CN108503580A - A kind of preparation method of Eliquis intermediate - Google Patents
A kind of preparation method of Eliquis intermediate Download PDFInfo
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- CN108503580A CN108503580A CN201810333139.6A CN201810333139A CN108503580A CN 108503580 A CN108503580 A CN 108503580A CN 201810333139 A CN201810333139 A CN 201810333139A CN 108503580 A CN108503580 A CN 108503580A
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- YUGIGSPFTMLIMA-UHFFFAOYSA-N Nc(cc1)ccc1N(CCC=C1N2CCOCC2)C1=O Chemical compound Nc(cc1)ccc1N(CCC=C1N2CCOCC2)C1=O YUGIGSPFTMLIMA-UHFFFAOYSA-N 0.000 description 2
- LBFAEOWNWSDWRZ-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1N(CCC=C1N2CCOCC2)C1=O)=O Chemical compound [O-][N+](c(cc1)ccc1N(CCC=C1N2CCOCC2)C1=O)=O LBFAEOWNWSDWRZ-UHFFFAOYSA-N 0.000 description 2
- OILJIEKQCVHNMM-UHFFFAOYSA-N CC(C)(C)N1CCOCC1 Chemical compound CC(C)(C)N1CCOCC1 OILJIEKQCVHNMM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
Abstract
The present invention relates to a kind of synthesis of Eliquis intermediate, the especially synthesis of 4 cyclic lactam base amino benzenes compounds.Implemented by such as following formula method, synthetic route of the present invention is novel, and easy to operate, high income, safety is good, is suitble to industrialized production.Wherein R group is
Description
Technical field：
The invention belongs to organic synthesis fields, are related to a kind of synthesis of Eliquis intermediate, especially 4- cyclic lactams
The synthesis of base amino benzenes compounds.
Background technology：
4- cyclic lactam base amino benzenes compounds (IV) are a kind of widely used medicine intermediates, can be used for Xa factor suppression
The synthesis of preparation, the especially synthesis of new oral anticoagulant Eliquis.
Eliquis (Apixaban, trade name Eliquis) be after dabigatran and razaxaban, it is a kind of oral
There is vein in Selective activation Xa factor inhibitor, the adult patients for preventing to receive to select a time hip joint or knee replacements
Thromboembolism (VTE) is developed jointly by Pfizer and Bristol Myers Squibb.Newest clinical research shows Eliquis not
It is only capable for the treatment of well, the symptom of reduction of patient, can more effectively reduce palsy or body circulation incidence of thrombus and bleeding episode
Danger, and the death rate is reduced, it brings glad tidings to many patients, therefore possess good market prospects.1- (4- aminophenyls)-
- 2 (1H)-pyridones of 5,6- dihydro -3- (4- morpholines) are a key intermediate for preparing Eliquis, Eliquis (III)
And the structure of key intermediate 1- (4- aminophenyls) -5,6- dihydros -3- (4- morpholines) -2 (1H)-pyridone (II) is as follows：
Patent CN101967145A, CN103626689A, CN104650072A, CN104844593A, IN
It is mentioned in 2012CH04558 and document Synthetic Communications 2013,1,43,72-79 and is with compound (I)
Raw material and vulcanized sodium under the conditions of 50~60 DEG C, carry out in alcohol solvent plus compound (II) are made in hydrogen-reduction, this method makes
Reagent vulcanized sodium smell is big, and Waste water is big, unfriendly to environment, and to be prepared due to system strong basicity
Compound (II) purity is not high, is often mixed with following by-product A, it is more difficult to remove.Patent CN103709095A also refers to this point.
It is mentioned in patent CN103709095A with compound (I) as raw material, it is molten in ethyl alcohol using sodium disulfide as reducing agent
It in agent under the conditions of 50~55 DEG C, carries out plus compound (II) is made in hydrogen-reduction, for this method as vulcanized sodium, there are smells, give up
The problems such as water, impurity.
It is mentioned in 2016067308 A1 of patent WO with compound (I) for raw material, with various metals reducing agent such as Pd C, Pt
C, iron powder, the methods of zinc powder carry out plus hydrogen-reduction, this method equipment requirement is high, safety is low and reducing agent used (palladium charcoal,
Platinum charcoal) price is high, or post-processing complexity (iron powder, zinc powder), and is susceptible to following by-product B, reduces yield, increase purifying
Difficulty.
