CN103951661B - A kind of preparation method of razaxaban - Google Patents
A kind of preparation method of razaxaban Download PDFInfo
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- CN103951661B CN103951661B CN201410176210.6A CN201410176210A CN103951661B CN 103951661 B CN103951661 B CN 103951661B CN 201410176210 A CN201410176210 A CN 201410176210A CN 103951661 B CN103951661 B CN 103951661B
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- C07—ORGANIC CHEMISTRY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention discloses a kind of preparation method of razaxaban, it is that amino replaces through five step reactions, chloro, cyclization, eliminates, and substitution obtains target product, raw material of the present invention is cheap and easily-available so that reaction cost reduction, stable reaction conditions, it is simple to operate, yield is high, and post processing is simple, and the crude product purity obtained after reaction is high, it is easy to purify the razaxaban for obtaining high-purity, more suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, and in particular to (chemistry is entitled for a kind of razaxaban：The chloro- N- of 5- [2- oxos-
3- [4- (3- oxygen morpholine -4- bases) phenyl] oxazolidone -5- bases] methyl } thiophene -2- carboxylic acid amides) synthetic method.
Background technology
Razaxaban (rivaroxaban, BAY5927939, trade name:Xarelto), domestic nomenclature of drug is auspicious appropriate to visit,
Chemistry is entitled：The chloro- N- of 5- [2- oxos -3- [4- (3- oxygen morpholine -4- bases) phenyl] oxazolidone -5- bases] methyl } thiophene -2-
Carboxylic acid amides, the formation for preventing VTE and pulmonary embolism after adult patients hip joint and replacement knee in arthroplasty.
There is certain controlling in the fields such as secondary prevention, treatment auricular fibrillation and acute coronary syndrome simultaneously in Chinese patients with deep venous thrombosis
Therapeutic effect.
Clinically usable anticoagulant includes unfractionated heparin (unfractionated heparin, UFH), low at present
Molecular heparin (low molecular weight heparin, LMWH), vitamin K antagon warfarin (warfarin) and
Pentasaccharide fondaparinux sodium (fondaparinux, Arixtra).
Heparin class material produces anticoagulation effect by cascading correlation factor interaction with various blood clottings, clinically mainly
Also often limited the use of in inpatient or short-term (≤2wk) prevention phlebothrombosis bolt for short-term antithrombotic heparin class material
Plug sexual behavior part).In view of the larger and existing medicine of the market opportunity is each defective, drugmaker to novel anticoagulation medicine research with open
The concern of hair and throwing people substantially increase.Certainly, the curative effect of these anticoagulation new drugs should at least correspond to existing medicine, but safety
Property must be improved, need to particularly reduce bleeding risk, be administered simultaneously scheme easy (if oral etc.).
Because Xa factor is that a kind of fibrin ferment forms necessary clotting factor direct thrombin inhibitor, Xa factor is studied
Inhibitor plays key effect to research anticoagulant.Receive much concern member in oral Selective activation Xa factor inhibitor
It is Eliquis (Apixaban, trade name Eliquis), dabigatran, three new oral anti-coagulants of razaxaban.In Europe
Approval these three oral anticoagulants in, with current bone surgery after prevent venous thromboembolism standard regimens according to promise
Heparin is compared, and razaxaban and Eliquis highlight advantage in RECORD experiments and ADVANCE experiments respectively.Expert represents,
The result that these are tested side by side from the point of view of, the curative effect of razaxaban seems more preferable.
Razaxaban is by Bayer and Johson ＆ Johnson's cooperative research and development.The medicine is the efficient oxazolidone obtained by high flux screening
Class FXa inhibitor is screened as lead compound, then in a series of oxazolidinones obtained from derivative optimization, is most passed through afterwards
Pharmacodynamics, pharmacokinetics etc. are investigated and turn into clinical candidate.It is clinical pass through for III phase at present, in September in 2008 15 days and October 1
Day obtains listing approval in Canada and European Union respectively.29 countries including including China are approved listing, for pre-
The formation of VTE and pulmonary embolism after anti-adult patients hip joint and replacement knee in arthroplasty.In theory, security
Better than conventional all of anti-coagulants.In July, 2011 is ratified to list by U.S. FDA, while two grades in Chinese patients with deep venous thrombosis pre-
There is certain therapeutic effect in the fields such as anti-, treatment auricular fibrillation and acute coronary syndrome.Razaxaban passes through high selection
Property directly suppress Xa factor and reach blood coagulation resisting function, compared with traditional anticoagulation medicine, with it is convenient to take, work rapid, peace
The features such as property is high entirely.
