CN105566354A - Preparation method of biapenem intermediate - Google Patents
Preparation method of biapenem intermediate Download PDFInfo
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- CN105566354A CN105566354A CN201510881101.9A CN201510881101A CN105566354A CN 105566354 A CN105566354 A CN 105566354A CN 201510881101 A CN201510881101 A CN 201510881101A CN 105566354 A CN105566354 A CN 105566354A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/06—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 containing at least one condensed beta-lactam ring system, provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00, e.g. a penem or a cepham system
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Abstract
The invention relates to a biapenem intermediate (biapenem condensate) and a preparation method thereof, namely a preparation method for formula I. A compound bis(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazole-6-yl) dithiodichloride (formula II) is added in a mixed solvent without preparing a compound 6,7-dihydro-6-thiol-5H-pyrazolo[1,2-1a][1,2,4] triazolium chloride (biapenem side chain) (formula III), a compound in formula IV (4R,5S,6S)-3-diphenoxyphosphonyloxy-6-[1R-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]heptyl-2-ene-2 p-nitrobenzyl carboxylate (bicyclic nucleus) is directly added, the biapenem condensate is prepared using one-pot procedure, production efficiency and yield of biapenem condensate are increased, and the prepared biapenem condensate is high in purity and can meet the biapenem synthesis requirements, and the method used has mild reaction conditions, is safe, is free of environmental pollution and is suitable for industrial production.
Description
Technical field:
The present invention relates to a kind of biapenem intermediate namely: 6-[[(4R, 5S, 6S)-2-(4-nitrobenzyloxycarbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3,2,0] hept-2-ene"-3-base] sulfenyl]-6,7-dihydro-5H-pyrazolos [1,2-a] [1,2,4] synthesis of triazole-4-muriate (biapenem condensation compound) and preparation method.
Background technology:
Biapenem is mainly used in treatment adult abdominal cavity infection, lower respiratory infection and urinary tract infections etc., and its has a broad antifungal spectrum, stable chemical nature, anti-microbial activity is strong, stablizes DHP enzyme.
Biapenem is developed by U.S. Hui Shi (wyeth), and authorize Japanese Meijiseika Pharmaceutical Co., Ltd November calendar year 2001, in June, 2002 goes on the market in Japan first.The base substance patent No. of biapenem is EP289801, and patent priority state is Japan, and patent priority day is on April 11st, 1987, and its structural formula is such as formula V:
The synthetic route of current biapenem has all used important intermediate-[[(4R mostly, 5S, 6S)-2-(4-nitrobenzyloxycarbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3,2,0] hept-2-ene"-3-base] sulfenyl]-6,7-dihydro-5H-pyrazolos [1,2-a] [1,2,4] triazole-4-muriate (hereinafter referred to as biapenem condensation compound), its structural formula is such as formula I:
Such as; Toshiokumagai equals to report synthetic route in 1998, wherein first synthesizes side chain for biapenem (formula III) by formula II, then docks with formula IV; obtain biapenem condensation compound formula I, then obtain biapenem (formula V) through shortening deprotection
It is harsh that reason formula II prepares formula III reaction requirement condition, long reaction time, although formula III and formula IV can reach 90 ~ 91% to acceptance rate, react completely to make formula IV, need to add excessive formula III compound (general 1mol compound IV needs to add 1.3mol formula III compound), make total recovery lower, by method and the experimental data of above-mentioned document addresses, calculating total recovery from formula II production V is 49%, contriver repeats experimental data, suitable minimizing formula III consumption, maximumly can bring up to 50 ~ 55% by yield.We have invented the method for being synthesized biapenem condensation compound (formula I) by formula II and formula IV direct reaction, shorten the reaction times, only need reaction 1 hour after raw material dropwises, and make overall yield of reaction be increased to 70 ~ 85%, reduce production cost.
