CN102731467B - Method for the preparation of intermediates and of ticagrelor Kage Lei - Google Patents

Method for the preparation of intermediates and of ticagrelor Kage Lei Download PDF

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CN102731467B
CN102731467B CN201110094639.7A CN201110094639A CN102731467B CN 102731467 B CN102731467 B CN 102731467B CN 201110094639 A CN201110094639 A CN 201110094639A CN 102731467 B CN102731467 B CN 102731467B
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ticagrelor
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袁建栋
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博瑞生物医药(苏州)股份有限公司
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D317/00Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of products other than chlorine, adipic acid, caprolactam, or chlorodifluoromethane, e.g. bulk or fine chemicals or pharmaceuticals
    • Y02P20/55Synthetic design, e.g. reducing the use of auxiliary or protecting groups

Abstract

本发明提供了式5所示的新的替卡格雷中间体或其盐,其中P1为羟基保护基团,以及这些中间体的制备方法;本发明还涉及利用式5所示的化合物制备替卡格雷的方法。 The present invention provides novel intermediates ticagrelor or a salt thereof, wherein P1 is a hydroxy protecting group, and methods for preparing such intermediates of Formula 5; FIG present invention also relates to the use of a compound of the formula 5 for the preparation of the card Gray's method. 利用式5所示的中间体制备替卡格雷的方法具有工艺简单、收率高、“三废”少的优点,能够满足工业化生产的需要。 Using the intermediate of formula 5 was prepared as shown in Method ticagrelor simple process, high yield, "waste" less advantage, to meet the needs of industrial production.

Description

替卡格雷的中间体及制备替卡格雷的方法 Method for the preparation of intermediates and of ticagrelor Kage Lei

技术领域 FIELD

[0001] 本发明涉及药物合成领域,具体涉及小分子抗凝血药替卡格雷的中间体、中间体制备方法以及利用这些中间体制备替卡格雷的方法。 [0001] The present invention relates to the field of drug synthesis, specifically relates to a method of small molecule anticoagulants ticagrelor intermediates, the preparation of intermediates and the preparation of these intermediates ticagrelor use.

背景技术 Background technique

[0002] 替卡格雷(Ticagrelor ;曾用代号:ADZ6140, ARC126532),属于环戊基三唑并嘧啶类化合物,化学名为(lS,2S,3R,5S)-3-[7-[(lR,2S)-2-(3,4-二氟苯基)环丙氨基]_5_(硫丙基)-3H-[l,2,3]三唑[4,5-d]嘧啶-3-基]-5-(2-羟基乙氧基)环戊烷-1, 2-二醇,是由美国阿斯利康(AstraZeneca)公司研发的一种新型的、具有选择性的小分子抗凝血药。 [0002] ticagrelor (Ticagrelor; have used code: ADZ6140, ARC126532), belonging cyclopentyl triazolopyrimidine compounds, chemical name (lS, 2S, 3R, 5S) -3- [7 - [(lR , 2S) -2- (3,4- difluorophenyl) cyclopropylamino] _5_ (sulfopropyl) -3H- [l, 2,3] triazolo [4,5-d] pyrimidin-3-yl ] -5- one kind of (2-hydroxyethoxy) cyclopentane-1,2-diol, by the US AstraZeneca (AstraZeneca) research and development of novel, small molecule selective anticoagulants . 该药能可逆性地作用于血管平滑肌细胞(VSMC)上的噪呤2受体(Purinoceptor 2,P2)亚型P2Y12,对ADP引起的血小板聚集有明显的抑制作用,且口服使用后起效迅速,因此能有效改善急性冠心病患者的症状。 Reversible drug can act on vascular smooth muscle cells (of VSMC) of methotrexate noise receptor (Purinoceptor 2, P2) the P2Y12 subtype, significantly inhibited platelet aggregation induced by ADP, and rapid onset of action for oral use and thus can effectively improve the symptoms of patients with acute coronary artery disease. 而因替卡格雷的抗血小板作用是可逆的,其对于那些需在先期进行抗凝治疗后再行手术的病人尤为适用。 And because Kage Lei for antiplatelet effect is reversible, which is particularly applicable to those patients for an early anticoagulation after the surgery. 替卡格雷的分子式:C 23H2SF2N604S, CAS号:274693-27-5,具有下式所示的化学结构: Ticagrelor formula: C 23H2SF2N604S, Number CAS: 274693-27-5, having the chemical structure represented by the following formula:

[0003] [0003]

Figure CN102731467BD00041

[0004] 英国阿斯特?立约品WI很公司在专利CN1270590、CN1334816中彼露J苷卞格雷的化学结构和药物用途,同时也披露了制备替卡格雷的方法,该方法的合成路线为下式所示: [0004] UK Astor? WI product is contracting company patent CN1270590, CN1334816 chemical structure and use in pharmaceutical he exposed Bian J Gray glycosides, but also discloses a method of preparing ticagrelor synthetic route of the process for the next formula:

[0005] L/1N丄U乙/O丄"±U/ D / wi - 厶/丄丄夕、 [0005] L / 1N Shang U B / O Shang "± U / D / wi - Si / Shang Shang Xi,

Figure CN102731467BD00051

[0006] 该制备方法中,收率低于30%,并且反应过程中需要使用剧毒而且昂贵的四氧化锇(锇酐)催化烯烃顺式氧化成二醇,这些不利因素限制了该方法在实际生产中的应用。 [0006] This production method, the yield of less than 30%, and the reaction process requires the use of toxic and expensive osmium tetroxide (Osmium anhydride) catalytic oxidation of olefins cis diols, these disadvantages limit the method application of actual production. 因此,开发性能优越的中间体和满足实际生产需要的制备方法仍然十分必要。 Therefore, the development of intermediate and superior performance to meet the actual needs of production preparation is still very necessary.

