CN103275087A - Triazolo pyrimidine derivative and preparation method thereof - Google Patents

Triazolo pyrimidine derivative and preparation method thereof Download PDF

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CN103275087A
CN103275087A CN2013102643523A CN201310264352A CN103275087A CN 103275087 A CN103275087 A CN 103275087A CN 2013102643523 A CN2013102643523 A CN 2013102643523A CN 201310264352 A CN201310264352 A CN 201310264352A CN 103275087 A CN103275087 A CN 103275087A
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徐浩
戴娟
刘艳
陈海霞
岳洪亮
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南京工业大学
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Abstract

The invention relates to a triazolo pyrimidine derivative and a preparation method thereof. A structural general formula of the triazolo pyrimidine derivative is as Formula (I) as shown in the specification, wherein R is hydroxyalkyl such as -CH(CH3)CH2OH, -CH(CH2CH3)CH2OH and -C(CH3)2CH2OH.

Description

—种三氮唑并嘧啶类衍生物及其制备方法 - Species triazolo pyrimidine derivatives and preparation method

技术领域 FIELD

[0001] 本发明涉及医药领域,具体地说是一种三氮唑并嘧啶类衍生物及其制备方法。 [0001] The present invention relates to the field of medicine, in particular to a triazole pyrimidine derivatives and their preparation.

背景技术 Background technique

[0002] 血栓是血流在心血管系统血管内面剥落处或修补处的表面所形成的小块。 [0002] Thrombosis is small at the surface of the blood vessel inner surface spalling cardiovascular system or patch formed at. 在可变的流体依赖型中,血栓由不溶性纤维蛋白,沉积的血小板,积聚的白细胞和陷入的红细胞组成。 In the fluid-dependent variable, the insoluble fibrin from the thrombus, platelet deposition, accumulation of white blood cells and red blood cells into the composition.

[0003] 人类血液内血小板主要有三种不同的ADP受体MX1、PZY1、P2Y12。 [0003] Human blood platelets are mainly three different ADP receptor MX1, PZY1, P2Y12. PZX1为ATP门控阳离子通道,P2Xi受体在兴奋和非兴奋性细胞介导的神经信号,是炎症和心血管功能的关键角色;Ρ2ΥρΡ2Υ12作为两种G蛋白偶联的受体。 PZX1 an ATP-gated cation channels, P2Xi receptors in the nervous excitement signal and the non-excitatory cell-mediated, is the key role of inflammation and cardiovascular function; Ρ2ΥρΡ2Υ12 as two kinds of G protein-coupled receptors. ADP与P2Yi受体结合后,P2Yi受体与Gq蛋白偶联激活磷酯酶C从而导致Ca2+从细胞外流入细胞内,细胞内Ca2+浓度的升高激活了蛋白激酶C引起血小板变形和聚集;ADP与P2Y12受体结合,P2Y12受体与Gi蛋白偶联,抑制血小板的腺苷酸环化酶(adenylylcyclase)的活化,降低了血小板中cAMP的水平,诱发血小板的聚集。 After binding of ADP receptors P2Yi, P2Yi and Gq-protein coupled receptors activate phospholipase C leading to the extracellular Ca2 + from intracellular flows, the intracellular Ca2 + concentration increased activation of protein kinase C induced platelet aggregation and deformation; ADP binding to the receptor P2Y12, P2Y12 receptor coupled to Gi protein to suppress adenylate cyclase activated platelets (adenylylcyclase), reducing the level of cAMP in platelets, to induce platelet aggregation. 所以说P2YpP2Y12是ADP受体阻断药的作用靶点。 So P2YpP2Y12 ADP receptor blocking drugs are targets. P2Y12在血小板上的数量大于P2t在血小板上的数量。 P2Y12 platelet number greater than the number P2t on platelets. 所以,ADP诱导血小板聚集反应中的主要受体是P2Y12。 Therefore, ADP-induced platelet aggregation is the major receptor P2Y12.

