CN109369642A - Related substance of a kind of Eliquis and its preparation method and application - Google Patents
Related substance of a kind of Eliquis and its preparation method and application Download PDFInfo
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- CN109369642A CN109369642A CN201811089190.3A CN201811089190A CN109369642A CN 109369642 A CN109369642 A CN 109369642A CN 201811089190 A CN201811089190 A CN 201811089190A CN 109369642 A CN109369642 A CN 109369642A
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- eliquis
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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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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
The invention discloses a kind of related substance As of Eliquis, so that the synthesis process to Eliquis carries out quality control；The invention also discloses the preparation methods of the substance, include the following steps: (1) under alkaline condition, 1- (4- methoxyphenyl) -7- oxo -6- [4- (2- oxo-piperidine -1- base) phenyl] -4,5,6,7- tetrahydro -1H- pyrazolo [3,4-C] pyridine-3-carboxylic acid ethyl ester and 5- chloro pentane acid ethyl ester occur nucleophilic substitution and obtain intermediate III；(2) for the intermediate III under highly basic effect, hydrolysis obtains compound A.Preparation method provided by the invention, reaction condition is mild, controllability is good, yield is higher, with high purity, can be used as standard items use, to carry out control research to the quality in Eliquis preparation process.
Description
Technical field
The present invention relates to medical manufacturing technology fields, and in particular to related substance of a kind of Eliquis and preparation method thereof and
Purposes.
Background technique
Eliquis (Apixaban), molecular formula C25H25N5O4, entitled 4,5,6,7- tetrahydro -1- (the 4- methoxy of chemistry
Base phenyl) -7- oxo -6- [4- (2- oxo -1- piperidyl) phenyl] -1H- azoles azoles simultaneously [3,4-C] pyridine -3- carbonyl amine.Ah piperazine is husky
Class is a kind of novel Xa factor inhibitor, is developed jointly by Pfizer and Bristol Myers Squibb, for preventing adult full hip or complete
The postoperative venous thromboembolism of knee prosthesis, medicine for preventing nonvalvular atrial patient stroke and Thrombosis, treatment and prevention
Deep vein thrombosis embolism disease and pulmonary embolism.
The patent literature reports such as WO2017187245, US20150353543, WO2014075648 and CN105254630
The synthesis of Eliquis, wherein the synthetic method of final step is as follows:
Inventor is using document route, such as WO2017187245, US20150353543 and WO2014075648 disclosure
Method carry out Eliquis final step synthesis when, find finished product in containing peak area be greater than 0.1% impurity, and should
Impurity is difficult to remove in Eliquis finished product.It is thus identified that the chemical structure and preparation method of the impurity, are detected to establishing
Method, thus carry out Eliquis quality control and clinical application safety monitoring play the role of it is vital.
Summary of the invention
It is an object of the invention to overcome above-mentioned technical deficiency, provide a kind of Eliquis related substance, so as to Ah piperazine
The synthesis process of husky class carries out quality control；The purpose of second aspect of the present invention is, provides a kind of Eliquis related substance
Preparation method, in order to prepare the impurity reference substance of high-purity；The purpose of third aspect present invention is, provides a kind of Ah piperazine
Purposes of the husky class in relation to substance.
To reach above-mentioned technical purpose, technical solution of the present invention provides a kind of Eliquis related substance A, has such as
Flowering structure:
Molecular formula: C25H26N4O6
Molecular weight: 478.51.
Technical solution of the present invention additionally provides a kind of preparation method of the Eliquis in relation to substance A, and synthetic route is such as
Under:
Include the following steps:
S1. under alkaline condition, compound II and 5- chloro pentane acid ethyl ester generation nucleophilic substitution obtain intermediate III；
S2. for the intermediate III under highly basic effect, hydrolysis obtains compound A.
Technical solution of the present invention additionally provides a kind of application of the Eliquis in relation to substance A, in Eliquis quality
Impurity reference substance is used as in control.
Compared with prior art, the beneficial effect comprise that
1, the present invention provides a kind of Eliquis related substances A, and are confirmed to the structure of the substance, to overcome
Impurity disadvantage not easy to control in existing Eliquis preparation process；
2, the present invention also provides the preparation method of Eliquis related substances A a kind of, this method preparation process reacts item
Part is mild, controllability is good, yield is higher, with high purity, is suitble to industrialized production；
3, Eliquis related substances A provided by the invention can be used as standard items use, to prepare to Eliquis
Quality in the process carries out control research.
