CN101538274B - Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives - Google Patents

Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives Download PDF

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CN101538274B
CN101538274B CN2009100464787A CN200910046478A CN101538274B CN 101538274 B CN101538274 B CN 101538274B CN 2009100464787 A CN2009100464787 A CN 2009100464787A CN 200910046478 A CN200910046478 A CN 200910046478A CN 101538274 B CN101538274 B CN 101538274B
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oxacephalosporin
derivatives
preparation
reaction
methyl
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CN101538274A (en
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刘相奎
袁哲东
胡志
俞雄
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Shanghai Institute of Pharmaceutical Industry
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Shanghai Institute of Pharmaceutical Industry
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to the technical field of a method for synthesizing 1-oxacephalosporin-3-chloromethyl derivatives, that is, intermediates for synthesizing antimicrobial 1-oxacephalosporin. The method of the invention comprises the following steps: carrying out the addition reaction between 1-oxacephalosporin-3-methylene derivatives and halogens under the action of halogenating agent; and generating the 1-oxacephalosporin-3-chloromethyl derivatives under the action of organics bases. In the method of the invention, the illumination reaction is avoided, the reaction is stable without instantaneously releasing an enormous amount of heat and the low-temperature reaction is not required, thereby greatly reducing the risk, eliminating the high-cost special facilities from the industrial production, reducing the investment on the production facilities and ensuring higher competitiveness in the industrial production; and on the other hand, since the illumination reaction is avoided, the method for obtaining 1-oxacephalosporin-3-chloromethyl derivatives becomes simple but high-yield.

Description

The preparation method of 1-oxacephalosporin-3-chloromethyl derivatives
Technical field
The present invention relates to a kind of synthetic compound method technical field of antimicrobial 1-oxa-cynnematin that can be used as with midbody 1-oxacephalosporin-3-chloromethyl derivatives.
Background technology
Shown in the following reaction formula, 1-oxacephalosporin-3-chloromethyl derivatives (formula I) is the 1-oxa-cynnematin important intermediate that for example high efficiency production is used in the industry of latamoxef (Latamoxef) or flomoxef (Flomoxef).
Figure G2009100464787D00011
The preparation of 1-oxacephalosporin-3-chloromethyl derivatives at present all is the starting raw material preparation with 6APA:
Figure G2009100464787D00012
The concrete working method of midbody 1-oxacephalosporin-3-chloromethyl derivatives also has disclosed bibliographical information; One of method is to use a kind of raw material 1-oxa-cynnematin-3-methylene compound after adding chlorine, to pass through illumination reaction generation addition reaction, and then interpolation alkali obtains the 1-oxacephalosporin-3-chloromethyl derivatives.Yet under illumination, chlorine is very active, and two key free radical addition reactions can either take place, and the radical substitution reaction of allyl group position also can take place, and replaces in order to suppress allyl group position radical, needs extremely low temperature of reaction.If illuminating area and energy shortage, chlorine can't in time be participated in reaction; And in case Kettenreaktion takes place; Violent reaction again can the abrupt release great amount of heat; Accidents caused easily, therefore on producing, require to use expensive special reaction equipment and extremely low temperature of reaction, and the measure that properly protects; This needs factory to drop into a large amount of funds and is used for equipment construction, thereby is not favourable on industrial production.
For example, Tetrahedron Letter1980,21,351-354 has described following reaction:
Figure G2009100464787D00021
1-oxa-cynnematin-3-methylene derivatives-20 ℃ of following and alkali DBU reactions, obtains the 1-oxacephalosporin-3-chloromethyl derivatives then at-20 ℃ of following chlorine illumination reactions that add.Find that in experiment the yield of chloro just depends on the energy and the area of illumination, if illumination is not enough, then most of product becomes impurity, causes the yield step-down; When removing hydrogenchloride,, reduce yield if temperature of reaction too high (being higher than-20 ℃) because DBU alkalescence is strong excessively, can destroy product.
Synthetic route below US4604460 has also reported:
Figure G2009100464787D00022
1-oxa-cynnematin-3-methylene derivatives adds reaction under the chlorine illumination down at-20 ℃, reacts with alkali CH3OLi at-50 ℃ then, obtains the 1-oxacephalosporin-3-chloromethyl derivatives.Remove hydrogenchloride with lithium methoxide, lithium methoxide need be with participating in reaction behind the dissolve with methanol, and this makes that reaction solvent is a mixed solvent, has increased the difficulty of solvent recuperation, has increased the cost expenditure.
