WO2018233562A1 - 一种奥司他韦及其异构体的制备方法 - Google Patents

一种奥司他韦及其异构体的制备方法 Download PDF

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WO2018233562A1
WO2018233562A1 PCT/CN2018/091465 CN2018091465W WO2018233562A1 WO 2018233562 A1 WO2018233562 A1 WO 2018233562A1 CN 2018091465 W CN2018091465 W CN 2018091465W WO 2018233562 A1 WO2018233562 A1 WO 2018233562A1
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compound
formula
oseltamivir
reaction
azodicarboxylate
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PCT/CN2018/091465
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English (en)
French (fr)
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陈红军
廖守主
王仲清
曾磊
刘壮丰
罗忠华
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广东东阳光药业有限公司
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Priority to CN201880003804.3A priority Critical patent/CN109890790B/zh
Publication of WO2018233562A1 publication Critical patent/WO2018233562A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/61—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals

Definitions

  • the invention relates to the field of medicinal chemistry, and more particularly to a method for preparing oseltamivir and its isomers.
  • oseltamivir C 16 H 28 N 2 O 4 , and the chemical name is: (3R, 4R, 5S)-4-acetamide-5-amino-3-(1-propoxyethyl)-1 - Ethyl cyclohexene-1-carboxylate having the formula:
  • Oseltamivir is a drug in the form of its phosphate. It was marketed in Switzerland in 1999 and approved to be marketed in China in 2002. It is currently recognized as the most effective anti-avian flu drug and a national strategic reserve drug; therefore its synthesis is very important.
  • CN1113053C discloses oseltamivir and its preparation method for the first time.
  • the method uses epoxide 1 as a starting material and undergoes ring-opening reaction under the action of Brnsted acid to obtain azide compound 2, which undergoes intramolecular nucleophilic substitution reaction to obtain aziridine 3, and compound 3
  • the ring-opening reaction occurs again under the action of Brnsted acid to obtain compound 4, which is protected by acetylation and azide reduction to obtain oseltamivir of formula A.
  • this method is more efficient, it needs to operate azide in the production process, which is highly toxic and explosive.
  • Roche discloses a new method for preparing oseltamivir in the patent CN100545145C.
  • the method still uses Compound 1 as a starting material, and uses a tert-butylamine-magnesium chloride system to carry out a ring-opening reaction to obtain a compound 6, and a hydroxyl group in the compound 6 is activated to undergo an intramolecular nucleophilic substitution reaction to obtain aziridine 7, a nitrogen heterocycle.
  • Propane 7 is subjected to ring-opening reaction under the action of diallylamine-Lewis acid to obtain compound 8, and compound 8 is subjected to an acetyl group protection reaction and a tert-butyl deprotection reaction to obtain compound 10, and compound 10 is in zero-valent palladium-triphenylbenzene.
  • the allyl group is transferred to 1,3-dimethylbarbituric acid catalyzed by a phosphine to give oseltamivir of formula A.
  • the compound of formula B is a common isomer impurity of oseltamivir, which is the free base form of oseltamivir phosphate G in the European Pharmacopoeia and is a common impurity in the production of oseltamivir.
  • Patent CN106278928A discloses a process for the preparation of oseltamivir impurity G.
  • the method comprises the compound 11 as a starting material, and the compound 12 is catalyzed by a chiral Lewis acid to obtain a compound 13 which is subjected to hydrogenolysis at room temperature by a catalyst such as 10% palladium carbon or Raney nickel to form a phosphate.
  • a catalyst such as 10% palladium carbon or Raney nickel to form a phosphate.
  • the first step of the method requires the use of a titanium chiral catalyst, which is highly toxic, high in cost, and low in yield (38%-41%). It is necessary to find a high-efficiency and low-toxic preparation method.
  • the present invention provides another intermediate III for preparing oseltamivir and its isomers as shown in the following formula III,
  • the method for preparing oseltamivir and its isomers provided by the invention has the advantages of safe and high efficiency, mild reaction, simple process, economical and environmental protection and the like.
  • the invention provides an intermediate for the preparation of oseltamivir and its isomers: a compound of formula III; and a process for the preparation of a compound of formula III.
  • the present invention provides a process for the preparation of oseltamivir and its isomers, wherein the compound of the above formula III is an important intermediate or the above process is an important step.
  • the numerical range of the present invention is intended to mean ⁇ 10% of the index value, whether or not it contains "about”.
  • the present invention provides an intermediate for the preparation of oseltamivir and its isomers: a compound of formula III; and a process for the preparation of a compound of formula III,
  • a process for the preparation of a compound of formula III comprising the steps of: a compound of formula II and phthalimide, in the presence of an organic phosphine reagent and an azodicarboxylate diester compound, in an organic Reacting in a solvent to give a compound of formula III,
  • the method of preparing the compound of Formula III compared to the prior art, the raw material is reacted under typical mitsunobu conditions, but the compound of Formula II does not undergo a conventional mitsunobu reaction.
  • the configuration of the hydroxyl group is reversed, but the azodicarboxylate compound and the organophosphine reagent activate the hydroxyl group of the compound of the formula II, and then undergo an intramolecular substitution reaction under the action of the ortho-amino group.
  • the aziridine transition state 15 is formed, and the transition state 15 undergoes stereoselective and regioselective substitution reaction with phthalimide to form the ortho-diamine-based compound III; the reaction mechanism is as follows:
  • the organophosphine reagent can be any organophosphorus reagent capable of participating in hydroxyl activation.
  • the organophosphine reagent is at least one of triphenylphosphine, benzyl diphenylphosphine, trihexylphosphine, tri-p-tolylphosphine, tributylphosphine, and tri-tert-butylphosphine.
  • the organophosphine reagent is used in an amount of from 0.8 mol to 3.0 mol based on 1 mol of the compound of the formula II. In some embodiments, the organophosphine reagent is used in an amount of from 1.0 mole to 2.0 moles relative to 1 mole of the compound of Formula II. In some embodiments, the organophosphine reagent is used in an amount of 1.5 moles relative to 1 mole of the compound of Formula II, which facilitates reaction control and performance.
  • the azodicarboxylate diester compound is at least one of diisopropyl azodicarboxylate, diethyl azodicarboxylate, di-tert-butyl azodicarboxylate and dibenzyl azodicarboxylate. .
  • the azodicarboxylate diester compound is diisopropyl azodicarboxylate or diethyl azodicarboxylate.
  • the azodicarboxylate diester compound is diisopropyl azodicarboxylate, which facilitates reaction control and performance.
  • the azodicarboxylic acid diester compound is used in an amount of from 0.8 mol to 3.0 mol based on 1 mol of the compound of the formula II. In some embodiments, the azodicarboxylate diester compound is used in an amount of from 1.0 mol to 2.0 mol, relative to 1 mol of the compound of Formula II. In some embodiments, the amount of the azodicarboxylate compound is 1.5 moles relative to 1 mole of the compound of Formula II, which facilitates reaction control and performance.
  • the phthalimide is used in an amount of from 0.8 mol to 3.0 mol based on 1 mol of the compound of the formula II. In some embodiments, the phthalimide is used in an amount from 1.0 mol to 2.0 mol relative to 1 mol of the compound of Formula II. In some embodiments, the amount of the phthalimide is 1.5 moles relative to 1 mole of the compound of Formula II, which facilitates reaction control and performance.
  • the organic solvent is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane and ethyl acetate. In some embodiments, the organic solvent is tetrahydrofuran or 2-methyltetrahydrofuran. In some embodiments, the organic solvent is tetrahydrofuran, which facilitates reaction control and performance.
  • the reaction is carried out at -20 ° C to 80 ° C.
  • the reaction temperature is from -5 ° C to 30 ° C to facilitate the reaction.