The route document of synthesis razaxaban has 40 at present, and now 8 main synthetic routes are summarized as follows：
Tri- patents of WO2013053739A1, US7157456 and US7351823 all refer to important intermediate 4- { 4- [(5S) -5- (amino
Methyl) -2- oxo -1,3- oxazolidine -3- bases] phenyl } morpholine -3- ketone (intermediate 3).WO2013053739A1 (route such as formulas
1) patent is with 4- (4- aminophenyls) morpholine -3- ketone and (S)-N- glycidol phthalimides as initiation material, through taking
Generation, cyclization is eliminated, into salt, finally replace and target product, the route is mainly intermediate purified；
US7157456 patents are reacted due to the intermediate 3 for directly being obtained using reaction, and the target product purity for obtaining is low, finally
Purified using column chromatography, should not be used in industrialized production, US7351823 is then to purify intermediate 3 and inorganic acids
Down react again afterwards, although target product purity has some improvement, but end-product optimal purity less than 94%, be not inconsistent still
The requirement of composite medicine purity, WO2013053739A1 patents are based on this, and intermediate 3 is purified, and purification process is
Intermediate 3 through obtaining first into salt, is then reacted with organic acid (oxalic acid, malonic acid), by trial series acid into salt
React again afterwards, the purified rear purity of product can reach more than 99.9% requirement, and control the generation of partial impurities.This route
It is disadvantageous in that in reacting and uses raw material CDI, this raw material is difficult to control due to that can decompose in reaction, and final step replaces very
It is possible to that dibasic impurity can be produced.
WO2013105100 (route such as formula 2) is to Rivaroxaban intermediate (R)-(2- oxos-3- (4- (3-oxomorpholins
Base) phenyl) oxazolidine -5- bases) and methyl butyrate (intermediate 3') synthesis compare comprehensively synthesis description.Initiation material
4- (4- aminophenyls) morpholine -3- ketone obtains intermediate 3' from cyclization after different substitution reagent reactings respectively, intermediate 3' with
There is substitution reaction with benzylamine again after p-methyl benzenesulfonic acid substitution, finally obtain target with the substitution of 5- chlorothiophene -2- formyl chlorides, reduction
Product.The advantage of this route (such as following formula) is that (4- (dislike by 5- ((benzylamino) methyl) -2- oxos due to intermediate (S) -4-
Oxazolidine -3- bases) phenyl) morpholine -3- ketone amino on a hydrogen replaced by benzyl, then taken with 5- chlorothiophene -2- formyl chlorides
Dai Shike avoids on amino two hydrogen by the 5- chlorothiophene simultaneously-substituted possibility of -2- formyl chlorides.But final step palpus Deprotection,
Now need to use cake carbon pressure reduction, cost operates more complicated than larger after pressurization, industrialized production security risk adds
Greatly, the route of this report low yield more long in addition, impurity obviously can increase, and operate also more complicated.
WO2012051692A1 (route such as formula 3) with 4- (4- aminophenyls) morpholine -3- ketone and chloromethyloxirane and
(R)-(-)-glycidol chloro thing is initiation material, successively experiences substitution reaction, and nucleophilic addition, substitution is acylated, last cyclization
Deprotection obtains target product simultaneously, and gross production rate is 34%.This route low yield, supplier is few for raw material methylchloroformate in the market
It is difficult to obtain, additionally, the 5th step needs column chromatography, it is difficult to carry out industrialized production.
The synthetic route of WO2012159992 (route such as formula 4) patent report is with 4- (4- aminophenyls) morpholine -3- ketone
It is initiation material with benzyl chloroformate, by substitution, cyclization, then replaces and eliminate four steps and obtain target product.This route it is excellent
Point is gross production rate higher, and reaction condition is gentleer, and gross production rate is 70-85%, but due to using tert-butyl lithium in reaction, operation
Numerous and diverse, cost is also higher, and industrialized production acquires a certain degree of difficulty.