In above reaction, all used illumination reaction, and reaction at low temperatures, this all is disadvantageous in industry; Removing in the hydrogenchloride with alkali, also is reaction under very low temperature, is unfavorable for suitability for industrialized production equally.
Summary of the invention
The object of the invention is exactly the above-mentioned defective that solves existing synthetic 1-oxacephalosporin-3-chloromethyl derivatives method, and a kind of preparation method that can adapt to suitability for industrialized production is provided, and the existing method of productivity ratio is high.
Through a large amount of experimental studies; Contriver of the present invention finds; Equally with 1-oxa-cynnematin-3-methylene derivatives as starting raw material; Need not use illumination reaction, only need through adding suitable halogenating agent catalyzed reaction, on the contrary can high yield obtain the 1-oxacephalosporin-3-chloromethyl derivatives.In the presence of halogenating agent, halogen produces positively charged halide-ions under halogenating agent catalysis, with two key generation electrophilic addition reactions, thereby can realize the addition of two keys smoothly.When removing hydrogen halide, remove reagent less than the alkali of DBU as hydrogen halide with alkalescence, also high yield has obtained the 1-oxacephalosporin-3-chloromethyl derivatives.
The concrete technical scheme that the present invention takes is following:
The preparation method of 1-oxacephalosporin-3-chloromethyl derivatives, its step comprises:
A, under the halogenating agent effect, 1-oxa-cynnematin-3-methylene derivatives (II) and halogen addition reaction generate oxa-cephalosporin compound (III)
Figure G2009100464787D00041
B, under the organic bases effect, oxa-cephalosporin compound (III) reaction generates 1-oxacephalosporin-3-chloromethyl derivatives (I)
R wherein 1Be acyl residue, R 2Be hydrogen or methoxyl group, R 3Be carboxyl-protecting group; Halogenating agent is inorganic salt R 4The halogenation hydrogen salt R of X, organic bases 5X or halo quaternary ammonium salt X represents chlorine or bromine, R 4Represent copper, iron, zinc or magnesium, R 5Represent nitrogenous aromatic heterocycle or aliphatics tertiary amine, R 6, R 7, R 8, R 9Represent the alkane of C1～C20, the unsaturated alkane of C2～C10 or the aromatic hydrocarbon of C6-C14, R 6, R 7, R 8, R 9Can be identical also can be different.
Above-mentioned R 1The acyl residue of representative is commonly used in the cephalosporin chemistry field, can use various acyl residue, if they be from can with the acyl group deutero-of 7-amino bonded on the oxa-cynnematin main chain.Such acyl group can be the acyl group that can generate the 7-position side chain of target Antibiotique composition; It also can be the acyl group that can in this compound synthetic, serve as amino protecting group; Such acyl group instance comprises any substituted phenyl or benzyl, and (substituting group can be: low alkyl group is (like methyl; Ethyl), lower alkoxy (as: methoxyl group; Oxyethyl group), halogen, nitro or Phenoxymethyl), be preferably phenyl, 4-aminomethyl phenyl, benzyl, 4-cyano-phenyl or 4-p-methoxy-phenyl, most preferably be phenyl, 4-aminomethyl phenyl or benzyl.
Above-mentioned R 3The carboxyl-protecting group of representative comprise in the cynnematin industry well-known can with carboxyl reaction or remove and do not cause these other parts of intramolecularly any do not hope the carboxyl-protecting group that changes.The ester forming alkyl that typical instance comprises C1～C8 is (like methyl; Methoxyl methyl; Ethyl; Ethoxyethyl; The iodine ethyl; Propyl group; Sec.-propyl; Butyl; Isobutyl-; Three chloroethyls; The tertiary butyl etc.); The alkenyl of C3～C8 is (like propenyl; Vinyl; Pseudoallyl; Cinnamyl group; Hexenyl); The aromatic alkyl of C7～C19 is (like benzyl; Methyl-benzyl; Dimethyl benzyl; Methoxy-benzyl; Ethoxy benzyl; Nitrobenzyl; Aminobenzyl; Diphenyl-methyl; Styroyl; Trityl; The di-t-butyl hydroxybenzyl; Phenacyl-etc.); The aromatic base of C6～C12 is (like phenyl; Tolyl; Diisopropyl phenyl; Xylyl; Trichlorophenyl; Five chlorophenyl etc.); Amino (as: the acetoxime of C1～C12; Acetophenone oxime etc.); Hydrocarbonylation methyl alkyl (as: the TMS of C3～C12; Dimethyl methyl TMOS base; Tertiary butyl dimethylsilyl etc.).Preferable is diphenyl-methyl, to nitrobenzyl, benzyl or to methoxy-benzyl, best is diphenyl-methyl.
