CN104610277B - A kind of method that allylic hydroxylating prepares oxacephems antibiotic key intermediate - Google Patents
A kind of method that allylic hydroxylating prepares oxacephems antibiotic key intermediate Download PDFInfo
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Abstract
The invention discloses a kind of method that allylic hydroxylating prepares oxacephems antibiotic key intermediate, belong to technical field of medicine synthesis.The present invention is with [1R[1 α, 5 α]] 3 methyl 2 (7 chloro 3 phenyl 4 oxa-s 2,6 diazabicylos [3.2.0] heptan 2 alkene 6 base) 3 butenoic acid benzhydryl esters (compound 1) are raw material, by allylic hydroxylating one-step synthesis [1R[1 α, 5 α]] 3 methylol 2 (7 chloro 3 phenyl 4 oxa-2,6 alkene 6 base in diazabicylo [3.2.0] heptan 2) 3 butenoic acid benzhydryl esters (compound 2).Compared with prior art, the present invention is effectively shortened the synthetic route of oxacephems antibiotic, has evaded the use of chlorine and Heavy Metal Reagent, in the industrial production without using lucifuge equipment, and convenient post-treatment, with low cost, it is especially suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of allylic hydroxylating and prepare the side of oxacephems antibiotic key intermediate
Method, belongs to technical field of medicine synthesis.
Background technology
Oxacephems antibiotic such as latamoxef (Latamoxef) or flomoxef (Flomoxef) are classes
Extensive pedigree antibiotic, it has good antibacterial activity to multiple gram negative bacteria, and effect is than general cephalosporin
Strong 4～16 times.
In commercial production, refer to United States Patent (USP) US4532233, US4138486 and Deutsche Bundespatent
The synthetic method of DE2355209, prepares oxacephems antibiotic latamoxef (Latamoxef) with compound 2
And flomoxef (Flomoxef).
Oxacephems antibiotic key intermediate 2 can be by 3-acetyl-o-methyl-5-sulfur-7-amino-8-oxygen-1-
Azabicyclic oct-2-ene-2 carboxylic acid (7-ACA) is prepared by raw material.List of references is shown in Tetrahedron Lett., 1982,
23,3379 and Synth Commun., 1988,18,763.Reaction scheme one is as follows:
This route, with 7-ACA as initiation material, is protected through multistep and aoxidizes to obtain intermediate 3, occurs under heating condition
[2,3]-δ-reset to obtain intermediate 4, then reacts generation intermediate 5, participates at chlorine with 2-mercaptobenzoxazole
Lower formation intermediate 2.The following place had much room for improvement of the method existence:
(1) intermediate 3 need to be formed by 7-ACA Multi-step conversion, and side reaction is many, should not control.
(2) preparation process needs to use chlorine, unfriendly to environment and higher to producing equipment requirements, it is unfavorable for
Industrialized production.
(3) intermediate 4 can be directly synthesized intermediate 2 under triphenyl phosphorus participates in, but produces substantial amounts of phosphorous refuse,
Being unfavorable for recrystallization, pilot scale repeatability is poor.
Oxacephems antibiotic key intermediate 2 can be also raw material system by 6-amino-penicillanic acid (6-APA)
Standby.List of references is shown in Tetrahedron Lett., 1975,2595；Tetrahedron Lett.,1980,21,351；
CN101538274；JP56012395；JP2004168775；US4366316.Reaction scheme two is as follows:
This route is with 6-APA as initiation material, and low price is easy to get, through amino, carboxy protective with aoxidize middle
Body 6, triphenyl phosphorus participates in lower generation rearrangement reaction and obtains intermediate 1, then forms intermediate with chlorine reaction
7, react formation intermediate 8 with sodium iodide effect lucifuge, the reaction of last silver nitrate, acidifying form intermediate 2.
Relatively route one, industrial repeatability is high, and product appearance is good.But still suffer from the following place had much room for improvement:
(1) commercial production uses chlorine, be unfavorable for environmental protection.Silver nitrate is expensive, introduces heavy metal, unfavorable
Remove in post processing.
(2) use of sodium iodide, needs lucifuge, there are certain requirements equipment.