发明内容 SUMMARY

[0007] 本发明的目的是提供合成替卡格雷过程中的关键中间体,以及这些中间体的合成方法。 [0007] The object of the present invention is to provide a key intermediate in the synthesis process Kage Lei, and synthetic intermediates for these methods. 本发明的另一目的是提供利用上述的中间体制备替卡格雷的方法。 Another object of the present invention to provide a process for preparing such intermediates using ticagrelor.

[0008] 为实现上述目的,本发明采用下述的技术方案: [0008] To achieve the above object, the present invention adopts the following technical solution:

[0009] 本发明首先提供了式5所示的替卡格雷的中间体或其盐: [0009] The present invention firstly provides ticagrelor intermediate of formula 5 or a salt thereof:

[0010] [0010]

[0011] 其中,Pi为羟基保护驻图。 [0011] wherein, Pi is a hydroxyl protecting in FIG.

Figure CN102731467BD00061

[0012] 优选地,Pi为硅烷基、三苯甲基或取代的三苯甲基、苄基或取代的苄基、烷氧基甲基或烷氧基取代甲基、酰基、烯丙基或取代的烯丙基或烷氧羰基。 [0012] Preferably, Pi is a silyl, trityl or substituted trityl, benzyl or substituted benzyl group, alkoxy group or substituted alkoxy group, an acyl group, an allyl group, or allyl or substituted alkoxycarbonyl group.

[0013] 进一步优选地,Pi为叔丁基二甲基硅烷基、叔丁基二苯基硅烷基、三苯甲基、苄基、 对甲氧基苄基、2-四氢吡喃基、甲氧基甲基、2-乙氧基乙基、乙酰基、苯甲酰基、特戊酰基、 烯丙基、叔丁氧羰基、苄氧羰基、笏甲氧羰基或烯丙氧羰基。 [0013] Further preferably, Pi is a t-butyldimethylsilyl group, t-butyldiphenylsilyl, trityl, benzyl, p-methoxybenzyl, 2-tetrahydropyranyl, methoxymethyl, 2-ethoxyethyl, acetyl, benzoyl, pivaloyl, allyl, tert-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl or Wat allyloxycarbonyl group.

[0014] 本发明还提供了制备式5化合物的方法,该方法包括如下步骤: [0014] The present invention also provides a process for preparing a compound of formula 5, the method comprising the steps of:

[0015] (a)对式1所示的化合物上的氨基进行保护得式2所示的化合物; [0015] (a) an amino compound represented by the formula 1 is protected to give compound of formula 2;

[0016] [0016]

Figure CN102731467BD00062

[0017] (b)式2化合物与式3化合物反应得式4所示的化合物; [0017] compound of formula 3 (b) a compound of Formula 2 represented by the reaction formula 4;

[0018] [0018]

Figure CN102731467BD00063

[0019] (c)脱去式4化合物上的氨基保护基团P2得到式5化合物; P2 amino protecting group on the [0019] (c) removing the compound of formula 4 to give a compound of formula 5;

[0020] [0020]

Figure CN102731467BD00064

[0021] 其中 [0021] in which

[0022] Pi羟基保护基,P 2为氨基保护基,L为离去基团。 [0022] Pi hydroxy protecting group, P 2 is an amino protecting group, L is a leaving group.

[0023] 优选地,Pi为硅烷基、三苯甲基或取代的三苯甲基、苄基或取代的苄基、烷氧基甲基或烷氧基取代甲基、酰基、烯丙基或取代的烯丙基、四氢吡喃基或取代的四氢吡喃基、烷氧幾基。 [0023] Preferably, Pi is a silyl, trityl or substituted trityl, benzyl or substituted benzyl group, alkoxy group or substituted alkoxy group, an acyl group, an allyl group, or substituted allyl, tetrahydropyranyl or substituted tetrahydropyranyl group, an alkoxy group few.

[0024] 优选地,P2为苄氧羰基、叔丁氧羰基、笏甲氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻硝基苯磺酰基、对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4-二甲氧基苄基、对甲氧基苄基或苄基。 [0024] Preferably, P2 is benzyloxycarbonyl, t-butoxycarbonyl, Wat methoxycarbonyl group, allyloxycarbonyl group, trimethylsilyl ethoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, phthaloyl group, for tosyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, pivaloyl, benzoyl, trityl, 2,4-dimethoxybenzyl group, p-methoxybenzyl benzyl or benzyl.

[0025] 优选地,L为对甲苯磺酰基、甲磺酰基、三氟乙酰基或卤素的离去基团。 [0025] Preferably, L is a leaving group, tosyl, mesyl, trifluoroacetyl or halogen. 卤素指氯、 溴或碘。 Halo means chloro, bromo or iodo.

[0026] 医药化学领域的普通技术人员应当知道这些常见的化学基团的结构及英文缩写, 例如:对甲苯磺酰基(_Ts)、甲磺酰基(_Ms)、三氟乙酰基(-Tfs)、苄氧羰基(Cbz)、叔丁氧羰基(Boc)、窃甲氧羰基(Fmoc)、稀丙氧羰基(Alloc)、三甲基娃乙氧羰基(Teoc)、三苯甲基(Trt)、2-四氢吡喃基(THP)、邻苯二甲酰基(Pht)、三氟乙酰基(Tfa)、苯甲酰基(Bz)、苄基(Bn)等等。 [0026] Pharmaceutical Chemistry of ordinary skill in the art should be understood that these common structures and the abbreviation of chemical groups, for example: p-toluenesulfonyl (_TS), methanesulfonyl group (_MS), trifluoroacetyl (-Tfs), benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc), burglary methoxycarbonyl (Fmoc), dilute propoxycarbonyl group (Alloc), trimethyl baby ethoxycarbonyl (Teoc), trityl (Trt), 2-tetrahydropyranyl (THP), phthaloyl (Pht), trifluoroacetyl (Tfa), benzoyl (Bz), benzyl (Bn) and the like.

