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CN107118224B - A kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and preparation method thereof - Google Patents

A kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and preparation method thereof Download PDF

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Publication number
CN107118224B
CN107118224B CN201710454606.6A CN201710454606A CN107118224B CN 107118224 B CN107118224 B CN 107118224B CN 201710454606 A CN201710454606 A CN 201710454606A CN 107118224 B CN107118224 B CN 107118224B
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preparation
cephalosporin nucleus
compound
oxygen cephalosporin
methyl
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CN107118224A (en
Inventor
张玉红
唐家兴
胡柏剡
鲁国彬
胡瑞君
钱洪胜
田金金
简海涛
张炎斌
杨芝
李其川
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SHANGYU XINHECHENG BIO-CHEMICAL Co Ltd
Zhejiang University ZJU
Zhejiang NHU Co Ltd
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SHANGYU XINHECHENG BIO-CHEMICAL Co Ltd
Zhejiang University ZJU
Zhejiang NHU Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
    • C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
    • C07D505/16—Nitrogen atoms
    • C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D505/02—Preparation
    • C07D505/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

The invention discloses a kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and preparation methods.The present invention prepares the oxygen cephalosporin nucleus intermediate using chlorination, selects specific catalyst, and being not required to additionally to add organic base can be in fast reaction, and reaction temperature is low, and by-product is few, products obtained therefrom quality height.The invention further relates to the intermediates to crystallize in the solution containing acetonitrile, and a kind of new solvated compounds can be formed with acetonitrile, and crystalline particle is big, and stability is good, and convenient for filtering and storage, product yield is high, is suitble to industrialized production.

Description

A kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and its preparation Method
Technical field
The present invention relates to antibiotic medicine preparation technical field, in particular to a kind of preparation side of oxygen cephalosporin nucleus intermediate Method and its solvated compounds and preparation method, belong to technical field of medicine synthesis.
Background technique
Oxacephems antibiotic such as latamoxef, Flomoxef etc. is because of its special structure, to a variety of gram-negative bacterias There is good antibacterial action.Further, since the performance of such resistance to beta-lactamase of antibiotic is strong, the product seldom occur for microorganism Drug resistance.Oxacephems antibiotic such as latamoxef compound, relates generally to key intermediate 3- chloromethyl compound (IV) Synthesis.
Wherein, R is H or methyl.
The complete synthetic method of the key intermediate 3- chloromethyl compound (IV) of existing oxacephems antibiotic, only Have has relevant report in US4366316 and Tetrahedron Letters 1980, Vol 21,351-354, and route is all The first addition chloro under low temperature/illumination condition, then the chlorine with the effect of organic or inorganic alkali elimination 3, to generate 3- chloromethyl Compound (IV), is shown below:
Wherein, R1For the common acyl residue in cephalosporin chemistry field, R2For carboxyl-protecting group.
Route first step addition chloro needs are completed under illumination condition, and light reaction generally requires special expensive Light reaction equipment, and energy can decay light in a solvent, lead to that reaction is uneven and speed is very slow, and raw material is difficult to convert Entirely, it is also easy to that allylic substitution occurs, generates more by-product.On the other hand, two-step reaction must maintain -30 DEG C of low temperature ~-20 DEG C, energy consumption is high, and yield is lower (50%-55%).
In addition, that recrystallisation solvent aspect patent US4366316 is methanol, non-patent literature Tetrahedron It is that first column chromatography recrystallizes again, and does not illustrate specific recrystallisation solvent, but it is produced in Letters 1980, Vol 21,351-354 The nuclear-magnetism of product1There is no the chemical shift of the related H of acetonitrile in H-NMR data, can determine its product not is crystallized with acetonitrile 's.Under the conditions of this, products obtained therefrom is without solvated compounds, and there are problems to have crystallization loss big for it, the low (60%- of yield 65%).And crystalline particle is very thin, the rate of filtration is very slow when filtering, filtration difficulty.It is unfavorable for industrialized production.
