cas 503614-91-3, 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

Articles about 503614-91-3Total 37 be found

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Synthesis method of apixaban intermediate
The invention discloses a synthesis method of an apixaban intermediate; the high-yield apixaban intermediate II is obtained by changing the reaction conditions of the apixaban intermediate, so that the yield of the apixaban is improved; specifically, raw materials a and b are subjected to an addition reaction in a toluene solution through base catalysis, after the reaction is completed, an elimination reaction is performed under the action of acid, and then a final product II is obtained through the processes of extraction, washing, concentration, refining and the like.
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Paragraph 0014; 0021-0022; 0023-0024; 0025-0026

(2021/07/14)

PROCESS FOR PREPARING APIXABAN
The present invention relates to process for preparing apixaban, in particular polymorphic form N-1 thereof, as well as to a method for the preparation of crystalline apixaban, especially apixaban polymorphic form N-1.
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(2020/07/07)

Method for preparing apixaban crystal form
The invention relates to a method for preparing an apixaban crystal form N-1. The method is characterized by comprising the following steps: adding an apixaban compound into a 85-95% C1-6alkyl alcohol, performing dissolution, performing crystal separation, performing filtering and washing, and performing drying, so as to obtain the target crystal form N-1. By adopting the technical scheme of the invention, a crystal conversion solvent is simple and easy to obtain, the operation method is simple, the condition is mild, equipment is not specifically required, special reaction condition and equipment are not needed, and the method is applicable to industrial production.
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Paragraph 0058-0059; 0062

(2020/03/17)

Method for preparing apixaban
The invention discloses a method for preparing apixaban, and relates to the field of medicinal chemistry. The preparation method comprises the following steps: (1) carrying out [3+2] cyclization reaction-elimination reaction on a compound 3 and a compound 4 in dimethyl carbonate under an alkaline condition to obtain an intermediate 2; and (2) carrying out aminolysis reaction on the intermediate 2to prepare the target apixaban. The preparation method has the advantages of mild reaction conditions, short reaction time, simple operation, high yield, high product purity and suitableness for industrial mass production, wherein the used solvent dimethyl carbonate is an environment-friendly organic solvent.
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Paragraph 0048-0079

(2020/07/02)

Preparation process of high-purity apixaban
The invention discloses a preparation process of apixaban. The method comprises the following steps of: performing amidation on an initial raw material compound (IV) and delta-valerolactone under pressure; performing a one-pot reaction on the obtained hydroxyl amide and p-toluenesulfonyl chloride (PTSC)to obtain a compound (III); carrying out a reaction with tetrabutylammonium fluoride trihydrateto obtain a cyclization product compound (II); preparing a compound (I) from 2,4-dichlorobenzaldehyde and formamide under the action of sodium methoxide and a molecular sieve; refining the crude product by adopting an optimized ethanol/dichloromethane mixed solvent, so that impurity A is removed well; by means of the method, the apixaban product with high yield and high purity is prepared, whereinthe purity of the apixaban product is not lower than 99.5%, the impurity A does not exceed 0.05%, and any single impurity does not exceed 0.1%.
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Page/Page column 4; 8; 10-12

(2020/01/08)

Preparation method of apixaban
The invention relates to a preparation method of apixaban, and provides a preparation method of apixaban shown in the formula I. The method can be used for effectively removing impurities introduced by raw materials and impurities generated by the process, especially the gene toxicity impurities. The formula is shown in the description.
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Paragraph 0033; 0034; 0039; 0040

(2019/05/04)

Preparation method of apixaban and intermediates thereof
The invention discloses a preparation method of apixaban and intermediates thereof. The invention provides a preparation method of an apixaban intermediate I. The preparation method of the apixaban intermediate I comprises the step of performing nucleophilic substitution reaction on an apixaban intermediate II and p-fluoronitrobenzene in an organic solvent in the presence of an alkali to obtain the apixaban intermediate I. The preparation method has short steps, simple and safe operation, simple post-treatment steps, environmental friendliness and high total yield, and the obtained product hashigh purity, low production cost and high atomic utilization, and is suitable for industrial production. The formula is shown in the description.
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(2018/05/16)

