WO2012139455A1 - Intermédiaires du ticagrelor et procédé de préparation du ticagrelor - Google Patents

Intermédiaires du ticagrelor et procédé de préparation du ticagrelor Download PDF

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WO2012139455A1
WO2012139455A1 PCT/CN2012/072775 CN2012072775W WO2012139455A1 WO 2012139455 A1 WO2012139455 A1 WO 2012139455A1 CN 2012072775 W CN2012072775 W CN 2012072775W WO 2012139455 A1 WO2012139455 A1 WO 2012139455A1
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袁建栋
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Brightgene Bio Medical Technology Co Ltd
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    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the field of drug synthesis, in particular to an intermediate of a small molecule anticoagulant drug ticagrelor, an intermediate preparation method and a method for preparing ticagrelor using the intermediate.
  • Ticagrelor (Ticagrelor; used code: ADZ6140, ARC126532), belongs to the cyclopentyl triazolopyrimidine compound, chemical name (IS, 2S, 3R, 5S)-3-[7- [(1R, 2S) -2 - (3, 4 difluorophenyl)cyclopropylamino] 5 (thiopropyl)-3H- [1, 2, 3]triazole [4, 5-d]pyrimidin-3-yl]- 5- (2-Hydroxyethoxy)cyclopentane-indole, 2 diol, is a novel, selective small molecule anticoagulant developed by AstraZeneca.
  • the drug can reversibly produce ⁇ 2 receptor (Purinoceptor 2, P2) subtype P2Y12' on vascular smooth muscle cells (VSMC), which has a significant inhibitory effect on platelet aggregation induced by ADP, and it has a rapid onset after oral administration. Therefore, it can effectively improve the symptoms of patients with acute coronary heart disease.
  • the antiplatelet effect of ticagrelor is reversible, especially for patients who need to undergo anticoagulation before surgery.
  • Molecular formula of ticagrelor C 23 H 2S F 2 N 6 0 4 S, CAS number; 274693 27 5, having the chemical structure shown below -
  • the yield is less than 30%, and it is necessary to use the highly toxic and expensive osmium tetroxide (phthalic anhydride) to catalyze the cis oxidation of the olefin to the diol during the reaction, which disadvantages the practical production of the method. Applications. Therefore, it is still necessary to develop intermediates with superior performance and preparation methods that meet actual production needs.
  • osmium tetroxide phthalic anhydride
  • the present invention first provides an intermediate of ticagrelor represented by formula 5 or a salt thereof -
  • Pi is H or a hydroxy protecting group.
  • ? H silyl, trityl or substituted trityl, benzyl or substituted benzyl, decyloxymethyl or alkoxy substituted methyl, acyl, allyl or substituted allyl Or alkoxycarbonyl.
  • Pi is tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzyl, benzyl, p-methoxybenzyl, 2-tetrahydropyranyl, methoxy Base, 2-ethoxyethyl, acetyl, benzoyl, pivaloyl, allyl, tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl or allyloxycarbonyl.
  • decyloxy (: ; - ; 0 alkyl substituted or unsubstituted aryl -).
  • Alkoxy groups or optionally linked together, form an alkyl or alkoxy substituted or unsubstituted 3- 10 membered cycloalkyl or heterocycloalkyl group.
  • each is preferably H; C straight or branched fluorenyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.; Propyl, cyclopentyl, cyclohexyl, etc.; alkoxy-C H5 fluorenyl, such as methoxymethyl, methoxyethyl, propoxyethyl, etc.: decyloxy (alkoxy Ci- 6) alkyl, such as methoxy ethoxymethyl and the like; c 3 - 7 cycloalkyl group embankment - alkyl with, for example, cyclopropylmethyl, cyclohexylethyl, and the like; c 3 - 7 cycloalkyl group embankment - 6 alkyl , for example, cyclopropyloxypropyl, etc.; aryl, such as phen
  • each is hydrazine; methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, phenyl, benzyl, phenethyl, benzene
  • the methoxy group, or ⁇ and any of them are bonded together to form an alkyl-substituted cyclopentane or a fluorenyl-substituted cyclohexanium or the like.
