CN101538274A - Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives - Google Patents
Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives Download PDFInfo
- Publication number
- CN101538274A CN101538274A CN200910046478A CN200910046478A CN101538274A CN 101538274 A CN101538274 A CN 101538274A CN 200910046478 A CN200910046478 A CN 200910046478A CN 200910046478 A CN200910046478 A CN 200910046478A CN 101538274 A CN101538274 A CN 101538274A
- Authority
- CN
- China
- Prior art keywords
- oxacephalosporin
- preparation
- derivatives
- chloromethyl derivatives
- chloromethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
Technical field
The present invention relates to a kind of synthetic synthetic method technical field of antimicrobial 1-oxa-cynnematin that can be used as with intermediate 1-oxacephalosporin-3-chloromethyl derivatives.
Background technology
Shown in the following reaction formula, 1-oxacephalosporin-3-chloromethyl derivatives (formula I) is for example important intermediate used of the industrial high efficiency production of latamoxef (Latamoxef) or flomoxef (Flomoxef) of 1-oxa-cynnematin.
The preparation of 1-oxacephalosporin-3-chloromethyl derivatives at present all is the starting raw material preparation with 6APA:
The concrete production method of intermediate 1-oxacephalosporin-3-chloromethyl derivatives also has disclosed bibliographical information, one of method be to use a kind of raw material 1-oxa-cynnematin-3-methylene compound after adding chlorine by illumination reaction generation addition reaction, and then add alkali and obtain 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 free radical substitution reaction of allyl group position also can take place, and replaces in order to suppress allyl group position free radical, needs extremely low temperature of reaction.If illuminating area and energy shortage, chlorine can't in time participate in reaction; And in case chain reaction takes place, violent reaction again can a large amount of heat of abrupt release, 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:
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 the illumination deficiency, 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:
1-oxa-cynnematin-3-methylene derivatives reacts under the illumination of interpolation chlorine down at-20 ℃ ,-50 ℃ and alkali CH3OLi reaction, obtains the 1-oxacephalosporin-3-chloromethyl derivatives then.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 at low temperatures the reaction, this industrial all be disadvantageous; Removing in the hydrogenchloride with alkali, also is to react under very low temperature, is unfavorable for suitability for industrialized production equally.
Summary of the invention
Purpose of the present 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 height of productivity ratio.
Through a large amount of experimental studies, the present inventor finds, equally with 1-oxa-cynnematin-3-methylene derivatives as starting raw material, do not need to use illumination reaction, only need by 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 as follows:
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)
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 example comprises the phenyl of any replacement or benzyl, and (substituting group can be: low alkyl group is (as 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 wish the carboxyl-protecting group that changes.Typical example comprises that the ester forming alkyl of C1～C8 is (as 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 (as propenyl, vinyl, pseudoallyl, cinnamyl group, hexenyl), the aromatic alkyl of C7～C19 is (as 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 (as 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, butenyl, 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, the 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 chlorides, cetyl trimethylammonium bromide, octadecyl trimethyl ammonium chloride, the octadecyl trimethylammonium bromide, tetradecyl trimethyl ammonium chloride or Tetradecyl Trimethyl Ammonium Bromide, 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, propylene diamine, butanediamine, 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 temperature of reaction of empirical tests the best 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 employed solvent of two-step reaction of the present invention is not particularly limited, as long as they do not produce harmful effect to this reaction, can select as follows: the halogenated alkane of C1～C4, as methylene dichloride, chloroform, ethylene dichloride etc.; The nitrile of C1～C4, as: acetonitrile or propionitrile etc.; C1～C8 acetic ester, as: ethyl acetate, methyl acetate etc.; The ether of C1～C4, as: ether, tetrahydrofuran (THF) etc.; The acid amides of C3～C4, as: dimethyl formamide, N,N-DIMETHYLACETAMIDE etc.; C6～C10 contains benzene solvent, as: toluene, dimethylbenzene, 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 does not need to use illumination reaction, only need to carry out the halogen addition by adding suitable halogenating agent, reacting balance, 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 hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, be cooled to 0 ℃, add the tetrabutylammonium chloride of 1.5 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to-5 ℃, adds the piperidines of 1.2 times of Compound I I molar masss, reacted 20 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 92%.MP?130-134℃
Embodiment 2
Compound I I (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount ethyl acetate, be cooled to 0 ℃, add the tetrabutylammonium chloride of 2 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to-5 ℃, adds the diethylamine of 1.2 times of Compound I I molar masss, reacted 180 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 65%.MP?130-134℃
Embodiment 3
Compound I I (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, be cooled to 0 ℃, add the benzyltriethylammoinium chloride of 5 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to-5 ℃, adds the piperidines of 1.2 times of Compound I I molar masss, reacted 30 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 87%.MP?130-134℃
Embodiment 4
Compound I I (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount acetonitriles, be cooled to 0 ℃, add the benzyltriethylammoinium chloride of 4.5 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to-5 ℃, adds the pyridine of 1.2 times of Compound I I molar masss, reacted 120 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 83%.MP?130-134℃
Embodiment 5