Patent JPS5967289A and CN1980939A improves the chloro technique of the first step, with catalyst and ties up Instead of illumination, specific route is as follows for sour agent:
Compared to illumination condition, reaction condition is mild very much, only reacts catalyst used, is selected from triphenylphosphine, three The organic matters such as benzene phosphine oxide, triethyl phosphite, hydroquinone.Organic impurities can be introduced in subsequent product, influence product quality. In addition, needing to be added the acid binding agents such as organic base (pyridine, piperidines, 2 picolines etc.) in reaction process, chlorine and organic base are one Determine to generate side reaction in degree, also can introduce organic impurities in subsequent product and waste water, influence product quality and increases waste water Treating capacity.
Summary of the invention
The present invention provides a kind of preparation methods of the high oxygen cephalosporin nucleus intermediate of yield and product quality and its solvent Compound and preparation method.The solvated compounds stability of this method environmental protection and economy, generation is good, is readily transported and stores, is suitable for Industrialized production.
A kind of preparation method of oxygen cephalosporin nucleus intermediate, comprising the following steps:
A) in organic solvent, 3- methylene compounds (I) and chlorine generate among chloro under the effect of the catalyst Body；
The chloro intermediate contains compound of dichloro (III) and three chlorinated compounds (II), wherein dichloro- chemical combination Object (III) is primary product, and three chlorinated compounds (II) are a small amount of；
B) three chlorinated compounds (II) in chloro intermediate restore to obtain compound of dichloro (III) through reducing agent；
C) compound of dichloro (III) generates oxygen cephalosporin nucleus intermediate (IV) under alkali effect；
The general structure of the oxygen cephalosporin nucleus intermediate (IV) are as follows:
Wherein, R is H or methyl.
Specific reaction equation is as follows:
Wherein, R is H or methyl.
Catalyst described in step (a), selected from including cobalt, iron, copper, silver, nickel, zinc, ferrous iron, cuprous halide, sulphur One or more of compound, sulfate, oxide or organophosphorus ligand compound of halide.Wherein, organophosphorus ligand Organophosphor ligand can be phosphorous acid di tert butyl carbonate, methyl triphenyl phosphine ethyl ester, diphenylphosphine, triphenylphosphine, double in compound (triphenylphosphine), three (triphenylphosphines), diphenyl phosphine oxide, triphenylphosphine oxide, ethyltriphenyl phosphonium chloride phosphorus, tributyl cetyl Phosphonium bromide, phenyl phosphonyl chloride, diphenyl -2- pyridine radicals phosphine, three (o-tolyl) phosphines, dichlorophenyl phosphine, two (diphenylphosphines Base) methane, bis- (diphenylphosphine) ethane of 1,2-, 1,3- bis- (diphenylphosphine) propane, bis- (diphenylphosphine) butane of 1,4-, 1,5- bis- (diphenylphosphino) pentane, diphenyl phosphorus chloride, benzyltriphenylphosphonium chloride, methyltriphenylphospbromide bromide phosphorus, (1- butyl) triphen One of base phosphorus chloride, normal-butyl tri-phenyl-phosphorus bromide, tributylphosphine oxide.