  • the invention relates to an intermediate for the preparation of ticagrelor of the following formula 5 1 ' :
  • P is preferably tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trityl, benzyl, p-methoxybenzyl, 2 tetrahydropyranyl, methoxymethyl, 2 ethoxyethyl, acetyl, benzoyl, pivaloyl, allyl, tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl or allyloxycarbonyl.
  • the invention relates to an intermediate for the preparation of ticagrelor of the following formula 5-2 ':
  • Is a hydroxy protecting group preferably a hydroxy protecting group is tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzyl, benzyl, p-methoxybenzyl, 2-tetrahydropyridyl Meryl, methoxyindenyl, 2-ethoxyethyl, acetyl, benzoyl, pivaloyl, allyl, tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl or allyloxycarbonyl .
  • the invention relates to an intermediate for the preparation of ticagrelor of the following formula 5 3 ':
  • each of R 2 is more preferably H, methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, phenyl, benzyl, Phenylethyl, benzyloxy, or Ri and ] are optionally bonded together to form an alkyl-substituted cyclopentane or an alkyl-substituted cyclohexane or the like.
  • the present invention also provides a process for the preparation of a compound of formula 5, which comprises the steps of - (a) protecting an amino group on a compound of formula 1 to give a compound of formula 2;
  • P 2 is an amino protecting group
  • L represents a leaving group.
  • P 2 is benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethyl Silicon ethoxycarbonyl, Methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrophenylsulfonyl, p-nitrophenylsulfonyl, pivaloyl, benzopyridyl, triphenyl Methyl, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl.
  • L. is a leaving group of p-toluenesulfonyl, carboxamyl, fluoromethyl oroyl or halogen. Halogen means chlorine, bromine or iodine.
  • each is preferably H ; C straight or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.; such as cyclopropyl, cyclopentyl, cyclohexyl and the like; c; - ⁇ alkoxy - - 6 alkyl, such as methoxy methyl, methoxy, ethyl, propoxyethyl and the like; [6 alkyl alkoxy group d- s C i mechanized group, e.g.
  • C 3 - 7 cycloalkyl - group for example cyclopropylmethyl, cyclohexylethyl and the like; C 3 a 7- cycloalkoxy-C alkyl group, such as a cyclopropyloxypropyl group; an aryl group, such as a phenyl group, a furyl group or the like; (5 fluorenyl substituted or unsubstituted aryl c ; - 6 alkyl group, For example, p-methylphenylmethyl, m-ethylphenylmethyl; alkyl-substituted aryl, as such; p-methylphenyl;
  • Alkoxy-substituted aryl for example: p-methoxyphenyl, etc.; ( -6 alkoxy, such as methoxy, ethoxy, t-butoxy, etc.; C M fluorenyl ( ⁇ alkoxy) a group such as methylpropoxy or the like; c alkyl-substituted or unsubstituted aryl-(: ; - 6 alkoxy group, such as phenyloxy group, p-tolylmethoxy group, etc.; or [and R 2 optional Linked together to form a benzyl or alkoxy substituted or unsubstituted 3 7 membered cyclodecyl or oxa heterocyclic or thioheterocyclyl group, such as cyclopentyl, cyclohexyl, pyran or hexahydropyran.
  • the condition is that when : is -, and when not, it is methyl.
  • the present invention also provides a method of preparing a compound of the following formula 5-3':
  • ⁇ is an amino protecting group
  • the condition is, and the difference 'is methyl.
  • the compound of the above formula 1 can be produced by a conventional method, for example, by reacting a compound represented by the formula or a salt thereof, or an acetal or ketal reaction:
  • the acetal or ketal reaction is prepared by reacting with a compound represented by the following formula (II):
  • amino moiety described in II can be protected with an amino protecting group, and then deprotected after completion of the acetal or ketal reaction.