Patent WO2013098833A2 is first adjacent to raw material 4- (4- aminophenyls) morpholine -3- ketone and (S)-N- glycidols
BIDA is synthesized (such as formula 5), then by substitution, cyclization and elimination, then replace obtain target product, product
It is heat-treated into again with methanol after salt with 50% hydrochloric acid solution, is obtained the razaxaban hydrochloride of purity 99.98%, the patent
The middle formyl chloride of 5- chlorothiophenes -2 is acylated with thionyl chloride by 5- chlor-2-thiophenecar-boxylic acids and obtained.This patent is numerous and diverse due to post-processing, place
The rate of recovery of gross production rate and product does not specifically give data after reason, it is difficult to assess its industrial value, additionally, for 4- (4- ammonia
Base phenyl) morpholine -3- ketone, (S)-N- glycidols phthalimide and the formyl chloride of 5- chlorothiophenes -2 can be purchased from the market
Can buy, if synthesis is relatively time consuming laborious, and there is a possibility that dopant species increase.
EP2354128 and WO2011098501A1 respectively with 5- chlorothiophene -2- formyl chlorides and 4- (4- aminophenyls) morpholine -
3- ketone is initiation material (formula 6), the former with (S) -3- amino -1,2-PD substitution after with p-methyl benzenesulfonic acid cyclization again with 4-
(4- aminophenyls) morpholine -3- ketone replaces, and last cyclization obtains target product, and the latter obtains isonitrile and directly exists with surpalite reaction
Tributyl phosphoxide effect is lower and the substitution of 5- chlorothiophene -2- formyl chlorides obtains target product.On razaxaban in two patents
Synthesis also can by (S) -3- amido-1,2-propanediols elder generation amino substitution again with p-methyl benzenesulfonic acid reaction with 4- (4- aminophenyls)
Cyclization obtains target product to morpholine -3- ketone direct reaction again.First route is due to all using surpalite or class in two patents
Like thing, operation is more complicated, and raw material tributyl phosphoxide price is higher in addition, and market sale is less to be difficult to obtain, it is difficult to realize work
Industry metaplasia is produced, and Article 2 route low yield, product purity difference is difficult to reach for requirements for pharmaceuticals.
WO200406088 is as initiation material (formula 6), first with (S) -3- amino -1,2- third with 5- chlorothiophene -2- formyl chlorides
There is substitution reaction, then bromo in diol hydrochloride, cyclization obtains mesh after bromo-derivative and the substitution of 4- (4- aminophenyls) morpholine -3- ketone
Mark product, gross production rate is 34%.This route low yield, additionally, due to as above-mentioned reaction, using raw material (S) -3- amino -1,
2- propanediol hydrochlorides, sell in the raw materials market and are difficult to obtain less, and price is unfavorable for industrialized production.
The content of the invention
The purpose of the present invention is directed to razaxaban raw material and is difficult to preserve, or byproduct of reaction is more, or purity is difficult to reach
It is required that, or post-processing operation it is numerous and diverse the problems such as, there is provided a kind of new preparation method of razaxaban.
The purpose of the present invention can be reached by following measures：
A kind of preparation method of razaxaban, it comprises the following steps：
The present invention is first with 4- (4- aminophenyls) morpholine -3- ketone and (R)-(-)-glycidol chloro thing as initiation material
Amino replaces, and substituent and phthalimide are reacted, and the cyclization in the presence of Boc acid anhydrides, deaminizating is protected and organic acid
Target product is obtained after into salt with the reaction of 5- chlorothiophene -2- formyl chlorides again.The course of reaction of each step described below.
