- Preparation method of A2A adenosine receptor agonist
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The invention discloses a preparation method of an A2A adenosine receptor agonist. The preparation method comprises the following steps of: (1) reacting 2-chloroadenosine with acetic anhydride by taking sodium acetate as a catalyst to prepare a compound shown in a formula (1); (2) reacting the compound shown in the formula (1) with hydrazine hydrate by taking methanol as a reaction medium to prepare a compound shown in a formula (2); (3) reacting the compound shown in the formula (2) with 2-formyl-3-oxoethyl propionate to prepare a compound shown in a formula (3); and (4) reacting the compound shown in the formula (3) with a methylamine water solution to prepare the A2A adenosine receptor agonist. According to the preparation method, the 2-chloroadenosine is taken as a starting raw material, and hydroxyl and amino are protected by using an AC protecting group, so that formation of relevant impurities is avoided effectively; and the dosage of a genotoxic reagent hydrazine hydrate is reduced greatly, excessive 2-formyl-3-oxoethyl propionate reacts with the compound shown in the genotoxic warning structural formula (2), the residue of the compound shown in the formula (2) is controlled at a very low level, and a relatively high-purity Regabardine product is obtained finally.
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- Preparation method of regadenoson
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The invention discloses a preparation method of regadenoson. The method comprises the following steps that 1, amino-2-chloropurine riboside and hydrazine hydrate react with each other by adopting potassium carbonate as a catalyst to prepare 2-hydrazino adenosine; 2, the 2-hydrazino adenosine and 2-formyl-3-oxo-ethyl propionate react with each other by adopting PEG and water as reaction media to obtain a compound of a formula (3); 3, the compound of the formula (3) and a 25-30% methyl amine water solution react with each other by adopting PEG as a reaction medium to obtain regadenoson. The amino-2-chloropurine riboside is adopted as a starting raw material, by adopting inorganic base potassium carbonate, the selectivity of the first-step reaction is improved, and the consumption of toxic substances hydrazine hydrates is lowered to the minimum. In the synthesis process, polyethylene glycol is adopted as the reaction medium, the reaction needed time is effectively shortened, and the reaction temperature is lowered; meanwhile, the good yield and purity are obtained.
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Paragraph 0032; 0049-0055
(2019/12/02)
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- NOVEL POLYMORPH OF REGADENOSON AND PROCESS FOR PREPARATION THEREOF
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Processes are provided for the preparation of a stable polymorphic form C of regadenoson, the process involving steps of a) obtaining a solution of regadenoson in benzyl alcohol solvent, b) maintaining the reaction mixture of step a) to about 10° C. to about 90° C., and c) isolating the stable polymorphic form C of regadenoson. Polymorphic form C may be characterized by an x-ray powder diffraction pattern with peaks at about 6.1, 10.2, 10.6, 19.0 and 25.4.±0.2 degrees 2-theta.
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Paragraph 0032; 0053
(2018/05/24)
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- ADENOSINE ANALOG AND ITS USE IN REGULATING THE CIRCADIAN CLOCK
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Provided are a kind of nucleoside analogue compounds, and compositions comprising these compounds and pentostatin, their use for modulating circadian rhythm, preferably, for shifting circadian phase, and methods for modulating circadian rhythm, preferably, for shifting circadian phase via these compounds or the compositions.
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Paragraph 0175; 0180; 0181; 0207
(2018/08/12)
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- Sweden deshong new intermediate and its preparation method and application
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The invention relates to new regadenoson intermediates, a preparation method and an application thereof, and a preparation method for preparing regadenoson with the intermediates. The invention discloses the new regadenoson intermediate represented as the general formula I, a method for preparing the intermediate with hydrazinoadenine, and also a method for preparing regadenoson, wherein the method for preparing regadenoson includes steps of preparing a compound represented as the formula III with the intermediate represented as the general formula I and a compound represented as the general formula II under a catalyst, and then converting the compound represented as the formula III into the regadenoson. The method is simple in operations, is high in yield, is low in cost and is very suitable for industrialized production.
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Paragraph 0079; 0080; 0081; 0082
(2017/08/25)
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- PROCESS OF MAKING REGADENOSON AND NOVEL POLYMORPH THEREOF
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Novel processes for making the N-pyrrazole substituted 2-adenosine derivative regadenoson and a novel polymorph thereof. The novel polymorph of regadenoson designated form H and drug substances and pharmaceutical compositions including the novel polymorph H are disclosed.
