CN110041245A - A kind of preparation of Eliquis and its intermediate - Google Patents
A kind of preparation of Eliquis and its intermediate Download PDFInfo
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- CN110041245A CN110041245A CN201910354006.1A CN201910354006A CN110041245A CN 110041245 A CN110041245 A CN 110041245A CN 201910354006 A CN201910354006 A CN 201910354006A CN 110041245 A CN110041245 A CN 110041245A
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- C07—ORGANIC CHEMISTRY
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- 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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member 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
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- 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
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Abstract
The present invention relates to the preparation methods of a kind of antithrombotic reagent Eliquis and related intermediate.Specifically, compound I is obtained by two step one pot reaction of amidation-cyclization with common reagent 5-Chlorovaleryl Chloride under alkaline condition using cheap paranitroanilinum as raw material；Compound I reacts under the conditions of lithium carbonate and organic solvent with 3,3- dihydroxypiperdine -2- ketone generates compound II；Compound II and compound III occurs cyclization-elimination reaction and generates compound IV；Compound IV hydrolyzes to obtain compound V, i.e. Eliquis.The synthetic method that the present invention uses, Process Route Planning is reasonable, and raw material is cheap and easily-available, does not use expensive reagent, the reaction condition of no harshness, and reaction yield and purity are higher, easy to operate, is easy to large-scale production.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular, to a kind of preparation method of new anticoagulant apixaban,
And related intermediate and its preparation.
Background technique
Eliquis (Apixaban) is a kind of anticoagulant blood products of Bristol Myers Squibb Yu Pfizer's cooperative research and development, for selecting
The prevention of phase hip joint or replacement knee in arthroplasty adult patient Venous Thrombosis.Eliquis is in March, 2011 in European Union batch
Quasi- listing, and obtain FDA in December, 2012 and ratify the medicine in U.S.'s listing, acquisition China national food and medicine supervision pipe in 2013
Import drug permit that reason office issues and in Discussion on Chinese Listed.
Bristol-Myers Squibb company gives one in the world patent WO2003/049681 disclosed in 2003
The route of the high organic reagent containing iodine of use cost, total recovery only have 5.2%, synthetic route such as route 1.Bristol-
Myers Squibb company disclosed the technique patent US2006/0069258 of the medicine again in 2006, was original with paranitroanilinum
Material, obtains compound 5,5 after phosphorus pentachloride dichloride by amidation cyclization reaction with 5- bromine valeric chloride, in lithium carbonate and chlorination
Heat condensation eliminates to obtain compound 8 in the presence of lithium.Another compound VI by starting material P-nethoxyaniline after diazotising with
2- chloroacetyl acetacetic ester occurs Japp-Klingmann hydrazone synthetic reaction and is made, and compound VI and compound 8 are through cyclization-elimination
Reaction obtains compound 9,9 and obtains amino-compound 10,10 and 5- bromine valeric chloride through palladium carbon hydro-reduction passing through amidation cyclization
Compound IX is reacted to obtain, finally obtains target compound Eliquis through ammonolysis in n,N-Dimethylformamide and formamide, is closed
At route such as route 2.Although the route avoids having used with raw material containing iodine at high cost but uses expensive palladium carbon hydrogenation conditions,
Total recovery also improves, but synthetic route is longer, and compound and finished product impurity are not easy to control；Simultaneously also using a large amount of
5- bromine valeric chloride and phosphorus pentachloride etc. be unstable and the raw material of difficult post-processing, these deficiencies all limit industrialized production；Finally
One step ammonolysis has used n,N-Dimethylformamide to make solvent, and solvent easily remains and is not easy to remove, and product is made to be extremely difficult to API mark
It is quasi-.
Route 1
Route 2
World patent WO2010/030983 disclosed in Auspex Pharmaceuticals companies in 2010 provides preparation
The route of Eliquis, such as route 3:
Route 3
Raw material containing iodine is used in the route, it is at high cost, and Ullmann severe reaction conditions, complicated for operation, single step yield
Low, by-product is more, so that highway route design is not reasonable, total recovery is lower, is not suitable for industrialized production.
