Wednesday, 25 March 2015

CN 103342704 A.........Preparation method of Apixaban as anti-thrombotic drug

Publication numberCN103342704 A
Publication typeApplication
Application numberCN 201310315775
Publication dateOct 9, 2013
Filing dateJul 25, 2013
Priority dateJul 25, 2013
Inventors薛吉军, 李毅, 王仕祥, 郑保富, 高强, 徐少军
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External Links: SIPO, Espacenet


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apixaban as shown in formula I, chemical name: 1- (4-methoxyphenyl) -7_ oxo-6- [4- (2_-oxo-piperidin-1-yl ) phenyl] -1H- _4,5,6,7- tetrahydro-pyrazolo [3,4-c] pyridine-3-carboxamide.
[0003] apixaban, compound Apixaban by Bristol-Myers Squibb and Pfizer jointly developed a new oral direct factor Xa inhibitor, in March 2011 approved the listing in the EU, the trade name Eliquis, clinically used Prevention of adult patients undergoing elective hip or knee replacement surgery venous thromboembolism occurs (VTE). Clinical study results show that, compared with the 40 mg once daily injections of enoxaparin (enoxaparin), twice daily oral administration of a better effect on the prevention of VTE after total hip and total knee arthroplasty appears, and does not increase the risk of bleeding . This product is a no cross-resistance and the advantages of fewer adverse reactions, etc., is expected to become the first-line oral antithrombotic drugs.
[0004] Currently, the preparation of the international literature Apixaban disclosed in the literature are as follows: (1) J.Med.Chem, 2007,50 (22), 5339 - 5356; (2) W02010 / 30983; (3. ) W02003 / 049681; (4) CN101967145
Literature (J.Med.Chem, 2007, 50 (22), 5339 -. 5356) for apixaban discovery process was discussed in detail and gives a pharmaceutical chemical synthesis route, see Formula 2,
Figure CN103342704AD00051
Route to iodine aniline and 5-bromo-pentyl chloride as raw materials by amidation - one-pot preparation of the compound 5,5 ring in chloroform and then with phosphorus pentachloride dichloride, condensation in the presence of excess morpholine - elimination reaction give intermediate 6. Then anisidine as starting material after diazotization of 2-chloro acetyl ethyl Japp-Klingmann hydrazone synthesis occurs continuously prepared pyrazole compound 3,3 and intermediate 6 via [3 + 2] cycloaddition co - elimination strategy generating compound 7,7 and δ - valerolactam Ullmann condensation reaction under similar conditions compound 8,8 glycol solution of ammonia in the ammonia solution to obtain the objective product Apixaban. Obviously 7 valerolactam condensation reaction of a low yield of 21% so that the actual application of these route very low value.
[0005] W02010 / 030983, in the same route to prepare the Apixaban, although the 7 δ - valerolactam condensation reaction yield was improved to 29%, but the total yield of only 1.3%.
[0006] World Patent Bristol-Myers Squibb company disclosed in 2003 W02003 / 049681 discloses two Apixaban of synthetic routes. Wherein a route as shown in formula 3:
Figure CN103342704AD00052
In line 3 in the formula δ- valerolactam as a raw material under the action of phosphorus pentachloride α- active hydrogen dichloride obtained under the action of the lithium carbonate compound 9,9 elimination of hydrogen chloride to a part 10 and 10 with morpholine to give the compound to a condensation reaction in the presence of triethylamine to form compounds 11 and 11 obtained by reacting compound 3 with compound 5 at 12, 12 and the effect of potassium iodide as a catalyst to give the compound 13, 13 via a coupling reaction with isobutyl chloroformate butyl mixed anhydride formed with excess ammonia ammonia solution and then get Apixaban. The route is only 5.2% total yield, reaction steps tedious, limiting the application of the route.
Another route [0007] has been disclosed as shown in Equation 4:
6 using the intermediate of formula 4 in the cesium carbonate and Cu (PPh3) 3Br and exists δ - valerolactam and 3 by the reaction of 14 and 14 [3 + 2] cyclization - 8,8 elimination reaction to give an excess of sodium methoxide in the presence of Under the action with formamide get Apixaban. Similarly, the total yield of this route is low, the reaction process using a larger amount of auxiliary reagents, limiting the application of the route. [0008] Chinese patent discloses a synthetic route Apixaban CN101967145, as shown in Equation 5:
Figure CN103342704AD00061
Formula 5 routes to p-nitroaniline as starting material under alkaline conditions and the 5-chloro-valeryl chloride after amidation - two-step one-pot cyclization reaction to give the compound 16, 16 dichloride, phosphorus pentachloride, and then with an excess of it morpholine condensation - an elimination reaction to give the compound 18, 18 5-chloro-valeryl chloride and amide compounds 17 and 17 is sodium sulfide - a two-step one-pot cyclization reaction after 14, 14 and 3 [3 + 2] cyclization - Elimination of reaction 8, the last aminolysis get Apixaban.

 formula 6:
Figure CN103342704AD00062

Figure CN103342704AD00071

 Figure CN103342704AD00081

The preparation of compound Apixaban
Compound 24 (0.3 g) was dissolved in 4.5mL of anhydrous tetrahydrofuran was added dropwise 5-bromo-Shu chloride (0.24g) was added triethylamine (0.16g), ice-water cooling. Naturally to room temperature, the reaction was stirred for half an hour, the reaction was quenched with 5mL of water and ethyl acetate (IOmLX 2), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product.
[0041] The crude product was dissolved in a mixed solvent of 2mL of ethanol and 2mL of tetrahydrofuran was added anhydrous magnesium hydroxide (0.47g), the reaction was heated at reflux for 12 hours, concentrated under reduced pressure, to the residue was added 5mL / K, dichloromethane (IOmLX 2), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated to recover the solvent pressure to give the crude product crystallized from ethyl acetate with petroleum ether to give an off-white solid 270mg, 75% yield.

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  1. Apixaban (INN, trade name Eliquis) is an anticoagulant for the prevention of venous thromboembolism and the prevention of stroke in atrial fibrillation. It is a direct factor Xa inhibitor. Apixaban has been available in Europe since May 2011. The drug was developed in a joint venture by Pfizer and Bristol-Myers Squibb. Apixaban