CN105777750A - Synthesis method for moxifloxacin side chain - Google Patents
Synthesis method for moxifloxacin side chain Download PDFInfo
- Publication number
- CN105777750A CN105777750A CN201610226627.8A CN201610226627A CN105777750A CN 105777750 A CN105777750 A CN 105777750A CN 201610226627 A CN201610226627 A CN 201610226627A CN 105777750 A CN105777750 A CN 105777750A
- Authority
- CN
- China
- Prior art keywords
- hours
- cooled
- toluene
- temperature
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a synthesis method for a moxifloxacin side chain.With 2,3-dipicolinic acid being a raw material, cyclization, catalytic hydrogenation, resolution and racemization are performed, and then chemical reduction and debenzylation are performed to obtain moxifloxacin side chain.Resolution, racemization and chemical reduction are performed in sequence, sodium borohydride is used for replacing high-risk lithium aluminum hydride to synthesize the moxifloxacin side chain, and the synthesis method has the advantages that industrial waste materials are reduced, the production cost is lowered, and productivity is increased.
Description
Technical field
The present invention relates to antimicrobial drug technical field, the synthetic method of a kind of moxifloxacin side chain.
Background technology
Moxifloxacin hydrochloride is the Comprecin of the novel 8 one methoxy fluoroquinolone class forth generation antimicrobial drug synthetic of Bayer company of Germany research and development, it it is the synthetic antibacterial drug that a class is newer, have that antibiotic property is strong, has a broad antifungal spectrum, be not likely to produce drug resistance and to common fastbacteria effectively, the advantage such as long half time, untoward reaction be few. Moxifloxacin dosage form is more, market consumption is big, has a extensive future.Synthesis difficult point is that moxifloxacin side chain synthesis technique is complicated now, and the conventional synthetic route of prior art is first to carry out electronation, then splits, and the yield obtaining moxifloxacin side chain is less than 45%, and operating procedure is many, and cost is high, and environmental pollution is serious.
Therefore, the synthetic method how providing a kind of moxifloxacin side chain having and reducing industrial waste, reduction production cost, raising productivity ratio feature is the problem that those skilled in the art need solution badly.
Summary of the invention
In view of this, the invention provides a kind of synthetic method having and reducing industrial waste, reduce the moxifloxacin side chain of production cost, raising productivity ratio feature.
For achieving the above object, the present invention provides following technical scheme:
The synthetic method of a kind of moxifloxacin side chain, it is characterised in that including: with 2,3-dipicolinic acid is raw material, and by cyclization, catalytic hydrogenation, fractionation, racemization, electronation, debenzylation obtains moxifloxacin side chain, and concrete synthetic method is:
S1, cyclization:
null120g2 is added in flask，3-dipicolinic acid，110g acetic anhydride，Agitating heating heats up，Solid gradually dissolves，As Nei Wenda 92 DEG C，Solid all dissolves，Control temperature 92～95 DEG C reaction 2～3 hours to 2，3-dipicolinic acid≤0.1%，Reaction is finished，It is cooled to 50～60 DEG C，Evaporated under reduced pressure，It is warming up to 80～85 DEG C，Continue decompression to steam to without flowing out，It is cooled to 50～60 DEG C，Add toluene 40g，Stirring heats up，Decompression steams toluene to dry，Carry out once with said method with 40g toluene again，Steamed，Add toluene 169g，It is heated to 40～50 DEG C to stir，It is cooled to 30～40 DEG C and is slowly added dropwise benzylamine 92.3g，Dropping process control temp is less than 55 DEG C，Within 2 hours, drip off，3～4 hours are reacted to 2 at a temperature of 40～50 DEG C，3-dipicolinic acid acid anhydride≤0.1%，Reaction is finished，Heating in water bath，Control 85 DEG C of evaporated under reduced pressure of outer temperature，Residue adds 110g acetic anhydride，Agitating heating heats up，Control temperature 92～95 DEG C reaction 1～2 hour to there being solid to separate out，Continue stirring and react 1～2 hour to ring-opening product≤0.1%，Reaction is finished，It is cooled to 50～60 DEG C of evaporated under reduced pressure，It is warming up to 80～85 DEG C，Continue decompression to steam to without flowing out，Temperature is down to room temperature，Add 200mL95% ethanol，It is cooled to 0 DEG C stir 5 hours，Filter，Filter cake washs three times with the 95% ethanol 28mLx3 being cooled to 5 DEG C，Drain，It is vacuum dried to obtain off-white color solid 6-benzyl-pyrrole also [3，4-b] pyridine-5，7-diketone 150g.
