CN109627242A - The preparation method of Eliquis - Google Patents
The preparation method of Eliquis Download PDFInfo
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- CN109627242A CN109627242A CN201811630308.9A CN201811630308A CN109627242A CN 109627242 A CN109627242 A CN 109627242A CN 201811630308 A CN201811630308 A CN 201811630308A CN 109627242 A CN109627242 A CN 109627242A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
The present invention relates to the preparation methods of Eliquis.The present invention provides a kind of preparation method of Eliquis shown in Formulas I, and this method can effectively remove the impurity that raw material introduces and technique generates, especially genotoxicity impurity.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of preparation method of Eliquis.
Background technique
Eliquis (Apixaban, trade name: Ai Le is appropriate, Ai Letong/Eliquis) is by Bristol Myers Squibb and Pfizer
The oral anticoagulant of joint development is a kind of new oral Xa factor inhibitor, a kind of for preventing and treating the medicine of thrombus
Product.
Eliquis can directly inhibit factor Xa, and conversion of prothrombin is at fibrin ferment during blocking coagulation cascade.
Factor Xa is the serine protease that a vitamin K relies on, and occupies the center in the reaction of blood coagulation waterfall, can
With by endogenous and exogenous cruor pathway activation, II factor of major catalytic (factor) is converted to the II a factor (fibrin ferment),
1mol factor Xa is inhibited just to be able to suppress the generation of 1000mol fibrin ferment, Eliquis is high to factor Xa selectivity,
Effect is strong.In addition to this, Eliquis not only can inhibit the Xa factor in free Xa factor and prothrombin complex, still
Inhibit the Xa factor in blood clot, and be not necessarily to antithrombin Ⅲ in process of inhibition, this reaches the liver last of the ten Heavenly stems with heparin class anticoagulation such as sulphur
The effect of sodium is different.
The medicine is in May, 2011 in the granted listing of European Union；Obtain FDA approval U.S.'s listing in December, 2012；In January, 2013 is obtained
CFDA approval enters China, and enters new medical insurance directory.
Although Eliquis is irresistible in foreign countries, at home due to lacking channel advantage, Eliquis exists within 2016
Chinese market sales volume is only 0.61 hundred million yuan.There is professional institution's analysis in the industry: before external husky class class drug patent expires, in
Sand class, state medicinal application scale will be extremely limited, but after 2022, with the listing of China imitation medicine, offshore company
The situation for monopolizing husky class class drug will be broken, and domestic market supply and demand scale expands rapidly, it is contemplated that the husky class's class of China in 2026
The market supply scale of drug is up to 284.7 hundred million yuan, and demand size is up to 274.8 hundred million yuan.
Raw material used in the synthesis process of Eliquis and intermediate majority have nitrobenzene, aniline, chloro thing etc.
Genotoxicity caution structure, according to ICH M7 " genotoxicity impurity is assessed and control ", above-mentioned Control of Impurities limit is lower, needs
Strict control is carried out to it in Eliquis synthesis technology.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation method of Eliquis, this method can effectively remove raw material introducing
And the impurity that technique generates, especially genotoxicity impurity.
The preparation method of Eliquis of the present invention, includes the following steps:
Step (1), raw material B and raw material A ring in the presence of triethylamine, toluene, ethyl acetate
1. addition obtains intermediate；
Step (2), intermediate is 1. in formamide, trifluoroacetic acid/trimethyl orthoformate, sodium methoxide
In the presence of through amidation process obtain apixaban crude；
Step (3), apixaban crude are refining to obtain Eliquis finished product in polar solvent.
The preparation method of Eliquis of the present invention, specific synthetic route are as follows:
The preparation method of Eliquis of the present invention, the molar ratio of raw material A, triethylamine and raw material B is in step (1)
1.1~1.5:3~5:1, preferably 1.2~1.3:3:1.
