CN104610277A - Method for preparing key intermediate of oxacephem antibiotic through allylic hydroxylation - Google Patents
Method for preparing key intermediate of oxacephem antibiotic through allylic hydroxylation Download PDFInfo
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- CN104610277A CN104610277A CN201510011336.2A CN201510011336A CN104610277A CN 104610277 A CN104610277 A CN 104610277A CN 201510011336 A CN201510011336 A CN 201510011336A CN 104610277 A CN104610277 A CN 104610277A
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- allylic
- compound
- key intermediate
- oxacephems
- hydroxylation
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- 0 *CC(C(C(OC(c1ccccc1)c1ccccc1)=O)N(C1OC(c2ccccc2)=NC11)C1=O)=C Chemical compound *CC(C(C(OC(c1ccccc1)c1ccccc1)=O)N(C1OC(c2ccccc2)=NC11)C1=O)=C 0.000 description 1
- UWXBDXSQNXLBHG-IJQWPOMLSA-N C=C(CCl)C(C(OC(c1ccccc1)c1ccccc1)=O)N([C@@H]1OC(c2ccccc2)=NC11)C1=O Chemical compound C=C(CCl)C(C(OC(c1ccccc1)c1ccccc1)=O)N([C@@H]1OC(c2ccccc2)=NC11)C1=O UWXBDXSQNXLBHG-IJQWPOMLSA-N 0.000 description 1
- URQPRGSODZZBBN-UHFFFAOYSA-N C=C(CI)C(C(OC(c1ccccc1)c1ccccc1)=O)N(C1OC(c2ccccc2)=NC11)C1=O Chemical compound C=C(CI)C(C(OC(c1ccccc1)c1ccccc1)=O)N(C1OC(c2ccccc2)=NC11)C1=O URQPRGSODZZBBN-UHFFFAOYSA-N 0.000 description 1
- KRRTWFHBKSHLSS-AGAMRWJHSA-N C=C(CO)C(C(OC(c1ccccc1)c1ccccc1)=O)N([C@@H]1OC(c2ccccc2)=N[C@@H]11)C1=O Chemical compound C=C(CO)C(C(OC(c1ccccc1)c1ccccc1)=O)N([C@@H]1OC(c2ccccc2)=N[C@@H]11)C1=O KRRTWFHBKSHLSS-AGAMRWJHSA-N 0.000 description 1
- IGDWUWXIYTUDBF-AGAMRWJHSA-N CC(C(C(OC(c1ccccc1)c1ccccc1)=O)N([C@@H]1OC(c2ccccc2)=N[C@@H]11)C1=O)=C Chemical compound CC(C(C(OC(c1ccccc1)c1ccccc1)=O)N([C@@H]1OC(c2ccccc2)=N[C@@H]11)C1=O)=C IGDWUWXIYTUDBF-AGAMRWJHSA-N 0.000 description 1
- CAUVODHUAAORCS-ZSGNRXJESA-N CC(C)([C@@H]1C(O)=O)SC(C2N=N)N1C2=O Chemical compound CC(C)([C@@H]1C(O)=O)SC(C2N=N)N1C2=O CAUVODHUAAORCS-ZSGNRXJESA-N 0.000 description 1
- MLNXEIRZOOBQQF-IJQWPOMLSA-N CC(C)C(C(OC(c1ccccc1)c1ccccc1)=O)N([C@@H]1OC(c2ccccc2)=NC11)C1=O Chemical compound CC(C)C(C(OC(c1ccccc1)c1ccccc1)=O)N([C@@H]1OC(c2ccccc2)=NC11)C1=O MLNXEIRZOOBQQF-IJQWPOMLSA-N 0.000 description 1
- AVTODTZUIRKILK-MBUFVENHSA-N CCC(C)(CN(C1[C@@H]2NC(c3ccccc3)=O)C2=O)S1=O Chemical compound CCC(C)(CN(C1[C@@H]2NC(c3ccccc3)=O)C2=O)S1=O AVTODTZUIRKILK-MBUFVENHSA-N 0.000 description 1
- NHPYITOADAEIFY-UHFFFAOYSA-N O=COC(c1ccccc1)c1ccccc1 Chemical compound O=COC(c1ccccc1)c1ccccc1 NHPYITOADAEIFY-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing key intermediate of an oxacephem antibiotic through allylic hydroxylation, and belongs to the technical field of pharmaceutical synthesis. The method disclosed by the invention uses [1R-[1 alpha, 5 alpha]]-3-methyl-2-(7-chloro-3-phenyl-4-oxa-2, 6-diazabicyclo [3.2.0] heptyl-2-alkene-6-base)-3-butenoic acid diphenyl methyl ester (compound 1) as a raw material, and [1R-[1 alpha, 5 alpha]]-3-hydroxyl-2-(7-chloro-3-phenyl-4-oxa-2, 6-diazabicyclo [3.2.0] heptyl-2-alkene-6-base)-3-butenoic acid diphenyl methyl ester (compound 2) is synthetized through allylic hydroxylation in one step. Compared with the prior art, the synthetic route of the oxacephem antibiotic is effectively shortened by the method disclosed by the invention, using chlorine and a heavy metal reagent is avoided, light resistant equipment is not needed in industrial production, and the method is convenient in postprocessing, is low in cost and is very suitable for the industrial production.