S2, catalytic hydrogenation:
nullToluene 400mL is added in autoclave，Aminate 100g，10%Pd/C5g，Nitrogen is forced into 5kg/cm2，Keep 30 minutes，Detection autoclave air-tightness is good，Nitrogen is replaced 3 times，Hydrogen exchange 3 times，Stirring is started with 200rpm，By pressurized with hydrogen to 20kg/cm2，Close hydrogen，It is warming up to 90 DEG C，Hydrogen is mended to 30kg/cm2 after temperature stabilization，Stirring is hydrogenated to pressure and is down to 20～25kg/cm2，Then hydrogen is mended to 35～40kg/cm2，Continue to mend hydrogen to not inhaling hydrogen，Continue to stir 2 hours at 87～93 DEG C，Hydrogenation is finished，It is cooled to 20～25 DEG C，Nitrogen filter pressing，5g toluene rinsing Pd/C is once，Pd/C recovery，Filtrate heating in water bath，Recovered under reduced pressure toluene is to dry，It is cooled to room temperature，Add isopropanol 200L，It is heated to 50～60 DEG C of stirrings molten clearly，It is cooled to-5～0 DEG C crystallize 6 hours，Filter，Filter cake cold isopropanol 10gx2 rinses 2 times，Drain，It is vacuum dried to obtain hydride 6-benzyl-hexahydro-pyrrolo-[3，4.b] pyridine-5，7-diketone 82～87g.
S3, fractionation, racemization:
A, 620g purified water is added in reaction bulb, 22.1gD-(-)-tartaric acid, stirring temperature control 19～21 DEG C molten clearly, add size-reduced hydride 80g, stir molten clearly, temperature control 19～21 DEG C be incorporated in 11.3gD-(-)-tartaric acid is dissolved in the solution of 20g purified water, solution temperature 25～30 DEG C, finish, stir 30 seconds, system is as still clarified, add a small amount of crystal seed, stir 3 times, stand crystallize 3 hours, crystallize is finished, it is slowly stirred crystallize, within 2～3 hours, it is cooled to 8 DEG C, keep 7～9 DEG C and be slowly stirred 2 hours, filter, by 20gx3 dichloromethane 3 times, drain to obtain tartrate；
B, merge above-mentioned filtrate and washing liquid, the lower 26.8g solid sodium bicarbonate that adds of stirring dissociates, and adjusts pH value 7～8, tune to finish, stratification, water layer dichloromethane 40gx3 extracts, and merges organic layer, and anhydrous sodium sulfate 8g is dried 5 hours, filter, filtrate decompression is evaporated, and obtains 48g and reclaims solid, for racemization；
C, being put in 50g water by above-mentioned tartrate, the lower 14.5g saturated sodium bicarbonate aqueous solution that adds of stirring dissociates, and adjusts pH value 7～8, adjusts and finish, extracting with dichloromethane 40gx4, merge organic layer, anhydrous sodium sulfate 5.5g is dried 5 hours, filtering, filtrate decompression is evaporated, and must split thing 26.5～28g；
D, reclaim solid 76g by above-mentioned two batches and put in toluene 167g, add 1,8-diazabicylo 11 carbon-7-alkene 9g agitating heating is dissolved, and is warming up to 105 DEG C and refluxes 9 hours, and racemization is finished, it is cooled to room temperature, washing with water 70gx4, to certain alkali 1,8-diazabicylo 11 carbon-7-alkene is washed to the greatest extent, organic layer heating in water bath, recovered under reduced pressure toluene, to dry, be cooled to room temperature, add isopropanol 126g, it is heated to 50～60 DEG C of stirrings molten clearly, being cooled to-5～0 DEG C crystallize 3 hours, filter, filter cake cold isopropanol 20gx2 rinses, drain, be vacuum dried to obtain hydride 48～54g.
