- Preparation method of beta-caraban
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The preparation method comprises the following steps: in liquid dimethylamine, a compound of the structural formula II or a salt thereof and MN (CH). 3 )2 The dimethylamine solution in the structural formula I is reacted to obtain the fritilth. M represents Li or MgX; and M is Li or Na. Wherein X is selected from one of Cl, Br and I. The preparation method disclosed by the invention is high in yield and high in product purity, can substantially avoid generation of single methyl ammonia impurities and dechlorination impurities, and greatly simplifies the subsequent refining process. In addition, the preparation method is single in solvent, the use of the mixed solvent is avoided, the later-stage solvent recovery is convenient, and the three wastes can be reduced.
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Paragraph 0022; 0084-0088
(2021/11/10)
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- Improved preparation method of beta-caraban
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The invention relates to the fields of organic chemistry and pharmacy, and particularly relates to an improved method for preparing betrixaban. Compared with the prior art, the method has the advantages that the defects of use of high-corrosion hydrogen chloride gas, heavy burden for 'three wastes' treatment, difficult refining and purification of products and the like can be overcome. The method is characterized in that a metal organic compound RMR' (M is selected from Mg and Zn, R is selected from Cl, Br, I, alkyl or aryl, and R' is selected from akly or aryl) is used for reacting with dimethylamine or salt thereof in an aprotic solvent; then the obtained reacting liquid reacts with the compound or salt thereof in a formula II to prepare betrixaban. The improved novel method has the advantages of use of easily available raw materials, mild reaction condition, convenience in operation, excellent product quality and low cost and is suitable for industrial large-scale production.
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Paragraph 0082; 0084
(2019/08/29)
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- Novel betrixaban intermediate and preparation method and application thereof
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The invention discloses a novel betrixaban intermediate and a preparation method and application thereof. The structure of the intermediate is shown in formula I. The intermediate can achieve efficient and high-yield construction of an N,N-dimethylcarbamimidoyl structure fragment in the betrixaban structure through a bio-enzyme catalysis method, and has the advantages of being green and environmentally friendly.
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- Synthetic process of betrixaban
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The invention provides a synthetic process of betrixaban, and particularly relates to the field of pharmaceutical manufacturing. S1, 1-(3-dimethyl amine propyl)-3-ethyl carbon imidodicarbonic diamide,N-hydroxysuccinimide (NHS) and paracyanobenzoic acid are introduced into a solution, and activation of cyanobenzoic acid is achieved; S2, the activated cyanobenzoic acid reacts with 2-amine-N-(5-chlorine group-2-pyridyl)-5-methoxybenzamide, appropriate methyl alcohol is added in a reaction container, cooling is conducted for devitrification, and a midbody I is obtained through filter; S3, moistureless condition is guaranteed, and acetylchloride is dropwise added; the midbody I is added, and evaporation is conducted until it is guaranteed that materials are dried; reaction with a tetrahydrofuran solution of dimethylamine is conducted, and a midbody II is generated under action of sodium hydroxide; and S4, the midbody II reacts with maleic acid at 60-70 DEG C to obtain the betrixaban. According to the synthetic process of the betrixaban, the reaction condition is mild, the yield is high, impurities are less, gas preparation is reduced, corrosion on equipment is reduced, and the cost oflater-stage environmental protective treatment is low.
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- Preparation method of betrixaban intermediate and betrixaban and product thereof
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The invention relates to a preparation method of a betrixaban intermediate or salt thereof. The method includes: under the action of a catalyst, adding an amide coupling reagent dropwise into a compound shown as formula SM-III and a compound shown as formula SM-I or salts thereof for condensation reaction in an organic solvent to form a compound shown as formula III or a salt thereof, and furtherpreparing the betrixaban intermediate or the salt thereof into betrixaban or a salt thereof. The betrixaban or the hydrochloride thereof prepared by the method provided by the invention basically doesnot contain dechlorinated impurity V or demethylated impurity VI, and has high purity. The method improves the product yield, reduces the use of high corrosive raw materials, is low in cost, and is suitable for industrial production.
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- SALTS OF BETRIXABAN AND PROCESSES FOR PREPARATION THEREOF
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The present application relates to novel acid addition salts of Betrixaban and processes for their preparation thereof. It further relates to crystalline forms including its solvates and hydrates of Betrixaban novel acid addition salts. The application further concerns pharmaceutical compositions comprising the novel acid addition salts of the Betrixaban, useful as potent fXa inhibitors.
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- Preparation method of betrixaban maleate
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The invention provides a preparation method of betrixaban maleate. According to the preparation method, paracyanobenzoic acid and 2-amino-N-(5-chloro-2-pyridyl)-5-methoxy benzamide are subjected to acoupled reaction; in a coupling process, a new coupling catalyst is selected for use; EDC and NHS are applied to a combined way; a coupling product reacts with alcohol under the acidic condition so asto generate pinner salt; in the process, acetyl chloride is enabled to react with alcohols, so that hydrogen chloride needed by the reaction is provided. The way of directly introducing hydrogen chloride gas is eliminated, so that gas preparation and corrosion of equipment are reduced. In a whole reaction process, the method is mild in reaction conditions and higher in yield, thus being suitablefor industrial production.