Description
Technical field
The present invention relates to a kind of method that allylic hydroxylation prepares oxacephems microbiotic key intermediate, belong to technical field of medicine synthesis.
Background technology
Oxacephems microbiotic such as latamoxef (Latamoxef) or flomoxef (Flomoxef) are class extensive pedigree antibiotics, it has good anti-microbial activity to multiple Gram-negative bacteria, and effect is stronger than general cynnematin 4 ~ 16 times.
In industrial production, with reference to the synthetic method of US Patent No. 4532233, US4138486 and German patent DE 2355209, oxacephems microbiotic latamoxef (Latamoxef) and flomoxef (Flomoxef) can be prepared with compound 2.
Oxacephems microbiotic key intermediate 2 can by 3-acetyl-o-methyl-5-sulphur-7-amino-8-oxygen-1-azabicyclic oct-2-ene-2 carboxylic acid (7-ACA) for prepared by raw material.Reference is shown in Tetrahedron Lett., 1982,23,3379 and Synth Commun., 1988,18,763.Reaction scheme one is as follows:
This route take 7-ACA as starting raw material, through multistep protection be oxidized to obtain intermediate 3, under heating condition, [2,3]-δ-reset to obtain intermediate 4 occurs, then react with 2-mercaptobenzoxazole and generate intermediate 5, in chlorine presence, form intermediate 2.There is the following place had much room for improvement in the method:
(1) intermediate 3 need be formed by 7-ACA Multi-step conversion, and side reaction is many, should not control.
(2) need in preparation process to use chlorine, unfriendly to environment, and require higher to production unit, be unfavorable for suitability for industrialized production.
(3) intermediate 4 can under triphenyl phosphorus participates in direct synthetic intermediate 2, but produce a large amount of phosphorous refuses, be unfavorable for recrystallization, pilot scale repeatability is poor.
Oxacephems microbiotic key intermediate 2 also can by 6-amino-penicillanic acid (6-APA) for prepared by raw material.Reference is shown in Tetrahedron Lett., 1975,2595; Tetrahedron Lett., 1980,21,351; CN101538274; JP56012395; JP2004168775; US4366316.Reaction scheme two is as follows:
This route take 6-APA as starting raw material; low price is easy to get; through amino, carboxy protective be oxidized to obtain intermediate 6; triphenyl phosphorus participates in lower generation rearrangement reaction and obtains intermediate 1; then intermediate 7 is formed with chlorine reaction; react with sodium iodide effect lucifuge and form intermediate 8, last Silver Nitrate reaction, acidifying form intermediate 2.Comparatively route one, industrial repeatability is high, and product appearance is good.But still there is the following place had much room for improvement:
(1) use chlorine in industrial production, be unfavorable for environmental protection.Silver Nitrate is expensive, introduces heavy metal, is unfavorable for that aftertreatment removes.
(2) use of sodium iodide, needs lucifuge, there are certain requirements equipment.
(3) hydrogen atom replacement of allylic is that the group of easily leaving away need through polystep reaction, and route is longer.
Summary of the invention
For reaction scheme two, the object of the invention is to overcome existing oxacephems production of antibiotics technological deficiency, shorten reaction scheme, the step minimizing that allylic hydrogen atom replace to allylic hydroxyl and evade the use of chlorine and expensive heavy metal, make production more environmental protection, easier.
For realizing the object of the invention, the present invention is with oxacephems microbiotic key intermediate 1 for raw material, and by adding suitable catalyzer and oxygenant, catalyzer and oxygenant coupling, a step can obtain intermediate 2.In allylic hydroxylating, catalyzer and oxygenant most important, phase-transfer catalyst can Reaction time shorten to a certain extent.
Its concrete steps are as follows:
Intermediate 1 is dissolved in a solvent, adds phase-transfer catalyst and catalyzer, room temperature reaction.Be cooled to-5 DEG C ~ 0 DEG C, slowly add oxygenant, TLC detection reaction is complete.Under room temperature, system is poured in sodium sulfite aqueous solution, stirs, stratification.Organic phase is with using saturated sodium bicarbonate solution successively, and water, saturated common salt water washing, through suction filtration, filtrate decompression evaporate to dryness, dry, recrystallization, obtains intermediate 2.
