CN105198864B - Non-solvent for the preparation of pyrimidine compounds cyclopentyl method - Google Patents

Non-solvent for the preparation of pyrimidine compounds cyclopentyl method Download PDF

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CN105198864B
CN105198864B CN201510687681.8A CN201510687681A CN105198864B CN 105198864 B CN105198864 B CN 105198864B CN 201510687681 A CN201510687681 A CN 201510687681A CN 105198864 B CN105198864 B CN 105198864B
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cyclopentyl
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冯新光
李学超
李伟
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华仁药业股份有限公司
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Abstract

本发明涉及种环戊基嘧啶化合物的无溶剂制备方法,属于化学制备方法领域。 Solventless preparation process of the present invention relates to pyrimidine compounds cyclopentyl species, belonging to the field of chemical preparation. 所述环戊基嘧啶化合物(SM‑C)的无溶剂制备方法,采用SM‑A在碱性条件下与SM‑B无溶剂反应生成SM‑C。 The solvent-free preparation of cyclopentyl pyrimidine compound (SM-C), the use of SM-A under basic conditions with no reaction of SM-B solvent SM-C. 本方法避免了有机溶剂的使用,降低了生产成本,减少环境污染,后处理简化无需除掉有机溶剂;由于是无溶剂反应,反应体积大幅缩小,提高了设备生产能力;由于是无溶剂反应,反应物浓度提高,反应原料转化率提高,反应速率提高,反应时间大幅缩短;同时,反应可在常压条件下生产,无需高压反应釜,有利于生产。 This process avoids the use of organic solvents, reduce production costs, reduce environmental pollution, the process can be simplified without removal of organic solvent; as solvent-free reaction, the reaction volume reduced significantly, increase the plant capacity; as the reaction solvent-free, increase reactant concentrations, the reaction rate increased feed conversion, reaction rate increased significantly shorten the reaction time; while, the reaction may be produced under normal pressure conditions, without autoclave, favor the production.

Description

一种环戊基嘧啶化合物的无溶剂制备方法 Non-solvent for the preparation of pyrimidine compounds cyclopentyl method

技术领域 FIELD

[0001] 本发明涉及一种环戊基喃啶化合物的无溶剂制备方法,属于化学制备方法领域。 [0001] The present invention relates to a piperidine compound cyclopentyl thiopyran solvent-free preparation method belongs to the field of chemical preparation.

背景技术 Background technique

[0002] 替格瑞洛是英国阿斯利康(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 a British 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)上的嘌呤2受体(purinoceptor 2,P2)亚型P2Y12,不需要代谢激活,对二磷酸腺苷(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,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) purine receptor (purinoceptor 2, P2) the P2Y12 subtype, does not require metabolic activation, platelet adenosine diphosphate (ADP) induced aggregation significantly inhibition and rapid onset of action for oral use, can effectively improve the symptoms of acute coronary.

[0003] 环戊基嘧啶化合物(SM-C)是替格瑞洛的重要中间体,其制备方法如下: [0003] cyclopentyl pyrimidine compound (SM-C) is an important intermediate ticagrelor, was prepared as follows:

Figure CN105198864BD00031

[0005] SM-A或其盐在碱性条件下,在有机溶剂中与SM-B反应生成SM-C。 [0005] SM-A or a salt thereof under basic conditions in an organic solvent and SM-B reaction SM-C.

[0006] SM-A盐类多为白色固体粉末,恪点较高,因此其与SM-B反应时,需要添加溶剂,使反应顺利进行。 [0006] SM-A Multi salt as a white solid powder, Ke higher point, so its reaction with SM-B, we need to add the solvent, smooth reaction. 专利WO 2001092263是SM-A的盐与SM-B在碱性条件、有机溶剂中加压反应生成SM-C;专利WO 2010030224是SM-A的盐与SM-B在碱性低氧条件、有机溶剂中加压反应生成SM-C;专利CN103626745是SM-A或其盐与SM-B在碱性条件、高沸点有机溶剂中常压反应生成SM-C,该方法避免了高压反应釜的使用,有利于生产。 Patent WO 2001092263 is SM-A and SM-B salt of a pressurized reaction SM-C in basic conditions, in an organic solvent; Patent WO 2010030224 is SM-A and SM-B salt in alkaline hypoxic conditions, organic pressurized reaction solvent SM-C; Patent CN103626745 is SM-a and SM-B or a salt thereof atmospheric reaction SM-C in alkaline conditions, high-boiling organic solvent, the method avoids the use of an autoclave conducive to production. 纵观现有技术,所述反应都是在有机溶剂条件下反应,虽然高沸点有机溶剂的使用可以避免高压反应釜的使用但是后期高沸点有机溶剂的除尽较困难。 Throughout the prior art, the reactions are in an organic solvent under the reaction conditions, but divisible late high-boiling organic solvent is difficult to use high-boiling organic solvent, although the use of an autoclave to be avoided.