[0004] 研究表明P2Y12受体参与纤维蛋白原受体激活、血栓形成、血栓素A2生成、外伤引发的血小板聚集等过程。 [0004] Studies have shown that P2Y12 receptor is involved in activation of the fibrinogen receptor, thrombosis, generating thromboxane A2, platelet aggregation caused by traumatic procedure. 人类的P2Y12由342个氨基酸组成,主要分布于血小板和脑组织中,是抗血栓吩吡啶类化合物的靶标。 By the human P2Y12 342 amino acids, mainly in the platelets and the brain tissue, the antithrombotic thiophene pyridine compound target. 内源性刺激因子如ADP等结合P2Y12受体会激活PI3K等通路而激活Paplb、Akt、ERK通路共同引起纤维蛋白原受体的激活,结合纤维蛋白原,从而引发血栓形成或血小板聚集。 Stimulating factors such as endogenous binding P2Y12 ADP receptor will activate other like PI3K pathway is activated Paplb, Akt, ERK pathway common cause activation of the fibrinogen receptor, fibrinogen binding, to initiate thrombosis or platelet aggregation. 这一过程必须在P2Y12受体同时激活的情况下才可以实现。 This process can be achieved in the case of P2Y12 receptor activated simultaneously. 因此阻断P2Y12受体可以显著抑制有ADP和其他刺激因子引发的徐小班聚集和血栓形成。 Thus P2Y12 receptor blockade significantly inhibit ADP-induced and other stimulating factors in small Xu aggregation and thrombosis.

[0005] 目前,公开申请P2Y12受体拮抗剂的专利申请包括W01999005143、W02000034283、W0200103642。 [0005] Currently, P2Y12 receptor antagonists published application include patent applications W01999005143, W02000034283, W0200103642.

[0006] 虽然已公开了一系列抗血小板聚集和血栓形成的药物,但仍需要开发新的以及具有更好药效的药物,本发明设计了通式(I)的新型结构的化合物。 [0006] While there has been disclosed a series of anti-platelet aggregation drugs and thrombosis, there remains a need to develop new and better drugs having efficacy, the present invention contemplates a compound of a novel structure of the general formula (I) is.

发明内容 SUMMARY

[0007] 本发明的目的在于提供通式(I)所示的新型三氮唑并嘧啶类衍生物。 [0007] The object of the present invention to provide a formula (I) shown in novel triazole and pyrimidine derivatives.

[0008] [0008]

Figure CN103275087AD00041

[0009]其中 R 为-CH (CH3) CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH20H 等羟烷基。 [0009] wherein R is -CH (CH3) hydroxyalkyl CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH20H like.

[0010] 通式(I)的中间体通式(II) [0010] Intermediates of general formula (I), (II)

[0011] [0011]

Figure CN103275087AD00042

[0012]其中 R 为-CH (CH3) CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH20H 等羟烷基。 [0012] wherein R is -CH (CH3) hydroxyalkyl CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH20H like.

附图说明 BRIEF DESCRIPTION

[0013] 图为化合物A的1H-NMR图谱。 [0013] 1H-NMR spectrum of compound A graph.

具体实施方式 Detailed ways

[0014] 下面通过实施例对本发明作进一步的详细说明,实施例的目的在于说明而非限定。 [0014] The following examples of the present invention will be further described in detail, the purpose of illustrating embodiments and not limitation.

