperidine or a combination thereof; in some embodiments, the base is N, N-diisopropylethylamine.
  • the molar ratio of the base to the compound of formula (IV) is from about 1 :1 to aboutl :5; in some embodiments, the molar ratio is 1 :1.5; in some embodiments, the molar ratio is 1 :3.
  • the chlorination reaction described herein is carried out at a temperature from room temperature to a reflux temperature; in some embodiments, the temperature is at about 60 °C to about 130 °C; in some embodiments, the temperature at about 80 °C to about 100 °C.
  • the process for preparing the compound of formula (II) as describes herein, the chlorination reaction and deprotection could be carried out in one-pot, which involves reduce reaction time, non-hazardous conditions, increased yield, be suitable for industrial scale, and can also be carried out in the absence of solvent and base.
  • a process for preparing the compound of (IV) comprising, alkylating a compound of formula (V),
  • LG (VI) wherein LG is a leaving group, wherein the leaving group is any pharmaceutically acceptable leaving group, for example sulfonic acid ester-OS0 2 CH 3 , -OS0 2 Ph, -OS0 2 Ph-Me; Carboxylic acid esters OCOR 6 . phosphonate OP (OR 6 ) 2 , or halogen (such as CI, Br or I); wherein R 6 is a straight-chain or branched alkyl.
  • LG is Br; in some embodiments, LG is CI; in certain embodiment, LG is I.
  • the compound of formula (VI) is 1-bromopropane; in some embodiments, the compound of formula (VI) is 1 -iodopropane.
  • the molar ratio of compound of formula (VI) to the compound of formula (V) is from about 1 :1 to aboutl :3; in some embodiments, the molar ratio of compound of formula (VI) to the compound of formula (V) is from 1 : 1 to aboutl :5.
  • the solvent is water, methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, pentanol, hexanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, tetrahydrofurans, dioxane, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, ⁇ , ⁇ -dimethyl formamide, N,N-diethyl acetamide, dimethyl sulfoxide or a combination thereof; in some embodiments, the solvent is water, methanol,
  • the base is organic base or inorganic base, wherein the organic base is triethylamine, trimethylamine, ⁇ , ⁇ -diisopropylethylamine, N-methyl morpholine or N-methyl-piperidine or a combination thereof; the inorganic base include, but not limited to alkali metal or alkaline earth metal hydroxide, alkali metal or alkaline earth metal alkoxides, alkali metal or alkaline earth metal carbonates, or ammonia.
  • the inorganic base is ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide or potassium tert-butoxide.
  • the alkylation reaction described herein could be carried out at a temperature from 0 °C to a reflux temperature; in some embodiments, the temperature is from about 10 °C to about 100 °C; in some embodiments, the temperature is from about 20 °C to about 70 °C.
  • a process for preparing trans- (1 R, 2R)-2-(3,4-difluorophenyl)cyclopropanamine (VIII) or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, or an acid addition salt thereof comprising: a) Condensation a compound of formula (X) or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, or an amine salt thereof with a hydroxylamine or an acid addition salt of the hydroxylamine in the presence of an activating agent and a base and a first solvent to produce compound of formula (IX), wherein, R 5 is selected from OH. F, CI, Br, I or alkoxy; b) Converting the compound of formula (IX) into the compound of formula (VIII) with an activating agent in the presence of a base and a second solvent, followed by treatment with an alcohol.
  • Compound of formula (X) can be prepared with the process disclosed in US 8,026,396.
  • the molar ratio of the acid addition salt of the hydroxylamine or hydroxylamine to the compound of formula (X) is about 1 :20; in some embodiments, the molar ratio is 1 : 10.
  • the first solvent used in the step a) is water, 4-methylmorpholine, N,N-dimethylacetamide, nitromethane. triethylamine, N-methylpyrrolidone, ether solvent, halogenated solvent, ester solvent, ketone solvent, aromatic hydrocarbon solvent or a combination thereof.
  • ether solvent is tetrahydrofuran, dioxane, methyl tert-butyl ether, dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether or a combination thereof;
  • halogenated solvent is dichloromethane or 1 ,2-dichloroethane or a combination thereof;
  • ketone solvent is acetone, methyl ethyl ketone or a combination thereof;
  • aromatic hydrocarbon solvent is benzene, toluene or xylene or a combination thereof; in some embodiments, the first solvent is tetrahydrofuran; In other embodiments, the first solvent is dichloromethane.