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Paragraph 0057
(2016/09/26)
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- Novel Polymorph of Regadenoson
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The invention provides a novel polymorph of Regadenoson. More particularly, the invention provides propylene glycol solvate of Regadenoson. The invention also provides a process for the preparation of propylene glycol solvate of Regadenoson.
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Paragraph 0043; 0044
(2016/05/19)
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- A PROCESS FOR THE PREPARATION OF REGADENOSON
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The present invention provides novel processes for the preparation of regadenoson having the formula (I). In some embodiments, the intermediates for the synthesis of regadenoson are also provided.
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- Novel Process for the Preparation of (1-pyrazole-4-yl)-N-methylcarboxamide
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The present invention relates to a novel process for the preparation of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide.
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Paragraph 0030; 0031
(2015/12/30)
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- STABLE SOLID FORMS OF REGADENOSON
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A process for the preparation of the amorphous form of Regadenoson of formula (I) is disclosed together with new crystalline polymorphic forms E, F and G and methods for their preparation. Regadenoson amorphous form can be prepared in mild reaction conditions with high chemical purity (>99.6%) and high stability to the heating. A particularly thermodynamically stable anhydrous crystalline form of Regadenoson (form G) is also disclosed, provided with high stability not when exposed to 90% RH at 25°C for 96 hour, but also to the heating up to 200°C.
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Page/Page column 14; 15
(2014/10/29)
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- Stable solid forms of regadenoson
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A process for the preparation of the amorphous form of Regadenoson of formula is disclosed together with new crystalline polymorphic forms E, F and G and methods for their preparation. Regadenoson amorphous form can be prepared in mild reaction conditions with high chemical purity (>99.6%) and high stability to the heating. A particularly thermodynamically stable anhydrous crystalline form of Regadenoson (form G) is also disclosed, provided with high stability not when exposed to 90% RH at 25°C for 96 hour, but also to the heating up to 200°C.
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- METHOD FOR THE PREPARATION OF 2-[4-[(METHYLAMINO)CARBONYL]-1-H-PYRAZOL-1-YL]ADENOSINE MONOHYDRATE
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A method for the preparation of 2-[4-[(methylamino)carbonyl]-1-H-pyrazol-1-yl]adenosine monohydrate of formula I by reaction of 2-(4-methoxycarbonylpyrazol-1-yl) adenosine of formula III with a solution of methylamine in a non-aqueous solvent, optionally in combination with another inert solvent, to produce anhydrous 2-[4-[(methylamino)carbonyl]-1-H-pyrazol-1-yl]adenosine, which is converted to 2-[4-[(methylamino)carbonyl]-1-H-pyrazol-1-yljadenosine monohydrate of formula I by addition of water.
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Paragraph 0029-0031
(2014/07/22)
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- POLYMORPH OF 2-[4-[(METHYLAMINO)CARBONYL]-1H-PYRAZOL-1-YL]ADENOSINE
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A new polymorph of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine (designated as polymorph E), characterized by an X-ray diffraction pattern of X-RPD showing the following reflections at 2 Theta=5.8°, 12.3°, 15.9°, 17.3°, 20.5°, 22.6°, 23.6°, 27.7°, and 29.2°, and further characterized by DSC showing marked endotherm in the range of 258 to 264° C., and further characterized by IR spectra, which is prepared by a procedure comprising the following operations: Mixing of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine with a polar aprotic solvent, preferably with dimethylsulfoxide, and heating to form a saturated solution;Cooling of the saturated solution with formation of a turbid solution of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine;Addition of the turbid solution of 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]adenosine to a protic solvent, preferably methanol, with separation of a gel-like precipitate;Heating of the separated gel-like precipitate in the protic solvent to the boil with formation of a suspension of polymorph E;Cooling of the suspension, isolation and drying of polymorph E.