[0027] 本发明还进一步提供利用式5化合物制备替卡格雷的方法,该方法包括如下步骤:(a)式5化合物与式6所示的4,6-二氯-2-(丙硫烷基)-5-嘧啶胺化合物反应,制得式7化合物; 5 [0027] The present invention further provides the use of a compound of Formula 5 prepared ticagrelor, the method comprising the steps of: 4,6-Dichloro shown in (a) with a compound of the formula 5 formula 6 2- (prop-sulfane yl) -5-pyrimidinamine compound, to obtain a compound of formula 7; 5

Figure CN102731467BD00071

7 7

[0029] (b)式7化合物与碱金属的亚硝酸盐反应,制得式8所示的化合物; [0029] The reaction of a nitrite compound 7 (b) of formula with an alkali metal, to obtain a compound represented by the formula 8;

Figure CN102731467BD00072

[0031] (c)式8所示的化合物与式9所示的化合物耦合制得式10所示的化合物; A compound represented by a compound represented by the formula [0031] (c) coupling the formula 89 prepared compounds of formula 10;

[0032] [0032]

Figure CN102731467BD00081

[0033] (d)将式10所示的化合物脱去羟基保护基团即得Ticagrelor; [0033] (d) The compound represented by the formula 10 i.e. removal of hydroxyl protecting groups to give Ticagrelor;

Figure CN102731467BD00082

[0035] 其中,PiS硅烷基、三苯甲基或取代的三苯甲基、苄基或取代的苄基、烷氧基甲基或烷氧基取代甲基、酰基、烯丙基或取代的烯丙基、四氢吡喃基或取代的四氢吡喃基、烷氧幾基。 [0035] wherein, PiS in silyl, trityl or substituted trityl, benzyl or substituted benzyl group, alkoxy group or substituted alkoxy group, an acyl group, an allyl group or a substituted allyl, tetrahydropyranyl or substituted tetrahydropyranyl group, an alkoxy group few.

[0036] 进一步地,步骤(b)中的碱金属的亚硝酸盐为亚硝酸钠或亚硝酸钾,优选亚硝酸钠。 [0036] Further, the nitrate step (b) alkali metal alkylene potassium nitrite or sodium nitrite, preferably sodium nitrite.

[0037] 本发明方案提供的化合物,是合成替卡格雷的重要中间体,利用这些中间体制备替卡格雷的工艺简单,收率较高,能够满足工业化生产的需要。 Compounds provided herein [0037] This is an important intermediate for the synthesis of Kage Lei, using these intermediates prepared ticagrelor simple process, high yield, to meet the needs of industrial production.

具体实施方式 Detailed ways

[0038] 为了使本发明所解决的技术问题、技术方案及有益效果更加清楚明白,以下结合具体实施例,对本发明作进一步的说明。 [0038] In order to solve the technical problem of the present invention, technical solution and advantageous effects are more apparent, the following embodiments with reference to specific embodiments, the present invention will be further described.

[0039] 实施例1将乙二醇的一端连h保护基闭、另一端连h离去基闭 [0039] Example 1 h is connected to one end of the ethylene glycol protective group closed and the other end closed h a leaving group

[0040] (1)步骤a先将乙二醇的一端连上保护基团 [0040] One end (1) a first step ethylene is attached on the protective group

[0041] 通过步骤al: [0041] step al:

[0042] [0042]

Figure CN102731467BD00083

[0043] 将100g乙二醇溶于150mlDMF中,加入219. 4g咪唑(2. 0eq,3. 22mol),冰盐浴冷却至0°C左右,分批缓慢加入362. 8g(1. 5eq,2. 42mol)TBDMSC1,加料完毕后室温搅拌lh,反应生成两个产物,即只保护一个羟基和两个羟基全保护,其中化合物3-TS约占40%。 [0043] 100g of ethylene glycol was dissolved in 150mlDMF, 219. 4g was added imidazole (2. 0eq, 3. 22mol), ice-salt bath cooled to about 0 ° C, was slowly added portionwise 362. 8g (1. 5eq, 2. 42mol) TBDMSC1, LH was stirred at room temperature Upon completion of addition, the reaction generates two products, i.e., only one hydroxyl group and two hydroxyl groups protected fully protected, wherein the compound 3-TS about 40%. 反应液用乙酸乙酯萃取三次,有机相依次用水,饱和氯化钠溶液洗三次,无水硫酸钠干燥,浓缩过柱得1l〇g化合物3-TS,收率39 %。 The reaction solution was extracted three times with ethyl acetate, the organic phase washed with water, saturated sodium chloride solution three times, dried over anhydrous sodium sulfate, and concentrated by column to give compound 1l〇g 3-TS, 39% yield.

[0044] 或者击碟, [0044] or strike plate,

[0045] [0045]

Figure CN102731467BD00091

[0046] 氮气保护下,将100g乙二醇溶于250ml吡啶,冰浴冷却至0°C以下,然后滴加281ml苯甲酰氯(1. 5eq,2. 42mol),滴加完毕后,搅拌反应lh,将反应液缓慢倒入冷的水溶液中,所得溶液用乙酸乙酯萃取三次,合并有机相,所得有机相分别用水和饱和食盐水洗涤三次,无水硫酸钠T燥,浓缩过柱得124. 8g化合物3-Bz,收率43 %。 Under [0046] nitrogen, 100g of ethylene glycol was dissolved in 250ml of pyridine, cooled in an ice bath to below 0 ° C, and then added dropwise 281ml of benzoyl chloride (1. 5eq, 2. 42mol), After the addition, the reaction was stirred LH, the reaction solution was slowly poured into cold aqueous solution, the resultant solution was extracted three times with ethyl acetate, the combined organic phases were washed with water and the organic phase was washed three times with water and saturated brine, dried over anhydrous sodium sulfate T, and concentrated by column to give 124 . compound 8g 3-Bz, yield 43%.