  • the base used in the step a) is an organic or inorganic base, preferably alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide; alkaline earth metal hydroxides, such as hydroxide, magnesium hydroxide, calcium or barium hydroxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate.
  • the base is potassium hydroxide; in some embodiments, the base is sodium hydroxide.
  • step a) is carried out at a temperature from -30 °C to the boiling point of the solvent used, preferably a temperature from 0 °C to room temperature.
  • the activating agent used in step b) is 1 ,1 -carbonyldiimidazole, l,l -carbonyl-di-(l,2,4-triazole), phosgene derivatives, alkyl chloroformates, arylchloroformates, 2-halo-4,6-dialkoxy-l,3,5-triazines, thionyl chloride, trialkyl phosphites, triarylphosphites, ⁇ , ⁇ -dialkylcarbodiimides, N,N-diarylcarbodiimides, diphenylphosphorylazide,l-chloro-N,N,2-trimethyl-l-propenylamine,
  • N/O-substituted benzotriazole salts/ derivatives 0-(2-oxo-l(2H)pyridyl)-N,N,N',N'- tetramethyluronium tetrafluoro borate, 0-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'- tetramethyluronium hexafluorophosphate (HOTU), O-
  • the activating agent is sulfonyl chloride, in some embodiments, the activating agent is 1 ,1 -carbonyldiimidazole.
  • the molar ratio of activator used in the step b) to the compound of formula (IX) is 1 :20, preferably 1 :10.
  • the second solvent is ether solvent, halogenated solvent, ester solvent, ketone solvent, aromatic solvent, or combinations thereof; in some embodiments, the second solvent is ethyl acetate, isopropyl acetate, isobutyl acetate, acetonitrile, propionitrile, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, toluene or xylene or a combination thereof.
  • step b) is carried out at the temperature from -30 °C to the boiling point of the solvent used.
  • reaction mixture is concentrated to dryness, alkaline aqueous solution or acidic aqueous solution is added to the reaction mass, stirred at room temperature for overnight.
  • the mixture is extracted with organic solvents, combined the organic layer, (R) - mandelic acid was added into the the organic layer and precipitation, filtered to obtain white solid Trans - ( 1 R.
  • alkaline aquenous solution preferably aqueous solution of an alkali metal or alkaline earth metal hydroxide
  • acidic aqueous solution preferably aqueous solution of inorganic acid, preferably hydrogen chloride, hydrogen bromide, hydrogen iodide sulfuric acid or nitric acid aqueous solution.
  • Trans - (1R, 2S) -2 - (3,4 - difluoro-substituted phenyl) cyclopropylamine prepared in the present invention can be used for preparation of any pharmaceutically acceptable salt thereof, include but not limited L-tartrate, dibenzoyl-L-tartrate, di-toluoyl tartaric acid salt, L-methoxy-dibenzoyl tartaric acid salt, (R)-mandelate, L-(-)- Applemaleate, ( 1 S)-(+)-l O-camphorsulfonate.
  • the process of preparation with the properties includes reduce reaction time, non-hazardous conditions, greater simplicity, increased yield, be suitable for industrial scale, and can also be carried out in the absence of sodium azide, diazomethane, hypochlorite and other explosive and corrosive reagent.
  • the present invention provided the intermediate compounds of formula (III), ( IV ) , (VII) and (XII), and the process for preparing Ticagrelor with making use of those intermediates aforementioned with the properties of greater simplity in post reaction opration and being suitable for industrial scale.
  • the present invention relates to a pyrimidine compound useful as a pharmaceutical intermediate, to a process for preparing said pynmidine compound, to intermediates used in said process, and to the use of said pyrimidine compound in the preparation of Ticagrelor.
  • the skilled in the art can learn from the present invention and improve the process parameters appropriately. It should be noted that it can be readily apparent to those of ordinary skill in the art that certain modifications may be made thereto within the scope of the invention. Some embodiments of the invention are disclosed herein, obviously, a skilled artisan can make any alterations, changes or combinations thereof appropriately to implement and apply the present invention without departing from the content, spirit and scope of the present invention.
