CN105693746B - The Preparation Method And Their Intermediate of oxazolidinone compounds - Google Patents

The Preparation Method And Their Intermediate of oxazolidinone compounds Download PDF

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CN105693746B
CN105693746B CN201510323912.7A CN201510323912A CN105693746B CN 105693746 B CN105693746 B CN 105693746B CN 201510323912 A CN201510323912 A CN 201510323912A CN 105693746 B CN105693746 B CN 105693746B
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solvent
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CN105693746A (en
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左应林
张瑾
郑金付
文亮
王晓军
张英俊
张健存
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

The invention discloses a kind of preparation methods of Xin oxazolidinone compounds, while also disclosing the important intermediate compound that the preparation method is related to.Preparation method raw material provided by the present invention is cheap, and mild condition is easy to operate, safely controllable, and total recovery is high, is suitble to industrial production.

Description

The Preparation Method And Their Intermediate of oxazolidinone compounds
Technical field
The present invention relates to medicinal chemistry art, Ju bodies She is Ji the chloro- N- of oxazolidinone compounds 5- (((3S, 3aS) -1- oxygen Generation -7- (3- oxo-morpholines) -1,3,3a, and 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methyl) thiophene - The Preparation Method And Their Intermediate of 2- formamides.
Background technology
Thrombotic disease, that is, thrombotic disease, refer to the lumen of vessels caused by thrombus it is narrow with occlusion, make main organs Ischemic occurs and blocks and cause the various diseases of dysfunction, belongs to cardiovascular and cerebrovascular disease.Cardiovascular and cerebrovascular disease has become entirely Ball causes a disease, one of the highest cause of disease of lethality.And main inducing of the thrombotic disease as cardiovascular and cerebrovascular disease, incidence are in increase year by year Add trend.
Blood coagulation Xa factor is a kind of serine protease, can be fibrin ferment by conversion of prothrombin, be one and great face The anticoagulation target spot of bed value has consequence in control fibrin ferment forms and activate blood coagulation waterfall.Blood coagulation Xa factor Positioned at the joint of inside and outside source property coagulation pathway, the major catalytic II factors are factor converting to IIa.Existing for coagulation process Bio signal amplifies, and a blood coagulation Xa factor inhibitor can inhibit the physiologic effect of 138 factor molecules, therefore, leads to It crosses and inhibits blood coagulation Xa factor that can effectively inhibit the generation of fibrin ferment and the formation of thrombus.Blood coagulation Xa factor it is effective and special Inhibitor potential valuable therapeutic agent can be used as to treat thromboembolic disorders.
The Shou Gong chloro- N- of Kai oxazolidinone compounds 5- (((3S, the 3aS) -1- of patent application WO 2014/110971 Oxo -7- (3- oxomorpholin -4- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methyl) Thiophene-2-carboxamide derivatives, shown in structure such as formula (I).The compound has strong anticoagulation Xa factor activity, can be used as anticoagulation Drug is diseases related for treating thrombus.
Above-mentioned patent also discloses the preparation method of compound shown in formula (I)：(3R, 3aS) -7- substitutions -3- (((tertiary fourths Base dimethyl silicon substrate) oxygen) methyl) -3a, 4- dihydrobenzos [b] oxazole [3,4-d] [1,4] (3H) -one of oxazine -1 and 3- morpholones Coupling reaction occurs in metal palladium catalyst and under the action of containing Phosphine ligands, products therefrom is through deprotection base, sulfonylation, adjacent benzene Intermediate (I-a) (compound shown in formula (I-a)), finally, intermediate (I- are obtained after diformyl substitution, ammonolysis four-step reaction A) condensation reaction occurs with 5- chlorothiophene -2- formyl chlorides, obtains compound shown in formula (I).
In the preparation method, the yield of coupling reaction is relatively low, and the metal palladium catalyst price used is high, is unsuitable for amplifying Production.In addition, intermediate (I-a) that this method is prepared is not purified to be directly used in next step condensation reaction so that condensation The post-processing of reaction is difficult, and influences the yield of reaction.
Patent application WO 2015/043364 also discloses that compound shown in formula (I), preparation method, pharmaceutical composition and Its purposes as anti-coagulants in treating and preventing thrombotic disease.Wherein, same in preparation method disclosed in this application Sample is related to intermediate (I-a) and preparation method thereof：It is prepared in this after hydroxy activated, then through azide substitution, reduction reaction Mesosome.In the synthetic method, severe toxicity, explosive sodium azide reagent are used, experimental risk is high, is unfavorable for industrial life Production.
Invention content
The present invention relates to the preparation methods and its important intermediate of compound shown in formula (I), and this method is easy to operate, safety Controllably, and yield is high, is suitble to industrialized production.
Present invention relates particularly to the preparation methods of compound shown in formula (I)：(3R, 3aS) -7- substitutions -3- (((tertiary butyls two Methylsilyl) oxygen) methyl) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one after coupling reaction, It is deprotected and obtains (3R, 3aS) -3- (methylol) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [1, 4] oxazines -1 (3H) -one, then after hydroxy activated, substitution reaction, ammonolysis reaction, acidification obtains (3S, 3aS) -3- (amino first Base) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [salt (formula (II) of 1,4] oxazines -1 (3H) -one Shown compound), finally with 5- chlorothiophene -2- formyl chlorides occur condensation reaction, obtain the chloro- N- of target compound 5- (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, and 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) first Base) thiophene-2-carboxamide derivatives.
Wherein, HX is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or P-methyl benzenesulfonic acid.
In preparation method of the present invention, the coupling reaction has used copper catalyst, and price is compared with catalyzing by metal palladium Agent is low, and production cost can be reduced using copper catalyst；Meanwhile coupling reaction post-processing letter under the conditions of of the present invention Single, yield is high.The method of the invention, which uses first to activate, to be replaced again (for example, phthalyl or o-benzoyl sulfonyl take Generation), then hydroxyl, is converted into amido by the method for ammonolysis, is avoided using severe toxicity, explosive reagent, safer controllable.Meanwhile In ammonolysis reaction of the present invention, the obtained acidified method at salt of crude product obtains corresponding salt so that ammonolysis is anti- The post-processing answered is simpler, and has obtained the high midbody product of purity, is conducive to the control and production of impurity in reacting in next step The raising of rate；Also, obtained intermediate salt is easier to preserve.In the condensation reaction of final step, using mixed solvent into One step improves the yield of reaction；Crude product obtained by the reaction uses recrystallization purifying, easy to operate.Generally speaking, of the invention The preparation method raw material of offer is cheap, of low cost, easy to operate, safely controllable, and total recovery is high；Especially by intermediate (I- A) acidification is at salt so that the processing of final step reaction is simpler, yield higher, is particularly suitable for industrial production.
The invention further relates to two important intermediates of compound shown in formula (I) (chemical combination shown in formula (II) and formula (III) Object) and preparation method thereof.
Wherein, Z is-C (=O)-or-S (=O)2-。
On the one hand, the present invention provides a kind of method preparing compound shown in formula (I) comprising：By formula (II) shownization It closes object and carries out condensation reaction with 5- chlorothiophene -2- formyl chlorides, obtain compound shown in formula (I)：
Wherein, HX is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or P-methyl benzenesulfonic acid.
