WO2022166436A1 - 一种制备莫西沙星中间体(s,s)-2,8-二氮杂二环[4,3,0]壬烷的方法 - Google Patents

一种制备莫西沙星中间体(s,s)-2,8-二氮杂二环[4,3,0]壬烷的方法 Download PDF

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WO2022166436A1
WO2022166436A1 PCT/CN2021/139394 CN2021139394W WO2022166436A1 WO 2022166436 A1 WO2022166436 A1 WO 2022166436A1 CN 2021139394 W CN2021139394 W CN 2021139394W WO 2022166436 A1 WO2022166436 A1 WO 2022166436A1
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acid
reaction
aminomethylpiperidine
chiral
present
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PCT/CN2021/139394
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French (fr)
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韩得满
李运广
武承林
贺娇娇
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台州市生物医化产业研究院有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • the invention relates to the technical field of organic synthesis, in particular to a method for preparing moxifloxacin intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane.
  • the current industrial synthesis of (S,S)-2,8-diazabicyclo[4,3,0]nonane is basically divided into two categories: (1) reduction of the pyridine ring by palladium carbon, and then by manual The total yield of this route is between 30% and 40%, the yield is low, and the cost is high; (2) through a chiral inducing reagent, such as (S)-4-benzene Base-2-oxazolidinone can be synthesized asymmetrically. This route generally has complicated reactions, long reaction steps, and high chiral inducing reagents, which increases the cost.
  • the present invention aims to provide a method for preparing moxifloxacin intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane.
  • the method provided by the invention does not need to carry out chiral resolution, the process is simple, the process steps are short, the cost is low, the chiral purity of the product is high, and the total yield is high.
  • the invention provides a method for preparing moxifloxacin intermediate (S, S)-2,8-diazabicyclo[4,3,0]nonane, comprising the following steps:
  • the azaphthalide is subjected to a hydrogenation reduction reaction under the action of a chiral catalyst and an initiator to obtain (4aR,7aS)furo[3,4-b]piperidin-5(1H)-one;
  • the (2S,3R)-2-hydroxymethylpiperidine-3-carboxamide is mixed with an organic acid and a boron-containing reducing agent to carry out a reduction reaction to obtain (2S,3S)- 2-Hydroxymethyl-3-aminomethylpiperidine;
  • organic acid is organic strong acid or organic superacid;
  • the initiator in the step (1) is iodine or a halogenated nitrogen heterocyclic compound
  • the mass of the initiator is 0.5-30% of the mass of the azaphthalide
  • the mass of the chiral catalyst is nitrogen 0.005 to 10% of the mass of heterophthalide.
  • the solvent of the hydrogenation reduction reaction in the step (1) is one or more of toluene, dioxane, benzene, xylene and tetrahydrofuran; the temperature of the hydrogenation reduction reaction is 55 to 70 °C °C, the pressure is 0.5 ⁇ 3.0MPa.
  • the ammonia-containing compound in the step (2) is one or more of urea, ammonia, ammonium chloride and ammonium acetate; the (4aR,7aS)furo[3,4-b]piperidine
  • the molar ratio of pyridine-5(1H)-one to ammonia in the ammonia-containing compound is 1:1.2-5.0.
  • the solvent of the aminolysis reaction of ester in the step (2) is one of N,N-dimethylformamide, toluene, xylene, N,N-dimethylacetamide, DMPU and DMI or several kinds; the temperature of the aminolysis reaction of the ester is 45-75°C, and the time is 3-5h.
  • the boron-containing reducing agent in the step (3) is one or more of sodium borohydride, sodium borohydride derivatives, potassium borohydride and potassium borohydride derivatives; the boron-containing reducing agent and The molar ratio of (2S,3R)-2-hydroxymethylpiperidine-3-carboxamide is 0.25 ⁇ 1:1; the organic acid is trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, boron trifluoride tetrahydrofuran One or more of the complex compound and the boron trifluoride ether complex; the molar ratio of the organic acid to the boron-containing reducing agent is 0.8-4:1.
  • the solvent of the reduction reaction in the step (3) is one or more of methanol, ethanol, water, acetic acid, tetrahydrofuran and dioxane; the temperature of the reduction reaction is room temperature, and the time is 1 ⁇ 5h.
  • the chlorinating reagent in the step (4) is one or more of N-chlorosuccinimide, chlorine, triphosgene, thionyl chloride, phosphorus oxychloride and phosphorus pentachloride species; the molar ratio of the (2S,3S)-2-hydroxymethyl-3-aminomethylpiperidine to the chlorinating reagent is 1:1-2.0.
  • the solvent of the chlorination reaction in the step (4) is one or more of dichloromethane, toluene, tetrahydrofuran, acetonitrile, dioxane, methyl tert-butyl ether and chloroform; the chlorine
  • the temperature of the chemical reaction is 30 ⁇ 50°C, and the time is 2 ⁇ 6h.
  • the molar ratio of potassium carbonate to (2S,3S)-2-chloromethyl-3-aminomethylpiperidine is 0.5-1.5:1;
  • the solvent for the cyclization reaction is One or more of tetrahydrofuran, alcohol solvent, dimethylformamide and toluene;
  • the temperature of the cyclization reaction is 55-70 DEG C, and the time is 5-8h.
  • the cyclization reaction in the step (5) it also includes:
  • the obtained cyclization reaction solution is filtered to obtain a crude product
  • the crude product is mixed and reacted with an acid to form a salt, and the obtained salt is recrystallized with absolute ethanol to obtain a crystal;
  • the acid is a kind of p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and oxalic acid or several;
  • the organic phase was decolorized and dried to obtain moxifloxacin intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane.
  • the present invention uses azaphthalide as a raw material, and due to the ring structure of azaphthalide itself, the other two non-corresponding chiral isomers that are not required in chiral reduction (ie, hydrogenation reduction reaction) are hardly produced. , the chiral purity of the reduced intermediate itself is very high, and no further splitting is required, and the moxifloxacin intermediate (S,S)-2,8 can be obtained directly through ammonolysis, reduction, chlorination and cyclization. - Diazabicyclo[4,3,0]nonane.
  • the method provided by the invention does not need to carry out chiral resolution, the process is simple, the process steps are short, the cost is low, the chiral purity of the product is high, and the total yield is high.
  • the carboxylic acid salt-forming containing chiral structure there is no need to use the carboxylic acid salt-forming containing chiral structure, and the common achiral carboxylic acid (p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and oxalic acid) is used. one or more of) can be purified to further improve the product purity.
  • the common achiral carboxylic acid p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and oxalic acid
  • Fig. 1 is the nuclear magnetic spectrum of the product prepared in Example 1.
  • the invention provides a method for preparing moxifloxacin intermediate (S, S)-2,8-diazabicyclo[4,3,0]nonane, comprising the following steps:
  • the azaphthalide is subjected to a hydrogenation reduction reaction under the action of a chiral catalyst and an initiator to obtain (4aR,7aS)furo[3,4-b]piperidin-5(1H)-one;
  • the (2S,3R)-2-hydroxymethylpiperidine-3-carboxamide is mixed with an organic acid and a boron-containing reducing agent to carry out a reduction reaction to obtain (2S,3S)- 2-Hydroxymethyl-3-aminomethylpiperidine;
  • organic acid is organic strong acid or organic superacid;
  • azaphthalide (the compound represented by formula 2) is subjected to hydrogenation reduction reaction under the action of a chiral catalyst and an initiator to obtain (4aR,7aS)furo[3,4-b]piperidine-5( 1H)-ketone (compound of formula 3).