Above-mentioned halogenating agent R 4X is preferably cupric chloride or cupric bromide; The halogenation hydrogen salt R of organic bases 5X, said R 5Represent nitrogenous aromatic heterocycle or aliphatics tertiary amine, wherein nitrogenous aromatic heterocycle comprises pyridine, 4-Dimethylamino pyridine, 2-picoline, 2,6-lutidine, 2 and pyrroles etc.; The aliphatics tertiary amine comprises Trimethylamine 99, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, N-crassitude, N-methyl piperidine and Tributylamine etc.The halogenation hydrogen salt R of organic bases 5X is pyridine hydrochloride or pyridine hydrobromide salt most preferably.
Above-mentioned R 6, R 7, R 8, R 9The alkane of the C1～C20 of representative comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, n-pentyl, hexyl, heptyl, nonyl, certain herbaceous plants with big flowers alkyl, octyl, dodecyl, tetradecyl and octadecyl; The unsaturated alkane of C2～C10 comprises vinyl, propenyl, pseudoallyl, crotonyl, pentenyl, isopentene group and hexenyl, and the aromatic hydrocarbon of C6-C14 comprises benzyl, methyl-benzyl, dimethyl benzyl, methoxy-benzyl, ethoxy benzyl, nitrobenzyl, aminobenzyl and diphenyl-methyl.
What the halo quaternary ammonium salt was preferable is: Tetrabutyl amonium bromide, tetrabutylammonium chloride, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, methyl triethyl brometo de amonio, methyl triethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, tri-n-octyl methyl ammonium chloride, two certain herbaceous plants with big flowers alkyl-dimethyl ammonium chloride, cetyl trimethylammonium bromide, OTAC, octadecyl trimethylammonium bromide, tetradecyl trimethyl ammonium chloride or TTAB, best is Tetrabutyl amonium bromide, tetrabutylammonium chloride, benzyl triethyl ammonium bromide or benzyltriethylammoinium chloride.
The said organic bases of step b is basic cpds such as aromatic nitrogen-contg heterocycle, aliphatics tertiary amine, aliphatic diamine; Wherein aromatic nitrogen-contg heterocycle organic bases comprises pyridine, 4-Dimethylamino pyridine, 2-picoline, 2; 6-lutidine, 2 and pyrroles; Aliphatics tertiary amine organic bases comprises Trimethylamine 99, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, N-crassitude, N-methyl piperidine and Tributylamine; The aliphatic diamine organic bases comprises quadrol, tn, tetramethylenediamine, piperidines, morpholine, methylethyl amine and Pyrrolidine etc.Most preferred organic bases is pyridine, piperidines or quadrol.
Among the above-mentioned step a, the consumption of halogenating agent is generally 0.1～20.0 times of 1-oxa-cynnematin-3-methylene derivatives molar weight, is preferably 1.0～10.0 times.The consumption of halogen is 1.0～10.0 times of 1-oxa-cynnematin-3-methylene derivatives molar weight.Temperature of reaction is advisable at-30 ℃～20 ℃, finds in the experiment, (is lower than-30 ℃) when temperature is too low, and speed of response is slow excessively, and the reaction times is oversize; Temperature is when too high (being higher than 20 ℃), and impurity is too many, and the best temperature of reaction of empirical tests is-5 ℃～5 ℃.Detect through TLC, the needed reaction times that reacts completely is generally at 1-20 hour.