A [...] intermediate 2 in the process of synthesis of the specific impurity S4 of removing method (by machine translation)
The invention discloses a [...] intermediate 2 in the process of synthesis of the specific impurity S4 of removing method, it comprises the following steps: ethyl acetate solvent is sequentially added in the compound 1, compound 2 and heating after triethylamine, ethyl acetate with compound 1, compound 2 and triethylamine to the equivalence ratio of 4.0 - 6.0: 1: 1.1 - 1.5: 3.0 - 5.0; the temperature of the solution is to 80 ± 5 °C after, stirring reflux reaction, in the process of returning the sustained added triethylamine, the amount of add triethylamine with compound 1 to the equivalence ratio of 1: 1.0 - 2.0; the reflux reaction 4 h after lowering the temperature to 10 °C after, temperature control ≤ 30 °C dropping under the 2 - 6 M dilute sulfuric acid, then stirring at room temperature 2 h after filtering to obtain intermediate 2, the [...] sulfuric acid and triethylamine to the equivalence ratio of 1:1. This invention is not changing the reaction that the organic alkali types of circumstances, by adding organic alkali, inhibit the impurities in the reaction process S4 generation, the impurity content is only 0.00% -0.02%, so as to effectively control the impurity S4 of the content. (by machine translation)
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Paragraph 0011; 0012; 0013; 0014; 0015; 0016; 0017

(2018/05/16)

Design, synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity
A series of novel tetrahydropyrazolopyridone derivatives containing 1,3,4-triazole, triazolylmethyl, and partially saturated heterocyclic moieties as P2 binding element was designed, synthesized, and evaluated in vitro for anticoagulant activity in human and rabbit plasma. All compounds showed moderate to significant potency, and compounds 15b, 15c, 20b, 20c, and 22b were further examined for their inhibitory activity against human FXa in vitro. While compounds 15c and 22b were tested for rat venous thrombosis in vivo. The most promising compound 15c, with an IC50 (FXa) value of 0.14?μM and 98% inhibition rate, warranted further investigation as an FXa inhibitor.
Sun, Xiaoqing,Hong, Zexin,Liu, Moyi,Guo, Su,Yang, Di,Wang, Yong,Lan, Tian,Gao, Linyu,Qi, Hongxia,Gong, Ping,Liu, Yajing
p. 2800 - 2810
(2017/04/18)

Apixaban derivatives as well as preparation method and application thereof
The invention belongs to the technical field of medicines and discloses apixaban derivatives and analogues as well as a preparation method and application thereof. The structure of the compounds is shown as the following formula. Cheap and readily available paranitroaniline serves as an initial raw material. The preparation method comprises the following steps: performing amidation-cyclization, chlorination, condensation-elimination, cyclization-elimination, reduction, amidation-cyclization so as to obtain a key intermediate; and dehydrating, performing ammonolysis or chlorination, and condensing to synthesize the target compound. The method is simple in operation, convenient in after-treatment and high in yield. The in-vitro anti-coagulant activity of the target compound is investigated by determining the activated partial thromboplastin time (APTT) and thromboplastin time (PT). The EC2X(APTT) of result compounds APX-02, APX-15 and APX-16 is respectively 2.15mug/L, 3.65mug/L and 2.35mug/L, the EC2X(PT) of the result compounds is respectively 0.12mug/L, 3.57mug/L and 1.57mug/L, which are higher than the EC2X(APTT) value of 3.78mug/L and the EC2X(PT) value of 1.59mug/L of a positive control agent Apixaban. The compounds have high anti-coagulant activities. The EC2X(APTT) value of the rest compounds is between 5mug/L and 65mug/L, and the EC2X(PT) value is between 3mug/L and 18mug/L. The structural formula is as shown in the specification.
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(2017/12/27)

A morpholine-free process amenable convergent synthesis of apixaban: a potent factor Xa inhibitor
A convergent synthesis of the anti-coagulant drug apixaban has been efficiently demonstrated on a multi-gram scale. The synthetic route is noteworthy for its brevity and fact that it completely avoids the use of morpholine, a toxic and flammable reagent, in constructing the 5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one core present in apixaban. Graphical abstract: [Figure not available: see fulltext.].
Nevuluri, Narasimha Rao,Rapolu, Rajesh Kumar,Iqbal, Javed,Kandagatla, Bhaskar,Sen, Saikat,Dahanukar, Vilas H.,Oruganti, Srinivas
p. 1477 - 1482
(2017/07/18)

PROCESS FOR THE PREPARATION OF APIXABAN
The present invention relates to an improved process for the preparation of Apixaban and its intermediates.
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Paragraph 0068