Summary of the invention:
Technical scheme of the present invention is as follows:
The synthetic method of a kind of biapenem condensation compound formula I; it comprises the following steps: under protection of inert gas; add Compound II per and compound IV; add water and organic solvent again, be cooled to 0 ~-5 DEG C, drip diisopropyl ethyl amine; dropwise; be warming up to 5 ~ 20 DEG C of reactions 1 hour, after HPLC detection reaction completes, add gac; stir decolouring 0.5 hour; filter, filtrate is cooled to-5 ± 2 DEG C, crystallization 2 hours; filter; dry, obtain biapenem condensation compound, HPLC detected result is equal to reacts gained formula I with formula III and formula IV.
Wherein rare gas element is preferably argon gas, nitrogen etc.
Described organic solvent is acetone, tetrahydrofuran (THF), ethanol, methyl alcohol or mixed solvent wherein.
Preferably, described organic solvent is tetrahydrofuran (THF), ethanol, two kinds in acetone.
Preferably, formula II: formula IV: the mol ratio of diisopropylethylamine is 0.5-0.6: 1-1.3: 1.15-1.7.
Biapenem condensation compound provided by the present invention, can be used for the preparation of biapenem.
Usefulness of the present invention is the feature that provided biapenem condensation compound has steady chemical structure.Described method reactions steps of the present invention is short simultaneously, and yield is high, and reaction conditions is gentle, and safety is pollution-free.
The finished product of this invention use through client, and its structure meets completely prepares biapenem requirement.
Embodiment:
For ease of describing, in following embodiment
Formula I is referred to as biapenem condensation compound
Formula II is referred to as Compound II per
Formula III is referred to as side chain for biapenem
Formula IV is referred to as parent nucleus
Embodiment 1:
Under nitrogen protection; Compound II per 19.5g (0.055mol) is added successively in reaction flask; parent nucleus 59.5g (0.1mol), acetone 100ml, tetrahydrofuran (THF) 100ml; water 300ml; be cooled to 0 ~-5 DEG C, drip diisopropyl ethyl amine 20ml (0.115mol), dropwise; be warming up to 5 ~ 10 DEG C, react 1 hour.After HPLC detection reaction completes, add gac 5g, stir 0.5 hour, filter, filtrate is cooled to-5 ± 2 DEG C, crystallization 2 hours, filters, and dries, obtains biapenem condensation compound 43.7g, yield 83.9%, purity 98.6%.Fusing point test 165.4 DEG C
Result verification: confirm through client, its structure and purity accords prepare biapenem requirement.
In following embodiment, gained the finished product are all identical with embodiment 1
Embodiment 2:
Under nitrogen protection; Compound II per 19.5g (0.055mol) is added successively, parent nucleus 65.5g (0.11mol), acetone 100ml in reaction flask; tetrahydrofuran (THF) 100ml; water 300ml, ethanol 200ml, be cooled to 0 ~-5 DEG C; drip diisopropyl ethyl amine 20ml (0.115moi); dropwise, be warming up to 5 ~ 10 DEG C, react 1 hour.After HPLC detection reaction completes, add gac 5g, stir 0.5 hour, suction filtration, filtrate is cooled to-5 ± 2 DEG C, crystallization 2 hours, filters, and dries, obtains biapenem condensation compound 43g, yield 75%, purity 98.2%.
Embodiment 3:
Under nitrogen protection; Compound II per 19.5g (0.055mol) is added successively, parent nucleus 59.5g (0.1mol), acetone 100ml in reaction flask; tetrahydrofuran (THF) 100ml; water 300ml, methyl alcohol 200ml, be cooled to 0 ~-5 DEG C; drip diisopropyl ethyl amine 22.5ml (0.13mol); dropwise, be warming up to 15 ~ 20 DEG C, react 1 hour.After HPLC detection reaction completes, add gac 7.5g, stir 0.5 hour, suction filtration, filtrate is cooled to-5 ± 2 DEG C, crystallization 2 hours, filters, and dries, obtains biapenem condensation compound 43.8g, yield 84.1, purity 98.6%.