Detailed description of the invention
Fig. 1 is the HPLC map of apixaban crude；
Fig. 2 is the HPLC map of the compound A prepared in embodiment 4.
Specific embodiment
A kind of preparation method of the Eliquis in relation to substance A is present embodiments provided, is included the following steps:
(1) in the first organic solvent, under alkaline condition, compound II (chemical name are as follows: 1- (4- methoxyphenyl) -7-
Oxo -6- [4- (2- oxo-piperidine -1- base) phenyl] -4,5,6,7- tetrahydro -1H- pyrazolo [3,4-c] pyridine-3-carboxylic acid second
Ester) with 5- chloro pentane acid ethyl ester occur nucleophilic substitution at 0~100 DEG C, reaction to compound II disappears, into reaction solution plus
After entering suitable quantity of water precipitation solid, filter, filter cake is washed with water and isopropanol, then after column chromatographic purifying, obtains intermediate III；
(2) intermediate III is dissolved in the second organic solvent, strong base solution is added into reaction solution under ice bath, it will be anti-
It answers the pH of liquid to be adjusted to 10~11, after adding, the temperature of reaction solution is adjusted to 0~40 DEG C, hydrolysis is until intermediate III disappears
It loses, temperature of reaction system is adjusted to 0 DEG C, and the pH of reaction system is adjusted to 4~5, after solid is precipitated, then successively pass through and filter,
Dry and recrystallization, obtains the related substance A of Eliquis.
In some preferred embodiments, the molar ratio of compound II, alkali and 5- chloro pentane acid ethyl ester be 1:1~3:1~
1.5, it is furthermore preferred that the molar ratio of compound II, alkali and 5- chloro pentane acid ethyl ester are 1:1.2~2:1.1~1.2, in the amount ratio
In range, it can guarantee that nucleophilic substitution more fully carries out, and avoid the waste of raw material.
In some preferred embodiments, the first organic solvent of 5~30mL is added in every g of compound II, it is furthermore preferred that
The first organic solvent of 6~10mL is added in every g of compound II, within the scope of the amount ratio, compound II can be made to be completely dissolved in the
In one organic solvent, come into full contact with compound II, alkali and 5- chloro pentane acid ethyl ester.
In some preferred embodiments, the first organic solvent is tetrahydrofuran, acetonitrile, n,N-Dimethylformamide and N-
One or more of methyl pyrrolidone, it is furthermore preferred that the first organic solvent is n,N-Dimethylformamide.
In some preferred embodiments, alkali from step S1 to reaction system that be added in is organic base, preferably triethylamine,
One of n,N-diisopropylethylamine, pyridine and 4-dimethylaminopyridine are a variety of, it is furthermore preferred that alkali is N, N- diisopropyl
Ethamine.
In some preferred embodiments, the temperature of nucleophilic substitution is 70~80 DEG C in step S1, in this temperature model
In enclosing, the yield of obtained intermediate III is higher.
In some preferred embodiments, the second organic solvent of 7~35mL is added in every gram of intermediate III, it is furthermore preferred that often
The second organic solvent of 8~12mL is added in gram intermediate III, to guarantee that compound III sufficiently dissolves.
In some preferred embodiments, the molar concentration of strong base solution is 1~10mol/L, it is furthermore preferred that its mole dense
Degree is 2~4mol/L.
In some preferred embodiments, the second organic solvent is tetrahydrofuran, methylene chloride, methanol, ethyl alcohol and N, N-
One or more of dimethylformamide, it is furthermore preferred that the second organic solvent is tetrahydrofuran.
In some preferred embodiments, the highly basic in strong base solution is in lithium hydroxide, sodium hydroxide and potassium hydroxide
One or more, it is furthermore preferred that highly basic be sodium hydroxide.
In some preferred embodiments, hydrolysising reacting temperature is 20~25 DEG C in step S2, in this temperature range, is obtained
Yield of the Eliquis arrived in relation to substance A is higher.
The reaction process of above-mentioned reaction can be used the routine monitoring method in this field be monitored (such as TLC, HPLC or
NMR), as the terminal of reaction when generally being disappeared using compound II and intermediate III.
The eluant, eluent of the step of above-mentioned reaction (1) center pillar chromatographic purifying is made of methylene chloride and methanol, methylene chloride: first
The volume ratio of alcohol is 100:1.