  • the initiator is preferably iodine or a halogenated nitrogen heterocyclic compound, and the halogenated nitrogen heterocyclic compound is preferably MCDMH (bromochlorohydantoin), DCDMH (dichlorohydantoin) or TCCA (trichlorohydantoin) isocyanuric acid); the mass of the initiator is preferably 0.5-30% of the mass of the azaphthalide, more preferably 1-10%.
  • MCDMH bromochlorohydantoin
  • DCDMH dichlorohydantoin
  • TCCA trichlorohydantoin
  • the iridium catalyst [Ir (cod)Cl] 2 refers to bis(1,5-cyclooctadiene) iridium(I) chloride dimer
  • chiral phosphorus ligand (R)-(+)-BINAP refers to (R)-(+) -2,2'-bis(diphenylphosphino)-1,1'-binaphthyl);
  • the mass of the chiral catalyst is preferably 0.005-10% of the mass of the azaphthalide
  • the solvent of the hydrogenation reduction reaction is preferably one or more of toluene, dioxane, benzene, xylene and tetrahydrofuran, and the quality of the solvent is preferably 2% of the quality of the azaphthalide. ⁇ 10 times.
  • the pressure of the hydrogenation reduction reaction is preferably 0.5-3.0 MPa, more preferably 1.5-2.0 MPa; the temperature of the hydrogenation reduction reaction is preferably 55-70°C, more preferably 60-65°C In the present invention, the time of the hydrogenation reduction reaction is determined by the criterion that the pressure does not drop within 1 hour, that is, the hydrogenation reduction reaction is considered to be completed when the pressure does not drop within 1 hour.
  • the hydrogenation reduction reaction is preferably carried out in a stainless steel autoclave.
  • the reaction formula of the hydrogenation reduction reaction is:
  • the specific operation of the hydrogenation reduction reaction is preferably: dissolving the azaphthalide in a solvent, first replacing it with nitrogen three times, and then replacing it with hydrogen; then adding the azaphthalide to the obtained azaphthalide solution
  • the chiral catalyst and initiator are replaced with hydrogen; the temperature of the obtained system is raised to 55-70° C., and the pressure is increased to 0.5-3.0 MPa to carry out the hydrogenation reduction reaction.
  • the present invention preferably performs post-processing on the obtained hydrogenation reduction reaction liquid; the method for the post treatment is preferably: filtering the obtained hydrogenation reduction reaction liquid into a common reactor, and the hydrogenation reduction reaction liquid is filtered. Wash with saturated aqueous sodium bicarbonate solution, separate the lower water layer, and collect the organic layer; the organic layer is refluxed with water for 1 to 2 hours, and then the solvents such as toluene in the organic layer are recovered, and the recovery finishes to obtain (4aR, 7aS) Furo[3,4-b]piperidin-5(1H)-one.
  • the method for washing the hydrogenation-reduction reaction solution with saturated aqueous sodium bicarbonate solution is as follows: adding saturated aqueous sodium bicarbonate solution to the hydrogenation-reduction reaction solution, stirring and then standing for stratification, and separating the lower layer of water layer; the number of times of the washing is preferably 2 times.
  • the method for recovering the solvent such as toluene in the organic layer is specifically as follows: the organic layer is first subjected to atmospheric distillation, and then subjected to reduced pressure distillation.
  • the present invention converts the (4aR,7aS)furo[3,4-b under nitrogen protection ]Piperidin-5(1H)-one is mixed with an ammonia-containing compound to carry out the aminolysis reaction of the ester to obtain (2S,3R)-2-hydroxymethylpiperidine-3-carboxamide (the compound represented by formula 4).
  • the ammonia compound is preferably one or more of urea, ammonia, ammonium chloride and ammonium acetate, more preferably ammonia, the ammonia includes liquid ammonia or ammonia water, and the mass concentration of the ammonia water is preferably is 30%; the molar ratio of the (4aR,7aS)furo[3,4-b]piperidin-5(1H)-one to ammonia in the ammonia-containing compound is preferably 1:1.2-5.0, more preferably 1 : 2 to 4.
  • the solvent of the aminolysis reaction of the ester is preferably one of N,N dimethylformamide (DMF), toluene, xylene, N,N-dimethylacetamide, DMPU and DMI or several, the quality of the solvent is preferably 2 to 15 times the quality of (4aR,7aS)furo[3,4-b]piperidin-5(1H)-one.
  • the temperature of the aminolysis reaction of the ester is preferably 45-75°C, more preferably 50-65°C, and the time is preferably 3-5h, more preferably 3.5-4.5h; the aminolysis of the ester is preferably 3-5h.
  • the reaction is preferably carried out under micro-pressure conditions, and the pressure of the micro-pressure is preferably less than one atmosphere.
  • the reaction formula of the aminolysis reaction of the ester is:
  • the specific operation of the aminolysis reaction of the ester is preferably: under nitrogen protection, dissolving (4aR,7aS)furo[3,4-b]piperidin-5(1H)-one
  • a solution of (4aR,7aS)furo[3,4-b]piperidin-5(1H)-one is obtained; in the (4aR,7aS)furo[3,4-b]piperidine
  • the ammonia-containing compound was slowly added to the -5(1H)-one solution, and then the system was heated to 45-75° C. to carry out the aminolysis reaction of the ester.
  • the rate of addition of the ammonia-containing compound is preferably such that there is no large fluctuation of the material and temperature.
  • the present invention preferably performs post-processing on the obtained ammonolysis reaction solution; the method for the post-treatment is preferably: filter the obtained ammonolysis reaction solution into an ammonium chloride solution for quenching, and then use formic acid to quench.
  • the methyl tert-butyl ether layer was extracted, and the methyl tert-butyl ether layer was collected; after the methyl tert-butyl ether layer was washed with water and dried in turn, the methyl tert-butyl ether layer was distilled off to obtain (2S, 3R) -2-Hydroxymethylpiperidine-3-carboxamide.
  • the mass concentration of the ammonium chloride solution is preferably 10%.
  • the present invention converts the (2S,3R)-2-hydroxymethylpiperidine-3-carboxamide under nitrogen protection conditions Mixed with an organic acid and a boron-containing reducing agent to carry out a reduction reaction to obtain (2S,3S)-2-hydroxymethyl-3-aminomethylpiperidine (the compound shown in formula 5);
  • the organic acid is an organic strong acid or an organic Super acid.
  • the boron-containing reducing agent is preferably sodium borohydride, sodium borohydride derivatives (such as sodium triacetoxyborohydride, sodium triethylborohydride, sodium tris(1-pyrazolyl)borohydride ), one or more of potassium borohydride and potassium borohydride derivatives (such as potassium triphenyl borohydride, potassium triisopropoxyborohydride, potassium triethyl borohydride), more preferably hydrogen borohydride sodium;
  • the molar ratio of the boron-containing reducing agent to (2S,3R)-2-hydroxymethylpiperidine-3-carboxamide is preferably 0.25-1:1, more preferably 0.5-0.8:1.