  • the reaction temperature is -5 ° C to 25 ° C, which facilitates the reaction.
  • the method of preparing the compound of Formula III, after completion of the reaction, may optionally be subjected to a conventional workup to give a relatively pure compound of Formula III.
  • the completion of the reaction means that the content of the compound represented by Formula II is less than or equal to 2.0% by HPLC or the like.
  • the compound of the above formula II can be obtained by reacting a compound of the formula I with a diallylamine in the presence of magnesium chloride in toluene.
  • the method of preparing a compound of Formula III comprising the steps of: reacting a compound of Formula I above with diallylamine in the presence of magnesium chloride in toluene to provide Formula II as defined above.
  • a compound of the formula (II) and a phthalimide are reacted in an organic solvent in the presence of an organophosphine reagent and an azodicarboxylate diester compound to obtain a compound of the above formula III.
  • the method of preparing a compound of Formula III comprising the steps of: the compound of Formula II above and phthalimide, in triphenylphosphine and diisopropyl azodicarboxylate The reaction is carried out in tetrahydrofuran under the presence of the compound to give the compound of the above formula III.
  • the present invention provides a process for the preparation of oseltamivir and its isomers using the compound of formula III as an important intermediate or the method of preparing the compound of formula III as an important step.
  • the method comprises the following steps: the compound of the above formula II and the phthalimide are reacted in an organic solvent in the presence of an organic phosphine reagent and an azodicarboxylic acid diester compound to obtain the compound of the above formula III.
  • an organic phosphine reagent and an azodicarboxylic acid diester compound to obtain the compound of the above formula III.
  • the definitions of the organic phosphine reagent, the azodicarboxylic acid diester compound, and the organic solvent are as described above.
  • a method of preparing oseltamivir of Formula A comprises the steps of: the compound of Formula III above, in 1,3-dimethylbarbituric acid, a palladium catalyst, an organophosphine ligand The reaction is carried out to obtain the compound of formula IV under the conditions present.
  • a method of preparing oseltamivir of Formula A comprising the step of reacting a compound of Formula IV with acetic anhydride under basic conditions to provide a compound of Formula V.
  • a method of preparing oseltamivir of Formula A comprising the steps of: a compound of Formula III in 1,3-dimethylbarbituric acid, a palladium catalyst, an organophosphine ligand The reaction is carried out under the conditions present to give a compound of formula IV; the compound of formula IV is reacted with acetic anhydride under basic conditions to provide the compound of formula V.
  • a method of preparing oseltamivir of Formula A comprising the steps of: a compound of Formula III in 1,3-dimethylbarbituric acid, a palladium catalyst, an organophosphine ligand The reaction is carried out to obtain a compound of the formula IV; the compound of the formula IV is reacted with acetic anhydride under basic conditions to give a compound of the formula V; the compound of the formula V is reacted under the action of hydrazine hydrate. The compound of formula A is obtained.
  • the method of preparing oseltamivir of Formula A comprises the steps of: a compound of Formula II and phthalimide, in an organophosphine reagent and an azodicarboxylate
  • the compound of the formula III is obtained by reacting in an organic solvent in the presence of a compound; the compound of the formula III is carried out in the presence of 1,3-dimethylbarbituric acid, a palladium catalyst, and an organophosphine ligand.
  • the reaction is carried out to obtain a compound of the formula IV; the compound of the formula IV is reacted with acetic anhydride under basic conditions to obtain a compound of the formula V; the compound of the formula V is reacted under the action of hydrazine hydrate to obtain the formula A. Show compound.
  • the method of preparing oseltamivir of Formula A comprises the steps of: a compound of Formula II and phthalimide, in the presence of triphenylphosphine and azodicarboxylic acid In the presence of isopropyl ester, it is reacted in tetrahydrofuran to give a compound of formula III; the compound of formula III is present in the presence of 1,3-dimethylbarbituric acid, palladium acetate or triphenylphosphine.
  • the reaction is carried out in ethanol to obtain a compound of the formula IV; the compound of the formula IV is reacted with acetic anhydride in the presence of sodium hydrogencarbonate to obtain a compound of the formula V; the compound of the formula V is subjected to the action of hydrazine hydrate.
  • the reaction is carried out in ethanol to give a compound of the formula A.
  • a method for preparing the oseltamivir isomer of the formula B comprising the steps of: the compound of the above formula III is reacted under the action of hydrazine hydrate to obtain a compound of the formula VI
  • the method of preparing the oseltamivir isomer of Formula B comprising the steps of: the compound of Formula II above and phthalimide, in the organophosphorus reagent and azodicarboxylic acid
  • the compound of the formula III is obtained by reacting in an organic solvent in the presence of a diester compound.
  • a method of preparing an oseltamivir isomer of Formula B comprising the steps of: reacting a compound of Formula VI above with acetic anhydride under basic conditions to provide a compound of Formula VII
  • a method for preparing the oseltamivir isomer of formula B comprising the steps of: reacting a compound of formula III under the action of hydrazine hydrate to obtain a compound of formula VI; the compound of formula VI is in basic condition The reaction is carried out with acetic anhydride to give a compound of the formula VII.
  • a method for preparing the oseltamivir isomer of formula B comprising the steps of: reacting a compound of formula III under the action of hydrazine hydrate to obtain a compound of formula VI; the compound of formula VI is in basic condition The reaction with acetic anhydride is carried out to obtain a compound of the formula VII; the compound of the formula VII is reacted in the presence of 1,3-dimethylbarbituric acid, a palladium catalyst and an organophosphine ligand to obtain a formula B. Show compound.
  • the method of preparing the oseltamivir isomer of Formula B comprises the steps of: a compound of Formula II and phthalimide, in an organophosphine reagent and azodicarboxylic acid In the presence of an ester compound, it is reacted in an organic solvent to obtain a compound of the formula III; the compound of the formula III is reacted under the action of hydrazine hydrate to obtain a compound of the formula VI; the compound of the formula VI is in a basic condition. The reaction is carried out with acetic anhydride to give a compound of the formula VII.
  • the method of preparing the oseltamivir isomer of Formula B comprises the steps of: a compound of Formula II and phthalimide, in an organophosphine reagent and azodicarboxylic acid In the presence of an ester compound, it is reacted in an organic solvent to obtain a compound of the formula III; the compound of the formula III is reacted under the action of hydrazine hydrate to obtain a compound of the formula VI; the compound of the formula VI is in a basic condition.
  • the reaction with acetic anhydride is carried out to obtain a compound of the formula VII; the compound of the formula VII is reacted in the presence of 1,3-dimethylbarbituric acid, a palladium catalyst and an organophosphine ligand to obtain a formula B. Show compound.
  • the method of preparing the oseltamivir isomer of Formula B comprises the steps of: a compound of Formula II and phthalimide, in triphenylphosphine and azodicarboxylic acid
  • the compound of the formula III is obtained by reacting in the presence of diisopropyl ester in tetrahydrofuran; the compound of the formula III is reacted in ethanol under the action of hydrazine hydrate to obtain a compound of the formula VI;
  • the compound is reacted with acetic anhydride in the presence of sodium hydrogencarbonate to give a compound of the formula VII; the compound of the formula VII is present in the presence of 1,3-dimethylbarbituric acid, palladium acetate, triphenylphosphine
  • the reaction is carried out in ethanol to give the compound of the formula B.
  • the method of preparing oseltamivir and its isomers of the present invention can be as shown in the following formula:
  • MgCl 2 is magnesium chloride
  • DIAD diisopropyl azodicarboxylate
  • PPh 3 is triphenylphosphine
  • 1,3-Dimethybarbituric is 1.3-dimethylbarbituric acid
  • Pd(OAc) 2 is palladium acetate.
