CN104230790A - Preparation method of sitafloxacin side chain intermediate - Google Patents
Preparation method of sitafloxacin side chain intermediate Download PDFInfo
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- CN104230790A CN104230790A CN201410446181.0A CN201410446181A CN104230790A CN 104230790 A CN104230790 A CN 104230790A CN 201410446181 A CN201410446181 A CN 201410446181A CN 104230790 A CN104230790 A CN 104230790A
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- C07—ORGANIC CHEMISTRY
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- 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
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- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
The invention relates to a preparation method of a sitafloxacin side chain intermediate. The preparation method comprises the following steps: synthesizing 4-methyl acetoacetate with 1,2-dibromoethane into a three-membered ring, synthesizing the three-membered ring with ammonia water into nitrogen heterocycle, synthesizing nitrogen heterocycle with R-1-phenyl ethylamine to generate chiral carbon, reducing through sodium borohydride, adding ditertbutyl dicarbonate to generate a protecting group, and finally performing carbonyl reduction to borane-dimethyl sulfide to obtain an intermediate. According to the preparation method, the atom utilization rate can be improved, the use of toxic reagents can be reduced, and the amplification of the technology can be facilitated.
Description
[technical field]
The present invention relates to biological pharmacy technical field, particularly a kind of simple environmental protection and the technique Sitafloxacin side chain Intermediate Preparation method of easily amplifying.
[background technology]
Sitafloxacin (sitafloxacin hydrate) chemistry 7-[(7S)-7-amino-5-azaspiro [2.4] heptane-5-base] fluoro-the 1-[(1R of the chloro-6-of-8-by name, 2S)-cis-2-fluorine cyclopropyl]-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, its structure is as follows:
This compound is the broad spectrum quinolone class antimicrobial drug developed by Japanese first pharmacy Sankyo Co., Ltd, clinically uses its monohydrate.It is a kind of classes of anti-infective medication, belongs to novel mouth class quinolone antibiotic, has very strong anti-microbial activity to methicillin-resistant staphylococcus aureus, false unicellular bacterium etc.It has simultaneously good pharmacokinetic properties, can alleviate untoward reaction, and the more most of similar drugs of its antibacterial activity in vitro obviously strengthens.The anti-microbial effect of Sitafloxacin, not only has anti-microbial activity to gram-negative bacteria, and has stronger anti-microbial activity to gram positive organism, anerobe and mycoplasma, chlamydozoan etc.Its oral tablet oral absorption is good, and bioavailability is greater than most of similar drugs, and tissue distribution is wide, and the drug level in the Various Tissues outside central nervous system is all higher than serum drug level.Therefore, Sitafloxacin becomes treatment respiratory tract, the important drugs that the single or mixt bacteria such as urogenital tract, abdominal cavity and skin soft tissue infects.
This structure is made up of parent nucleus I, side chain II and side chain III, and wherein side chain II is introduced by following intermediate, and this intermediate is chiral molecules:
The synthetic route of its existing technique is as follows:
There are problems in this synthetic method:
(1) this route intermediate product is many, and preparation time is long, and atom utilization is low, and side reaction is many, and total recovery only has 8%;
(2) second step can use a large amount of bromo elements, and without bromine in intermediate, therefore reacted rear bromo element enters into waste water as the acid, difficult treatment, large to environmental influence;
The purifying of (3) the 3rd step products must adopt column chromatography method to carry out, and chromatography is the maximum bottleneck place that technique is amplified;
The LiAlH4 reagent used in (4) the 6th steps is met water and can blasting property be reacted, and amplifies to produce to have very large danger.
Therefore above defect makes, and needs a kind of new preparation method of exploitation to avoid above problem.
[summary of the invention]
Main purpose of the present invention is to provide a kind of simple environmental protection and the technique Sitafloxacin side chain Intermediate Preparation method of easily amplifying.