[0015] 实施例 [0015] Example

Figure CN103275087AD00051

[0016]第一步 [0016] The first step

[0017] N- [ (3aS,4R,6S,6aR) _6_ 羟基_2,2_ 二甲基-四氢_3aH_ 环戊烯并_ [d] [ I,3] - 二氧杂环戊环-4-醇]氨基甲酸苄酯合成 [0017] N- [(3aS, 4R, 6S, 6aR) _6_ _2,2_ dimethyl hydroxy - tetrahydro _3aH_ cyclopenteno _ [d] [I, 3] - dioxol ring - 4- ol] carbamate synthesis

[0018] 在500mL三口瓶中,加入(3aR,4S,6R,6aS) _6_氨基_2,2_ 二甲基四氢环戊二烯并[d][l,3] 二氧杂环戍烧-4-醇(5.0Og, 28.87mmol, 1.0eq)、碳酸钠(6.12g, 57.74mmol,2.0eq)、乙酸乙酯(200mL)磁力搅拌、冰盐浴降温至_20°C,体系为固液浑悬,开始缓慢滴加氯甲酸苄酯(5.42g,31.77mm0l,l.1eq)的乙酸乙酯溶液,维持温度在_20°C〜15°C,滴毕。 [0018] in 500mL three-neck flask, was added (3aR, 4S, 6R, 6aS) _6_ amino _2,2_ dimethyl-tetrahydro-cyclopenta [d] [l, 3] dioxol-burning Shu 4-ol (5.0Og, 28.87mmol, 1.0eq), sodium carbonate (6.12g, 57.74mmol, 2.0eq), ethyl acetate (200mL) magnetically stirred, ice-salt bath cooling to _20 ° C, a solid system muddy liquid suspension, slowly dropwise benzyl chloroformate (5.42g, 31.77mm0l, l.1eq) ethyl acetate solution, maintaining the temperature at _20 ° C~15 ° C, dropwise. TLC跟踪反应,自然升温至室温,搅拌2h反应结束。 Reaction was followed by TLC, naturally warmed to room temperature, the reaction was stirred for 2h ends. 抽滤固体,滤饼用乙酸乙酯(10mLX3)冲洗,合并滤液和冲洗液,无水硫酸钠干燥,减压旋转蒸干溶剂乙酸乙酯,得到白色固体(8.0lg, 26.06mmol),粗产率90.31 %,产物不经提纯直接投入下一步。 Solid was filtered off with suction, the filter cake with ethyl acetate (10 mL x 3) rinsing, the filtrate and washing liquid were combined, dried over anhydrous sodium sulfate, and rotary evaporated to dryness under reduced pressure ethyl acetate solvent, to give a white solid (8.0lg, 26.06mmol), the crude product rate of 90.31%, the product directly into the next step without purification.

[0019]第二步 [0019] The second step

[0020] 2-[ [ (3aS, 4R, 6S, 6aR) _6_ 苄氧基羧基氨基_2,2_ 二甲基4,5,6,6a_ 四氢_3aH_ 环戊烯并[d][l,3] 二氧杂环戊环-4-基]氧]-2-丙酸乙酯合成 [0020] 2- [[(3aS, 4R, 6S, 6aR) _6_ benzyloxy carboxyamino _2,2_ dimethyl-tetrahydro _3aH_ 4,5,6,6a_ cyclopenta [d] [l, 3] dioxol-4-yl] oxy] -2-propanoate synthesized

[0021] 在冷阱中放置250mL三口烧瓶,加入化合物I (8.0lg, 26.06mmol, 1.0eq)、无水四氢呋喃(IOOmL),机械搅拌至体系降温为-20°C,分批次加入叔丁醇钾(3.51g,31.28mol,1.2eq),加毕,维持_20°C搅拌lh。 [0021] placed in a cold trap 250mL three-neck flask, compound I (8.0lg, 26.06mmol, 1.0eq), anhydrous tetrahydrofuran (IOOmL), the cooling system is mechanically stirred until -20 ° C, was added tert-butyl batches potassium alcohol (3.51g, 31.28mol, 1.2eq), the addition, to maintain _20 ° C stirred lh. 缓慢滴加溴乙酸乙酯(5.66g,31.27m m0l,1.3eq)保持-20°C反应2h后,三口烧瓶移出冷阱,自然升温TLC跟踪反应,反应5h反应结束。 Was slowly added dropwise ethyl bromoacetate (5.66g, 31.27m m0l, 1.3eq) maintaining -20 ° C After 2h the reaction, three-necked flask cold trap was removed, the reaction followed by TLC natural temperature rise, the end of the reaction for 5h. 加入水(IOOmL),搅拌0.5h,用乙酸乙酯(100mLX3)萃取,合并有机相,无水硫酸钠干燥,减压旋转蒸干溶剂乙酸乙酯和四氢呋喃,得到无色油状液体(8.53g,20.93mol),粗产率80.32%。 Water was added (IOOmL), stirred 0.5h, and extracted with ethyl acetate (100 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure rotary ethyl acetate and tetrahydrofuran, to give colorless oil (8.53 g, 20.93mol), a crude yield of 80.32%.

