CN105503859B

CN105503859B - The purification process of Eliquis

Info

Publication number: CN105503859B
Application number: CN201510651339.2A
Authority: CN
Inventors: 田辉; 于海州; 余俊; 杨宝海
Original assignee: Jiangsu Hausen Pharmaceutical Group Co Ltd
Current assignee: Changzhou Hengbang Pharmaceutical Co Ltd
Priority date: 2014-10-10
Filing date: 2015-10-10
Publication date: 2019-11-12
Anticipated expiration: 2035-10-10
Also published as: CN105503859A

Abstract

The present invention provides a kind of purification process of Eliquis, and this method is by the way that by apixaban crude n,N-Dimethylformamide hot-melt cold precipitation, the solid after precipitation flows back mashing with organic solvent to purify to obtain Eliquis finished product.Operation of the present invention is simple, is suitble to industrialized production, and 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 more particularly to a kind of purification process of Eliquis.

Background technique

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

Eliquis is a kind of anticoagulant declared jointly by Pfizer company and Bristol-Myers Squibb Co., directly Factor Xa is acted on, includes deep vein thrombosis (deep venous thrombosis, DVT) and pulmonary embolism for treating The adverse reaction of phlebothrombosis disease including (pulmonary embolism, PE), bleeding is lower than old medicine warfarin.2011 May, European Union ratify direct inhibitor Eliquis (trade name Eliquis) listing of oral Xa factor, for select a time hip joint or The adult patients of replacement knee in arthroplasty, to prevent venous thronbosis (venous thrombembolic events, VTE). It obtains EMA approval in November, 2012, FDA and PMDA approval is obtained in December, 2012 respectively, for preventing atrial fibrillation patients apoplexy.

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

In the route, refining methd generallys use n,N-Dimethylformamide and apixaban crude is heated dissolved clarification, to The method that the crystallization that cools down after buck is added dropwise in reaction solution obtains Eliquis finished product, as follows:

The Eliquis finished color that this method obtains is deeper, and related substance is poor and partial size is larger, needs using spy Different High shear device, which carries out partial size processing, can just obtain the product for being suitble to formulation development.

Summary of the invention

The purpose of invention is to solve above-mentioned technical problem, provides a kind of purity is high, high income and is suitble to formulation development The purification process of Eliquis, this method is easy to operate, is suitble to industrial production.

Purification process of the invention the following steps are included:

Apixaban crude is added to n,N-Dimethylformamide, agitating and heating, once cool down crystallization, filtering.Gained Solid is flowed back with organic solvent and is beaten, reducing temperature twice crystallization, and filtering, solid forced air drying obtains Eliquis finished product.

The Eliquis and the w/v of n,N-Dimethylformamide are 1:5-10, preferably 1:6-8, most preferably 1: 7。

Preferably, the temperature of the agitating and heating is 70~80 DEG C.

Preferably, the time of the agitating and heating is 30~40min.

Preferably, the crystallization temperature of the primary cooling crystallization is 20~30 DEG C.

Preferably, the crystallization time of the primary cooling crystallization is 9~10h.

Preferably, the organic solvent is methanol, ethyl alcohol, isopropanol, ethyl acetate.

The w/v of the apixaban crude and organic solvent is 1:5-20, preferably 1:10-15, most preferably 1: 12.5。

Preferably, the time of the organic solvent reflux mashing is 7~8h.

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

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

Eliquis finished color obtained by preparation method of the present invention is shallow, purity is high, partial size is small, yield is good, this method operation Simply, it is suitble to industrial production.

Specific embodiment

Technical solution in order to further illustrate the present invention carries out furtherly the present invention below in conjunction with specific implementation It is bright, but the contents of the present invention are not limited to specific embodiment.

Embodiment 1: the purifying of Eliquis

N,N-Dimethylformamide 1.4L is added into 5L reaction flask, opens stirring, apixaban crude 200g is added.Add Heat is warming up to 70~80 DEG C, stirs 30 minutes, and cool down crystallization.Filtering, solid are beaten 7h with 2.5L alcohol reflux, are cooled to room temperature Filtering, the forced air drying 10 hours of 60 DEG C of solid obtain finished product 169.3g.HPLC:99.83%, carboxylic acid impurities: 0.04%, partial size: 24nm。¹H NMR(500MHz,DMSO-d₆), 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)；¹³C NMR (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:

N,N-Dimethylformamide 1.4L is added into 5L reaction flask, opens stirring, apixaban crude 200g is added.Add Heat is warming up to 70~80 DEG C, stirs 30 minutes, and cool down crystallization.Filtering, solid are beaten 7h with 2.5L isopropyl alcohol reflux, are down to room temperature After filter, the forced air drying 10 hours of 60 DEG C of solid obtains finished product 161.8g.HPLC:99.81%, carboxylic acid impurities: 0.02%, partial size (D90): 19nm.