The preparation method of Eliquis of the present invention, the volume ratio of toluene and ethyl acetate is 1:1~3 in step (1),
It is preferred that 1:1~2.
The preparation method of Eliquis of the present invention, the mixed volume and raw material B of toluene and ethyl acetate in step (1)
Mass ratio ml/g be 15~25:1, preferably 16~20:1.
The preparation method of Eliquis of the present invention, the reaction temperature of step (1) are 80-90 DEG C, preferably 80-85 DEG C.
The preparation method of Eliquis of the present invention, in step (2) formamide and the molar ratio of intermediate 1. be 18~
22:1, preferably 18~20:1.
The preparation method of Eliquis of the present invention, in step (2) sodium methoxide and the molar ratio of intermediate 1. be 1.5~
2.5:1, preferably 1.8~2.0:1.
The preparation method of Eliquis of the present invention, trifluoroacetic acid in step (2): trimethyl orthoformate: intermediate is 1.
Molar ratio be 0.1~0.5:0.3~0.8:1, preferably 0.2~0.3:0.5:1.
The preparation method of Eliquis of the present invention, the reaction temperature of step (2) are 50-70 DEG C, preferably 50~60 DEG C.
The preparation method of Eliquis of the present invention, polar solvent described in step (3) are DMF/ isopropanol.
The volume mass ratio ml/g of the preparation method of Eliquis of the present invention, DMF and Eliquis is 5~10:1,
The volume mass of isopropanol and Eliquis ratio ml/g is 10~15:1；It is preferred that the volume mass of DMF and Eliquis ratio ml/g
For 7.5~8.5:1, the volume mass ratio ml/g of isopropanol and Eliquis is 10~12:1.
The present inventor it has been investigated that, in raw material A, raw material B and reaction process may introduce genotoxicity impurity master
Have following several:
Wherein, impurity A -1~A-4 contains chloro thing caution structure, and with reference to ICH M7 guideline, the impurity is according to third
Kind control strategy, according to higher limit handling in raw material A, and is studied in finished product；Impurity A -5 is diazonium salt, is latent
Genotoxicity impurity, the compound property is active, and with reference to ICH M7 guideline, the impurity is according to the 4th kind of control plan
Slightly, without research；Raw material A itself contains chloro thing, is potential genotoxicity impurity, should with reference to ICH M7 guideline
Impurity is controlled in finished product according to the first control strategy.
Impurity B -1~B-7 contains nitrobenzene caution structure, and with reference to ICH M7 guideline, the impurity is according to the third control
System strategy, according to higher limit handling in raw material B, and is studied in finished product；Impurity B -8~B-9 refers to reference to ICH M7
Principle is led, is controlled according to the first control strategy, and in finished product.
Surprisingly, it was found that the preparation of the Eliquis through the invention, can effectively remove Ah piperazine's sand
Genotoxicity impurity in class's finished product can effectively remove most gene especially with toluene/ethyl acetate mixed system
Impurity removes remaining a small amount of impurity subsequently through purification.The preparation of Eliquis of the present invention can control Ah piperazine
The content of genotoxicity impurity in husky class's finished product is lower than 0.0002%, preferably genotoxicity impurity in Eliquis finished product
Content is lower than 0.0001%, -1~A-5 of genotoxicity impurity A, impurity B -1~B-2, impurity in more preferable Eliquis finished product
B-6~B-9 is not detected.
Specific embodiment
For the technical problems, technical solutions and beneficial effects solved by the present invention is more clearly understood, below in conjunction with reality
Example is applied, the present invention will be described in further detail.But it is not limitation of the present invention, it is all according to the disclosure of invention
The same replacement of made any this field, all belongs to the scope of protection of the present invention.
Embodiment 1: the synthesis of intermediate 1.