[0047] 或者步骤a3 : [0047] or Step a3:

[0048] [0048]

Figure CN102731467BD00092

[0049] 氮气保护下,将100g乙二醇溶于200ml四氢呋喃中,冰浴冷却至0°C左右,然后加入674. 6g三苯甲基氯(1. 5eq,2. 42mol),搅拌后再加入465. 5ml三乙胺(2. Oeq,3. 22mol), 加热回流2h后,冷却至室温,浓缩除去溶剂,残留物用300ml乙酸乙酯溶解,所得有机相用水和饱和食盐水各洗三次,无水硫酸钠干燥,浓缩过柱得220. 5g化合物3-Trt,收率45%。 [0049] Under nitrogen, 100g of ethylene glycol was dissolved in about 200ml of tetrahydrofuran, with ice-cooling to 0 ° C, then 674. 6g was added trityl chloride (1. 5eq, 2. 42mol), and then stirring after addition of triethylamine 465. 5ml (2. Oeq, 3. 22mol), heated at reflux for 2h, cooled to room temperature, concentrated to remove the solvent, the residue was dissolved with 300ml of ethyl acetate, the organic phase was washed with water and saturated brine washed three times each , dried over anhydrous sodium sulfate, and concentrated by column to give compound 220. 5g 3-Trt, yield 45%. (2)再将另一端连上离去基团 (2) a leaving group and then the other end is connected

[0050] 通过步骤bl: [0050] step bl:

[0051] [0051]

Figure CN102731467BD00093

[0052] 氮气保护下,将189. 2g三苯基磷(1. 2eq,0. 72mol)溶于300ml二氯甲烷中,加入81. 6g 咪唑(2. Oeq,1. 2mol),然后降温至_5°C后,加入91. 4g 碘(1. 2eq,0• 72mol),搅拌反应约lh后,滴加100g化合物3-Bz (溶于200ml二氯甲烷),滴加完毕后搅拌反应lh。 [0052] Under nitrogen atmosphere, the triphenylphosphonium 189. 2g (1. 2eq, 0. 72mol) was dissolved in 300ml of dichloromethane was added imidazole 81. 6g (2. Oeq, 1. 2mol), then cooled to after _5 ° C, iodine was added 91. 4g (1. 2eq, 0 • 72mol), the reaction mixture was stirred for about lh, 100g added dropwise compound 3-Bz (was dissolved in 200ml dichloromethane), after the addition was complete the reaction was stirred for lh . 将反应液倾入500ml水中,搅拌分层,水层再用二氯甲烷萃取两次,合并有机层,有机层再用饱和食盐水洗涤两次,无水硫酸钠干燥浓缩过柱得140. 8g化合物3-1,收率85 %。 The reaction solution was poured into 500ml water, stirred layers were separated aqueous layer was extracted twice with dichloromethane, the organic layers were combined, and the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated by column to give 140. 8g compound 3-1, yield 85%.

[0053] 或步骤b2 : [0053] or Step b2:

[0054] [0054]

Figure CN102731467BD00094

[0055] 氮气保护下,将100g化合物3-Bz溶于250ml吡啶,冰浴冷却至0°C,缓慢分批加入171.6g(1.5eq,0. 9mol)对甲苯磺酰氯,加料完毕后室温搅拌反应1.5h,将反应液倒入300ml水中,水相用乙酸乙酯萃取三次,合并有机相,有机相用IN盐酸洗至中性,然后用水和饱和食盐水洗涤三次,无水硫酸钠干燥,浓缩过柱得147. 8g化合物3-2,收率76. 9 %。 Under [0055] nitrogen, 100g of compound 3-Bz was dissolved in 250ml of pyridine, cooled to ice bath 0 ° C, was slowly added portionwise 171.6g (1.5eq, 0. 9mol) p-toluenesulfonyl chloride, stirred at room temperature Upon completion of addition the reaction 1.5h, the reaction mixture was poured into 300ml water and the aqueous phase extracted three times with ethyl acetate, washed combined organic phases, the organic phase was washed with IN hydrochloric acid until neutral, and then washed three times with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by column to give compound 3-2 147. 8g, 76.9% yield.

[0056] 或步骤b3 : [0056] or Step b3:

[0057] [0057]

Figure CN102731467BD00101

[0058] 氮气保护下,将102. 3g三苯基磷(1. 2eq,0. 39mol)溶于300ml二氯甲烷中,加入44. 7g 咪挫(2. Oeq,0• 66mol),然后降温至_5°C后,加入91. 4g 碘(1. 2eq,0• 39mol),搅拌反应约lh后,滴加100g化合物3-Trt (溶于200ml二氯甲烷),滴加完毕后搅拌反应lh。 Under [0058] nitrogen atmosphere, 102. 3g of triphenylphosphine (1. 2eq, 0. 39mol) was dissolved in 300ml of dichloromethane was added imidazole frustrated 44. 7g (2. Oeq, 0 • 66mol), then cooled to _5 ° C, a solution of 91. 4g of iodine (1. 2eq, 0 • 39mol), the reaction mixture was stirred for about LH, 100g added dropwise compound 3-Trt (dissolved in 200ml dichloromethane), after the addition was complete the reaction was stirred lh. 将反应液倾入500ml水中,搅拌分层,水层再用二氯甲烷萃取两次,合并有机层,有机层再用饱和食盐水洗涤两次,无水硫酸钠干燥浓缩过柱得115. 7g的化合物3-3,收率85%。 The reaction solution was poured into 500ml water, stirred layers were separated aqueous layer was extracted twice with dichloromethane, the organic layers were combined, and the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 115. 7g by column compound 3-3 in 85% yield.