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Paragraph 0041-0043
(2014/11/11)
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- NEW POLYMORPH OF 2-[4-F(METHYLAMINO)CARBONYL]-1H-PYRAZOL-1-YL]ADENOSINE AND METHOD OF ITS PREPARATION
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A new polymorph of 2-[4-[(methylamino)carbonyl]-1 H-pyrazol-1- yl]adenosine (designated as polymorph E), of formula I, characterized by an X-ray diffraction pattern of X-RPD showing the following reflections at 2 Theta = 5.8°, 12.3°, 15.9°, 17.3°, 20.5°, 22.6°, 23.6°, 27.7°, and 29.2°, and further characterized by DSC showing marked endotherm in the range of 258 to 264 °C, and further characterized by IR spectra, which is prepared by a procedure comprising the following operations: ? a. Mixing of 2-[4-[(methylamino)carbonyl]-1 H-pyrazol-1- yl]adenosine with a polar aprotic solvent, preferably with dimethylsulfoxide, and heating to form a saturated solution; ? b. Cooling of the saturated solution with formation of a turbid solution of 2-[4: [(methylamino)carbonyl]-1 H-pyrazol-1- yl]adenosine; ? c. Addition of the turbid solution of 2-[4-[(methylamino)carbonyl]-1 H-pyrazol-l-yl]adenosine to a protic solvent, preferably methanol, with separation of a gel-like precipitate; ? d. Heating of the separated gel-like precipitate in the protic solvent to the boil with formation of a suspension of polymorph E; ? e. Cooling of the suspension, isolation and drying of polymorph E.
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Page/Page column 6; 7
(2014/11/13)
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- A METHOD FOR THE PREPARATION OF 2-[4-[(METHYLAMINO) CARBONYL] -1-H-PYRAZOL-1-YL] ADENOSINE MONOHYDRATE
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A method for the' preparation of 2-[4-[(methylamino)carbonyl]-1-H-pyrazol-1- yl]adenosine monohydrate of formula I by reaction of 2-(4-methoxycarbonylpyrazol-1-yl) adenosine of formula III with a solution of methylamine in a non-aqueous solvent, optionally in combination with another inert solvent, to produce anhydrous 2-[4-[(methylamino)carbonyl]- 1-H-pyrazol-1-yl]adenosine, which is converted to 2-[4-[(methylamino)carbonyl]-1-H - pyrazol-1-yljadenosine monohydrate of formula I by addition of water.
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Page/Page column 6; 7
(2013/03/26)
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- IMPROVED PROCESSES FOR THE PREPARATION OF REGADENOSON AND A NEW CRYSTALLINE FORM THEREOF
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This disclosure relates to an improved process for the preparation of regadenoson, pharmaceutically acceptable salts thereof, and hydrates thereof, and for the preparation of intermediates useful in the synthesis of regadenoson. The disclosure also relates to a new crystalline form of regadenoson. Processes for the preparation of the crystalline form, compositions containing the crystalline form, and methods of use thereof are also described.
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Page/Page column 16; 17
(2012/11/13)
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- METHODS AND COMPOSITIONS FOR INCREASING PATIENT TOLERABILITY DURING MYOCARDIAL IMAGING METHODS
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The present application discloses methods and compositions for increasing patient tolerability during myocardial imaging comprising the administration of doses of caffeine and one or more adenosine A2A receptor agonists to a mammal undergoing myocardial imaging.
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Page/Page column 28-29
(2008/06/13)
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- Structure-affinity relationships of the affinity of 2-pyrazolyl adenosine analogues for the adenosine A2A receptor
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The structure-affinity relationships of two novel 2-substituted adenosine series containing a substituted pyrazole attached at the N-1 or C-4 position for the adenosine (ADO) A2A receptor are described. Compounds in the 2-(N-1-pyrazolyl) adenos
- Palle, Venkata P.,Elzein, Elfatih O.,Gothe, Scott A.,Li, Zhihe,Gao, Zhenhai,Meyer, Stephanie,Blackburn, Brent,Zablocki, Jeff A.
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p. 2935 - 2939
(2007/10/03)
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- 2-Substituted PI system derivatives of adenosine that are coronary vasodilators acting via the A2A adenosine receptor
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Compound 20 (CVT-3146 - a 2-[(N-1-(4-N-methylcarboxamidopyrazolyl)] adenosine derivative) and compound 31 (CVT-3033 - a 2-[(4-(1-N-pentyl-pyrazolyl)] adenosine derivative), were found to be short acting functionally selective coronary vasodilators (CV ts
- Zablocki,Palle,Blackburn,Elzein,Nudelman,Gothe,Gao,Li,Meyer,Belardinelli
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p. 343 - 360
(2007/10/03)
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