Toluene (25mL), triethylamine (2.60g, 25.7mmol) and ethyl acetate (25mL) are added in reaction flask, is added former
Expect A (2.80g, 10.9mmol) and raw material B (3.00g, 8.4mmol), be heated to 85 DEG C, stirs 7 hours.Liquid cooling will be reacted
But to 25 DEG C.Hydrochloric acid solution is added dropwise into reaction solution, at 25 minutes, temperature was controlled at 30 DEG C for time for adding control, was added dropwise
Afterwards, it is stirred to react 1 hour for 30 DEG C.Purified water 15mL is added, stirs 30 minutes.Filter cake is filtered to obtain, isopropanol 20mL washing is added,
Dry Eliquis intermediate 1. 3.12g, molar yield 76.0%.
Embodiment 2: the preparation of apixaban crude
DMF (25mL) and formamide (5.80g, 128mmol) is added and opens stirring, addition intermediate 1. (3.12g,
Feed opening 6.4mmol) is closed, 50 DEG C of temperature control are stirred 30 minutes.Trimethyl orthoformate (0.34g, 3.2mmol) and trifluoro second is added
50 DEG C of sour (0.15g, 1.3mmol) temperature control stirs 1 hour.It is added sodium methoxide-methanol solution (30wt%, 2.10g), 50 DEG C of temperature control
It is stirred to react 3 hours.It is added purified water (5mL), time for adding control was stirred 1 hour 15 minutes, 50 DEG C of temperature control.Purifying is added dropwise
Water (25mL), time for adding were controlled at 40 minutes.25 DEG C are cooled to, stirring and crystallizing 9 hours, filtering was dry that Eliquis is thick
Product 2.54g, molar yield 86.4%.
The preparation of embodiment 3, Eliquis
DMF 20mL is added in reaction flask, opens stirring, is added apixaban crude (2.54g, 5.5mmol), temperature rises to
It is stirred 30 minutes after 75 DEG C.Temperature is down to 25 DEG C, and stirring and crystallizing 9 hours, filtering was added isopropanol 25mL and is heated to 80 DEG C, protects
Temperature stirring 7 hours.After stirring, 25 DEG C are cooled the temperature to, stirring and crystallizing 12 hours, filtering, dry Eliquis
2.32g, molar yield 91.3%.
Embodiment 4: the synthesis of intermediate 1.
Toluene (20mL), triethylamine (2.6g, 25.7mmol) and ethyl acetate (40mL) are added in reaction flask, raw material is added
A (2.80g, 10.9mmol) and raw material B (3.00g, 8.4mmol) is heated to 85 DEG C, stirs 7 hours.Reaction solution is cooling
To 25 DEG C.Hydrochloric acid solution is added dropwise into reaction solution, at 25 minutes, temperature was controlled at 30 DEG C for time for adding control, after being added dropwise,
30 DEG C are stirred to react 1 hour.Purified water 15mL is added, stirs 30 minutes.Filter cake is filtered to obtain, isopropanol 20mL washing is added, does
It is dry to obtain Eliquis intermediate 1. 3.05g, molar yield 74.3%.
The preparation of embodiment 5, apixaban crude
DMF (25mL) and formamide (5.10g, 113mmol) is added and opens stirring, addition intermediate 1. (3.05g,
Feed opening 6.2mmol) is closed, 50 DEG C of temperature control are stirred 30 minutes.Trimethyl orthoformate (0.34g, 3.2mmol) and trifluoro second is added
50 DEG C of sour (0.15g, 1.3mmol) temperature control stirs 1 hour.It is added sodium methoxide-methanol solution (30wt%, 2.2g), 50 DEG C of temperature control
It is stirred to react 3 hours.It is added purified water (5mL), time for adding control was stirred 1 hour 15 minutes, 50 DEG C of temperature control.Purifying is added dropwise
Water (25L), time for adding were controlled at 40 minutes.It is cooled to 25 DEG C, stirring and crystallizing 9 hours, filtering, dry apixaban crude
2.50g, molar yield 87.2%.
