- Preparation method of ticagrelor intermediate
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The invention provides a preparation method as shown in a formula I shown in the specification, especially, a preparation method of 4, 6-dichloro-2-(propylthio)-5-aminopyrimidine. The invention provides a novel method for preparing the ticagrelor intermediate.
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Paragraph 0004; 0006-0009
(2021/07/09)
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- Synthesis method of 4,6-dichloro-2-propylmercapto-5-aminopridine
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The invention discloses a synthesis method of 4,6-dichloro-2-propylmercapto-5-aminopridine. The synthesis method comprises the following synthesis steps: (1) dissolving diethyl aminomalonate with a protecting group and thiourea in an organic solvent, and conducting reacting under the catalysis of alkali to obtain a compound 1; (2) dissolving the compound 1 in a sodium hydroxide or potassium hydroxide solution, adding an organic solvent, then adding bromopropane into the mixed solvent, and carrying out a propane alkylation reaction to obtain a compound 2; (3) removing an amino protecting group from the compound 2 to obtain a compound 3; and (4) adding organic alkali and a chlorination reagent into the compound 3 for a chlorination reaction to obtain a target compound 4. The synthesis method disclosed by the invention has the advantages of high propane alkylation reaction selectivity, no need for a high-risk nitration reaction, no need for a metal reduction nitro reaction producing high content of solid waste, no need for a high-cost metal catalytic hydrogenation step, cheap and easily available equipment and suitability for industrial production.
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Paragraph 0059-0061
(2021/06/26)
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- Pyrimido triazole compound and medical application thereof (by machine translation)
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The present invention relates to a compound of general (I) or a hydrate thereof or a pharmaceutically acceptable salt, thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same or a pharmaceutically acceptable salt thereof, and use, of the compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament . The medicament is for anti-platelet aggregation and treatment of related diseases such as antithrombotic . (by machine translation)
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Paragraph 0043; 0076-0079
(2020/05/30)
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- Purification method of 4,6-dichloro-2-(thiopropyl)-5-aminopyrimidine
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The invention discloses a purification method of 4,6-dichloro-2-(thiopropyl)-5-aminopyrimidine. The method comprises steps including oil removal, salification, dissociation and recrystallization purification of a crude 4,6-dichloro-2-(thiopropyl)-5-aminopyrimidine product to finally obtain high-purity 4,6-dichloro-2-(thiopropyl)-5-aminopyrimidine. The purification method disclosed by the inventionis simple and convenient to operate, high in yield and suitable for large-scale production.
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Paragraph 0060-0069
(2020/10/21)
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- Synthesis method of ticagrelor intermediate
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The invention provides a synthesis method of a ticagrelor intermediate 1. By selecting a more stable amino protecting group, the formation of by-products in the cyclization step is favorably controlled, the reaction conditions in each step are mild, the conversion rate is higher, the cost is effectively reduced, and the method is suitable for industrial production.
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Paragraph 0056-0058
(2020/06/16)
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- Design, synthesis and in vitro biological evaluation of novel [1,2,3]triazolo[4,5-d]pyrimidine derivatives containing a thiosemicarbazide moiety
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A series of hybrid molecules containing [1,2,3]triazolo[4,5-d]pyrimidine and thiosemicarbazide moieties were designed, synthesized and evaluated for their antiproliferative activities against MGC-803, NCI-H1650 and PC-3 human cancer cells. Some of the synthesized compounds showed moderate to good activity against three selected cancer cell lines. Among these compounds, compound 29 displayed the most potent antiproliferative activity as well as good selectivity between cancer cells and normal cells. Further mechanism studies revealed that compound 29 could obviously inhibit the colony formation and migration of MGC-803 as well as induced apoptosis.