  • a C2 O is acetic anhydride
  • NaHCO 3 is sodium hydrogencarbonate
  • H 2 O is hydrazine hydrate
  • EtOH is ethanol.
  • the organophosphine ligand of the present invention may be a class of organophosphines of triphenylphosphine, benzyldiphenylphosphine, trihexylphosphine, tri-p-tolylphosphorus, tributylphosphine or tri-tert-butylphosphine. body.
  • the method for preparing the compound of the formula III or other compounds according to the present invention may appropriately adjust the reaction conditions according to the disclosure, such as selecting other suitable reaction solvents, Adjust the temperature of the reaction, and appropriately extend the reaction time to obtain a better reaction effect.
  • R 1 may be hydrogen, allyl, tert-butyl, benzyl, C1-C4 alkoxy-substituted benzyl, trityl, nitro, C1-C4 alkyl-substituted benzene Sulfonyl, benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl or fluorenylmethoxycarbonyl;
  • the R 2 may be hydrogen, allyl, tert-butyl, benzyl, C1-C4 alkoxy-substituted benzyl, trityl, nitro, C1-C4 alkyl-substituted benzenesulfonyl , benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl or fluorenylmethoxycarbonyl;
  • the R 1 may also be ring-formed with R 2 together to represent a phthaloyl group, a C1-C4 alkyl group or an alkoxy-substituted phthaloyl group;
  • the R 3 may be hydrogen, allyl, tert-butyl, benzyl, C1-C4 alkoxy-substituted benzyl, trityl, nitro, C1-C4 alkyl-substituted benzenesulfonyl , benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl or fluorenylmethoxycarbonyl;
  • the R 4 may be hydrogen, allyl, tert-butyl, benzyl, C1-C4 alkoxy-substituted benzyl, trityl, nitro, C1-C4 alkyl-substituted benzenesulfonyl , benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl or fluorenylmethoxycarbonyl;
  • the R 3 may also be ring-formed with R 4 together to represent a phthaloyl group, a C1-C4 alkyl group or an alkoxy-substituted phthaloyl group;
  • the present invention also provides a process for the preparation of a compound of formula IX at room temperature using the participation of an ortho group under mitsunobu reaction conditions.
  • a process for the preparation of a compound of the formula IX comprising the steps of: a compound of the formula VIII and an organic amine of the formula XV, in the presence of an organic phosphine reagent and an azodicarboxylic acid diester compound, in an organic Reaction in a solvent to give a compound of formula IX
  • R 1 , R 2 , R 3 and R 4 have the same meanings as defined above.
  • the present invention also provides a process for preparing oseltamivir or an isomer thereof of the formula A, wherein the compound of the formula IX is used as an intermediate or the method for preparing the compound of the formula IX described above is a key step.
  • the method for preparing oseltamivir and the isomer of the formula B represented by the formula A comprising the steps of: the compound represented by the above formula VIII and the organic amine represented by the above formula XV, in an organophosphorus reagent and
  • the compound represented by the above formula IX is obtained by reacting in an organic solvent in the presence of an azodicarboxylic acid diester compound.
  • R 1 , R 2 , R 3 and R 4 have the same meanings as defined above.
  • the method of preparing oseltamivir of Formula A comprises the steps of:
  • the compound of the formula VIII and the organic amine of the formula XV are reacted in an organic solvent in the presence of an organic phosphine reagent and an azodicarboxylic acid diester compound to obtain a compound of the formula IX; a compound of the formula IX;
  • the reaction is carried out under deprotection to obtain a compound of the formula X;
  • the compound of the formula X is reacted with acetic anhydride under basic conditions to give a compound of the formula XI;
  • the compound of the formula XI is subjected to deprotection. Carry out the reaction to obtain the compound of formula A
  • a method of preparing the oseltamivir isomer of Formula B comprising the steps of:
  • the compound of the formula VIII and the organic amine of the formula XV are reacted in an organic solvent in the presence of an organic phosphine reagent and an azodicarboxylic acid diester compound to obtain a compound of the formula IX; a compound of the formula IX;
  • the deprotection reaction is carried out under deprotection to obtain a compound of the formula XII; the compound of the formula XII is reacted with acetic anhydride under basic conditions to obtain a compound of the formula XIII; the compound of the formula XIII is deprotected.
  • the method of preparing oseltamivir and its isomers of the present invention can be as shown in the following formula:
  • MgCl 2 is magnesium chloride
  • DIAD is diisopropyl azodicarboxylate
  • PPh 3 is triphenylphosphine
  • a C2 O is acetic anhydride.
  • the present invention exemplarily provides a part of the preparation examples, and further non-limiting examples are further disclosed below to further explain the present invention.
  • reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
  • mmol means mmol
  • mol/L and N means mole/liter
  • h means hour
  • g means gram
  • ml means liter
  • L means liter
  • °C means celsius
  • HPLC means high performance liquid chromatography
  • HRMS means high resolution Mass spectrometry
  • QTOF/ESI+ indicates electrospray-quadrupole time-of-flight tandem mass spectrometry
  • CDCl3 deuterated chloroform
  • PE petroleum ether
  • EA ethyl acetate
  • the reaction was heated to 25 ° C and stirred for about 6 h.
  • the reaction solution was concentrated to dryness in vacuo at 35 ° C, then added with cyclohexane (200 ml) and water (200 ml).
  • the mixture was stirred for 1 hour, and then allowed to stand.
  • the upper part was cyclohexane/water, and the lower part was insoluble semi-solid, and the upper part was divided.
  • the liquid and the aqueous phase were transferred to a semi-solid, and then the mixture was added to hexane (200 ml).
  • the mixture was stirred and stirred for 1 h, and then the mixture was evaporated to give the crude crystals of crude product (54.96 g). step.
  • the reaction solution was concentrated to dryness in vacuo at 35 °C. After adding 20% aqueous phosphoric acid solution (200 ml) and dichloromethane (150 ml), the mixture was stirred for 30 min, and then left to stand. The aqueous phase was washed twice with dichloromethane (2*150 ml) and then dichloromethane (300 ml) was added. Then, the pH of the aqueous phase was adjusted to 8 with sodium carbonate solid, and the mixture was allowed to stand for separation. The aqueous phase was extracted twice with dichloromethane (100 ml ⁇ 2), and the combined dichloromethane phases were dried over anhydrous sodium sulfate and filtered.
  • the synthetic method provided by the present invention can efficiently prepare the compound represented by the formula III, and further synthesize oseltamivir and its isomer impurities by the compound represented by the formula III.
  • the method of the invention has the advantages of easy availability of raw materials, mild and efficient reaction, simple process, economy and environmental protection.