S4, electronation:
E, under nitrogen protection, glycol dimethyl ether 74g is added in reaction bulb, stirring is cooled to-5 DEG C, add sodium borohydride 10.5g the most altogether, control temperature less than 10 DEG C, finish, stirring is cooled to 0 DEG C, add aluminum trichloride (anhydrous) 12.0g the most altogether to finish, it is cooled to-5 DEG C, dropping splits thing solution, control temperature less than 10 DEG C, within 2～3 hours, add, finish, it is to slowly warm up to be stirred at room temperature 2 hours, it is to slowly warm up to 50 DEG C and is incubated 2 hours, 85 DEG C it are warming up to after Wen Ding, reflux 5 hours, backflow is finished, normal pressure steams glycol dimethyl ether, decompression distillation is to dry, it is cooled to room temperature, add 30g toluene and stir standby；
nullf、40.5g concentrated hydrochloric acid and 68g pure water is added in reaction bulb，It is cooled to-5 DEG C，Drip above-mentioned toluene liquid，Control temperature less than 10 DEG C，Within 1～2 hour, add，Finish，It is warming up to be stirred at room temperature 2 hours，Insulation is finished，It is warming up to 50 DEG C and is incubated 0.5 hour，90 DEG C it are warming up to after Wen Ding，Stir 1～2 hour to clarification，Clarify latter 90 DEG C to stir 2 hours，It is cooled to room temperature，Stratification，Water layer toluene 10gx2 extracts，Toluene layer goes to reclaim toluene，Water layer is cooled to-5 DEG C，With sheet adjusting PH with base 14，Temperature is less than 10 DEG C，Adjust and finish，Extract with toluene 21gx4，Combining methylbenzene layer，4g anhydrous sodium sulfate is dried 5 hours，Filter，Evaporated under reduced pressure obtains pale yellow oil (s，S)-6-benzyl-hexahydro-pyrrolo-[3，4.b] pyridine-5，7-diketone 13.5g.
S5, debenzylation:
nullTo above-mentioned (s，S)-6-benzyl-hexahydro-pyrrolo-[3，4.b] pyridine-5，7-diketone 13.5g adds methanol 100mL stirring and dissolving，Put in autoclave，Add 10%Pd/C 2.5kg，Nitrogen is forced into 5kg/cm2，Keep 30 minutes，Detection autoclave does not leaks，Nitrogen is replaced 3 times，Hydrogen exchange 3 times，Stirring is started with 200rpm，By pressurized with hydrogen to 20kg/cm2，Close hydrogen，It is warming up to 90 DEG C，Hydrogen is mended to 90kg/cm2 after temperature stabilization，Stirring hydrogenation，Mend hydrogen to not inhaling hydrogen，Continue to stir 2 hours at 87～93 DEG C，Hydrogenation is finished，It is cooled to 20～25 DEG C，Sucking filtration，5g methanol rinse Pd/C is once，Pd/C recovery，Filtrate heating in water bath，Evaporated under reduced pressure，Residue is dissolved in water 50mL，Extract with hexamethylene 50mLx3，Merge that hexamethylene layer water 60mLx3 is counter carries，Combining water layer，Add NaOH4.5g，Extract with chloroform 60mLx3，Combined chloroform layer anhydrous sodium sulfate is dried，After filtration, filtrate decompression is evaporated，Obtain light yellow mucus (s，S)-6-benzyl-octahydro-pyrrolo-[3，4-b] pyridine 7g.
Understand via above-mentioned technical scheme, compared with prior art, the present invention is by with 2,3-dipicolinic acid is raw material, by cyclization, catalytic hydrogenation, fractionation, racemization, electronation, debenzylation obtains moxifloxacin side chain, and synthetic method has and decreases industrial waste, reduces production cost, puies forward large-duty feature.
Detailed description of the invention
It is presented herein below and the technical scheme in the embodiment of the present invention is clearly and completely described, it is clear that described embodiment is only a part of embodiment of the present invention rather than whole embodiments.Based on the embodiment in the present invention, the every other embodiment that those of ordinary skill in the art are obtained under not making creative work premise, broadly fall into the scope of protection of the invention.