发明内容 SUMMARY

[0007] 本发明的目的是提供一种环戊基嘧啶化合物的无溶剂制备方法,所述制备方法以SM-A与SM-B在碱性条件下,不加有机溶剂,加热反应制备环戊基嘧啶化合物SM-C;本方法避免了有机溶剂的使用,后处理简化无需除掉有机溶剂,反应可在常压条件下生产,无需高压反应釜,反应体积大幅缩小,反应时间大幅缩短,有利于生产。 [0007] The object of the present invention is to provide a pyrimidine compound cyclopentyl solvent-free production method, the preparation method SM-A and SM-B under basic conditions, without addition of an organic solvent and heating the reaction cyclopentanol pyrimidine compound of SM-C; the present process avoids the use of organic solvents, the process can be simplified without removal of the organic solvent, the reaction may be produced under normal pressure conditions, without autoclave, significantly reduced the volume of the reaction, the reaction time is significantly reduced, there conducive to the production.

[0008] 本发明的技术方案为: [0008] The aspect of the present invention is:

[0009] —种环戊基嘧啶化合物(SM-C)的无溶剂制备方法,采用如下反应式进行缩合反应: [0009] - a solvent-free method of producing an cyclopentyl pyrimidine compound (SM-C), using a condensation reaction following reaction formula:

Figure CN105198864BD00041

[0011] 其中:SM-A在碱性条件下与SM-B无溶剂反应生成SM-C。 [0011] wherein: SM-A under basic conditions with no reaction of SM-B solvent SM-C.

[0012] 进一步地,所述的碱为三乙胺或N,N-二异丙基乙胺,尤其优选N,N-二异丙基乙胺。 [0012] Preferably, the base is triethylamine or N, N- diisopropylethylamine, particularly preferably N, N- diisopropylethylamine.

[0013] 进一步地,所述反应温度为90-140°C,优选120-130°C。 [0013] Further, the reaction temperature is 90-140 ° C, preferably 120-130 ° C.

[0014] 进一步地,所述反应时间为5-50小时,优选8-12小时。 [0014] Further, the reaction time is 5-50 hours, preferably 8-12 hours.

[0015] 进一步地,所述反应物投料摩尔比为SM-A: SM-B:碱=1:1:1-10,优选SM-A: SM-B: 碱=1:1:1.5-2.5〇 [0015] Further, the feed molar ratio of reactants as SM-A: SM-B: base = 1: 1: 1-10, preferably SM-A: SM-B: base = 1: 1: 1.5-2.5 〇

[0016] 与现有技术相比,本发明的有益效果为: [0016] Compared with the prior art, the beneficial effects of the present invention are:

[0017] (1)本发明中SM-A熔点较低,加热条件下为溶液,在反应时可不使用有机溶剂,降低了生产成本,减少环境污染,后处理简化无需除掉有机溶剂。 [0017] (1) of the present invention is SM-A lower melting point, a solution under heating, without using an organic solvent in the reaction, reduce production costs, reduce environmental pollution, the process can be simplified without removal of the organic solvent.

[0018] (2)由于是无溶剂反应,反应体积大幅缩小,提高了设备生产能力。 [0018] (2) Since the solvent-free reaction, the reaction volume reduced significantly, increase the plant capacity.

[0019] (3)由于是无溶剂反应,反应物浓度提高,反应原料转化率提高,反应速率提高,反应时间大幅缩短。 [0019] (3) Since the solvent-free reaction, the reactant concentration is increased, the reaction rate increased feed conversion, reaction rate increased significantly shorten the reaction time.

[0020] ⑷同时,反应可在常压条件下生产,无需高压反应釜,有利于生产。 [0020] ⑷ Meanwhile, the reaction may be produced under normal pressure conditions, without autoclave, favor the production.