Embodiment 4:
Under nitrogen protection; Compound II per 19.5g (0.055mol) is added successively in reaction flask; parent nucleus 59.5g (0.1mol), tetrahydrofuran (THF) 150ml, water 300ml; ethanol 200ml; be cooled to 0 ~-5 DEG C, drip diisopropyl ethyl amine 22.5ml (0.13mol), dropwise; be warming up to 15 ~ 20 DEG C, react 1 hour.After HPLC detection reaction completes, add gac 7.5g, stir 0.5 hour, suction filtration, filtrate is cooled to-5 ± 2 DEG C, crystallization 2 hours, filters, and dries, obtains biapenem condensation compound 43.7g, yield, 83.9%, purity 98.8%.
Embodiment 5:
Under nitrogen protection; Compound II per 19.5g (0.055mol) is added successively in reaction flask; parent nucleus 59.5g (0.1mol); acetone 150ml, water 300ml, be cooled to 0 ~-5 DEG C; drip diisopropyl ethyl amine 22.5ml (0.13mol); dropwise, be warming up to 15 ~ 20 DEG C, react 1 hour.After HPLC detection reaction completes, add gac 7.5g, stir 0.5 hour, suction filtration, filtrate is cooled to-5 ± 2 DEG C, crystallization 2 hours, filters, and dries, obtains biapenem condensation compound 43.1g, yield, 82.7%, purity 98.8%.
Above one embodiment of the present of invention have been described in detail, but described content being only preferred embodiment of the present invention, can not thinking for limiting practical range of the present invention.All equivalent variations and improvement etc. complied with according to the present patent application scope, still all should belong to patent covering scope of the present invention.
Claims (7)
1. a preparation method for biapenem intermediate compound I, is characterized in that reaction equation is as follows:
Specifically comprise the steps: under protection of inert gas, Compound II per and compound IV are reacted in water and organic solvent, cooling, drip diisopropyl ethyl amine, after dropwising, more slowly temperature reaction, obtain biapenem intermediate compound I.
2. the preparation method of biapenem intermediate compound I as claimed in claim 1, it is characterized in that described cooling step reduces the temperature to 0 ~-5 DEG C, temperature reaction is elevated to 5 ~ 20 DEG C.
3. the preparation method of biapenem intermediate compound I as claimed in claim 1, is characterized in that comprising the steps:
(a): by formula II compound and formula IV compound dissolution in a kind of organic solvent;
(b): add remaining organic solvent and water;
(c): 0 ~-5 DEG C drips diisopropylethylamine;
(d): 5 ~ 20 DEG C of reactions 1 hour after dropwising;
E (): add activated carbon decolorizing 0.5 hour, filter liquor is cooled to-5 ± 2 DEG C of crystallizatioies 1 ~ 2 hour, filters, and dries, obtains formula I.
4. the preparation method of biapenem condensation compound as claimed in claim 1, is characterized in that; Organic solvent is selected from the mixed solvent of one or more in acetone, tetrachloro furans, ethanol, methyl alcohol.
5. the preparation method of biapenem condensation compound as described in any one of claim 1-4, is characterized in that described organic solvent is tetrahydrofuran (THF), ethanol, two kinds in acetone.
6. the preparation method of the biapenem condensation compound as described in any one of claim 1-4, is characterized in that the rare gas element rare gas element used is preferably argon gas, nitrogen etc.
7. the preparation method of biapenem condensation compound as claimed in claim 1, is characterized in that: formula II: formula IV: the mol ratio of diisopropylethylamine is 0.5-0.6: 1-1.3: 1.15-1.7.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111366644A (en) * | 2018-12-25 | 2020-07-03 | 江苏先声药业有限公司 | HPLC detection method for biapenem side chain related substances |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111366644A (en) * | 2018-12-25 | 2020-07-03 | 江苏先声药业有限公司 | HPLC detection method for biapenem side chain related substances |
| CN111366644B (en) * | 2018-12-25 | 2022-07-26 | 江苏先声药业有限公司 | HPLC detection method for biapenem side chain related substances |
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Application publication date: 20160511 |
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