Among the above-mentioned step b, the consumption of organic bases is generally 1.0～10.0 times of oxa-cephalosporin compound molar weight, preferred 1.0～5.0 times, most preferably is 1.0～2.0 times.Temperature of reaction is-30 ℃～20 ℃, and best is-10 ℃～5 ℃.Detect through TLC, the needed reaction times that reacts completely was generally 0.3～3 hour.
The not special restriction of the employed solvent of two-step reaction of the present invention, as long as they do not produce harmful effect to this reaction, can select as follows: the halogenated alkane of C1～C4, like methylene dichloride, chloroform, ethylene dichloride etc.; The nitrile of C1～C4, as: acetonitrile or propionitrile etc.; C1～C8 acetic ester, as: ETHYLE ACETATE, methyl acetate etc.; The ether of C1～C4, as: ether, THF etc.; The acid amides of C3～C4, as: N, N,N-DIMETHYLACETAMIDE etc.; C6～C10 contains benzene solvent, as: toluene, YLENE, chlorobenzene etc.If select ester class, hydro carbons for use, benzene class, ether solvent, because less than normal to halogenating agent solubleness, the reaction times, the president was a little; If select nitrile, amide solvent for use, after reaction finishes, need extract with acetic ester or hydrochloric ether, increased post-processing difficulty, increased production cost.So most preferred solvent is a methylene dichloride.
Reagent that the inventive method is used and raw material are all commercially available to be got.
Each step reaction can be carried out according to this area conventional treatment method after finishing.
Beneficial effect of the present invention: method of the present invention need not used illumination reaction, only needs to carry out halogen addition, reacting balance through adding suitable halogenating agent; Can the huge heat of abrupt release; Do not need the very low temperature reaction, greatly reduce dangerous odds, therefore avoided in industrial production, using expensive specific installation; Reduce investment of production equipment, in industrial production, had bigger competitive power.On the other hand, this method is owing to avoiding illumination reaction to become simply, on the contrary can high yield obtain the 1-oxacephalosporin-3-chloromethyl derivatives.
Embodiment
Embodiment 1
Compound I I (R1 is a phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, is cooled to 0 ℃, adds the tetrabutylammonium chloride of 1.5 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to-5 ℃, adds the piperidines of 1.2 times of compound I I molar masss, reacts 20 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 92%.MP?130-134℃
Embodiment 2
Compound I I (R1 is a phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount ETHYLE ACETATE, is cooled to 0 ℃, adds the tetrabutylammonium chloride of 2 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to-5 ℃, adds the diethylamine of 1.2 times of compound I I molar masss, reacts 180 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 65%.MP?130-134℃
Embodiment 3
Compound I I (R1 is a phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, is cooled to 0 ℃, adds the benzyltriethylammoinium chloride of 5 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to-5 ℃, adds the piperidines of 1.2 times of compound I I molar masss, reacts 30 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 87%.MP?130-134℃
Embodiment 4
Compound I I (R1 is a phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount acetonitriles, is cooled to 0 ℃, adds the benzyltriethylammoinium chloride of 4.5 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs dichloromethane extraction; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to-5 ℃, adds the pyridine of 1.2 times of compound I I molar masss, reacts 120 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 83%.MP?130-134℃
Embodiment 5
Compound I I (R1 is a phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, is cooled to 0 ℃, adds the pyridine hydrochloride of 8 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to-5 ℃, adds the piperidines of 1.2 times of compound I I molar masss, reacts 30 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 75%.MP?130-134℃
Embodiment 6
Compound I I (R1 is a phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, is cooled to 0 ℃, adds the anhydrous cupric chloride of 10 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to-10 ℃, adds the piperidines of 1.2 times of compound I I molar masss, reacts 30 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 80%.MP?130-134℃
Embodiment 7
Compound I I (R1 is a phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, is cooled to 0 ℃, adds the tetrabutylammonium chloride of 3.0 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to 0 ℃, adds the diethylamine of 1.2 times of compound I I molar masss, reacts 180 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 89%.MP?130-134℃