The present invention is achieved through the following technical solutions above-mentioned purpose: a kind of Sitafloxacin side chain Intermediate Preparation method, comprises the steps:
1. synthesis of ternary ring: the 4-chloro methyl acetoacetate of every 1kg dissolves with 5-6L acetonitrile, add proline 3 8-40g, add 1 again, 2-ethylene dibromide 1.25kg, add salt of wormwood 2.3-25kg under stirring, then reaction solution control temperature 30-36 DEG C is stirred 30-36 hour, filters, filtrate reduced in volume, to dry, obtains ternary carbon cyclic cpds A;
2. synthesis of azacyclic: obtained A is slowly added in the ammoniacal liquor of 5L concentration 25%, stirring at normal temperature 2.5-3 hour, be then warmed up to 38-40 ° of reaction 8-10 hour, then suction filtration, washing is dried, and obtains penta azacyclo compd B;
3. generate chiral carbon: be dissolved in by B in 2-2.5L toluene, add the R-1-phenyl-ethyl amine of B quality 111%, reflux water-dividing 10-12 hour under whipped state, the chipal compounds C obtained after cooling concentration;
4. reduce: by C stirring and dissolving in 2-2.5L methyl alcohol, be placed in ice bath and add the sodium borohydride of C quality 70%, reacting and be warmed up to 28-30 DEG C after 1 hour, continue reaction 5-6 hour, then slowly add saturated sodium bicarbonate solution 1L, concentrating under reduced pressure, obtain chipal compounds D;
5. protecting group is gone up: D and the tert-Butyl dicarbonate being equivalent to D quality 95% are dissolved in 2.5-3L methyl alcohol altogether, add 5%Pd/C catalyzer, drain in system with hydrogen and after air, be forced into 10 normal atmosphere, reaction 20-24 hour, then reaction solution suction filtration is concentrated into dry, obtains the chipal compounds E being with protecting group;
6. carbonyl reduction: E be dissolved in anhydrous tetrahydro furan 2.5-3L and be placed in ice bath, drip 10mol/L borane dimethylsulf iotade 370-400ml, then room temperature reaction 12-15 hour, then methyl alcohol 500ml is dripped, stir 2-2.5 hour, then be warming up to 45-50 DEG C to stir 5 hours, be evaporated to dry, obtain intermediate.
Preferably, step 1. in salt of wormwood divide 8-10 to criticize to add.
Preferably, step 4. in the method for purification of D for be dissolved in 3L water, employing extraction into ethyl acetate obtains organic phase, adds anhydrous sodium sulfate drying, is evaporated to dry, recrystallization in residue Virahol.
Preferably, step 4. described in extraction be divided into three times, each use 1L ethyl acetate, three oil phases merge and obtain organic phase.
Preferably, step 5. in the method for purification of E be by its recrystallization in ethyl acetate petroleum ether 1: 10 mixed solution.
Preferably, step 6. in the method for purification of intermediate for be dissolved in 3L water, adopt extraction into ethyl acetate to obtain organic phase, dry concentrated, the residue obtained adds 2L sherwood oil, stirring to pulp, filters, then washes with cold sherwood oil, and collection solid is dried.
Preferably, step 6. described in extraction be divided into three times, each use 1.5L ethyl acetate, three oil phases merge and obtain organic phase.
Compared with prior art, the beneficial effect of a kind of Sitafloxacin side chain of the present invention Intermediate Preparation method is:
1, hinge structure intermediate product is few, and product yield is high.
2, avoid to use and pollute larger bromine and the higher LiAlH4 of danger, environmental influence is little, and it is high that technique amplifies security.
3, purifying all can adopt recrystallization, avoids using this method of purification being difficult to amplify of chromatography.
