A kind of preparation method of razaxabanTechnical 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 thrombosisTherapeutic effect.
Clinically usable anticoagulant includes unfractionated heparin (unfractionated heparin, UFH), low at presentMolecular heparin (low molecular weight heparin, LMWH), vitamin K antagon warfarin (warfarin) andPentasaccharide fondaparinux sodium (fondaparinux, Arixtra).
Heparin class material produces anticoagulation effect by cascading correlation factor interaction with various blood clottings, clinically mainlyAlso often limited the use of in inpatient or short-term (≤2wk) prevention phlebothrombosis bolt for short-term antithrombotic heparin class materialPlug 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 openThe 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 safetyProperty 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 studiedInhibitor plays key effect to research anticoagulant.Receive much concern member in oral Selective activation Xa factor inhibitorIt is Eliquis (Apixaban, trade name Eliquis), dabigatran, three new oral anti-coagulants of razaxaban.In EuropeApproval these three oral anticoagulants in, with current bone surgery after prevent venous thromboembolism standard regimens according to promiseHeparin 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 screeningClass FXa inhibitor is screened as lead compound, then in a series of oxazolidinones obtained from derivative optimization, is most passed through afterwardsPharmacodynamics, 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 1Day 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, securityBetter 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 selectionProperty directly suppress Xa factor and reach blood coagulation resisting function, compared with traditional anticoagulation medicine, with it is convenient to take, work rapid, peaceThe 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- (aminoMethyl) -2- oxo -1,3- oxazolidine -3- bases] phenyl } morpholine -3- ketone (intermediate 3).WO2013053739A1 (route such as formulas1) patent is with 4- (4- aminophenyls) morpholine -3- ketone and (S)-N- glycidol phthalimides as initiation material, through takingGeneration, 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, finallyPurified using column chromatography, should not be used in industrialized production, US7351823 is then to purify intermediate 3 and inorganic acidsDown react again afterwards, although target product purity has some improvement, but end-product optimal purity less than 94%, be not inconsistent stillThe requirement of composite medicine purity, WO2013053739A1 patents are based on this, and intermediate 3 is purified, and purification process isIntermediate 3 through obtaining first into salt, is then reacted with organic acid (oxalic acid, malonic acid), by trial series acid into saltReact again afterwards, the purified rear purity of product can reach more than 99.9% requirement, and control the generation of partial impurities.This routeIt 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 veryIt 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-oxomorpholinsBase) phenyl) oxazolidine -5- bases) and methyl butyrate (intermediate 3') synthesis compare comprehensively synthesis description.Initiation material4- (4- aminophenyls) morpholine -3- ketone obtains intermediate 3' from cyclization after different substitution reagent reactings respectively, intermediate 3' withThere is substitution reaction with benzylamine again after p-methyl benzenesulfonic acid substitution, finally obtain target with the substitution of 5- chlorothiophene -2- formyl chlorides, reductionProduct.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 chloridesDai 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 addsGreatly, 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 cyclizationDeprotection obtains target product simultaneously, and gross production rate is 34%.This route low yield, supplier is few for raw material methylchloroformate in the marketIt 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- ketoneIt is initiation material with benzyl chloroformate, by substitution, cyclization, then replaces and eliminate four steps and obtain target product.This route it is excellentPoint 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, operationNumerous 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- glycidolsBIDA is synthesized (such as formula 5), then by substitution, cyclization and elimination, then replace obtain target product, productIt is heat-treated into again with methanol after salt with 50% hydrochloric acid solution, is obtained the razaxaban hydrochloride of purity 99.98%, the patentThe 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, placeThe 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- ammoniaBase phenyl) morpholine -3- ketone, (S)-N- glycidols phthalimide and the formyl chloride of 5- chlorothiophenes -2 can be purchased from the marketCan 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 reactionTributyl phosphoxide effect is lower and the substitution of 5- chlorothiophene -2- formyl chlorides obtains target product.On razaxaban in two patentsSynthesis 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 patentsLike 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 workIndustry 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 chloridesThere is substitution reaction, then bromo in diol hydrochloride, cyclization obtains mesh after bromo-derivative and the substitution of 4- (4- aminophenyls) morpholine -3- ketoneMark 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 reachIt 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 materialAmino replaces, and substituent and phthalimide are reacted, and the cyclization in the presence of Boc acid anhydrides, deaminizating is protected and organic acidTarget 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 compound3 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- diketoneSynthesis：Compound 4 first acts on into carbonium ion with alkali, then is reacted in intensive polar solvent with compound 5, obtains compound 6.OnePlant 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 fromOne or more in dichloromethane, n-hexane；The carbonium ion is 70-110 DEG C with the reaction temperature of compound 5.WhereinAlkali be selected from NaOH, potassium hydroxide, sodium alkoxide, sodium carbonate, potassium carbonate in one or more；The intensive polar solvent is selected fromOne 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 alkaliHeating 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 reactionFormula is as follows：