Catalyst described in step (a), wherein halide can be cobalt chloride, iron chloride, copper chloride, silver chlorate, chlorine Change nickel, zinc chloride, frerrous chloride, stannous chloride, cobaltous bromide, ferric bromide, copper bromide, silver bromide, nickelous bromide, zinc bromide, bromination Ferrous iron, cuprous bromide, cobaltous iodide, ferric iodide, cupric iodide, silver iodide, nickel iodide, zinc iodide, iron iodide, in cuprous iodide It is a kind of；
Sulfide can be cobalt sulfide, ironic sulfide, copper sulfide, silver sulfide, nickel sulfide, zinc sulphide, ferrous sulfide, sulphur Change one of cuprous；
Sulfate can be sub- for cobaltous sulfate, ferric sulfate, copper sulphate, silver sulfate, nickel sulfate, zinc sulfate, ferrous sulfate, sulfuric acid One of copper；
Oxide can be sub- for cobalt oxide, iron oxide, copper oxide, silver oxide, nickel oxide, zinc oxide, ferrous oxide, oxidation One of copper；
The organophosphorus ligand compound of halide can be phosphorous acid di tert butyl carbonate complex, the first of above-mentioned halide Base triphenylphosphine ethyl ester complex, diphenylphosphine complex, triphenylphosphine complex, bis- (triphenylphosphines) are matched Position compound, three (triphenylphosphine) complexes, diphenyl phosphine oxide complex, triphenylphosphine oxide complex, second Base triphenylphosphonium chloride complex, tributyl cetyl phosphonium bromide complex, phenyl phosphonyl chloride ligand compound Object, diphenyl -2- pyridine radicals phosphine complex, three (o-tolyl) phosphine complexes, dichlorophenyl phosphine complex, Two (diphenylphosphino) methane complexes, bis- (diphenylphosphine) the ethane complexes of 1,2-, 1,3- bis- (diphenylphosphine) Bis- (diphenylphosphine) the butane complexes of propane complex, 1,4-, 1,5- bis- (diphenylphosphino) pentane ligand compound Object, diphenyl phosphorus chloride complex, benzyltriphenylphosphonium chloride complex, methyltriphenylphospbromide bromide phosphorus ligand compound Object, (1- butyl) triphenylphosphonium chloride complex, normal-butyl tri-phenyl-phosphorus bromide complex, tributylphosphine oxide are matched One of position compound.
The dosage of catalyst described in step (a) is 0.01~0.2 parts by weight relative to compound (I).Preferably, The dosage of catalyst described in step (a) is 0.03~0.1 parts by weight relative to compound (I).As further preferred, step Suddenly the dosage of catalyst described in (a) is 0.04~0.07 parts by weight relative to compound (I).
Addition reaction temperature described in step (a) is -40 DEG C~10 DEG C, preferably -10 DEG C~0 DEG C.
Chlorine dosage described in step (a) relative to compound (I) be 1.0~3.0 molar equivalents, preferably 1.5~ 2.5 molar equivalent.
Organic solvent described in step (a) is selected from one or more of halogenated alkane, ester, ether.The alkyl halide Hydrocarbon is selected from one or more of methylene chloride, chloroform, carbon tetrachloride, trichloroethanes；The ester is selected from ethyl acetate, acetic acid One or more of propyl ester；The ether is selected from one or more of glycol dimethyl ether, tetrahydrofuran.Preferably, The organic solvent includes at least one or more of methylene chloride, chloroform.
Reducing agent described in step (b) can be in sodium sulfite, sodium hydrogensulfite, sodium thiosulfate, dimethyl sulfide One or more, preferably sodium sulfite or sodium thiosulfate.The reducing agent is preferably added in form of an aqueous solutions, and concentration is excellent It is selected as 5wt%~10wt%.
In the present invention, step (a)~(c) can be carried out in identical solvent, can after the reaction of step (a) is completed To be directly added into the reaction that reducing agent carries out step (b)；After the reaction of step (b) terminates, step can be entered after washing Suddenly (c) is reacted.
The invention further relates to a kind of its general structures of oxygen cephalosporin nucleus intermediate solvated compounds are as follows:When R is methyl, the crystal that parses after X diffraction characterization Structure is as follows:
The present invention also provides the preparation methods of the oxygen cephalosporin nucleus intermediate solvated compounds (V), comprising: changes It closes object (IV) to be crystallized in acetonitrile or organic solvent containing acetonitrile, forms single acetonitrile solvent compound (V).
Reaction equation is as follows:
Wherein, R is H or methyl.
Above-mentioned compound (IV) can be used method described in this patent and obtain, or be obtained using method disclosed in the prior art It arrives, the compound (IV) that chloro obtains under illumination condition as disclosed in US4366316.
The above-mentioned organic solvent containing acetonitrile is methylene chloride, chloroform, n-hexane, ethyl acetate, petroleum ether, isopropyl Ether, methyl acetate, methanol, ethyl alcohol, isopropanol it is one or more.
Molar ratio >=1 of above-mentioned acetonitrile and compound (IV).
Compared with the existing technology, the beneficial effects of the present invention are embodied in:
(1) catalyst of chlorination selection is not required to additionally add organic base energy fast reaction.Reaction temperature is low, secondary Product is few, and products obtained therefrom quality is high.