China Patent Publication No. is to disclose the conjunction of Apixaban in CN101967145 (applying date 2010.09.09) patent
At route, such as route 4.The route passes through amidation-ring with 5-Chlorovaleryl Chloride under alkaline condition using paranitroanilinum as raw material
It closes two step one pot reactions and obtains compound 6,6 with phosphorus pentachloride progress dichloride, then be condensed-eliminate with excessive morpholine
Reaction obtains compound 12,12 and cures sodium reduction as compound 13,13 and 5-Chlorovaleryl Chloride progress two step one of amidation-cyclization
Pot boil reaction obtain 14,14 and 3 process [3+2] cyclization-elimination reactions obtain IX, last ammonolysis obtains Eliquis.This route
It is prepared using one kettle way, is difficult to control although route impurity can be reduced, low yield, and consume excessive morpholine, leads to shape
At the compound of the dimorpholine substitution as by-product.Wherein, the compound that dimorpholine replaces is converted into the change that single morpholine replaces
Closing object is a cumbersome job, to increase production cost.In addition, reaction in use a large amount of phosphorus pentachlorides etc. it is unstable and
The raw material of hardly possible post-processing, limits it and is used for industrialized production.
Route 4
The method such as route 5 of document (Synth.Comm., 2013,72) report, the route use cheap to nitro
Aniline is raw material, synthesizes compound 2.Compound 2 synthesizes compound 4 with the coupling reaction of compound 3.Compound 4 is in catalyst
Palladium carbon effect is lower to obtain key intermediate 1 by hydro-reduction.Compound 5 can synthesize Eliquis through two-step reaction.This
Method is needed using expensive palladium catalyst, while hydrogenation the high requirements on the equipment, and there is also safety for the use of hydrogen
Hidden danger.Also it has been reported that with iron powder reducing compound 4 and synthesizes compound 1.But iron powder reducing post-processing is difficult, while generating
Iron cement causes serious pollution to the environment.
Route 5
The common reactant of ammonolysis can be liquefied ammonia, ammonium hydroxide, gaseous ammonia or the compound containing amino, such as urea, carbon
Sour hydrogen amine/formamide and azanol etc..For liquid phase ammonia solution preocess, ammonium hydroxide is most widely used ammonolysis agent.But ammonium hydroxide is to certain
The solubility of a little organic matters is small, causes hydrolytic side reactions sometimes.Wherein, more publications include patent WO03026652,
The Eliquis of the reports such as WO2010/030983, WO03049681, CN101967145B, CN102675314A, US7396932
Synthetic route all includes following aminolysis step, i.e., prepares Eliquis by ammonolysis reaction by ester type compound 2:
Patent WO2010/030983 disclosed in (1) 2010 year provides the route for preparing Eliquis, as shown in Scheme 6.
Wherein the ester aminolysis reaction of final step is carried out in the ethylene glycol solution of ammonia, and reaction need to carry out 7h at a high temperature of 120 DEG C.
Route 6
(2) Chinese patent CN101967145B discloses the synthetic route of Apixaban, as shown in Scheme 7.II is dissolved in
In the methanol solution of ammonium hydroxide, heating reaction is until thorough ammonolysis is converted into I in stainless steel pressure kettle.Reaction yield is up to
90%, but need to limit industrialized application using pressure vessel.
Route 7
(3) patent WO030498681 reports another amidation method, using carboxylic acid as raw material, with isobutyl chlorocarbonate
Acid anhydrides is prepared under alkaline condition, then reacts with ammonia water synthesis Eliquis.Although this method mild, nothing with reaction condition
The advantages that needing pressure vessel and anhydrous response condition, but the isobutyl chlorocarbonate big using toxicity is needed, reaction step is relatively multiple
It is miscellaneous.