[embodiment]
A kind of Sitafloxacin side chain Intermediate Preparation method, comprises the steps:
1. synthesis of ternary ring: the 4-chloro methyl acetoacetate of every 1kg dissolves with 5-6L acetonitrile, add proline 3 8-40g, add 1 again, 2-ethylene dibromide 1.25kg, add salt of wormwood 2.3-2.5kg under stirring, then reaction solution control temperature 30-36 DEG C is stirred 30-36 hour, filters, filtrate reduced in volume, to dry, obtains ternary carbon cyclic cpds A;
2. synthesis of azacyclic: obtained A is slowly added in the ammoniacal liquor of 5L concentration 25%, stirring at normal temperature 2.5-3 hour, be then warmed up to 38-40 ° of reaction 8-10 hour, then suction filtration, washing is dried, and obtains penta azacyclo compd B;
3. generate chiral carbon: be dissolved in by B in 2-2.5L toluene, add the R-1-phenyl-ethyl amine of B quality 111%, reflux water-dividing 10-12 hour under whipped state, the chipal compounds C obtained after cooling concentration;
4. reduce: by C stirring and dissolving in 2-2.5L methyl alcohol, be placed in ice bath and add the sodium borohydride of C quality 70%, reacting and be warmed up to 28-30 DEG C after 1 hour, continue reaction 5-6 hour, then slowly add saturated sodium bicarbonate solution 1L, concentrating under reduced pressure, obtain chipal compounds D;
5. protecting group is gone up: D and the tert-Butyl dicarbonate being equivalent to D quality 95% are dissolved in 2.5-3L methyl alcohol altogether, add 5%Pd/C catalyzer, drain in system with hydrogen and after air, be forced into 10 normal atmosphere, reaction 20-24 hour, then reaction solution suction filtration is concentrated into dry, obtains the chipal compounds E being with protecting group;
6. carbonyl reduction: E be dissolved in anhydrous tetrahydro furan 2.5-3L and be placed in ice bath, drip 10mol/L borane dimethylsulf iotade 370-400ml, then room temperature reaction 12-15 hour, then methyl alcohol 500ml is dripped, stir 2-2.5 hour, then be warming up to 45-50 DEG C to stir 5 hours, be evaporated to dry, obtain intermediate.
Below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1:
1. dissolved by 1kg 4-chloro methyl acetoacetate 6L acetonitrile, add proline 3 8g and glycol dibromide 1.25kg, stir lower point and add 2.3kg salt of wormwood altogether 10 times, then reaction solution stirs 36 hours at 35 DEG C.Filter, filtrate reduced in volume, obtains colorless oil ternary carbon cyclic cpds A.
2. above A is continued to join in the ammoniacal liquor of 5L concentration 25%, stir 3 hours, be then warming up to 40 DEG C, continue reaction 10 hours.Suction filtration, solid is washed, and dries, obtains 300g white solid powder shape penta azacyclo compd B.
3. above powder B 2L toluene is dissolved, then add R-1-phenyl-ethyl amine 333g, under stirring, reflux water-dividing 10 hours.Cooling, concentrating under reduced pressure is done, and obtains solid chiral Compound C.
4. above solid C is added 2L dissolve with methanol, under stirring, until completely dissolved system is placed in ice bath, under continuing stirring, slowly add sodium borohydride 209g.Keep ice bath temperature 1 hour, be then slowly warming up to 30 DEG C, and this thermotonus 5 hours.Slowly add saturated sodium bicarbonate aqueous solution 1L, then concentrating under reduced pressure, add 3L water, extraction into ethyl acetate (1L × 3), merges organic phase, with anhydrous sodium sulfate drying, concentrating under reduced pressure is done, and recrystallization in residue Virahol, obtains 430g white solid state chipal compounds D.
5. above solid D and tert-Butyl dicarbonate 408g is added 3L methyl alcohol, be stirred to and dissolve completely, add 21g 5%Pd/C, after 4 times being replaced repeatedly to the air in system with hydrogen, be forced into 10 normal atmosphere, react 24 hours under nitrogen atmosphere.Suction filtration, concentrated dry, residue is dissolved in recrystallization in ethyl acetate petroleum ether mixed solution (1: 10), obtains the chipal compounds E of the solid-state band protecting group of 338g off-white color.