The preparation of embodiment 6, Eliquis
DMF 20mL is added in reaction flask, opens stirring, is added apixaban crude (2.50g, 5.4mmol), temperature rises to
It is stirred 30 minutes after 70 DEG C.Temperature is down to 25 DEG C, and stirring and crystallizing 9 hours, filtering was added isopropanol 30mL and is heated to 80 DEG C, protects
Temperature stirring 7 hours.After stirring, 25 DEG C are cooled the temperature to, stirring and crystallizing 12 hours, filtering, dry Eliquis
2.25g, molar yield 90.2%.
7 genotoxicity defects inspecting of embodiment
By LC-MS (HPLC-MS), genotoxicity impurity content in embodiment 1-6 product is detected, concrete condition is such as
Tables 1 and 2.
The genotoxicity impurity content of 1 embodiment 1-3 of table
| Impurity code name | Raw material | 1 intermediate of embodiment is 1. | 2 crude product of embodiment | 3 finished product of embodiment |
| Impurity A -1 | 0.42% | 0.011% | 0.006% | It is not detected |
| Impurity A -2 | 0.67% | 0.023% | 0.005% | It is not detected |
| Impurity A -3 | 0.33% | 0.008% | 0.003% | It is not detected |
| Impurity A -4 | 0.2% | 0.024% | 0.004% | It is not detected |
| Raw material A | / | / | / | It is not detected |
| Impurity B -1 | 0.25% | 0.009% | 0.003% | It is not detected |
| Impurity B -2 | 0.44% | 0.010% | 0.003% | It is not detected |
| Impurity B -3 | 0.35% | 0.008% | 0.002% | 0.00003% |
| Impurity B -4 | 0.40% | 0.028% | 0.009% | 0.00002% |
| Impurity B -5 | 0.40% | 0.017% | 0.004% | 0.00002% |
| Impurity B -6 | 1.0% | 0.016% | 0.001% | It is not detected |
| Impurity B -7 | 0.4% | 0.026% | 0.003% | It is not detected |
| Impurity B -8 | / | 0.022% | 0.004% | It is not detected |
| Impurity B -9 | / | 0.041% | 0.002% | It is not detected |
| Raw material B | / | / | / | It is not detected |
The genotoxicity impurity content of embodiment 4-6
| Impurity code name | Raw material | 4 intermediate of embodiment is 1. | 5 crude product of embodiment | 6 finished product of embodiment |
| Impurity A -1 | 0.42% | 0.015% | 0.011% | It is not detected |
| Impurity A -2 | 0.67% | 0.029% | 0.004% | It is not detected |
| Impurity A -3 | 0.33% | 0.012% | 0.003% | It is not detected |
| Impurity A -4 | 0.2% | 0.021% | 0.005% | It is not detected |
| Raw material A | / | / | / | It is not detected |
| Impurity B -1 | 0.25% | 0.012% | 0.005% | It is not detected |
| Impurity B -2 | 0.44% | 0.014% | 0.004% | It is not detected |
| Impurity B -3 | 0.35% | 0.007% | 0.003% | 0.00002% |
| Impurity B -4 | 0.40% | 0.031% | 0.007% | 0.00003% |
| Impurity B -5 | 0.40% | 0.018% | 0.002% | 0.00003% |
| Impurity B -6 | 1.0% | 0.020% | 0.001% | It is not detected |
| Impurity B -7 | 0.4% | 0.022% | 0.005% | It is not detected |
| Impurity B -8 | / | 0.020% | 0.006% | It is not detected |
| Impurity B -9 | / | 0.045% | 0.002% | It is not detected |
| Raw material B | / | / | / | It is not detected |
"/" expression does not detect.