(3) hydrogen atom replacement of allylic is that the group easily left away need to be through multistep reaction, and route is longer.
Summary of the invention
For reaction scheme two, it is an object of the invention to overcome existing oxacephems production of antibiotics skill
Art defect, shortens reaction scheme, and the step making allylic hydrogen atom replace to allylic hydroxyl reduces and evades chlorine
Gas and the use of expensive heavy metal, make production more environmentally friendly, easier.
For realizing the object of the invention, the present invention with oxacephems antibiotic key intermediate 1 as raw material,
By adding suitable catalyst and oxidant, catalyst is combined with oxidant, a step can obtain intermediate 2.
In allylic hydroxylating, catalyst and oxidant are most important, and phase transfer catalyst can be to a certain degree
The upper shortening response time.
It specifically comprises the following steps that
Intermediate 1 is dissolved in a solvent, adds phase transfer catalyst and catalyst, room temperature reaction.Cold
But to-5 DEG C～0 DEG C, being slowly added to oxidant, TLC detection reaction is completely.Under room temperature, system is poured into sulfurous
In acid sodium aqueous solution, stirring, stratification.Organic facies is used and is used saturated sodium bicarbonate solution successively, and water is saturated
Brine It, through sucking filtration, filtrate decompression is evaporated, and is dried, recrystallization, obtains intermediate 2.
In above-mentioned steps allylic hydroxylating, catalyst be selenium dioxide, VAAC,
Diphenyl disenenide, Hydro-Giene (Water Science). one of them or several mixture.
In above-mentioned steps allylic hydroxylating, phase transfer catalyst be tetrabutyl ammonium bromide, beta-schardinger dextrin-,
Tetraphenyl phosphonium bromide, tetramethylammonium hydroxide one of them.
In above-mentioned steps allylic hydroxylating, solvent be acetone, DMF, acetonitrile,
Ethanol, methanol, isopropanol, 1,2-dichloroethanes, dichloromethane, chloroform, oxolane, dioxane,
Distilled water, toluene one of them or the mixture of the most any two or three.
In above-mentioned steps allylic hydroxylating, oxidant is oxygen, tert-Butanol peroxide, m-chloro peroxide
Benzoic acid, sodium hypochlorite, calcium hypochlorite, peracetic acid, hydrogen peroxide, sodium dichromate one of them or several
Mixture.
In above-mentioned steps allylic hydroxylating, catalyst amount is the 0.5～3.0 of compound 1 mole
Times, oxidizer is 0.1～3.0 times of compound 1 mole, and phase transfer catalyst consumption is compound 1
0.05～0.5 times of mole.
In above-mentioned steps allylic hydroxylating, recrystallization solvent is methanol, ethanol, isopropanol, just
Butanol, the tert-butyl alcohol, ethylene glycol.
Use and have the beneficial effects that produced by technique scheme:
(1) present invention, avoiding the use of chlorine and heavy metal, reaction condition is gentle, easily-controllable, environmental protection.
(2) present invention is effectively shortened process route, and a step realizes allylic hydroxylating, and yield reaches more than 30%,
Production competitiveness significantly improves.
(3) present invention, avoiding resistance to chlorine equipment and the use of lucifuge equipment, production cost reduces.
(4) product of the present invention is single, and post processing is simple, and purity is high.
Detailed description of the invention
For the present invention is better described, as follows for embodiment:
Embodiment 1
10g intermediate 1 is dissolved in 80ml dichloromethane, adds 3g selenium dioxide and 0.4g tetrabutyl phosphonium bromide
Ammonium, room temperature reaction 2h.Being cooled to-5 DEG C, be slowly added to 7ml tertbutanol peroxide, TLC detection has been reacted
Entirely.Under room temperature, system is poured in 100ml 20% sodium sulfite aqueous solution, stirs 1h, stratification.
Organic facies is with using 80ml saturated sodium bicarbonate solution, 80ml water successively, and 80ml saturated aqueous common salt washed once,
It is eventually adding 7g anhydrous sodium sulfate and is dried 10h.Sucking filtration, filtrate decompression is evaporated, and residue 5ml ethanol is heavily tied
Crystalline substance, obtains intermediate 2.Yield 33%.