In above-mentioned steps allylic hydroxylating, catalyzer is tin anhydride, VAAC, diphenyl disenenide, cuprous iodide one of them or several mixtures.
In above-mentioned steps allylic hydroxylating, phase-transfer catalyst be Tetrabutyl amonium bromide, beta-cyclodextrin, Tetraphenylphosphonium Bromide, tetramethylammonium hydroxide one of them.
In above-mentioned steps allylic hydroxylating, solvent is acetone, N, dinethylformamide, acetonitrile, ethanol, methyl alcohol, Virahol, 1,2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, distilled water, toluene one of them or wherein any two or three mixture.
In above-mentioned steps allylic hydroxylating, oxygenant is oxygen, peroxy tert-butyl alcohol, metachloroperbenzoic acid, clorox, Losantin, Peracetic Acid, hydrogen peroxide, sodium dichromate 99 one of them or several mixtures.
In above-mentioned steps allylic hydroxylating, catalyst levels is 0.5 ~ 3.0 times of compound 1 molar weight, and oxygenant consumption is 0.1 ~ 3.0 times of compound 1 molar weight, and phase-transfer catalyst consumption is 0.05 ~ 0.5 times of compound 1 molar weight.
In above-mentioned steps allylic hydroxylating, recrystallization solvent is methyl alcohol, ethanol, Virahol, propyl carbinol, the trimethyl carbinol, ethylene glycol.
The beneficial effect adopting technique scheme to produce is:
(1) present invention, avoiding the use of chlorine and heavy metal, reaction conditions is gentle, easily control, environmental protection.
(2) the present invention effectively shortens operational path, and a step realizes allylic hydroxylating, and yield reaches more than 30%, and production competitive power significantly improves.
(3) present invention, avoiding the use of resistance to chlorine equipment and lucifuge equipment, production cost reduces.
(4) product of the present invention is single, and aftertreatment is simple, and purity is high.
Embodiment
For illustrating better the present invention, as follows for embodiment:
Embodiment 1
10g intermediate 1 is dissolved in 80ml methylene dichloride, adds 3g tin anhydride and 0.4g Tetrabutyl amonium bromide, room temperature reaction 2h.Be cooled to-5 DEG C, slowly add 7ml tertbutanol peroxide, TLC detection reaction is complete.Under room temperature, system is poured in 100ml 20% sodium sulfite aqueous solution, stirs 1h, stratification.Organic phase is with using 80ml saturated sodium bicarbonate solution successively, and 80ml water, the water washing of 80ml saturated common salt once, finally adds 7g anhydrous sodium sulfate drying 10h.Suction filtration, filtrate decompression evaporate to dryness, residue 5ml ethyl alcohol recrystallization, obtains intermediate 2.Yield 33%.
The nuclear magnetic data of intermediate 1 is as follows:
1h NMR (400MHz, CDCl
3) 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(100MHz,CDCl
3)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, CDCl
3) 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=3.3Hz, 1H), 5.28 (s, 1H), 5.12 (s, 1H), 4.11 ~ 3.99 (m, 2H).
13C NMR(100MHz,CDCl
3)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 methylene dichloride, adds 30g tin anhydride and 4g Tetrabutyl amonium bromide, room temperature reaction 2h.Be cooled to-5 DEG C, slowly add 70ml tertbutanol peroxide, TLC detection reaction is complete.Under room temperature, system is poured in 1L 20% sodium sulfite aqueous solution, stirs 1h, stratification.Organic phase uses 800ml saturated sodium bicarbonate solution successively, 800ml water, and the water washing of 800ml saturated common salt once, finally adds 70g anhydrous sodium sulfate drying 10h.Suction filtration, filtrate decompression evaporate to dryness, residue 60ml ethyl alcohol recrystallization, obtains intermediate 2.Yield 32%.
Embodiment 3
1kg intermediate 1 is dissolved in 10L methylene dichloride, adds 300g tin anhydride and 40g Tetrabutyl amonium bromide, room temperature reaction 2h.Be cooled to-5 DEG C, slowly add 700ml tertbutanol peroxide, TLC detection reaction is complete.Under room temperature, system is poured in 8L 20% sodium sulfite aqueous solution, stirs 1h, stratification.Organic phase uses 8L saturated sodium bicarbonate solution successively, 8L water, and the water washing of 8L saturated common salt once, finally adds 700g anhydrous sodium sulfate drying 10h.Suction filtration, filtrate decompression evaporate to dryness, residue 600ml ethyl alcohol recrystallization, obtains intermediate 2.Yield 30%.