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Abstract

本发明涉及一种制备奥司他韦及其异构体的中间体，本发明所述的中间体，是在mitsunobu反应条件下利用邻基参与作用在室温下制备获得。更进一步的，本发明还提供了一种以上述中间体或者上述制备方法为关键步骤的制备奥司他韦及其异构体的方法。本发明所述的方法具有高效、温和、低毒、经济环保等优点，非常适合工业化生产。

Description

一种奥司他韦及其异构体的制备方法 技术领域
本发明涉及医药化工领域，更具体地涉及一种奥司他韦及其异构体的制备方法。
背景技术
奥司他韦的分子式为C 16H 28N 2O 4,化学名为：(3R,4R,5S)-4-乙酰胺-5-胺基-3-(1-丙氧乙酯)-1-环己烯-1-羧酸乙酯，结构式如下式A所示：
Figure PCTCN2018091465-appb-000001
奥司他韦以其磷酸盐形式成药，1999年在瑞士上市，2002年获准在中国上市，是目前公认的抗禽流感最为有效的药物，也是国家战略储备药物；因此它的合成非常重要。
现有技术中公开了一些奥司他韦的制备方法，如：
CN1113053C首次公开了奥司他韦及其制备方法。该方法以环氧化物1为起始物料，在布朗斯特酸的作用下进行开环反应得到叠氮化合物2，该化合物发生分子内的亲核取代反应得到氮杂环丙烷3，化合物3在布朗斯特酸的作用下再次发生开环反应得到化合物4，化合物4经过上乙酰基保护及叠氮化物还原反应得到式A所示的奥司他韦。该方法虽然比较高效，但是，在生产过程中需要操作叠氮化物，剧毒易爆，同时，使用叠氮化物还会发生竞争性的叠氮化物共轭加成反应，从而导致少量β-叠氮酯副产物生成及最终产物的埃姆斯实验呈阳性结果。该路线的反应式如下：
Figure PCTCN2018091465-appb-000002
为避免合成操作中使用叠氮化物，罗氏在专利CN100545145C公开了一种新的制备奥司他韦的方法。该方法仍以化合物1为起始物料，使用叔丁胺-氯化镁体系进行开环反应得到化合物6，化合物6中的羟基被活化后发生分子内的亲核取代反应得到氮杂环丙烷7，氮杂环丙烷7在二烯丙基胺-路易斯酸的作用下进行开环反应得到化合物8，化合物8经过乙酰基上保护反应和叔丁基脱保护反应得到化合物10，化合物10在零价钯-三苯基膦的催化下将烯丙基转移至1,3-二甲基巴比妥酸得到式A所示的奥司他韦。该方法虽然解决了叠氮操作及埃姆斯实试验的问题，但是在氮杂环丙烷成环及开环一步反应条件均较为苛刻，操作复杂。反应路线如下：
Figure PCTCN2018091465-appb-000003
综上所述，找到一条安全、高效、温和且操作简单的奥司他韦的合成路线十分必要。
式B所示的化合物为奥司他韦常见的异构体杂质，为欧洲药典中磷酸奥司他韦杂质G的游离碱形式，是奥司他韦生产中一种常见的杂质。找到一种高效简便的合成杂质G游离碱的方法，可为奥司他韦质量标准研究中杂质G的定量分析及奥司他韦生产中产品质量控制提供帮助，从而为广大群众的安全用药提供保障。
Figure PCTCN2018091465-appb-000004
专利CN106278928A公开了奥司他韦杂质G的制备方法。该方法以化合物11为起始原料，与化合物12在手性路易斯酸催化下得到化合物13，化合物13通过10％钯碳或雷尼镍等催化剂在室温下氢解脱去氨基保护并成磷酸盐。反应式如下：
Figure PCTCN2018091465-appb-000005
该方法中第一步反应需要使用钛手性催化剂，毒性大，成本高，且收率较低(38％-41％)，找到一种高效低毒的制备方法十分必要。
发明内容
发明概述
相比现有技术，本发明提供另一种如下式III所示的用于制备奥司他韦及其异构体的中间体III，
Figure PCTCN2018091465-appb-000006
本发明所提供的制备奥司他韦及其异构体的方法具有安全高效、反应温和、工艺简洁、经济环保等优点。
第一方面，本发明提供了一种制备奥司他韦及其异构体的中间体：如式III所示的化合物；并提供了制备式III所示的化合物的方法。
第二方面，本发明提供一种以上述式III所示化合物为重要中间体或者以上述方法为重要步骤的制备奥司他韦及其异构体的方法。
术语定义
本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意合适的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和1994年第75版《化学和物理手册》一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
本发明的数值范围之前不管是否含“约”，均指所指数值的±10％。
发明详述
第一方面，本发明提供了一种制备奥司他韦及其异构体的中间体：如式III所示的化合物；并提供了制备式III所示的化合物的方法，
Figure PCTCN2018091465-appb-000007
一种制备式III所示的化合物的方法，包括以下步骤：式II所示化合物与邻苯二甲酰亚胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到式III所示化合物，
Figure PCTCN2018091465-appb-000008
在一些实施方式中，所述制备式III所示的化合物的方法，相比于现有技术，原料虽然在典型的mitsunobu条件下进行反应，但是式II所示的化合物并未发生传统的mitsunobu反应，实现羟基位置的构型翻转，而是偶氮二甲酸二酯类化合物和有机膦试剂对式II所示化合物的羟基进行活化后，在邻位氨基的作用下，发生了分子内的取代反应，形成了氮杂环丙烷过渡态15，过渡态15与邻苯二甲酰亚胺发生立体选 择性及区域选择性的取代反应形成邻位双胺基化合物III；反应机理如下式所示：
Figure PCTCN2018091465-appb-000009
所述有机膦试剂可以是任意能够参与羟基活化的有机膦试剂。在一些实施例中，所述有机膦试剂为三苯基膦，苄基二苯基膦、三己基膦、三对甲苯基磷、三丁基膦和三叔丁基膦中的至少一种。
相对于1mol的式II所示化合物，所述有机膦试剂用量为0.8mol-3.0mol。在一些实施例中，相对于1mol的式II所示化合物，所述有机膦试剂用量为1.0mol-2.0mol。在一些实施例中，相对于1mol的式II所示化合物，所述有机膦试剂用量为1.5mol，有利于反应控制和进行。
所述的偶氮二甲酸二酯类化合物为偶氮二甲酸二异丙酯、偶氮二甲酸二乙酯、偶氮二甲酸二叔丁酯及偶氮二甲酸二苄酯中的至少一种。在一些实施例中，所述的偶氮二甲酸二酯类化合物为偶氮二甲酸二异丙酯或偶氮二甲酸二乙酯。在一些实施例中，所述的偶氮二甲酸二酯类化合物为偶氮二甲酸二异丙酯，有利于反应控制和进行。
相对于1mol的式II所示化合物，所述偶氮二甲酸二酯类化合物用量为0.8mol-3.0mol。在一些实施例中，相对于1mol的式II所示化合物，所述偶氮二甲酸二酯类化合物用量为1.0mol-2.0mol。在一些实施例中，相对于1mol的式II所示化合物，所述偶氮二甲酸二酯类化合物用量为1.5mol，有利于反应控制和进行。
相对于1mol的式II所示化合物，所述邻苯二甲酰亚胺用量为0.8mol-3.0mol。在一些实施例中，相对于1mol的式II所示化合物，所述邻苯二甲酰亚胺用量为1.0mol-2.0mol。在一些实施例中，相对于1mol的式II所示化合物，所述邻苯二甲酰亚胺用量为1.5mol，有利于反应控制和进行。
所述的有机溶剂为四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、二氯甲烷及乙酸乙酯中的至少一种。在一些实施例中，所述的有机溶剂为四氢呋喃或2-甲基四氢呋喃。在一些实施例中，所述的有机溶剂为四氢呋喃，有利于反应控制和进行。
所述制备式III所示的化合物的方法中，反应在-20℃-80℃下进行。在一些实施例中，所述制备式III所示的化合物的方法中，反应温度为-5℃-30℃，有利于反应进行。在一些实施例中，所述制备式III所示的化合物的方法中，反应温度为-5℃-25℃，有利于反应进行。