[0059] 实施例2式5-1化合物的合成 Example 2 Synthesis of compound of Formula 5-1 [0059] Embodiment

[0060] 步骤(a): [0060] Step (a):

[0061] [0061]

Figure CN102731467BD00102

[0062] 氮气保护下,将138g化合物1 (1. Oeq,0• 8mol)(按照CN1432017A披露方法制备) 溶于250ml四氢咲喃中和67g碳酸氢钠(1. 0eq,0. 80mol)的混合溶液中,冰浴冷却至0°C 以下,滴加128ml丙烯氧羰基氯(1. 5eq,1. 2mol),滴加完毕后室温反应12h,将反应液倒入600ml水中,分出有机层,浓缩得残留物用300ml乙酸乙酯溶解,水层再用乙酸乙酯萃取两次,合并乙酸乙酯层,有机层用1N盐酸洗至中性,饱和食盐水洗,无水硫酸钠干燥得168. lg 化合物2-1,收率82. 0%。 [0062] Under nitrogen atmosphere, 138g compound 1 (1. Oeq, 0 • 8mol) (prepared according to the method disclosed in CN1432017A) was dissolved in 250ml tetrahydro-thiopyran Kou and 67g of sodium bicarbonate (1. 0eq, 0. 80mol) of the mixed solution in an ice bath to below 0 ° C, was added dropwise 128ml propenyloxy carbonyl chloride (1. 5eq, 1. 2mol), after the addition was complete the reaction at room temperature 12h, the reaction mixture was poured into 600ml water and the organic layer was separated , and concentrated to give the residue was dissolved with 300ml of ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, ethyl acetate layers were combined, the organic layer was washed with 1N hydrochloric acid until neutral, washed with brine, dried over anhydrous sodium sulfate to give 168 . LG compound 2-1, 82.0% yield.

[0063] 步骤(b): [0063] Step (b):

[0064] [0064]

Figure CN102731467BD00103

[0065] 氮气保护下,将50g化合物2-l(leq,0. 19mol)溶于150ml无水四氢呋喃中,冰盐浴降温至〇°C以下,分批缓慢加入9. 3g NaH(l. 2eq,0. 23mol),搅拌反应0. 5h,滴加95. 3g化合物3-3(1. 2eq,0. 23mol)的四氢呋喃溶液100ml,滴加完毕后搅拌反应lh,将反应液倒入300ml饱和氯化铵溶液中淬灭,搅拌分层,有机层浓缩,残留物用乙酸乙酯溶解,水层再用乙酸乙酯萃取两次,合并有机相,并用饱和食盐水洗涤三次,无水硫酸钠干燥,浓缩得81. 0g 化合物4-1,收率78. 4%。 [0065] Under nitrogen, 50g of compound 2-l (leq, 0. 19mol) was dissolved in 150ml of anhydrous tetrahydrofuran, cooled to ice-salt bath square ° C below, was slowly added portionwise 9. 3g NaH (l. 2eq , 0. 23mol), the reaction was stirred for 0. 5h, 95. 3g dropwise compound 3-3 (1. 2eq, 0. 23mol) in tetrahydrofuran 100ml, after the addition was complete the reaction was stirred for lh, the reaction mixture was poured into saturated 300ml quenched with ammonium chloride solution, stirred, and the organic layer was concentrated, the residue was dissolved in ethyl acetate, the aqueous layer extracted with ethyl acetate twice and the combined organic phase was washed three times with saturated brine, dried over anhydrous sodium dried, and concentrated to give compound 4-1 81. 0g, yield 78.4%.

[0066] 步骤(c): [0066] Step (c):

[0067] [0067]

Figure CN102731467BD00111

[0068] 将70g(leq,0. 13mol)化合物4-1溶于500ml二氯甲烷中,冰浴冷却至0°C左右,然后氮气保护下加入5ml 水,5. 5g PdCl2(PPh3)2(0. 06eq,0. 078mol)和170. 3g Bu3SnH(4. 5eq, 0. 585mol),加料完毕后,保持0°C反应20min,然后将反应液倒入水中,搅拌分出有机层,水层用二氯甲烷萃取两次,减压浓缩出大部分溶剂后,有沉淀产生,滤去不溶物,滤液浓缩过柱得45. 4g化合物5-1,收率76 %。 [0068] The approximately 70g (leq, 0. 13mol) Compound 4-1 was dissolved in 500ml of dichloromethane, ice-bath cooled to 0 ° C, and under nitrogen was added 5ml of water, 5. 5g PdCl2 (PPh3) 2 ( 0. 06eq, 0. 078mol) and 170. 3g Bu3SnH (4. 5eq, 0. 585mol), after the addition was complete, maintaining 0 ° C the reaction 20min, then the reaction mixture was poured into water, stirred organic layer was separated, the aqueous layer after extracted twice with dichloromethane, and concentrated under reduced pressure and most of the solvent, to produce a precipitate, insoluble matter was filtered off, the filtrate was concentrated by column to give compound 5-1 45. 4g, yield 76%.