(2) the invention patent technique uses the solvent crystallization containing acetonitrile, and final products are acetonitrile solvent compound, benefit It is exactly that small, high income (90%-95%) is lost in crystallization, product purity >=99.0%, filtering is conveniently.Acetonitrile solvent compound is stablized Property it is good, 25 DEG C of room temperature can be reserved for 6 months or more, be readily transported and store, be conducive to industrialized production.
Detailed description of the invention
Fig. 1 is the crystal knot that single acetonitrile solvent compound (V) that embodiment 1 obtains parses after X diffraction characterization Composition.
Specific embodiment
The present invention is further illustrated by the following examples, but not as limitation of the present invention.
Embodiment 1
7- benzamido -3- chloromethyl -8- oxo -5- oxa- -1- azabicyclo [4.2.0] oct-2-ene -2- formic acid two The preparation method of benzene methyl list acetonitrile solvent compound (V):
Chemical equation
1,7- benzamido -3- chloromethyl -8- oxo -5- oxa- -1- azabicyclo [4.2.0] oct-2-ene -2- formic acid The preparation method of benzhydryl ester:
Wherein, R H
2,7- benzamido -3- chloromethyl -8- oxo -5- oxa- -1- azabicyclo [4.2.0] oct-2-ene -2- formic acid The preparation method of benzhydryl ester list acetonitrile solvent compound
Wherein, R H
Operating process:
In having churned mechanically 100mL there-necked flask, by 5.0g (10.68mmol) compound (I), 0.25g frerrous chloride It is mixed with 10ml methylene chloride, is cooled to -20 DEG C, 10% chlorine/dichloromethane solution 17.6g (2.3eq) is added, continued anti- 60min, HPLC is answered to detect fully reacting, 7% sodium sulfite aqueous solution 70mL (3.6eq) is added, separates organic layer, uses carbonic acid The washing of hydrogen sodium water solution, adjusts PH to 7-8.
Organic layer obtained above is cooled to 0 DEG C, is added piperidines 0.97g (1.07eq), HPLC detects fully reacting, adds Enter dilute hydrochloric acid tune PH to 5-7, with water 50mL water washing 1 time, water phase is extracted 1 time with 20ml methylene chloride, merges organic layer.Decompression Dry solvent is concentrated, obtains concentrate (IV).
Acetonitrile is added in concentrate obtained above (IV), 0 DEG C of crystallization is cooled to after dissolution.Obtain single acetonitrile solvent Object (V) (R=H) 5.36g, yield 92.0% are closed, HPLC detects purity 99.3%.
X diffraction characterize data structure obtained after parsing is as shown in Figure 1.
According to the method for embodiment 1, the items such as feed change structure, catalyst and its dosage, chlorine dosage, recrystallisation solvent Part, according to the process of embodiment 1, obtain a series of intermediate 3- chloromethyl list acetonitrile solvent compounds (V) (R=H or Methyl).Specific data are as shown in the table:
Comparative example 1
Compound 7- benzamido -3- chloromethyl -8- oxo -5- oxa- -1- azabicyclo [4.2.0] oct-2-ene -2- The preparation method of formic acid benzhydryl ester (IV):
Wherein, R=H.
5.0g (10.68mmol) compound (II) and 0.25g triphenylphosphine are dissolved in 10mL methylene chloride, are cooled to 3 DEG C, Constant temperature stirs 5 minutes, is added 2- picoline 1.0g (1.01eq), and after 20min, 10% chlorine/dichloromethane solution is added dropwise After 25g (3.3eq), 3 DEG C of reaction 2h, after HPLC detects fully reacting, 7% sodium sulfite solution 50mL (2.6eq) is added, point Organic layer out is washed with sodium bicarbonate aqueous solution.
Organic layer obtained above is cooled to 0 DEG C, is added piperidines 0.97g (1.07eq), maintains 0 DEG C to react 3 hours, After HPLC detects fully reacting,
Dilute hydrochloric acid tune PH to 5-7 is added, with water 50mL water washing 1 time, water phase is extracted 1 time with 20ml methylene chloride, is merged Organic layer.Dry solvent is concentrated under reduced pressure, obtains concentrate (IV) 4.34g, product purity 80.7%, yield 65.3%.