It is analyzed by the above prior art as it can be seen that the condition of ammonolysis reaction has many, generally existing reaction item
The cumbersome harshness of part, the drawbacks such as auxiliary reagent dosage is larger, and yield is relatively low, such as using high-tension apparatus, the methanol of stability in use difference
Sodium or higher reaction temperature etc., are unfavorable for large-scale production.Thus research is optimized to ammonolysis reaction in we.
To sum up, following defect is primarily present during preparing Eliquis:
(1) raw and auxiliary material is expensive, such as contains iodine reagent using expensive, uses expensive palladium carbon hydrogenation conditions etc.；
(2) limitation of reaction condition causes gross production rate too low, is unfavorable for industrialized production；
(3) using the raw material of the unstable and difficult post-processings such as a large amount of phosphorus pentachlorides in reaction, the use of a large amount of morpholines causes
By-product generates, and the use of 5- bromine valeric chloride makes quality control difficulty is larger to limit it and be used for industrialized production；
(4) a large amount of acid and waste water and dregs containing heavy metal are generated in reaction process to cause serious pollution to the environment；
(5) sodium hydrogen belongs to hazardous agents, there is very big security risk, and post-processes cumbersome, control of product quality difficulty.
Therefore, it there is an urgent need to develop a kind of synthetic route is reasonable, does not need using the expensive or biggish examination of toxicity, irritation
Agent, byproduct of reaction is few, easy to operate, and reaction condition is mild, the synthetic method of yield and the higher Eliquis of purity.
Summary of the invention
The purpose of the present invention is overcoming deficiency in the prior art, a kind of synthetic method of new Eliquis is provided, with
And intermediate and preparation method thereof.
One aspect of the present invention provides a kind of compound, and structure is as shown in Formula II:
Second aspect of the present invention is to provide a kind of preparation method of Formula II, the specific steps are as follows:
Compound I and 3,3- dihydroxypiperdine -2- ketone react under the conditions of inorganic metal alkali and organic solvent generates chemical combination
Object II.
Wherein, the organic solvent in methanol, ethyl alcohol, propyl alcohol, tetrahydrofuran, toluene, methylene chloride or DMF one
Kind is a variety of；It is preferred that DMF.
The inorganic metal alkali cpd is selected from potassium carbonate, lithium carbonate or magnesium carbonate；It is preferred that lithium carbonate.
The compound I:3,3- dihydroxypiperdine -2- ketone: the molar ratio of inorganic metal alkali is 1:1~3:1~4；It is preferred that
1:2:3。
The compound I's the preparation method is as follows:
Parachloroanilinum reacts in tertiary amine organic base and anhydrous solvent with 5-Chlorovaleryl Chloride generates the chloro- N- of 5- (4- chlorphenyl)
Pentanamide, then reaction generates compound I under the effect of cyclization condensing agent.
Wherein, the anhydrous solvent is selected from one of anhydrous tetrahydro furan, anhydrous acetonitrile or anhydrous dimethyl formamide
Or it is a variety of；It is preferred that anhydrous tetrahydro furan.
The tertiary amine organic base is triethylamine.
The parachloroanilinum: tertiary amine organic base: the molar ratio of 5-Chlorovaleryl Chloride is 1:1:1~1:3:2；Preferred molar ratio is
1:2:2。
The cyclization condensing agent is metal organic base or inorganic alkaline agents；It is preferred that sodium tert-butoxide, potassium tert-butoxide or sodium hydride；
Further preferred sodium tert-butoxide.
The molar ratio of the parachloroanilinum and cyclization condensing agent is 1:1~1:6；It is preferred that 1:2~1:4；Further preferred 1:
3。
Further, compound II can be used to prepare intermediate compound IV:
Compound II reacts under the conditions of metal alkali cpd and organic solvent with compound III generates compound IV.
Wherein, the organic solvent is in alcohol organic solvent, ethyl acetate, methylene chloride, tetrahydrofuran or DMF
It is one or more；It is preferred that methanol, ethyl alcohol, propyl alcohol or isopropanol；Further preferred methanol.