  • the organic acid is preferably one or more of trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, boron trifluoride tetrahydrofuran complex and boron trifluoride ether complex (in this
  • trifluoromethanesulfonic acid is an organic superacid
  • trifluoroacetic acid, acetic acid, boron trifluoride tetrahydrofuran complex and boron trifluoride ether complex are organic strong acids
  • the molar ratio of the organic acid to the boron-containing reducing agent is preferably 0.8-4:1, more preferably 1-3:1.
  • the solvent of the reduction reaction is preferably one or more of methanol, ethanol, water, acetic acid, tetrahydrofuran and dioxane; the quality of the solvent is preferably (2S,3R)-2- 2 to 15 times the mass of hydroxymethylpiperidine-3-carboxamide.
  • the temperature of the reduction reaction is preferably room temperature, and the time is preferably 1-5 h, more preferably 2 h.
  • the reaction is preferably terminated by adding acetic acid.
  • the reaction formula of the reduction reaction is:
  • the specific operation of the reduction reaction is preferably as follows: under nitrogen protection, add the solvent and organic acid to (2S,3R)-2-hydroxymethylpiperidine-3-carboxamide to dissolve , obtain a mixed solution; add a boron-containing reducing agent in batches to the mixed solution, carry out a reduction reaction under stirring conditions, and add acetic acid to terminate the reaction after the reaction is completed.
  • the obtained reduction reaction solution is subjected to vacuum distillation to recover the solvent to obtain (2S,3S)-2-hydroxymethyl-3-aminomethylpiperidine.
  • the present invention combines the (2S,3S)-2-hydroxymethyl-3-aminomethylpiperidine with a chlorinating reagent Mixing, heating and refluxing to carry out chlorination reaction to obtain (2S,3S)-2-chloromethyl-3-aminomethylpiperidine (the compound represented by formula 6).
  • the chlorinating reagent is preferably one or more of N-chlorosuccinimide (NCS), chlorine, triphosgene, thionyl chloride, phosphorus oxychloride and phosphorus pentachloride species, more preferably N-chlorosuccinimide;
  • NCS N-chlorosuccinimide
  • the molar ratio of the (2S,3S)-2-hydroxymethyl-3-aminomethylpiperidine to the chlorinating reagent is preferably 1:1 ⁇ 2.0 , more preferably 1:1.2 to 1.5.
  • the solvent of the chlorination reaction is preferably one or more of dichloromethane, toluene, tetrahydrofuran, acetonitrile, dioxane, methyl tert-butyl ether and chloroform, more preferably dichloromethane Methane;
  • the quality of the solvent is preferably 2 to 15 times the quality of (2S,3S)-2-hydroxymethyl-3-aminomethylpiperidine.
  • the temperature of the chlorination reaction ie the temperature of heating and refluxing
  • the time is preferably 2-6h, more preferably 3h.
  • the reaction formula of described chlorination reaction is:
  • the specific operation of the chlorination reaction is preferably as follows: (2S,3S)-2-hydroxymethyl-3-aminomethylpiperidine is dissolved in the solvent to obtain (2S,3S)- 2-Hydroxymethyl-3-aminomethylpiperidine solution; add a chlorinating reagent in batches to the (2S,3S)-2-hydroxymethyl-3-aminomethylpiperidine solution, then heat the system The chlorination reaction was carried out to reflux temperature.
  • the chlorination reagent is preferably added in 3 to 5 times.
  • the present invention preferably washes the obtained chlorination reaction solution with a saturated aqueous sodium bicarbonate solution, separates the water layer, and collects the organic layer; reclaim the solvent in the organic layer (first atmospheric distillation, then decompression). After distillation), (2S,3S)-2-chloromethyl-3-aminomethylpiperidine was obtained.
  • the present invention will under nitrogen protection conditions, the (2S,3S)-2-chloromethyl-3-aminomethyl Under the action of potassium carbonate, the cyclization reaction of the base piperidine is carried out to obtain the moxifloxacin intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane (the compound shown in formula 1) ).
  • the molar ratio of the potassium carbonate to (2S,3S)-2-chloromethyl-3-aminomethylpiperidine is preferably 0.5-1.5:1, more preferably 0.8-1.3:1;
  • the potassium carbonate is both a catalyst and an acid binding agent.
  • the solvent of the cyclization reaction is preferably one or more of tetrahydrofuran, alcohol solvent, dimethylformamide and toluene, more preferably tetrahydrofuran; the quality of the solvent is preferably (2S, 3S)-2-chloromethyl-3-aminomethylpiperidine is 2 to 15 times the mass.
  • the temperature of the cyclization reaction is preferably 55-70°C, more preferably 60-65°C; the time is preferably 5-8h, more preferably 6h.
  • the reaction formula of the cyclization reaction is:
  • the specific operation of the cyclization reaction is preferably: under nitrogen protection, dissolving (2S,3S)-2-chloromethyl-3-aminomethylpiperidine in the solvent to obtain (2S,3S)-2-chloromethyl-3-aminomethylpiperidine solution; add potassium carbonate in batches to the (2S,3S)-2-chloromethyl-3-aminomethylpiperidine solution , and then the system was heated to 55-70 °C, and the cyclization reaction was carried out under stirring conditions.
  • the potassium carbonate is preferably added in 3 to 5 times.
  • the present invention also preferably includes:
  • the obtained cyclization reaction solution is filtered to obtain a crude product
  • the crude product is mixed and reacted with an acid to form a salt, and the obtained salt is recrystallized with absolute ethanol to obtain a crystal;
  • the acid is a kind of p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and oxalic acid or several;
  • the organic phase was decolorized and dried to obtain moxifloxacin intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane.
  • the present invention has no special requirements on the filtering method, and a filtering method well known to those skilled in the art can be used.
  • the molar ratio of the (2S,3S)-2-chloromethyl-3-aminomethylpiperidine to the acid is preferably 1:1 to 2;
  • the reaction time for salt formation is preferably 1 hour ;
  • the acid and the crude product form a salt and solidify into a solid, which is convenient for recrystallization to obtain a product with higher purity.
  • the reaction formula of the acid and the crude product forming a salt is as follows (the compound shown in formula 7 is a salt-forming product, wherein TsOH represents p-toluenesulfonic acid):
  • the present invention has no special requirements on the operation method of the recrystallization, and a method well known to those skilled in the art can be used.
  • the method that the crystallized substance is freed with a saturated aqueous sodium carbonate solution is specifically: adding a saturated aqueous sodium carbonate solution to the crystallized substance, the sodium carbonate reacts with the acid (that is, acid-base neutralization reaction), and the salt-forming substance changes. become a monomer (ie, the compound represented by formula 7 is converted into the compound represented by formula 1).
  • the dichloromethane is added to the obtained mixed solution after the saturated aqueous sodium carbonate solution is freed and extracted.
  • the decolorizing agent for decolorization is preferably activated carbon
  • the desiccant for drying is preferably yuanming powder.
  • the present invention does not need to use a carboxylic acid containing a chiral structure for salt-forming, and can use common achiral carboxylic acid p-toluenesulfonic acid for refining to further improve product purity.
  • the method provided by the invention does not need to carry out chiral resolution, the process is simple, the process steps are short, the cost is low, the chiral purity of the product is high, and the total yield is high.