[0069] 实施例3式5-2化合物的合成 Example 3 Synthesis of compounds of Formula 5-2 [0069] Embodiment

[0070] [0070]

Figure CN102731467BD00112

[0071] 氮气保护下,将138g化合物1(1. 0eq,0. 78mol)(按照CN1432017A披露方法制备) 溶于400ml四氢呋喃中,冰浴冷却至0°C左右,加入228ml三乙胺(2. Oeq,1. 44mol),搅拌〇. 5h后,分批加入204g CbzCl(l. 5eq,l. 2mol),完毕后室温反应2h,将反应液倒入600ml水中,分出有机层,浓缩得残留物用300ml乙酸乙酯溶解,水层再用乙酸乙酯萃取两次,合并乙酸乙酯层,有机层用水洗至中性,饱和食盐水洗,无水硫酸钠干燥得225g化合物2-2,收率92%。 Under [0071] nitrogen atmosphere, 138g compound 1 (1. 0eq, 0. 78mol) (prepared according to the method disclosed in CN1432017A) was dissolved in about 400ml of tetrahydrofuran, with ice-cooling to 0 ° C, was added 228ml of triethylamine (2. Oeq, 1. 44mol), stirred square. after 5h, was added portionwise 204g CbzCl (l. 5eq, l. 2mol), after completion of the reaction at room temperature 2h, the reaction mixture was poured into 600ml water and the organic layer was separated and concentrated to a residue was dissolved with 300ml of ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, ethyl acetate layers were combined, the organic layer was washed with water until neutral, washed with brine, dried over anhydrous sodium sulfate to give compound 2-2 225g, yield rate of 92%.

[0072] 步骤(b): [0072] Step (b):

[0073] [0073]

Figure CN102731467BD00113

[0074] 在氮气保护下,将50g化合物2-2(leq,0. 16mol)溶于150ml无水四氢呋喃中, 冰盐浴降温至〇°C以下,分批缓慢加入7. 7g NaH(l. 2eq,0. 19mol),搅拌反应0. 5h,滴加48. 6g(l. 2eq,0. 19mol)的3_4(可按照类似于实施例1的方法合成)的四氢咲喃溶液100ml,滴加完毕后搅拌反应lh,将反应液倒入300ml饱和氯化铵溶液中淬灭,搅拌分层,有机层浓缩,残留物用乙酸乙酯溶解,水层再用乙酸乙酯萃取两次,合并有机相,并用饱和食盐水洗涤三次,无水硫酸钠干燥,浓缩得56. 5g化合物4-2,收率80. 1 %。 [0074] Under nitrogen atmosphere, 50g of compound 2-2 (leq, 0. 16mol) was dissolved in 150ml of anhydrous tetrahydrofuran, cooled to ice-salt bath square ° C below, was slowly added portionwise 7. 7g NaH (l. tetrahydro-thiopyran Kou solution 100ml 2eq, 0. 19mol), the reaction was stirred for 0. 5h, dropwise 48. 6g (l. 2eq, 0. 19mol) of 3_4 (method of Example 1 may be synthesized embodiment) in a manner similar to dropwise after the addition is complete the reaction LH stirring, the reaction mixture was poured into 300ml quenched with saturated ammonium chloride solution, stirred, and the organic layer was concentrated, the residue was dissolved in ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, and the combined The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 4-2 56. 5g, 80.1% yield.

[0075] 步骤(c): [0075] Step (c):

[0076] [0076]

Figure CN102731467BD00121

[0077] 将140g化合物4-2(leq,0. 32mol)溶于300ml 乙醇中,然后加入10g 10%得Pd-C, 保持氢气压力2atm,室温搅拌反应2h,原料反应完全,滤去Pd-C,滤液浓缩过柱得87. 3g化合物5-2,收率90. 3%。 [0077] The compound was dissolved in 300ml of ethanol 140g 4-2 (leq, 0. 32mol), then added to give 10g 10% Pd-C, 2 atm hydrogen pressure maintained, the reaction was stirred at room temperature 2h, starting material the reaction was complete, filtered off Pd- C, the filtrate was concentrated by column to give compound 5-2 87. 3g, yield 90.3%.

[0078] 实施例4替卡格雷的合成 Ticagrelor Synthesis Example 4 [0078] Embodiment

[0079] 步骤(a): [0079] Step (a):

Figure CN102731467BD00122

[0081] 取42. 7g式6化合物(1. leq,0. 18mol)4,6_二氯_2_(丙硫烷基)_5_嘧啶胺溶于200ml乙醇,搅拌下加入75g化合物5-1 (leq,0. 16mol),然后加入125ml三乙胺,温度保持20~25°C之间,将反应器密封,温度升高到120~125°C,反应混合液保持在该温度范围之内30小时,然后冷却至75°C,释放压力。 [0081] 42. A compound taken (1. leq, 0. 18mol) 4,6_ dichloro _2_ (prop-ylsulfanyl) _5_ pyrimidinamine was dissolved in 200ml of ethanol was added with stirring 6 75g ​​7g Compound of formula 5-1 (leq, 0. 16mol), and then added 125ml of triethylamine, keeping the temperature between 20 ~ 25 ° C, the reactor was sealed, the temperature was raised to 120 ~ 125 ° C, the reaction mixture was kept within this temperature range 30 hours, then cooled to 75 ° C, the pressure was released. 将混合液得温度调至50°C,在30~40°C下减压蒸去溶剂,加入乙酸乙酯200ml和水300ml,用3M的盐酸溶液将混合液的pH值调至5,分离两相,有机相用15%的食盐水洗涤,有机相减压浓缩得化合物7-1。 The mixture was adjusted to have a temperature of 50 ° C, under reduced pressure at 30 ~ 40 ° C the solvent was evaporated, ethyl acetate 200ml and water 300ml, 3M hydrochloric acid solution with the pH of the mixture was adjusted to 5, were separated the organic phase was washed with 15% brine, the organic phase was concentrated under reduced pressure to give compound 7-1.