(2017/11/16)

AN IMPROVED PROCESS FOR THE PREPARATION OF APIXABAN
The present invention relates to an improved process for the preparation of Apixaban and its intermediates.
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Page/Page column 13; 14

(2017/12/09)

A antithrombotic drug [...] preparation method
The invention relates to the field of medicine preparation and particularly relates to a preparation method of Apixaban. The preparation method comprises the following steps: carrying out amidation-cyclization on starting raw materials (p-chloroaniline and acyl chloride) to obtain a compound III, namely 1-(4-chlorphenyl)-2-piperidone; carrying out diazotization on raw materials (p-methoxyaniline and ethyl 2-chloroacetoacetate and then further generating Japp-Klingmann hydrazone synthesis reaction to obtain a compound VI, namely ethyl [(4-methoxyphenyl) diazanyl] chloroacetate; enabling the compound III to have a substitution reaction with raw material 5,6-dihydro-3-(4-morpholine)-2(1h)-pyridone in the presence of a catalyst to obtain a compound 2, namely 5,6-dihydro-3-(4-morpholine)-1-[4-(2-oxo-1-piperidyl) phenyl]-2(1H)-pyridone; carrying out [3+2] cyclization-elimination on the compound III and the compound VI to obtain a compound IX; reacting the compound IX with ammonia to obtain Apixaban; and washing the crude product with alcohol to obtain high-purity Apixaban, wherein the total yield is 40-50%. The preparation method has the advantages that the raw materials are simple and easily available; the cost is low; the reaction conditions are mild; the high-purity product can be obtained by simple purification since few byproducts are generated; therefore, the preparation method of Apixaban is suitable for industrial production.
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(2017/10/06)

PROCESS FOR THE PREPARATION OF APIXABAN AND INTERMEDIATES THEREOF
The present invention refers to novel process for the preparation of Apixaban. Further, the invention also related to a process for the preparation of intermediate of Apixaban from very basic and cheap row material i.e. Aniline which is widely commercially available. The present invention provides process for preparation of Apixaban using a different sequence of synthetic steps and does not involve use of Ullmann reaction.
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(2017/06/12)

DIMER IMPURITIES OF APIXABAN AND METHOD TO REMOVE THEM
Object of the present invention are dimer impurities of the active ingredient Apixaban, analytical methods for identifying and/or quantifying them and a synthetic method for removing or limiting said impurities from Apixaban and synthetic precursors thereof.
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Paragraph 00188; 00190

(2017/02/09)

LACTAM-CONTAINING COMPOUNDS AND DERIVATIVES THEREOF AS FACTOR XA INHIBITORS
The present application describes lactam-containing compounds and derivatives thereof of Formula I: P4—P-M-M4??I or pharmaceutically acceptable salt forms thereof, wherein ring P, if present is a 5-7 membered carbocycle or heterocycle and ring M is a 5-7 membered carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.
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Paragraph 0885

(2017/04/28)

Preparing method for apixaban
The invention provides a preparing method for apixaban. A compound of a structure in the formula II and a compound of a structure in the formula III react to obtain a compound of a structure in the formula IV, and then the compound of the structure in the formula IV is converted into aphixaban. As the compound of the structure in the formula II and the compound of the structure in the formula III are selected to react to obtain the compound of the structure in the formula IV, the preparing method for the compound in the formula IV is simplified, the yield is high, and then the total yield is greatly increased.
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(2017/01/19)

A method for preparing [...]
The invention discloses an Apixaban preparation method. The Apixaban preparation method comprises that 1, an intermediate I and an intermediate II undergo a [3+2] cyclization addition reaction under the alkali action to produce a compound B, and the compound B undergoes a morpholine ring removal reaction under the acid condition to produce a compound C, 2, the compound C is reduced by iron powder to form a corresponding amino compound D, 3, the amino compound D and 5-chlorovaleryl chloride undergo an amidation reaction under the triethylamine action to produce a compound E, 4, the compound E undergoes a cyclization reaction under the strong base action to produce a compound F, 5, the compound F undergoes a hydrolysis reaction under the strong base action to produce a corresponding carboxyl compound G, and 6, the carboxyl compound G and CDI undergo a reaction to produce an active intermediate H and the active intermediate H and ammonia water undergo an aminolysis reaction to produce the desired compound A. The Apixaban preparation method has simple processes, does not need strict reaction conditions, has low equipment requirements, has high reaction yield, utilizes stable intermediates thereby solving intermediate storage problems, and effectively improves product purity.
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(2017/02/28)

