CN105503859A

CN105503859A - Apixaban purification method

Info

Publication number: CN105503859A
Application number: CN201510651339.2A
Authority: CN
Inventors: 田辉; 于海州; 余俊; 杨宝海
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd
Current assignee: Changzhou Hengbang Pharmaceutical Co Ltd
Priority date: 2014-10-10
Filing date: 2015-10-10
Publication date: 2016-04-20
Anticipated expiration: 2035-10-10
Also published as: CN105503859B

Abstract

The present invention provides an apixaban purification method, the method is as follows: N, N-dimethylformamide is used for hot dissolving and cold precipitation of an apixaban crude product, an organic solvent is used for refluxing and beating of a precipitated solid for purification to obtain an apixaban finished product. The method is simple in reaction operation and suitable for industrial production, yield is high, and purity is good.

Description

The purification process of Eliquis

Technical field

The present invention relates to the field of chemical synthesis, particularly relate to a kind of purification process of Eliquis.

Background technology

Eliquis, chemical name: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c]-pyridine-3-carboxamides, CAS:503612-47-3, structure:

Eliquis is a kind of anticoagulant jointly declared by Pfizer company and Bristol-Myers Squibb Co., directly act on factor Xa, be used for the treatment of and comprise deep venous thrombosis (deepvenousthrombosis, and pulmonary infarction (pulmonaryembolism DVT), PE) in interior phlebothrombosis disease, hemorrhage untoward reaction is lower than old medicine warfarin.In May, 2011, European Union ratifies direct inhibitor Eliquis (trade(brand)name Eliquis) listing of oral Xa factor, for the adult patients of select a time hip joint or replacement knee in arthroplasty, to prevent venous thrombosis (venousthrombembolicevents, VTE).Obtaining EMA approval in November, 2012, obtaining FDA and PMDA approval in December, 2012 respectively, for preventing atrial fibrillation patients apoplexy.

At present, the preparation method of Eliquis disclosed in document and similar approach comprise following documents report: WO2007001385A2, WO03026652A1, WO0039131A1, can be summarized as following route:

In this route, it is clear that process for purification adopts DMF Eliquis crude product to be added thermosol usually, and the method for crystallization of lowering the temperature drip buck in reaction solution after is to obtain Eliquis finished product, as follows:

The Eliquis finished color that the method obtains is comparatively dark, and related substance is poor and particle diameter is comparatively large, needs to use special High shear device to carry out the product that particle diameter process just can obtain applicable formulation development.

Summary of the invention

The object of invention is to solve the problems of the technologies described above, and provides that a kind of purity is high, yield is high and the purification process of the Eliquis of applicable formulation development, and the method is simple to operate, be applicable to industrial production.

Purification process of the present invention comprises the following steps:

Eliquis crude product is joined DMF, stirring heating, crystallization of once lowering the temperature, filter.The organic solvent backflow making beating of gained solid, reducing temperature twice crystallization, filter, solid forced air drying, obtains Eliquis finished product.

The weightmeasurement ratio of described Eliquis and DMF is 1:5-10, preferred 1:6-8, most preferably 1:7.

Preferably, the temperature of described stirring heating is 70 ~ 80 DEG C.

Preferably, the time of described stirring heating is 30 ~ 40min.

Preferably, the recrystallization temperature of described crystallization of once lowering the temperature is 20 ~ 30 DEG C.

Preferably, the crystallization time of described crystallization of once lowering the temperature is 9 ~ 10h.

Preferably, described organic solvent is methyl alcohol, ethanol, Virahol, ethyl acetate.

The weightmeasurement ratio of described Eliquis crude product and organic solvent is 1:5-20, preferred 1:10-15, most preferably 1:12.5.

Preferably, the time of described organic solvent backflow making beating is 7 ~ 8h.

Preferably, the recrystallization temperature of described reducing temperature twice crystallization is 20 ~ 30 DEG C.