  • amino protecting groups are benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, propyloxycarbonyl, methylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluene Acyl, trifluoroacetyl, o-ylbenzenesulfonyl, p-nitrophenylsulfonyl, pivaloyl, benzoic acid, benzyl, 2,4-dimethoxybenzyl, p-methoxybenzyl Or benzyl.
  • each is preferably a --: C straight or branched alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.; C 3 -7 naphthenic a group such as a cyclopropyl group, a cyclopentyl group, a cyclohexyl group or the like; an alkoxy group (- 6 fluorenyl group such as a methoxymethyl group, a methoxyethyl group, a propoxyethyl group or the like: a decyloxy group (alkane) An oxy-Ci- 6 alkyl group, such as methoxyethoxymethyl group; C 3 _- 7 cycloalkyl group [ 6 fluorenyl group, ⁇ such as cyclopropyl group, cyclohexylethyl group, etc.; C 3 _- a
  • - methoxy-substituted aryl for example: p-methoxyphenyl, etc. a methoxy group, such as methoxy, ethoxy, t-butoxy, etc.; ( 6 alkyl-C ; 6 alkoxy, such as methylpropoxy; etc.; fluorenyl substituted or unsubstituted aryl - C; - 6 alkoxy such as phenylmethoxy , Tolyl or methoxy; or is optionally linked together to form and ⁇ 6 alkyl group or a substituted or unsubstituted embankment 6 of the 3-7 membered cycloalkyl or heterocyclic oxygen or sulfur heterocyclic group, such as a ring Butyl, cyclohexyl, pyran or hexahydropyran.
  • the compound of formula 1 can also be prepared by the method disclosed in W02011017108; or by reference to the method disclosed by Ingall, Anthony H et al. (Journal of the Chemical Society, Chemical Communications, (1), 83-4; 1994), cited herein as reference.
  • the invention still further provides a process for the preparation of ticagrelor using a compound of formula 5, the process comprising the steps of: (a') a compound of formula 5 and 4,6-dichloro-2-(propylsulfanyl) of formula 6 -5-pyrimidinamine compound is reacted to obtain a compound of formula 7;
  • ⁇ silane, trityl or substituted trityl, benzyl or substituted benzyl, alkoxymethyl or alkoxy substituted methyl, acyl, allyl or substituted Allyl, tetrahydropyranyl or substituted tetrahydropyranyl, m oxycarbonyl.
  • each is preferably H; (- 6 straight or branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like; (7 cyclic alkyl with , for example, cyclopropyl, cyclopentyl, cyclohexyl, etc.; C ; - s alkoxy ( 6 alkyl, such as methoxymethyl, methoxyethyl, propoxyethyl, etc.; C- 5 alkane group - ( ⁇ 6 alkoxy - (- 6 alkyl, e.g.
  • each is H; CH straight or branched fluorenyl; C 3 -7 cycloalkyl; alkoxy [alkyl; [alkoxy-- 4 ; acetoxy-C-45 ⁇ 4 ⁇ 4; C 3 —?
  • the alkali metal nitrite in the step (b') is sodium nitrite or potassium nitrite, preferably sodium nitrite.
  • each is preferably a --: C straight or branched alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.; C 3 -7 naphthenic a group such as a cyclopropyl group, a cyclopentyl group, a cyclohexyl group or the like; an alkoxy group (- 6 fluorenyl group such as a methoxymethyl group, a methoxyethyl group, a propoxyethyl group or the like: an oxiranyl group (alkane) An oxy-Ci- 6 alkyl group, such as methoxyethoxymethyl group; C 3 _- 7 cycloalkyl group [ 6 fluorenyl group, ⁇ such as cyclopropyl group, cyclohexylethyl group, etc.; C 3 _- a 7
  • An oxy-substituted aryl group for example: p-methoxyphenyl group; methoxy group, such as methoxy group, ethoxy group, t-butoxy group, etc.; 6 alkyl C ; - s decyloxy group, for example Methylpropoxy or the like; fluorenyl substituted or unsubstituted aryl C ; 6 alkoxy, such as phenylmethoxy, p-tolylmethoxy, etc.; or ⁇ and optionally joined together to form a 6 alkyl group Or a 6- methoxy substituted or unsubstituted 3- 7-membered cycloalkyl or oxa heterocyclic or thioheterocyclic group, such as cyclopentyl, cyclohexyl, pyran or hexahydropyran.