5- chlorothiophenes -2- formyl chlorides of the present invention can be directly added dropwise in the solution of compound shown in formula (II), Certain density solution can also be configured to the second solvent to be added dropwise.Second solvent is not specifically limited, and can be dissolved The solvent that 5- chlorothiophene -2- formyl chlorides have no effect on reaction is included in the present invention comprising but it is not limited to toluene or dichloro Methane etc..The certain density solution is not specifically limited, and the solution of all each concentration for not influencing reaction is included in In the present invention.In some embodiments, the 5- chlorothiophenes-that the certain density 5- chlorothiophenes -2- formyl solutions of chlorine is 48% 2- formyl chloride toluene solutions；In further embodiments, the certain density 5- chlorothiophenes -2- formyl solutions of chlorine be 1.6M or 5- chlorothiophene -2- formyl chloride the toluene solutions of 2.1M.
5- chlorothiophenes -2- formyl chlorides of the present invention are added dropwise to the molten of compound shown in formula (II) at 0 DEG C~50 DEG C In liquid；In some embodiments, the 5- chlorothiophene -2- formyl chlorides are added dropwise to chemical combination shown in formula (II) at 30 DEG C~50 DEG C In the solution of object；In another embodiment, the 5- chlorothiophene -2- formyl chlorides are added dropwise to chemical combination shown in formula (II) at 0 DEG C In the solution of object；In another embodiment, the 5- chlorothiophene -2- formyl chlorides are added dropwise to chemical combination shown in formula (II) at 35 DEG C In the solution of object；In another embodiment, the 5- chlorothiophene -2- formyl chlorides are added dropwise to chemical combination shown in formula (II) at 45 DEG C In the solution of object.
Condensation reaction of the present invention carries out at 0 DEG C~50 DEG C；In some embodiments, the condensation is anti- It should be carried out at 20 DEG C~30 DEG C；In another embodiment, the condensation reaction carries out at 0 DEG C；In another embodiment, The condensation reaction carries out at 20 DEG C；In another embodiment, the condensation reaction carries out at 25 DEG C.
Condensation reaction of the present invention carries out in the first solvent, wherein and first solvent is ether solvent, Ketones solvent, dichloromethane, toluene, water or combination thereof.In some embodiments, first solvent is tetrahydrofuran, Dioxane, diisopropyl ether, methyl tertiary butyl ether(MTBE), methyl ethyl ketone, methyl iso-butyl ketone (MIBK), acetone, dichloromethane, toluene, water or Combination thereof.In further embodiments, first solvent is acetone, toluene, water or combination thereof.In other realities It applies in example, the first solvent of the present invention is acetone, water or combination thereof.
In some embodiments, the first solvent of the present invention is the mixed solvent of acetone and water, and volume ratio is 1/2~3/ 1, that is, the volume ratio of acetone and water is 1：(1/3~2).In some embodiments, first solvent is the mixing of acetone and water Solvent, volume ratio are 1/2~3/2, that is, the volume ratio of acetone and water is 1：(2/3~2).In further embodiments, described One solvent is the mixed solvent of acetone and water, and volume ratio is 7/10~9/10, that is, the volume ratio of acetone and water is 1：(10/9~ 10/7).In further embodiments, first solvent is the mixed solvent of acetone and water, volume ratio 1/2,3/4 or 8/ 11。
Condensation reaction of the present invention carries out under the action of the first alkali, and first alkali can be organic base or nothing Machine alkali.The organic base can be triethylamine, trimethylamine, n,N-diisopropylethylamine, N- methylmorpholines, N- methyl piperazines Pyridine, pyridine or combination thereof.The inorganic base includes, but are not limited to alkali or alkaline earth metal hydroxide, alkali metal Or the carbonate or bicarbonate or phosphate or hydrophosphate of alkaline-earth metal alkyl oxide, alkali or alkaline earth metal, ammonia or Combination thereof.In some embodiments, the first alkali of the present invention is organic base；In some embodiments, first alkali For inorganic base.In some embodiments, first alkali is triethylamine, trimethylamine, n,N-diisopropylethylamine, N- methylmorphines Quinoline, N- methyl piperidines, pyridine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, saleratus, sodium bicarbonate, sodium phosphate, Potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or combination thereof.In some embodiments, the first alkali of the present invention is hydrogen Sodium oxide molybdena, potassium hydroxide, potassium carbonate, sodium carbonate, saleratus, sodium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, phosphoric acid Hydrogen dipotassium or combination thereof.
In method of the present invention, further comprise the purification process of compound shown in formula (I), the purification process packet Include but be not limited to recrystallization purifying etc..Wherein, the recrystallization purifying carries out in third solvent, and the third solvent does not have There are special limitation, any crude product that can dissolve the condensation reaction to a certain extent that crystallization simultaneously can be precipitated under certain condition Solvent be included in the present invention.The third solvent includes but not limited to acetic acid, water or their arbitrary combination etc..One In a little embodiments, the third solvent is acetic acid；In further embodiments, the third solvent is water；In some embodiments In, the third solvent is the mixed solvent of acetic acid and water.In further embodiments, the third solvent is acetic acid and water Mixed solvent, volume ratio are 1/2~3/2, i.e., the volume ratio of acetic acid and water is 1：(2/3~2).The specific mistake of the recrystallization Journey includes：The crude product is suspended in third solvent, after heating for dissolving, cooling crystallization or anti-solvent additive process crystallization.Example Such as, the crude product of embodiment 7 is suspended in acetic acid or water or their in the mixed solvent, after heating for dissolving, slow cooling is precipitated Solid；Or after dissolving by heating, another solvent (can be water or acetic acid or their mixing) is added while keeping temperature, Then solid is precipitated in slow cooling.
Condensation reaction yield of the present invention is high, and the method that post-processing uses recrystallization, and operation is simple, is suitble to Amplification production.The present invention provides the embodiment of condensation reaction amplification synthesis, from the experimental result it is found that the reaction is in the present invention Under conditions of described, amplification production remains to reach 77% yield.
On the one hand, the present invention provides a kind of intermediate being used for preparing compound shown in formula (I), structure such as formula (II) institute Show：
Wherein, HX is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or P-methyl benzenesulfonic acid.
On the other hand, the present invention provides a kind of method preparing the compound as shown in formula (II) comprising：(1) formula (III) ammonolysis reaction occurs for compound shown in；And the product of the ammonolysis reaction is carried out salt-forming reaction by (2), is obtained described Compound shown in formula (II)：
Wherein, Z is-C (=O)-or-S (=O)2-；HX is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, the third two Acid, oxalic acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid.
Ammonolysis reaction of the present invention carries out at 50 DEG C~100 DEG C；In some embodiments, the ammonolysis reaction exists It is carried out at 60 DEG C~90 DEG C；In some embodiments, the ammonolysis reaction carries out at 85 DEG C；In further embodiments, institute Ammonolysis reaction is stated to carry out at 90 DEG C；In some embodiments, the ammonolysis reaction carries out at 85 DEG C~90 DEG C.At other In embodiment, the ammonolysis reaction carries out at the temperature at which reaction dissolvent flows back, the reflux temperature with specifically react phase It closes, is varied from according to the difference of actual conditions.In another embodiment, the ammonolysis reaction is under the reflux temperature of ethyl alcohol It carries out；In another embodiment, the ammonolysis reaction carries out under the reflux temperature of ethanol/water mixed solvent.
Ammonolysis reaction of the present invention carries out under the action of amination reagent, the amination reagent be ammonia, ammonium hydroxide, Primary amine or hydrazine.Wherein, the primary amine is methylamine, ethamine, propylamine or butylamine；The hydrazine is hydrazine or hydrazine hydrate.
In some embodiments, primary amine used in the ammonolysis reaction is methylamine, wherein the methylamine can be one Determine the methylamine solution of concentration comprising but be not limited to, certain density methylamine water solution, methylamine methanol solution, methylethylolamine is molten Liquid or methylamine aqueous isopropanol etc..In some embodiments, the certain density methylamine solution be 40% methylamine water solution or 33% methylethylolamine solution.