The embodiment of the invention discloses the synthetic method of the moxifloxacin side chain that a kind of industrial waste is few, production cost is low, productivity ratio is high, with 2,3-dipicolinic acid is raw material, by cyclization, catalytic hydrogenation, fractionation, racemization, electronation, debenzylation obtains moxifloxacin side chain, and concrete synthetic method is:
S1, cyclization:
null120g2 is added in flask，3-dipicolinic acid，110g acetic anhydride，Agitating heating heats up，Solid gradually dissolves，As Nei Wenda 92 DEG C，Solid all dissolves，Control temperature 92～95 DEG C reaction 2～3 hours to 2，3-dipicolinic acid≤0.1%，Reaction is finished，It is cooled to 50～60 DEG C，Evaporated under reduced pressure，It is warming up to 80～85 DEG C，Continue decompression to steam to without flowing out，It is cooled to 50～60 DEG C，Add toluene 40g，Stirring heats up，Decompression steams toluene to dry，Carry out once with said method with 40g toluene again，Steamed，Add toluene 169g，It is heated to 40～50 DEG C to stir，It is cooled to 30～40 DEG C and is slowly added dropwise benzylamine 92.3g，Dropping process control temp is less than 55 DEG C，Within 2 hours, drip off，3～4 hours are reacted to 2 at a temperature of 40～50 DEG C，3-dipicolinic acid acid anhydride≤0.1%，Reaction is finished，Heating in water bath，Control 85 DEG C of evaporated under reduced pressure of outer temperature，Residue adds 110g acetic anhydride，Agitating heating heats up，Control temperature 92～95 DEG C reaction 1～2 hour to there being solid to separate out，Continue stirring and react 1～2 hour to ring-opening product≤0.1%，Reaction is finished，It is cooled to 50～60 DEG C of evaporated under reduced pressure，It is warming up to 80～85 DEG C，Continue decompression to steam to without flowing out，Temperature is down to room temperature，Add 200mL95% ethanol，It is cooled to 0 DEG C stir 5 hours，Filter，Filter cake washs three times with the 95% ethanol 28mLx3 being cooled to 5 DEG C，Drain，It is vacuum dried to obtain off-white color solid 6-benzyl-pyrrole also [3，4-b] pyridine-5，7-diketone 150g，Yield 88～90%，Mp163～165 DEG C，Content >=97%.
S2, catalytic hydrogenation:
nullToluene 400mL is added in autoclave，Aminate 100g，10%Pd/C5g，Nitrogen is forced into 5kg/cm2，Keep 30 minutes，Detection autoclave air-tightness is good，Nitrogen is replaced 3 times，Hydrogen exchange 3 times，Stirring is started with 200rpm，By pressurized with hydrogen to 20kg/cm2，Close hydrogen，It is warming up to 90 DEG C，Hydrogen is mended to 30kg/cm2 after temperature stabilization，Stirring is hydrogenated to pressure and is down to 20～25kg/cm2，Then hydrogen is mended to 35～40kg/cm2，Continue to mend hydrogen to not inhaling hydrogen，Continue to stir 2 hours at 87～93 DEG C，Hydrogenation is finished，It is cooled to 20～25 DEG C，Nitrogen filter pressing，5g toluene rinsing Pd/C is once，Pd/C recovery，Filtrate heating in water bath，Recovered under reduced pressure toluene is to dry，It is cooled to room temperature，Add isopropanol 200L，It is heated to 50～60 DEG C of stirrings molten clearly，It is cooled to-5～0 DEG C crystallize 6 hours，Filter，Filter cake cold isopropanol 10gx2 rinses 2 times，Drain，It is vacuum dried to obtain hydride 6-benzyl-hexahydro-pyrrolo-[3，4.b] pyridine-5，7-diketone 82～87g，Yield 80～85%，Mp60～62 DEG C，Purity >=98%.
Isopropanol mother solution recovered under reduced pressure isopropanol, residue adds 2 times amount isopropanols can obtain part hydride with method crystallization.