Comparative example 1 the result shows that, using acid binding agent/catalyst system in the prior art, obtained product yield and Purity is substantially reduced.
Embodiment 33
Crystallization in acetonitrile is added in the 4.34g concentrate (IV) that comparative example 1 obtains and obtains single acetonitrile solvent compound (V) 3.23g, crystallization yield 92%, HPLC detect purity 99.1%.
Comparative example 2
According to the method for comparative example 1, the case where for R=methyl, use pyridine as acid-binding agent, triethylamine is as step 2 use alkali, according to the process of comparative example 1, obtain compound (IV) (R=methyl) addition methanol and are crystallized, obtain chemical combination Object (IV) 3.51g, yield 60.1%, HPLC detect purity 98.2%.
Comparative example 3
Compound 7- benzamido -3- chloromethyl -8- oxo -5- oxa- -1- azabicyclo [4.2.0] oct-2-ene -2- The preparation method of formic acid benzhydryl ester (IV):
Wherein, R=H.
5.0g (10.68mmol) compound (II) is dissolved in 50mL methylene chloride, -10 DEG C is cooled to, 10% chlorine is added Gas/dichloromethane solution 30g (3.96eq).Illumination is opened, after -10 DEG C of reaction 1h, after HPLC detects fully reacting, stopping light According to 7% sodium sulfite solution 58mL (3.0eq) is added, separates organic layer, is washed with sodium bicarbonate aqueous solution.
Organic layer obtained above is cooled to 0 DEG C, is added piperidines 0.97g (1.07eq), maintains 0 DEG C to react 3 hours, After HPLC detects fully reacting,
Dilute hydrochloric acid tune PH to 5-7 is added, with water 50mL water washing 1 time, water phase is extracted 1 time with 20ml methylene chloride, is merged Organic layer.Dry solvent is concentrated under reduced pressure, obtains concentrate (IV) 3.78g, product purity 72.9%, yield 52.1%.
Comparative example 3 the result shows that, using illumination system in the prior art, obtained product yield and purity obviously drops It is low.
Embodiment 34
Crystallization in acetonitrile is added in the 3.78g concentrate (IV) that comparative example 3 obtains and obtains single acetonitrile solvent compound (V) 2.75g, crystallization yield 90%, HPLC detect purity 99.0%,
Comparative example 4
Compound 7- benzamido -3- chloromethyl -8- oxo -5- oxa- -1- azabicyclo [4.2.0] oct-2-ene -2- The preparation method of formic acid benzhydryl ester (IV):
Wherein, R=H.
5.0g (10.68mmol) compound (I) and 0.25g (0.05 weight ratio) triphenylphosphine are dissolved in 50mL dichloromethane Alkane is cooled to 3 DEG C, and constant temperature stirs 5 minutes, is added 2- picoline 1.0g (1.01eq), and after 20min, iodine monochloride is added After 5.7g (3.3eq), 3 DEG C of reaction 1h, HPLC detects fully reacting, and 7% sodium sulfite solution 50mL (2.6eq) reaction is added After 30min, separates organic layer and washed with sodium bicarbonate aqueous solution.
Organic layer obtained above is cooled to 0 DEG C, is added piperidines 0.97g (1.07eq), maintains 0 DEG C to react 3 hours, After HPLC detects fully reacting, dilute hydrochloric acid is added and neutralizes, with water 50mL water washing 1 time, water phase extracts 1 with 20ml methylene chloride It is secondary, merge organic layer.Dry solvent is concentrated under reduced pressure, obtains concentrate (IV) 5.5g, product purity 85.4%, yield 87.5%.
According to the method for comparative example 4, the conditions such as feed change structure, catalyst, acid binding agent, according to the technique of comparative example 4 Method obtains a series of halogenating reaction data.Specific data are as shown in the table:
Comparative example 4 the result shows that catalyst system of the invention is suitable for chlorine as chlorinating agent, when with monochlor(in)ate When iodine is as chlorinating agent, reaction effect is bad.