In some embodiments, amination reagent used in the ammonolysis reaction is the methanol solution of ammonia.In some realities It applies in example, the amination reagent is 33% ammonia methanol solution.
The dosage of amination reagent of the present invention is usually excessive, is the more of the mole of compound shown in formula (III) Times.In some embodiments, the dosage of the amination reagent is 2-10 times of mole of compound shown in formula (III).One In a little embodiments, the dosage of the amination reagent is 2-7 times of the mole of compound shown in formula (III)；In other implementations In example, the dosage of the amination reagent is 2.5 times, 5.0 times or 7.0 times of the mole of compound shown in (III).
Ammonolysis reaction of the present invention carries out in the first polar solvent, and first polar solvent is methanol, second Alcohol, isopropanol, water or combination thereof.
Salt-forming reaction of the present invention is included in the 4th solvent, and the product of the ammonolysis reaction and acid appropriate are carried out Reaction, obtains corresponding salt.Wherein, the 4th solvent is not specifically limited, and the product of the ammonolysis reaction can be made completely molten The solvent that solution has no effect on into salt is included in the present invention comprising but be not limited to methanol, ethyl alcohol, isopropanol, water or it It is arbitrary combination etc..The acid appropriate is not specifically limited, and can form stable salt with the product of the ammonolysis reaction Acid is included in the present invention comprising but be not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, grass Acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid etc..The salt-forming reaction can be by being adjusted with acid pH value of solution to acid side Formula is realized.
In some embodiments, salt-forming reaction of the present invention carries out in the 4th solvent, and the 4th solvent is Methanol, ethyl alcohol, isopropanol, water or their arbitrary combination.In some embodiments, the salt-forming reaction includes by the ammonolysis The product of reaction is reacted with acid HX or its solution, obtains compound shown in formula (II).In some embodiments, the acid HX For hydrochloric acid.
In some embodiments, the salt that the product of ammonolysis reaction of the present invention is formed is hydrochloride, the hydrochloride Salifying method includes：In the 4th solvent, product and concentrated hydrochloric acid or the solution of hydrogen chloride gas or hydrochloric acid of the ammonolysis reaction Salt is reacted into, the solution of the hydrochloric acid includes but is not limited to the ethyl acetate solution of hydrochloric acid.In further embodiments, described The salifying method of hydrochloride include：In the 4th solvent, the product of the ammonolysis reaction reacts into salt with concentrated hydrochloric acid.At some In embodiment, the salifying method of the hydrochloride includes：It (can be first that the product of the ammonolysis reaction, which is dissolved in the 4th solvent, Alcohol, ethyl alcohol, isopropanol or water etc.) in, concentrated hydrochloric acid is then added dropwise to system in acidity, target hydrochloride product is made.Wherein, it drips The temperature of reaction system can be kept in a certain range (for example, maintaining the temperature at 0 DEG C or so or no more than 25 DEG C during adding Or it is no more than 40 DEG C)；After being added dropwise, can reduction temperature appropriate, so that the salt is precipitated as far as possible, it is unnecessary to avoid Loss.
The product of ammonolysis reaction of the present invention is the corresponding amine of compound, i.e. chemical combination shown in formula (I-a) shown in formula (II) Object.
Product obtained by ammonolysis reaction of the present invention takes into the mode purification process of salt, easy to operate, avoids column The more complex operation such as chromatographic purifying.Meanwhile being reused after the purified processing of product, be conducive to the control reacted in next step The raising of processing and yield.The salt of the high amine of purity can be prepared in salifying method of the present invention, and stability is high, compared with amine shape The midbody product of formula is easier to preserve.
Compound shown in the formula (II) is further purified using the methods of mashing in the present invention.Wherein, the mashing is made Solvent is not particularly limited, including but not limited to, dichloromethane, ethyl acetate, methanol, ethyl alcohol, isopropanol, diisopropyl ether Or their arbitrary combination etc..
In some embodiments, the present invention provides a kind of intermediate being used for preparing compound shown in formula (II), structure As shown in formula (III)：
Wherein, Z is-C (=O)-or-S (=O)2-。
In some embodiments, the present invention provides a kind of methods preparing the compound as shown in formula (III) comprising： Compound shown in formula (IV) and phthalimide or o-benzoic sulfimide or their salt are subjected to substitution reaction, obtained To compound shown in formula (III)：
Wherein, R is acetyl group, and mesyl, trifyl or 4- replace benzenesulfonyl, wherein the 4- substitutions Substituent group in benzenesulfonyl is methyl, trifluoromethyl, nitro, chlorine or bromine；Z is-C (=O)-or-S (=O)2-。
The salt of phthalimide or o-benzoic sulfimide of the present invention is its sylvite or sodium salt.At some In embodiment, the salt of the phthalimide or o-benzoic sulfimide is the sylvite of phthalimide.Another In some embodiments, the salt of the phthalimide or o-benzoic sulfimide is the sodium of o-benzoic sulfimide Salt, i.e. saccharin sodium.
The dosage of the salt of phthalimide or o-benzoic sulfimide of the present invention is chemical combination shown in formula (IV) 1 times or more times of the mole of object.In some embodiments, the salt of the phthalimide or o-benzoic sulfimide Dosage be 1.0~2.0 times of mole of compound shown in formula (IV).In further embodiments, the phthalyl The salt of imines or o-benzoic sulfimide is the sylvite of phthalimide, and dosage is rubbing for compound shown in formula (IV) 1.0~2.0 times of that amount；In further embodiments, the salt of the phthalimide or o-benzoic sulfimide is The sylvite of phthalimide, dosage are 1.2 times or 1.5 times of the mole of compound shown in formula (IV).In some realities It applies in example, the salt of the phthalimide or o-benzoic sulfimide is the sodium salt of o-benzoic sulfimide, is used Amount is 1.0~2.0 times of the mole of compound shown in formula (IV).In some embodiments, the phthalimide or The salt of o-benzoic sulfimide is the sodium salt of o-benzoic sulfimide, and dosage is the mole of compound shown in formula (IV) 1.5 times.
Substitution reaction of the present invention carries out at 50 DEG C~100 DEG C；In some embodiments, the substitution reaction is 65 DEG C~90 DEG C at carry out；In another embodiment, the substitution reaction carries out at 65 DEG C；In another embodiment, described to take Generation reaction carries out at 72 DEG C；In another embodiment, the substitution reaction carries out at 75 DEG C；In another embodiment, institute Substitution reaction is stated to carry out at 90 DEG C.
Substitution reaction of the present invention carries out in the second polar solvent, and second polar solvent is N, N- diformazans Base formamide, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, acetone or combination thereof.
Substitution reaction of the present invention can be carried out directly in the absence of a catalyst, can also be in catalyst Effect is lower to be carried out.In some embodiments, the substitution reaction carries out under the action of the first catalyst, and described One catalyst is triethyl benzyl ammonia chloride, tetrabutylammonium chloride or potassium iodide.
In some embodiments, the present invention also provides the preparation methods of compound shown in the formula (IV) comprising following Step：
A, compound shown in formula (VII) and 3- morpholones are subjected to coupling reaction, obtain compound shown in formula (VI)；
B, compound shown in formula (VI) is deprotected under the action of fluorine reagent and obtains compound shown in formula (V)；
C, in non-protonic solvent, compound shown in formula (V) is reacted with RCl, obtains chemical combination shown in formula (IV) Object；
Wherein, Hal OTf, I, Br or Cl；R is acetyl group, and mesyl, trifyl or 4- replace benzene sulfonyl Base, wherein the substituent group in the 4- substitutions benzenesulfonyl is methyl, trifluoromethyl, nitro, chlorine or bromine.