  • Moxifloxacin intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane was prepared as follows:
  • the reaction was finished, and the obtained hydrogenation reduction reaction was hydraulically filtered into a common reactor, washed twice with saturated aqueous sodium bicarbonate solution, and refluxed with water for 2 hours, then reclaimed toluene, and the recovery finished to obtain (4aR, 7aS) furano[3, 4-b]Piperidin-5(1H)-one, under nitrogen protection, put into 200 mL of DMF to dissolve, and directly used in the next reaction.
  • Moxifloxacin intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane was prepared as follows:
  • the reaction was finished, and the obtained hydrogenation reduction reaction was hydraulically filtered into a common reactor, washed twice with saturated aqueous sodium bicarbonate solution, and refluxed with water for 2 hours, then reclaimed toluene, and the recovery finished to obtain (4aR, 7aS) furano[3, 4-b]Piperidin-5(1H)-one, under nitrogen protection, put into 200 mL of DMF to dissolve, and directly used in the next reaction.
  • the method provided by the present invention does not require chiral resolution, the process is simple, the process steps are short, the cost is low, and the product has high chiral purity and high total yield.

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Abstract

本发明提供了一种制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷的方法，涉及有机合成技术领域。本发明以氮杂苯酞为原料，由于氮杂苯酞本身的环状结构，使得手性还原中不需要的另外两种非对应手性异构体几乎不会产生，还原出来的中间体本身的手性纯度非常高，无需再进行拆分，后续直接通过氨解、还原、氯化和环合即可得到(S,S)-2,8-二氮杂二环[4,3,0]壬烷。本发明提供的方法无需进行手性拆分，过程简单，工艺步骤短，成本低，且产物手性纯度高，总收率高。进一步地，在后续产品成盐精制的步骤中，也无需使用含有手性结构的羧酸成盐，采用普通非手性羧酸即可进行精制进一步提高产物纯度。

Description

一种制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷的方法
本申请要求于2021年02月06日提交中国专利局、申请号为202110165275.0、发明名称为“一种制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷的方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及有机合成技术领域，特别涉及一种制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷的方法。
背景技术
莫西沙星作为新一代的喹诺酮类抗菌药，具有良好的经济价值和广阔的市场前景，(S,S)-2,8-二氮杂二环[4,3,0]壬烷是合成莫西沙星重要的中间体。目前工业上合成(S,S)-2,8-二氮杂二环[4,3,0]壬烷的路线基本上分成两类：(1)通过钯碳还原吡啶环，然后再通过手性拆分剂进行拆分，这种路线的总收率在30％～40％之间，收率较低，且成本高；(2)通过手性诱导试剂，如(S)-4-苯基-2-恶唑烷酮，进行不对称合成，这种路线一般反应比较复杂，反应步骤长，且手性诱导试剂价格高，增加了成本。
发明内容
有鉴于此，本发明目的在于提供一种制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷的方法。本发明提供的方法无需进行手性拆分，过程简单，工艺步骤短，成本低，且产物手性纯度高，总收率高。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷的方法，包括以下步骤:
(1)将氮杂苯酞在手性催化剂和引发剂的作用下进行加氢还原反应，得到(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮；所述手性催化剂为[Ir(cod)Cl] 2·n(R)-(+)-BINAP，n＝0.5～3；
(2)在氮气保护条件下，将所述(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮与含氨化合物混合进行酯的氨解反应，得到(2S,3R)-2-羟甲基哌啶-3-甲 酰胺；
(3)在氮气保护条件下，将所述(2S,3R)-2-羟甲基哌啶-3-甲酰胺与有机酸和含硼还原剂混合进行还原反应，得到(2S,3S)-2-羟甲基-3-氨甲基哌啶；所述有机酸为有机强酸或有机超酸；
(4)将所述(2S,3S)-2-羟甲基-3-氨甲基哌啶与氯化试剂混合，加热回流进行氯化反应，得到(2S,3S)-2-氯甲基-3-氨甲基哌啶；
(5)在氮气保护条件下，将所述(2S,3S)-2-氯甲基-3-氨甲基哌啶在碳酸钾的作用下进行环合反应，得到莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷。
优选地，所述步骤(1)中的引发剂为碘或卤代氮杂环化合物，所述引发剂的质量为氮杂苯酞质量的0.5～30％；所述手性催化剂的质量为氮杂苯酞质量的0.005～10％。
优选地，所述步骤(1)中加氢还原反应的溶剂为甲苯、二氧六环、苯、二甲苯和四氢呋喃中的一种或几种；所述加氢还原反应的温度为55～70℃，压力为0.5～3.0MPa。
优选地，所述步骤(2)中的含氨化合物为尿素、氨、氯化铵和醋酸铵中的一种或几种；所述(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮与含氨化合物中氨的摩尔比为1：1.2～5.0。