[0022] 第三步 [0022] Step

[0023] N- [ (3aS,4R,6S,6aR) -6- (2-丙酸乙酯基)-2,2- 二甲基-4,5,6,6a_ 四氢-3aH_ 环戊烯并[d][l,3] 二氧杂环戊环-4-基]氨基甲酸苄酯合成 [0023] N- [(3aS, 4R, 6S, 6aR) -6- (2- ethyl-yl) -2,2-dimethyl-tetrahydro -3aH_ cyclopentene -4,5,6,6a_ and [d] [l, 3] dioxol-4-yl] carbamate synthesis

[0024] 在冷阱中放置500mL三口烧瓶,加入无水四氢呋喃(200mL)、氯化锂(1.79g,42.23mmol, 2.0eq)、机械搅拌至体系降温为-20 °C,分批次加入硼氢化钾(2.28g,42.27mmol,2.0eq),加毕,维持_15°C搅拌2h。 [0024] placed in a cold trap 500mL three-necked flask was added anhydrous tetrahydrofuran (200 mL), lithium chloride (1.79g, 42.23mmol, 2.0eq), stirred mechanically to a cooling system is -20 ° C, was added boron batches potassium hydride (2.28g, 42.27mmol, 2.0eq), the addition, to maintain _15 ° C stirred for 2h. 缓慢滴加化合物2 (8.53g,20.93mmol, 1.0eq)的无水四氢呋喃溶液,维持_20°C〜-10°C。 Was slowly added dropwise compound 2 (8.53g, 20.93mmol, 1.0eq) in anhydrous tetrahydrofuran, maintained _20 ° C~-10 ° C. 滴毕,自然升温TLC跟踪反应,室温反应4h后反应结束。 Dropwise, followed by TLC natural warming of the reaction, the reaction for 4h at room temperature the reaction was completed. 体系降温至-10°c滴加饱和氯化铵水溶液,体系放热冒泡,加毕,用乙酸乙酯(IOOmLX 3)萃取,合并有机相,无水硫酸钠干燥,减压旋转蒸干溶剂乙酸乙酯和四氢呋喃,得到无色油状液体(4.85g,13.27mol),粗产率63.40%。 Cooled to -10 ° c System dropwise addition of saturated aqueous ammonium chloride solution, bubbling system exothermic, the addition was completed, extracted with ethyl acetate (IOOmLX 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure rotating ethyl acetate and tetrahydrofuran, to give colorless oil (4.85g, 13.27mol), a crude yield of 63.40%.

[0025] 第四步 [0025] The fourth step

[0026] 2~ {[ (3aS, 4R, 6S, 6aR) -6-氛基-2, 2- 二甲基-4, 5,6,6a-四氧-3aH-环戍稀并[d][1,3] 二氧杂环戍烧-4-基]氧基} -2-丙醇合成 [0026] 2 ~ {[(3aS, 4R, 6S, 6aR) -6- atmosphere-2, 2-methyl -4, 5,6,6a- four dilute oxygen -3aH- ring and Shu [d] [1,3] dioxin Shu burning 4-yl] oxy} -2-propanol synthesized

[0027]在 250mL 单口烧瓶中,加入化合物3 (4.85g,13.27mmol,1.0eq)、钯碳(0.5g, [0027] in 250mL single-necked flask, compound 3 (4.85g, 13.27mmol, 1.0eq), palladium on carbon (0.5g,