Embodiment 3:

N,N-Dimethylformamide 1.4L is added into 5L reaction flask, opens stirring, apixaban crude 200g is added.Add Heat is warming up to 70~80 DEG C, stirs 30 minutes, and cool down crystallization.Filtering, solid are beaten 7h with 2.5L ethyl acetate backflow, are down to room It is filtered after temperature, the forced air drying 10 hours of 60 DEG C of solid obtains finished product 158.2g.HPLC:99.67%, carboxylic acid impurities: 0.05%, grain Diameter: 26nm.

Comparative example 1:

N,N-Dimethylformamide 140mL, apixaban crude 20g are added into 250mL reaction flask.It is heated to 70 ~80 DEG C, 150ml water is added dropwise in stirring and dissolving, and cool down crystallization after drop is complete.The forced air drying 10 hours of 60 DEG C of the solid being obtained by filtration, Obtain finished product 15.2g.HPLC:99.31%, carboxylic acid impurities: 0.20%, partial size (D90): 820nm.

Comparative example 2:

N,N-Dimethylformamide 140mL, apixaban crude 20g are added into 250mL reaction flask.It is heated to 70 ~80 DEG C, stirring and dissolving is added dropwise 150ml sodium hydrate aqueous solution (0.1mol/L), and cool down crystallization after drop is complete, and solid is obtained by filtration 60 DEG C forced air drying 10 hours, obtain finished product 14.6g.HPLC:99.77%, carboxylic acid impurities: 0.10%, partial size (D90): 780nm.

Table 1- table 3 is please referred to, table 1 is the chromatography table for the Eliquis that the embodiment of the present invention 2 obtains, and table 2 is comparison The chromatography table for the Eliquis that example 1 obtains, table 3 are the chromatography tables for 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

Can be seen that from the content of above-mentioned table 1- table 3 in relative retention time is near 0.27, and the embodiment of the present invention obtains The carboxylic acid impurities of Eliquis that are obtained with comparative example of Eliquis significantly reduce.By the methods of beating that flows back, keep partial size aobvious Work becomes smaller, and can be directly used for formulation development, therefore the purification process of the embodiment of the present invention has significant effect.

Claims

1. a kind of purification process of Eliquis, comprising the following steps:

1) apixaban crude is added to n,N-Dimethylformamide, agitating and heating obtains the N of Eliquis, N- dimethyl The w/v of formamide solution, the apixaban crude and n,N-Dimethylformamide is 1:5-10；

2) crystallization object is collected in cooling crystallization, filtering for the first time；

3) crystallization object is flowed back with organic solvent and is beaten, second of crystallization that cools down, filtering, and forced air drying obtains Eliquis finished product, institute Organic solvent is stated as one of ethyl alcohol or isopropanol or a variety of, and the w/v of apixaban crude and organic solvent For 1:5-20.

2. the purification process of Eliquis according to claim 1, which is characterized in that the apixaban crude and N, N- The w/v of dimethylformamide is 1:6-8.

3. the purification process of Eliquis according to claim 2, which is characterized in that the apixaban crude and N, N- The w/v of dimethylformamide is 1:7.

4. the purification process of Eliquis according to claim 1, which is characterized in that the temperature of the agitating and heating is 70 ~80 DEG C.

5. the purification process of Eliquis according to claim 1, which is characterized in that the time of the agitating and heating is 30 ~40min.

6. the purification process of Eliquis according to claim 1, which is characterized in that the analysis of the first time cooling crystallization Brilliant temperature is 20~30 DEG C.

7. the purification process of Eliquis according to claim 1, which is characterized in that the analysis of the first time cooling crystallization The brilliant time is 9~10h.

8. the purification process of Eliquis according to claim 1, which is characterized in that the apixaban crude with it is organic The w/v of solvent is 1:10-15.

9. the purification process of Eliquis according to claim 8, which is characterized in that the apixaban crude with it is organic The w/v of solvent is 1:12.5.

10. the purification process of Eliquis according to claim 1, which is characterized in that the organic solvent solution reflux The time of mashing is 7~8h.

11. the purification process of Eliquis according to claim 1, which is characterized in that second of cooling crystallization Crystallization temperature is 20~30 DEG C.

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