优选地，所述步骤(2)中酯的氨解反应的溶剂为N,N二甲基甲酰胺、甲苯、二甲苯、N,N-二甲基乙酰胺、DMPU和DMI中的一种或几种；所述酯的氨解反应的温度为45～75℃，时间为3～5h。
优选地，所述步骤(3)中的含硼还原剂为硼氢化钠、硼氢化钠衍生物、硼氢化钾和硼氢化钾衍生物中的一种或几种；所述含硼还原剂与(2S,3R)-2-羟甲基哌啶-3-甲酰胺的摩尔比为0.25～1：1；所述有机酸为三氟乙酸、醋酸、三氟甲磺酸、三氟化硼四氢呋喃络合物和三氟化硼乙醚络合物中的一种或几种；所述有机酸与含硼还原剂的摩尔比为0.8～4:1。
优选地，所述步骤(3)中还原反应的溶剂为甲醇、乙醇、水、醋酸、四氢呋喃和二氧六环中的一种或几种；所述还原反应的温度为室温，时间为1～5h。
优选地，所述步骤(4)中的氯化试剂为N-氯代丁二酰亚胺、氯气、三光气、氯化亚砜、三氯氧磷和五氯化磷中的一种或几种；所述(2S,3S)-2-羟甲基-3-氨甲基哌啶与氯化试剂的摩尔比为1:1～2.0。
优选地，所述步骤(4)中氯化反应的溶剂为二氯甲烷、甲苯、四氢呋喃、乙腈、二氧六环、甲基叔丁基醚和氯仿中的一种或几种；所述氯化反应的温度为30～50℃，时间为2～6h。
优选地，所述步骤(5)中碳酸钾与(2S,3S)-2-氯甲基-3-氨甲基哌啶的摩尔比为0.5～1.5：1；所述环合反应的溶剂为四氢呋喃、醇类溶剂、二甲基甲酰胺和甲苯中的一种或几种；所述环合反应的温度为55～70℃，时间为5～8h。
优选地，所述步骤(5)中环合反应后，还包括：
将所得环合反应液过滤，得到粗产物；
将所述粗产物与酸混合反应成盐，将所得盐用无水乙醇进行重结晶，得到结晶物；所述酸为对甲苯磺酸、盐酸、硫酸、磷酸、柠檬酸和草酸中的一种或几种；
将所述结晶物用饱和碳酸钠水溶液游离后，用二氯甲烷萃取，得到有机相；
将所述有机相进行脱色和干燥，得到莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷。
本发明提供了一种制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷的方法，包括以下步骤：(1)将氮杂苯酞在手性催化剂和引发剂的作用下进行加氢还原反应，得到(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮；所述手性催化剂为[Ir(cod)Cl] 2·n(R)-(+)-BINAP，n＝0.5～3；(2)在氮气保护条件下，将所述(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮与含氨化合物混合进行酯的氨解反应，得到(2S,3R)-2-羟甲基哌啶-3-甲酰胺；(3)在氮气保护条件下，将所述(2S,3R)-2-羟甲基哌啶-3-甲酰胺与有机酸和含硼还原剂混合进行还原反应，得到(2S,3S)-2-羟甲基-3-氨甲基哌啶；所述有机酸为有机强酸或有机超酸；(4)将所述(2S,3S)-2-羟甲基-3-氨甲基哌啶与氯化试剂混合，加热回流进行氯化反应，得到(2S,3S)-2-氯甲基-3-氨甲基哌啶； (5)在氮气保护条件下，将所述(2S,3S)-2-氯甲基-3-氨甲基哌啶在碳酸钾的作用下进行环合反应，得到莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷。本发明以氮杂苯酞为原料，由于氮杂苯酞本身的环状结构，使得手性还原(即加氢还原反应)中不需要的另外两种非对应手性异构体几乎不会产生，还原出来的中间体本身的手性纯度非常高，无需再进行拆分，后续直接通过氨解、还原、氯化和环合即可得到莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷。本发明提供的方法无需进行手性拆分，过程简单，工艺步骤短，成本低，且产物手性纯度高，总收率高。
进一步地，在后续产品成盐精制的步骤中，也无需使用含有手性结构的羧酸成盐，采用普通非手性羧酸(对甲苯磺酸、盐酸、硫酸、磷酸、柠檬酸和草酸中的一种或几种)即可进行精制进一步提高产物纯度。
实施例结果表明，采用本发明提供的方法制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷，收率达到82％，产物的化学纯度达到99.8％，手性纯度达到99.5％。
说明书附图
图1为实施例1制备得到的产物的核磁谱图。
具体实施方式
本发明提供了一种制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷的方法，包括以下步骤:
(1)将氮杂苯酞在手性催化剂和引发剂的作用下进行加氢还原反应，得到(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮；所述手性催化剂为[Ir(cod)Cl] 2·n(R)-(+)-BINAP，n＝0.5～3；
(2)在氮气保护条件下，将所述(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮与含氨化合物混合进行酯的氨解反应，得到(2S,3R)-2-羟甲基哌啶-3-甲酰胺；
(3)在氮气保护条件下，将所述(2S,3R)-2-羟甲基哌啶-3-甲酰胺与有机酸和含硼还原剂混合进行还原反应，得到(2S,3S)-2-羟甲基-3-氨甲基哌啶；所述有机酸为有机强酸或有机超酸；
(4)将所述(2S,3S)-2-羟甲基-3-氨甲基哌啶与氯化试剂混合，加热回 流进行氯化反应，得到(2S,3S)-2-氯甲基-3-氨甲基哌啶；
(5)在氮气保护条件下，将所述(2S,3S)-2-氯甲基-3-氨甲基哌啶在碳酸钾的作用下进行环合反应，得到莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷。
本发明将氮杂苯酞(式2所示化合物)在手性催化剂和引发剂的作用下进行加氢还原反应，得到(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮(式3所示化合物)。在本发明中，所述引发剂优选为碘或卤代氮杂环化合物，所述卤代氮杂环化合物优选为MCDMH(溴氯海因)、DCDMH(二氯海因)或TCCA(三氯异氰尿酸)；所述引发剂的质量优选为氮杂苯酞质量的0.5～30％，更优选为1～10％。
在本发明中，所述手性催化剂为[Ir(cod)Cl] 2·n(R)-(+)-BINAP，n＝0.5～3，优选为1～2，即所述手性催化剂为铱催化剂[Ir(cod)Cl] 2和手性磷配体(R)-(+)-BINAP以1:0.5～3的摩尔比形成的络合物(注：手性催化剂中铱催化剂[Ir(cod)Cl] 2指双(1,5-环辛二烯)氯化铱(I)二聚体，手性磷配体(R)-(+)-BINAP指(R)-(+)-2,2'-双(二苯基膦基)-1,1'-联萘)；所述手性催化剂的质量优选为氮杂苯酞质量的0.005～10％，更优选为0.005～1％；本发明对所述手性催化剂的来源没有特别的要求，采用本领域技术人员熟知的市售商品或采用本领域技术人员熟知的方法自行制备均可。
在本发明中，所述加氢还原反应的溶剂优选为甲苯、二氧六环、苯、二甲苯和四氢呋喃中的一种或几种，所述溶剂的质量优选为氮杂苯酞质量的2～10倍。