[0082]步骤(b): [0082] Step (b):

[0083] [0083]

Figure CN102731467BD00131

[0084] 将上一步所得化合物7-1溶解于350ml乙酸和50ml水的混合溶液中,并冷却至2°C,加入亚硝酸钠(15g)的水(65ml)溶液,将混合物的温度保持在7°C以下。 [0084] The compound obtained in Step 7-1 was dissolved in a mixed solution of acetic acid and 50ml water 350ml and cooled to 2 ° C, was added sodium nitrite (15g) in water (65 ml of) was added and the mixture was kept at the temperature of 7 ° C or less. 然后将混合液温热至7°C,加入500ml乙酸乙酯,然后加入200ml 37%的碳酸钾水溶液,分层,有机相再用21 %的碳酸钾溶液洗涤除去乙酸,弃去水相,有机相减压浓缩得化合物8-1。 The mixture was then allowed to warm to 7 ° C, 500ml of ethyl acetate was added, followed by addition of 200ml 37% aqueous potassium carbonate solution, separated and the organic phase was washed with 21% potassium carbonate solution to remove acetic acid, the aqueous phase was discarded and the organic phase concentrated under reduced pressure to give compound 8-1.

[0085] 步骤(c): [0085] Step (c):

Figure CN102731467BD00132

[0087] 将上一步制得的化合物8-1溶于200ml乙腈中,然后加入50g式9所示的反式-(1R,2S) _2_ (3,4-二氣苯基)-环丙胺(2R) _2_羟基_2_苯基乙酸盐,揽摔均勾后,向混合溶液中缓慢加入63ml三乙胺,保持反应温度在20~25°C之间,将反应混合物搅拌10小时,然后在30°C下减压浓缩。 [0087] The compound obtained in the previous step 8-1 was dissolved in 200ml of acetonitrile, followed by addition of 50g of formula 9 shown trans - (1R, 2S) _2_ (3,4- two gas-phenyl) - cyclopropylamine ( 2R) _2_ _2_ hydroxy phenyl acetate, embrace all fall after the hook, 63ml of triethylamine was slowly added to the mixed solution, maintaining the reaction temperature between 20 ~ 25 ° C, the reaction mixture was stirred for 10 hours, at 30 ° C and then concentrated under reduced pressure. 向残留物中加入500ml乙酸乙酯和250ml水,然后用3M的盐酸将混合溶液中的PH值调至4左右,分层,有机相用15 %的食盐水溶液洗涤,减压浓缩得化合物10-1。 250ml water and 500ml ethyl acetate was added to the residue, followed by 3M hydrochloric acid mixed solution was adjusted to PH value of about 4, layered organic phase was washed with 15% saline solution, and concentrated under reduced pressure to give compound 10- 1.

[0088] 步骤(d): [0088] Step (d):

Figure CN102731467BD00133

[0090] 将化合物10-1溶于200ml的90 %的三氟乙酸(TFA)水溶液中,室温下搅拌反应l〇h,再加入200g的碳酸氢钠,将反应液中和,然后向水相中加入500ml乙酸乙酯,搅拌下将混合液加热至45°C,分出水层。 [0090] Compound 10-1 was dissolved in 200ml of 90% trifluoroacetic acid (TFA) aqueous solution, stirred at room temperature l〇h, 200g of sodium bicarbonate was added, and the reaction mixture, then the aqueous phase 500ml of ethyl acetate was added, the mixture was heated under stirring to 45 ° C, the aqueous layer was separated. 将乙酸乙酯溶液加热至47°C,然后加入125ml异辛烷,将混合溶液搅拌20分钟,然后再加入125ml异辛烷,将混合溶液加热至47°C,加热搅拌0. 5h,常温缓慢冷却,过滤,用异辛烷和乙酸乙酯的混合溶液洗涤,干燥得62g替卡格雷(Ticagrelor)〇Ms :523[M+H]+ The ethyl acetate solution was heated to 47 ° C, then 125ml of isooctane was added, the mixed solution was stirred for 20 minutes, and then added 125ml of isooctane, the mixed solution was heated to 47 ° C, heating and stirring 0. 5h, room temperature slow cooled, filtered, washed with a mixed solution of isooctane and ethyl acetate, and dried to give 62g ticagrelor (ticagrelor) 〇Ms: 523 [M + H] +

[0091] 应当说明的是,以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。 [0091] It should be noted that the above description is only preferred embodiments of the present invention, but not intended to limit the present invention, any modifications within the spirit and principle of the present invention, equivalent replacements and improvements, It should be included within the scope of the present invention.

Claims (7)

