CN104803999A - Preparation method of moxifloxacin side chain intermediate - Google Patents
Preparation method of moxifloxacin side chain intermediate Download PDFInfo
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- CN104803999A CN104803999A CN201510136753.XA CN201510136753A CN104803999A CN 104803999 A CN104803999 A CN 104803999A CN 201510136753 A CN201510136753 A CN 201510136753A CN 104803999 A CN104803999 A CN 104803999A
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- RRBLNPCNHNHAFW-UHFFFAOYSA-N O=C(C1C2NCCC1)N(Cc1ccccc1)C2=O Chemical compound O=C(C1C2NCCC1)N(Cc1ccccc1)C2=O RRBLNPCNHNHAFW-UHFFFAOYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
The invention discloses a preparation method of a moxifloxacin side chain intermediate. The method comprises steps as follows: (1R,6S)-cis8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, an organic solvent and an organic strong base are taken, heated to the temperature of 40-80 DEG C, stirred and insulated for reactions for 3-6 h; a reaction liquid is cooled to the room temperature, an organic acid is added, and the mixture is stirred until the color turns green from orange; a prepared sodium chloride-sodium carbonate mixed solution is dropwise added to the reaction liquid within 1 h, and the mixture is stirred for 30 min; the mixture is left to stand for layering, a water layer is removed, the solvent is removed from an organic layer under reduced pressure, and high-purity racemic cis8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane is obtained. The preparation method has the advantages as follows: no hydrogenation reaction is required, the safety is improved, and the production cost is reduced. The reaction time is short, reaction conditions are mild, reaction reagents are simple, cheap and easy to obtain, the safety is improved, the cost is reduced, and the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation of compound, especially a kind of preparation method of Moses's side chain intermediate.
Background technology
Moses's side chain intermediate 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane is synthesis forth generation fluoroquinolone antibacterial agent-moxifloxacin side chain (S, S)-2, the intermediate that 8-diazabicyclo [4,3,0] nonane is important.
From upper chemical reaction: only have (1S, 6R)-cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane can participate in reaction, and (1R, the recycling of 6S)-cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane then becomes industrial urgent problem.
From (1R, 6S)--cis 8-benzyl-7,9-dioxo-2, the structural formula of 8-diazabicyclo [4.3.0] nonane can be found out, only have and its chirality is disappeared, make it to become 8-benzyl-7,9-dioxo-2, the racemization product of 8-diazabicyclo [4.3.0] nonane, could realize the object of recycling.
At present, the preparation method of racemize cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane is had been reported in patent.
Such as patent CN101429199A, describes (1R, 6S)--and the dehydrogenation under the katalysis of Manganse Dioxide of cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane changes into.
6-benzyl-5,7-dioxo-1,2,3,3-tetrahydrochysene-pyrrolo-[3,4-b] pyridine, is then reduced into racemize cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane by the method for high-pressure hydrogenation.
In patent EP61982, then description palladium is catalyzer, under high temperature more than 200 DEG C, 6-benzyl-5,7-dioxo-1,2 is prepared with oxygen dehydrogenation, 3,3-tetrahydrochysene-pyrrolo-[3,4-b] pyridine, and then high-pressure hydrogenation is reduced into racemize cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane.
US Patent No. 4051140 description vanadium metals are catalyzer, under high temperature more than 260 DEG C, in the gas phase, 6-benzyl-5 is prepared with oxygen dehydrogenation, 7-dioxo-1,2,3,3-tetrahydrochysene-pyrrolo-[3,4-b] pyridine, and then high-pressure hydrogenation is reduced into racemize cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane.
These all above methods all employ fiercer reaction conditions and expensive reaction reagent, and operation steps is complicated, and the by product that reaction produces is more, and not easily aftertreatment, is industrially difficult to be widely used.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of Moses's side chain intermediate, the method operational path is simple, with low cost, the racemize Moses side chain intermediate that product purity is high, and the product yield obtained by the method is more than 85%.