The preparation method of compound shown in formula (IV) of the present invention, wherein in step, the coupling reaction is 60 DEG C~140 DEG C at carry out；In some embodiments, in step, the coupling reaction carries out at 90 DEG C~130 DEG C；One In a little embodiments, in step, the coupling reaction carries out at 100 DEG C~130 DEG C；In some embodiments, in step A In, the coupling reaction carries out at 90 DEG C~120 DEG C；In further embodiments, in step, the coupling reaction exists It is carried out at 115 DEG C~118 DEG C.In further embodiments, temperature of the coupling reaction described in step A when reaction dissolvent flows back Degree is lower to carry out, and the reflux temperature is slightly changed according to the difference of specific reaction condition；In further embodiments, step Coupling reaction described in A carries out under the reflux temperature of toluene.
The preparation method of compound shown in formula (IV) of the present invention, wherein the coupling reaction described in step A is in third It is carried out in polar solvent, the third polar solvent can be：N,N-Dimethylformamide, dimethyl sulfoxide, N- crassitudes Ketone, toluene, dioxane, tetrahydrofuran, dimethylbenzene, glycol dimethyl ether or combination thereof.
The preparation method of compound shown in formula (IV) of the present invention, wherein the coupling reaction described in step A is second It is carried out under the action of alkali, second alkali is potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium phosphate or combination thereof.
The preparation method of compound shown in formula (IV) of the present invention, wherein the coupling reaction described in step A is second It being carried out under the action of catalyst, second catalyst includes the metallic catalyst that common promotion coupling reaction carries out, including Palladium catalyst, rhodium catalyst, Raney nickel or copper catalyst etc..In some embodiments, the second catalyst of the present invention is Copper catalyst；In further embodiments, second catalyst be copper powder, cuprous iodide, stannous chloride, cuprous sulfocyanide, Cuprous oxide, cuprous acetate or acetylacetone copper.
The preparation method of compound shown in formula (IV) of the present invention, wherein the dosage of the second catalyst described in step A It is 5%~20% of the mole of compound shown in formula (VII).In some embodiments, the second catalyst described in step A Dosage is 10%~20% of the mole of compound shown in formula (VII)；In further embodiments, second described in step A The dosage of catalyst is 15% of the mole of compound shown in formula (VII).
The preparation method of compound shown in formula (IV) of the present invention, wherein coupling reaction described in step A with It is carried out in the presence of body, the ligand is common ligand in coupling reaction, wherein the use of specific ligand is according to catalyst Type determines that the ligand to match with second catalyst is in the scope of the invention.In some embodiments, described Ligand is 8-hydroxyquinoline, proline, sarcosine, n,N-Dimethylglycine, N, N '-dimethyl ethylenediamine, trans-- N, N '-dimethyl cyclohexanediamine or N, N- dimethyl-ethylenediamine.
The preparation method of compound shown in formula (IV) of the present invention, wherein the dosage of the ligand described in step A is formula (VII) the 10%~40% of the mole of compound shown in.In some embodiments, the dosage of ligand described in step A is formula (VII) the 20%~40% of the mole of compound shown in；In further embodiments, the dosage of ligand described in step A is The 30% of the mole of compound shown in formula (VII).
The preparation method of compound, further comprises formula (VI) shownization in step A shown in formula (IV) of the present invention The purification process of object is closed, the purification process includes but not limited to be beaten purifying etc..Wherein, molten used in the mashing purifying Agent is not particularly limited, including but not limited to, dichloromethane, ethyl acetate, methanol, ethyl alcohol, isopropanol, diisopropyl ether or they It is arbitrary combination etc..
The preparation method of compound shown in formula (IV) of the present invention, wherein step A has used copper catalyst and nitrogenous matched Body, it is cheap, and post-process the method for taking mashing and purified, it is easy to operate, it is suitable for industrial production.
The preparation method of compound shown in formula (IV) of the present invention, wherein the fluorine reagent described in step B is the tetrabutyl Ammonium fluoride；Deprotection reaction described in step B carries out in quadripolarity solvent, and the quadripolarity solvent is tetrahydrofuran Or glycol dimethyl ether etc..
The preparation method of compound shown in formula (IV) of the present invention, wherein the reaction of the step C is in certain reaction temperature Degree is lower to carry out, and the reaction temperature is -20 DEG C~50 DEG C；In some embodiments, the reaction temperature of the step C is -10 DEG C~40 DEG C；In some embodiments, the reaction temperature of the step C is -10 DEG C~20 DEG C；In further embodiments, institute The reaction temperature for stating step C is 0 DEG C~20 DEG C；In further embodiments, the reaction of the step C at ambient temperature into Row.
The preparation method of compound shown in formula (IV) of the present invention, wherein the RCl in the step C is -20 DEG C~10 It is added dropwise at DEG C in the solution of compound shown in formula (V)；In some embodiments, the RCl in the step C is at -10 DEG C~0 DEG C Under be added dropwise in the solution of compound shown in formula (V)；In further embodiments, the RCl in the step C is under condition of ice bath It is added dropwise in the solution of compound shown in formula (V).
The preparation method of compound shown in formula (IV) of the present invention, wherein the reaction in the step C is in third alkali In the presence of carry out, the third alkali is triethylamine, n,N-diisopropylethylamine, pyridine or combination thereof.
The preparation method of compound shown in formula (IV) of the present invention, wherein the aprotic described in the step C is molten Agent is dichloromethane, tetrahydrofuran, n,N-Dimethylformamide, ether or combination thereof.
The preparation method of compound shown in formula (IV) of the present invention, wherein the reaction of the step C can not urged It directly carries out, can also carry out under the effect of the catalyst in the presence of agent.In some embodiments, in the step C Reaction carries out in the presence of third catalyst, and the third catalyst is 4-dimethylaminopyridine.
The preparation method of compound shown in formula (IV) of the present invention, wherein the method for mashing can be taken to step B institutes Compound is purified shown in formula (IV) obtained by compound and step C shown in the formula (V) obtained, is avoided using column chromatography purifying etc. More complex operation.Wherein, solvent used in the mashing is not particularly limited, including but not limited to, dichloromethane, acetic acid Ethyl ester, methanol, ethyl alcohol, isopropanol, diisopropyl ether or their arbitrary combination etc..
Definition and general terms
" room temperature " refers to temperature by about 10 DEG C to about 40 DEG C in the present invention.In some embodiments, " room temperature " refers to Be temperature by about 20 DEG C to about 30 DEG C；In other embodiments, " room temperature " refers to 20 DEG C, 22.5 DEG C, 25 DEG C, 27.5 DEG C etc..
In the context of the present invention, all numbers being disclosed that are approximation.The numerical value of each number has It is possible that the differences such as 1%, 2%, 5%, 7%, 8% or 10%.Whenever disclosing a number with N values, any tool There is the number within N+/- 1%, N+/- 2%, N+/- 3%, N+/- 5%, N+/- 7%, N+/- 8% or the values of N+/- 10% can be bright It is really open, wherein " +/- " refers to adding deduct.Whenever disclosing a lower limit in a numberical range, DL and upper limit, DU, when, any numerical value within the scope of the disclosed can be specifically disclosed.