(1) synthesis of (R) -4- (4- (3- chlorine-2-hydroxyls propylcarbamic) phenyl) morpholine -3- ketone：Compound 2 and compound
3 react in alcoholic solvent, obtain compound 4.A kind of reaction equation is as follows：
In step (1), alcoholic solvent is selected from one or more in ethanol, methyl alcohol, isopropanol；Its reaction temperature is 40-
85℃；Compound 2 is 1 with the mol ratio of compound 3:1.1-1.6.A kind of preferred scheme is：4- (4- aminophenyls) morpholine -3-
Room temperature reaction 2h obtains white crystals intermediate 4 about 80 after ketone and R- epoxychloropropane are heated to reflux 8h in alcoholic solventg。
(2) (R) -2- (2- hydroxyls -3- (4- (3- oxo-morpholines) phenyl amino) propyl group) isoindoline -1,3- diketone
Synthesis：Compound 4 first acts on into carbonium ion with alkali, then is reacted in intensive polar solvent with compound 5, obtains compound 6.One
Plant reaction equation as follows：
In step (2), compound 4 first acts on into carbonium ion with aqueous slkali at 20-70 DEG C, and its reaction dissolvent is selected from
One or more in dichloromethane, n-hexane；The carbonium ion is 70-110 DEG C with the reaction temperature of compound 5.Wherein
Alkali be selected from NaOH, potassium hydroxide, sodium alkoxide, sodium carbonate, potassium carbonate in one or more；The intensive polar solvent is selected from
One kind in N,N-dimethylformamide, dimethyl sulfoxide, 1,4- dioxane.A kind of preferred scheme is：(R) ((3- is chloro- for 4- for -4-
2- hydroxypropylaminos) phenyl) morpholine -3- ketone first acted on into after carbonium ion with potassium phthalimide in strong pole with alkali
Heating response 3h obtains product 6 in property solvent.
(3) (S) -2- ((2- oxos -3- (4- (3- oxo-morpholines) phenyl) oxazolidine -5- bases) methyl) isoindoline -
The synthesis of 1,3- diketone：Compound 6 reacts with di-tert-butyl dicarbonate under catalyst action, obtains compound 7.One kind reaction
Formula is as follows：
In step (3), the catalyst is selected from sodium methoxide, caustic alcohol or sodium hydride；Synthesize the reaction temperature of compound 7
It is 60-120 DEG C, preferably 105-120 DEG C.A kind of preferred scheme is as follows：(R) -2- (2- hydroxyls -3- (4- (3- oxo-morpholines) benzene
Base amino) propyl group) isoindoline -1,3- diketone is heated to reflux with di-tert-butyl dicarbonate under catalyst action, by a point water
The off-white color crystal of compound 7 is obtained after the alcohol 48h of device receiving generation.The dimethyl dicarbonate fourth of compound 6 and two is used in this step
Ester reacts, and di-tert-butyl dicarbonate is stable in properties, and consumption is few, and compound 6 only need to be 1 with the mol ratio of di-tert-butyl dicarbonate：1
~3 or so, it is 1：1~2 can be reacted, and it is 1：1~1.3 can reach preferably reaction effect.Can in this reaction
Not use reaction dissolvent or reaction dissolvent to be selected from toluene, it is preferred to use toluene is used as solvent, and experiment finds, normal using other
Rule solvent can cause the reaction cannot to carry out or be greatly reduced reaction yield.
(4) synthesis of (S) -4- (4- (5- (amino methyl) -2- oxo oxazolidine -3- bases) phenyl) morpholine -3- ketone：Chemical combination
Thing 7 reacts with methylamine solution in alcoholic solvent, is acidified with acid after reaction, obtains compound 8.A kind of reaction equation is as follows.
In the reaction of synthesis compound 8, the alcoholic solvent is selected from methyl alcohol or ethanol, and its reaction temperature is 30-80 DEG C, institute
Acid is stated selected from the one kind in hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, malonic acid, formic acid, pH value 2-3 is acidified to acid.It is a kind of preferred
Scheme is：(S) -2- ((2- oxos -3- (4- (3-oxomorpholino) phenyl) oxazolidine -5- bases) methyl) isoindoline -1,
3- diketone and methylamine solution heating response in alcoholic solvent, pH to 2.5 or so is adjusted after 1h with acid solution, is filtrated to get respective acids
The white solid salt of compound 7.
(5) the chloro- N- of 5- (((5S) -2- oxos -3- (4- (3- oxomorpholin -4- bases) phenyl) -1,3- oxazoline -5- bases)
Methyl) thiophene-2-carboxamide derivatives synthesis：After compound 8 dissociates under alkali effect, reacted with compound 9, obtain compound 1；Enter
One step, compound 8 dissociates in alkali lye and organic solvent, then reacts prepare compound 1 with compound 9 in a solvent；One
Plant reaction equation as follows.