  • the compound provided by the scheme of the present invention is an important intermediate for synthesizing ticagrelor.
  • the preparation of ticagrelor by using these intermediates is simple in process and high in yield, and can meet the needs of industrial production.
  • the compound of formula 5 of the present invention is used as an intermediate to prepare ticagrelor, and the products of each reaction are easy to crystallize, which is particularly advantageous for controlling impurities during the reaction, and for improving the product of ticagrelor in the future. Stability, it is particularly advantageous to avoid impurities in the reaction step causing a decrease in product stability.
  • Example 1 One end of ethylene glycol was attached to a protecting group and the other end was attached to a leaving group.
  • Step a First attach one end of the ethylene glycol to the protecting group
  • step a
  • reaction liquid was extracted with ethyl acetate three times, and the organic phase was sequentially washed with water and saturated sodium chloride solution three times, dried over anhydrous sodium sulfate, and concentrated to obtain 1 l Og of compound 3 TS in a yield of 39%.
  • step a2
  • step a3
  • step bl
  • Step b
  • the compound of formula b prepared in step a was dissolved in acetonitrile mlli and added to isoamyl nitrite i s ml 2 for 1 hour and concentrated. 6M HCl (50 ml) and 96% methanol (50 m) _ solution were added to the concentrate and stirred for 18 hours. Concentration, and toluene (4 x 100 ml) were azeotroped to give a powdery solid 4.5 g (Formula 1).
  • B8g compound 1 (1.Oeq, 0.78mol) (prepared according to the method disclosed in CN1432017A) was dissolved in 400 ml of tetrahydrofuran, cooled to about 228 «11-; ethylamine (2.06, 1.44 niol) After stirring for 0.5 h, 204 g of CbzCl (I.5 eq, I. 2 moi) was added in portions. After completion, the reaction was carried out for 2 h at room temperature. The reaction solution was poured into 600 ml of water, and the organic layer was separated and concentrated to give a residue.
  • the ethyl acetate was dissolved, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layer was combined, and the organic layer was washed with water to neutral, washed with saturated brine and dried over anhydrous sodium sulfate. %.
  • the compound of the formula I (132g) obtained in Example 2 was subjected to amino-protection according to the procedure of step 4).
  • the amino-protected product and a catalytic amount of p-toluenesulfonic acid were dissolved in 200 ml of methyl orthoformate and stirred at room temperature for 3 hours.
  • the solvent was evaporated under reduced pressure.
  • EtOAc was evaporated, evaporated, evaporated.
  • Soluble in ethanol] 0% Pd-C keep hydrogen pressure 2atm, stir the reaction at room temperature for 2h, complete the reaction of the raw materials, filter off Pd-C, concentrate the filtrate, and obtain the compound of formula 1-3 (155g) by column chromatography, yield 95%:
  • step b) The product of step b) (50 g) was dissolved in 200 ml of tetrahydrofuran under a nitrogen atmosphere, and a solution of potassium t-butoxide in tetrahydrofuran was slowly added at 0 Torr (20 mD, after 15 min, bromoacetic acid B was added dropwise at 0 Torr. A solution of the ester in tetrahydrofuran (21.5 ml) was maintained at the reaction temperature and stirred for 2 hours. Then, sodium borohydride (3,2 g) was added portionwise to the reaction mixture, and the mixture was stirred for a small amount of 16 hours.
  • the compound of the following formula 1-4 is prepared by the method of performing the fifth step a), using benzaldehyde and the compound of the formula I as raw materials.
  • the amino-protected compound was prepared according to the procedure of Example 5, step b), using the compound of the product of formula 1-4 as a starting material.
  • the compound of formula 54 is prepared according to the procedure of step c) of Example 5, using the product of step b).