在本发明中，所述加氢还原反应的压力优选为0.5～3.0MPa，更优选为1.5～2.0MPa；所述加氢还原反应的温度优选为55～70℃，更优选为60～65℃；在本发明中，所述加氢还原反应的时间以压力在1小时内不再下降为判断标准，即当压力在1小时内不再下降即认为加氢还原反应完成。在本发明中，所述加氢还原反应优选在不锈钢高压反应釜中进行。在本发明中，所述加氢还原反应的反应式为：
Figure PCTCN2021139394-appb-000001
在本发明中，所述加氢还原反应的具体操作优选为：将所述氮杂苯酞用溶剂溶解，先用氮气置换三次，再用氢气置换；然后向所得氮杂苯酞溶液中加入所述手性催化剂和引发剂，再用氢气置换；将所得体系的温度升温至55～70℃、加压至0.5～3.0MPa进行加氢还原反应。
加氢还原反应完成后，本发明优选对所得加氢还原反应液进行后处理；所述后处理的方法优选为：将所得加氢还原反应液压滤至普通反应釜中，将加氢还原反应液用饱和碳酸氢钠水溶液洗涤，分掉下层水层，收集有机层；将所述有机层回流带水1～2小时，然后回收有机层中的甲苯等溶剂，回收结束，得到(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮。在本发明中，将加氢还原反应液用饱和碳酸氢钠水溶液洗涤的方法具体为：在所述加氢还原反应液中加入饱和碳酸氢钠水溶液，搅拌后静置分层，分掉下层水层；所述洗涤的次数优选为2次。在本发明中，所述回收有机层中的甲苯等溶剂的方法具体为：将所述有机层先进行常压蒸馏，再进行减压蒸馏。
得到(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮后，本发明在氮气保护条件下，将所述(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮与含氨化合物混合进行酯的氨解反应，得到(2S,3R)-2-羟甲基哌啶-3-甲酰胺(式4所示化合物)。在本发明中，所述氨化合物优选为尿素、氨、氯化铵和醋酸铵中的一种或几种，更优选为氨，所述氨包括液氨或氨水，所述氨水的质量浓度优选为30％；所述(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮与含氨化合物中氨的摩尔比优选为1：1.2～5.0，更优选为1:2～4。在本发明中，所述酯的氨解反应的溶剂优选为N,N二甲基甲酰胺(DMF)、甲苯、二甲苯、N,N-二甲基乙酰胺、DMPU和DMI中的一种或几种，所述溶剂的质量优选为(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮质量的2～15倍。
在本发明中，所述酯的氨解反应的温度优选为45～75℃，更优选为50～65℃，时间优选为3～5h，更优选为3.5～4.5h；所述酯的氨解反应优选 在微压条件下进行，所述微压的压力优选小于一个大气压。在本发明中，所述酯的氨解反应的反应式为：
Figure PCTCN2021139394-appb-000002
在本发明中，所述酯的氨解反应的具体操作优选为：在氮气保护条件下，将(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮溶于所述溶剂中，得到(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮溶液；在所述(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮溶液中缓慢加入含氨化合物，然后将体系升温至45～75℃进行酯的氨解反应。在本发明中，所述含氨化合物的加入速度以不发生冲料和温度较大波动为宜。
酯的氨解反应完成后，本发明优选对所得氨解反应液进行后处理；所述后处理的方法优选为：将所得氨解反应液压滤至氯化铵溶液中进行淬灭，然后用甲基叔丁基醚提取，收集甲基叔丁基醚层；将所述甲基叔丁基醚层依次进行水洗和干燥后，进行蒸馏除去甲基叔丁基醚层，得到(2S,3R)-2-羟甲基哌啶-3-甲酰胺。在本发明中，所述氯化铵溶液的质量浓度优选为10％。
得到(2S,3R)-2-羟甲基哌啶-3-甲酰胺后，本发明在氮气保护条件下，将所述(2S,3R)-2-羟甲基哌啶-3-甲酰胺与有机酸和含硼还原剂混合进行还原反应，得到(2S,3S)-2-羟甲基-3-氨甲基哌啶(式5所示化合物)；所述有机酸为有机强酸或有机超酸。在本发明中，所述含硼还原剂优选为硼氢化钠、硼氢化钠衍生物(如三乙酰氧基硼氢化钠、三乙基硼氢化钠、三(1-吡唑基)硼氢化钠)、硼氢化钾和硼氢化钾衍生物(如三苯基硼氢化钾、三异丙氧基硼氢化钾、三乙基氢硼化钾)中的一种或几种，更优选为硼氢化钠；所述含硼还原剂与(2S,3R)-2-羟甲基哌啶-3-甲酰胺的摩尔比优选为0.25～1：1，更优选为0.5～0.8：1。在本发明中，所述有机酸优选为三氟乙酸、醋酸、三氟甲磺酸、三氟化硼四氢呋喃络合物和三氟化硼乙醚络合 物中的一种或几种(在本发明中，三氟甲磺酸为有机超酸，三氟乙酸、醋酸、三氟化硼四氢呋喃络合物和三氟化硼乙醚络合物为有机强酸)，更优选为三氟化硼四氢呋喃络合物；所述有机酸与含硼还原剂的摩尔比优选为0.8～4:1，更优选为1～3:1。在本发明中，所述还原反应的溶剂优选为甲醇、乙醇、水、醋酸、四氢呋喃和二氧六环中的一种或几种；所述溶剂的质量优选为(2S,3R)-2-羟甲基哌啶-3-甲酰胺质量的2～15倍。在本发明中，所述还原反应的温度优选为室温，时间优选为1～5h，更优选为2h。在本发明中，所述还原反应完成后优选通过加入醋酸来终止反应。在本发明中，所述还原反应的反应式为：
Figure PCTCN2021139394-appb-000003
在本发明中，所述还原反应的具体操作优选为：在氮气保护条件下，在(2S,3R)-2-羟甲基哌啶-3-甲酰胺中加入所述溶剂和有机酸进行溶解，得到混合溶液；在所述混合溶液中分批加入含硼还原剂，在搅拌条件下进行还原反应，反应完成后加入醋酸终止反应。
所述还原反应后，本发明优选将所得还原反应液进行减压蒸馏回收溶剂后，得到(2S,3S)-2-羟甲基-3-氨甲基哌啶。
得到(2S,3S)-2-羟甲基-3-氨甲基哌啶后，本发明将所述(2S,3S)-2-羟甲基-3-氨甲基哌啶与氯化试剂混合，加热回流进行氯化反应，得到(2S,3S)-2-氯甲基-3-氨甲基哌啶(式6所示化合物)。在本发明中，所述氯化试剂优选为N-氯代丁二酰亚胺(NCS)、氯气、三光气、氯化亚砜、三氯氧磷和五氯化磷中的一种或几种，更优选为N-氯代丁二酰亚胺；所述(2S,3S)-2-羟甲基-3-氨甲基哌啶与氯化试剂的摩尔比优选为1:1～2.0，更优选为1:1.2～1.5。在本发明中，所述氯化反应的溶剂优选为二氯甲烷、甲苯、四氢呋喃、乙腈、二氧六环、甲基叔丁基醚和氯仿中的一种或几种，更优选为二氯甲烷；所述溶剂的质量优选为(2S,3S)-2-羟甲基-3-氨甲基哌 啶质量的2～15倍。在本发明中，所述氯化反应的温度(即加热回流的温度)优选为30～50℃，更优选为40℃，时间优选为2～6h，更优选为3h。在本发明中，所述氯化反应的反应式为：
Figure PCTCN2021139394-appb-000004
在本发明中，所述氯化反应的具体操作优选为：将(2S,3S)-2-羟甲基-3-氨甲基哌啶溶解于所述溶剂中，得到(2S,3S)-2-羟甲基-3-氨甲基哌啶溶液；在所述(2S,3S)-2-羟甲基-3-氨甲基哌啶溶液中分批加入氯化试剂，然后将体系升温至回流温度进行氯化反应。在本发明实施例中，所述氯化试剂优选分为3～5次加入。
