- Preparation method of apixaban intermediate suitable for industrial production
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The invention discloses a synthesis method of an apixaban intermediate suitable for industrial production. The method comprises the following steps: carrying out phase-transfer catalytic amidation reaction on paranitroaniline and 5-chlorovaleryl chloride in an organic phase and water phase two-phase system under an inorganic weakly alkaline condition to obtain an APM01 solution, and adding a sodium hydroxide water solution, and cyclizing in a pot to obtain an APM02 solution; directly carrying out alpha-reactive hydrogen dichlorination on an APM02 organic solution and phosphorus pentachloride after simple acid pickling, liquid separation and drying to obtain an APM03 solution; carrying out condensation-elimination reaction on the APM03 solution and excessive morpholine after simple acid pickling and liquid separation, and carrying out simple crystallization and purification treatment to separate out an APM04 solid, and reducing the APM04 into APM05 by sodium sulfide; and carrying out amidation-cyclization two-step one-pot reaction on the APM05 and 5-chlorovaleryl chloride to prepare a key intermediate APM07. According to the method, the synthesis efficiency of the apixaban intermediate is improved, the reaction is mild, and dangerous NaH and other expensive reagents are not used, so that the production cost is saved, the operation is simple, and the method is suitable for industrial popularization.
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- Simple preparation method of 5,6-dihydropyridine-2 (1H)-one derivative
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The invention provides a simple and convenient preparation method of a 5,6-dihydropyridine-2(1H)-one derivative. The preparation method comprises the following steps: amidating p-phenylenediamine as araw material and delta-valerolactone, and reacting and condensing the hydroxyl of the obtained amidation product and a halogenating reagent 1 or sulfonyl chloride to obtain 1,4-bis(piperidine-2-keto-1-yl)benzene; carrying out carbonyl ortho-halogenation and elimination to obtain 1-(piperidine-2-keto-1-yl)-4-(5,6-dihydropyridine-2(1H)-keto-1-yl)benzene, and carrying out addition and elimination with a halogenating reagent 3 or carrying out elimination substitution in the presence of morpholine to obtain the 5,6-dihydropyridine-2(1H)-one derivative (I). The preparation method has the advantagesof cheap and easily available raw materials, short steps and low cost; the process operation is simple, reaction conditions are easy to realize, the wastewater yield is low, and safety and greennessare realized; and the reaction selectivity of each step is high, the product yield and purity are high, and industrial production is facilitated.
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- Preparation method of 5,6-dihydropyridine-2 (1H)-one derivative
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The invention provides a preparation method of a 5,6-dihydropyridine-2 (1H)-one derivative, and particularly relates to a 1-(piperidine-2-keto-1-yl)-4-(5,6-dihydro-3-R substituent pyridine-2 (1H)-keto-1-yl) benzene preparation method, wherein the R substituent is chlorine or morpholine-4-yl. According to the invention, p-acetamido aniline is used as a raw material, and amidation with delta-valerolactone, halogenation with a halogenation reagent or sulfonylation with sulfonyl chloride, condensation, deacetylation, amidation with 2,2-dichloro-delta-valerolactone, halogenation with a halogenationreagent or sulfonylation with sulfonyl chloride, condensation elimination or condensation elimination substitution in the presence of morpholine are performed to obtain the target product. Accordingto the invention, the raw materials used in the preparation method are cheap, easy to obtain and low in cost; the process operation is simple, reaction conditions are easy to realize, the wastewater yield is low, and safety and greenness are realized; and the reaction selectivity of each step is high, the product yield and purity are high, and industrial production is facilitated.
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- Apixaban intermediate and preparation method thereof
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The embodiment of the invention discloses an apixaban intermediate and a preparation method thereof. The preparation method comprises the following steps: preparation of an intermediate 2, preparationof an intermediate 3, preparation of an intermediate 4, preparation of an intermediate 5, and preparation of apixaban key intermediate 5, 6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidyl) phenyl]-2 (1H)-pyridone. According to the apixaban intermediate 5, 6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidyl) phenyl]-2 (1H)-pyridone and the preparation method thereof provided by the invention, the operation is simple, the reaction condition is mild, the requirement on equipment is low, scale-up production is easier, the yield is high, and the purity of the product is greater than 99%.
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- Preparation method of dihydropyridone derivatives
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The invention belongs to the technical field of medicines, and particularly relates to a preparation method of dihydropyridone derivatives. The preparation method comprises the following steps: reacting 1-(4-aminophenyl)-3-morpholinyl-5,6-dihydropyridin-2(1H)-one serving as a raw material with a first reactant in a first solvent under the condition of a first alkali to generate an amide compound;under the condition of a second alkali, heating the amide compound to obtain an intermediate; reacting the intermediate with a second reactant in a second solvent at room temperature; after the reaction is finished, performing reduced-pressure distillation to obtain the second solvent; and under an ice bath condition, adding a third alkali, and carrying out a reaction in a third solvent to obtainthe dihydropyridone derivatives. According to the preparation method of the dihydropyridone derivatives provided by the invention, the preparation method of the dihydropyridone derivatives of 3-morpholinyl-1-(4-(2-oxopiperidine-1-yl)phenyl)pyridin-2(1H)-one is provided for the first time, and the preparation method has important significance for effective control of the quality of apixaban.