In step (5), alkali is selected from the hydroxide such as NaOH, potassium hydroxide of alkali metal；The carbonate of alkali metal,
Such as sodium carbonate, potassium carbonate；Amine organic base, such as triethylamine, and alkali and the consumption molar ratio range of compound 8 are 1:1 to 2:1.
The organic solvent is selected from acetone；Solvent when being reacted with compound 9 is selected from toluene, and reaction temperature is 40-60 DEG C.It is a kind of preferred
Scheme is：(S) -4- (4- (5- (amino methyl) -2- oxo oxazolidine -3- bases) phenyl) morpholine -3- ketone dissociates in alkali systems
Afterwards razaxaban crude product is can obtain with the substitution of 5- chlorothiophene -2- formyl chlorides.Yield is that 90%, HPLC is 99.64%.Crude product is used
70% acetic acid 200mL backflow 1h, the white crystalline powder sterling that HPLC is 99.90% is filtrated to get after being cooled to room temperature.
The present invention is main with 4- (4- aminophenyls) morpholine -3- ketone and (R)-(-)-glycidol chloro thing as initiation material
Will be to important intermediate (S) -2- ((2- oxos -3- (4- (3- oxo-morpholines) phenyl) oxazolidine -5- bases) methyl) iso-indoles
The synthesis of quinoline -1,3- diketone has carried out process modification.Raw material of the present invention is cheap and easily-available so that reaction cost reduction, reaction condition
Stabilization, simple to operate, yield is high, and post processing is simple, and the crude product purity obtained after reaction is high, it is easy to which purifying obtains the profit of high-purity
Cut down husky class, HPLC>99.6%, more suitable for industrialized production.The present invention is that amino replaces through five step reactions, and chloro, cyclization disappears
Remove, replace and obtain target product, gross production rate 66.0% or so, purity is 99.89%.
Specific embodiment
Embodiment 1
Step one：60g (0.31mol) 4- (4- aminophenyls) morpholine -3- ketone and 420mL isopropyls are added in 1L there-necked flasks
Alcohol, is heated to reflux starting that 39.1mL (0.499mol) R- epoxychloropropane is added dropwise in batches, and 8h drops finish, and stopping is heated to room temperature reaction
2h, filtering, solid isopropanol 2X60mL is washed twice, and 50 DEG C of vacuum drying 12h obtain the about 80g of white crystals intermediate 4
(90%, yield, similarly hereinafter), mp.=136-137.2 DEG C.
Step 2：During above-mentioned 57.6g intermediates 4 and 400mL dichloromethane put into 1L there-necked flasks, it is added dropwise at room temperature
The alkali lye that 17.8gNaOH and 60mL water is configured to, 60mL saturated common salts are used in organic layer 120mL washings again after 6h is stirred at room temperature
Washing, organic layer anhydrous sodium sulfate drying, filtering is concentrated to 180mL liquid, adds 360mL n-hexanes to be heated to reflux
30min, system is stirred for 2h after being cooled to room temperature, filtering, filter cake dichloromethane and n-hexane (1:3) wash, filter cake vacuum is done
Dry 12h obtains off-white color crystal 48.2g.
In above-mentioned solid 48g (0.17mol) and 240mL1,4- dioxane input 500mL there-necked flasks, stirring is lower to be added
34.4g (0.19mol) potassium phthalimide, system is progressively heated at 100 DEG C, stirs 3h, is cooled to room temperature, adds
60mL water stirs 15min, and filtering, filter cake is washed with 2X100mL, obtains 50 DEG C of vacuum drying 10h of white crystal and obtains 60.2gization
The mp.=211.7-211.9 DEG C of of compound 6 (92%)
Step 3：60g (0.25mol) compound 6 and 400mL toluene are put into the dry there-necked flasks of 500mL, stirring
Lower addition 62.3g (0.3mol) di-tert-butyl dicarbonate (Boc acid anhydrides) and 0.6g sodium hydrides, system backflow 48h, TLC detect to
Raw material reaction completely, steams off-white color crystal 47.4g (93.2%) mp.=that partial solvent is recrystallized to give compound 7
220.7-221.3℃。
Step 4：40g (0.09mol) compound 7, the methylamine solution and 1L methyl alcohol of 36.7g40% (0.42mol) are put into
In the there-necked flask of 2L, system is warmed up to the mixed solution drop of 65 DEG C of heating 1h, 62.2g (0.49mol) oxalic acid and 200mL methyl alcohol
The pH until system is added in system for 2-3 stops being added dropwise, now there are a large amount of solids to separate out in system, system is heated to reflux 1h,
Room temperature is cooled to, is filtered, filter cake is washed with methyl alcohol, 50 DEG C of vacuum drying obtain 34.2g compounds 8 (95.1%), more than 250 DEG C points
Solution.