S3, fractionation, racemization:
A, 620g purified water is added in reaction bulb, 22.1gD-(-)-tartaric acid, stirring temperature control 19～21 DEG C molten clearly, add size-reduced hydride 80g, stir molten clearly, temperature control 19～21 DEG C be incorporated in 11.3gD-(-)-tartaric acid is dissolved in the solution of 20g purified water, solution temperature 25～30 DEG C, finish, stir 30 seconds, system is as still clarified, add a small amount of crystal seed, stir 3 times, stand crystallize 3 hours, crystallize is finished, it is slowly stirred crystallize, within 2～3 hours, it is cooled to 8 DEG C, keep 7～9 DEG C and be slowly stirred 2 hours, filter, by 20gx3 dichloromethane 3 times, drain to obtain tartrate；
B, merging above-mentioned filtrate and washing liquid, the lower 26.8g solid sodium bicarbonate that adds of stirring dissociates, and adjusts pH value 7～8, adjust and finish, stratification, water layer dichloromethane 40gx3 extracts, merge organic layer, anhydrous sodium sulfate 8g is dried 5 hours, filters, and filtrate decompression is evaporated, obtain 48g and reclaim solid, the response rate 60%, purity >=99%, for racemization；
C, above-mentioned tartrate is put in 50g water, the lower 14.5g saturated sodium bicarbonate aqueous solution that adds of stirring dissociates, and adjusts pH value 7～8, tune to finish, extract with dichloromethane 40gx4, merging organic layer, anhydrous sodium sulfate 5.5g is dried 5 hours, filters, filtrate decompression is evaporated, thing 26.5～28g, yield 33～35%, purity >=98% must be split；
D, reclaim solid 76g by above-mentioned two batches and put in toluene 167g, add 1,8-diazabicylo 11 carbon-7-alkene 9g agitating heating is dissolved, and is warming up to 105 DEG C and refluxes 9 hours, and racemization is finished, it is cooled to room temperature, washing with water 70gx4, to 1,8-diazabicylo 11 carbon-7-alkene is washed to the greatest extent, organic layer heating in water bath, recovered under reduced pressure toluene, to dry, be cooled to room temperature, add isopropanol 126g, it is heated to 50～60 DEG C of stirrings molten clearly, being cooled to-5～0 DEG C crystallize 3 hours, filter, filter cake cold isopropanol 20gx2 rinses, drain, be vacuum dried to obtain hydride 48～54g.Purity >=99%, mother solution recovered under reduced pressure isopropanol is to dry, and residue can continue purification with isopropanol.
S4, electronation:
E, under nitrogen protection, glycol dimethyl ether 74g is added in reaction bulb, stirring is cooled to-5 DEG C, add sodium borohydride 10.5g the most altogether, control temperature less than 10 DEG C, finish, stirring is cooled to 0 DEG C, add aluminum trichloride (anhydrous) 12.0g the most altogether to finish, it is cooled to-5 DEG C, dropping splits thing solution, control temperature less than 10 DEG C, within 2～3 hours, add, finish, it is to slowly warm up to be stirred at room temperature 2 hours, it is to slowly warm up to 50 DEG C and is incubated 2 hours, 85 DEG C it are warming up to after Wen Ding, reflux 5 hours, backflow is finished, normal pressure steams glycol dimethyl ether, decompression distillation is to dry, it is cooled to room temperature, add 30g toluene and stir standby；
nullf、40.5g concentrated hydrochloric acid and 68g pure water is added in reaction bulb，It is cooled to-5 DEG C，Drip above-mentioned toluene liquid，Control temperature less than 10 DEG C，Within 1～2 hour, add，Finish，It is warming up to be stirred at room temperature 2 hours，Insulation is finished，It is warming up to 50 DEG C and is incubated 0.5 hour，90 DEG C it are warming up to after Wen Ding，Stir 1～2 hour to clarification，Clarify latter 90 DEG C to stir 2 hours，It is cooled to room temperature，Stratification，Water layer toluene 10gx2 extracts，Toluene layer goes to reclaim toluene，Water layer is cooled to-5 DEG C，With sheet adjusting PH with base 14，Temperature is less than 10 DEG C，Adjust and finish，Extract with toluene 21gx4，Combining methylbenzene layer，4g anhydrous sodium sulfate is dried 5 hours，Filter，Evaporated under reduced pressure obtains pale yellow oil (s，S)-6-benzyl-hexahydro-pyrrolo-[3，4.b] pyridine-5，7-diketone 13.5g，Yield 90%，Purity >=98.3%，Chirality 98.7%.