The nuclear magnetic data of intermediate 1 is as follows:1H NMR(400MHz,CDCl3) δ 7.92 (d, J=7.3Hz,
2H), 7.55～7.30 (m, 13H), 6.93 (s, 1H), 6.34 (d, J=3.3Hz, 1H), 5.35 (d, J=3.3Hz,
1H), 5.07 (d, J=1.1Hz, 1H), 5.03 (s, 1H), 4.91 (s, 1H), 1.76 (s, 3H).13C NMR(100
MHz,CDCl3)δ168.18,167.07,166.87,139.10,137.98,132.21,128.68,128.61,
128.55,128.39,128.32,127.26,127.07,117.50,86.45,82.04,78.66,58.92,20.57。
The nuclear magnetic data of intermediate 2 is as follows:1H NMR(400MHz,CDCl3) δ 7.90 (d, J=7.3Hz, 2H),
7.58～7.22 (m, 15H), 6.92 (s, 1H), 6.30 (d, J=3.3Hz, 1H), 5.47 (s, 1H), 5.37 (d, J=3.3
Hz, 1H), 5.28 (s, 1H), 5.12 (s, 1H), 4.11～3.99 (m, 2H).13C NMR(100MHz,CDCl3)
δ167.70,166.80,166.76,138.94,138.88,138.26,132.34,128.70,128.62,128.38,
127.26,127.02,126.84,120.49,86.25,82.14,79.09,55.09,45.60。
Embodiment 2
100g intermediate 1 is dissolved in 800ml dichloromethane, adds 30g selenium dioxide and 4g tetra-fourth
Base ammonium bromide, room temperature reaction 2h.Being cooled to-5 DEG C, be slowly added to 70ml tertbutanol peroxide, TLC detects
Reaction is completely.Under room temperature, system is poured in 1L 20% sodium sulfite aqueous solution, stirs 1h, stratification.
Organic facies uses 800ml saturated sodium bicarbonate solution, 800ml water successively, and 800ml saturated aqueous common salt washed once,
It is eventually adding 70g anhydrous sodium sulfate and is dried 10h.Sucking filtration, filtrate decompression is evaporated, residue 60ml ethanol weight
Crystallization, obtains intermediate 2.Yield 32%.
Embodiment 3
1kg intermediate 1 is dissolved in 10L dichloromethane, adds 300g selenium dioxide and the 40g tetrabutyl
Ammonium bromide, room temperature reaction 2h.Being cooled to-5 DEG C, be slowly added to 700ml tertbutanol peroxide, TLC detects
Reaction is completely.Under room temperature, system is poured in 8L 20% sodium sulfite aqueous solution, stirs 1h, stratification.
Organic facies uses 8L saturated sodium bicarbonate solution, 8L water successively, and 8L saturated aqueous common salt washed once, and finally adds
Enter 700g anhydrous sodium sulfate and be dried 10h.Sucking filtration, filtrate decompression is evaporated, residue 600ml ethyl alcohol recrystallization,
Obtain intermediate 2.Yield 30%.
Embodiment 4
1kg intermediate 1 is dissolved in 10L ethanol, adds 100g Hydro-Giene (Water Science)., 60g tetraphenyl bromine
Change phosphorus, room temperature reaction 2h.Being cooled to-5 DEG C, be slowly added to 600g calcium hypochlorite, TLC detection reaction is completely.
Under room temperature, system is poured in 8L 20% sodium sulfite aqueous solution, stirs 1h, stratification.Organic facies depends on
Secondary 8L saturated sodium bicarbonate solution, 8L water, 8L saturated aqueous common salt washed once, be eventually adding 700g without
Aqueous sodium persulfate is dried 10h.Sucking filtration, filtrate decompression is evaporated, residue 600ml ethyl alcohol recrystallization, obtains centre
Body 2.Yield 31%.