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Paragraph 0059-0063; 0069; 0073-0077; 0082-0086; 0091-0095
(2020/05/30)
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- Preparation method of apixaban intermediate
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The invention relates to a preparation method of an apixaban intermediate. The preparation method of the apixaban intermediate I comprises the following steps: p-chloroaniline, used as a raw material,and halide undergo an amidation and cyclization reaction under an alkaline condition to obtain 1-(4-chlorophenyl)piperidine-2-one, the 1-(4-chlorophenyl)piperidine-2-one and phosphorus pentachlorideundergo dichloro substitution, condensation-elimination and morpholine substitution to obtain the apixaban intermediate I. The method has the advantages of low cost, high reaction yield, and suitableness for industrial operation.
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- Preparation method of apixaban pyridone impurity
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The invention provides a preparation method of an apixaban pyridone impurity. The preparation method of the apixaban pyridone impurity comprises two steps that 1, a condensation and cyclization reaction is carried out, specifically, 1-(4-aminophenyl)-5,6-dihydro-3-(4-morpholine)-2(1H)-pyridone and a compound 5-chlorovaleryl chloride are subjected to the condensation and cyclization reaction to prepare 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridone; and 2, dehydrogenation oxidation is carried out, specifically, after the dehydrogenation oxidation is carried out on 2,3-dicyano-5,6-dichlorobenzoquinone, APSB-1 obtains a target. The preparation method of the apixaban pyridone impurity is high inefficiency, high in yield and high in purity, material and quality assurance is provided for study on related substances of apixaban, and strong data support is provided for subsequent relevant declaration registration.
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Paragraph 0010; 0022-0023; 0025-0026; 0028-0029; 0031-0032
(2019/11/13)
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- PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS AND INTERMEDIATES THEREOF
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The present invention provides processes for the preparation of active pharmaceutical ingredients and intermediates thereof in an aqueous designer smart surfactant solution.
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Page/Page column 28; 30
(2018/09/21)
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- Synthesizing method of intermediate of Apixaban
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The invention belongs to the technical field of synthesizing of medicine intermediates, and particularly relates to a synthesizing method of an intermediate of Apixaban. The method includes the step of making 4-R-aniline and 5-chlorovaleryl chloride make contact for reaction in an inert solvent in the presence of amine quarter alkali to obtain the intermediate, namely 1-(4-R-aniline)piperidine-2-ketone, of Apixaban, wherein the reaction formula is shown as the formula I (the formula I is seen in the description). By means of the synthesizing method, the reaction efficiency and conversion rateof the intermediate of Apixaban are improved, there is no need to add tertiary amine organic base or use expensive NaH cyclization reagents, and production cost is saved.
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Paragraph 0036; 0042-0054
(2018/10/19)
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- A antithrombotic drug [...] preparation method
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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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- PROCESS FOR THE PREPARATION OF APIXABAN
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The present invention relates to an improved process for the preparation of Apixaban and its intermediates.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF APIXABAN
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The present invention relates to an improved process for the preparation of Apixaban and its intermediates.
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- PROCESS FOR THE PREPARATION OF APIXABAN AND INTERMEDIATES THEREOF
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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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- DIMER IMPURITIES OF APIXABAN AND METHOD TO REMOVE THEM
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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 00187
(2017/02/09)
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- A method of preparing intermediates [...]
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A disclosed preparation method for an apixaban intermediate comprises the following steps: step (1), performing an amidation reaction shown in the specification on a compound 3 and a compound M in an organic solvent under the effect of an organic alkali to obtain a reaction solution containing a compound 3'; and step (2), under the effect of an inorganic base, directly performing an nucleophilic substitution reaction shown in the specification on the reaction solution obtained in the step (1) to prepare a compound 4, and performing a nitration reaction on the compound 4 under the effect of concentrated sulfuric acid and concentrated nitric acid to prepare a compound 5. The preparation method provided by the invention is low in cost, simple in operation and suitable for industrialization.
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- Preparing method for apixaban
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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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Paragraph 0051; 0052; 0053
(2017/01/19)
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- NOVEL METHOD FOR SYNTHESIZING KEY INTERMEDIATE OF APIXABAN
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The invention relates to a method for synthesizing an intermediate of Apixaban comprising reacting a compound of formula I with 5-chloro-valeryl chloride in the presence of inorganic base in an inert solvent to obtain a compound of formula II, with the reaction formula of (A), wherein R is selected from nitro group and the group (B). The method is mild in reaction condition, simple in operation, easy in purification, inexpensive in production cost, environmental-friendly, and suitable for industrial production.
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Paragraph 0026
(2016/10/17)
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- A pyridine derivative
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The present invention relates to the field of pharmaceutical chemistry, specifically to a class of compounds containing lactam and derivative thereof, and especially to a pyridine derivative as shown in general formula (I), preparation method and the use thereof as a Factor Xa inhibitor. The present invention further relates to the medical use of the compound and derivative thereof in preparation of anticoagulant drugs, particularly to the use in preparation of drugs for preventing or treating thrombosis or embolism.
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- 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
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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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- Alternate synthesis of apixaban (BMS-562247), an inhibitor of blood coagulation factor Xa
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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
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- Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
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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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