Method for preparing drug Apixaban for preventing or treating venous thrombus after joint replacement
The invention discloses a method for preparing a drug Apixaban for preventing or treating venous thrombus after joint replacement. The method comprises the steps as follows: 1) p-tolylhydrazine and ethyl glyoxylate are subjected to a reaction by catalysis of cuprous bromide in the presence of an alkali and are filtered after the reaction is completed, a borane-methyl sulfide complex is added to a filtrate, a compound shown as the formula I is then added for stirred and mixed reaction, and a reaction mixture L is obtained; 2) the reaction mixture L obtained in the step 1) is stirred under the acidic condition; 3) 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidine-1-yl 3)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carboxylate in the step 1) is subjected to ammonolysis, and Apixaban with the formula shown in the specification is obtained. The method for preparing Apixaban has the advantages of mild condition and higher yield, a pyrazole ring product is generated with a one-pot method, the process is easier, the cost is greatly reduced, and the diazo-reaction widely adopted in the prior art is avoided.
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Paragraph 0028; 0032-0045; 0049-0052

(2017/06/02)

One anticoagulant [...] method and the preparation of key intermediate
The invention provides a preparation method and a key intermediate of an anticoagulant apixaban. The method comprises the following steps: (1) by taking N-(4-nitrophenyl)-3,3-dichloro-2-oxopiperidine (compound 15) as an initial raw material, carrying out a reduction reaction to obtain a compound 16; (2) carrying out an acylation reaction between the compound 16 and 5-valeryl chloride bromine to obtain a compound 17; (3) reacting the compound 17 to obtain a compound 18 in the presence of a cyclic condensation agent; (4) carrying out an elimination reaction between the compound 18 and alkali to obtain a compound 19; (5) reacting the compound 19 with a compound 4 to obtain a compound 6; and (6) finally performing ammonolysis on the compound 6 to obtain apixaban. The method has the advantages that (1) the synthetic route is more reasonable; (2) an expensive or toxic reagent with high irritation is avoided; (3) reaction by-products are fewer and are easily purified; (4) the total yield is high; and (5) the reaction is suitable for industrial production. The reaction route is shown as the following formula.
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(2017/01/23)

A method for synthesizing [...]
The invention discloses a synthetic method of novel Apixaban. The method comprises the following steps: (i) hydrolyzing an Apixaban precursor compound (II) to obtain a carboxylic acid product; and (ii) mixing the carboxylic acid product obtained in the step (i) with ethyl chloroformate, reacting in the presence of diisopropylethylamine at the temperature of 0-5 DEG C for 3-5 hours; then introducing ammonia gas and reacting to obtain an ammonolysis product, namely, Apixaban. By adopting the method for preparing Apixaban by using the Apixaban precursor compound (II), the yield of Apixaban can be up to 93 percent. In the entire synthesis route, the minimum yield in each step is over 76 percent at least, and the total yield is about 33 percent. In the entire process, the use of precious catalysts or auxiliary reagents is avoided.
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(2017/01/09)

Design, synthesis, and structure–activity relationship of novel and effective apixaban derivatives as FXa inhibitors containing 1,2,4-triazole/pyrrole derivatives as P2 binding element
Four series of novel and potent FXa inhibitors possessing the 1,2,4-triazole moiety and pyrrole moiety as P2 binding element and dihydroimidazole/tetrahydropyrimidine groups as P4 binding element were designed, synthesized, and evaluated for their anticoagulant activity in human and rabbit plasma in vitro. Most compounds showed moderate to excellent activity. Compounds 14a, 16, 18c, 26c, 35a, and 35b were further examined for their inhibition activity against human FXa in vitro and rat venous thrombosis in vivo. The most promising compound 14a, with an IC50(FXa) value of 0.15?μM and 99% inhibition rate, was identified for further evaluation as an FXa inhibitor.
Wang, Yong,Sun, Xiaoqing,Yang, Di,Guo, Zhuang,Fan, Xuxu,Nie, Minhua,Zhang, Feng,Liu, Yue,Li, Yue,Wang, Yulin,Gong, Ping,Liu, Yajing
p. 5646 - 5661
(2016/10/24)