Technical scheme of the present invention is: the first step: (the 1R taking 1 part, 6S)-cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane, the organic solvent of 6-20 part, join in three-necked bottle, under normal temperature, add the organic alkali of 1/10-1/15 part, be warming up to 40-80 DEG C and stir insulation reaction 3-6 hour; Second step: reaction solution is down to room temperature, adds the organic acid of 1/5-1/10 part, is stirred to color and changes green into by orange; 3rd step: take 1/2 part of sodium-chlor and 1/4 part of sodium carbonate and be dissolved in 6-10 part water and be made into sodium-chlor-sodium carbonate mixture; 4th step: sodium-chlor-sodium carbonate mixture of preparing is added drop-wise in reaction solution in 1 hour, stirs 30 minutes.5th step: stratification, water layer discarded, organic layer decompression is sloughed solvent and is obtained highly purified racemize cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane.
Above-mentioned organic alkali can be: sodium methylate, sodium ethylate organic alkali.
Above-mentioned organic acid can be used: formic acid, acetic acid, propionic acid.
Above-mentioned organic solvent can be: benzene, toluene, methylene dichloride, ethylene dichloride organic solvent.
Chemical equation is:
We have researched and developed a kind of operational path, under suitable solvent condition, by (1R under the catalysis of organic alkali, 6S)-direct racemization of cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane becomes racemize cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane, does not need first dehydrogenation repeated hydrogenation, thus overcomes reaction conditions fierceness, the complicated operation of prior art, the shortcoming such as by product is many, reaction cost is high.
Here (the 1R of indication, 6S)-cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane comprises: pure optically active (1R, 6S)-cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane, or with part (1S, 6R)-cis 8-benzyl-7,9-dioxo-2, (the 1R of 8-diazabicyclo [4.3.0] nonane, 6S)-cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane.
The invention has the advantages that: it is racemization agent that the present invention has started with organic bases, directly synthesize racemize cis 8-benzyl-7,9-dioxo-2 at low temperatures, the method of 8-diazabicyclo [4.3.0] nonane, reaction times is shortened greatly, reduces energy consumption, improve the feature of environmental protection.Present invention obviates dehydrogenation reaction, temperature of reaction between 40-70 DEG C, reaction temperature and, avoid the dehydrating agent using high temperature and some costlinesses.The present invention does not need to carry out hydrogenation reaction, avoids using palladium-carbon and logical hydrogen, improves security, reduces production cost.The organic bases that the present invention uses is converted into alcohol, recoverable after adding the aqueous solution, can not to environment.Reaction times of the present invention short, reaction temperature and, reaction reagent is simple, cheap, be easy to get, improve security, reduce cost, suitability for industrialized is produced.
Embodiment
Embodiment 1:
500ml toluene is added in the three-necked bottle of 1000ml, (the 1R of 50g, 6S)-cis 8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, stirring and dissolving, 8g sodium methylate is added under stirring, be warming up to 65 DEG C, be incubated 3 hours at this temperature, be down to 25 DEG C, drip the formic acid of 5 milliliters, stir, solution changes yellow-green colour into by orange, sodium-chlor-the sodium carbonate mixture (30g sodium-chlor+15g sodium carbonate is dissolved in the water of 300ml) adding 300ml stirs 30 minutes, leave standstill, layering, water layer discarded, organic phase less than 90 DEG C pressure reducing and steaming toluene, obtain yellow-green colour oily liquids 43g, be racemize cis 8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, yield 86%.
Embodiment 2:
500ml toluene is added in the three-necked bottle of 1000ml, (the 1R of 50g, 6S)-cis 8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, stirring and dissolving, 10g sodium ethylate is added under stirring, be warming up to 65 DEG C, be incubated 3 hours at this temperature, be down to 25 DEG C, drip the acetic acid of 8 milliliters, stir, solution changes yellow-green colour into by orange, sodium-chlor-the sodium carbonate mixture (30g sodium-chlor+15g sodium carbonate is dissolved in the water of 300ml) adding 300ml stirs 30 minutes, leave standstill, layering, water layer discarded, organic phase less than 90 DEG C pressure reducing and steaming toluene, obtain yellow-green colour oily liquids 45g, be racemize cis 8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane.Yield 90%.