Step 5：8.25g (0.078mol) sodium carbonate, 90mL water, 24g (0.06mol) compound 8, and 180mL acetone point
In not putting into 500mL there-necked flasks, system is cooled to 8-10 DEG C, 22.8g (0.12mol) 5- chlorothiophene -2- formyl chlorides and
The mixed solution of 72mL toluene is slowly dropped in system, and drop finishes, and system is gradually heating to 50-55 DEG C of stirring 1h, and system is cold again
But room temperature is arrived, is filtered, 80 DEG C of vacuum drying of filter cake obtain 24.6g products, and HPLC is 99.64%.Crude product is tied again with 200mL acetic acid
Crystalline substance, is filtrated to get white crystalline powder 22.1g (yield 90%), and HPLC is 99.90%, mp.=229.2-230.2 DEG C,
[α]D 25=-39.5 ° (c=0.01, DMSO).
Embodiment 2
Step one：Added in 1L there-necked flasks 30g (0.156mol) 4- (4- aminophenyls) morpholine -3- ketone and 420mL without
Water-ethanol, is heated to reflux starting that 23.1g (0.25mol) R- epoxychloropropane is added dropwise in batches, and 8h drops finish, and it is anti-that stopping is heated to room temperature
2h is answered, is filtered, solid absolute ethyl alcohol 2X60mL is washed twice, 50 DEG C of vacuum drying 12h obtain white crystals intermediate 4 about
38.2g (86%), mp.=136-137.2 DEG C.
Step 2：During above-mentioned 38g intermediates 4 and 400mL dichloromethane put into 1L there-necked flasks, it is added dropwise at room temperature
The alkali lye that 11.7gKOH and 60mL water is configured to, 60mL saturated common salts are used in organic layer 100mL washings again after 6h is stirred at room temperature
Washing, organic layer anhydrous sodium sulfate drying, filtering is concentrated to 180mL liquid, adds 360mL n-hexanes to be heated to reflux
30min, system is stirred for 2h after being cooled to room temperature, filtering, filter cake dichloromethane and n-hexane (1:3) wash, filter cake vacuum is done
Dry 12h obtains off-white color crystal 31.8g.
In above-mentioned solid 31.8g (0.11mol) and 200mL DMFs input 500mL there-necked flasks, stirring
Lower addition 22.7g (0.126mol) potassium phthalimide, system is progressively heated at 100 DEG C, stirs 3h, is cooled to room
Temperature, adds 60mL water stirring 15min, filtering, filter cake to be washed with 2X100mL, obtains 50 DEG C of vacuum drying 10h of white crystal and obtains
The mp.=211.7-211.9 DEG C of of 47.5g compounds 6 (90%)
Step 3：45g (0.114mol) compound 6 and 300mL toluene are put into the dry there-necked flasks of 500mL, are stirred
Mix lower addition 46.7g (0.225mol) di-tert-butyl dicarbonate (Boc acid anhydrides) and 1g sodium methoxides, system backflow 48h, TLC detection
To raw material reaction completely, off-white color crystal 46g (86%) that partial solvent is recrystallized to give compound 7, mp.=220.7- are steamed
221.3℃。
Step 4：40g (0.09mol) compound 7, the methylamine solution and 1L methyl alcohol of 36.7g40% (0.42mol) are put into
In the there-necked flask of 2L, system is warmed up to 65 DEG C of heating 1h, 20% aqueous hydrochloric acid solution is added drop-wise in system until the pH of system
For 2-3 stops being added dropwise, now there are a large amount of solids to separate out in system, be cooled to room temperature, filter, filter cake is washed with methyl alcohol, 50 DEG C of vacuum
It is dried to obtain 29.6g compounds 8 (95.1%), more than 250 DEG C decomposition.