The compound of the present invention II is purchased from Suzhou Kapp Wei Er Pharmaceutical Technology Co., Ltd；Other chemistry examinations in the present invention
Agent is market purchase gained.
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to the accompanying drawings and embodiments, right
The present invention is further elaborated.Experimental method in the present invention is unless otherwise specified conventional method.It should manage
Solution, the specific embodiments described herein are merely illustrative of the present invention, is not intended to limit the present invention.
Liquid-phase condition in the following example are as follows: C18 bonded silica gel column (GL Sciences Inc.Inertsil ODS-
C18,4.6mm × 250mm, 5 μm of SP equal columns) it is chromatographic column, using deionized water as mobile phase A, to be containing percent by volume
The acetonitrile of 0.1% trifluoroacetic acid is Mobile phase B, and according to the form below carries out gradient elution:
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 87 | 13 |
| 3 | 87 | 13 |
| 17 | 65 | 35 |
| 25 | 10 | 90 |
| 30 | 10 | 90 |
| 30.01 | 87 | 13 |
| 35 | 87 | 13 |
Flow velocity is 1.0ml/min, and column temperature is 35 DEG C, Detection wavelength 280nm.
Embodiment 1:
The embodiment of the present invention 1 provides a kind of preparation method of intermediate III, and synthetic route is as follows:
Specifically prepare with the following method:
By compound II (2.0g, 4.9mmol), n,N-diisopropylethylamine (1.2mL, 7.4mmol), 5- chloro pentane acid ethyl ester
(0.97g, 5.9mmol) and n,N-Dimethylformamide (12mL) are added in reaction flask and are uniformly mixed, by reaction solution at 80 DEG C
Reaction 7 hours, water (12mL) is added into reaction solution until compound II disappearance in TLC detection reaction, after solid is precipitated, continues
Stirring 0.5 hour filters, and filter cake is washed with water and isopropanol, obtains crude product, crude product obtains pale yellow colored solid through column chromatographic purifying
Body, i.e. compound III.
The faint yellow solid 1.8g obtained using this method, yield 68%.
Intermediate III obtained in the present embodiment is identified, following result is obtained:
ESI-MS (m/z): 535.2；
1H NMR(500MHz,CDCl3): δ 8.02-7.80 (m, 1H), 7.37-7.22 (m, 1H), 7.11-7.01 (m, 1H),
6.84-6.65 (m, 1H), 4.31-4.15 (m, 2H), 4.01 (q, J=11.8Hz, 1H), 3.79 (s, 2H), 3.30 (t, J=
11.6Hz, 2H), 2.32 (t, J=15.0Hz, 1H), 1.72-1.56 (m, 1H), 1.48 (m, 1H), 1.30 (t, J=11.8Hz,
1H), 1.07 (t, J=11.8Hz, 1H).
Embodiment 2:
The embodiment of the present invention 2 provides a kind of preparation method of intermediate III, specifically prepares with the following method:
By compound II (1.3g, 3.2mmol), triethylamine (0.7mL, 4.8mmol), 5- chloro pentane acid ethyl ester (0.63g,
It 3.8mmol) is added in reaction flask and is uniformly mixed with n,N-Dimethylformamide (8mL), it is small that reaction solution is reacted to 7 at 80 DEG C
When, until compound II disappears, after solid is precipitated, it is small to continue stirring 0.5 for addition water (8mL) into reaction solution for TLC detection reaction
When, it filters, filter cake is washed with water and isopropanol, obtains crude product, crude product obtains faint yellow solid, i.e. compound through column chromatographic purifying
III。
The faint yellow solid 1.1g obtained using this method, yield 64%.
Embodiment 3:
The embodiment of the present invention 3 provides a kind of preparation method of intermediate III, specifically prepares with the following method:
By compound II (1.5g, 3.7mmol), potassium carbonate (0.77g, 5.5mmol), 5- chloro pentane acid ethyl ester (0.73g,
It 4.4mmol) is added in reaction flask and is uniformly mixed with n,N-Dimethylformamide (10mL), it is small that reaction solution is reacted to 7 at 80 DEG C
When, TLC detection reaction is until compound II disappears, and into reaction solution, addition water (10mL) continues stirring 0.5 after solid is precipitated
Hour, it filters, filter cake is washed with water and isopropanol, obtains crude product, crude product obtains faint yellow solid, i.e. chemical combination through column chromatographic purifying
Object III.
The faint yellow solid 1.0g obtained using this method, yield 51%.