所述制备式III所示的化合物的方法，反应结束后，可以任选地进行常规的后处理以得到较纯的式III所示的化合物。所述的反应结束，是指通过HPLC等方法检测，式II所示的化合物含量小于或等于2.0％。
上述式II所示的化合物，可以通过式I所示化合物与二烯丙基胺在氯化镁存在的条件下在甲苯中反应 制备获得，
Figure PCTCN2018091465-appb-000010
在一些实施例中，所述制备式III所示化合物的方法，包括以下步骤：前述式I所示化合物与二烯丙基胺在氯化镁存在的条件下在甲苯中反应，得到前述式II所示化合物；式II所示化合物与邻苯二甲酰亚胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到前述式III所示化合物。
在一些实施例中，所述制备式III所示化合物的方法，包括以下步骤：前述式II所示化合物与邻苯二甲酰亚胺，在三苯基膦与偶氮二甲酸二异丙酯存在的条件下，在四氢呋喃中反应，得到前述式III所示化合物。
第二方面，本发明提供一种以式III所示化合物为重要中间体或者以上述制备式III所示化合物方法为重要步骤的制备奥司他韦及其异构体的方法。
一种制备式A所示的奥司他韦及式B所示的其异构体的方法
Figure PCTCN2018091465-appb-000011
包括以下步骤：前述式II所示化合物与邻苯二甲酰亚胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到前述式III所示化合物；其中，有机膦试剂、偶氮二甲酸二酯类化合物、有机溶剂的定义如前所述。
在一些实施例中，一种制备式A所示的奥司他韦的方法包括以下步骤：前述式III所示化合物在1,3-二甲基巴比妥酸、钯催化剂、有机膦配体存在的条件下，进行反应得到式IV所示化合物
Figure PCTCN2018091465-appb-000012
在一些实施例中，一种制备式A所示的奥司他韦的方法，包括以下步骤：式IV所示化合物在碱性条件下与乙酸酐进行反应，得到式V所示化合物
Figure PCTCN2018091465-appb-000013
在一些实施例中，一种制备式A所示的奥司他韦的方法，包括以下步骤：式III所示化合物在1,3-二甲基巴比妥酸、钯催化剂、有机膦配体存在的条件下，进行反应得到式IV所示化合物；式IV所示化合物在碱性条件下与乙酸酐进行反应，得到式V所示化合物。
在一些实施例中，一种制备式A所示的奥司他韦的方法，包括以下步骤：式III所示化合物在1,3-二甲基巴比妥酸、钯催化剂、有机膦配体存在的条件下，进行反应得到式IV所示化合物；式IV所示化合物在碱性条件下与乙酸酐进行反应，得到式V所示化合物；式V所示化合物在水合肼的作用下进行反应，得到式A所示化合物。
在一些实施例中，所述制备式A所示的奥司他韦的方法，包括以下步骤：式II所示化合物与邻苯二甲酰亚胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到式III所示化合物；式III所示化合物在1,3-二甲基巴比妥酸、钯催化剂、有机膦配体存在的条件下进行反应，得到式IV所示化合物；式IV所示化合物在碱性条件下与乙酸酐进行反应，得到式V所示化合物；式V所示化合物在水合肼的作用下进行反应，得到式A所示化合物。
在一些实施例中，所述制备式A所示的奥司他韦的方法，包括以下步骤：式II所示化合物与邻苯二甲酰亚胺，在三苯基膦与偶氮二甲酸二异丙酯存在的条件下，在四氢呋喃中反应，得到式III所示化合物；式III所示化合物在1,3-二甲基巴比妥酸、醋酸钯、三苯基膦存在的条件下在乙醇中进行反应，得到式IV所示化合物；式IV所示化合物在碳酸氢钠存在的条件下与乙酸酐进行反应，得到式V所示化合物；式V所 示化合物在水合肼的作用下在乙醇中进行反应，得到式A所示化合物。
一种制备式B所示的奥司他韦异构体的方法，包括以下步骤：前述式III所示化合物在水合肼的作用下进行反应，得到式VI所示化合物
Figure PCTCN2018091465-appb-000014
在一些实施例中，所述制备式B所示的奥司他韦异构体的方法，包括以下步骤：前述式II所示化合物与邻苯二甲酰亚胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到式III所示化合物。
在一些实施方式中，一种制备式B所示的奥司他韦异构体的方法，包括以下步骤：前述式VI所示化合物在碱性条件下与乙酸酐进行反应，得到式VII所示化合物
Figure PCTCN2018091465-appb-000015
一种制备式B所示的奥司他韦异构体的方法，包括以下步骤：式III所示化合物在水合肼的作用下进行反应，得到式VI所示化合物；式VI所示化合物在碱性条件下与乙酸酐进行反应，得到式VII所示化合物。
一种制备式B所示的奥司他韦异构体的方法，包括以下步骤：式III所示化合物在水合肼的作用下进行反应，得到式VI所示化合物；式VI所示化合物在碱性条件下与乙酸酐进行反应，得到式VII所示化合物；式VII所示化合物在1,3-二甲基巴比妥酸、钯催化剂、有机膦配体存在的条件下进行反应，得到式B所示化合物。
在一些实施例中，所述制备式B所示的奥司他韦异构体的方法，包括以下步骤：式II所示化合物与邻苯二甲酰亚胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到式III所示化合物；式III所示化合物在水合肼的作用下进行反应得到式VI所示化合物；式VI所示化合物在碱性条件下与乙酸酐进行反应，得到式VII所示化合物。
在一些实施例中，所述制备式B所示的奥司他韦异构体的方法，包括以下步骤：式II所示化合物与邻苯二甲酰亚胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到式III所示化合物；式III所示化合物在水合肼的作用下进行反应得到式VI所示化合物；式VI所示化合物在碱性条件下与乙酸酐进行反应，得到式VII所示化合物；式VII所示化合物在1,3-二甲基巴比妥酸、钯催化剂、有机膦配体存在的条件下进行反应，得到式B所示化合物。
在一些实施例中，所述制备式B所示的奥司他韦异构体的方法，包括以下步骤：式II所示化合物与邻苯二甲酰亚胺，在三苯基膦与偶氮二甲酸二异丙酯存在的条件下，在四氢呋喃中反应，得到式III所示化合物；式III所示化合物在水合肼的作用下，在乙醇中进行反应，得到式VI所示化合物；式VI所示化合物在碳酸氢钠存在的条件下与乙酸酐进行反应，得到式VII所示化合物；式VII所示化合物在1,3-二甲基巴比妥酸、醋酸钯、三苯基膦存在的条件下在乙醇中进行反应，得到式B所示化合物。
在一些实施方式中，本发明所述的制备奥司他韦及其异构体的方法，可以如下述通式所示：
Figure PCTCN2018091465-appb-000016
其中，MgCl 2为氯化镁，DIAD为偶氮二甲酸二异丙酯，PPh 3为三苯基膦，1,3-Dimethybarbituric为1.3-二甲基巴比妥酸，Pd(OAc) 2为醋酸钯，A C2O为醋酸酐，NaHCO 3为碳酸氢钠，NH 2NH 2 .H 2O为水合肼，EtOH为乙醇。
本发明所述的有机膦配体可以为三苯基膦、苄基二苯基膦、三己基膦、三对甲苯基磷、三丁基膦、或三叔丁基膦的一类有机膦配体。
本发明所述的制备式III化合物或其它化合物的方法，本领域技术人员，在本发明的构思下，可以根据公开的内容，视情况需要适当地调整反应条件，如选择其他适当的反应溶剂，调整反应的温度，适当延长反应时间以获得更好的反应效果等。
此外，本发明所述的制备奥司他韦及其异构体的中间体，可以由式III所示的化合物扩展至式IX所示的通式化合物：
Figure PCTCN2018091465-appb-000017
其中，所述R 1可以为氢、烯丙基、叔丁基、苄基、C1-C4的烷氧基取代的苄基、三苯甲基、硝基、C1-C4的烷基取代的苯磺酰基、苯甲酰基、苄氧羰基、叔丁氧羰基、烯丙氧羰基或芴甲氧羰基；
所述R 2可以为氢、烯丙基、叔丁基、苄基、C1-C4的烷氧基取代的苄基、三苯甲基、硝基、C1-C4的烷基取代的苯磺酰基、苯甲酰基、苄氧羰基、叔丁氧羰基、烯丙氧羰基或芴甲氧羰基；