It also refers to carry out this using Raney's nickel, hydrazine hydrate in 2016067308 A1 of patent WO, WO 2016035007A2
Walk nitro reduction, reagent Raney's nickel that this method uses is easy spontaneous combustion, and when burning generates pernicious gas, exists in plant produced
Security risk, and equipment requirement is high, operation difficulty is big, the generation of by-product B, C, D of meeting removal in distress in reaction.
In addition, inventor has found on the basis of repeating existing patent, document, in step reaction, in addition to it will produce on
It states outside by-product A, B, C, the D mentioned, the generation of also following by-product E, F, the quality of strong influence product and reaction
Yield, while production to API and declaring totally unfavorable.
In conclusion that there are environment is unfriendly, equipment requirement is high, amplification is dangerous, product for the prior art of step reaction
The of low quality, unfavorable factors such as yield is undesirable, therefore, it is necessary to develop a kind of new simple, economical and efficient, safety, high quality
In high yield, and it can be used for the systems of industrialized production 1- (4- aminophenyls)--2 (1H)-pyridones of 5,6- dihydros -3- (4- morpholines)
Preparation Method.
Invention content：
It is high technical problem to be solved by the invention is to provide a kind of at low cost, yield and suitable for industrialized production
The preparation method of 4- cyclic lactam base amino benzenes compounds.
The present invention provides the preparation methods of 4- cyclic lactams base amino benzenes compounds shown in a kind of formula (IV).It is specific to close
It is as follows at scheme：
Compound (V) is dissolved in solvent, thunder Buddhist nun cobalt is added, hydrazine hydrate carries out nitro-reduction reaction and obtains compound
(IV)。
Wherein, R group is
The solvent is the mixed solvent of water-miscible organic solvent or water-miscible organic solvent and water.
The water-miscible organic solvent is selected from methanol, ethyl alcohol, propyl alcohol, isopropanol, butanol, tetrahydrofuran, 1,4- dioxies
It is one or more in six rings or acetonitrile.
The thunder Buddhist nun cobalt and the mass ratio of compound (V) are 0.05:1.0~1.0:1.0, preferably 0.1:1.0~
0.3:1.0。
The molar ratio of the hydrazine hydrate and compound (V) is 1.0:1.0~30.0:1.0, preferably 3.0:1.0~
5.0:1.0。
The mass percent concentration of the hydrazine hydrate aqueous solution is 20%-100%, preferably 40%-80%.
Experimenter can be adjusted reaction temperature in conjunction in due course temperature environment, and reaction temperature of the invention preferably exists
30~80 DEG C, the reaction time according to detection subject to the reaction was complete, generally 1-4 hours.
When the R group of compound (IV) isWhen as compound (II), that is, Eliquis intermediate：
1- (4- aminophenyls) -5,6- dihydros -3- (4- morpholines) -2 (1H)-pyridone.
Compound (I) is restored prepare compound (II) by inventor's discovery using the method for the present invention by nitro, can be effective
The generation of control side reaction object can obtain compound (II) by common post-processing scheme after reaction.It is especially gratifying
, only by simply filtering, solvent replacement operator, the solution of compound (II) can be directly used for reacting in next step, to
Simplify entire technological process.
The advantages of the method for the present invention, essentially consists in：
1. the present invention provides one it is completely new can the route of industrialized production be used to prepare 4- cyclic lactam base phenyl amines
Compound；
2. the route high income, up to 99%；
3. the route methods are simple, economical and efficient, safety, and can be used for industrialized production；
4. the route discloses a kind of method of new synthesis 4- cyclic lactam base amino benzenes compounds, wherein R group isA new thinking is provided for similar nitro-reduction reaction.
Specific embodiment：
Present invention will be further explained below with reference to specific examples.These embodiments are merely to illustrate the present invention and do not have to
In limiting the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, carries out usually according to normal condition.
Raw material used in embodiment or reagent are commercially available in addition to special instruction.
Room temperature described in embodiment refers both to 20~35 DEG C.Unless otherwise indicated, the reagent directly makes without further purification
With.All solvents are purchased from commercialization supplier, such as aldrich (Aldrich), and just can be used without processing.Reaction
It is analyzed by TLC or is analyzed by LC-MS, the termination of reaction is judged by the consumption of starting material.The thin layer of analysis
Analysis (TLC) is the glass plate (EMD chemical companies (EMD Chemicals)) in 0.25 millimeter of plate of pre-coated silica gel 60F254
Upper progress, with the iodine developing on UV light (254nm) and/or silica gel, and/or with TLC product dyed therebies such as alcohol phosphomolybdic acid, hydration indenes
Triketone solution, liquor potassic permanganate or ceric sulfate solution heat together.