- Geng, Peng-Fei,Liu, Xue-Qi,Zhao, Tao-Qian,Wang, Cong-Cong,Li, Zhong-Hua,Zhang, Ji,Wei, Hao-Ming,Hu, Biao,Ma, Li-Ying,Liu, Hong-Min
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p. 147 - 156
(2018/02/10)
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- Synthesis, Antiplatelet Aggregation Activity Evaluation and 3D-QSAR of a Series of Novel 6-Alkylamino(Alkoxyl)-2-Propylthio-8-Azapurine Nucleosides
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A series of novel 6-alkylamino(alkoxyl)-2-propylthio-8-azapurine nucleosides were synthesized by an improved route, and the human antiplatelet aggregation activities of these new compounds were evaluated. A self-organizing molecular field analysis method was used to study the three-dimensional quantitative structure–activity relationship of these novel nucleosides. The results of the antiplatelet aggregation activity evaluation and analysis of the self-organizing molecular field analysis models through shape and electrostatic grids may provide a basis for the development of new and potent antiplatelet agents.
- Du,Yu,Deng,Lu,Li
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p. 436 - 449
(2017/02/05)
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- Pyrimidine and triazole containing LSD1 inhibitor and preparation method and application thereof
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The invention belongs to the field of medicinal chemistry, and discloses a pyrimidine and triazole containing compound and a preparation method and application thereof in preparation of anti-cancer medicine with lysine specific demethylase 1 (LSD1) being a target. The general formula of the compound is shown in the drawing I. In-vitro LSD1 enzyme inhibition activity experiments prove that by inhibiting LSD1 activity, the compound has obvious inhibiting and killing effects on kinds of cancer cells and can be applied to preparation of the anti-cancer medicine as a further developed lead compound.
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Paragraph 0086; 0087
(2017/04/03)
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- Design, synthesis and antiproliferative activity of thiazolo[5,4-d]pyrimidine derivatives through the atom replacement strategy
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A series of thiazolo[5,4-d]pyrimidine derivatives were designed through the atom replacement strategy based on biologically validated scaffolds and then evaluated for their antiproliferative activities on cancer cell lines. The structure-activity relationship studies were conducted, leading to the identification of compound 22, which exhibited good antiproliferative activity against HGC-27 with an IC50 value of 1.22 μM and low toxicity against GES-1 cells. Mechanistic studies showed that compound 22 inhibited the colony formation and migration of HGC-27 as well as induced apoptosis. The western blot experiments proved that compound 22 up-regulated expression of Bax, down-regulated expression levels of Bcl-2 and cleaved caspased-3/9. These findings indicate that compound 22 may serve as a template for designing new agents for the treatment of human gastric cancers. The atom replacement strategy could be viable strategy for designing new anticancer drugs and may find its applications in drug design.
- Li, Zhong-Hua,Liu, Xue-Qi,Geng, Peng-Fei,Zhang, Ji,Ma, Jin-Lian,Wang, Bo,Zhao, Tao-Qian,Zhao, Bing,Zhang, Xin-Hui,Yu, Bin,Liu, Hong-Min
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p. 1034 - 1041
(2017/08/02)
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- Design, synthesis, and biological evaluation of new thiazolo[5,4-: D] pyrimidine derivatives as potent antiproliferative agents
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A series of thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activities against several human cancer cell lines. Structure-activity relationship studies were carried out, showing that most of the target compounds had good inhibition against the tested cell lines. Among them, compound 7i exhibited potent inhibition against human gastric cancer cells MGC-803 and HGC-27 with IC50 values of 4.64 and 5.07 μM, respectively and around 12-fold selectivity between MGC-803 and GES-1, indicating a relatively low toxicity to normal cells. The potency and low toxicity of compound 7i make the thiazolo[5,4-d]pyrimidine an attractive scaffold for designing new derivatives selectively targeting MGC-803 cells.