The metal alkali cpd is selected from sodium hydroxide, potassium hydroxide, aluminium hydroxide, sodium tert-butoxide, potassium tert-butoxide or hydrogen
Change one of sodium or a variety of；It is preferred that sodium hydroxide, potassium hydroxide or aluminium hydroxide；Further preferred aluminium hydroxide.
The compound II: compound III: the molar ratio of metal alkali cpd is 1:1~2:1~3；It is preferred that 1:1.5:2.
Further, intermediate compound IV can be used to prepare Eliquis, the specific steps are as follows:
Compound IV reacts in water with trimethysilyl chloride generates compound V, i.e. Eliquis.
Wherein, the compound IV: the molar ratio of trimethysilyl chloride is 1:1~6；It is preferred that 1:1~3；It is further excellent
Select 1:2.
Another aspect of the present invention provides a kind of preparation method of Eliquis, the specific steps are as follows:
(a) parachloroanilinum reacts in tertiary amine organic base and anhydrous solvent with 5-Chlorovaleryl Chloride generates the chloro- N- of 5- (4- chlorobenzene
Base) pentanamide, then reaction generates compound I under the effect of cyclization condensing agent；
(b) compound I and 3,3- dihydroxypiperdine -2- ketone react generationization under the conditions of inorganic metal alkali and organic solvent
Close object II；
(c) compound II reacts under the conditions of metal alkali cpd and organic solvent with compound III generates compound IV；
(d) compound IV reacts in water with trimethysilyl chloride generates compound V.
Design of the invention are as follows: using cheap paranitroanilinum as raw material under alkaline condition with common reagent 5- chlorine valeryl
Chlorine obtains compound I by two step one pot reaction of amidation-cyclization；Compound I and 3,3- dihydroxypiperdine -2- ketone are in carbonic acid
Reaction generates compound II under the conditions of lithium and organic solvent；Cyclization-elimination reaction generationization occurs for compound II and compound III
Close object IV；Compound IV hydrolyzes to obtain compound V, i.e. Eliquis.
A kind of preparation method of antithrombotic reagent Eliquis, the specific steps are that:
The preparation of step 1:1- (4- chlorphenyl) piperidines -2- ketone
Successively parachloroanilinum, tertiary amine organic base are added in anhydrous organic solvent, kept in cooling conditions toward reaction
The mixed solution of 5-Chlorovaleryl Chloride and anhydrous solvent is slowly added dropwise in mixed liquor, drips and is to slowly warm up to be stirred at room temperature after finishing reaction solution
Reaction, until paranitroanilinum spot disappears；Continue in reaction solution be added cyclization condensing agent, be stirred at room temperature reaction until
Intermediate state spot disappears；Revolving removes solvent, extracts, recrystallizes final yellow powder crystal I；
Wherein, the anhydrous solvent is aprotic polar organic solvent；It is preferred that anhydrous tetrahydro furan, anhydrous acetonitrile or nothing
One of water dimethylformamide (DMF) is a variety of；Further preferred anhydrous tetrahydro furan；
The tertiary amine organic base, preferably cheap triethylamine；
Wherein, the molar ratio of parachloroanilinum, tertiary amine organic base and 5-Chlorovaleryl Chloride is 1:1:1~1:3:2, preferred molar ratio
For 1:2:2；
The cyclization condensing agent is metal organic base or inorganic alkaline agents；It is preferred that sodium tert-butoxide, potassium tert-butoxide or hydrogenation
Sodium, preferably sodium tert-butoxide；
The molar ratio of parachloroanilinum and cyclization condensing agent is 1:1~1:6, and preferred molar ratio is 1:2~1:4；More preferable 1:
3；
Reaction does not have special requirement to the control of temperature, can carry out within the scope of -5 DEG C~60 DEG C of temperature；Preferably
25℃-50℃；Further preferably 45 DEG C.
The preparation of step 2:3,3- dihydroxy -1- (4- (2- Oxypertine -1- base) phenyl) piperidines -2- ketone
Successively by compound I and 3,3- dihydroxypiperdine -2- ketone is added in organic solvent, and slowly into mixed solution
Inorganic metal alkali cpd is added, heating makes system heat up after addition, is stirred to react until the reaction is complete.