Preferably, the crystallization time of described reducing temperature twice crystallization is 12 ~ 13h.

Preparation method's gained Eliquis finished color of the present invention is shallow, purity is high, particle diameter is little, yield is good, the method industrial production simple to operate, applicable.

Embodiment

In order to further illustrate technical scheme of the present invention, below in conjunction with concrete enforcement, the present invention is further described, but content of the present invention is not limited to specific embodiment.

Embodiment 1: the purifying of Eliquis

In 5L reaction flask, add DMF 1.4L, open and stir, add Eliquis crude product 200g.Be heated to 70 ~ 80 DEG C, stir 30 minutes, cooling crystallization.Filter, solid 2.5L alcohol reflux making beating 7h, filter after being down to room temperature, solid 60 DEG C of forced air dryings 10 hours, obtain finished product 169.3g.HPLC:99.83%, carboxylic acid impurities: 0.04%, particle diameter: 24nm. ¹HNMR(500MHz,DMSO-d ₆)，δ：1.81-1.85(m,4H)，2.38(t,J＝6.5Hz,2H)，3.21(t,J＝6.6Hz,2H)，3.58(t,J＝6.0Hz,2H)，3.79(s,3H)，4.03(t,J＝6.6Hz,2H)，6.98-7.00(d,J＝9.0Hz,2H)，7.26-7.27(d,J＝8.8Hz,2H)，7.33-7.35(d,J＝8.8Hz,2H)，7.42(s,1H)，7.49-7.51(d,J＝9.0Hz,2H)，7.69(s,1H)； ¹³CNMR(100MHz)，δ：20.8，21.0，22.9，32.5，50.7，50.9，55.4，113.3，125.2，125.9，126.2，126.7，132.5，132.9，139.7，141.3，141.4，165.6，159.1，163.1，168.8；IR(KBr):：3480，3310，3090，2972，2935，1682，1632，1596，1512，1547，1401，1374，1296，1031，1253，1152，845，818cm ^-1；MS(m/z)：460.2[M+H] ⁺。

Embodiment 2:

In 5L reaction flask, add DMF 1.4L, open and stir, add Eliquis crude product 200g.Be heated to 70 ~ 80 DEG C, stir 30 minutes, cooling crystallization.Filter, solid 2.5L Virahol backflow making beating 7h, filter after being down to room temperature, solid 60 DEG C of forced air dryings 10 hours, obtain finished product 161.8g.HPLC:99.81%, carboxylic acid impurities: 0.02%, particle diameter (D90): 19nm.

Embodiment 3:

In 5L reaction flask, add DMF 1.4L, open and stir, add Eliquis crude product 200g.Be heated to 70 ~ 80 DEG C, stir 30 minutes, cooling crystallization.Filter, solid 2.5L ethyl acetate backflow making beating 7h, filter after being down to room temperature, solid 60 DEG C of forced air dryings 10 hours, obtain finished product 158.2g.HPLC:99.67%, carboxylic acid impurities: 0.05%, particle diameter: 26nm.

Comparative example 1:

DMF 140mL is added, Eliquis crude product 20g in 250mL reaction flask.Be heated to 70 ~ 80 DEG C, stirring and dissolving, drip 150ml water, drip crystallization of lowering the temperature after finishing.Solid 60 DEG C of forced air dryings that filtration obtains 10 hours, obtain finished product 15.2g.HPLC:99.31%, carboxylic acid impurities: 0.20%, particle diameter (D90): 820nm.

Comparative example 2:

DMF 140mL is added, Eliquis crude product 20g in 250mL reaction flask.Be heated to 70 ~ 80 DEG C, stirring and dissolving, drip 150ml aqueous sodium hydroxide solution (0.1mol/L), drip after finishing and to lower the temperature crystallization, filter and obtain solid 60 DEG C of forced air dryings 10 hours, obtain finished product 14.6g.HPLC:99.77%, carboxylic acid impurities: 0.10%, particle diameter (D90): 780nm.