All reaction steps reaction of the present invention is more than to a certain extent as consumption of raw materials is approximately greater than 70% 80%, it is more than 90%, is more than 95%, or post-processed after reaction raw materials have been exhausted after testing, it is such as cooling, it collects, Extraction is filtered, separation, purified treatment or combinations thereof.Conventional method such as thin layer chromatography (TLC), efficient liquid phase can be passed through The methods of chromatography (HPLC), gas chromatography (GC) detect the extent of reaction.May be used conventional method to reaction solution into Row post-processing is direct plungeed into and is reacted in next step for example, by collecting crude product after reduction vaporization or conventional distil-lation reaction dissolvent； Or crude product is directly obtained by filtration, it direct plunges into and reacts in next step；Or after standing, supernatant liquor is poured out and obtains crude product, directly Input is connect to react in next step；Or selection organic solvent appropriate or combinations thereof is extracted, and is distilled, crystallization, column chromatography, rinse, The purification steps such as mashing.
Each dropwise addition process of the present invention and each step reaction carry out under the conditions of certain temperature, Ren Heshi Conjunction is used in each dropwise addition process or the temperature of each reaction process is included in the present invention.In addition, many of this field similar change It is dynamic, equivalent replacement, or it is equal to temperature and temperature range described in the invention, it is accordingly to be regarded as the scope of the present invention.This hair It is bright to give the preferable temperature of each dropwise addition process or temperature range, and respectively react preferable reaction temperature.
Solvent is not particularly limited used in each reaction step of the present invention, any to dissolve to a certain extent Starting material and do not inhibit reaction solvent be included in the present invention.In addition, many similar changes of this field, are equally replaced It changes, or is equal to solvent described in the invention, the different proportion of solvent combination and solvent combination is accordingly to be regarded as the packet of the present invention Containing range.The present invention gives preferable solvents used in each reaction step.
Recrystallization solvent used in the present invention is not particularly limited, it is any can dissolve to a certain extent crude product and The solvent that crystallization can be precipitated under certain condition is included in the present invention.In addition, many similar changes of this field, are equally replaced It changes, or is equal to solvent described in the invention, the different proportion of solvent combination and solvent combination is accordingly to be regarded as the packet of the present invention Containing range.Wherein, the solvent can be alcohols, ethers, alkanes, halogenated hydrocarbon, esters, ketone, aromatic hydrocarbons, acetonitrile, Acetic acid, water, DMF or combination thereof.Such as water, acetic acid, methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, uncle Butanol, petroleum ether, pentane, n-hexane, normal heptane, hexamethylene, DMF, tetrahydrofuran, ether, isopropyl ether, dioxane, first Base tertbutyl ether, dimethoxy, diethylene glycol dimethyl ether, triglyme, dichloromethane, 1,2- dichloroethanes, chloroform, Carbon tetrachloride, ethyl acetate, isopropyl acetate, acetone, butanone, benzene, toluene, dimethylbenzene or combination thereof.
The content of moisture, is not particularly limited in solvent of the present invention.It is any to a certain extent can be in this hair The bright middle solvent content used, is accordingly to be regarded as solvent of the present invention.It is small if the content of moisture in solvent approximately is less than 0.05% In 0.1%, it is less than 0.2%, is less than 0.5%, be less than 5%, be less than 10%, be less than 25%, be less than 30%, or is 0%.
In the present invention, the similar terms such as " first ", " second " are used for description purposes only, and are not understood to indicate or imply Relative importance or the quantity for implicitly indicating indicated technical characteristic.Define " first " as a result, the feature of " second " can To express or implicitly include at least one this feature.In the description of the present invention, unless otherwise specifically defined, The meaning of " plurality " is at least two, such as two, three etc..
General synthetic method
In the present specification, if there are any differences, structure to be dominant between chemical name and chemical constitution.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius (DEG C).Unless other Aspect shows reagent purchase in goods providers such as Aladdin reagent (Shanghai) Co., Ltd., and Shanghai Ling Kai medical sci-teches are limited Company, Shanghai De Mo Pharmaceutical Technology Co., Ltd, Beijing are coupled Science and Technology Ltd., all without by further impure when use Change.General reagent is from Chengdu Ke Long chemical reagents factory, Taizhou Hai Chuan Chemical Co., Ltd.s, the big rich limited public affairs of development in science and technology in Sichuan Department, Zhejiang Pu Kang Chemical Co., Ltd.s are commercially available.
Spectroscopic data of the nuclear magnetic resonance is measured by 400 nuclear magnetic resonance spectrometers of Bruker Avance, with CDC13,d6- DMSO,CD3OD,D2O or d6Acetone is solvent (report as unit of ppm), use TMS (0ppm) or chloroform (7.25ppm) as Reference standard.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), T (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), and dt (doublet of triplets, double triplets), td (triplet of doublets, three pairs Weight peak), dd (doublet of doublet of doublets, in pairs doublet), ddt (doublet of doublet of Triplets, in pairs triplet), and dddd (doublet of doublet of doublet of doublets, in pairs double two Weight peak).Coupling constant is indicated with hertz (Hz).
By outfit G1312A binary pumps and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) the spectrometer of Agilent6320 series LC-MS measure, G1329A automatic samplers and G1315B DAD detectors Applied to analysis, the sources ESI are applied to LC-MS spectrometers.
Algorithm (MS) data are by being equipped with G1311A quaternary pumps and G1316A TCC (column temperature is maintained at 30 DEG C) 6120 series LC-MS of Agilent spectrometer come what is measured, G1329A automatic samplers and G1315D DAD detectors are answered For analyzing, the sources ESI are applied to LC-MS spectrometers.
Both the above spectrometer is provided with Agilent Zorbax SB-C18 columns, and specification is 2.1 × 30mm, 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Mobile phase is that 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid are ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1：
Table 1：The condition of gradient elution of Algorithm mobile phase
Time (min) A(CH3CN, 0.1%HCOOH) B(H2O, 0.1%HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purifying is evaluated by 1260 high performance liquid chromatography of Agilent (HPLC).Wherein, efficient liquid phase Chromatograph is equipped with G1311B quaternary pumps, G1329B automatic samplers, G1316A TCC (column temperature is maintained at 35 DEG C) and G1315D DAD detectors.Chromatographic column is Agilent Zorbax Extend C18 (specification be 4.6 × 150mm, 5 μm)；Flow velocity is 1.0mL/min；Detection wavelength 250nm；Mobile phase and its condition of gradient elution are as shown in table 2-5：
Table 2：HPLC mobile phases and its condition of gradient elution 1
Time (min) A (acetonitrile) B(H2O)
0-10 30-90 70-10
10-25 90 10
25-26 10 90
26-31 90 10
Table 3：HPLC mobile phases and its condition of gradient elution 2
Time (min) A (acetonitrile) B(H2O)
0-10 10-30 90-70
10-15 30-90 70-10
15-20 90 10
20-21 10 90
21-26 10 90
Table 4：HPLC mobile phases and its condition of gradient elution 3
Time (min) A (acetonitrile) B(H2O)
0-15 10-90 90-10
15-25 90 10
25-26 10 90
26-31 10 90
Table 5：HPLC mobile phases and its condition of gradient elution 4
Time (min) A (acetonitrile) B (0.05% ammonium hydroxide (pH8.0))
0-8 10-25 90-75
8-15 25-75 75-25
15-20 75 25
20-21 10 90
21-26 10 90
The use of brief word below is through the present invention：
CDC13Deuterochloroform
D2O heavy water
DMSO-d6Deuterated dimethyl sulfoxide
K2CO3Potassium carbonate
CuI cuprous iodides
HCl hydrochloric acid
EDTA ethylenediamine tetra-acetic acids
TBAF tetrabutyl ammonium fluorides
MsCl mesyl chlorides
DIEA, DIPEA N, N- diisopropylethylamine
DMF N,N-dimethylformamides
OTf trifyls
Kg kilograms
G grams
Mg milligrams
Mol moles
Mmol mMs
L liters
ML milliliters
TLC thin-layered chromatography
HPLC high performance liquid chromatographies
Following reaction scheme describes the step of preparing disclosed compound of present invention.