Embodiment 8
Compound I I (R1 is a phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, is cooled to 0 ℃, adds the tetrabutylammonium chloride of 2.5 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to 5 ℃, adds the pyridine of 1.2 times of compound I I molar masss, reacts 120 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 85%.MP?130-134℃
Embodiment 9
Compound I I (R1 is a phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, is cooled to 0 ℃, adds the tri-n-octyl methyl ammonium chloride of 2.5 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to 5 ℃, adds the pyridine of 1.2 times of compound I I molar masss, reacts 120 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 83%.MP?130-134℃
Embodiment 10
Compound I I (R1 is a phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, is cooled to 0 ℃, adds the methyl triethyl ammonium chloride of 3.0 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to 5 ℃, adds the pyridine of 1.2 times of compound I I molar masss, reacts 120 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 80%.MP?130-134℃
Embodiment 11
Compound I I (R1 is the 4-aminomethyl phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 15 times of amount methylene dichloride, is cooled to 0 ℃, adds the OTAC of 5.0 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to-5 ℃, adds the piperidines of 1.2 times of compound I I molar masss, reacts 30 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is the 4-aminomethyl phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 91%.MP?185-188℃
Embodiment 12
Compound I I (R1 is the 4-aminomethyl phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 20 times of amount methylene dichloride, is cooled to 0 ℃, adds the tetrabutylammonium chloride of 5.0 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to 0 ℃, adds the diethylamine of 1.2 times of compound I I molar masss, reacts 150 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is the 4-aminomethyl phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 87%.MP?185-188℃
Embodiment 13
Compound I I (R1 is the 4-aminomethyl phenyl, and R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl) is dissolved in 15 times of amount methylene dichloride, is cooled to 0 ℃, adds the benzyltriethylammoinium chloride of 2.0 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, and brine wash, anhydrous sodium sulfate drying filters; Filtrating is cooled to-5 ℃, adds the pyridine of 1.2 times of compound I I molar masss, reacts 110 minutes, adds the Hydrogen chloride washing; Brine wash, evaporated under reduced pressure, methanol crystallization, (R1 is the 4-aminomethyl phenyl to obtain compound I; R2 is a Wasserstoffatoms, and R3 is a diphenyl-methyl, and X is a chlorine), yield 85%.MP?185-188℃
Embodiment 14
Compound I I (R1 is a benzyl, and R2 is a hydrogen, and R3 is a diphenyl-methyl) is dissolved in 8 times of amount methylene dichloride, is cooled to 0 ℃, adds the pyridine hydrochloride of 10 times of compound I I molar masss, and uniform temp slowly feeds chlorine down; The TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stir, and separatory, organic phase is washed with sodium bicarbonate aqueous solution; Organic phase water washing then, brine wash, anhydrous sodium sulfate drying filters, and filtrating is cooled to-5 ℃; Add the piperidines of 2 times of compound I I molar masss, reacted 60 minutes, add the Hydrogen chloride washing, brine wash, evaporated under reduced pressure; Obtain compound I (R1 is a benzyl, and R2 is a hydrogen, and R3 is a diphenyl-methyl, and X is a chlorine), yield 76%.MP?175-179℃
Embodiment 15
Compound I I (R1 is a benzyl, and R2 is a hydrogen, and R3 is a diphenyl-methyl) is dissolved in 15 times of amount methylene dichloride, is cooled to 0 ℃, adds the methyl triethyl ammonium chloride of 6 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, brine wash, anhydrous sodium sulfate drying; Filter, filtrating is cooled to-5 ℃, adds the diethylamine of 2 times of compound I I molar masss, reacts 160 minutes; Add the Hydrogen chloride washing, brine wash, evaporated under reduced pressure, (R1 is a benzyl to obtain compound I; R2 is a hydrogen, and R3 is a diphenyl-methyl, and X is a chlorine), yield 87%.MP?175-179℃
Embodiment 16
Compound I I (R1 is a thiophene acetyl, and R2 is a methoxyl group, and R3 is a diphenyl-methyl) is dissolved in 20 times of amount methylene dichloride, is cooled to 0 ℃, adds the methyl triethyl ammonium chloride of 3.0 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, brine wash, anhydrous sodium sulfate drying; Filter, filtrating is cooled to-5 ℃, adds the piperidines of 2 times of compound I I molar masss, reacts 40 minutes; Add the Hydrogen chloride washing, brine wash, evaporated under reduced pressure, (R1 is a benzyl to obtain compound I; R2 is a hydrogen, and R3 is a diphenyl-methyl, and X is a chlorine), yield 87%.MP?175-179℃