Embodiment 35
The crystalline product of the crystalline product to single acetonitrile solvent compound (V) and compound (IV) does stability and grinds respectively Study carefully, as a result, it has been found that crystallization of the stability of the crystalline product of single acetonitrile solvent compound (V) significantly better than compound (IV) produces Product.Specific data are as follows:

Claims (9)

1. a kind of preparation method of oxygen cephalosporin nucleus intermediate solvated compounds, which comprises the following steps:
A) in organic solvent, 3- methylene compounds (I) and chlorine generate chloro intermediate under the effect of the catalyst；
The structural formula of 3- methylene compounds (I) is as follows:
Wherein, R is H or methyl；
Wherein chloro intermediate contains compound of dichloro (III) and three chlorinated compounds (II)；
The structural formula of compound of dichloro (III) is as follows:
Wherein, R is H or methyl；
The structural formula of three chlorinated compounds (II) is as follows:
Wherein, R is H or methyl；
B) three chlorinated compounds (II) in chloro intermediate restore to obtain compound of dichloro (III) through reducing agent；
C) compound of dichloro (III) generates oxygen cephalosporin nucleus intermediate (IV) under alkali effect；
The general structure of the oxygen cephalosporin nucleus intermediate (IV) are as follows:
Wherein, R is H or methyl；
D) oxygen cephalosporin nucleus intermediate (IV) is crystallized in acetonitrile or organic solvent containing acetonitrile, forms the oxygen Cephalosporin nucleus intermediate solvated compounds；
The structure of the oxygen cephalosporin nucleus intermediate solvated compounds is such as shown in (V):
Wherein, R is H or methyl；
Catalyst described in step (a), selected from cobalt, iron, copper, silver, nickel, zinc, ferrous iron, cuprous halide, sulfide, sulfuric acid One or more of organophosphorus ligand compound of salt, oxide or halide；
The dosage of catalyst described in step (a) is 0.01~0.2 parts by weight relative to compound (I).
2. the preparation method of oxygen cephalosporin nucleus intermediate solvated compounds according to claim 1, which is characterized in that described Halide be one of chloride, bromide, iodide；
Organophosphor ligand is phosphorous acid di tert butyl carbonate, methyl triphenyl phosphine second in the organophosphorus ligand compound of the halide Ester, diphenylphosphine, triphenylphosphine, bis- (triphenylphosphines), three (triphenylphosphines), diphenyl phosphine oxide, triphenylphosphine oxide, ethyl triphen Base phosphorus chloride, tributyl cetyl phosphonium bromide, phenyl phosphonyl chloride, diphenyl -2- pyridine radicals phosphine, three (o-tolyl) phosphines, Dichlorophenyl phosphine, two (diphenylphosphino) methane, bis- (diphenylphosphine) ethane of 1,2-, 1,3- bis- (diphenylphosphine) propane, 1,4- Bis- (diphenylphosphine) butane, 1,5- bis- (diphenylphosphino) pentane, diphenyl phosphorus chloride, benzyltriphenylphosphonium chloride, methyl three One of phenyl phosphonium bromide, (1- butyl) triphenylphosphonium chloride, normal-butyl tri-phenyl-phosphorus bromide, tributylphosphine oxide.
3. the preparation method of oxygen cephalosporin nucleus intermediate solvated compounds according to claim 1, which is characterized in that step (a) reaction temperature in is -40 DEG C~10 DEG C.
4. the preparation method of oxygen cephalosporin nucleus intermediate solvated compounds according to claim 1, which is characterized in that step (a) chlorine dosage described in is 1.0~3.0 molar equivalents relative to compound (I).
5. the preparation method of oxygen cephalosporin nucleus intermediate solvated compounds according to claim 1, which is characterized in that step (a) organic solvent described in is selected from one or more of halogenated alkane, ester, ether；The halogenated alkane is selected from dichloromethane One or more of alkane, chloroform, carbon tetrachloride, trichloroethanes；
The ester is selected from one or more of ethyl acetate, propyl acetate；
The ether is selected from one or more of glycol dimethyl ether, tetrahydrofuran.