By Tables 1 and 2 it is found that even if impurity A -1, impurity A -2, impurity A -3, impurity A -4 content in raw material A are higher,
Impurity B -1, impurity B -2, impurity B -3, impurity B -4, impurity B -5, impurity B -6, impurity B -7 content in raw material B are higher, pass through
Preparation method of the present invention, the available good control of genotoxicity impurity described in Eliquis finished product, and impurity
B-8, impurity B -9 are not detected in finished product.
Claims (10)
1. the preparation method of Eliquis, it is characterised in that:
Step (1): 1. raw material B and raw material A cycloaddition in the presence of triethylamine, toluene, ethyl acetate obtain intermediate；
Step (2): 1. intermediate obtains in the presence of formamide, trifluoroacetic acid/trimethyl orthoformate, sodium methoxide through amidation process
To apixaban crude；
Step (3): apixaban crude is refining to obtain Eliquis finished product in polar solvent.
2. preparation method according to claim 1, it is characterised in that: raw material A in step (1), triethylamine and raw material B rub
You are than being 1.1~1.5:3~5:1, preferably 1.2~1.3:3:1.
3. preparation method according to claim 1, it is characterised in that: the volume ratio of toluene and ethyl acetate in step (1)
For 1:1~3, preferably 1:1~2.
4. preparation method according to claim 1, it is characterised in that: the mixture of toluene and ethyl acetate in step (1)
The long-pending mass ratio ml/g with raw material B is 15~20:1, preferably 16~20:1.
5. preparation method according to claim 1, it is characterised in that: the reaction temperature of step (1) is 80-90 DEG C, preferably
80-85℃。
6. preparation method according to claim 1, it is characterised in that: formamide and mole of intermediate 1. in step (2)
Than for 18~22:1, preferably 18~20:1.
7. preparation method according to claim 1, it is characterised in that: sodium methoxide and mole of intermediate 1. in step (2)
Than for 1.5~2.5:1, preferably 1.8~2.0:1.
8. preparation method according to claim 1, it is characterised in that: trifluoroacetic acid in step (2): trimethyl orthoformate:
The molar ratio of intermediate 1. is 0.1~0.5:0.3~0.8:1, preferably 0.2~0.3:0.5:1.
9. preparation method according to claim 1, it is characterised in that: polar solvent described in step (3) is DMF/ isopropyl
Alcohol.
10. preparation method according to claim 9, it is characterised in that: the volume mass of DMF and Eliquis ratio ml/g is
The volume mass ratio ml/g of 5~10:1, isopropanol and Eliquis is 10~15:1；It is preferred that the volume matter of DMF and Eliquis
Amount is 7.5~8.5:1 than ml/g, and the volume mass ratio ml/g of isopropanol and Eliquis is 10~12:1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113105449A (en) * | 2021-04-06 | 2021-07-13 | 山东新华制药股份有限公司 | Synthetic method of apixaban intermediate |
| CN113504317A (en) * | 2021-06-22 | 2021-10-15 | 哈尔滨珍宝制药有限公司 | Detection method and application of genotoxic impurities in apixaban |
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| CN107955003A (en) * | 2017-12-28 | 2018-04-24 | 河北常山生化药业股份有限公司 | The sweep-out method of specific impurities S4 in a kind of 2 building-up process of Eliquis intermediate |
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2018
- 2018-12-29 CN CN201811630308.9A patent/CN109627242A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107955003A (en) * | 2017-12-28 | 2018-04-24 | 河北常山生化药业股份有限公司 | The sweep-out method of specific impurities S4 in a kind of 2 building-up process of Eliquis intermediate |
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| 梁兴运: "阿哌沙班的合成及工艺优化", 《中国优秀硕士学位论文全文数据库·医药卫生科技辑》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113105449A (en) * | 2021-04-06 | 2021-07-13 | 山东新华制药股份有限公司 | Synthetic method of apixaban intermediate |
| CN113504317A (en) * | 2021-06-22 | 2021-10-15 | 哈尔滨珍宝制药有限公司 | Detection method and application of genotoxic impurities in apixaban |
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