Refer to table 1-table 3, table 1 is the stratographic analysis table of the Eliquis that the embodiment of the present invention 2 obtains, and table 2 is the stratographic analysis tables of the Eliquis that comparative example 1 obtains, and table 3 is the stratographic analysis tables of the Eliquis that comparative example 2 obtains.

Table 1

Retention time	Relative retention time	Peak area	Peak area %
				2.415	0.27	1.462	0.021
3.360	0.29	1.230	0.018
				8.979	1.00	6949.069	99.806
11.606	1.29	2.600	0.037
				12.192	1.36	1.615	0.023
13.798	1.54	4.707	0.069
				15.641	1.74	1.869	0.027

Table 2

Retention time	Relative retention time	Peak area	Peak area %
				2.621	0.29	14.455	0.200
3.561	0.39	1.371	0.019
				6.634	0.56	2.519	0.035
7.696	0.62	20.683	0.287
				9.170	1.00	7159.703	99.309
11.810	1.29	1.569	0.022
				12.393	1.35	1.267	0.018
13.988	1.53	6.823	0.095
				16.305	1.78	1.159	0.016

Table 3

Retention time	Relative retention time	Peak area	Peak area %
				2.462	0.27	7.178	0.098
9.161	1.00	7308.936	99.773
				11.834	1.29	2.471	0.034
12.417	1.36	1.360	0.019
				14.039	1.53	4.285	0.058
15.889	1.73	1.360	0.019

As can be seen from the content of above-mentioned table 1-table 3, be near 0.27 in relative retention time, the carboxylic acid impurities of the Eliquis that the embodiment of the present invention obtains and the Eliquis that comparative example obtains obviously reduces.By backflow methods of beating, particle diameter is significantly diminished, can be directly used in formulation development, therefore the purification process of the embodiment of the present invention has significant effect.

Claims

1. a purification process for Eliquis, comprises the following steps:

1) Eliquis crude product is joined DMF, stirring heating, obtain the DMF solution of Eliquis;

2) first time lowers the temperature crystallization, filters, and collects crystallization thing;

3) crystallization thing organic solvent backflow making beating, crystallization of lowering the temperature for the second time, filter, forced air drying, obtains Eliquis finished product.

2. the purification process of Eliquis according to claim 1, is characterized in that, the weightmeasurement ratio of described Eliquis crude product and DMF is 1:5-10, preferred 1:6-8, most preferably 1:7.

3. the purification process of Eliquis according to claim 1, is characterized in that, the temperature of described stirring heating is 70 ~ 80 DEG C.

4. the purification process of Eliquis according to claim 1, is characterized in that, the time of described stirring heating is 30 ~ 40min.

5. the purification process of Eliquis according to claim 1, is characterized in that, the recrystallization temperature of described first time cooling crystallization is 20 ~ 30 DEG C.

6. the purification process of Eliquis according to claim 1, is characterized in that, the crystallization time of described first time cooling crystallization is 9 ~ 10h.

7. the purification process of Eliquis according to claim 1, is characterized in that, described organic solvent is one or more in methyl alcohol, ethanol, Virahol or ethyl acetate.

8. the purification process of Eliquis according to claim 1, is characterized in that, the weightmeasurement ratio of described Eliquis crude product and organic solvent is 1:5-20, preferred 1:10-15, most preferably 1:12.5.

9. the purification process of Eliquis according to claim 1, is characterized in that, the time of described organic solvent solution backflow making beating is 7 ~ 8h.

10. the purification process of Eliquis according to claim 1, is characterized in that, the recrystallization temperature of described second time cooling crystallization is 20 ~ 30 DEG C.

The purification process of 11. Eliquis according to claim 1, is characterized in that, the crystallization time of described second time cooling crystallization is 12 ~ 13h.