Embodiment 4:
The embodiment of the present invention 4 provides the preparation method of compound A a kind of, and synthetic route is as follows:
Specifically prepare with the following method:
Compound III (1.5g, 2.8mmol) and tetrahydrofuran (12mL) are added in reaction flask, to reaction under ice bath
Sodium hydrate aqueous solution (2mL, 2mol/L) is added in liquid, the pH of reaction solution is adjusted to 11, reaction solution is risen to 25 DEG C after adding
Temperature of reaction system is down to 0 DEG C, with dilute hydrochloric acid (2mol/L) until compound III disappearance by reaction 1 hour, TLC detection reaction
The pH of reaction system is adjusted to 4~5, after solid is precipitated, continues stirring 1 hour, filters, crude product after 45 DEG C of vacuum drying 12h,
Again white solid, i.e. compound A will be obtained after crude product ethyl alcohol recrystallization.
The white solid 0.9g obtained using this method, yield 67%, purity 99.1%.
Compound A obtained in the present embodiment is identified, following result is obtained:
ESI-MS (m/z): 479.1；
1HNMR(500MHz,DMSO-d6): δ 12.41 (s, 1H), 11.78 (s, 1H), 7.95 (s, 2H), 7.27 (s, 2H),
7.08 (s, 2H), 6.77 (s, 2H), 4.28 (d, J=3.5Hz, 2H), 3.79 (s, 3H), 3.50 (s, 1H), 3.30 (s, 4H),
2.21 (s, 2H), 1.50 (d, J=20.0Hz, 4H).
Apixaban crude HPLC map is shown in Fig. 1, and as seen from Figure 1, appearance time of the impurity content greater than 1% is
3.739；The HPLC map of compound A obtained is shown in Fig. 2 in the present embodiment, and as shown in Figure 2, the appearance time of compound A is
3.737；By nuclear-magnetism, mass spectrum and retention time is compared, further confirms the structure of compound A.
Embodiment 5:
The embodiment of the present invention 5 provides the preparation method of compound A a kind of, specifically prepares with the following method:
Compound III (1.5g, 2.8mmol) and n,N-Dimethylformamide (12mL) are added in reaction flask, in ice bath
It is lower that sodium hydrate aqueous solution (2mL, 2mol/L) is added into reaction solution, the pH of reaction solution is adjusted to 11, by reaction solution after adding
It rises to 25 DEG C to react 1 hour, temperature of reaction system is down to 0 DEG C, uses dilute hydrochloric acid by TLC detection reaction until compound III disappearance
The pH of system is adjusted to 4~5 by (2mol/L), after solid is precipitated, is continued stirring 1 hour, is filtered, crude product is dried in vacuo at 45 DEG C
After 12h, then crude product obtained into white solid, i.e. compound A with ethyl alcohol recrystallization.
The white solid 0.7g obtained using this method, yield 52%, purity 98.3%.
Embodiment 6:
The embodiment of the present invention 6 provides the preparation method of compound A a kind of, specifically prepares with the following method:
Compound III (1.5g, 2.8mmol) and n,N-Dimethylformamide (12mL) are added in reaction flask, in ice bath
It is lower that lithium hydroxide aqueous solution (2mL, 2mol/L) is added into reaction solution, the pH of reaction solution is adjusted to 11, by reaction solution after adding
It rises to 25 DEG C to react 1 hour, temperature of reaction system is down to 0 DEG C, uses dilute hydrochloric acid by TLC detection reaction until compound III disappearance
The pH of system is adjusted to 4~5 by (2mol/L), there is solid precipitation, continues stirring 1 hour, is filtered, and crude product is dried in vacuo at 45 DEG C
After 12h, then crude product obtained into white solid, i.e. compound A with ethyl alcohol recrystallization.
The white solid 0.6g obtained using this method, yield 45%, purity 98.6%.
Embodiment 7:
The embodiment of the present invention 7 provides the preparation method of compound A a kind of, specifically prepares with the following method:
Compound III (1.5g, 2.8mmol) and methanol (12mL) are added in reaction flask, under ice bath into reaction solution
It is added sodium hydrate aqueous solution (2mL, 2mol/L), the pH of reaction solution is adjusted to 11, reaction solution is risen into 25 DEG C of reactions 1 after adding
Hour, TLC detection reaction is until compound III disappears, by near 0 DEG C of system temperature, with dilute hydrochloric acid (2mol/L) by system
PH is adjusted to 4~5, there is solid precipitation, continues stirring 1 hour, filters, and crude product is after 45 DEG C of vacuum drying 12h, then by crude product second
Alcohol is recrystallized to give white solid, i.e. compound A.