所述R 1也可以和R 2成环，一起表示邻苯二甲酰基、C1-C4的烷基或烷氧基取代的邻苯二甲酰基；
所述R 3可以为氢、烯丙基、叔丁基、苄基、C1-C4的烷氧基取代的苄基、三苯甲基、硝基、C1-C4的烷基取代的苯磺酰基、苯甲酰基、苄氧羰基、叔丁氧羰基、烯丙氧羰基或芴甲氧羰基；
所述R 4可以为氢、烯丙基、叔丁基、苄基、C1-C4的烷氧基取代的苄基、三苯甲基、硝基、C1-C4的烷基取代的苯磺酰基、苯甲酰基、苄氧羰基、叔丁氧羰基、烯丙氧羰基或芴甲氧羰基；
所述R 3也可以和R 4成环，一起表示邻苯二甲酰基、C1-C4的烷基或烷氧基取代的邻苯二甲酰基；
本发明还提供在mitsunobu反应条件下利用邻基参与作用在室温下制备式IX所示的化合物的方法。
一种制备式IX所示的化合物的方法，包括以下步骤：式VIII所示化合物与式XV所示的有机胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到式IX所示化合物
Figure PCTCN2018091465-appb-000018
其中，R 1、R 2、R 3、R 4的含义如前所述。
本发明还提供一种以式IX所示化合物为中间体或者以上述制备式IX所示化合物的方法为关键步骤的制备式A所示的奥司他韦或其异构体的方法。
所述制备式A所示的奥司他韦及其式B所示的异构体的方法，包括以下步骤：前述式VIII所示化合物与前述式XV所示的有机胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到前述式IX所示化合物
Figure PCTCN2018091465-appb-000019
其中，R 1、R 2、R 3、R 4的含义如前所述。
在一些实施例中，所述制备式A所示的奥司他韦的方法，包括以下步骤：
Figure PCTCN2018091465-appb-000020
式VIII所示化合物与式XV所示的有机胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到式IX所示化合物；式IX所示化合物在脱保护的条件下进行反应，得到式X所示化合物；式X所示化合物在碱性条件下与乙酸酐进行反应，得到式XI所示化合物；式XI所示化合物在脱保护的条件下进行反应，得到式A所示化合物
Figure PCTCN2018091465-appb-000021
一种制备式B所示的奥司他韦异构体的方法，包括以下步骤：
Figure PCTCN2018091465-appb-000022
式VIII所示化合物与式XV所示的有机胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到式IX所示化合物；式IX所示化合物在脱保护的条件下进行脱保护反应，得到式XII所示化合物；式XII所示化合物在碱性条件下与乙酸酐进行反应，得到式XIII所示化合物；式XIII所示化合物在脱保护的条件下进行脱保护反应，得到式B所示化合物
Figure PCTCN2018091465-appb-000023
在一些实施方式中，本发明所述的制备奥司他韦及其异构体的方法，可以如下述通式所示：
Figure PCTCN2018091465-appb-000024
其中，MgCl 2为氯化镁，DIAD为偶氮二甲酸二异丙酯，PPh 3为三苯基膦，A C2O为醋酸酐。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，本发明示例地提供一部分制备实施例，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
本发明中，mmol表示毫摩尔，mol/L及N表示摩尔/升，h表示小时，g表示克，ml表示毫升，L表示升，℃表示摄氏度，HPLC表示高效液相色谱，HRMS表示高分辨质谱，QTOF/ESI+表示电喷雾-四级杆飞行时间串联质谱，TLC表示薄层色谱法；CDCl3：氘代氯仿；PE：石油醚，EA：乙酸乙酯；。
实施例1 制备(3R,4S,5R)-5-(二烯丙基氨基)-4-羟基-3-(戊-3-基氧基)环己-1-烯甲酸乙酯II
Figure PCTCN2018091465-appb-000025
将氯化镁(11.23g，1.0eq)、甲苯(180ml)加入到500ml单口瓶中，氮气保护下滴加二烯丙基胺(13.75g，1.2eq)，25℃搅拌6h。然后向体系中滴加(1S,5R,6S)-5-(戊-3-基氧基)-7-氧杂并环[4.1.0]庚-3-烯-3-甲酸乙酯I(30.00g)的甲苯(120ml)溶液，体系升温至50℃搅拌1.5h后加入二烯丙基胺(13.75g，1.2eq)，反应约12h。反应完毕后，体系降温至25℃，向反应体系加入200.0ml 10％柠檬酸水溶液，搅拌30min后静置、分液，有机相用无水硫酸钠(10.00g)干燥1h，过滤后浓缩得到40.52g淡黄色油状物粗产品，粗品产率为97.7％，所得粗品直接用于下一步合成。取样5.0g进行柱层析(PE:EA＝30mL:1mL，Rf＝0.3)分离得到淡黄色油状物4.72g。1H NMR(400MHz,CDCl3)δ6.68(dd,J＝5.4,1.8Hz,1H),5.72–5.62(m,2H),5.06(d,J＝17.4Hz,2H),4.99(d,J＝10.2Hz,2H),4.13-4.09(m,1H),4.05(q,J＝7.4Hz,2H),3.55-3.43(m,2H),3.27-3.14(m,3H),2.91(dd,J＝14.1,7.8Hz,2H),2.49(dd,J＝17.6,5.2Hz,1H),1.99(ddd,J＝17.6,10.8,2.0Hz,1H),1.51–1.30(m,4H),1.15(t,J＝7.4Hz,3H),0.82(t,J＝7.4Hz,3H),0.76(t,J＝7.4Hz,3H)；13C NMR(151MHz,CDCl3)δ166.33,136.08,134.77,131.59,117.28,82.79,70.67,69.81,60.53,54.63,52.52,26.70,26.41,23.40,14.09,10.14,9.08；HRMS(QTOF/ESI+)，m/z：352.2496，(M+H+)，C20H34NO4：352.2488。
实施例2 制备(3R,4R,5S)-4-(二烯丙基氨基)-5-(1,3-二氧代异吲哚-2-基)-3-(戊-3-基氧基)环己-1-烯
甲酸乙酯III
Figure PCTCN2018091465-appb-000026
将化合物(3R,4S,5R)-5-(二烯丙基氨基)-4-羟基-3-(戊-3-基氧基)环己-1-烯甲酸乙酯II(40.00g)、三苯基膦(44.77g，1.5eq)、邻苯二甲酰亚胺(25.12g，1.5eq)和THF(400ml)加入1000ml单口瓶中，在氮气球保护下于-5℃中搅拌0.5h。然后滴加偶氮二甲酸二异丙酯(34.52g，1.5eq)，约1.0h滴加完毕，将反应体系升温至25℃搅拌约6h。反应液35℃真空浓缩干，然后加入环己烷(200ml)和水(200ml)打浆搅拌1h后静置，上部分为环己烷/水，下部分为不溶的半固体，将上部分进行分液，水相转移至半固体加入正己烷(200ml)继续打浆搅拌1h后重复上述操作，合并的有机相浓缩得到黄色油状物粗产品(54.96g)，粗品产率为100.5％，直接用于下一步。取样5.00g进行柱层析(PE:EA＝40mL:1mL，Rf＝0.3)分离得到淡黄色油状物4.16g。1H NMR(400MHz,CDCl3)δ7.81(dd,J＝5.2,3.2Hz,2H),7.74-7.66(m,2H),6.92(s,1H),5.46-5.36(m,2H),4.93(dd,J＝17.2,1.2Hz,2H),4.86(d,J＝10.0Hz,2H),4.44-4.37(m,2H),4.16(q,J＝6.8Hz,2H),3.75(dd,J＝11.8,8.2Hz,1H),3.52-3.46(m,1H),3.27-3.18(m,5H),2.63(dd,J＝17.2,5.2Hz,1H),1.73-1.49(m,4H),1.24(t,J＝7.2Hz,3H),0.92(t,J＝7.2Hz,3H),0.90(t,J＝7.2Hz,3H)；13C NMR(151MHz,CDCl3)δ168.17,166.10,138.18,137.30,128.78,116.20,78.80,73.32,60.72,59.68,53.46,47.39,28.94,26.00,25.11,14.18,9.45,9.26；HRMS(QTOF/ESI+),m/z 481.2697,(M+H+),C28H37N2O5:481.2702。