Wherein, the organic solvent is in methanol, ethyl alcohol, propyl alcohol, tetrahydrofuran, toluene, methylene chloride or DMF
It is one or more；It is preferred that DMF；
The inorganic metal alkali cpd is selected from potassium carbonate, lithium carbonate or magnesium carbonate；It is preferred that lithium carbonate；
The compound I:3,3- dihydroxypiperdine -2- ketone: the molar ratio of lithium carbonate is 1:1~3:1~4；It is preferred that 1:
2:3；
The temperature of reaction is 35 DEG C -80 DEG C；It is preferred that 40 DEG C -60 DEG C；Further preferred 55 DEG C.
Step 3:1- (4- methoxyphenyl) -7- oxo -6- (4- (2- oxo-piperidine -1- base) phenyl) -4,5,6,7- four
The preparation of hydrogen -1H- pyrazolo [3,4-c] pyridine -3- nitrile
Compound II and compound III are added in organic solvent, and are slowly added to metal base chemical combination into reaction solution
Object, and reaction system is heated up, it is stirred to react and obtains compound IV until the reaction is complete.
Wherein, the organic solvent is in alcohol organic solvent, ethyl acetate, methylene chloride, tetrahydrofuran or DMF
It is one or more；It is preferred that methanol, ethyl alcohol, propyl alcohol or isopropanol；Further preferred methanol；
The metal alkali cpd is selected from sodium hydroxide, sodium hydroxide potassium, aluminium hydroxide, sodium tert-butoxide, potassium tert-butoxide
Or one of sodium hydride or a variety of；It is preferred that sodium hydroxide, sodium hydroxide potassium or aluminium hydroxide；Further preferred aluminium hydroxide；
Compound II: compound III: the molar ratio of aluminium hydroxide is 1:1~2:1~3；It is preferred that 1:1.5:2；
The temperature of reaction system is 40 DEG C -90 DEG C；It is preferred that 60 DEG C -85 DEG C；Further preferred 65 DEG C.
Step 4:1- (4- methoxyphenyl) -7- oxo -6- (4- (2- oxo-piperidine -1- base) phenyl) -4,5,6,7- four
The preparation of hydrogen -1H- pyrazolo [3,4-c] pyridine-3-carboxamide
Compound IV is slowly added into water, and trimethysilyl chloride is slowly added dropwise into reaction solution, and certain
Reaction until the reaction is complete, obtains compound V in temperature range.
Wherein, the compound IV: the molar ratio of trimethysilyl chloride is 1:1~6；It is preferred that 1:1~3；Further
It is preferred that 1:2；
The reaction temperature is 0 DEG C~room temperature；It is preferred that 20 DEG C.
The synthetic method of Eliquis is specific as follows:
The preparation method of Eliquis of the present invention has the advantages that compared with prior art
(1) Process Route Planning of the invention is reasonable, and reaction step is succinct, avoids unstable and difficult using phosphorus pentachloride etc.
The raw material of post-processing does not need the defect high so as to cause by-product using morpholine；
(2) reaction raw materials of the present invention are cheap and easily-available, do not need using expensive iodide and bromo-acid amide compound；
(3) present invention is not needed using dangerous raw material or reagent, if the use of NaH leads to the generation of a large amount of hydrogen, no
It is easy to industrialized production；
(4) operation of the present invention is easy, the reaction condition of no harshness, such as ullmann reaction, catalytic hydrogenation, high temperature and pressure
Ammonolysis and etc., it is easy to large-scale production.
(5) each step reaction yield of the invention and purity are higher.
Specific embodiment
A kind of specific embodiment of the preparation method of antithrombotic reagent Eliquis of the present invention presented below.
Compound synthesized by the present invention is with thin-layer chromatography chromatography (TLC), mass spectrum (MS) test and nuclear magnetic resonance spectroscopy
(1H NMR) it tests to confirm the structure of compound.