Compound I I (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, be cooled to 0 ℃, add the pyridine hydrochloride of 8 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to-5 ℃, adds the piperidines of 1.2 times of Compound I I molar masss, reacted 30 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 75%.MP?130-134℃
Embodiment 6
Compound I I (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, be cooled to 0 ℃, add the anhydrous cupric chloride of 10 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to-10 ℃, adds the piperidines of 1.2 times of Compound I I molar masss, reacted 30 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 80%.MP?130-134℃
Embodiment 7
Compound I I (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, be cooled to 0 ℃, add the tetrabutylammonium chloride of 3.0 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to 0 ℃, adds the diethylamine of 1.2 times of Compound I I molar masss, reacted 180 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 89%.MP?130-134℃
Embodiment 8
Compound I I (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, be cooled to 0 ℃, add the tetrabutylammonium chloride of 2.5 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to 5 ℃, adds the pyridine of 1.2 times of Compound I I molar masss, reacted 120 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 85%.MP?130-134℃
Embodiment 9
Compound I I (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, be cooled to 0 ℃, add the tri-n-octyl methyl ammonium chloride of 2.5 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to 5 ℃, adds the pyridine of 1.2 times of Compound I I molar masss, reacted 120 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 83%.MP?130-134℃
Embodiment 10
Compound I I (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 10 times of amount methylene dichloride, be cooled to 0 ℃, add the methyl triethyl ammonium chloride of 3.0 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to 5 ℃, adds the pyridine of 1.2 times of Compound I I molar masss, reacted 120 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is a phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 80%.MP?130-134℃
Embodiment 11
Compound I I (R1 is the 4-aminomethyl phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 15 times of amount methylene dichloride, be cooled to 0 ℃, add the octadecyl trimethyl ammonium chloride of 5.0 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to-5 ℃, adds the piperidines of 1.2 times of Compound I I molar masss, reacted 30 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is the 4-aminomethyl phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 91%.MP?185-188℃
Embodiment 12
Compound I I (R1 is the 4-aminomethyl phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 20 times of amount methylene dichloride, be cooled to 0 ℃, add the tetrabutylammonium chloride of 5.0 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to 0 ℃, adds the diethylamine of 1.2 times of Compound I I molar masss, reacted 150 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is the 4-aminomethyl phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, X is a chlorine), yield 87%.MP?185-188℃
Embodiment 13
Compound I I (R1 is the 4-aminomethyl phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl) is dissolved in 15 times of amount methylene dichloride, be cooled to 0 ℃, add the benzyltriethylammoinium chloride of 2.0 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, 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, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to-5 ℃, adds the pyridine of 1.2 times of Compound I I molar masss, reacted 110 minutes, add the dilute hydrochloric acid washing, salt water washing, evaporated under reduced pressure, methanol crystallization, (R1 is the 4-aminomethyl phenyl, and R2 is a hydrogen atom, and R3 is a diphenyl-methyl to obtain Compound I, 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, be cooled to 0 ℃, add the pyridine hydrochloride of 10 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, the TLC detection reaction is complete, be poured in the sodium sulfite aqueous solution, stir separatory, organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to-5 ℃, adds the piperidines of 2 times of Compound I I molar masss, reacts 60 minutes, add the dilute hydrochloric acid washing, the salt water washing, evaporated under reduced pressure, (R1 is a benzyl to obtain Compound I, R2 is a hydrogen, 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, be cooled to 0 ℃, add the methyl triethyl ammonium chloride of 6 times of Compound I I molar masss, uniform temp slowly feeds chlorine down, the TLC detection reaction is complete, be poured in the sodium sulfite aqueous solution, stir separatory, organic phase is washed with sodium bicarbonate aqueous solution, organic phase water washing then, salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to-5 ℃, adds the diethylamine of 2 times of Compound I I molar masss, reacts 160 minutes, add the dilute hydrochloric acid washing, the salt water washing, evaporated under reduced pressure, (R1 is a benzyl to obtain Compound I, R2 is a hydrogen, 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; be cooled to 0 ℃, add the methyl triethyl ammonium chloride of 3.0 times of Compound I I molar masss, uniform temp slowly feeds chlorine down; the TLC detection reaction is complete; be poured in the sodium sulfite aqueous solution, stir separatory; organic phase is washed with sodium bicarbonate aqueous solution; organic phase water washing then, salt water washing, anhydrous sodium sulfate drying; filter; filtrate is cooled to-5 ℃, adds the piperidines of 2 times of Compound I I molar masss, reacts 40 minutes; add the dilute hydrochloric acid washing; the salt water washing, evaporated under reduced pressure, (R1 is a benzyl to obtain Compound I; R2 is a hydrogen; 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; be cooled to 0 ℃, add the octadecyl trimethyl ammonium chloride of 4.0 times of Compound I I molar masss, uniform temp slowly feeds chlorine down; the TLC detection reaction is complete; be poured in the sodium sulfite aqueous solution, stir separatory; organic phase is washed with sodium bicarbonate aqueous solution; organic phase water washing then, salt water washing, anhydrous sodium sulfate drying; filter; filtrate is cooled to-5 ℃, adds the piperidines of 2 times of Compound I I molar masss, reacts 40 minutes; add the dilute hydrochloric acid washing; the salt water washing, evaporated under reduced pressure, (R1 is a benzyl to obtain Compound I; R2 is a hydrogen; 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
Claims (25)
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)
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.