实施例3 制备(3R,4R,5S)-4-氨基-5-(1,3-二氧代异吲哚-2-基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯IV
Figure PCTCN2018091465-appb-000027
将化合物(3R,4R,5S)-4-(二烯丙基氨基)-5-(1,3-二氧代异吲哚-2-基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯III(28.00g)、1,3-二甲基巴比妥酸(13.65g，1.5eq)、醋酸钯(0.26g，0.02eq)、三苯基膦(1.22g，0.08eq)和乙醇(200ml)加入到500ml单口瓶中，体系在氮气保护下35℃搅拌3h。反应液35℃真空浓缩干。加入20％的磷酸水溶液(200ml)和二氯甲烷(150ml)，搅拌30min后静置、分液，水相再用二氯甲烷(2*150ml)洗涤2次后加入 二氯甲烷(300ml)，然后用碳酸钠固体调节水相PH至8，静置、分液，水相再用二氯甲烷(100ml×2)萃取2次，合并的二氯甲烷相用无水硫酸钠干燥，过滤，滤液30℃浓缩得到白色固体产品(19.62g)，产率为84.1％。1H NMR(400MHz,CDCl3)δ7.84-7.80(m,2H),7.72-7.62(m,2H),6.86(s,1H),4.26(td,J＝11.2,5.6Hz,1H),4.22-4.14(m,2H),3.90-3.87(m,1H),3.69(dd,J＝11.6,8.8Hz,1H),3.41(p,J＝5.6Hz,1H),3.10-3.01(m,1H),2.61(dd,J＝17.6,5.6Hz,1H),1.63-1.45(m,4H),1.26(t,J＝7.2Hz,3H),0.94(t,J＝7.2Hz,3H),0.90(t,J＝7.2Hz,3H)；13C NMR(151MHz,CDCl3)δ168.36,165.99,137.78,134.07,131.79,129.20,123.33,81.07,79.60,60.82,52.61,51.03,28.40,26.45,25.63,14.19,9.74,9.39；HRMS(QTOF/ESI+),m/z 401.2076,(M+H+),C22H28N2O5:401.2076.
实施例4 制备(3R,4R,5S)-4-乙酰氨基-5-(1,3-二氧代异吲哚-2-基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯V
Figure PCTCN2018091465-appb-000028
将化合物(3R,4R,5S)-4-氨基-5-(1,3-二氧代异吲哚-2-基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯IV(19.00g)、碳酸氢钠(7.97g，2.0eq)和乙酸乙酯(190ml)混合，25℃搅拌30min后加入乙醋酐(5.81g，1.2eq)，搅拌3h。向反应体系中加入水(100ml)，搅拌30min后静置、分液，有机相再用饱和氯化钠水溶液(150ml)洗涤一次后真空浓缩干得到白色固体产品(20.50g)，产率为97.6％。HRMS(QTOF/ESI+),m/z 443.2176,(M+H+),C24H31N2O6:443.2182.
实施例5 制备奥司他韦A
Figure PCTCN2018091465-appb-000029
将化合物(3R,4R,5S)-4-乙酰氨基-5-(1,3-二氧代异吲哚-2-基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯V(20.00g)、80％水合肼(5.66g，2.0eq)和乙醇(200ml)加入到500ml单口瓶中，体系60℃加热搅拌3h。然后将反应液降温至35℃真空浓缩干。加入20％的磷酸水溶液(200ml)和二氯甲烷(150ml)，搅拌30min后静置、分 液，水相再用二氯甲烷(2*150ml)洗涤2次后加入二氯甲烷(300ml)，然后用碳酸钠固体调节水相PH至8，静置、分液，有机相再用饱和氯化钠水溶液(150ml)洗涤一次后真空浓缩干得到的淡黄色油状物，在正己烷中打浆搅拌5h，过滤后40℃真空干燥6h得到化合物A的白色固体(12.05g)，产率为85.3％。1H NMR(600MHz,CDCl3)δ6.79-6.78(d,J＝2.0Hz,1H),5.71(d,J＝7.8Hz,1H),4.24-4.18(m,3H),3.55-3.50(m,1H),3.34(p,J＝5.4Hz,1H),3.23(td,J＝10.2,5.4Hz,1H),2.75(dd,J＝18.0,5.4Hz,1H),2.18-2.13(m,1H),2.04(s,3H),1.55-1.48(m,4H),1.29(t,J＝7.2Hz,3H),0.91(t,J＝7.2Hz,3H),0.90(t,J＝7.2Hz,3H)；13C NMR(151MHz,CDCl3)δ170.92,166.34,137.57,129.56,81.65,74.81,60.86,59.03,49.17,33.66,26.25,25.72,23.69,14.20,9.56,9.35；HRMS(QTOF/ESI+),m/z 313.2130,(M+H+),C16H29N2O4:313.2127.
实施例6 制备(3R,4R,5S)-5-氨基-4-(二烯丙基氨基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯VI
Figure PCTCN2018091465-appb-000030
将化合物(3R,4R,5S)-4-(二烯丙基氨基)-5-(1,3-二氧代异吲哚-2-基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯III(30.00g)、80％水合肼(6.25g，2.0eq)和乙醇(240ml)加入到500ml单口瓶中，60℃加热搅拌3h。反应完全后将反应液降温至35℃真空浓缩干。加入20％的磷酸水溶液(200ml)和二氯甲烷(150ml)，搅拌30min后静置、分液，水相再用二氯甲烷(2*150ml)洗涤2次后加入二氯甲烷(300ml)，然后用碳酸钠固体调节水相PH至8，静置、分液，有机相再用饱和氯化钠水溶液(150ml)洗涤一次后真空浓缩干，得到黄色油状物产品(16.05g)，产率为73.4％。1H NMR(400MHz,CDCl3)δ6.68(s,1H),5.69-59(m,2H),4.99(dd,J＝17.2,1.2Hz,2H),4.90(d,J＝10.0Hz,2H),4.11(d,J＝8.8Hz,1H),3.99(q,J＝6.8Hz,2H),3.33-3.28(m,1H),3.18(d,J＝6.4Hz,4H),2.75-2.69(m,1H),2.62(dd,J＝17.6,5.2Hz,1H),2.51(dd,J＝10.8,8.8Hz,1H),2.29(s,2H),1.92-1.83(m,1H),1.58-1.47(m,1H),1.45-1.27(m,3H),1.09(t,J＝7.2Hz,4H),0.75(t,J＝7.2Hz,3H),0.74(t,J＝7.2Hz,3H)；13C NMR(101MHz,CDCl3)δ166.26,137.71,137.45,128.68,116.31,78.56,72.47,65.36,60.30,53.73,47.30,33.89,25.86,25.01,14.00,9.24,9.04；HRMS(QTOF/ESI+),m/z 351.2657,(M+H+),C20H34N2O3:351.2648.