6. above solid E is dissolved in 2.5L anhydrous tetrahydro furan; under nitrogen protection; reaction system is placed in ice bath; drip 10mol/L borane dimethylsulf iotade 370ml, after dripping off, slowly rise to room temperature; react 15 hours; slowly drip methyl alcohol 500ml again, stir 2 hours, be then slowly warming up to 50 DEG C and stir 5 hours.Concentrating under reduced pressure is done, and adds 3L water, extraction into ethyl acetate (1.5L × 3), merges organic phase, dry, concentrated.Sherwood oil 2L is added, stirring to pulp in residue.Filter, the cold sherwood oil of solid is washed, and collects solid and dries, obtain intermediate 253g.
Embodiment 2:
1. dissolved by 10kg 4-chloro methyl acetoacetate 50L acetonitrile, add proline-4 00g and glycol dibromide 12.5kg, stir lower point and add 24kg salt of wormwood altogether 9 times, then reaction solution stirs 36 hours at 30 DEG C.Filter, filtrate reduced in volume, obtains colorless oil ternary carbon cyclic cpds A.
2. above ternary carbon cyclic cpds is continued to join in the ammoniacal liquor of 5L concentration 25%, stir 2.5 hours, be then warming up to 38 DEG C, continue reaction 8 hours.Suction filtration, solid is washed, and dries, obtains 3078g white solid powder shape penta azacyclo compd B.
3. above powder B 25L toluene is dissolved, then add R-1-phenyl-ethyl amine 3.4kg, under stirring, reflux water-dividing 12 hours.Cooling, concentrating under reduced pressure is done, and obtains solid chiral Compound C.
4. above solid C is added 25L dissolve with methanol, under stirring, until completely dissolved system is placed in ice bath, under continuing stirring, slowly add sodium borohydride 2120g.Keep ice bath temperature 1 hour, be then slowly warming up to 28 DEG C, and this thermotonus 6 hours.Slowly add saturated sodium bicarbonate aqueous solution 10L, then concentrating under reduced pressure, add 25L water, extraction into ethyl acetate (10L × 3), merges organic phase, with anhydrous sodium sulfate drying, concentrating under reduced pressure is done, and recrystallization in residue Virahol, obtains 4323g white solid state chipal compounds D.
5. above solid D and tert-Butyl dicarbonate 4.1kg is added 25L methyl alcohol, be stirred to and dissolve completely, add 220g 5%Pd/C, after 4 times being replaced repeatedly to the air in system with hydrogen, be forced into 10 normal atmosphere, react 20 hours under nitrogen atmosphere.Suction filtration, concentrated dry, residue is dissolved in recrystallization in ethyl acetate petroleum ether mixed solution (1: 10), obtains the chipal compounds E of the solid-state band protecting group of 3380g off-white color.
6. above solid E is dissolved in 25L anhydrous tetrahydro furan; under nitrogen protection; reaction system is placed in ice bath; drip 10mol/L borane dimethylsulf iotade 4L, after dripping off, slowly rise to room temperature; react 12 hours; slowly drip methyl alcohol 5L again, stir 2.5 hours, be then slowly warming up to 45 DEG C and stir 5 hours.Concentrating under reduced pressure is done, and adds 30L water, extraction into ethyl acetate (15L × 3), merges organic phase, dry, concentrated.Sherwood oil 20L is added, stirring to pulp in residue.Filter, the cold sherwood oil of solid is washed, and collects solid and dries, obtain intermediate 2550g.
Embodiment 3:
1. dissolved by 100kg 4-chloro methyl acetoacetate 550L acetonitrile, add lower point of proline 3 .9kg and glycol dibromide 125kg stirring and add 250kg salt of wormwood altogether 8 times, then reaction solution 36 DEG C stirs 36 hours.Filter, filtrate reduced in volume, obtains colorless oil ternary carbon cyclic cpds A.