  • Step 3 5-tert-butoxycarbonyl-amino-2-propyl-thio-pyrimidine-4,6-diol,
  • Step 4 4,6-dichloro-5-amino-2- (n-propyl sulfonyl)-pyrimidine,
  • Step 1 (lR,2S)-2-(3,4-difluorophenyl)-N-hydroxycyclopropanecarboxamide,
  • Step 2 Trans - (1R, 2S) -2 - (3,4 - difluoro-phenyl)-cyclopropylamine,
  • Step 1 the preparation of the compound of formula 01 : n 33--ppeennttaannoonnee , ⁇ , preparation, ⁇ OMe
  • Step 2 the preparation of the compound of formula 03:
  • Step 3 the preparation of the compound of formula 06:
  • Step 4 the preparation of (3aR,4S,6R,6aS) -6-amino - 2,2-diethyltetrahydro - 3aH-cyclopenta [d][ l ,3] dioxol-4-ol (XII):
  • Example 6 provided the process of preparing [1 S-[l a, 2a, 3 ⁇ (Is*, 2R*), 5 ]]-3-[7-[2-(3,4-difluorophenyl yl) cyclo-propyl-amino]-5-(propylthio)-3H-l ,2,3- triazolo [4,5-d]pyrimidin-3-yl]-5-(2- hydroxyethoxy) cyclopentane-1 ,2- diol (formula A)
  • Step 1 the preparation of 2-(((3aR,4S,6R,6aS) -6-((5-amino-6-chloro- 2-(propylthio) pyrimidin-4-yl)amino)-2,2-diethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol (formula I):
  • the organic layer was concentrated under reduced pressure at 55 °C to get some oil.
  • Isopropyl acetate (8.2 ml) was added to the oil to form a mixture, the mixture was heated to 60 °C to form a solution, to the solution added isooctane, stirred for 30 min at 63 °C. then the mixture was cooled to room temperature, further stirred for 5 hours, then cooled to 0 ° C, stirred and separated out yellow precipitate, filtered and the cake was washed with isooctane, dried in vaccum to obtain the title compound: 2.3g.
  • Step 2 the preparation of 2-(((3aR,4S,6R.6aS) -6-(7-chloro-5-(propylthio) -3H- [1,2,3] triazolo[4,5-d]pyrimidin-3-yl)-2,2-diethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-yl)oxy)eth anol(formula VII):
  • Step 3 the preparation of 2-(((3aR,4S,6R.6aS)-6-(7-(((l R,2S)-2-(3,4-difluorophenyl) cyclopropyl)amino)-5-(propylthio)-3H-[l ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-diethyltetrahyd ro-3aH-cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol (formula Villi):
  • step 2 The solution prepared from step 2 was added to a flask, to the flask added trans-( l R, 2S)-2-(3.4-difluorophenyl)cyclopropanaminium(2R)-2-hydroxy-2-phenylethanoate (0.85 g). and a solution of potassium carbonate (0.85 g) in water (10 ml) at 30 °C to form a mixture, after stirred at room temperature for 5 hours, the aqueous layer was separated and the organic layer was washed with a mixture of brine and acetic acid, the organic layer was used directly in the next step.
  • Step 4 the preparation of (I S, 2S, 3R. 5S)-3-[7-[(l R, 2S)-2-(3,4-difluorophenyl yl)-cyclopropylamino]-5-(thio-propyl)-3H-[-l ,2,3]triazolo[4,5-d]pyrimidine-3-yl]-5- (2-hydroxyethoxy) cyclopentane-l ,2-diol (formula A).

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un composé de pyrimidine de formule (I) utile en tant qu'intermédiaire pharmaceutique. Dans la formule, Q est choisi parmi les groupes suivants : -C(R1R2), -(C=O), -BR3. L'invention porte également sur un procédé pour la préparation dudit composé de pyrimidine, sur des intermédiaires utilisés dans ledit procédé et sur l'utilisation dudit composé de pyrimidine dans la préparation de ticagrelor.
