- 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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Read Online
- Synthetic method of betrixaban intermediate
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The invention discloses a simple, safe and high-yield method for preparing a betrixaban intermediate, wherein the method is characterized in that a compound A is dissolved in an organic solvent and ishydrogenated and reduced into a compound B under the condition of a catalyst, the compound B reacts with 4-cyanobenzoyl chloride to generate a compound C, and the compound C is subjected to ammonolysis to prepare a compound D.
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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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- 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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Paragraph 0018-0020; 0023-0025; 0028-0030
(2019/11/12)
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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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Paragraph 0068; 0069
(2018/10/11)
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- Preparation method of betrixaban intermediate N-(5-chloro-2-pyridyl)-2-[(4-cyanobenzoyl)amino]-5-methoxybenzamide
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The invention discloses a preparation method of betrixaban intermediate N-(5-chloro-2-pyridyl)-2-[(4-cyanobenzoyl)amino]-5-methoxybenzamide. The preparation method is characterized by comprising the following steps: carrying out a chlorination reaction between 1,5-methoxy-2-nitrobenzoic acid (1) and phosphorus oxychloride, and then carrying out an amidation reaction between a chlorination productand 2-aminopyridine to obtain a compound 2; 2, performing catalytic hydrogenation on the compound 2 to obtain a compound 3; 3, performing a condensation reaction on the compound 3 and p-cyanobenzoyl chloride to obtain a compound 4; 4, performing a chlorination reaction on the compound 4 to obtain a compound 5, wherein the total yield is 57.2%. The preparation method has the main advantages as follows: materials are easy to obtain, operation is simple and convenient, the cost is relatively low, production of byproducts is reduced, and industrial production is facilitated.
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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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Paragraph 0033-0034; 0040-0041; 0047-0048
(2018/03/24)
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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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Page/Page column 12
(2018/03/23)
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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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Paragraph 0093; 0094; 0095
(2018/01/11)
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- Preparation method of Betrixaban intermediate N-(5-chloro-2-pyridyl)-2-(4-cyanobenzeneformamido)-5-metoxybenzamide
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The invention discloses a preparation method of a Betrixaban intermediate N-(5-chloro-2-pyridyl)-2-(4-cyanobenzeneformamido)-5-metoxybenzamide (a compound II). The synthetic route is as shown in the graphs in the specification. According to the new method, different starting materials, different reaction conditions and different reaction routes are adopted. Thus, the step of reduction of nitro into amino in original patents is avoided. By the adoption of protection of carboxyl group, generation of by-products is greatly reduced. During palladium carbon catalytic hydrogenation, there exist no dechlorination products.
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Paragraph 0070; 0071; 0072
(2017/06/02)
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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 0245; 0247; 0248; 0249
(2017/08/29)
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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 33-34
(2008/12/05)
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- Benzamides and related inhibitors of factor Xa
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Novel benzamide compounds including their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives having activity against mammalian factor Xa are described. Compositions containing such compounds are also described. The comp
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- Benzamides and related inhibitors of factor Xa
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Novel benzamide compounds including their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives having activity against mammalian factor Xa are described. Compositions containing such compounds are also described. The comp
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