2. above ternary carbon cyclic cpds is continued to join in the ammoniacal liquor of 500L concentration 25%, stir 3 hours, be then warming up to 39 DEG C, continue reaction 9 hours.Suction filtration, solid is washed, and dries, obtains 30.4kg white solid powder shape penta azacyclo compd B.
3. above powder B 200L toluene is dissolved, then add R-1-phenyl-ethyl amine 33.7kg, under stirring, reflux water-dividing 9 hours.Cooling, concentrating under reduced pressure is done, and obtains solid chiral Compound C.
4. above solid C is added 200L dissolve with methanol, under stirring, until completely dissolved system is placed in ice bath, under continuing stirring, slowly add sodium borohydride 20.5kg.Keep ice bath temperature 1 hour, be then slowly warming up to 29 DEG C, and this thermotonus 5.5 hours.Slowly add saturated sodium bicarbonate aqueous solution 100L, then concentrating under reduced pressure, add 300L water, extraction into ethyl acetate (100L × 3), merges organic phase, with anhydrous sodium sulfate drying, concentrating under reduced pressure is done, and recrystallization in residue Virahol, obtains 42.5kg white solid state chipal compounds D.
5. above solid D and tert-Butyl dicarbonate 40kg is added 300L methyl alcohol, be stirred to and dissolve completely, add 2kg 5%Pd/C, after 4 times being replaced repeatedly to the air in system with hydrogen, be forced into 10 normal atmosphere, react 21 hours under nitrogen atmosphere.Suction filtration, concentrated dry, residue is dissolved in recrystallization in ethyl acetate petroleum ether mixed solution (1: 10), obtains the chipal compounds E of the solid-state band protecting group of 33.4kg off-white color.
6. above solid E is dissolved in 250L anhydrous tetrahydro furan; under nitrogen protection; reaction system is placed in ice bath; drip 10mol/L borane dimethylsulf iotade 38L, after dripping off, slowly rise to room temperature; react 14 hours; slowly drip methyl alcohol 50L again, stir 2 hours, be then slowly warming up to 48 DEG C and stir 5 hours.Concentrating under reduced pressure is done, and adds 300L water, extraction into ethyl acetate (150L × 3), merges organic phase, dry, concentrated.Sherwood oil 200L is added, stirring to pulp in residue.Filter, the cold sherwood oil of solid is washed, and collects solid and dries, obtain intermediate 24.8kg.
The Sitafloxacin side chain intermediate yield prepared by this technique can reach about 20%, far above 8% yield of prior art; Intermediate product in this technique has 5, is less than 7 of prior art; Avoid the reagent producing a large amount of acid waste water and use high risk; Purifying many employings recrystallization method, technique is amplified easily.
Above-described is only some embodiments of the present invention.For the person of ordinary skill of the art, without departing from the concept of the premise of the invention, can also make some distortion and improvement, these all belong to protection scope of the present invention.