Compound (8) can be prepared by the method that above-mentioned reaction scheme describes, wherein R1For halogen or C1-4Alkane Base, R2For substituted or non-substituted heterocycle, R3For substituted or non-substituted aryl or heteroaryl, Y+For Na+Or K+, n 0,1,2 Or 3, R, Z, X have meaning of the present invention.Compound (1) and R2H is in solvent appropriate, (such as phosphorus under alkaline condition Sour potassium, potassium carbonate or cesium carbonate etc.), catalyst (such as cuprous iodide, cuprous oxide or stannous chloride etc.) and ligand (such as N, N '-dimethyl ethylenediamine or trans--N, N '-dimethyl cyclohexanediamine etc.) in the presence of compound (2) is obtained by the reaction.Compound (2) in the presence of fluorine-containing reagent (such as tetra-n-butyl ammonium fluoride), in polar solvent (such as tetrahydrofuran or glycol dimethyl ether) Deprotection generates compound (3).The work of compound (3) and RCl in alkali (such as triethylamine, N, N- diisopropylethylamine or pyridine etc.) Compound (4) is obtained by the reaction under.With compound (5) in polar solvent, substitution occurs in a heated condition for compound (4) anti- It should obtain compound (6).Ammonolysis reaction occurs under the action of primary amine or hydrazine for compound (6), then obtains compound at salt (7).Compound (7) and acyl chlorides (R3C (=O) Cl) it is anti-under the existence condition of alkali (such as sodium carbonate, potassium carbonate or potassium phosphate etc.) It should obtain compound (8).
Specific implementation method
The embodiment of the invention discloses the methods of oxazolidinones class compound processed.Those skilled in the art can use for reference this Invention content is suitably modified technological parameter to realize.In particular, it should be pointed out that all similar substitutions and modifications are to this field It is it will be apparent that they are considered as being included in the invention for technical staff.The method of the present invention is by preferable Embodiment is described, related personnel obviously can not depart from the content of present invention, in spirit and scope to side as described herein Method is modified or suitably changes and combines, to realize and apply the technology of the present invention.
For a further understanding of the present invention, the following describes the present invention in detail with reference to examples.
Embodiment
Embodiment 1 (3R, 3aS) -3- (((t-Butyldimethylsilyl) oxygen) methyl) -7- (3- oxo-morpholines) -3a, 4- Dihydrobenzo [b] oxazoles [3,4-d] [1,4] oxazines -1 (3H) -one
By the bromo- 3- of (3R, 3aS) -7- (((t-Butyldimethylsilyl) oxygen) methyl) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [1,4] oxazines-1 (3H) -one (J.Med.Chem., 2011,54,7493-7502) (1.96kg, 4.70mol) and 3- Morpholone (574g, 5.60mol) is suspended in toluene (13L), and K is added2CO3(1.31kg, 9.40mol) is added under nitrogen protection CuI (130g, 0.70mol) and N1,N2Dimethyl ethyl -1,2- diamines (124g, 1.40mol), reaction system are heated to 115 DEG C ~118 DEG C are reacted 36 hours, HPLC tracking reactions.Reaction finishes, and is cooled to room temperature, and filtering, filtrate decompression is evaporated, and concentrate is molten In dichloromethane (10L), 1M HCl/waters solution (10L), EDETATE SODIUM salt saturated solution (10L × 2), water (10L) are used successively Washing, organic phase decompression boil off solvent, and crude product is beaten with isopropanol (2L) and is purified, obtain white solid (1.86kg, 91.5%)
MS(ESI,pos.ion)m/z:435.2(M+1)；
1H NMR(400MHz,CDCl3)δ:8.03 (d, J=8.7Hz, 1H), 6.99 (d, J=1.9Hz, 1H), 6.94 (dd, J=8.7,1.9Hz, 1H), 4.46 (dd, J=10.4,3.1Hz, 1H), 4.33 (s, 2H), 4.31-4.26 (m, 1H), 4.15- 4.08(m,1H),4.06–3.99(m,2H),3.96–3.86(m,3H),3.75–3.69(m,2H),0.90(s,9H),0.11(d, J=2.6Hz, 6H)
Embodiment 2 (3R, 3aS) -3- (methylol) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4- D] [1,4] oxazines -1 (3H) -one
By (3R, 3aS) -3- (((t-Butyldimethylsilyl) oxygen) methyl) -7- (3- oxo-morpholines) -3a, 4- dihydros [[Isosorbide-5-Nitrae] oxazines -1 (3H) -one (1.86kg, 4.30mol) is dissolved in tetrahydrofuran (5L) b] oxazoles [3,4-d] benzo, at room temperature The TBAF tetrahydrofuran solutions (4.70L, 4.70mol) of 1M are added；It is added dropwise, stirs 1 hour at room temperature, TLC tracking reactions. Reaction finishes, and is concentrated under reduced pressure, obtains oily liquids.Water (7L) is added into oily liquids under stiring, continues stirring 30 minutes, Filter, filter cake wash with cold water (1L), and crude product is beaten purifying with isopropanol (3L), obtain white solid (1.35kg, 98.0%).
MS(ESI,pos.ion)m/z:321.1(M+1)；
1H NMR(400MHz,DMSO-d6)δ:7.85 (d, J=8.7Hz, 1H), 7.05 (d, J=2.2Hz, 1H), 7.01 (dd, J=8.7,2.3Hz, 1H), 5.31 (s, 1H), 4.59-4.51 (m, 1H), 4.47-4.41 (m, 1H), 4.18 (s, 2H), 4.07–3.98(m,2H),3.98–3.91(m,2H),3.80–3.64(m,4H).
Embodiment 3 ((3R, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3, 4-d] [1,4] oxazine -3- bases) methylmethanesulfonate ester
By (3R, 3aS) -3- (methylol) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [1, 4] oxazines -1 (3H) -one (1.35kg, 4.20mol) and DIPEA (1.09kg, 8.43mol) are added to dry DMF (6.5L) In, in ice bath, MsCl (530g, 4.60mol) is slowly added dropwise under nitrogen protection, is added dropwise, continuation reacts 30 in ice bath Minute, being warming up to room temperature, the reaction was continued 30 minutes, TLC tracking reactions.Reaction finishes, and pure water (7L) is added into system, in ice It stirs 30 minutes, filters in bath, filter cake is beaten with isopropanol (4L) and is purified, and obtains white solid (1.55kg, 92.7%).
MS(ESI,pos.ion)m/z:399.1(M+1)；
1H NMR(400MHz,DMSO-d6)δ:7.85 (d, J=8.7Hz, 1H), 7.07 (d, J=2.2Hz, 1H), 7.03 (dd, J=8.7,2.3Hz, 1H), 4.83-4.75 (m, 1H), 4.67-4.54 (m, 3H), 4.18 (s, 2H), 4.11-4.03 (m, 2H),3.98–3.92(m,2H),3.73–3.65(m,2H),3.28(s,3H).