Embodiment 3:
600ml methylene dichloride is added in the three-necked bottle of 1000ml, (the 1R of 50g, 6S)-cis 8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, stirring and dissolving, 10g sodium methylate is added under stirring, be warming up to 40 DEG C, be incubated 3 hours at this temperature, be down to 25 DEG C, drip the acetic acid of 8 milliliters, stir, solution changes yellow-green colour into by orange, sodium-chlor-the sodium carbonate mixture (30g sodium-chlor+15g sodium carbonate is dissolved in the water of 300ml) adding 300ml stirs 30 minutes, leave standstill, layering, water layer discarded, organic phase less than 50 DEG C pressure reducing and steaming methylene dichloride, obtain yellow-green colour oily liquids 47g, be racemize cis 8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane.Yield 94%.
Embodiment 4:
500ml methylene dichloride is added in the three-necked bottle of 1000ml, (the 1R of 50g, 6S)-cis 8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, stirring and dissolving, 10g sodium ethylate is added under stirring, be warming up to 40 DEG C, be incubated 3 hours at this temperature, be down to 25 DEG C, drip the acetic acid of 8 milliliters, stir, solution changes yellow-green colour into by orange, sodium-chlor-the sodium carbonate mixture (30g sodium-chlor+15g sodium carbonate is dissolved in the water of 300ml) adding 300ml stirs 30 minutes, leave standstill, layering, water layer discarded, organic phase less than 50 DEG C pressure reducing and steaming methylene dichloride, obtain yellow-green colour oily liquids 45.5g, be racemize cis 8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane.Yield 91%.
Claims (5)
1. a preparation method for Moses's side chain intermediate, its step:
The first step: (1R taking 1 part, 6S)-cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane, the organic solvent of 6-20 part, join in three-necked bottle, under normal temperature, add the organic alkali of 1/10-1/15 part, be warming up to 40-80 DEG C and stir insulation reaction 3-6 hour;
Second step: reaction solution is down to room temperature, adds the organic acid of 1/5-1/10 part, is stirred to color and changes green into by orange;
3rd step: take 1/2 part of sodium-chlor and 1/4 part of sodium carbonate and be dissolved in 6-10 part water and be made into sodium-chlor-sodium carbonate mixture;
4th step: sodium-chlor-sodium carbonate mixture of preparing is added drop-wise in reaction solution in 1 hour, stirs 30 minutes;
5th step: stratification, water layer discarded, organic layer decompression is sloughed solvent and is obtained highly purified racemize cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane.
2. the preparation method of Moses's side chain intermediate according to claim 1, is characterized in that: above-mentioned organic alkali can be: sodium methylate, sodium ethylate organic alkali.
3. the preparation method of Moses's side chain intermediate according to claim 1, is characterized in that: above-mentioned organic acid can be used: formic acid, acetic acid, propionic acid.
4. the preparation method of Moses's side chain intermediate according to claim 1, is characterized in that: above-mentioned organic solvent can be: benzene, toluene, methylene dichloride, ethylene dichloride organic solvent.
5. the preparation method of Moses's side chain intermediate according to claim 1, is characterized in that: chemical equation is:
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1280981A (en) * | 1999-07-06 | 2001-01-24 | 拜尔公司 | Racemization of R,S-dioxo-benzyl pyrrolopiperidine |
| CN104163821A (en) * | 2014-03-27 | 2014-11-26 | 江苏永达药业有限公司 | Diazabicyclo compound preparation method |
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- 2015-03-27 CN CN201510136753.XA patent/CN104803999A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1280981A (en) * | 1999-07-06 | 2001-01-24 | 拜尔公司 | Racemization of R,S-dioxo-benzyl pyrrolopiperidine |
| CN104163821A (en) * | 2014-03-27 | 2014-11-26 | 江苏永达药业有限公司 | Diazabicyclo compound preparation method |
Non-Patent Citations (2)
| Title |
|---|
| JIGAR BHAVSAR ET AL.: "Racemisation of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane using halogenated solvent in basic medium", 《ORIENTAL JOURNAL OF CHEMISTRY》, vol. 29, no. 1, 13 March 2013 (2013-03-13), pages 241 - 246 * |
| MARCO PALLAVICINI ET AL.: "Highly efficient racemisation of a key intermediate of the antibiotic moxifloxacin", 《TETRAHEDRON: ASYMMETRY》, vol. 22, no. 4, 14 March 2011 (2011-03-14), pages 379 - 380, XP028189166, DOI: doi:10.1016/j.tetasy.2011.02.007 * |
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Application publication date: 20150729 |