- Li, Zhong-Hua,Liu, Xue-Qi,Geng, Peng-Fei,Ma, Jin-Lian,Zhao, Tao-Qian,Wei, Hao-Ming,Yu, Bin,Liu, Hong-Min
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p. 1655 - 1658
(2017/08/22)
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- Pyrimidotriazole-containing LSD1 inhibitor, preparation method and application
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Belonging to the field of pharmaceutical chemistry, the invention discloses a pyrimidotriazole compound, a preparation method and application of the compound with lysine specific demethylase 1 (LSD1) as the target in preparation of antitumor drugs. The general formula of the compound is shown as I in the specification. In vitro LSD1 enzyme inhibitory activity experiments prove that by inhibiting the activity of LSD1, the compound has obvious inhibition and killing effects on multiple tumor cells, can be applied as a lead compound for further development in preparation of antitumor drugs.
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Paragraph 0058; 0059
(2017/08/31)
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- Inhibitor with pyrimido-triazole-tetrazole-thione LSD1 (lysine specific demethylase 1), preparation method of inhibitor and application
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The invention belongs to the field of medicinal chemistry, and discloses a compound with pyrimido-triazole-tetrazole-thione structures, a preparation method of the compound and an application of the compound to preparation of anti-tumor medicines by taking lysine specific demethylase 1 (hereinafter referred to as LSD1) as a target. The general formula of the compound is as shown in the specification. In-vitro LSD1 inhibitory activity tests show that the compound has obvious inhibiting and killing functions on various tumor cells by inhibiting activity of the LSD1, can serve as a further developed lead and is applied to preparation of anti-tumor medicines.
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Paragraph 0060; 0061
(2017/09/05)
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- Synthesis method of ticagrelor
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The invention discloses a synthesis method of ticagrelor. The method comprises the steps of 1, adding thiourea and alkali to a solution where bi-aminomalonic acid diethyl ester is dissolved, wherein the mole ratio of bi-aminomalonic acid diethyl ester, thiourea and alkali is 1:(1.0-1.5):(2-2.3), and performing a reaction under the protection of nitrogen at 25-100 DEG C for 5-72 h to obtain a compound 2; 2, adding bromopropane to a solution where the compound 2 is dissolved at -2 DEG C-2 DEG C, and conducting stirring at 25-50 DEG C for 2-72 h to obtain a compound 3; 3, adding organic alkali and a chloride agent to the compound 3, raising the temperature to 20-75 DEG C, and performing a reaction for 3-8 h to obtain a compound 4; 4, synthesizing ticagrelor, wherein the compound ticagrelor is obtained by conducting substitution, loop closing, substitution and a hydrolysis reaction on the compound 4 (4,6-dichloro-2-propylthiopyrimidine-5-amine), the operation steps are greatly simplified, and the yield is drastically increased. The synthesis method of ticagrelor is simple in operation and high in reaction yield.
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Paragraph 0038; 0050; 0059; 0068
(2017/09/26)
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- Pyrimidotriazole compounds containing hydrazone bonds as well as preparation method and application of pyrimidotriazole compounds
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The invention belongs to the field of medicinal chemistry and discloses pyrimidotriazole compounds containing hydrazine bonds as well as a preparation method and an application of the pyrimidotriazole compounds in drug preparation. The general formula I of the compounds is shown in the specification. The compounds have remarkable inhibition and killing functions on multiple tumor cells such as MGC-803, MCF-7 and EC-109, can serve as candidate or lead compounds for further development and are applied to preparation of an anti-tumor drug.
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Paragraph 0055; 0081; 0082; 0084
(2017/04/03)
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- Preparation method of ticagrelor intermediate
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The invention provides a preparation method of 4,6-dihalo-2-(propylthio)-5-aminopyrimidine disclosed as structural formula II, which comprises the following steps: 1) reacting a compound disclosed as structural formula V with 1-propyl hydrosulfide or 1-halopropane in the presence of alkali to obtain 5-halo-2-propylthiopyrimidine disclosed as structural formula IV; 2) reacting the 5-halo-2-propylthiopyrimidine disclosed as structural formula IV with ammonia gas, ammonia water or ammonium salt in the presence or absence of alkali to obtain 5-amino-2-propylthiopyrimidine disclosed as structural formula III; and 3) reacting the 5-amino-2-propylthiopyrimidine disclosed as structural formula III with a halogenating reagent to obtain the 4,6-dihalo-2-(propylthio)-5-aminopyrimidine disclosed as structural formula II. The preparation method has the advantages of short reaction route, high product purity and cheap and accessible raw materials, and is suitable for industrialized mass production. In the formulae, Q and X are respectively and independently selected from chlorine, bromine or iodine; and Y is OH or SH.