具体实施方式 Detailed ways

[0021] 以下结合实施例对本发明进行详细的阐述。 [0021] The following embodiments in conjunction with the present invention in detail.

[0022] 实施例1 [0022] Example 1

[0023] 取500ml三口烧瓶,配有冷凝回流管和氮气球保护,加入2- [ [ (3AR,4S,6R,6AS) -6-氨基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂环戊烷-4-基]氧基]乙醇(88.7g, 408.3mmol,I · Oeq)、4,6_二氯-2-(丙硫基)-5-氨基喃啶(98 · 0g,408 · 3mmol,I · Oeq)、N,N_二异丙基乙胺(79. lg,612.5mmol,1.5eq),120-125°C加热搅拌10小时(HPLC检测,峰面积百分比4,6_二氯-2-(丙硫基)-5-氨基嘧啶<1.0%),停止加热降温至<60°C,加入乙酸乙酯和水洗涤萃取。 [0023] Take 500ml three-necked flask, equipped with a reflux condenser and nitrogen balloon protection tube was added 2- [[(3AR, 4S, 6R, 6AS) -6- amino-tetrahydro-2,2-dimethyl-ring -4H- pentene-1,3-dioxolan-4-yl] oxy] ethanol (88.7g, 408.3mmol, I · Oeq), 4,6_-dichloro-2- (propylthio) - 5-amino-pyran-piperidine (98 · 0g, 408 · 3mmol, I · Oeq), N, N_-diisopropylethylamine (79. lg, 612.5mmol, 1.5eq), 120-125 ° C was heated with stirring 10 hours (HPLC detection, the peak area percentage 4,6_-dichloro-2- (propylthio) -5-amino-pyrimidine <1.0%), heating was stopped and cooled to <60 ° C, washed with ethyl acetate and water were added and extracted. 减压浓缩至乙酸乙酯剩余200ml,加入石油醚重结晶,得类白色固体160g,收率93.5%,HPLC峰面积百分比SM-C彡98.5%。 Ethyl acetate was concentrated under reduced pressure to a residual 200ml, was added petroleum ether, to give 160g white solid, yield 93.5%, HPLC peak area percentage 98.5% San SM-C.

[0024] 实施例2 [0024] Example 2

[0025] 取500ml三口烧瓶,配有冷凝回流管和氮气球保护,加入2- [ [ (3AR,4S,6R,6AS) -6-氨基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂环戊烷-4-基]氧基]乙醇(88.7g, 408.3mmol,I · Oeq)、4,6_二氯-2-(丙硫基)-5-氨基喃啶(98 · 0g,408 · 3mmol,I · Oeq)、N,N_二异丙基乙胺(105.58,816.6!11111〇1,2.069),120-125°(:加热搅拌10小时0^1^(:检测,峰面积百分比4,6_二氯-2-(丙硫基)-5-氨基嘧啶<1.0%),停止加热降温至<60°C,加入乙酸乙酯和水洗涤萃取。减压浓缩至乙酸乙酯剩余200ml,加入石油醚重结晶,得类白色固体152.7g, 收率89 %,HPLC峰面积百分比SM-C彡98.5 %。 [0025] Take 500ml three-necked flask, equipped with a reflux condenser and nitrogen balloon protection tube was added 2- [[(3AR, 4S, 6R, 6AS) -6- amino-tetrahydro-2,2-dimethyl-ring -4H- pentene-1,3-dioxolan-4-yl] oxy] ethanol (88.7g, 408.3mmol, I · Oeq), 4,6_-dichloro-2- (propylthio) - 5-amino-pyran-piperidine (98 · 0g, 408 · 3mmol, I · Oeq), N, N_-diisopropylethylamine (105.58,816.6 11111〇1,2.069!), 120-125 ° (: heating and stirring 10 h ^ 1 ^ 0 (: detecting, peak area percent 4,6_-dichloro-2- (propylthio) -5-amino-pyrimidine <1.0%), heating was stopped and cooled to <60 ° C, ethyl acetate and extract was washed with water. ethyl acetate was concentrated under reduced pressure to a residual 200ml, petroleum ether was added to give an off-white solid 152.7g, yield 89%, HPLC peak area percentage 98.5% San SM-C.