In step (3), the catalyst is selected from sodium methoxide, caustic alcohol or sodium hydride；Synthesize the reaction temperature of compound 7It 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) benzeneBase amino) propyl group) isoindoline -1,3- diketone is heated to reflux with di-tert-butyl dicarbonate under catalyst action, by a point waterThe 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 stepEster 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 reactionNot 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 otherRule 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 combinationThing 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, instituteAcid 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 preferredScheme 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 acidsThe 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；EnterOne step, compound 8 dissociates in alkali lye and organic solvent, then reacts prepare compound 1 with compound 9 in a solvent；OnePlant 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 preferredScheme is：(S) -4- (4- (5- (amino methyl) -2- oxo oxazolidine -3- bases) phenyl) morpholine -3- ketone dissociates in alkali systemsAfterwards 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 used70% 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 materialWill be to important intermediate (S) -2- ((2- oxos -3- (4- (3- oxo-morpholines) phenyl) oxazolidine -5- bases) methyl) iso-indolesThe 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 conditionStabilization, 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-purityCut 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 disappearsRemove, 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 flasksAlcohol, 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 reaction2h, 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 temperatureThe 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 temperatureWashing, organic layer anhydrous sodium sulfate drying, filtering is concentrated to 180mL liquid, adds 360mL n-hexanes to be heated to reflux30min, 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 doneDry 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 added34.4g (0.19mol) potassium phthalimide, system is progressively heated at 100 DEG C, stirs 3h, is cooled to room temperature, adds60mL water stirs 15min, and filtering, filter cake is washed with 2X100mL, obtains 50 DEG C of vacuum drying 10h of white crystal and obtains 60.2gizationThe 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, stirringLower addition 62.3g (0.3mol) di-tert-butyl dicarbonate (Boc acid anhydrides) and 0.6g sodium hydrides, system backflow 48h, TLC detect toRaw material reaction completely, steams off-white color crystal 47.4g (93.2%) mp.=that partial solvent is recrystallized to give compound 7220.7-221.3℃。
Step 4：40g (0.09mol) compound 7, the methylamine solution and 1L methyl alcohol of 36.7g40% (0.42mol) are put intoIn 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 alcoholThe 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 pointsSolution.
Step 5：8.25g (0.078mol) sodium carbonate, 90mL water, 24g (0.06mol) compound 8, and 180mL acetone pointIn not putting into 500mL there-necked flasks, system is cooled to 8-10 DEG C, 22.8g (0.12mol) 5- chlorothiophene -2- formyl chlorides andThe 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 againBut 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 acidCrystalline 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]D25=-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 withoutWater-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 temperature2h is answered, is filtered, solid absolute ethyl alcohol 2X60mL is washed twice, 50 DEG C of vacuum drying 12h obtain white crystals intermediate 4 about38.2g (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 temperatureThe 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 temperatureWashing, organic layer anhydrous sodium sulfate drying, filtering is concentrated to 180mL liquid, adds 360mL n-hexanes to be heated to reflux30min, 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 doneDry 12h obtains off-white color crystal 31.8g.
In above-mentioned solid 31.8g (0.11mol) and 200mL DMFs input 500mL there-necked flasks, stirringLower addition 22.7g (0.126mol) potassium phthalimide, system is progressively heated at 100 DEG C, stirs 3h, is cooled to roomTemperature, 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 obtainsThe 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 stirredMix lower addition 46.7g (0.225mol) di-tert-butyl dicarbonate (Boc acid anhydrides) and 1g sodium methoxides, system backflow 48h, TLC detectionTo raw material reaction completely, off-white color crystal 46g (86%) that partial solvent is recrystallized to give compound 7, mp.=220.7- are steamed221.3℃。
Step 4：40g (0.09mol) compound 7, the methylamine solution and 1L methyl alcohol of 36.7g40% (0.42mol) are put intoIn 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 systemFor 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 vacuumIt 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 acetoneIn putting into 500mL there-necked flasks respectively, system is cooled to 8-10 DEG C, 21.7g (0.12mol) 5- chlorothiophene -2- formyl chlorides andThe 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 againBut 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 acidCrystalline substance, is filtrated to get white crystalline powder 24g (yield 83%), and HPLC is 99.90%, mp.=229.2-230.2 DEG C, [α]D25=-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 flasksAlcohol, 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 reaction2h, 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 temperatureThe 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 temperatureWash, organic layer anhydrous sodium sulfate drying, filter, be concentrated to 80mL liquid, add 360mL n-hexanes to be heated to reflux 30min, bodySystem 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 classWhite crystal 16.7g.
In above-mentioned solid 16.7g (0.058mol) and 100mL DMFs input 250mL there-necked flasks, stirLower addition 11.9g (0.064mol) potassium phthalimide is mixed, system is progressively heated at 100 DEG C, stirs 3h, is cooled to roomTemperature, 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 obtainsThe 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 stirredMix lower addition 33g (0.152mol) di-tert-butyl dicarbonate (Boc acid anhydrides) and 0.8g caustic alcohols, system backflow 48h, TLC detectionTo raw material reaction completely, off-white color crystal 25.9g (81%) that partial solvent is recrystallized to give compound 7, mp.=are steamed220.7-221.3℃。
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 systemPH 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 CVacuum 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 respectivelyTo in 500mL there-necked flasks, system is cooled to 8-10 DEG C, 9g (0.05mol) 5- chlorothiophene -2- formyl chlorides and 50mL tetrahydrofuransMixed 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, mistakeFilter, 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 whiteColor crystalline powder 16g (yield 85%), HPLC is 99.90%, mp.=229.2-230.2 DEG C, [α]D25=-39.5 ° of (c=0.01,DMSO)。