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Paragraph 0099; 0100; 0101
(2016/10/09)
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- PROCESS FOR THE PREPARATION OF AN INTERMEDIATE FOR A TRIAZOLOPYRIMIDINE CARBONUCLEOSIDE
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A process for the preparation of 4,6-dihalopyrimidin-5-amines of formula (II), or salts thereof, which comprises reacting 5-aminopyrimidin-4,6-diols of formula (III), or salts thereof, or a solvate either of the compound of formula (III) or of a salt thereof, with a halogenating agent, new intermediates useful in the preparation of the compound of formula (II) and processes for the preparation of these intermediates. The invention also refers to a process for the preparation of ticagrelor or a pharmaceutically acceptable salt thereof from 4,6-dihalo-2-(propylthio)pyrimidin-5-amine of formula (IIA).
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- A PROCESS FOR THE PREPARATION OF AN INTERMEDIATE FOR A TRIAZOLOPYRIMIDINE CARBONUCLEOSIDE
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A process for the preparation of 4,6-dihalopyrimidin-5-aminesof formula (II), or salts thereof, which comprises reacting 5-aminopyrimidin-4,6-diols of formula (III), or salts thereof, or a solvate either of the compound of formula (III) or of a salt thereof, with a halogenating agent, new intermediates useful in the preparation of the compound of formula (II) and processes for the preparation of these intermediates. The invention also refers to a process for the preparation of ticagrelor or a pharmaceutically acceptable saltthereoffrom 4,6-dihalo-2- (propylthio)pyrimidin-5-amine of formula (IIA).
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Page/Page column 30; 31
(2014/03/21)
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- Synthesis of Triazolopyrimidine Compounds
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The present invention relates to the field of organic synthesis and describes the synthesis of specific triazolopyrimidine compounds and intermediates thereof as well as related derivatives.
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Paragraph 0059-0060
(2013/05/09)
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- SYNTHESIS OF TRIAZOLOPYRIMIDINE COMPOUNDS
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The present invention relates to the field of organic synthesis and describes the synthesis of specific triazolopyrimidine compounds and intermediates thereof as well as related derivatives.
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Page/Page column 26
(2013/05/21)
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- NOVEL TRIAZOLO PYRIMIDINE COMPOUNDS AND A PROCESS OF PREPARATION THEREOF
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Provided is a pyrimidine compound of formula (I) useful as a pharmaceutical intermediate, wherein Q is selected from the following groups: -C(R1R2), -(C=0), -BR3. Also provided are a process for preparing said pyrimidine compound, intermediates used in said process, and the use of said pyrimidine compound in the preparation of ticagrelor.
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Page/Page column 14
(2013/11/19)
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- NEW INTERMEDIATES AND PROCESSES FOR PREPARING TICAGRELOR
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The present invention is related to new intermediates and processes for preparing Ticagrelor disclosed in this patent application.
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Page/Page column 49
(2012/10/18)
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- Synthesis and biological evaluation of ticagrelor derivatives as novel antiplatelet agents
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Ticagrelor (1) is the first reversible P2Y12 receptor antagonist blocking adenine diphosphate (ADP)-induced platelet aggregation with rapid onset and offset of effects. In this study, synthesis of ticagrelor and its derivatives has been accomplished in a convergent way. The compound design was based on modifications of ticagrelor and its major metabolite (33) in order to ameliorate their pharmacokinetic properties and dosing profile. The final compounds (1a-g, 35a-g) were evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats. The assay results showed that some compounds (e.g., 1b, 1d, 33, 35b, 35f) exhibited comparable potency with that of ticagrelor.