[0026] 实施例3 [0026] Example 3

[0027] 取500ml三口烧瓶,配有冷凝回流管和氮气球保护,加入2- [ [ (3AR,4S,6R,6AS) -6-氨基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂环戊烷-4-基]氧基]乙醇(88.7g, 408.3mmol,I · Oeq)、4,6_二氯-2-(丙硫基)-5-氨基喃啶(98 · 0g,408 · 3mmol,I · Oeq)、N,N_二异丙基乙胺(131.98,1020.75臟〇1,2.569),125-130°(:加热搅拌8小时(即1^(:检测,峰面积百分比4,6_二氯-2-(丙硫基)-5-氨基嘧啶<1.0%),停止加热降温至<60°C,加入乙酸乙酯和水洗涤萃取。减压浓缩至乙酸乙酯剩余200ml,加入石油醚重结晶,得类白色固体150.5g, 收率88 %,HPLC峰面积百分比SM-C彡98.5 %。 [0027] Take 500ml three-necked flask, equipped with a reflux condenser and nitrogen balloon protection tube was added 2- [[(3AR, 4S, 6R, 6AS) -6- amino-tetrahydro-2,2-dimethyl-ring -4H- pentene-1,3-dioxolan-4-yl] oxy] ethanol (88.7g, 408.3mmol, I · Oeq), 4,6_-dichloro-2- (propylthio) - 5-amino-pyran-piperidine (98 · 0g, 408 · 3mmol, I · Oeq), N, N_-diisopropylethylamine (131.98,1020.75 dirty 〇1,2.569), 125-130 ° (: heating for 8 hours (i.e., 1 ^ (: detecting, peak area percent 4,6_-dichloro-2- (propylthio) -5-amino-pyrimidine <1.0%), heating was stopped and cooled to <60 ° C, was added ethyl acetate and water extract was washed with. ethyl acetate was concentrated under reduced pressure to a residual 200ml, petroleum ether was added to give an off-white solid 150.5 g, yield 88%, HPLC peak area percentage 98.5% San SM-C.

[0028] 实施例4 [0028] Example 4

[0029] 取500ml三口烧瓶,配有冷凝回流管和氮气球保护,加入2- [ [ (3AR,4S,6R,6AS) -6-氨基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂环戊烷-4-基]氧基]乙醇(88.7g, 408.3mmol,I · Oeq)、4,6_二氯-2-(丙硫基)-5-氨基喃啶(98 · 0g,408 · 3mmol,I · Oeq)、N,N_二异丙基乙胺(79. lg,612.5mmol,1.5eq),110-115°C加热搅拌20-30小时(HPLC检测,峰面积百分比4,6_二氯-2-(丙硫基)-5-氨基嘧啶<1.0%),停止加热降温至<60°C,加入乙酸乙酯和水洗涤萃取。 [0029] Take 500ml three-necked flask, equipped with a reflux condenser and nitrogen balloon protection tube was added 2- [[(3AR, 4S, 6R, 6AS) -6- amino-tetrahydro-2,2-dimethyl-ring -4H- pentene-1,3-dioxolan-4-yl] oxy] ethanol (88.7g, 408.3mmol, I · Oeq), 4,6_-dichloro-2- (propylthio) - 5-amino-pyran-piperidine (98 · 0g, 408 · 3mmol, I · Oeq), N, N_-diisopropylethylamine (79. lg, 612.5mmol, 1.5eq), 110-115 ° C was heated with stirring 20 30 (HPLC detection, the peak area percentage 4,6_-dichloro-2- (propylthio) -5-amino-pyrimidine <1.0%), heating was stopped and cooled to <60 ° C, water was added and extracted with ethyl acetate and washed with h . 减压浓缩至乙酸乙酯剩余200ml,加入石油醚重结晶,得类白色固体158.7g,收率92.5 %,HPLC峰面积百分比SM-C彡98.5 %。 Ethyl acetate was concentrated under reduced pressure to a residual 200ml, petroleum ether was added to give an off-white solid 158.7 g, yield 92.5%, HPLC peak area percentage 98.5% San SM-C.