0.leq)、甲醇(IOOmL),油泵置换气体3次;磁力搅拌通氢气反应,TLC跟踪反应,室温搅拌4h反应结束。 0.leq), methanol (IOOmL), pump displacement gas three times; magnetic stirring the reaction through hydrogen, the reaction was followed TLC, the reaction was stirred at room temperature 4h end. 抽滤钯碳,滤饼用甲醇(10mLX3)冲洗,合并滤液和冲洗液,无水硫酸钠干燥,减压旋转蒸干溶剂甲醇,得到无色油状液体(2.82g,12.1911111101),粗产率91.86(%。 Palladium carbon was filtered off with suction, the filter cake was rinsed with methanol (10 mL x 3), the combined filtrate and rinse solution, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure rotary methanol to give colorless oil (2.82g, 12.1911111101), crude yield 91.86 (%.

[0028] 第五步 [0028] The fifth step

[0029] 2- {[ (3aS, 4R, 6S, 6aR) _6_[ (5_ 氛基-6-氣~2~ 丙硫基-卩密唳~4~ 基)氛基]~2,2_ 二甲基-4, 5,6,6a-四氧_3aH_环戍稀并[d] [I, 3] 二氧杂环戍烧~4~基]氧基} ~2~丙醇合成 [0029] 2- {[(3aS, 4R, 6S, 6aR) _6_ [(5_-6-gas atmosphere propylthio ~ 2 ~ - ~ 4 ~ Jie Li adhesion yl) atmosphere yl] dimethyl ~ 2,2_ group -4, 5,6,6a- four ring Shu dilute oxygen _3aH_ and [d] [I, 3] dioxol-4 ~ yl ~ Shu burning] oxy} ~ 2 ~ propanol synthesis

[0030]在 250mL 三口烧瓶中,加入化合物4 (2.82g,12.19mmol,1.0eq)、4,6_ 二氯_2_ (丙硫基)卩密唳-5-氛基(2.90g, 12.1 QmmoI, 1.0eq)、N, N- 二异丙基乙胺(2.00g, 15.5ImmoI, [0030] in 250mL three-necked flask was added compound 4 (2.82g, 12.19mmol, 1.0eq), 4,6_-dichloro _2_ (propylthio) -5- Jie Li dense atmosphere yl (2.90g, 12.1 QmmoI, 1.0eq), N, N- diisopropylethylamine (2.00g, 15.5ImmoI,

1.2eq),油浴加热磁力搅拌,加热回流,TLC跟踪反应,搅拌4h反应结束。 1.2 eq), was heated in an oil bath with magnetic stirring, heated to reflux, TLC trace of the reaction, the reaction was stirred for 4h end. 加入水(IOOmL),搅拌30min,用乙酸乙酯(IOOmLX3)萃取,合并有机相,用水(50mLX3)洗漆有机层,无水硫酸钠干燥,减压旋转蒸干溶剂乙酸乙酯,得到淡黄色油状液体(4.57g,10.78mmol),粗产率86.55%0 Water was added (IOOmL), stirred for 30min, extracted with ethyl acetate (IOOmLX3), the combined organic phases were washed with water (50 ml x 3) The organic layer was washed paint, dried over anhydrous sodium sulfate, and rotary evaporated to dryness under reduced pressure ethyl acetate solvent, to give a pale yellow oily liquid (4.57g, 10.78mmol), a crude yield of 86.55% 0

[0031] 第六步 [0031] The sixth step

[0032] 2-{[(3aR,4S,6R,6aS)-6_[7-氯-5-丙基硫基-三唑并[4,5_d]嘧啶_3_ 基]2,2_ 二甲基-4, 5,6,6a-四氧_3aH_环戍稀并[d] [I, 3] 二氧杂环戍烧~4~基]氧基} ~2~丙醇合成 [0032] 2 - {[(3aR, 4S, 6R, 6aS) -6_ [7- chloro-5-thio - triazolo [4,5_d] pyrimidin _3_ yl] 2,2_ dimethyl - 4, 5,6,6a- four ring Shu dilute oxygen _3aH_ and [d] [I, 3] dioxol-2 ~ propanol synthesized Shu burn ~ ~ 4-yl] oxy} ~