  • the compound of the following formula 1-5 is prepared by using cyclohexanalcarbaldehyde and a compound of the formula as a raw material.
  • the mixture was evaporated to a solvent under reduced pressure at 30 to 40 ° CT, 200 ml of ethyl acetate and 300 ml of water were added, and the pH of the mixture was adjusted to 5 with a 0.5 M hydrochloric acid solution to separate the two phases. Wash with 0% saline, concentrate the organic phase under reduced pressure, and recrystallize from acetone to give compound 7 ⁇ 1.
  • the compound 7- ⁇ obtained in the previous step was dissolved in a mixed solution of 350 ml of acetic acid and 50 ml of water, and cooled to 2 Torr, and a solution of sodium sulphate (15 g) in water (65 ml) was added to maintain the temperature of the mixture at 7 Torr. Take T. Then warm the mixture to rC, add 500 mi of ethyl acetate, then add 200 mi of 37% potassium carbonate aqueous solution, layer, organic phase and then wash with 21% potassium carbonate solution to remove acetic acid, discard the aqueous phase, organic The phase was concentrated under reduced pressure to give compound 8 ⁇ 1.
  • the compound 8 1 obtained in the previous oxime was dissolved in 200 ml of acetonitrile, and then 50 g of trans-1R,2S)-2- 4-difluorophenyl)-cyclopropylamine (2R 2-hydroxy-) represented by the formula 9 was added.
  • 2 Phenylacetate after stirring uniformly, 63 mi of triethylamine was slowly added to the mixed solution, maintaining the reaction temperature between 20 and 25 C, and the reaction mixture was stirred for 10 hours, and then concentrated under reduced pressure at 3 CTC.
  • the compound 10-1 was dissolved in 200 ml of a 90% aqueous solution of trifluoroacetic acid (TFA), and the reaction was stirred at room temperature for 10 hours, and then the mixture was neutralized with aqueous sodium hydrogen carbonate, and then 500 ml of ethyl acetate was added to the aqueous phase. Add the mixture with stirring Heat to 45 ° C, separate the water layer. The ethyl acetate solution was heated to 47 ° C, then i25 mi isooctane was added, the mixed solution was stirred for 20 minutes, then 125 mi of isooctane was added, the mixed solution was heated to 47 Torr, heated to stir for 0, 5 h, and slowly cooled at room temperature. Filtration, washing with a mixed solution of isooctane and ethyl acetate, and drying 62 g of ticagrete fTk r or). Slave
  • the yield of the compound of 5-1 to ticagrelor was 75%.
  • Step a) The obtained compound 7-4 was dissolved in acetic acid (400mi) and water (50ml), stirred and cooled to 0, and a solution of sodium nitrite (20g) in water (65 mi) was added to maintain the temperature of the mixture. Below 7 °C. The mixture was then warmed to 7 Torr, 500 mmol of ethyl acetate was added, then 200 ml of 37% aqueous potassium carbonate solution was added, the layers were separated, and the organic phase was washed with 21% potassium carbonate solution to remove acetic acid, and the aqueous phase was discarded. The phase was concentrated under reduced pressure to give Compound 8-4.
  • the compound 8-4 obtained in the previous step was dissolved in 200 ml of acetonitrile, and then 50 g of the trans form shown in Formula 9 was added.
  • the solvent was evaporated under reduced pressure at 30 ⁇ 40 C, and ethyl acetate 200 nil and water 300 ml were added, and the pH of the mixture was adjusted to 5 by a ffi 0.5 M hydrochloric acid solution. The two phases were separated and 10% of the phase was used. The mixture was washed with brine, and the organic layer was evaporated.
  • the compound 7- ⁇ obtained in the previous step was dissolved in a mixed solution of 350 ml of acetic acid and 50 ml of water, and cooled to 2 Torr, and a solution of sodium sulphate (15 g) in water (65 ml) was added to maintain the temperature of the mixture at 7 Torr. Take T. Then warm the mixture to rC, add 500 mi of ethyl acetate, then add 200 mi of 37% potassium carbonate aqueous solution, layer, organic phase and then wash with 21% potassium carbonate solution to remove acetic acid, discard the aqueous phase, organic The phase was concentrated under reduced pressure to give compound 8 ⁇ 1.