Embodiment 17
Compound I I (R1 is a thiophene acetyl, and R2 is a methoxyl group, and R3 is a diphenyl-methyl) is dissolved in 20 times of amount methylene dichloride, is cooled to 0 ℃, adds the OTAC of 4.0 times of compound I I molar masss; Uniform temp slowly feeds chlorine down, and the TLC detection reaction is complete, is poured in the sodium sulfite aqueous solution, stirs separatory; Organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, brine wash, anhydrous sodium sulfate drying; Filter, filtrating is cooled to-5 ℃, adds the piperidines of 2 times of compound I I molar masss, reacts 40 minutes; Add the Hydrogen chloride washing, brine wash, evaporated under reduced pressure, (R1 is a benzyl to obtain compound I; R2 is a hydrogen, and R3 is a diphenyl-methyl, and X is a chlorine), yield 85%.MP?175-179℃
Embodiment 18～26
Reaction uses solvent to be the methylene dichloride of 15 times of feed molar amounts, and organic bases is a piperidines, 1.2 times of feed molar amount.Concrete experimental implementation is with above embodiment.The concrete raw material of its result and use etc. sees the following form 1:
Table 1
Figure G2009100464787D00141

Claims (14)

1.1-the preparation method of oxacephalosporin-3-chloromethyl derivatives, its step comprises:
A, under the halogenating agent effect, 1-oxa-cynnematin-3-methylene derivatives (II) and halogen addition reaction generate oxa-cephalosporin compound (III)
Figure FSB00000661774700011
B, under organic bases pyridine, piperidines or quadrol effect, oxa-cephalosporin compound (III) reaction generates 1-oxacephalosporin-3-chloromethyl derivatives (I)
Figure FSB00000661774700012
R wherein 1Be phenyl, 4-aminomethyl phenyl, benzyl, 4-cyano-phenyl or 4-p-methoxy-phenyl, R 2Be hydrogen or methoxyl group, R 3Be carboxyl-protecting group; Halogenating agent is cupric chloride, cupric bromide, pyridine hydrochloride, pyridine hydrobromide salt or halo quaternary ammonium salt; X represents chlorine or bromine, and said halo quaternary ammonium salt is: Tetrabutyl amonium bromide, tetrabutylammonium chloride, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, methyl triethyl brometo de amonio, stearyl dimethyl benzyl ammonium chloride, tri-n-octyl methyl ammonium chloride, two certain herbaceous plants with big flowers alkyl-dimethyl ammonium chloride, cetyl trimethylammonium bromide, OTAC, octadecyl trimethylammonium bromide, tetradecyl trimethyl ammonium chloride or TTAB.
2. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: R 1Be phenyl, 4-aminomethyl phenyl or benzyl.
3. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: R 3For diphenyl-methyl, to nitrobenzyl, benzyl or to methoxy-benzyl.
4. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 3 is characterized in that: R 3Be diphenyl-methyl.
5. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: said halo quaternary ammonium salt is Tetrabutyl amonium bromide, tetrabutylammonium chloride, benzyl triethyl ammonium bromide or benzyltriethylammoinium chloride.
6. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: among the step a, the consumption of halogenating agent is 0.1～20.0 times of 1-oxa-cynnematin-3-methylene derivatives molar weight.
7. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 6 is characterized in that: among the step a, the consumption of halogenating agent is 1.0～10.0 times of 1-oxa-cynnematin-3-methylene derivatives molar weight.
8. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: among the step a, the consumption of halogen is 1.0～10.0 times of 1-oxa-cynnematin-3-methylene derivatives molar weight.
9. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: the temperature of reaction of step a is-30 ℃～20 ℃.
10. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 9 is characterized in that: the temperature of reaction of step a is-5 ℃～5 ℃.
11. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: the consumption of organic bases is 1.0～10.0 times of oxa-cephalosporin compound molar weight among the step b.
12. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 22 is characterized in that: the consumption of organic bases is 1.0～2.0 times of oxa-cephalosporin compound molar weight among the step b.
13. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: the temperature of reaction of step b is-30 ℃～20 ℃.
14. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: the temperature of reaction of step b is-10 ℃～5 ℃.
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CN102827191B (en) * 2012-09-24 2015-03-11 浙江东邦药业有限公司 Method for preparing oxygen cephalosporin compound
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