[0033]在25011^三口烧瓶中,加入化合物5(4.57g,10.78mmol, 1.0eq)、亚硝酸钠(0.87g,12.61mmol, 1.2eq)、乙酸(3.80g, 63.28mmol,6.0eq)、甲苯(IOOmL)、水(20mL),磁力揽祥,室温TLC跟踪反应,搅拌30min反应结束。 [0033] 25011 ^ in three-necked flask, compound 5 (4.57g, 10.78mmol, 1.0eq), sodium nitrite (0.87g, 12.61mmol, 1.2eq), acetic acid (3.80g, 63.28mmol, 6.0eq), toluene (IOOmL), water (20 mL), magnetic embrace Xiang, the reaction followed by TLC at room temperature, the reaction was stirred for 30min ends. 加入饱和碳酸钠水溶液,调节pH为8〜9,分出有机层,无水硫酸钠干燥,减压旋转蒸干溶剂甲苯,得到淡黄色油状液体(3.41g,7.68mmol),粗产率72.71%。 Saturated aqueous sodium carbonate solution, adjusted to pH 8-9, the organic layer was separated, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure rotary toluene to give a pale yellow oily liquid (3.41g, 7.68mmol), crude yield 72.71% . [0034] 第七步 [0034] The seventh step

[0035] N-{[(IR,2S)-2-(3,4-二氟苯基)环丙基]_6-[7_氯_5_丙基硫基-三唑并[4,5_d] B密唳-3-基]_2,2_ 二甲基_4,5,6,6a_四氧_3aH_环戍稀并[d] [I, 3] 二氧杂环戍烷-4-基]氧基} -2-丙醇合成 [0035] N - {[(IR, 2S) -2- (3,4- difluorophenyl) cyclopropyl] _6- [7_ chloro _5_ propylthio - triazolo [4,5_d ] B dense Li 3-yl] _2,2_ dimethyl _4,5,6,6a_ four ring Shu dilute oxygen _3aH_ and [d] [I, 3] dioxin-4-shu yl] oxy} -2-propanol synthesized

[0036]在 IOOmL 三口烧瓶中,加入化合物5(3.41g,7.68mmol,1.0eq)、(1R,2S) -2-(3,4- 二氟苯基)环丙胺(1.30g, 7.68mmol, 1.0eq)、N, N- 二异丙基乙胺(1.27g, 9.78mmol,1.3eq)、二氯甲烷(70mL),磁力搅拌,室温TLC跟踪反应,搅拌15h反应结束。 [0036] In IOOmL three-necked flask, compound 5 (3.41g, 7.68mmol, 1.0eq), (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (1.30g, 7.68mmol, 1.0eq), N, N- diisopropylethylamine (1.27g, 9.78mmol, 1.3eq), dichloromethane (70 mL), stirred magnetically, the reaction followed by TLC at room temperature, the reaction was stirred 15h ends. 用0.0lmol/L稀盐酸洗涤体系至体系pH为7,分出有机层,无水硫酸钠干燥,减压旋转蒸干溶剂二氯甲烷,得到无色油状液体(3.50g, 6.07mmol),粗产率81 %。 With 0.0lmol / L System was washed with dilute hydrochloric acid to a pH of 7 system, the organic layer was separated, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure rotary dichloromethane, to give colorless oil (3.50g, 6.07mmol), the crude yield 81%.