PROCESS FOR THE PREPARATION OF APIXABAN
The object of the invention is a process for the preparation of 1-(4-methoxyphenyl)-7-oxo-6-[4- (2-oxopiperidin- 1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide of formula 1 (apixaban), as well as the intermediates used in the process.
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(2016/04/26)

NOVEL PROCESS FOR THE PREPARATION OF A LACTAM-CONTAINING COMPOUND
Provided herein is a novel, commercially viable and industrially advantageous process for the preparation of 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole-[3,4-c]pyridine-3-carboxamide, in high yield and with high purity, using a novel intermediate 3-chloro-1-(4-iodophenyl)-5,6-dihydropyridin-2(1H)-one.
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(2015/12/08)

A PROCESS FOR THE PREPARATION OF APIXABAN AND ITS INTERMEDIATES
The present invention discloses the novel process for preparation of Apixaban intermediate formula (D), intermediate formula (E) and preparation of Apixaban from theses intermediates.
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(2015/11/27)

Novel intermediate and polymorphs of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetra hydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and process thereof
The present invention provides a novel intermediate as well as novel polymorphs of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound represented by the following structural formula-1 and processes for their preparation.
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(2016/01/10)

PROCESS FOR THE PREPARATION OF APIXABAN
The present disclosure provides processes and intermediates for the preparation of apixaban.
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(2015/11/10)

A METHOD OF PREPARING APIXABAN
The object of the present solution provides a method preparing apixaban of formula (I) in which ethyl 6-(4-iodophenyl)- 1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4- c]pyridine-3-carboxylate of formula (III) is reacted with piperidin-2-one of formula (IV) in the presence of a base and a ligand and under catalysis by copper or by copper (II) ions, wherein a phosphoric acid salt is used as the base and an amine from the group of 1,2-diamines is used as the ligand in an aprotic solvent, and ethyl 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1- piperidin-1-yl)phenyl] -4, 5,6,7-tetrahydro-1H-pyrazol-[3,4-c]pyridine-3-carbvoxylate is prepared, which is converted, by reaction with ammonia in a suitable solvent, to apixaban of formula (I), which is isolated and optionally crystallized.
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(2014/06/11)

PROCESS FOR THE PREPARATION AND PURIFICATION OF APIXABAN
The present invention provides a process for the preparation and purification of apixaban.
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Paragraph 0134

(2014/08/06)

PROCESS FOR THE SYNTHESIS OF APIXABAN
The present invention relates to the Process for the preparation of Apixaban and novel intermediates useful in the synthesis of Apixaban (I).
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(2014/05/24)

SOLID STATE FORMS OF APIXABAN
The present invention is directed to solid state forms of Apixaban, processes for preparing the solid state forms, and pharmaceutical compositions thereof.
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Paragraph 0033; 0034; 0035

(2013/08/28)

Alternate synthesis of apixaban (BMS-562247), an inhibitor of blood coagulation factor Xa
An alternate approach to apixaban was described. The synthesis features a novel and cost-effective synthetic strategy to construct a key N-phenylvalerolactam intermediate 4 from 4-nitroaniline. In addition, the modified synthetic route avoids the use of expensive reagents and significantly improves reaction yields. As demonstrated practically, apixaban was successfully synthesized in overall good yield (35%). Copyright Taylor & Francis Group, LLC.
Jiang, Jian'An,Ji, Yafei
p. 72 - 79
(2012/10/30)

APIXABAN PREPARATION PROCESS
Process for the preparation of apixaban and intermediates useful for the preparation thereof.
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(2013/02/27)

PYRAZOLE CARBOXAMIDE INHIBITORS OF FACTOR XA
The present invention relates to new pyrazole carboxamide inhibitors of factor Xa, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 31-32

(2010/04/06)

Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa
Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P1 moieties that resulted in the identification of the p-methoxyphenyl P1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.
Pinto, Donald J. P.,Orwat, Michael J.,Koch, Stephanie,Rossi, Karen A.,Alexander, Richard S.,Smallwood, Angela,Wong, Paneras C.,Rendina, Alan R.,Luettgen, Joseph M.,Knabb, Robert M.,He, Kan,Xin, Baomin,Wexler, Ruth R.,Lam, Patrick Y. S.
p. 5339 - 5356
(2008/03/13)

Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
A novel process and intermediates thereof for making 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones of the type shown below from appropriate phenyl hydrazines is described. These compounds are useful as factor Xa inhibitors.
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(2008/06/13)