- Zhang, Hao,Liu, Jun,Zhang, Luyong,Kong, Lingyi,Yao, Hequan,Sun, Hongbin
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supporting information; experimental part
p. 3598 - 3602
(2012/07/14)
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- Process And Catalyst
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Aromatic or heteroaromatic nitro compounds are catalytically hydrogenated to the corresponding amines in the presence of a platinum catalyst comprising elemental platinum on a support; the platinum catalyst is modified with a molybdenum compound and a phosphorus compound wherein the phosphorus has an oxidation state of less than +5, e.g. hypophosphorous acid; the catalyst is particularly useful in the hydrogenation of nitro compounds with halogen and/or sulfur-containing substituents.
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Page/Page column 3
(2011/04/18)
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- 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
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The present invention is directed to a process for preparing [1S-[1α,2α,3β(1S*,2R*),5β]]- 3-[7-[2-(3,4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol and to intermediates useful in the process.
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Page/Page column 7
(2010/04/06)
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- REDUCTION OF 5-(ARYL-DIAZENYL)-4,6-DIHALO-PYRIMIDINE
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Method of synthesizing a compound of formula (I), wherein Rl, R2 are, independently, chloro or fluoro, and wherein R3 is H, alkyl, aralkyl or is an alkylether or alkylthioether comprising the steps of firstly reducing a diazeny compound of formula (II) non-catalytically or with a catalytic amount of an homogenous organic, non-metal catalyst to the corresponding hydrazo compound of formula (III) and in a second step catalytically hydrogenating said hydrazo compound in with a heterogeneous Ni-catalyst to the compound of formula (I).
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Page/Page column 10-11
(2010/11/28)
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- CHEMICAL PROCESS
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The present invention provides a process for the preparation of a compound of formula (I); wherein X is halogen; Y is ZR1; Z is oxygen or sulphur; and R1 is C 1-6 alkyl, C1-6 haloalkyl or C3-7 cloalkyl; the process comprising either: hydrogenating a compound of formula (II); with a suitable transition metal catalyst in a C1-6 aliphatic alcohol, an ether, an hydrocarbon as solvent; or, b) conducting a one-pot hydrogenation of a compound of formula (III): wherein R2 is phenyl optionally substituted by chloro,C1-6 alkyl, C1-6 alkoxy or (C1-6 alkyl)2N; firstly at about 20°C to form a compound of formula (IV): and then at about 40°C; both steps (I) and (ii) being carried out in the presence of a suitable catalyst and in the presence of a suitable solvent.
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Page/Page column 5
(2008/06/13)
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- Novel triazolo pyrimidine compounds
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The present invention relates to a pyrimidine compound (I) useful as a pharmaceutical intermediate, to a process for preparing said pyrimidine compound, to intermediates used in said process, and to the use of said pyrimidine compound in the preparation of pharmaceuticals.
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- ADP and ATP analogues, process for making and administration to inhibit ADP-induced platelet aggregation
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There are disclosed compounds of formula I, STR1 wherein Q represents CR 1 R 2,R represents O or CR 3 R 4,W represents O or CH 2,R 1, R 2, R 3 and R 4 independently represent hydrogen or halogen,X represents S(O) n R 5, alkyl C 1-6 alkoxy C 1-6, acylamino C 1-6, CONR 6 R 7, NR 8 R 9, halogen, a 5- or 6-membered S containing heterocycle, or phenyl optionally substituted by alkyl C 1-6,n represents 0, 1 or 2,R 5 represents aryl or alkyl C 1-6 optionally substituted by one or more substituents selected from hydroxy, alkoxy C 1-6, halogen and aryl;R 6, R 7, R 8 and R 9 independently represent hydrogen or alkyl C 1-6,Y represents NH 2 or alkoxy C 1-6, andZ represents an acidic moiety,in addition, when R represents CR 3 R 4, then --Q--Z may also represent hydroxy or --OP(O)(OH) 2,and pharmaceutically acceptable salts thereof, with certain provisos, for use as pharmaceuticals.
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