[0037] 第八步 [0037] Eighth Step

[0038] (11?,21?,35,510-3-{5-硫丙基-7-[[(11?,25)-2-(3,4-二氟苯基)环丙基]氨基]三唑并[4,5-d]嘧啶-3-基}-5 (2-羟基异丙氧基)环戊基-1,2-二醇合成及表征 [0038] (11, 21, 35,510-3- {5-epithiopropyl -7--?? [[(11, 25) -2- (3,4-difluorophenyl) cyclopropyl]? amino] triazolo [4,5-d] pyrimidine-3} -5 (2-hydroxy-isopropoxy) cyclopentyl-yl-1,2-diol synthesis and Characterization

[0039]在 IOOmL 单口烧瓶中,加入化合物7 (3.50g,6.07mmol, 1.0eq)、12mol/L 浓盐酸(5mL)、甲醇(80mL),磁力搅拌,室温TLC跟踪反应,搅拌4h反应结束。 [0039] In IOOmL-neck flask, was added compound 7 (3.50g, 6.07mmol, 1.0eq), 12mol / L of concentrated hydrochloric acid (5 mL), methanol (80 mL), stirred magnetically, the reaction followed by TLC at room temperature, the reaction was stirred for 4h end. 加入碳酸钠调节pH为8〜9,抽滤出固体,滤饼用甲醇(IOmLX 3)冲洗,无水硫酸钠干燥,减压旋转蒸干溶剂,得到无色油状液体(2.80g,5.22mmol),粗产率86.00%。 Sodium carbonate was added to adjust the pH 8-9, the solid was filtered off with suction, the filter cake was rinsed with methanol (IOmLX 3), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and rotation, to obtain a colorless oily liquid (2.80g, 5.22mmol) crude yield of 86.00%. 将产品用柱层析色谱提纯,洗脱剂(二氯甲烷:甲醇=60: 1),得到白色固体,即为化合物A(l.lg,2.05mmol)。 The product was purified by column chromatography, eluent (methylene chloride: methanol = 60: 1) to give a white solid, i.e. Compound A (l.lg, 2.05mmol).

IHNMR (CD3OD, 400MHz):0.97 (t, J = 7.5Ηζ,3Η,CH3), 1.18 (t, J = 7.5Ηζ,3Η,CH3),1.31 〜1.41 (m,2H, CH2),L 47 〜L 52 (m, 1H, CH),L 58 〜L 64 (m, 2H, CH2),2.17 〜2.23 (m,2H, CH2),2.76 〜2.82 (m, 1H, CH),2.96 〜3.02 (m, 1H, CH),3.03-3.06 (m, 1H, CH),3.08 (S,1H, CH),3.53 〜3.57 (m, 2H, CH2),3.64-3.78 (m, 1H, CH),4.07 (t, 1H, CH),4.10 (t, 1H, CH), IHNMR (CD3OD, 400MHz): 0.97 (t, J = 7.5Ηζ, 3Η, CH3), 1.18 (t, J = 7.5Ηζ, 3Η, CH3), 1.31 ~1.41 (m, 2H, CH2), L 47 ~L 52 (m, 1H, CH), L 58 ~L 64 (m, 2H, CH2), 2.17 ~2.23 (m, 2H, CH2), 2.76 ~2.82 (m, 1H, CH), 2.96 ~3.02 (m, 1H, CH), 3.03-3.06 (m, 1H, CH), 3.08 (S, 1H, CH), 3.53 ~3.57 (m, 2H, CH2), 3.64-3.78 (m, 1H, CH), 4.07 (t , 1H, CH), 4.10 (t, 1H, CH),

4.78 (t, 1H, CH),4.83 (br, 4H, OH, NH),5.10 〜5.16 (m, 1H, CH),7.09 (s,1H, C6H5),7.15 〜7.26 (m, 2H, C6H5)。 4.78 (t, 1H, CH), 4.83 (br, 4H, OH, NH), 5.10 ~5.16 (m, 1H, CH), 7.09 (s, 1H, C6H5), 7.15 ~7.26 (m, 2H, C6H5) .