Claims (7)
1. a Sitafloxacin side chain Intermediate Preparation method, is characterized in that comprising the steps:
1. synthesis of ternary ring: the 4-chloro methyl acetoacetate of every 1kg dissolves with 5-6L acetonitrile, add proline 3 8-40g, add 1 again, 2-ethylene dibromide 1.25kg, add salt of wormwood 2.3-2.5kg under stirring, then reaction solution control temperature 30-36 DEG C is stirred 30-36 hour, filters, filtrate reduced in volume, to dry, obtains ternary carbon cyclic cpds A;
2. synthesis of azacyclic: obtained A is slowly added in the ammoniacal liquor of 5L concentration 25%, stirring at normal temperature 2.5-3 hour, be then warmed up to 38-40 ° of reaction 8-10 hour, then suction filtration, washing is dried, and obtains penta azacyclo compd B;
3. generate chiral carbon: be dissolved in by B in 2-2.5L toluene, add the R-1-phenyl-ethyl amine of B quality 111%, reflux water-dividing 10-12 hour under whipped state, the chipal compounds C obtained after cooling concentration;
4. reduce: by C stirring and dissolving in 2-2.5L methyl alcohol, be placed in ice bath and add the sodium borohydride of C quality 70%, reacting and be warmed up to 28-30 DEG C after 1 hour, continue reaction 5-6 hour, then slowly add saturated sodium bicarbonate solution 1L, concentrating under reduced pressure, obtain chipal compounds D;
5. protecting group is gone up: D and the tert-Butyl dicarbonate being equivalent to D quality 95% are dissolved in 2.5-3L methyl alcohol altogether, add 5%Pd/C catalyzer, drain in system with hydrogen and after air, be forced into 10 normal atmosphere, reaction 20-24 hour, then reaction solution suction filtration is concentrated into dry, obtains the chipal compounds E being with protecting group;
6. carbonyl reduction: E be dissolved in anhydrous tetrahydro furan 2.5-3L and be placed in ice bath, drip 10mol/L borane dimethylsulf iotade 370-400ml, then room temperature reaction 12-15 hour, then methyl alcohol 500ml is dripped, stir 2-2.5 hour, then be warming up to 45-50 DEG C to stir 5 hours, be evaporated to dry, obtain intermediate.
2. Sitafloxacin side chain Intermediate Preparation method according to claim 1, is characterized in that: step 1. in salt of wormwood divide 8-10 to criticize to add.
3. Sitafloxacin side chain Intermediate Preparation method according to claim 1, it is characterized in that: step 4. in the method for purification of D for be dissolved in 3L water, employing extraction into ethyl acetate obtains organic phase, adds anhydrous sodium sulfate drying, be evaporated to dry, recrystallization in residue Virahol.
4. Sitafloxacin side chain Intermediate Preparation method according to claim 3, is characterized in that: step 4. described in extraction be divided into three times, each use 1.5L ethyl acetate, three oil phases merge and obtain organic phase.
5. Sitafloxacin side chain Intermediate Preparation method according to claim 1, is characterized in that: step 5. in the method for purification of E for by its recrystallization in ethyl acetate petroleum ether 1: 10 mixed solution.
6. Sitafloxacin side chain Intermediate Preparation method according to claim 1, it is characterized in that: step 6. in the method for purification of intermediate for be dissolved in 3L water, extraction into ethyl acetate is adopted to obtain organic phase, dry concentrated, the residue obtained adds 2L sherwood oil, stirring to pulp, filters, wash with cold sherwood oil again, collect remaining solid and dry.
7. Sitafloxacin side chain Intermediate Preparation method according to claim 6, is characterized in that: step 6. described in extraction be divided into three times, each use 1L ethyl acetate, three oil phases merge and obtain organic phase.
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Cited By (2)
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| CN109232530A (en) * | 2018-10-25 | 2019-01-18 | 苏州东瑞制药有限公司 | A kind of sitafloxacin preparation method |
| US10358417B2 (en) | 2016-05-06 | 2019-07-23 | Chen-Stone (Guangzhou) Co., Ltd. | Method for preparing efficiently synthetic sitafloxacin intermediate (7S)-5-azaspiro[2.4]heptane-7-yl tert-butyl carbamate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US10358417B2 (en) | 2016-05-06 | 2019-07-23 | Chen-Stone (Guangzhou) Co., Ltd. | Method for preparing efficiently synthetic sitafloxacin intermediate (7S)-5-azaspiro[2.4]heptane-7-yl tert-butyl carbamate |
| CN109232530A (en) * | 2018-10-25 | 2019-01-18 | 苏州东瑞制药有限公司 | A kind of sitafloxacin preparation method |
| CN109232530B (en) * | 2018-10-25 | 2020-05-22 | 苏州东瑞制药有限公司 | Preparation method of sitafloxacin hydrate |
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