所述氯化反应后，本发明优选将所得氯化反应液用饱和碳酸氢钠水溶液洗涤，分掉水层，收集有机层；回收所述有机层中的溶剂(先常压蒸馏，再减压蒸馏)后，得到(2S,3S)-2-氯甲基-3-氨甲基哌啶。
得到(2S,3S)-2-氯甲基-3-氨甲基哌啶后，本发明将在氮气保护条件下，将所述(2S,3S)-2-氯甲基-3-氨甲基哌啶在碳酸钾的作用下进行环合反应，得到莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷(式1所示化合物)。在本发明中，所述碳酸钾与(2S,3S)-2-氯甲基-3-氨甲基哌啶的摩尔比优选为0.5～1.5：1，更优选为0.8～1.3:1；所述碳酸钾既是催化剂也是缚酸剂。在本发明中，所述环合反应的溶剂优选为四氢呋喃、醇类溶剂、二甲基甲酰胺和甲苯中的一种或几种，更优选为四氢呋喃；所述溶剂的质量优选为(2S,3S)-2-氯甲基-3-氨甲基哌啶质量的2～15倍。在本发明中，所述环合反应的温度优选为55～70℃，更优选为60～65℃；时间优选为5～8h，更优选为6h。在本发明中，所述环合反应的反应式为：
Figure PCTCN2021139394-appb-000005
在本发明中，所述环合反应的具体操作优选为：在氮气保护条件下，将(2S,3S)-2-氯甲基-3-氨甲基哌啶溶于所述溶剂中，得到(2S,3S)-2-氯甲基-3-氨甲基哌啶溶液；在所述(2S,3S)-2-氯甲基-3-氨甲基哌啶溶液中分批加入碳酸钾，然后将体系升温至55～70℃，在搅拌条件下进行环合反应。在本发明实施例中，所述碳酸钾优选分为3～5次加入。
所述环合反应后，本发明还优选包括：
将所得环合反应液过滤，得到粗产物；
将所述粗产物与酸混合反应成盐，将所得盐用无水乙醇进行重结晶，得到结晶物；所述酸为对甲苯磺酸、盐酸、硫酸、磷酸、柠檬酸和草酸中的一种或几种；
将所述结晶物用饱和碳酸钠水溶液游离后，用二氯甲烷萃取，得到有机相；
将所述有机相进行脱色和干燥，得到莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷。
本发明对所述过滤的方法没有特别的要求，采用本领域技术人员熟知的过滤方法即可。在本发明中，所述(2S,3S)-2-氯甲基-3-氨甲基哌啶与酸的摩尔比优选为1:1～2；所述反应成盐的时间优选为1小时；所述酸和粗产物成盐固化为固体，便于进行重结晶，得到纯度更高的产品。在本发明中，以酸为对甲苯磺酸为例，所述酸和粗产物成盐的反应式如下(式7所示化合物为成盐物，其中TsOH表示对甲苯磺酸)：
Figure PCTCN2021139394-appb-000006
本发明对所述重结晶的操作方法没有特别的要求，采用本领域技术人员熟知的方法即可。在本发明中，所述结晶物用饱和碳酸钠水溶液游离的方法具体为：向结晶物中滴加饱和碳酸钠水溶液，碳酸钠和酸发生反应(即酸碱中和反应)，成盐物转变成为单体(即式7所示化合物转化为式1所示化合物)。在本发明中，所述二氯甲烷加入到饱和碳酸钠水溶液游离 后所得混合液中进行萃取即可。在本发明中，所述脱色用脱色剂优选为活性炭，所述干燥用干燥剂优选为元明粉。本发明在产品成盐精制的步骤中，无需使用含有手性结构的羧酸成盐，采用普通非手性羧酸对甲苯磺酸即可进行精制进一步提高产物纯度。
本发明提供的方法无需进行手性拆分，过程简单，工艺步骤短，成本低，且产物手性纯度高，总收率高。
下面结合实施例对本发明提供的制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷的方法进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
实施例1
制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷，方法如下：
(1)(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮的制备：取40g氮杂苯酞，用100mL甲苯溶解到250mL的高压釜中，先用氮气置换三次，再用氢气置换，加入手性催化剂0.002g([Ir(cod)Cl] 2·2(R)-(+)-BINAP)和1g碘后再用氢气置换，升温至65℃，加压至1.5MPa进行加氢还原。反应结束，将所得加氢还原反应液压滤至普通反应釜，用饱和碳酸氢钠水溶液洗涤2次，回流带水2小时，然后回收甲苯，回收结束，得到(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮，氮气保护下，投入200mL DMF溶解，直接用于下一步反应。
(2)(2S,3R)-2-羟甲基哌啶-3-甲酰胺的制备：在氮气保护下，在步骤(1)得到的(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮的DMF溶液中缓慢投入50g的氨水(30wt％)，升温至50℃进行氨解反应，微压保温反应5小时，反应结束，将所得氨解反应液压滤至100mL 10wt％的氯化铵溶液中，然后用甲基叔丁基醚提取，水洗干燥，回收甲基叔丁基醚，得到(2S,3R)-2-羟甲基哌啶-3-甲酰胺。
(3)(2S,3S)-2-羟甲基-3-氨甲基哌啶的制备：向含有(2S,3R)-2-羟甲基哌啶-3-甲酰胺的反应釜中，投入200mL的甲醇和3mL三氟化硼四氢呋喃络合物溶解，氮气保护下分批投入硼氢化钠进行还原反应，加毕搅拌2 小时取样，确认反应完全，加入少量醋酸，搅拌10min；然后将所得还原反应液减压蒸馏回收甲醇，得到(2S,3S)-2-羟甲基-3-氨甲基哌啶，用250mL的二氯甲烷溶解。
(4)(2S,3S)-2-氯甲基-3-氨甲基哌啶的制备：向(2S,3S)-2-羟甲基-3-氨甲基哌啶的二氯甲烷溶液中分批加入NCS，加毕升温至40℃，回流3小时进行氯化反应，取样TLC，(2S,3S)-2-羟甲基-3-氨甲基哌啶反应完全，用饱和碳酸氢钠水溶液200mL洗涤一次，回收溶剂得(2S,3S)-2-氯甲基-3-氨甲基哌啶。
(5)(S,S)-2,8-二氮杂二环[4,3,0]壬烷对甲苯磺酸盐的制备：氮气保护下，(2S,3S)-2-氯甲基-3-氨甲基哌啶用100mL四氢呋喃溶解，然后分批投入32g的碳酸钾，升温至70℃进行环合反应，加毕搅拌6小时取样，确认反应完全；然后过滤出固体，投入对甲苯磺酸，室温搅拌1小时，回收溶剂，然后用无水乙醇重结晶，得到成盐结晶物，HPLC检测纯度在99.5％以上(检测需要衍生化)。
(6)(S,S)-2,8-二氮杂二环[4,3,0]壬烷的制备：将步骤(5)的成盐结晶物用饱和碳酸钠水溶液游离，用200mL二甲烷萃取，用1g活性炭和2g元明粉脱色干燥，过滤，蒸干，得到22.1g的莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷。收率82％，化学纯度99.8％，手性纯度99.5％。核磁确认数据如下(核磁谱图见图1)：
1H NMR(400MHz,Chloroform-d)δ3.10(td,J＝4.6,1.5Hz,1H),2.99–2.80(m,4H),2.71(dd,J＝11.3,1.5Hz,1H),2.55(ddd,J＝12.1,11.0,2.9Hz,1H),2.08–1.96(m,1H),1.85(s,2H),1.68–1.58(m,2H),1.58–1.42(m,1H),1.42–1.30(m,1H).