The white solid 0.8g obtained using this method, yield 60%, purity 99.0%.
The preparation method of compound A provided in the present invention, the related substance A purity is high of obtained Eliquis, can be used as
Standard items in relation to substance A use, and facilitate the quality controling research in Eliquis preparation process, to clinical application safety monitoring
Play the role of vital.
The above described specific embodiments of the present invention are not intended to limit the scope of the present invention..Any basis
Any other various changes and modifications that technical concept of the invention is made should be included in the guarantor of the claims in the present invention
It protects in range.
Claims (10)
1. a kind of related substance A of Eliquis, which is characterized in that its structural formula are as follows:
2. a kind of preparation method of the Eliquis as described in claim 1 in relation to substance A, which is characterized in that including walking as follows
It is rapid:
S1. under alkaline condition, compound II and 5- chloro pentane acid ethyl ester generation nucleophilic substitution obtain intermediate III；
S2. for the intermediate III under highly basic effect, hydrolysis obtains compound A.
3. preparation method according to claim 2, which is characterized in that the step S1 specifically comprises the following steps:
In one organic solvent, under alkaline condition, nucleophilic substitution occurs for the compound II and the 5- chloro pentane acid ethyl ester to reacting
Completely, after product being precipitated, the product is filtered, washed and after purification, obtains intermediate III.
4. preparation method according to claim 3, which is characterized in that compound II, alkali and 5- chlorine penta in the step S1
The molar ratio of acetoacetic ester is 1:1~3:1~1.5.
5. preparation method according to claim 3, which is characterized in that the temperature of the nucleophilic substitution is 0~100
℃。
It is organic molten that 6. first is added described in 5~30mL preparation method according to claim 3, in every gram of compound II
Agent；First organic solvent be one of tetrahydrofuran, acetonitrile, N,N-dimethylformamide and N-Methyl pyrrolidone or
It is several；The alkali is triethylamine, N, one of N- diisopropylethylamine, pyridine and 4-dimethylaminopyridine or a variety of.
7. preparation method according to claim 2, which is characterized in that the step S2 specifically comprises the following steps: centre
Body III is dissolved in the second organic solvent, and strong base solution is added into reaction solution, and the pH of the reaction solution is adjusted to 10~11
Afterwards, it is hydrolyzed and reacts to fully reacting, adjust product system and tied by suction filtration, drying and again to after being precipitated solid, then successively
Crystalline substance obtains compound A.
8. preparation method according to claim 7, which is characterized in that the temperature of the hydrolysis is 0~40 DEG C.
9. preparation method according to claim 7, which is characterized in that 7~35mL institute is added in every gram of intermediate III
State the second organic solvent；Second organic solvent is tetrahydrofuran, methylene chloride, methanol, ethyl alcohol and N, N- dimethyl formyl
One or more of amine；The highly basic is one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.
10. a kind of application of the Eliquis as described in claim 1 in relation to substance A, which is characterized in that it is in Eliquis matter
Impurity reference substance is used as in amount control.
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| CN201811089190.3A CN109369642B (en) | 2018-09-18 | 2018-09-18 | Related substance of a kind of Eliquis and its preparation method and application |
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| CN201811089190.3A CN109369642B (en) | 2018-09-18 | 2018-09-18 | Related substance of a kind of Eliquis and its preparation method and application |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014075648A1 (en) * | 2012-11-13 | 2014-05-22 | Zentiva, K.S. | A method of preparing apixaban |
| CN105254630A (en) * | 2015-11-16 | 2016-01-20 | 江苏康缘药业股份有限公司 | Preparing method for apixaban |
| CN108864084A (en) * | 2018-06-14 | 2018-11-23 | 成都倍特药业有限公司 | Related substance of one group of Eliquis and preparation method thereof |
-
2018
- 2018-09-18 CN CN201811089190.3A patent/CN109369642B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014075648A1 (en) * | 2012-11-13 | 2014-05-22 | Zentiva, K.S. | A method of preparing apixaban |
| CN105254630A (en) * | 2015-11-16 | 2016-01-20 | 江苏康缘药业股份有限公司 | Preparing method for apixaban |
| CN108864084A (en) * | 2018-06-14 | 2018-11-23 | 成都倍特药业有限公司 | Related substance of one group of Eliquis and preparation method thereof |
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