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Preparation method for apixaban intermediate

A technology of intermediates and compounds, which is applied in the field of preparation of intermediates, can solve problems affecting the smooth progress of acylation reactions, and achieve the effect of low cost and simple operation

Inactive Publication Date: 2014-03-12
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw material cost of this method is relatively low, but p-nitroaniline will affect the smooth progress of the acylation reaction due to the strong electron-withdrawing effect of the nitro group, as also reported in literature (Eur.J.Org.Chem.2004, 1254-1260)

Method used

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  • Preparation method for apixaban intermediate
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  • Preparation method for apixaban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Preparation of 3-morpholin-1-[4-(2-carbonylpiperidinyl)phenyl]-5,6-dihydropyridin-2(1H)-one

[0034] first step:

[0035]

[0036] Compound 3 (24g, 0.26mol), 83ml of triethylamine, and 240ml of tetrahydrofuran were added to the reaction flask. 0°C, 5-chloropentanoyl chloride (63g, 0.4mol) was added, and reacted for 1h (the product in the reaction solution was detected as compound 3', X=Cl, MS (ESI, m / z): 212.08[M+1] ; X=Br, MS (ESI, m / z): 256.03, 258.02[M+1]); Sodium hydrogen (15.5g, 0.64mol) was added at 0°C, reacted at room temperature for 4h, evaporated THF, added dichloromethane 200ml, separated, extracted the aqueous layer with dichloromethane, washed once with saturated brine, dried over anhydrous magnesium sulfate, and spin-dried to obtain 49g of a solid, recrystallized from ethyl acetate, filtered to obtain an off-white solid, which weighed 32g after drying. The yield is 70%, and the melting point is 99-100°C.

[0037] MS (ESI, m / z): 176.11 [M+1...

Embodiment 2

[0059] Example 2: Preparation of 3-morpholin-1-[4-(2-carbonylpiperidinyl)phenyl]-5,6-dihydropyridin-2(1H)-one

[0060] The first step of acylation and cyclization reaction feeds compound 3 (10.7g, 0.12mol), triethylamine 37.2ml, 5-bromopentanoyl chloride (30g, 0.14mol), tert-butanol methyl (33.6g, 0.3mol), An off-white solid was obtained, weighing 16 g after drying. Yield 74%, melting point 98-100°C. The remaining steps were repeated in Example 1 to obtain Compound 2. Each identification data is the same as in Example 1.

Embodiment 3

[0061] Example 3: Preparation of 3-morpholin-1-[4-(2-carbonylpiperidinyl)phenyl]-5,6-dihydropyridin-2(1H)-one

[0062] The first step of acylation and cyclization reaction feeds compound 3 (6.2g, 0.07mol), 37.2ml of triethylamine, 5-bromopentanoyl chloride (30g, 0.14mol), tert-butanol methyl (33.6g, 0.3mol), Dichloromethane was used as a solvent to obtain an off-white solid weighing 9.6 g after drying. The yield is 75%, and the melting point is 98-99°C. The remaining steps were repeated in Example 1 to obtain Compound 2. Each identification data is the same as in Example 1.

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Abstract

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.

Description

technical field [0001] The present invention specifically relates to a preparation method of an intermediate of apixaban. Background technique [0002] Thrombosis is mainly divided into arterial thrombosis and venous thrombosis. Venous thromboembolism (VET) is induced by various reasons in venous blood vessels, and its main clinical manifestations are deep venous thrombosis (DVT) and pulmonary embolism (pulmonary embolism, PE), which is a serious hazard to human health. Pulmonary embolism is one of the common respiratory and cardiovascular diseases. Deep vein thrombosis mainly occurs after major orthopedic surgery. Taking anticoagulant drugs is the main method to prevent thrombosis, which can effectively reduce mortality and prevent recurrence. [0003] Apixaban (Apixaban, 1) is a new oral inhibitor of factor Xa. Factor Xa is a key regulator in the coagulation cascade, located at the upper end of thrombin, and the coagulation cascade is a process of gradual amplification ,...

Claims

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Application Information

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IPC IPC(8): C07D211/76
CPCC07D211/76
Inventor 霍韶伟郭晔堃钟静芬时惠麟
Owner SHANGHAI INST OF PHARMA IND
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