实施例2
制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷，方法如下：
(1)(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮的制备：取40g氮杂苯酞，用100mL甲苯溶解到250ml的高压釜中，先用氮气置换三次，再用氢气置换，加入手性催化剂0.002g([Ir(cod)Cl] 2·(R)-(+)-BINAP)和0.5g溴氯 海因后再用氢气置换，升温至70℃，加压至1.7MPa进行加氢还原。反应结束，将所得加氢还原反应液压滤至普通反应釜，用饱和碳酸氢钠水溶液洗涤2次，回流带水2小时，然后回收甲苯，回收结束，得到(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮，氮气保护下，投入200mL DMF溶解，直接用于下一步反应。
(2)(2S,3R)-2-羟甲基哌啶-3-甲酰胺的制备：在氮气保护下，在步骤(1)得到的(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮的DMF溶液中缓慢投入20g的醋酸铵(30wt％)，升温至70℃进行氨解反应，微压保温反应6小时，反应结束，将所得氨解反应液压滤至100mL 10wt％的氯化铵溶液中，然后用甲基叔丁基醚提取，水洗干燥，回收甲基叔丁基醚，得到(2S,3R)-2-羟甲基哌啶-3-甲酰胺。
(3)(2S,3S)-2-羟甲基-3-氨甲基哌啶的制备：向含有(2S,3R)-2-羟甲基哌啶-3-甲酰胺的反应釜中，投入200mL的甲醇和2mL三氟乙酸，氮气保护下分批投入0.25eq的硼氢化钠进行还原反应，加毕搅拌3小时取样，确认反应完全，加入少量醋酸，搅拌10min；然后将所得还原反应液减压蒸馏回收甲醇，得到(2S,3S)-2-羟甲基-3-氨甲基哌啶，用250mL的二氯甲烷溶解。
(4)(2S,3S)-2-氯甲基-3-氨甲基哌啶的制备：向(2S,3S)-2-羟甲基-3-氨甲基哌啶的二氯甲烷溶液中分批加入三光气25g，加毕升温至45℃，回流2.5小时进行氯化反应，取样TLC，(2S,3S)-2-羟甲基-3-氨甲基哌啶反应完全，用饱和碳酸氢钠水溶液200mL洗涤一次，回收溶剂得(2S,3S)-2-氯甲基-3-氨甲基哌啶。
(5)(S,S)-2,8-二氮杂二环[4,3,0]壬烷草酸盐的制备：氮气保护下，(2S,3S)-2-氯甲基-3-氨甲基哌啶用100mL四氢呋喃溶解，然后分批投入32g的碳酸钾，升温至70℃进行环合反应，加毕搅拌6小时取样，确认反应完全；然后过滤出固体，投入草酸，室温搅拌1小时，回收溶剂，然后用无水乙醇重结晶，得到成盐结晶物，HPLC检测纯度在99.5％以上(检测需要衍生化)。
(6)(S,S)-2,8-二氮杂二环[4,3,0]壬烷的制备：将步骤(5)的 成盐结晶物用饱和碳酸钠水溶液游离，用200mL二甲烷萃取，用1g活性炭和2g元明粉脱色干燥，过滤，蒸干，得到20.5g的莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷。收率76％，化学纯度99.0％，手性纯度99.3％。
由以上实施例可以看出，本发明提供的方法无需进行手性拆分，过程简单，工艺步骤短，成本低，且产物手性纯度高，总收率高。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (13)

  1. 一种制备莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷的方法，其特征在于，包括以下步骤:
    (1)将氮杂苯酞在手性催化剂和引发剂的作用下进行加氢还原反应，得到(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮；所述手性催化剂为[Ir(cod)Cl] 2·n(R)-(+)-BINAP，n＝0.5～3；
    (2)在氮气保护条件下，将所述(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮与含氨化合物混合进行酯的氨解反应，得到(2S,3R)-2-羟甲基哌啶-3-甲酰胺；
    (3)在氮气保护条件下，将所述(2S,3R)-2-羟甲基哌啶-3-甲酰胺与有机酸和含硼还原剂混合进行还原反应，得到(2S,3S)-2-羟甲基-3-氨甲基哌啶；所述有机酸为有机强酸或有机超酸；
    (4)将所述(2S,3S)-2-羟甲基-3-氨甲基哌啶与氯化试剂混合，加热回流进行氯化反应，得到(2S,3S)-2-氯甲基-3-氨甲基哌啶；
    (5)在氮气保护条件下，将所述(2S,3S)-2-氯甲基-3-氨甲基哌啶在碳酸钾的作用下进行环合反应，得到莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷。
  2. 根据权利要求1所述的方法，其特征在于，所述步骤(1)中的引发剂为碘或卤代氮杂环化合物，所述引发剂的质量为氮杂苯酞质量的0.5～30％；所述手性催化剂的质量为氮杂苯酞质量的0.005～10％；
    所述加氢还原反应的溶剂为甲苯、二氧六环、苯、二甲苯和四氢呋喃中的一种或几种；所述加氢还原反应的温度为55～70℃，压力为0.5～3.0MPa。
  3. 根据权利要求2所述的方法，其特征在于，所述卤代氮杂环化合物优选为溴氯海因、二氯海因或三氯异氰尿酸。
  4. 根据权利要求1所述的方法，其特征在于，所述步骤(2)中的含氨化合物为尿素、氨、氯化铵和醋酸铵中的一种或几种；所述(4aR,7aS)呋喃并[3,4-b]哌啶-5(1H)-酮与含氨化合物中氨的摩尔比为1：1.2～5.0。
  5. 根据权利要求1所述的方法，其特征在于，所述步骤(2)中酯的 氨解反应的溶剂为N,N二甲基甲酰胺、甲苯、二甲苯、N,N-二甲基乙酰胺、DMPU和DMI中的一种或几种；所述酯的氨解反应的温度为45～75℃，时间为3～5h。
  6. 根据权利要求1所述的方法，其特征在于，所述步骤(2)中酯的氨解反应在微压条件下进行，所述微压的压力小于一个大气压。
  7. 根据权利要求1所述的方法，其特征在于，所述步骤(3)中的含硼还原剂为硼氢化钠、硼氢化钠衍生物、硼氢化钾和硼氢化钾衍生物中的一种或几种；所述含硼还原剂与(2S,3R)-2-羟甲基哌啶-3-甲酰胺的摩尔比为0.25～1：1；所述有机酸为三氟乙酸、醋酸、三氟甲磺酸、三氟化硼四氢呋喃络合物和三氟化硼乙醚络合物中的一种或几种；所述有机酸与含硼还原剂的摩尔比为0.8～4:1。
  8. 根据权利要求1所述的方法，其特征在于，所述步骤(3)中还原反应的溶剂为甲醇、乙醇、水、醋酸、四氢呋喃和二氧六环中的一种或几种；所述还原反应的温度为室温，时间为1～5h。
  9. 根据权利要求1所述的方法，其特征在于，所述步骤(4)中的氯化试剂为N-氯代丁二酰亚胺、氯气、三光气、氯化亚砜、三氯氧磷和五氯化磷中的一种或几种；所述(2S,3S)-2-羟甲基-3-氨甲基哌啶与氯化试剂的摩尔比为1:1～2.0。
  10. 根据权利要求1或9所述的方法，其特征在于，所述步骤(4)中氯化反应的溶剂为二氯甲烷、甲苯、四氢呋喃、乙腈、二氧六环、甲基叔丁基醚和氯仿中的一种或几种；所述氯化反应的温度为30～50℃，时间为2～6h。
  11. 根据权利要求1所述的方法，其特征在于，所述步骤(5)中碳酸钾与(2S,3S)-2-氯甲基-3-氨甲基哌啶的摩尔比为0.5～1.5：1；所述环合反应的溶剂为四氢呋喃、醇类溶剂、二甲基甲酰胺和甲苯中的一种或几种；所述环合反应的温度为55～70℃，时间为5～8h。
  12. 根据权利要求1或11所述的方法，其特征在于，所述步骤(5)中环合反应后，还包括：
    将所得环合反应液过滤，得到粗产物；
    将所述粗产物与酸反应成盐，将所得盐用无水乙醇进行重结晶，得到结晶物；所述酸为对甲苯磺酸、盐酸、硫酸、磷酸、柠檬酸和草酸中的一种或几种；
    将所述结晶物用饱和碳酸钠水溶液游离后，用二氯甲烷萃取，得到有机相；
    将所述有机相进行脱色和干燥，得到莫西沙星中间体(S,S)-2,8-二氮杂二环[4,3,0]壬烷。
  13. 根据权利要求12所述的方法，其特征在于，所述(2S,3S)-2-氯甲基-3-氨甲基哌啶与酸的摩尔比为1:1～2；所述反应成盐的时间为1小时。
PCT/CN2021/139394 2021-02-06 2021-12-18 一种制备莫西沙星中间体(s,s)-2,8-二氮杂二环[4,3,0]壬烷的方法 WO2022166436A1 (zh)

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