6. the preparation method of oxygen cephalosporin nucleus intermediate solvated compounds according to claim 1, which is characterized in that step (b) reducing agent described in is one or more of sodium sulfite, sodium hydrogensulfite, sodium thiosulfate, dimethyl sulfide.
7. the preparation method of oxygen cephalosporin nucleus intermediate solvated compounds according to claim 1, which is characterized in that described The organic solvent containing acetonitrile be methylene chloride, chloroform, n-hexane, ethyl acetate, petroleum ether, isopropyl ether, methyl acetate, first One of alcohol, ethyl alcohol, isopropanol are a variety of.
8. the preparation method of oxygen cephalosporin nucleus intermediate solvated compounds according to claim 1 or claim 7, which is characterized in that Molar ratio >=1 of the acetonitrile and oxygen cephalosporin nucleus intermediate (IV).
9. a kind of oxygen cephalosporin nucleus intermediate solvated compounds, which is characterized in that structure is such as shown in (V):
Wherein, R is methyl；
The crystal structure parsed after its X diffraction characterization is as shown in Figure 1.
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4042585A (en) * 1976-03-22 1977-08-16 Eli Lilly And Company Process for preparation of 3-halomethylcephems
US4048163A (en) * 1976-03-22 1977-09-13 Eli Lilly And Company Process for preparation of 7-alkoxy-3-chloromethylcephems
US4354022A (en) * 1981-06-05 1982-10-12 Fujisawa Pharmaceutical Co., Ltd. Process for preparing 3-methylenecepham compounds or a salt thereof
US4366316A (en) * 1977-02-15 1982-12-28 Shionogi & Co., Ltd. 1-Oxadethiacepham compounds and process for producing said compounds
JPS5967289A (en) * 1982-10-08 1984-04-16 Shionogi & Co Ltd N-haloacylaminooxacepham derivative
CN101538274A (en) * 2009-02-23 2009-09-23 上海医药工业研究院 Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives
CN1980939B (en) * 2004-07-08 2012-05-30 盐野义制药株式会社 Process for producing 1-oxacephalosporin-7 alpha-methoxy-3-chloromethyl derivatives
CN106749335A (en) * 2016-11-29 2017-05-31 浙江新和成股份有限公司 A kind of preparation method and application of halo oxygen cephalo-type intermediate

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102443013B (en) * 2010-10-10 2014-09-17 石药集团中奇制药技术（石家庄）有限公司 Method for preparing cefprozil dimethyl formamide solvate
CN102295655B (en) * 2011-07-05 2013-05-29 山东睿鹰先锋制药有限公司 Oxacephem antibiotic intermediate solvate and preparation method thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4042585A (en) * 1976-03-22 1977-08-16 Eli Lilly And Company Process for preparation of 3-halomethylcephems
US4048163A (en) * 1976-03-22 1977-09-13 Eli Lilly And Company Process for preparation of 7-alkoxy-3-chloromethylcephems
US4366316A (en) * 1977-02-15 1982-12-28 Shionogi & Co., Ltd. 1-Oxadethiacepham compounds and process for producing said compounds
US4354022A (en) * 1981-06-05 1982-10-12 Fujisawa Pharmaceutical Co., Ltd. Process for preparing 3-methylenecepham compounds or a salt thereof
JPS5967289A (en) * 1982-10-08 1984-04-16 Shionogi & Co Ltd N-haloacylaminooxacepham derivative
CN1980939B (en) * 2004-07-08 2012-05-30 盐野义制药株式会社 Process for producing 1-oxacephalosporin-7 alpha-methoxy-3-chloromethyl derivatives
CN101538274A (en) * 2009-02-23 2009-09-23 上海医药工业研究院 Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives
CN106749335A (en) * 2016-11-29 2017-05-31 浙江新和成股份有限公司 A kind of preparation method and application of halo oxygen cephalo-type intermediate

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Synthesis and antibacterial activity of novel 2-methyl-1-oxacephalosporins;Tsuneo Okonogi,等;《THE JOURNAL OF ANTIBIOTICS》;19900430;第XLIII卷(第4期);第357-371页
氟氧头孢母核的合成;邵波;《重庆医科大学硕士学位论文》;20140615;第22页

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