The preparation of embodiment 1:3,3- dihydroxypiperdine -2- ketone
By the Na of 50ml2CO3Aqueous solution is added in reaction flask, then by 3,3-, bis- Chloperastine -2- ketone (33.60g,
It 0.2mol) is added in above-mentioned solution, is stirred to react at room temperature 2 hours, reaction is completed, by reaction solution 100ml water washing 2
Secondary, stratification, water layer is dry with anhydrous sodium sulfate, depressurizes to take off and do, residue obtains white solid with recrystallize with dichloromethane
Compound 3,3- dihydroxypiperdine -2- ketone 25.16g, molar yield 96%.
1H NMR(400MHz,CDCl3)δ1.85(m,2H),1.90(m,2H),3.31(m,2H),4.52(s,2H),7.5
(s,1H)；
MS m/z(ESI):131.1[M+H]+.
The preparation of embodiment 2:1- (4- chlorphenyl) piperidines -2- ketone
40ml anhydrous tetrahydro furan is added in reaction flask, sequentially added under stirring parachloroanilinum (12.76g,
0.1mol), triethylamine (20.2g, 0.2mol).Reaction solution is cooled to 0 DEG C with ice salt bath, and 5-Chlorovaleryl Chloride is slowly added dropwise
(31.0g, 0.2mol), control system temperature is in 0~5 DEG C of range during dropwise addition.It finishes, it is anti-that reaction solution is to slowly warm up to room temperature
It answers 4 hours, TLC tracking reaction is until paranitroanilinum spot disappears.Reaction solution is cooled to 0 DEG C with ice salt bath, is slowly added to uncle
Sodium butoxide (19.22g, 0.2mol), finishes, and reaction solution is to slowly warm up to 45 DEG C and reacts 1 hour, and TLC tracking is until intermediate state spot
Point disappears.Stop reaction, vacuum rotary steam removes solvent and obtains solid residue；50ml ethyl acetate is added and the stirring of 100ml water is molten
Solution separates organic layer, and water phase extracts (3 × 50ml) with ethyl acetate, merges organic layer.Organic phase is successively washed with distilled water (3
× 30ml), saturated common salt water washing (2 × 30ml), anhydrous sodium sulfate is dried overnight.It filters, vacuum rotary steam removes solvent and obtains
Solid residue, solid residue is to obtain 19.50g yellow powder crystal I, molar yield 93% after re-crystallizing in ethyl acetate.
1H NMR(400MHz,CDCl3)δ1.79(m,2H),1.92(m,2H),2.42(t,2H),4.06(t,2H),7.35
(s,4H)；
MS m/z(ESI):209.1[M+H]+.
The preparation of embodiment 3:3,3- dihydroxy -1- (4- (2- Oxypertine -1- base) phenyl) piperidines -2- ketone
50ml DMF is added in reaction flask, compound I (19.50g, 0.093mol) and 3,3- is sequentially added under stirring
Dihydroxypiperdine -2- ketone (24.39g, 0.186mol), and be slowly added into mixed solution lithium carbonate (20.62g,
0.279mol), heating makes 55 DEG C of temperature of reaction system after addition, and reacts 6 hours under agitation.It has reacted
Finish, vacuum rotary steam removes solvent and obtains solid residue；50ml methylene chloride and 100ml water stirring and dissolving is added, separates organic layer,
Water phase extracts (3 × 50ml) with methylene chloride, merges organic layer.Organic phase is successively washed with distilled water (3 × 30ml), saturation food
Salt water washing (2 × 30ml), anhydrous sodium sulfate is dried overnight.It filters, vacuum rotary steam removes solvent and obtains solid residue, and solid is residual
Slag is to obtain solid chemical compound II 25.19g, molar yield 89% after recrystallize with dichloromethane.
1H NMR(400MHz,CDCl3)δ1.79(m,4H),1.92(m,2H),1.95(t,2H),2.42(t,2H),4.06
(t, 4H), 4.52 (s, 2H), 6.82 (s, 4H)；
MS m/z(ESI):304.1[M+H]+.