  • the compound 8-1 obtained in the previous step was dissolved in ethanol, and palladium on carbon was added thereto, and the mixture was stirred at 25 Torr, 4 atm overnight.
  • the compound 8,1 obtained in the previous step was dissolved in 200 ml of acetonitrile, and then 50 g of trans-(1 R,2S)-2-(3,4-difluorophenyl)- represented by the formula 9 was added.
  • Cyclopropylamine (2R)-2-hydroxy-2-phenylacetate after stirring evenly, slowly add 63 mi of triethylamine to the mixed solution, keep the reaction temperature between 20 and 25, and stir the reaction mixture for 10 hours. Then concentrated under reduced pressure at 30 ° T.
  • the ethyl acetate solution was heated to 47 Torr, then 125 ml of isooctane was added, the mixed solution was stirred with 20 125 ml of isooctane, the mixed solution was heated to 47 Torr, heated and stirred for 0.5 h, slowly cooled at room temperature, filtered, and treated with isoxin and The mixed solution of ethyl acetate was washed and dried to obtain 62 g of Tkagrelor.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux intermédiaires du ticagrelor (ou des sels desdits intermédiaires) représentés par la formule 5, dans laquelle P1 est un atome d'hydrogène ou un groupe protecteur hydroxyle, R1 et R2 sont respectivement un atome d'hydrogène, un alkyle, un alcoxy et un phényle; ainsi que des procédés de préparation desdits intermédiaires. L'invention concerne également un procédé de préparation du ticagrelor utilisant les composés représentés par la formule 5, ledit procédé étant simple, à rendement élevé, produisant des quantités moindres des « trois déchets » et étant capable de répondre aux impératifs d'une production à l'échelle industrielle.
PCT/CN2012/072775 2011-04-15 2012-03-22 Intermédiaires du ticagrelor et procédé de préparation du ticagrelor Ceased WO2012139455A1 (fr)

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CN201110094639.7 2011-04-15

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WO2013092900A1 (fr) * 2011-12-23 2013-06-27 Lek Pharmaceuticals D.D. Synthèse de composés de triazolopyrimidine
WO2013163892A1 (fr) * 2012-05-02 2013-11-07 Sunshine Lake Pharma Co., Ltd. Nouveaux composés de triazolopyrimidine et leur procédé de préparation
CN104045620A (zh) * 2013-03-12 2014-09-17 博瑞生物医药技术(苏州)有限公司 一种替卡格雷中间体的制备方法
ITMI20130487A1 (it) * 2013-03-29 2014-09-30 Chemo Res S L Alchilazione selettiva di ciclopentilalcoli
CN104650160A (zh) * 2015-01-13 2015-05-27 济南大学 卡培他滨关键中间体1,2,3-o-三乙酰基-5-脱氧-d-核糖的合成新方法
US9604991B2 (en) 2013-06-24 2017-03-28 Suzhou Miracpharma Technology Co., Ltd. Preparation method of ticagrelor and intermediates thereof

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WO2014155389A2 (fr) * 2013-03-25 2014-10-02 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Procédé de préparation de ticagrelor
CN103288836B (zh) * 2013-06-27 2015-03-11 苏州明锐医药科技有限公司 替卡格雷的制备方法
CN103304567B (zh) * 2013-06-27 2015-05-20 苏州明锐医药科技有限公司 一种替卡格雷的制备方法
CN103288837B (zh) * 2013-06-27 2015-08-05 苏州明锐医药科技有限公司 替格瑞洛的制备方法
CN104744424B (zh) * 2013-12-27 2018-12-25 博瑞生物医药（苏州）股份有限公司 一种替卡格雷中间体的制备方法
CN105968113B (zh) * 2015-03-12 2019-06-07 四川海思科制药有限公司 一种三唑并嘧啶衍生物及其应用
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