Step 5：10.8g (0.078mol) potassium carbonate, 90mL water, 19.7g (0.06mol) compound 8, and 180mL acetone
In putting into 500mL there-necked flasks respectively, system is cooled to 8-10 DEG C, 21.7g (0.12mol) 5- chlorothiophene -2- formyl chlorides and
The mixed solution of 72mL toluene is slowly dropped in system, and drop finishes, and system is gradually heating to 50-55 DEG C of stirring 1h, and system is cold again
But room temperature is arrived, is filtered, 80 DEG C of vacuum drying of filter cake obtain 26g products, and HPLC is 99.64%.Crude product is tied again with 200mL acetic acid
Crystalline substance, is filtrated to get white crystalline powder 24g (yield 83%), and HPLC is 99.90%, mp.=229.2-230.2 DEG C, [α]D 25
=-39.5 ° (c=0.01, DMSO).
Embodiment 3
Step one：20g (0.104mol) 4- (4- aminophenyls) morpholine -3- ketone and 200mL first are added in 1L there-necked flasks
Alcohol, is heated to reflux starting that 14.2g (0.15mol) R- epoxychloropropane is added dropwise in batches, and 8h drops finish, and stopping is heated to room temperature reaction
2h, filtering, solid methyl alcohol 2X60mL is washed twice, and 50 DEG C of vacuum drying 12h obtain the about 24.6g of white crystals intermediate 4
(83%), mp.=136-137.2 DEG C.
Step 2：During above-mentioned 20g intermediates 4 and 200mL dichloromethane put into 1L there-necked flasks, it is added dropwise at room temperature
The alkali lye that 6gNaOH and 20mL water is configured to, 30mL saturated aqueous common salts are used in organic layer 50mL washings again after 6h is stirred at room temperature
Wash, organic layer anhydrous sodium sulfate drying, filter, be concentrated to 80mL liquid, add 360mL n-hexanes to be heated to reflux 30min, body
System is stirred for 2h after being cooled to room temperature, filters, filter cake dichloromethane and n-hexane (1:3) wash, filter cake vacuum drying 12h obtains class
White crystal 16.7g.
In above-mentioned solid 16.7g (0.058mol) and 100mL DMFs input 250mL there-necked flasks, stir
Lower addition 11.9g (0.064mol) potassium phthalimide is mixed, system is progressively heated at 100 DEG C, stirs 3h, is cooled to room
Temperature, adds 30mL water stirring 15min, filtering, filter cake to be washed with 2X50mL, obtains 50 DEG C of vacuum drying 10h of white crystal and obtains
The mp.=211.7-211.9 DEG C of of 31.6g compounds 6 (90%)
Step 3：30g (0.076mol) compound 6 and 200mL toluene are put into the dry there-necked flasks of 500mL, are stirred
Mix lower addition 33g (0.152mol) di-tert-butyl dicarbonate (Boc acid anhydrides) and 0.8g caustic alcohols, system backflow 48h, TLC detection
To raw material reaction completely, off-white color crystal 25.9g (81%) that partial solvent is recrystallized to give compound 7, mp.=are steamed
220.7-221.3℃。
Step 4：20g (0.047mol) compound 7, methylamine solution and 250ml the methyl alcohol input of 15g40% (0.19mol)
To in the there-necked flask of 500ml, system is warmed up to 65 DEG C of heating 1h, and 30% aqueous sulfuric acid is added drop-wise in system until system
PH stop being added dropwise for 2-3, now there are a large amount of solids to separate out in system, be cooled to room temperature, filter, filter cake is washed with methyl alcohol, 50 DEG C
Vacuum drying obtains 17g compounds 8 (92%), more than 250 DEG C decomposition.