4 2- of embodiment (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methyl) isoindoline -1,3- diketone
Method 1：
Potassium phthalimide (1.08kg, 5.84mol) is scattered in dry DMF (12L), is warming up to 72 DEG C, ((3R, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [Isosorbide-5-Nitrae] are added Oxazine -3- bases) methylmethanesulfonate ester (1.55kg, 3.89mol), keep temperature to continue stirring 3 hours, HPLC tracking reactions.Instead It should finish, system is cooled to 20 DEG C, water (12L) is added, white solid is precipitated, continues stirring 1 hour, is filtered, filter cake second Alcohol (2L) washs, dry, obtains white solid (1.55kg, 88.7%).MS(ESI,pos.ion)m/z:450.4(M+1)；
1H NMR(400MHz,DMSO-d6)δ:7.96-7.90 (m, 2H), 7.90-7.85 (m, 2H), 7.81 (d, J= 8.7Hz, 1H), 7.05 (d, J=2.2Hz, 1H), 7.00 (dd, J=8.7,2.3Hz, 1H), 4.76-4.68 (m, 1H), 4.64 (dd, J=10.4,3.1Hz, 1H), 4.22-4.15 (m, 3H), 4.14-4.00 (m, 3H), 3.95 (t, J=5.0Hz, 2H), 3.71–3.65(m,2H).
Method 2：
By potassium phthalimide (112mg, 0.61mmol) and ((3R, 3aS) -1- oxos -7- (3- oxomorpholins Base) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methylmethanesulfonate ester (200mg, It 0.50mmol) is scattered in DMF (2mL), is heated to 65 DEG C and reacts 3 hours, HPLC tracking reactions.Reaction finishes, and system is dropped Water (2mL) is added to 20 DEG C in temperature, stirs 1 hour, filters, dry, obtains white solid (203mg, 74.5%).
Method 3：
By potassium phthalimide (112mg, 0.61mmol) and ((3R, 3aS) -1- oxos -7- (3- oxomorpholins Base) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methylmethanesulfonate ester (200mg, It 0.50mmol) is scattered in DMF (2mL), is heated to 90 DEG C and reacts 3 hours, HPLC tracking reactions.Reaction finishes, and system is dropped Water (2mL) is added to 20 DEG C in temperature, stirs 1 hour, filters, dry, obtains white solid (210mg, 78.5%).
Method 4：
By potassium phthalimide (223mg, 1.21mmol), triethyl benzyl ammonia chloride (27mg, 0.12mmol) ((3R, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazines - 3- yls) methylmethanesulfonate ester (400mg, 1.01mmol) is scattered in DMF (5mL), be heated to 65 DEG C and react 3 hours, HPLC with Track reacts.Reaction finishes, and system is cooled to 20 DEG C, water (2mL) is added, is stirred 1 hour, is filtered, dry, obtains white solid (458mg, 85.4%).
Embodiment 5 (3S, 3aS) -3- ((1,1- titanium dioxides -3- oxos benzo [d] isothiazole -2 (3H)-yl) methyl) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [1,4] oxazines -1 (3H) -one
By saccharin sodium (770mg, 3.75mmol) and ((3R, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- Tetrahydro benzo [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methylmethanesulfonate ester (1.0g, 2.51mmol) is dissolved in DMF (5mL) In, it is heated to 75 DEG C of reactions overnight.Reaction finishes, and system is cooled to 20 DEG C, water (10mL) and ethyl acetate (10mL) is added, After liquid separation, organic phase is dried with anhydrous sodium sulfate, crude product through column chromatography (EtOAc) purify, obtain white solid (430mg, 34%).
Embodiment 6 (3S, 3aS) -3- (amino methyl) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3, 4-d] [1,4] oxazines -1 (3H) -one hydrochlorides
Method 1：
By 2- (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4- D] [1,4] oxazine -3- bases) methyl) isoindoline -1,3- diketone (2.00g, 4.45mmol) is suspended in absolute ethyl alcohol (20mL) In, 85 DEG C are heated to, 40% methylamine water solution (1.70g, 22.27mmol) is added, continues back flow reaction 1 hour, HPLC tracking Reaction.Reaction finishes, and is cooled to room temperature, evaporated under reduced pressure solvent, and ethyl alcohol (40mL) is added into residue, and pH is adjusted with concentrated hydrochloric acid It to 2~3, filters, filter cake is washed with ethyl alcohol (5mL), dry, obtains white solid (1.27g, 80.2%).
MS(ESI,pos.ion)m/z:320.2(M+1)；
1H NMR(400MHz,D2O)δ:7.95 (d, J=8.9Hz, 1H), 7.09-7.04 (m, 2H), 4.93-4.86 (m, 1H), 4.70 (dd, J=10.5,2.9Hz, 1H), 4.39 (s, 2H), 4.24-4.18 (m, 1H), 4.16-4.09 (m, 3H), 3.83–3.77(m,2H),3.66–3.52(m,2H).
Method 2：
By 2- (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4- D] [1,4] oxazine -3- bases) methyl) isoindoline -1,3- diketone (3.00g, 6.68mmol) is suspended in absolute ethyl alcohol (40mL) In, 90 DEG C are heated to, 40% methylamine water solution (1.30g, 16.70mmol) is added, continues back flow reaction 1 hour, HPLC tracking Reaction.Reaction finishes, and is cooled to room temperature, evaporated under reduced pressure solvent, and ethyl alcohol (40mL) is added into residue, and pH is adjusted with concentrated hydrochloric acid It to 2~3, filters, filter cake is washed with ethyl alcohol (5mL), dry, obtains white solid (1.73g, 73.0%).
Method 3：
By 2- (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4- D] [1,4] oxazine -3- bases) methyl) isoindoline -1,3- diketone (2.00g, 4.45mmol) is suspended in absolute ethyl alcohol (20mL) In, 85 DEG C are heated to, 40% methylamine water solution (2.40g, 31.15mmol) is added, continues back flow reaction 1 hour, HPLC tracking Reaction.Reaction finishes, and is cooled to room temperature, evaporated under reduced pressure solvent, and ethyl alcohol (40mL) is added into residue, and pH is adjusted with concentrated hydrochloric acid It to 2~3, filters, filter cake is washed with ethyl alcohol (5mL), obtains white solid (1.31g, 82.0%).
Method 4：
By 2- (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4- D] [1,4] oxazine -3- bases) methyl) isoindoline -1,3- diketone (3.20g, 7.13mmol) is suspended in absolute ethyl alcohol (30mL) In, be heated to 85 DEG C, 33% methylethylolamine solution (3.60g, 35.63mmol) be added, continue back flow reaction 1 hour, HPLC with Track reacts.Reaction finishes, and is cooled to room temperature, evaporated under reduced pressure solvent, and ethyl alcohol (24mL) is added into residue, is adjusted with concentrated hydrochloric acid PH to 2~3.It filters, filter cake is washed with ethyl alcohol (10mL), and crude product is beaten with dichloromethane (20mL) and is purified, and obtains white solid (2.30g, 87.0%).
Method 5：
By 2- (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4- D] [Isosorbide-5-Nitrae] oxazine -3- bases) methyl) isoindoline -1,3- diketone (1.55kg, 3.45mol) is suspended in absolute ethyl alcohol (6L), It is heated to reflux, 40% methylamine water solution (1.3kg, 17.3mol) is added, continue back flow reaction 1 hour, HPLC tracking reactions.Instead It should finish, be cooled to room temperature, evaporated under reduced pressure solvent, the addition ethyl alcohol (6L) into residue, dropwise addition concentrated hydrochloric acid, adjusting pH to 2~ 3.Filter, filter cake wash with ethyl alcohol (500mL), and crude product is beaten purifying with dichloromethane (9L), obtain white solid (0.8kg, 65%).