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- Bei quxi class crystal form and its preparation and use
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The invention discloses crystal forms of a factor Xa inhibitor betrixaban, a preparing method thereof, pharmaceutical compositions comprising the crystal forms of the betrixaban, and uses of the crystal forms of the betrixaban in preparation of medicines used for preventing or treating mammal diseases characterized by adverse thrombus formation.
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Paragraph 0089; 0102-0104
(2018/10/11)
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- Midbody for betrixaban, preparation method and application of midbody
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The invention discloses a midbody for betrixaban, a preparation method and application of the midbody. The structure of the midbody is as shown in formula I described in specification. The midbody can be effectively compounded by using the low-cost easily acquired raw materials, and meanwhile, the subsequent reaction yield is high and the post-processing is simple when the raw materials are used for compounding the betrixaban, and the acquired product is high in purity and has wide industrial application prospect.
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- Preparation method of Betrixaban or analogue thereof
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The invention discloses a preparation method of Betrixaban or an analogue thereof. The preparation method of the Betrixaban comprises the steps of adopting N-(5-chloropyridine-2-radical)-5-methoxyl-2-aminobenzamide (A) as a raw material, carrying out amide condensation reaction on the raw material and cyanobenzoyl chloride (B), treating through an alkali liquor, and obtaining a formula D compound. Amino magnesium chloride and the formula D compound or salt thereof are adopted to prepare a Betrixaban free alkali compound (I) or the analogue thereof.
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Paragraph 0229; 0230; 0231; 0237; 0241
(2017/08/29)
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- Preparation method of betrixaban
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The invention provides a method for preparing betrixaban. The method comprises the following steps: performing the nucleophilic addition elimination on 5-methoxyisatoic anhydride used as a raw material and 2-amino-5-chloropyridine under the condition of potassium tert-butoxide to obtain N-(5-chloro-2-pyridyl)-5-methoxyl-2-aminobenzamide, allowing a compound 4 to react with cyanobenzoyl chloride to obtain N-(5-chloro-2-pyridyl)-2-[(4-cyano benzoyl) amino]-5-methoxyl benzamide hydrochloride, and finally performing the nucleophilic addition with dimethylamine to obtain a target product betrixaban, wherein the total yield is 57.8 percent. By adopting the preparation method, the raw materials are low in price and easy to get, the reaction conditions are moderate, the reaction controllability is high, and the industrialized application prospect is good.
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- A facile method for the synthesis of Betrixaban
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A facile method for the synthesis of N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide (Betrixaban) from 5-methoxy-2-nitrobenzoic acid is achieved by reduction, acylation, chlorination, acylation and the formation of the amidine. A dechlorinated impurity is avoided in this method. Using tetrahydrofuran as the solvent in the four steps makes its recovery easier. The total yield of the target compound is about 40% and this method is suitable for large-scale production.
- Li, Jianye,Chen, Ligong,Yan, Xilong,Li, Yang,Wei, Daiyan,Wang, Donghua
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p. 524 - 526
(2015/11/27)
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- CRYSTALLINE FORMS OF A FACTOR Xa INHIBITOR
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Provided herein are crystalline forms of a maleate salt of betrixaban, compositions and methods of preparation or use thereof.
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Page/Page column 44
(2012/03/26)
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- METHODS OF SYNTHESIZING FACTOR XA INHIBITORS
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Described herein are novel methods of preparing a compound of Formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for preparing betrixaban or a pharmaceutically acceptable salt thereof. Also described are compositions comprising substantially pure betrixaban free base or salt thereof.
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- Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor
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Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.
- Zhang, Penglie,Huang, Wenrong,Wang, Lingyan,Bao, Liang,Jia, Zhaozhong J.,Bauer, Shawn M.,Goldman, Erick A.,Probst, Gary D.,Song, Yonghong,Su, Ting,Fan, Jingmei,Wu, Yanhong,Li, Wenhao,Woolfrey, John,Sinha, Uma,Wong, Paul W.,Edwards, Susan T.,Arfsten, Ann E.,Clizbe, Lane A.,Kanter, James,Pandey, Anjali,Park, Gary,Hutchaleelaha, Athiwat,Lambing, Joseph L.,Hollenbach, Stanley J.,Scarborough, Robert M.,Zhu, Bing-Yan
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scheme or table
p. 2179 - 2185
(2009/12/07)
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- METHODS OF SYNTHESIZING PHARMACEUTICAL SALTS OF A FACTOR XA INHIBITOR
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Novel methods of preparing a compound of Formula I which is an inhibitor of Factor Xa and its maleate salt, are described herein.
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Page/Page column 42-43
(2008/12/05)
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- Unit dose formulations and methods of treating thrombosis with an oral factor Xa inhibitor
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Unit doses of factor Xa inhibitor compounds and methods of using these compounds for inhibiting blood coagulation in a human patient are taught herein. The unit dose of the factor Xa inhibitor compounds disclosed herein required to inhibit coagulation in a primate is lower than the unit dose required to obtain similar levels of coagulation inhibition in other animal models, such as rodents. Also taught are in vitro assays useful in predicting in vivo antithrombotic activity in humans.
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Page/Page column 23
(2008/12/06)
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- Novel pharmaceutical salts and polymorphs of a factor Xa inhibitor
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The present invention provides for salts comprising a compound of Formula I and an acid that has activity against mammalian factor Xa. The present invention is also directed to methods of making the compound of Formula I.
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Page/Page column 9
(2008/06/13)
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