S5, debenzylation:
nullTo above-mentioned (s，S)-6-benzyl-hexahydro-pyrrolo-[3，4.b] pyridine-5，7-diketone 13.5g adds methanol 100mL stirring and dissolving，Put in autoclave，Add 10%Pd/C 2.5kg，Nitrogen is forced into 5kg/cm2，Keep 30 minutes，Detection autoclave does not leaks，Nitrogen is replaced 3 times，Hydrogen exchange 3 times，Stirring is started with 200rpm，By pressurized with hydrogen to 20kg/cm2，Close hydrogen，It is warming up to 90 DEG C，Hydrogen is mended to 90kg/cm2 after temperature stabilization，Stirring hydrogenation，Mend hydrogen to not inhaling hydrogen，Continue to stir 2 hours at 87～93 DEG C，Hydrogenation is finished，It is cooled to 20～25 DEG C，Sucking filtration，5g methanol rinse Pd/C is once，Pd/C recovery，Filtrate heating in water bath，Evaporated under reduced pressure，Residue is dissolved in water 50mL，Extract with hexamethylene 50mLx3，Merge that hexamethylene layer water 60mLx3 is counter carries，Combining water layer，Add NaOH4.5g，Extract with chloroform 60mLx3，Combined chloroform layer anhydrous sodium sulfate is dried，After filtration, filtrate decompression is evaporated，Obtain light yellow mucus (s，S)-6-benzyl-octahydro-pyrrolo-[3，4-b] pyridine 7g.
The chemical reaction process of the present invention is:
In this specification, each embodiment uses the mode gone forward one by one to describe, and what each embodiment stressed is the difference with other embodiments, and between each embodiment, identical similar portion sees mutually.For device disclosed in embodiment, owing to it corresponds to the method disclosed in Example, so describe is fairly simple, relevant part sees method part and illustrates.
Described above to the disclosed embodiments, makes professional and technical personnel in the field be capable of or uses the present invention.Multiple amendment to these embodiments will be apparent from for those skilled in the art, and generic principles defined herein can realize without departing from the spirit or scope of the present invention in other embodiments.Therefore, the present invention is not intended to be limited to the embodiments shown herein, and is to fit to the widest scope consistent with principles disclosed herein and features of novelty.
Claims (1)
1. the synthetic method of a moxifloxacin side chain, it is characterised in that including: with 2,3-dipicolinic acid is
Raw material, by cyclization, catalytic hydrogenation, fractionation, racemization, electronation, debenzylation obtains Moxifloxacin
Side chain, concrete synthetic method is:
S1, cyclization:
Adding 120g2,3-dipicolinic acid, 110g acetic anhydride in flask, agitating heating heats up, and solid is the most molten
Solve, as Nei Wenda 92 DEG C, solid all dissolves, control temperature 92～95 DEG C reaction 2～3 hours to 2,3-
Dipicolinic acid≤0.1%, reaction is complete, is cooled to 50～60 DEG C, and evaporated under reduced pressure is warming up to 80～85 DEG C,
Continuing decompression to steam to without flowing out, be cooled to 50～60 DEG C, add toluene 40g, stirring heats up, and decompression is steamed
Toluene is to dry, then carries out once with said method with 40g toluene, steamed, adds toluene 169g, heating
Stir to 40～50 DEG C, be cooled to 30～40 DEG C and be slowly added dropwise benzylamine 92.3g, drip process control
Temperature be less than 55 DEG C, within 2 hours, drip off, at a temperature of 40～50 DEG C react 3～4 hours to 2,3-pyridine
Dicarboxylic anhydride≤0.1%, reaction is complete, heating in water bath, controls 85 DEG C of evaporated under reduced pressure of outer temperature, and residue adds
110g acetic anhydride, agitating heating heat up, control temperature 92～95 DEG C reaction 1～2 hour to there being solid to separate out,
Continue stirring reaction to finish to ring-opening product≤0.1%, reaction, be cooled to 50～60 DEG C of evaporated under reduced pressure for 1～2 hour,
Being warming up to 80～85 DEG C, continue decompression and steam to without flowing out, temperature is down to room temperature, adds 200mL95% second
Alcohol, is cooled to 0 DEG C and stirs 5 hours, filter, and filter cake is washed with the 95% ethanol 28mLx3 being cooled to 5 DEG C
Wash three times, drain, be vacuum dried to obtain off-white color solid 6-benzyl-pyrrole also [3,4-b] pyridine-5,7-diketone 150g.