Method 6：
By (3S, 3aS) -3- ((1,1- titanium dioxides -3- oxos benzo [d] isothiazole -2 (3H)-yl) methyl) -7- (3- oxygen For morpholinyl) -3a, [[1,4] oxazines -1 (3H) -one (400mg, 0.82mmol) are dissolved in nothing to b] oxazoles [3,4-d] to 4- dihydrobenzos It in water-ethanol (2mL), is heated to reflux, 33% ammonia methanol solution (320mg, 5.7mmol) is added, continue back flow reaction 1 hour. Reaction finishes, and is cooled to room temperature, evaporated under reduced pressure solvent, and ethyl alcohol (5mL) is added into residue, and concentrated hydrochloric acid is added dropwise, and adjusts pH to 2 ~3.It filters, obtains white solid (280mg, 88%).
The chloro- N- of 7 5- of embodiment (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methyl) thiophene-2-carboxamide derivatives
Method 1：
By (3S, 3aS) -3- (amino methyl) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzo [b] oxazoles [3,4-d] [- 1 (3H) -one hydrochloride (800g, 2.25mol) of Isosorbide-5-Nitrae] oxazines is dissolved in water (2.2L), and acetone (1.6L) and sodium carbonate is added (300g, 2.83mol) is heated to 35 DEG C, be added dropwise 48% 5- chlorothiophene -2- formyl chlorides toluene solution (430g, 2.37mol)；It is added dropwise, is cooled to 25 DEG C and is stirred to react 0.5 hour, TLC tracking reactions.Reaction finishes, and it is small to continue stirring 2 When, it filtering, filter cake is washed with water/acetone (1L, v/v=4/1), and crude product is recrystallized with acetic acid/water (3.8L, v/v=10/9), Obtain white solid (8.10g, 77.6%).
MS(ESI,pos.ion)m/z:464.1(M+1)；
1H NMR(400MHz,DMSO-d6)δ:8.98 (t, J=5.8Hz, 1H), 7.85 (d, J=8.7Hz, 1H), 7.71 (d, J=4.1Hz, 1H), 7.20 (d, J=4.0Hz, 1H), 7.05 (d, J=2.2Hz, 1H), 7.01 (dd, J=8.7,2.3Hz, 1H), 4.64-4.52 (m, 2H), 4.17 (s, 2H), 4.12-4.00 (m, 2H), 3.98-3.91 (m, 2H), 3.73 (t, J= 5.5Hz,2H),3.70–3.64(m,2H).
Method 2：
Sodium carbonate (3.50g, 33.0mmol) is dissolved in water (30mL), (3S, 3aS) -3- (amino methyl)-is sequentially added 7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [- 1 (3H) -one hydrochloride of 1,4] oxazines (10.0g, 28.1mmol) with acetone (15mL), reaction system is cooled to 0 DEG C, the chloro- 2- thiophene acyl chlorides (5.30g, 29.0mmol) of 5- are added dropwise Toluene (18mL) solution, be added dropwise, keep 0 DEG C the reaction was continued 2 hours, TLC detection reaction.Reaction finishes, and filters, obtains White solid (13.6g, 96.1%).
Method 3：
Sodium carbonate (5.50g, 51.9mmol) is dissolved in water (40mL), (3S, 3aS) -3- (amino methyl)-is sequentially added 7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [- 1 (3H) -one hydrochloride of 1,4] oxazines (15.0g, 42.3mmol) with acetone (30mL), 45 DEG C are heated to, the toluene of the chloro- 2- thiophene acyl chlorides (7.80g, 43.3mmol) of 5- is added dropwise (20mL) solution, is added dropwise, and reaction temperature is down to 20 DEG C and is stirred 1 hour, TLC tracking reactions.Reaction finishes, and is cooled to room Temperature filters, obtains white solid (18.3g, 93.1%).

Claims (8)

1. a kind of method preparing compound shown in formula (I) comprising：By compound shown in formula (II) and 5- chlorothiophene -2- first Acyl chlorides carries out condensation reaction, obtains compound shown in formula (I)：
Wherein, HX is hydrochloric acid；
The condensation reaction carries out in the first solvent, and first solvent is the mixed solvent of acetone and water；Described first is molten The volume ratio of acetone and water is 1/2~3/1 in agent；The condensation reaction carries out at 0 DEG C~50 DEG C；
Wherein, compound shown in formula (II) is prepared via a method which to obtain：
(1) make compound shown in formula (III) that ammonolysis reaction occur；And
(2) product of the ammonolysis reaction is subjected to salt-forming reaction, obtains compound shown in the formula (II),
Wherein, compound shown in formula (III) obtains in the following way：By compound and phthalyl shown in formula (IV) Imines or its salt carry out substitution reaction, obtain compound shown in formula (III)：
Wherein, Z is-C (=O)-；
HX is hydrochloric acid；
R is mesyl；
The ammonolysis reaction carries out under the action of amination reagent, and the amination reagent is methylamine；
The dosage of the amination reagent is 2-10 times of the mole of compound shown in the formula (III)；
The ammonolysis reaction carries out in the first polar solvent, and first polar solvent is ethyl alcohol, water or combination thereof；
The ammonolysis reaction carries out at 85 DEG C~90 DEG C；
The ammonolysis reaction further comprises that the purification process of compound shown in formula (II), the purification process are that mashing purifies；
The salt-forming reaction carries out in the 4th solvent, the 4th solvent be methanol, ethyl alcohol, isopropanol, water or they Combination；
The salt of the phthalimide is its sylvite or sodium salt；
The dosage of the salt of the phthalimide is 1.0~2.0 times of the mole of compound shown in formula (IV)；
The substitution reaction carries out in the second polar solvent, and second polar solvent is n,N-Dimethylformamide；
The substitution reaction carries out at 72 DEG C；
Wherein, method acquisition is prepared by the following procedure in compound shown in formula (IV)：
A, compound shown in formula (VII) and 3- morpholones are subjected to coupling reaction, obtain compound shown in formula (VI)；
B, compound shown in formula (VI) is deprotected under the action of fluorine reagent and obtains compound shown in formula (V)；
C, in non-protonic solvent, compound shown in formula (V) is reacted with RCl, obtains compound shown in formula (IV)；
Wherein, Hal Br；
R is mesyl；
Wherein, the coupling reaction described in step A carries out at 90 DEG C~120 DEG C；
Coupling reaction described in step A carries out under the action of the second catalyst, and second catalyst is cuprous iodide, In, the dosage of second catalyst is 5%~20% of the mole of compound shown in formula (VII)；
Coupling reaction described in step A carries out in the presence of ligand, and the ligand is N, N '-dimethyl ethylenediamine, wherein The dosage of the ligand is 10%~40% of the mole of compound shown in formula (VII)；
Coupling reaction described in step A carries out under the action of the second alkali, and second alkali is：Potassium carbonate；
Coupling reaction described in step A carries out in toluene；
Step A further comprises that the purification process of compound shown in formula (VI), the purification process are that mashing purifies.
2. according to the method described in claim 1, wherein, at 0 DEG C~50 DEG C, the 5- chlorothiophene -2- formyl chlorides are dripped It adds in the solution of compound shown in formula (II).
3. according to the method described in claim 1, wherein, at 30 DEG C~50 DEG C, the 5- chlorothiophene -2- formyl chlorides are dripped It adds in the solution of compound shown in formula (II).
4. according to the method described in claim 1, wherein, the condensation reaction carries out at 20 DEG C~30 DEG C.
5. according to the method described in claim 1, wherein, the volume ratio of acetone and water is 7/10~9/ in first solvent 10。
6. according to the method described in claim 1, wherein, the condensation reaction carries out in the presence of the first alkali, described First alkali is potassium carbonate, sodium carbonate or combination thereof.
7. described pure according to the method described in claim 1, wherein, further comprise the purification process of compound shown in formula (I) Change method is recrystallization purifying.
8. according to the method described in claim 7, wherein, the recrystallization purifying carries out in third solvent, described Three solvents are acetic acid and water.
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