Claims (3)

1.一种通式(I)所示的三氮唑并嘧啶类衍生物 Triazole represented by (I) 1. and pyrimidine derivatives of general formula
Figure CN103275087AC00021
其中R 为-CH(CH3)CH2OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH 等羟烷基;优选-CH(CH3)CH2OH, -CH(CH2CH3) CH2OH, -C (CH3)2CH2OH0 Wherein R is -CH (CH3) CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH2OH hydroxyalkyl group and the like; preferably -CH (CH3) CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH2OH0
2.根据权利要求1所述通式(I),其为中间体通式(II)所示的三氮唑并嘧啶类衍生物 According to claim 1 of the formula (I), its derivatives and pyrimidine intermediates of formula (II) azole-triazole represented by
Figure CN103275087AC00022
其中R 为-CH(CH3)CH2OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH 等羟烷基;优选-CH(CH3)CH2OH, -CH(CH2CH3) CH2OH, -C (CH3)2CH2OH0 Wherein R is -CH (CH3) CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH2OH hydroxyalkyl group and the like; preferably -CH (CH3) CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH2OH0
3.根据权利要求1所述通式(I),当R为-CH(CH3)CH2OH基团时,化合物的结构为 1 according to the formula (I) as claimed in claim, when R is -CH (CH3) CH2OH group, the compound of structure
Figure CN103275087AC00023
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CN1680340A (en) * 2000-06-02 2005-10-12 阿斯特拉曾尼卡有限公司 Novel triazolo pyrimidine compounds
US20080312257A1 (en) * 2006-10-31 2008-12-18 Han-Cheng Zhang Triazolopyrimidine derivatives as ADP P2Y12 receptor antagonists
WO2010030224A1 (en) * 2008-09-09 2010-03-18 Astrazeneca Ab A process for preparing [1s- [1-alpha, 2-alpha, 3-beta (1s*, 2r*) 5-beta] ] -3- [7- [2- (3, 4-dif luorophenyl) -cyclopropylamino] - 5- (propylthio) -3h-1, 2, 3-triazolo [4, 5-d] pyrimidin-3-yl] -5- (2- hydroxyethoxy) cyclopentane-1, 2-diol and to its intermediates
WO2011017108A2 (en) * 2009-07-27 2011-02-10 Auspex Pharmaceuticals, Inc. Cyclopropyl modulators of p2y12 receptor
CN102311437A (en) * 2010-07-01 2012-01-11 北京迈劲医药科技有限公司 Preparation method of platelet-aggregation-resisting medicament Ticagrelor
CN102924457A (en) * 2011-08-12 2013-02-13 上海恒瑞医药有限公司 Triazolopyrimidine derivatives, preparation method and uses thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1680340A (en) * 2000-06-02 2005-10-12 阿斯特拉曾尼卡有限公司 Novel triazolo pyrimidine compounds
US20080312257A1 (en) * 2006-10-31 2008-12-18 Han-Cheng Zhang Triazolopyrimidine derivatives as ADP P2Y12 receptor antagonists
WO2010030224A1 (en) * 2008-09-09 2010-03-18 Astrazeneca Ab A process for preparing [1s- [1-alpha, 2-alpha, 3-beta (1s*, 2r*) 5-beta] ] -3- [7- [2- (3, 4-dif luorophenyl) -cyclopropylamino] - 5- (propylthio) -3h-1, 2, 3-triazolo [4, 5-d] pyrimidin-3-yl] -5- (2- hydroxyethoxy) cyclopentane-1, 2-diol and to its intermediates
WO2011017108A2 (en) * 2009-07-27 2011-02-10 Auspex Pharmaceuticals, Inc. Cyclopropyl modulators of p2y12 receptor
CN102311437A (en) * 2010-07-01 2012-01-11 北京迈劲医药科技有限公司 Preparation method of platelet-aggregation-resisting medicament Ticagrelor
CN102924457A (en) * 2011-08-12 2013-02-13 上海恒瑞医药有限公司 Triazolopyrimidine derivatives, preparation method and uses thereof

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