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, benzyl, 4-cyano-phenyl or 4-p-methoxy-phenyl.
3. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 2 is characterized in that: R
1Be phenyl, 4-aminomethyl phenyl or benzyl.
4. 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.
5. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 4 is characterized in that: R
3Be diphenyl-methyl.
6. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: halogenating agent R
4X is cupric chloride or cupric bromide.
7. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: said nitrogenous heteroaromatic compound R
5Be meant pyridine, 4-Dimethylamino pyridine, 2-picoline, 2,6-lutidine, 2 or pyrroles.
8. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: said aliphatics tertiary amine R
5Be meant Trimethylamine 99, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, N-crassitude, N-methyl piperidine or Tributylamine.
9. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 7 is characterized in that: the halogenation hydrogen salt R of organic bases
5X is pyridine hydrochloride or pyridine hydrobromide salt.
10. 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, 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, octadecyl trimethyl ammonium chloride, octadecyl trimethylammonium bromide, tetradecyl trimethyl ammonium chloride or Tetradecyl Trimethyl Ammonium Bromide
11. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 10 is characterized in that: said halo quaternary ammonium salt is Tetrabutyl amonium bromide, tetrabutylammonium chloride, benzyl triethyl ammonium bromide or benzyltriethylammoinium chloride.
12. 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.
13. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 12 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.
14. 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.
15. 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 ℃.
16. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 15 is characterized in that: the temperature of reaction of step a is-5 ℃～5 ℃.
17. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 1 is characterized in that: the said organic bases of step b is aromatic nitrogen-contg heterocycle, aliphatics tertiary amine or aliphatic diamine basic cpd.
18. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 17, it is characterized in that: said aromatic nitrogen-contg heterocycle organic bases comprises pyridine, 4-Dimethylamino pyridine, 2-picoline, 2,6-lutidine, 2 and pyrroles.
19. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 18 is characterized in that: said aliphatics tertiary amine organic bases comprises Trimethylamine 99, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, N-crassitude, N-methyl piperidine and Tributylamine.
20. the preparation method of 1-oxacephalosporin-3-chloromethyl derivatives as claimed in claim 17 is characterized in that: said aliphatic diamine organic bases comprises quadrol, propylene diamine, butanediamine, piperidines, morpholine, methylethyl amine and Pyrrolidine.
21. the preparation method as the described arbitrary 1-oxacephalosporin-3-chloromethyl derivatives of claim 18-19 is characterized in that: the organic bases that step b uses is pyridine, piperidines or quadrol.
22. 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.
23. 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.
24. 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 ℃.