1. 式5所示的替卡格雷的中间体或其盐: 1. ticagrelor intermediate of formula or a salt thereof 5:
Figure CN102731467BC00021
其中,P1S硅烷基、三苯甲基、苄基、对甲氧基苄基、2-四氢吡喃基、酰基、或烯丙基。 Wherein, P1S silyl, trityl, benzyl, p-methoxybenzyl, 2-tetrahydropyranyl group, an acyl group, or an allyl group.
2. 根据权利要求1所述的替卡格雷中间体或其盐,其特征在于,P i为叔丁基二甲基硅烷基、叔丁基二苯基硅烷基、三苯甲基、苄基、对甲氧基苄基、2-四氢吡喃基、乙酰基、苯甲酰基、特戊酰基、或烯丙基。 According to claim 1 or a salt thereof ticagrelor intermediate, wherein, P i is the t-butyldimethylsilyl group, t-butyldiphenylsilyl, trityl, benzyl , p-methoxybenzyl group, 2-tetrahydropyranyl, acetyl, benzoyl, pivaloyl, or allyl.
3. 制备权利要求1所述的式5化合物的方法,其特征在于,该方法包括如下步骤: (a) 对式1所示的化合物上的氨基进行保护得式2所示的化合物; 3. The method of preparing a compound of formula as claimed in claim 5, characterized in that the method comprises the steps of: the amino compound (a), the protected compound of Formula 1 is shown in formula 2;
Figure CN102731467BC00022
(b) 式2化合物与式3化合物反应得式4所示的化合物; (B) a compound of formula 2 with a compound of formula 3 reacted compounds of formula 4;
Figure CN102731467BC00023
(c) 脱去式4化合物上的氨基保护基团P2得到式5化合物; (C) P2 amino protecting groups off the compound of formula 4 to give a compound of formula 5;
Figure CN102731467BC00024
其中,P1S硅烷基、三苯甲基、苄基、对甲氧基苄基、2-四氢吡喃基、酰基、或烯丙基,P2为氨基保护基,L为离去基团。 Wherein, P1S silyl, trityl, benzyl, p-methoxybenzyl, 2-tetrahydropyranyl group, an acyl group, or an allyl group, P2 is an amino-protecting group, L is a leaving group.
4. 根据权利要求3所述的制备替卡格雷中间体的方法,其特征在于,P2为苄氧羰基、叔丁氧羰基、芴甲氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻硝基苯磺酰基、对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2, 4-二甲氧基苄基、对甲氧基苄基或苄基。 4. The preparation method of claim 3 for intermediate Kage Lei, wherein, P2 is benzyloxycarbonyl, tert-butoxycarbonyl group, fluorenyl methoxy carbonyl group, allyloxycarbonyl group, trimethylsilyl ethoxycarbonyl , methoxycarbonyl, ethoxycarbonyl, phthalyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, pivaloyl, benzoyl, trityl group, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl.
5. 根据权利要求3所述的制备替卡格雷中间体的方法,其特征在于,L为对甲苯磺酰基、甲磺酰基、三氟乙酰基或卤素的离去基团。 5. Preparation according to claim 3 for the method of Intermediate Kage Lei, wherein, L is tosyl, mesyl, trifluoroacetyl, or halogen leaving group.
6. 利用权利要求1所述的中间体制备替卡格雷的方法,其特征在于,该方法包括如下步骤: (a) 式5化合物与式6所示的4,6-二氯-2-(丙硫烷基)-5-嘧啶胺化合物反应,制得式7化合物; Intermediate 6. The use according to claim 1 prepared ticagrelor, characterized in that, the method comprising the steps of: 4,6-Dichloro shown in (a) with a compound of the formula 5 formula 6 2- ( propan-sulfanyl) -5-pyrimidinamine compound, to obtain a compound of formula 7;
Figure CN102731467BC00031
(b) 式7化合物与碱金属的亚硝酸盐反应,制得式8所示的化合物; The reaction nitrite compound 7 (b) of formula with an alkali metal, to obtain compounds of formula 8;
Figure CN102731467BC00032
(c) 式8所示的化合物与式9所示的化合物耦合制得式10所示的化合物; A compound represented by a compound represented by the formula (c) coupling the formula 89 prepared compounds of formula 10;
Figure CN102731467BC00033
(d) 将式10所示的化合物脱去PjP得Ticagrelor ; And (d) the compound of Formula 10 to give off PjP Ticagrelor;
Figure CN102731467BC00034
其中,P1S硅烷基、三苯甲基、苄基、对甲氧基苄基、酰基、烯丙基、或2-四氢吡喃基。 Wherein, P1S silyl, trityl, benzyl, p-methoxybenzyl, acyl, allyl, or 2-tetrahydropyranyl.
7. 根据权利要求6所述的制备替卡格雷的方法,其特征为,步骤(b)中所述的碱金属的亚硝酸盐为亚硝酸钠或亚硝酸钾。 The preparation according to claim 6 ticagrelor method, wherein, in step (b) the alkali metal nitrate is sodium nitrite alkylene or potassium nitrite.
CN201110094639.7A 2011-04-15 2011-04-15 Method for the preparation of intermediates and of ticagrelor Kage Lei CN102731467B (en)

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CN103626743B (en) * 2012-08-23 2018-06-08 广东东阳光药业有限公司 And novel intermediates for the preparation of Kage Lei
CN103772393B (en) * 2012-10-18 2017-08-04 博瑞生物医药(苏州)股份有限公司 Form and preparation method for the Kage Lei
CN103848834B (en) * 2012-12-06 2017-09-22 博瑞生物医药(苏州)股份有限公司 A process and intermediates for the preparation of ticagrelor
CN104045620B (en) * 2013-03-12 2017-05-10 博瑞生物医药(苏州)股份有限公司 A method for preparing one kind of intermediate Kage Lei
IN2013MU01111A (en) * 2013-03-25 2015-05-01 Glenmark Generics Limited "process for preparation of ticagrelor"
ITMI20130487A1 (en) * 2013-03-29 2014-09-30 Chemo Res S L selective ciclopentilalcoli Alkylation
WO2014206187A1 (en) 2013-06-24 2014-12-31 苏州明锐医药科技有限公司 Preparation method of ticagrelor and intermediates thereof
CN103288836B (en) * 2013-06-27 2015-03-11 苏州明锐医药科技有限公司 Preparation method of ticagrelor
CN103304567B (en) * 2013-06-27 2015-05-20 苏州明锐医药科技有限公司 Preparation method of ticagrelor
CN103288837B (en) * 2013-06-27 2015-08-05 苏州明锐医药科技有限公司 Method for the preparation of ticagrelor
CN104341402B (en) * 2013-07-23 2018-04-27 博瑞生物医药(苏州)股份有限公司 A method for the preparation of Intermediate ticagrelor
CN104744424B (en) * 2013-12-27 2018-12-25 博瑞生物医药(苏州)股份有限公司 A kind of preparation method of ticagrelor midbody
CN104650160A (en) * 2015-01-13 2015-05-27 济南大学 Novel synthesis method of capecitabine key intermediate 1,2,3-O-triacetyl-5-deoxy-D-ribose
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CN107141298A (en) * 2017-07-24 2017-09-08 苏州信恩医药科技有限公司 Method of synthesis of Ticagrelor
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