The abbreviation used in the present invention has this field conventional sense, such as：MTBE indicates methyl tertiary butyl ether(MTBE).
Embodiment 1
Using Raney's nickel, hydrazine hydrate scheme prepare compound (II) in foundation patent WO2016067308A1.Feed intake chemical combination
Object (I) 1.0kg, yield 0.81kg, yield 90%, purity 99.6%.
Embodiment 2
10L methanol is added in 50L reaction kettles, is added with stirring 1.0kg compounds (I), 100g thunder Buddhist nun's cobalts, is warming up to 40-
50 DEG C, 800g hydrazine hydrates (content 80%) are slowly added dropwise, keep the temperature 70-80 DEG C, reacts 2h, is filtered with diatomite after the reaction was complete,
Concentration removes solvent, and MTBE mashing is added in filtering, filter cake, obtains 0.87kg white solids, yield 97%, purity 99.8%.
Embodiment 3
15L Isosorbide-5-Nitraes-dioxane is added in 50L reaction kettles, is added with stirring 1.0kg compounds (I), 100g thunder Buddhist nun's cobalts,
It is warming up to 40-50 DEG C, 800g hydrazine hydrates (content 80%) are slowly added dropwise, keeps the temperature 70-80 DEG C, 2h is reacted, silicon is used after the reaction was complete
Diatomaceous earth filters, and concentration removes solvent, and MTBE mashing is added in filtering, filter cake, obtains 0.86kg white solids, yield 95% is pure
Degree 99.6%.
Embodiment 4
10L methanol is added in 50L reaction kettles, is added with stirring 1.0kg compounds (I), 80g thunder Buddhist nun's cobalts, is warming up to 40-50
DEG C, 800g hydrazine hydrates (content 80%) are slowly added dropwise, keep the temperature 70-80 DEG C, reacts 2h, is filtered with diatomite after the reaction was complete, it is dense
Contracting removes solvent, and MTBE mashing is added in filtering, filter cake, obtains 0.77kg white solids, yield 85%, purity 99.0%.
Embodiment 5
25L water, 25L methanol are added in 500L reaction kettles, is added with stirring 2.5kg compounds (I), 250g thunder Buddhist nun's cobalts, rises
2.0kg hydrazine hydrates (content 80%) are slowly added dropwise to 40-50 DEG C in temperature, keep the temperature 60-70 DEG C, react 3h, diatom is used after the reaction was complete
Soil filtering, concentration remove solvent, MTBE mashing are added in filter cake, obtains 2.20kg white solids, yield 98%, purity
99.8%.
Embodiment 6
12.5L water, 37.5L methanol are added in 100L reaction kettles, is added with stirring 2.5kg compounds (I), 500g thunder Buddhist nuns
Cobalt is warming up to 50-60 DEG C, and 2.0kg hydrazine hydrates (content 80%) are slowly added dropwise, and keeps the temperature 50-60 DEG C, diatomite is used after the reaction was complete
Filtering, dichloromethane extraction, magnesium sulfate drying are filtered, vacuum distillation, and detecting it three times, after displacement to constant weight with THF displacements contains
Amount is more than 98%, is directly used in next step, yield 99% in situ.
Embodiment 7
30mL methanol is added in 100mL reaction bulbs, is added with stirring 3.0g 5,6- dihydros -3- (4- methyl-1s-piperazine
Base) -2 (1H)-pyridones of -1- (4- nitrobenzophenones), 1.0g thunder Buddhist nun's cobalts, be warming up to 40-50 DEG C, 2.4g hydrazine hydrates be slowly added dropwise
(content 80%) keeps the temperature 50-60 DEG C, reacts 2h, filtered with diatomite after the reaction was complete, and concentration removes solvent, and MTBE is used in filtering
Recrystallization, obtains 2.6g white solids, yield 94%, purity 99.6%.