Step 5：9g (0.089mol) triethylamine, 17g (0.042mol) compound 8 and 250mL tetrahydrofurans put into respectively
To in 500mL there-necked flasks, system is cooled to 8-10 DEG C, 9g (0.05mol) 5- chlorothiophene -2- formyl chlorides and 50mL tetrahydrofurans
Mixed solution be slowly dropped in system, drop finishes, and system is gradually heating to 40 DEG C of stirring 1h, and system is cooled back to room temperature, mistake
Filter, 80 DEG C of vacuum drying of filter cake obtain 18g products, and HPLC is 99.64%.Crude product 150mL Recrystallisation from acetic acid, is filtrated to get white
Color crystalline powder 16g (yield 85%), HPLC is 99.90%, mp.=229.2-230.2 DEG C, [α]D 25=-39.5 ° of (c=
0.01,DMSO)。
Claims (8)
1. a kind of preparation method of razaxaban, it is characterised in that it comprises the following steps：
Wherein, compound 6 exists under catalyst action with di-tert-butyl dicarbonate in 105-120 DEG C and reaction dissolvent toluene
Lower reaction, obtains compound 7, and the catalyst is selected from sodium methoxide, caustic alcohol or sodium hydride, the dimethyl dicarbonate fourth of compound 6 and two
The mol ratio of ester is 1：1~3；Compound 7 reacts with methylamine solution in alcoholic solvent, is acidified with acid after reaction, obtains compound
8；Wherein HX is acid.
2. preparation method according to claim 1, it is characterised in that compound 2 reacts with compound 3 in alcoholic solvent, obtains
To compound 4；The alcoholic solvent is selected from one or more in ethanol, methyl alcohol, isopropanol；Its reaction temperature is 40-85 DEG C；Change
Compound 2 is 1 with the mol ratio of compound 3:1.1-1.6.
3. preparation method according to claim 1, it is characterised in that compound 4 first acts on into carbonium ion with alkali, then with
Compound 5 reacts in intensive polar solvent, obtains compound 6；The intensive polar solvent is selected from N,N-dimethylformamide, diformazan
One kind in sulfoxide, 1,4- dioxane.
4. preparation method according to claim 3, it is characterised in that in the reaction of synthesis compound 6, the alkali is selected from
One or more in NaOH, potassium hydroxide, sodium alkoxide, sodium carbonate, potassium carbonate.
5. preparation method according to claim 3, it is characterised in that in the reaction of synthesis compound 6, compound 4 first with
Aqueous slkali acts on into carbonium ion at 20-70 DEG C, and its reaction dissolvent is selected from one or more in dichloromethane, n-hexane；
The carbonium ion is 70-110 DEG C with the reaction temperature of compound 5.
6. preparation method according to claim 1, it is characterised in that in the reaction of synthesis compound 8, the alcoholic solvent
Selected from methyl alcohol or ethanol, its reaction temperature is 30-80 DEG C, and the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, malonic acid, ant
One kind in acid, pH value 2-3 is acidified to acid.
7. preparation method according to claim 1, it is characterised in that after compound 8 dissociates under alkali effect, with compound 9
Reaction, obtains compound 1；Wherein alkali is selected from alkali metal hydroxide, alkali carbonate or amine organic base, and alkali and chemical combination
The consumption molar ratio range of thing 8 is 1:1 to 2:1；Solvent when being reacted with compound 9 is selected from toluene, tetrahydrofuran, reaction temperature
It is 40-60 DEG C.
8. preparation method according to claim 7, it is characterised in that compound 8 dissociates in alkali lye and organic solvent, so
React prepare compound 1 with compound 9 in a solvent afterwards；Wherein alkali is selected from NaOH, potassium hydroxide, sodium carbonate, potassium carbonate
Or triethylamine.
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| CN102311400A (en) * | 2010-06-29 | 2012-01-11 | 翔真生物科技股份有限公司 | Method for preparing 5(S)-aminomethyl-3-aryl-2-oxazolidinone |
| WO2012051692A1 (en) * | 2010-10-18 | 2012-04-26 | Apotex Pharmachem Inc. | Processes for the preparation of rivaroxaban and intermediates thereof |
| CN102844309A (en) * | 2009-04-28 | 2012-12-26 | 阿普泰克斯药物化学公司 | Processes for the preparation of rivaroxaban and intermediates thereof |
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102844309A (en) * | 2009-04-28 | 2012-12-26 | 阿普泰克斯药物化学公司 | Processes for the preparation of rivaroxaban and intermediates thereof |
| CN102311400A (en) * | 2010-06-29 | 2012-01-11 | 翔真生物科技股份有限公司 | Method for preparing 5(S)-aminomethyl-3-aryl-2-oxazolidinone |
| WO2012051692A1 (en) * | 2010-10-18 | 2012-04-26 | Apotex Pharmachem Inc. | Processes for the preparation of rivaroxaban and intermediates thereof |
| WO2013098833A2 (en) * | 2011-09-08 | 2013-07-04 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
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