Embodiment 5
1kg intermediate 1 is dissolved in 10L ethanol and acetone, adds 100g Hydro-Giene (Water Science)., 100g bis-
Phenyl two selenium, 60g tetraphenyl phosphonium bromide, room temperature reaction 2h.It is cooled to-5 DEG C, is slowly added to 600g chlorine
Acid calcium, 500g peracetic acid, TLC detection reaction is completely.Under room temperature, system is poured into 8L 20% sulfurous acid
In sodium water solution, stir 1h, stratification.Organic facies uses 8L saturated sodium bicarbonate solution successively, 8L water,
8L saturated aqueous common salt washed once, and is eventually adding 700g anhydrous sodium sulfate and is dried 10h.Sucking filtration, filtrate decompression
It is evaporated, residue 600ml ethyl alcohol recrystallization, obtains intermediate 2.Yield 30%.
Claims (3)
1. the method that an allylic hydroxylating prepares oxacephems antibiotic key intermediate, it is characterised in that with compound1Compound is synthesized through allylic hydroxylating for raw material2, step is as follows:
By compound1Dissolve in a solvent, add phase transfer catalyst and catalyst, room temperature reaction；Being cooled to-5 DEG C ~ 0 DEG C, be slowly added to oxidant, TLC detection reaction is completely；Under room temperature, system is poured in sodium sulfite aqueous solution, stirring, stratification；Organic facies is with using saturated sodium bicarbonate solution, water successively, and saturated aqueous common salt washs, and through sucking filtration, filtrate decompression is evaporated, and is dried, recrystallization, obtains compound2；
Described catalyst is one of selenium dioxide, VAAC, diphenyl disenenide, Hydro-Giene (Water Science). or several mixture；
Described oxidant is one of oxygen, tert-Butanol peroxide, metachloroperbenzoic acid, sodium hypochlorite, calcium hypochlorite, peracetic acid, hydrogen peroxide, sodium dichromate or several mixture；
Described phase transfer catalyst be in tetrabutyl ammonium bromide, beta-schardinger dextrin-, tetraphenylphosphonibromide bromide, tetramethylammonium hydroxide any one；
Described solvent is one of acetone, N,N-dimethylformamide, acetonitrile, ethanol, methanol, isopropanol, 1,2-dichloroethanes, dichloromethane, chloroform, oxolane, dioxane, distilled water, toluene or the mixture of the most any two or three.
2. the method that allylic hydroxylating as claimed in claim 1 prepares oxacephems antibiotic key intermediate, it is characterised in that catalyst amount is compound10.5 ~ 3.0 times of mole.
3. the method that allylic hydroxylating as claimed in claim 1 prepares oxacephems antibiotic key intermediate, it is characterised in that oxidizer is compound10.1 ~ 3.0 times of mole.
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| US4443598A (en) * | 1977-02-15 | 1984-04-17 | Shionogi & Co., Ltd. | 1-Oxadethiacepham compounds |
| 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 |
| CN103254215A (en) * | 2013-05-24 | 2013-08-21 | 浙江东邦药业有限公司 | Preparation method of allyl chlorooxyl cephalosporin compound |
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|---|---|---|---|---|
| JPS5944390A (en) * | 1982-09-07 | 1984-03-12 | Shionogi & Co Ltd | Preparation of oxazoline compound |
| JPS5973587A (en) * | 1982-10-18 | 1984-04-25 | Shionogi & Co Ltd | Novel method for preparing oxazoline compound |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4443598A (en) * | 1977-02-15 | 1984-04-17 | Shionogi & Co., Ltd. | 1-Oxadethiacepham compounds |
| 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 |
| CN103254215A (en) * | 2013-05-24 | 2013-08-21 | 浙江东邦药业有限公司 | Preparation method of allyl chlorooxyl cephalosporin compound |
Non-Patent Citations (2)
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| （6R,7R）-7-苯甲酰胺基-3-氯甲基-7-甲氧基-8-氧代-5-氧杂-1-氮杂二环[4.2.0]辛-2-烯-2-羧酸二苯甲酯的合成;胡志，等，;《中国医药工业杂志》;20071231;第38卷(第11期);第755-757页 * |
| CONVERSION OF CEPHAM-l-OXIDE INTO l-OXADETHIACEPHAM;Hiroakl Yanaglsawa,et al.,;《Tetrahedron Letters》;19821231;第23卷(第33期);第3379-3382页 * |
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