Embodiment 8
30mL methanol is added in 100mL reaction bulbs, is added with stirring 2.9g 5,6- dihydros -3- (1- piperazinyls) -1- (4-
Nitrobenzophenone) -2 (1H)-pyridone 1.0g thunder Buddhist nun's cobalts, it is warming up to 40-50 DEG C, 2.4g hydrazine hydrates (content 80%) are slowly added dropwise,
50-60 DEG C of heat preservation is reacted 2h, is filtered with diatomite after the reaction was complete, and concentration removes solvent, and filtering is recrystallized with MTBE, obtained
2.3g white solids, yield 90%, purity 99.5%.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To be made various changes or modifications to the present invention, such equivalent forms are equally fallen within defined by the application the appended claims.
Claims (6)
1. the present invention provides the preparation methods of 4- cyclic lactams base amino benzenes compounds shown in a kind of formula (IV).Its feature exists
In：
Compound (V) is dissolved in solvent, thunder Buddhist nun cobalt is added, hydrazine hydrate carries out nitro-reduction reaction and obtains compound (IV).
Wherein, R group is
2. preparation method as described in claim 1, it is characterised in that the solvent is water-miscible organic solvent or water solubility
The mixed solvent of organic solvent and water.
3. preparation method as described in claim 1, it is characterised in that the water-miscible organic solvent be selected from methanol, ethyl alcohol,
It is one or more in propyl alcohol, isopropanol, butanol, tetrahydrofuran, 1,4- dioxane or acetonitrile.
4. preparation method as described in claim 1, it is characterised in that the thunder Buddhist nun cobalt and the mass ratio of compound (V) are
0.05:1.0~1.0:1.0.
5. preparation method as described in claim 1, it is characterised in that the molar ratio of the hydrazine hydrate and compound (V) is
1.0:1.0~30.0:1.0.
6. the mass percent concentration of preparation method as described in claim 1, the hydrazine hydrate aqueous solution is 20%-
100%.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810333139.6A CN108503580A (en) | 2018-04-13 | 2018-04-13 | A kind of preparation method of Eliquis intermediate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810333139.6A CN108503580A (en) | 2018-04-13 | 2018-04-13 | A kind of preparation method of Eliquis intermediate |
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| CN108503580A true CN108503580A (en) | 2018-09-07 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114910596A (en) * | 2021-02-07 | 2022-08-16 | 南京正大天晴制药有限公司 | Analytical method for determining substances related to pyridone compounds |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989007096A1 (en) * | 1988-02-03 | 1989-08-10 | Eastman Kodak Company | Hydrogenation of halonitroaromatic compounds |
| WO2015162551A1 (en) * | 2014-04-21 | 2015-10-29 | Mylan Laboratories Ltd | Process for the preparation of apixaban |
| WO2016035007A2 (en) * | 2014-09-05 | 2016-03-10 | Unichem Laboratories Limited | An improved process for the preparation of apixaban and intermediates thereof |
| WO2016067308A1 (en) * | 2014-10-28 | 2016-05-06 | Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) | Process for the preparation of apixaban and intermediates thereof |
-
2018
- 2018-04-13 CN CN201810333139.6A patent/CN108503580A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989007096A1 (en) * | 1988-02-03 | 1989-08-10 | Eastman Kodak Company | Hydrogenation of halonitroaromatic compounds |
| WO2015162551A1 (en) * | 2014-04-21 | 2015-10-29 | Mylan Laboratories Ltd | Process for the preparation of apixaban |
| WO2016035007A2 (en) * | 2014-09-05 | 2016-03-10 | Unichem Laboratories Limited | An improved process for the preparation of apixaban and intermediates thereof |
| WO2016067308A1 (en) * | 2014-10-28 | 2016-05-06 | Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) | Process for the preparation of apixaban and intermediates thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114910596A (en) * | 2021-02-07 | 2022-08-16 | 南京正大天晴制药有限公司 | Analytical method for determining substances related to pyridone compounds |
| CN114910596B (en) * | 2021-02-07 | 2024-01-26 | 南京正大天晴制药有限公司 | Analysis method for determining related substances of pyridone compounds |
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Address after: 201203 Lane 3, 1999, Zhangheng Road, Pudong New Area, Shanghai Applicant after: Shanghai Hao Yuan pharmaceutical Limited by Share Ltd Address before: 201203 Room 304, Lane 720, Cailun Road, Zhangjiang High-tech Park, Pudong New Area, Shanghai Applicant before: Shanghai Hao Yuan pharmaceutical Limited by Share Ltd |
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Application publication date: 20180907 |