S2, catalytic hydrogenation:
Adding toluene 400mL in autoclave, aminate 100g, 10%Pd/C5g, nitrogen is forced into 5kg/cm2,
Keeping 30 minutes, detection autoclave air-tightness is good, and nitrogen is replaced 3 times, and hydrogen exchange 3 times, with 200rpm
Start stirring, by pressurized with hydrogen to 20kg/cm2, close hydrogen, be warming up to 90 DEG C, after temperature stabilization, mend hydrogen extremely
30kg/cm2, stirring is hydrogenated to pressure and is down to 20～25kg/cm2, then mend hydrogen to 35～40kg/cm2, continue to mend
Hydrogen, to not inhaling hydrogen, continues to stir 2 hours at 87～93 DEG C, and hydrogenation is finished, and is cooled to 20～25 DEG C,
Nitrogen filter pressing, 5g toluene rinses Pd/C once, Pd/C recovery, and filtrate heating in water bath reduces pressure back
Receive toluene the most dry, be cooled to room temperature, add isopropanol 200L, be heated to 50～60 DEG C of stirrings molten clearly, cooling
Crystallizing 6 hours to-5～0 DEG C, filter, filter cake cold isopropanol 10gx2 rinses 2 times, drains, vacuum
It is dried to obtain hydride 6-benzyl-hexahydro-pyrrolo-[3,4.b] pyridine-5,7-diketone 82～87g.
S3, fractionation, racemization:
A, in reaction bulb add 620g purified water, 22.1gD-(-)-tartaric acid, stirring temperature control 19～21 DEG C molten clearly,
Add size-reduced hydride 80g, stir molten clearly, temperature control 19～21 DEG C be incorporated in 11.3gD-(-)-tartaric acid
Being dissolved in the solution of 20g purified water, solution temperature 25～30 DEG C, finish, stir 30 seconds, system is as still
Clarification, adds a small amount of crystal seed, stirs 3 times, stands crystallize 3 hours, and crystallize is finished, and is slowly stirred crystallize,
Within 2～3 hours, it is cooled to 8 DEG C, keeps 7～9 DEG C and be slowly stirred 2 hours, filter, use 20gx3 dichloromethane
Alkane rinses 3 times, drains to obtain tartrate；
B, merging above-mentioned filtrate and washing liquid, the lower 26.8g solid sodium bicarbonate that adds of stirring dissociates, and adjusts pH
Value 7～8, adjusts and finishes, stratification, and water layer dichloromethane 40gx3 extracts, and merges organic layer, anhydrous
Sodium sulfate 8g is dried 5 hours, filters, and filtrate decompression is evaporated, and obtains 48g and reclaims solid, for racemization；
C, being put in 50g water by above-mentioned tartrate, the lower 14.5g saturated sodium bicarbonate aqueous solution that adds of stirring enters
Row is free, adjusts pH value 7～8, adjusts and finishes, and extracts with dichloromethane 40gx4, merges organic layer, anhydrous
Sodium sulfate 5.5g is dried 5 hours, filters, and filtrate decompression is evaporated, and must split thing 26.5～28g；
D, reclaim solid 76g by above-mentioned two batches and put in toluene 167g, add 1,8-diazabicylo 11 carbon-7-
Alkene 9g agitating heating is dissolved, and is warming up to 105 DEG C and refluxes 9 hours, and racemization is finished, and is cooled to room temperature, uses water
70gx4 washs, and to 1,8-diazabicylo 11 carbon-7-alkene is washed to the greatest extent, organic layer heating in water bath, recovered under reduced pressure
Toluene, to dry, be cooled to room temperature, add isopropanol 126g, is heated to 50～60 DEG C of stirrings molten clearly, be cooled to-5～
0 DEG C crystallizes 3 hours, filters, and filter cake cold isopropanol 20gx2 rinses, and drains, and is vacuum dried to obtain hydrogenation
Thing 48～54g.