PCT/CN2013/000495 2012-05-02 2013-05-02 Nouveaux composés de triazolopyrimidine et leur procédé de préparation WO2013163892A1 (fr)

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CN103772295A (zh) * 2014-01-26 2014-05-07 苏州立新制药有限公司 替格瑞洛中间体4,6-二氯-2-(丙巯基)-5-氨基嘧啶的制备方法
WO2014086291A1 (fr) * 2012-12-06 2014-06-12 博瑞生物医药技术(苏州)有限公司 Procédé de la préparation de ticagrelor et ses intermédiaires
CN104130297A (zh) * 2014-08-11 2014-11-05 济南大学 一种使用高效脱水剂合成卡培他滨关键中间体的方法
CN104710425A (zh) * 2013-12-16 2015-06-17 石药集团中奇制药技术（石家庄）有限公司 一种替格瑞洛新结晶及其制备方法
CN105294573A (zh) * 2015-06-16 2016-02-03 厦门医学高等专科学校 一种合成4,6-二氯-2-(丙硫基)-5-氨基嘧啶的方法
WO2016117852A3 (fr) * 2015-01-22 2016-10-27 동아에스티 주식회사 Procédé pour la préparation du ticagrelor et nouveaux intermédiaires à cet effet
CN106279095A (zh) * 2015-06-01 2017-01-04 重庆圣华曦药业股份有限公司 一种替格瑞洛关键中间体的制备方法
CN106905182A (zh) * 2017-01-12 2017-06-30 淮阴工学院 一种替格瑞洛中间体的合成方法及其中间体
CN107089984A (zh) * 2017-04-11 2017-08-25 荆楚理工学院 一种替卡格雷的合成方法
KR101870918B1 (ko) * 2015-01-22 2018-06-25 동아에스티 주식회사 티카그렐러 제조방법 및 이를 위한 신규한 중간체
CN111205232A (zh) * 2020-02-26 2020-05-29 浙江天宇药业股份有限公司 一种替格瑞洛中间体的合成方法

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WO2014086291A1 (fr) * 2012-12-06 2014-06-12 博瑞生物医药技术(苏州)有限公司 Procédé de la préparation de ticagrelor et ses intermédiaires
CN104710425A (zh) * 2013-12-16 2015-06-17 石药集团中奇制药技术（石家庄）有限公司 一种替格瑞洛新结晶及其制备方法
CN103772295A (zh) * 2014-01-26 2014-05-07 苏州立新制药有限公司 替格瑞洛中间体4,6-二氯-2-(丙巯基)-5-氨基嘧啶的制备方法
CN103772295B (zh) * 2014-01-26 2015-12-02 苏州立新制药有限公司 替格瑞洛中间体4,6-二氯-2-(丙巯基)-5-氨基嘧啶的制备方法
CN104130297A (zh) * 2014-08-11 2014-11-05 济南大学 一种使用高效脱水剂合成卡培他滨关键中间体的方法
WO2016117852A3 (fr) * 2015-01-22 2016-10-27 동아에스티 주식회사 Procédé pour la préparation du ticagrelor et nouveaux intermédiaires à cet effet
KR101870918B1 (ko) * 2015-01-22 2018-06-25 동아에스티 주식회사 티카그렐러 제조방법 및 이를 위한 신규한 중간체
CN106279095A (zh) * 2015-06-01 2017-01-04 重庆圣华曦药业股份有限公司 一种替格瑞洛关键中间体的制备方法
CN105294573A (zh) * 2015-06-16 2016-02-03 厦门医学高等专科学校 一种合成4,6-二氯-2-(丙硫基)-5-氨基嘧啶的方法
CN105294573B (zh) * 2015-06-16 2018-07-10 厦门医学院 一种合成4,6-二氯-2-(丙硫基)-5-氨基嘧啶的方法
CN106905182A (zh) * 2017-01-12 2017-06-30 淮阴工学院 一种替格瑞洛中间体的合成方法及其中间体
CN107089984A (zh) * 2017-04-11 2017-08-25 荆楚理工学院 一种替卡格雷的合成方法
CN111205232A (zh) * 2020-02-26 2020-05-29 浙江天宇药业股份有限公司 一种替格瑞洛中间体的合成方法

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