Embodiment 4
1kg intermediate 1 is dissolved in 10L ethanol, adds 100g cuprous iodide, 60g Tetraphenylphosphonium Bromide, room temperature reaction 2h.Be cooled to-5 DEG C, slowly add 600g Losantin, TLC detection reaction is complete.Under room temperature, system is poured in 8L 20% sodium sulfite aqueous solution, stirs 1h, stratification.Organic phase uses 8L saturated sodium bicarbonate solution successively, 8L water, and the water washing of 8L saturated common salt once, finally adds 700g anhydrous sodium sulfate drying 10h.Suction filtration, filtrate decompression evaporate to dryness, residue 600ml ethyl alcohol recrystallization, obtains intermediate 2.Yield 31%.
Embodiment 5
1kg intermediate 1 is dissolved in 10L ethanol and acetone, adds 100g cuprous iodide, 100g diphenyl disenenide, 60g Tetraphenylphosphonium Bromide, room temperature reaction 2h.Be cooled to-5 DEG C, slowly add 600g Losantin, 500g Peracetic Acid, TLC detection reaction is complete.Under room temperature, system is poured in 8L 20% sodium sulfite aqueous solution, stirs 1h, stratification.Organic phase uses 8L saturated sodium bicarbonate solution successively, 8L water, and the water washing of 8L saturated common salt once, finally adds 700g anhydrous sodium sulfate drying 10h.Suction filtration, filtrate decompression evaporate to dryness, residue 600ml ethyl alcohol recrystallization, obtains intermediate 2.Yield 30%.
Claims (3)
1. allylic hydroxylation prepares a method for oxacephems microbiotic key intermediate, it is characterized in that, with compound
1for raw material is through allylic hydroxylation synthetic compound
2, step is as follows:
By intermediate
1dissolve in a solvent, add phase-transfer catalyst and catalyzer, room temperature reaction; Be cooled to-5 DEG C ~ 0 DEG C, slowly add oxygenant, TLC detection reaction is complete; Under room temperature, system is poured in sodium sulfite aqueous solution, stirs, stratification; Organic phase is with using saturated sodium bicarbonate solution successively, and water, saturated common salt water washing, through suction filtration, filtrate decompression evaporate to dryness, dry, recrystallization, obtains intermediate
2;
Described catalyzer is one or several the mixture in tin anhydride, VAAC, diphenyl disenenide, cuprous iodide;
Described oxygenant is one or several the mixture in oxygen, peroxy tert-butyl alcohol, metachloroperbenzoic acid, clorox, Losantin, Peracetic Acid, hydrogen peroxide, sodium dichromate 99;
Described phase-transfer catalyst be in Tetrabutyl amonium bromide, beta-cyclodextrin, Tetraphenylphosphonium Bromide, tetramethylammonium hydroxide any one;
Described solvent is acetone, N, one of in dinethylformamide, acetonitrile, ethanol, methyl alcohol, Virahol, 1,2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, distilled water, toluene or the wherein mixture of any two or three.
2. allylic hydroxylation as claimed in claim 1 prepares the method for oxacephems microbiotic key intermediate, and it is characterized in that, catalyst levels is compound
10.5 ~ 3.0 times of molar weight.
3. allylic hydroxylation as claimed in claim 1 prepares the method for oxacephems microbiotic key intermediate, and it is characterized in that, oxygenant consumption is compound
10.1 ~ 3.0 times of molar weight.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315858A (en) * | 2022-01-11 | 2022-04-12 | 深圳市立国药物研究有限公司 | Synthesis method of flomoxef intermediate |
Citations (5)
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|---|---|---|---|---|
| JPS5944390A (en) * | 1982-09-07 | 1984-03-12 | Shionogi & Co Ltd | Preparation of oxazoline compound |
| US4443598A (en) * | 1977-02-15 | 1984-04-17 | Shionogi & Co., Ltd. | 1-Oxadethiacepham compounds |
| JPS5973587A (en) * | 1982-10-18 | 1984-04-25 | Shionogi & Co Ltd | Novel method for preparing oxazoline compound |
| 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 |
-
2015
- 2015-01-09 CN CN201510011336.2A patent/CN104610277B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4443598A (en) * | 1977-02-15 | 1984-04-17 | Shionogi & Co., Ltd. | 1-Oxadethiacepham compounds |
| 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 |
| 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)
| Title |
|---|
| HIROAKL YANAGLSAWA,ET AL.,: "CONVERSION OF CEPHAM-l-OXIDE INTO l-OXADETHIACEPHAM", 《TETRAHEDRON LETTERS》 * |
| 胡志，等，: "（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", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315858A (en) * | 2022-01-11 | 2022-04-12 | 深圳市立国药物研究有限公司 | Synthesis method of flomoxef intermediate |
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