实施例7 制备(3R,4R,5S)-5-乙酰氨基-4-(二烯丙基氨基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯VII
Figure PCTCN2018091465-appb-000031
将化合物(3R,4R,5S)-5-氨基-4-(二烯丙基氨基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯VI(16.00g)、碳酸氢钠(7.67g，2.0eq)和乙酸乙酯(160ml)在25℃搅拌30min后加入乙醋酐(5.59g，1.2eq)，搅拌3h。反应完全后向体系中加入水(100ml)，搅拌30min后静置、分液，有机相再用饱和氯化钠水溶液(150ml)洗涤一次，真空浓缩得到黄色油状物产品(17.50g)，产率为97.7％。1H NMR(400MHz,CDCl3)δ6.62(s,1H),6.56(d,J＝6.0Hz,1H),5.60-5.50(m,2H),4.94(d,J＝16.8Hz,2H),4.86(d,J＝10.0Hz,2H),4.10(d,J＝7.6Hz,1H),3.94(q,J＝7.2Hz,2H),3.74-3.66(m,1H),3.30-3.24(m,1H),3.15-3.06(m,4H),2.81(dd,J＝17.6,4.8Hz,1H),2.72(dd,J＝10.4,8.4Hz,1H),1.94-1.87(m,1H),1.75(s,3H),1.50-1.23(m,4H),1.04(t,J＝7.2Hz,3H),0.71(t,J＝7.2Hz,3H),0.70(t,J＝7.2Hz,3H)；13C NMR(101MHz,CDCl3)δ170.05,166.00,137.13,136.81,128.92,116.58,72.83,61.70,60.36,53.31,45.89,25.77,25.11,22.93,21.74,13.92,9.21,9.00；HRMS(QTOF/ESI+),m/z393.2756,(M+H+),C22H37N2O4:393.2753.
实施例8 制备(3R,4R,5S)-5-乙酰氨基-4-氨基-3-(戊-3-基氧基)环己-1-烯甲酸乙酯B
Figure PCTCN2018091465-appb-000032
将化合物(3R,4R,5S)-5-乙酰氨基-4-(二烯丙基氨基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯VII(17.5g)、1,3-二甲基巴比妥酸(10.44g，1.5eq)、醋酸钯(0.20g，0.02eq)、三苯基膦(0.94g，0.08eq)和乙醇(200ml)加入到500ml单口瓶中，体系氮气保护下35℃搅拌3h。反应液35℃真空浓缩干。加入20％的磷酸水溶液(200ml)和二氯甲烷(150ml)，搅拌30min后静置、分液，水相再用二氯甲烷(2*150ml)洗涤2次，加入二氯甲烷(300ml)，用碳酸钠固体调节水相PH至8，静置、分液，水相再用二氯甲烷(100ml×2)萃取2次，合并的二氯甲烷相用无水硫酸钠干燥。过滤，滤液30℃浓缩得到白色固体产品(12.01g)，产率为86.2％。1H NMR(600MHz,CDCl3)δ6.86-6.85(m,1H),6.29(d,J＝7.8Hz,1H),4.20(q,J＝7.2Hz,2H),4.09-4.05(m,1H),3.81(d,J＝2.4Hz,1H),3.42(p,J＝6.0Hz,1H),2.94(dd,J＝8.4,6.0Hz,1H),2.80(dd,J＝18.6,5.4Hz,1H),2.33-2.29(m, 1H),1.98(s,3H),1.61-1.50(m,4H),1.29(t,J＝7.2Hz,3H),0.93(t,J＝7.2Hz,6H)；13C NMR(151MHz,CDCl3)δ170.05,166.39,135.82,129.49,81.53,77.88,60.89,53.95,48.45,29.46,26.28,25.86,23.49,14.21,9.58,9.55；HRMS(QTOF/ESI+),m/z 313.2131,(M+H+),C16H29N2O4:313.2127.
综上实施例所述，本发明提供的合成方法能够有效制备式III所示的化合物，并通过所述的式III所示的化合物进一步合成奥司他韦及其异构体杂质。本发明所述的方法具有原料易得、反应温和高效、工艺简洁、经济环保等优点。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。

Claims (13)

  1. 化合物，选自：
    式II所示的(3R,4S,5R)-5-(二烯丙基氨基)-4-羟基-3-(戊-3-基氧基)环己-1-烯甲酸乙酯
    Figure PCTCN2018091465-appb-100001
    式III所示的(3R,4R,5S)-4-(二烯丙基氨基)-5-(1,3-二氧代异吲哚-2-基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯
    Figure PCTCN2018091465-appb-100002
    式IV所示的(3R,4R,5S)-4-氨基-5-(1,3-二氧代异吲哚-2-基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯
    Figure PCTCN2018091465-appb-100003
    式VI所示的(3R,4R,5S)-5-氨基-4-(二烯丙基氨基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯
    Figure PCTCN2018091465-appb-100004
    和
    式VII所示的(3R,4R,5S)-5-乙酰氨基-4-(二烯丙基氨基)-3-(戊-3-基氧基)环己-1-烯甲酸乙酯
    Figure PCTCN2018091465-appb-100005
  2. 一种制备式III所示化合物的方法，包括以下步骤：式II所示化合物与邻苯二甲酰亚胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到式III所示化合物，
    Figure PCTCN2018091465-appb-100006
  3. 权利要求2所述的制备式III所示化合物的方法，还包括以下步骤：式I所示化合物与二烯丙基胺，在氯化镁存在的条件下，在甲苯中反应，得到式II所示化合物
    Figure PCTCN2018091465-appb-100007
  4. 根据权利要求2所述的方法，其中所述的有机膦试剂为三苯基膦。
  5. 根据权利要求2所述的方法，相对于1mol的式II所示化合物，所述的有机膦试剂用量为0.8mol-3.0mol。
  6. 根据权利要求2所述的方法，其中所述的偶氮二甲酸二酯类化合物为偶氮二甲酸二异丙酯、偶氮二甲酸二乙酯、偶氮二甲酸二叔丁酯及偶氮二甲酸二苄酯中的一种或几种。
  7. 根据权利要求2所述的方法，相对于1mol的式II所示化合物，所述的偶氮二甲酸二酯类化合物用量为0.8mol-3.0mol。
  8. 根据权利要求2所述的方法，其中所述的有机溶剂为四氢呋喃、2-甲基四氢呋喃、1.4-二氧六环、二氯甲烷及乙酸乙酯中的至少一种。
  9. 根据权利要求2所述的方法，其中，反应的反应温度为-20℃-80℃。
  10. 一种制备式A所示的奥司他韦的方法，包括以下步骤：
    Figure PCTCN2018091465-appb-100008
    式III所示化合物在1,3-二甲基巴比妥酸、钯催化剂、有机膦配体存在的条件下进行反应，得到式IV所示化合物，
    Figure PCTCN2018091465-appb-100009
    式IV所示化合物在碱性条件下与乙酸酐进行反应，得到式V所示化合物，
    Figure PCTCN2018091465-appb-100010
    式V所示化合物在水合肼的作用下进行反应得到式A所示化合物。
  11. 权利要求10所述的制备式A所示的奥司他韦的方法，还包括以下步骤：式II所示化合物与邻苯二甲酰亚胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到式III所示化合物，
    Figure PCTCN2018091465-appb-100011
  12. 一种制备式B所示的奥司他韦异构体的方法，包括以下步骤：
    Figure PCTCN2018091465-appb-100012
    式III所示化合物在水合肼的作用下进行反应，得到式VI所示化合物，
    Figure PCTCN2018091465-appb-100013
    式VI所示化合物在碱性条件下与乙酸酐进行乙酰基上保护反应，得到式VII所示化合物，
    Figure PCTCN2018091465-appb-100014
    式VII所示化合物在1,3-二甲基巴比妥酸、钯催化剂、有机膦配体存在的条件下进行反应，得到式B所示化合物。
  13. 权利要求12所述的制备式B所示的奥司他韦异构体的方法，还包括以下步骤：式II所示化合物与邻苯二甲酰亚胺，在有机膦试剂与偶氮二甲酸二酯类化合物存在的条件下，在有机溶剂中反应，得到式 III所示化合物，
    Figure PCTCN2018091465-appb-100015
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