[0030] 实施例5 [0030] Example 5

[0031] 取500ml三口烧瓶,配有冷凝回流管和氮气球保护,加入2- [ [ (3AR,4S,6R,6AS) -6-氨基四氢-2,2-二甲基-4H-环戊烯并-1,3-二氧杂环戊烷-4-基]氧基]乙醇(88.7g, 408 · 3mmol,I .Oeq)、4,6_二氯-2-(丙硫基)-5-氨基喃啶(98.0g,408.3mmol,I .Oeq)、三乙胺(124g,1226mmol,3. Oeq),加热至回流搅拌48小时(HPLC检测,峰面积百分比4,6-二氯-2-(丙硫基)-5-氨基嘧啶<8.0%),停止加热降温至<60°C,加入乙酸乙酯和水洗涤萃取。 [0031] Take 500ml three-necked flask, equipped with a reflux condenser and nitrogen balloon protection tube was added 2- [[(3AR, 4S, 6R, 6AS) -6- amino-tetrahydro-2,2-dimethyl-ring -4H- pentene-1,3-dioxolan-4-yl] oxy] ethanol (88.7g, 408 · 3mmol, I .Oeq), 4,6_-dichloro-2- (propylthio) thiopyran-5-amino pyridine (98.0g, 408.3mmol, I .Oeq), triethylamine (124g, 1226mmol, 3. Oeq), was heated to reflux for 48 hours (HPLC detection, peak area percentage of 4,6-dichloro 2- (propylthio) -5-amino-pyrimidine <8.0%), heating was stopped and cooled to <60 ° C, washed with ethyl acetate and water were added and extracted. 减压浓缩至乙酸乙酯剩余200ml,加入石油醚重结晶,得类白色固体154.8g,收率90.5 %,HPLC 峰面积百分比SM-C彡98.5 %。 Ethyl acetate was concentrated under reduced pressure to a residual 200ml, petroleum ether was added to give an off-white solid 154.8 g, yield 90.5%, HPLC peak area percentage 98.5% San SM-C.

Claims (5)

1. 一种环戊基嘧啶化合物的无溶剂制备方法,其特征在于,采用如下反应式进行缩合反应: 1. A solvent-free method for preparing pyrimidine compounds cyclopentyl, characterized in that, using the following condensation reaction of reaction formula:
Figure CN105198864BC00021
其中:SM-A在碱性条件下与SM-B无溶剂反应生成SM-C; 所述反应物投料摩尔比为SM-A: SM-B:碱=1:1:1.5-2.5; 所述的碱为三乙胺或N,N-二异丙基乙胺; 反应温度为110-130 °C。 Wherein: SM-A under basic conditions with no reaction of SM-B solvent SM-C; the molar ratio of reactant feed of SM-A: SM-B: base = 1: 1: 1.5-2.5; the the base is triethylamine or N, N- diisopropylethylamine; reaction temperature is 110-130 ° C.
2. 根据权利要求1所述的环戊基嘧啶化合物的无溶剂制备方法,其特征在于,所述的碱为N,N-二异丙基乙胺。 The preparation method of solvent-free cyclopentyl pyrimidine compound according to claim 1, wherein said base is N, N- diisopropylethylamine.
3. 根据权利要求1所述的环戊基嘧啶化合物的无溶剂制备方法,其特征在于:所述反应温度为120-130°C。 The preparation method of solvent-free 1-cyclopentyl-pyrimidine compounds as claimed in claim, characterized in that: the reaction temperature is 120-130 ° C.
4. 根据权利要求1所述的环戊基嘧啶化合物的无溶剂制备方法,其特征在于:所述反应时间为5-50小时。 The preparation method of solvent-free 1-cyclopentyl-pyrimidine compounds as claimed in claim, characterized in that: the reaction time is 5-50 hours.
5. 根据权利要求4所述的环戊基嘧啶化合物的无溶剂制备方法,其特征在于:所述反应时间为8-12小时。 5. Preparation of a solvent-free cyclopentyl pyrimidine compounds as claimed in claim 4, wherein: the reaction time is 8-12 hours.
CN201510687681.8A 2015-10-21 2015-10-21 Non-solvent for the preparation of pyrimidine compounds cyclopentyl method CN105198864B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103626745A (en) * 2013-12-04 2014-03-12 青岛黄海制药有限责任公司 Preparation method for ticagrelor intermediate

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GB0013488D0 (en) * 2000-06-02 2000-07-26 Astrazeneca Ab Chemical compound

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103626745A (en) * 2013-12-04 2014-03-12 青岛黄海制药有限责任公司 Preparation method for ticagrelor intermediate

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