25. 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 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100464787A CN101538274B (en) | 2009-02-23 | 2009-02-23 | Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100464787A CN101538274B (en) | 2009-02-23 | 2009-02-23 | Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101538274A true CN101538274A (en) | 2009-09-23 |
| CN101538274B CN101538274B (en) | 2012-06-27 |
Family
ID=41121684
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100464787A Expired - Fee Related CN101538274B (en) | 2009-02-23 | 2009-02-23 | Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101538274B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827191A (en) * | 2012-09-24 | 2012-12-19 | 浙江东邦药业有限公司 | Method for preparing oxygen cephalosporin compound |
| CN104086563A (en) * | 2014-07-03 | 2014-10-08 | 江苏沙星化工有限公司 | Method for preparing olefine acid diphenylmethyl ether |
| CN104610277A (en) * | 2015-01-09 | 2015-05-13 | 郑州大学 | Method for preparing key intermediate of oxacephem antibiotic through allylic hydroxylation |
| CN104610278A (en) * | 2015-01-09 | 2015-05-13 | 郑州大学 | Safety production method of oxacephem antibiotic intermediate sulfoxide ester |
| CN106188097A (en) * | 2016-07-08 | 2016-12-07 | 郑州大学 | A kind of preparation method of 3 chloromethyl oxacephems antibiotic parent nucleus |
| CN107118224A (en) * | 2017-06-15 | 2017-09-01 | 浙江新和成股份有限公司 | A kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and preparation method thereof |
| CN109485660A (en) * | 2018-12-21 | 2019-03-19 | 齐鲁安替制药有限公司 | A kind of synthetic method of oxygen cephalosporin nucleus |
-
2009
- 2009-02-23 CN CN2009100464787A patent/CN101538274B/en not_active Expired - Fee Related
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827191A (en) * | 2012-09-24 | 2012-12-19 | 浙江东邦药业有限公司 | Method for preparing oxygen cephalosporin compound |
| CN102827191B (en) * | 2012-09-24 | 2015-03-11 | 浙江东邦药业有限公司 | Method for preparing oxygen cephalosporin compound |
| CN104086563A (en) * | 2014-07-03 | 2014-10-08 | 江苏沙星化工有限公司 | Method for preparing olefine acid diphenylmethyl ether |
| CN104610277A (en) * | 2015-01-09 | 2015-05-13 | 郑州大学 | Method for preparing key intermediate of oxacephem antibiotic through allylic hydroxylation |
| CN104610278A (en) * | 2015-01-09 | 2015-05-13 | 郑州大学 | Safety production method of oxacephem antibiotic intermediate sulfoxide ester |
| CN104610277B (en) * | 2015-01-09 | 2016-07-13 | 郑州大学 | A kind of method that allylic hydroxylating prepares oxacephems antibiotic key intermediate |
| CN106188097A (en) * | 2016-07-08 | 2016-12-07 | 郑州大学 | A kind of preparation method of 3 chloromethyl oxacephems antibiotic parent nucleus |
| CN107118224A (en) * | 2017-06-15 | 2017-09-01 | 浙江新和成股份有限公司 | A kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and preparation method thereof |
| CN107118224B (en) * | 2017-06-15 | 2019-09-17 | 浙江新和成股份有限公司 | A kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and preparation method thereof |
| CN109485660A (en) * | 2018-12-21 | 2019-03-19 | 齐鲁安替制药有限公司 | A kind of synthetic method of oxygen cephalosporin nucleus |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101538274B (en) | 2012-06-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101538274B (en) | Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives | |
| CN105461654B (en) | A kind of benzothiazole ionic liquid and its preparation method and application | |
| CN104530476B (en) | A kind of multi-functional collaborative polymer antioxidative stabilizer and its preparation method and application | |
| CN101792400A (en) | Synthetic method for agomelatine | |
| EP3397621B1 (en) | Process for preparing 1,1,3-trioxo-1,2-benzothiazole-6-carboxamide | |
| CN104262194A (en) | Method of preparing 1,5-diazido-3-nitryl azapentane | |
| CN104530475A (en) | Preparation method of multifunctional synergistic antioxidative stabilizer | |
| CN104945325A (en) | Preparation method for pyrazolecarboxylic acid derivative | |
| CN103524489B (en) | The synthesis technique of 2 chlorine 5 ((base of 2 (Nitromethylene) imidazolidine 1) methyl) pyridines | |
| CN101654419A (en) | Preparation method of fluvoxamine maleate | |
| CN108164514B (en) | Preparation method of epoxiconazole | |
| CN104744266A (en) | Preparation method of ticagrelor intermediate | |
| CN105968040A (en) | Preparation method of ledipasvir intermediate | |
| CN113039175B (en) | Method for preparing arylsulfonyl acrylonitrile | |
| CN108409557A (en) | Bu Waxitan new intermediates and its synthetic method and application | |
| CN103193666A (en) | Preparation method of 2-amino-3-chlorobenzoic methyl ester | |
| CN103664675A (en) | Method for preparing 2-chloro-N-(4-fluorophenyl)-N-isopropylacetamide | |
| CN100554235C (en) | Preparation method to alkoxyl mandelic acid | |
| CN102531983A (en) | Chemical synthesis method of S-phenyl-4-tosylate | |
| CN102838514A (en) | Synthetic method of hexamethylene flusulfamide | |
| CN102190569B (en) | Method for preparing Prasugrel intermediate alpha-cyclopropylcarbonyl-2-fluorobenzyl bromide | |
| CN101985451A (en) | Preparation method of prasugrel intermediate | |
| CN106083668A (en) | A kind of preparation method of 3 bromomethyl 2 halo 4 alkyl sulphonyl benzoate | |
| CN106243079A (en) | The Preparation Method And Their Intermediate compound of bicyclol | |
| CN104447511A (en) | Synthetic method of N-t-butyloxycarboryl-3-piperidone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160629 Address after: 200040 Beijing West Road, Shanghai, No. 1320, No. Patentee after: Shanghai Institute of pharmaceutical industry Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: 200040 Beijing West Road, Shanghai, No. 1320, No. Patentee before: Shanghai Institute of pharmaceutical industry |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120627 Termination date: 20180223 |