Embodiment 4:1- (4- methoxyphenyl) -7- oxo -6- (4- (2- oxo-piperidine -1- base) phenyl) -4,5,6,7-
The preparation of tetrahydro -1H- pyrazolo [3,4-c] pyridine -3- nitrile
100ml methanol is added in reaction flask, and by compound II (25.19g, 0.083mol) and compound III
(26.20,0.125mol) are added sequentially in reaction flask, are stirred evenly, and aluminium hydroxide is slowly added into reaction solution
(12.95g, 0.166mol), finishes, and heating makes the temperature of reaction system be increased to 65 DEG C of reactions 3 hours, after completion of the reaction, will
Reaction solution is with 100ml water washing 2 times, and stratification, organic layer is dry with anhydrous sodium sulfate, depressurizes de- dry, residue ethyl alcohol
It is recrystallized to give compound as white solid IV34.88g, molar yield 95%.
1H NMR(400MHz,CDCl3)δ1.79(m,2H),1.92(m,2H),2.42(t,2H),3.30(t,2H),3.81
(s, 3H), 3.96 (t, 2H), 4.06 (t, 2H), 6.87 (m, 2H), 6.96 (m, 2H), 7.23 (m, 2H), 7.61 (m, 2H)；
MS m/z(ESI):441.5[M+H]+.
Embodiment 5:1- (4- methoxyphenyl) -7- oxo -6- (4- (2- oxo-piperidine -1- base) phenyl) -4,5,6,7-
The preparation of tetrahydro -1H- pyrazolo [3,4-c] pyridine-3-carboxamide
100ml water is added in reaction flask, and compound IV (34.88g, 0.079mol) is added to the water, is stirred
It is uniformly mixed solution, and trimethysilyl chloride (15.21g, 0.14mol) is slowly added dropwise into reaction solution, keeps temperature
It is stirred to react 4 hours at 20 DEG C to fully reacting, is concentrated under reduced pressure, obtained solid is with 100ml water washing 2 times, filtering, and gained is solid
Body ethyl alcohol recrystallization, obtains white crystalline Compound V 35.36g, molar yield 97.5% after vacuum drying, purity is
99.94%.
1H NMR(400MHz,CDCl3)δ1.79(m,2H),1.92(m,2H),2.42(t,2H),3.30(t,2H),3.81
(s, 3H), 3.96 (t, 2H), 4.06 (t, 2H), 6.87 (m, 2H), 6.96 (m, 2H), 7.23 (m, 2H), 7.61 (m, 2H), 8.18
(s,2H)；
MS m/z(ESI):459.2[M+H]+.
Embodiment 6: the measurement of impurity content
The impurity in embodiment 1-5 is detected by LC-MS (HPLC-MS), specific data see the table below:
Claims (18)
1. a kind of compound, structure is as shown in Formula II:
2. a kind of method of preparation formula II, the specific steps are as follows:
Compound I and 3,3- dihydroxypiperdine -2- ketone react under the conditions of inorganic metal alkali and organic solvent generates compound II.
3. preparation method according to claim 2, which is characterized in that the organic solvent be selected from methanol, ethyl alcohol, propyl alcohol,
One of tetrahydrofuran, toluene, methylene chloride or DMF or a variety of；It is preferred that DMF.
4. preparation method according to claim 2, which is characterized in that the inorganic metal alkali cpd be selected from potassium carbonate,
Lithium carbonate or magnesium carbonate；It is preferred that lithium carbonate.
5. preparation method according to claim 2, which is characterized in that the compound I:3,3- dihydroxypiperdine -2- ketone:
The molar ratio of inorganic metal alkali is 1:1~3:1~4；It is preferred that 1:2:3.
6. preparation method according to claim 2, which is characterized in that further prepare intermediate compound IV:
Compound II reacts under the conditions of metal alkali cpd and organic solvent with compound III generates compound IV.
7. preparation method according to claim 6, which is characterized in that the organic solvent is selected from alcohol organic solvent, second
One of acetoacetic ester, methylene chloride, tetrahydrofuran or DMF or a variety of；It is preferred that methanol, ethyl alcohol, propyl alcohol or isopropanol；Further
It is preferred that methanol.
8. preparation method according to claim 6, which is characterized in that the metal alkali cpd is selected from sodium hydroxide, hydrogen
One of potassium oxide, aluminium hydroxide, sodium tert-butoxide, potassium tert-butoxide or sodium hydride are a variety of；It is preferred that sodium hydroxide, potassium hydroxide
Or aluminium hydroxide；Further preferred aluminium hydroxide.
9. preparation method according to claim 6, which is characterized in that the compound II: compound III: metal alkalization
The molar ratio for closing object is 1:1~2:1~3；It is preferred that 1:1.5:2.
10. preparation method according to claim 6, which is characterized in that further prepare Eliquis compound V, specifically
Steps are as follows:
Compound IV reacts in water with trimethysilyl chloride generates compound V, i.e. Eliquis.
11. preparation method according to claim 10, which is characterized in that the compound IV: trimethysilyl chloride
Molar ratio is 1:1~6；It is preferred that 1:1~3；Further preferred 1:2.
12. preparation method according to claim 2, which is characterized in that the compound I's the preparation method is as follows:
Parachloroanilinum reacts in tertiary amine organic base and anhydrous solvent with 5-Chlorovaleryl Chloride generates the chloro- N- of 5- (4- chlorphenyl) valeryl
Amine, then reaction generates compound I under the effect of cyclization condensing agent.
13. preparation method according to claim 12, which is characterized in that the anhydrous solvent be selected from anhydrous tetrahydro furan,
One of anhydrous acetonitrile or anhydrous dimethyl formamide are a variety of；It is preferred that anhydrous tetrahydro furan.
14. the preparation method of Eliquis according to claim 12, which is characterized in that the tertiary amine organic base is three second
Amine.
15. preparation method according to claim 12, which is characterized in that the parachloroanilinum: tertiary amine organic base: 5- chlorine penta
The molar ratio of acyl chlorides is 1:1:1~1:3:2；Preferred molar ratio is 1:2:2.
16. preparation method according to claim 12, which is characterized in that the cyclization condensing agent is metal organic base or nothing
Machine base reagent；It is preferred that sodium tert-butoxide, potassium tert-butoxide or sodium hydride；Further preferred sodium tert-butoxide.
17. preparation method according to claim 12, which is characterized in that mole of the parachloroanilinum and cyclization condensing agent
Than for 1:1~1:6；It is preferred that 1:2~1:4；Further preferred 1:3.
18. according to any preparation method of claim 2-17, which is characterized in that specific step is as follows:
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| CN112142736A (en) * | 2020-10-29 | 2020-12-29 | 怀化学院 | Preparation method of apixaban impurity 1 |
| CN113912598A (en) * | 2020-07-07 | 2022-01-11 | 上海茂晟康慧科技有限公司 | Synthesis method of apixaban and intermediate thereof |
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| CN103923080A (en) * | 2014-04-04 | 2014-07-16 | 苏州景泓生物技术有限公司 | Method for preparing antithrombotic drug apixaban |
| CN104262338A (en) * | 2014-09-28 | 2015-01-07 | 浙江天宇药业股份有限公司 | Synthetic method of apixaban and intermediate thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103923080A (en) * | 2014-04-04 | 2014-07-16 | 苏州景泓生物技术有限公司 | Method for preparing antithrombotic drug apixaban |
| CN104262338A (en) * | 2014-09-28 | 2015-01-07 | 浙江天宇药业股份有限公司 | Synthetic method of apixaban and intermediate thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113912598A (en) * | 2020-07-07 | 2022-01-11 | 上海茂晟康慧科技有限公司 | Synthesis method of apixaban and intermediate thereof |
| CN112142736A (en) * | 2020-10-29 | 2020-12-29 | 怀化学院 | Preparation method of apixaban impurity 1 |
| CN112142736B (en) * | 2020-10-29 | 2021-08-10 | 怀化学院 | Preparation method of apixaban impurity 1 |
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