S4, electronation:
Under the protection of e, nitrogen, adding glycol dimethyl ether 74g in reaction bulb, stirring is cooled to-5 DEG C, divides three
Criticizing and add sodium borohydride 10.5g altogether, control temperature and be less than 10 DEG C, finish, stirring is cooled to 0 DEG C, divides
Three batches add aluminum trichloride (anhydrous) 12.0g altogether and finish, are cooled to-5 DEG C, and dropping splits thing solution, controls temperature
Degree, less than 10 DEG C, adds, finishes, be to slowly warm up to be stirred at room temperature 2 hours, slowly rise for 2～3 hours
Temperature is incubated 2 hours to 50 DEG C, is warming up to 85 DEG C, refluxes 5 hours after stablizing, and backflow is finished, and normal pressure steams
Glycol dimethyl ether, decompression distillation, to dry, is cooled to room temperature, adds 30g toluene and stirs standby；
F, in reaction bulb, add 40.5g concentrated hydrochloric acid and 68g pure water, be cooled to-5 DEG C, drip above-mentioned toluene liquid,
Control temperature and be less than 10 DEG C, within 1～2 hour, add, finish, be warming up to be stirred at room temperature 2 hours, insulation
Finish, be warming up to 50 DEG C and be incubated 0.5 hour, after stablizing, be warming up to 90 DEG C, stir extremely clarification in 1～2 hour,
Clarifying latter 90 DEG C to stir 2 hours, be cooled to room temperature, stratification, water layer toluene 10gx2 extracts,
Toluene layer goes to reclaim toluene, and water layer is cooled to-5 DEG C, and with sheet adjusting PH with base 14, temperature is less than 10 DEG C, adjusts
Finishing, extract with toluene 21gx4, combining methylbenzene layer, 4g anhydrous sodium sulfate is dried 5 hours, filters, subtracts
Pressure is evaporated to obtain pale yellow oil (s, s)-6-benzyl-hexahydro-pyrrolo-[3,4.b] pyridine-5,7-diketone 13.5g.
S5, debenzylation:
(s, s)-6-benzyl-hexahydro-pyrrolo-[3,4.b] pyridine-5,7-diketone 13.5g adds methanol 100mL and stirs to above-mentioned
Mixing dissolving, put in autoclave, add 10%Pd/C 2.5kg, nitrogen is forced into 5kg/cm2, keep 30 points
Clock, detection autoclave does not leaks, and nitrogen is replaced 3 times, and hydrogen exchange 3 times starts stirring with 200rpm,
By pressurized with hydrogen to 20kg/cm2, close hydrogen, be warming up to 90 DEG C, mend hydrogen after temperature stabilization to 90kg/cm2,
Stirring hydrogenation, benefit hydrogen, to not inhaling hydrogen, continues to stir 2 hours at 87～93 DEG C, and hydrogenation is finished, and lowers the temperature
To 20～25 DEG C, sucking filtration, 5g methanol rinse Pd/C once, Pd/C recovery, filtrate heating in water bath,
Evaporated under reduced pressure, residue is dissolved in water 50mL, extracts with hexamethylene 50mLx3, merges hexamethylene layer water
60mLx3 is counter to be carried, combining water layer, adds NaOH4.5g, extracts with chloroform 60mLx3, combined chloroform
Layer anhydrous sodium sulfate is dried, and after filtration, filtrate decompression is evaporated, obtain light yellow mucus (s, s)-6-benzyl-octahydro-
Pyrrolo-[3,4-b] pyridine 7g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610226627.8A CN105777750A (en) | 2016-04-13 | 2016-04-13 | Synthesis method for moxifloxacin side chain |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610226627.8A CN105777750A (en) | 2016-04-13 | 2016-04-13 | Synthesis method for moxifloxacin side chain |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105777750A true CN105777750A (en) | 2016-07-20 |
Family
ID=56397414
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610226627.8A Pending CN105777750A (en) | 2016-04-13 | 2016-04-13 | Synthesis method for moxifloxacin side chain |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105777750A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108623583A (en) * | 2018-05-04 | 2018-10-09 | 新乡学院 | A kind of preparation method of the moxifloxacin side chain intermediate of iridium catalysis |
| CN110105273A (en) * | 2019-06-11 | 2019-08-09 | 江苏省药物研究所有限公司 | A kind of preparation method of Moxifloxacin important intermediate |
| CN110903285A (en) * | 2019-12-13 | 2020-03-24 | 南京恒道医药科技有限公司 | Method for producing moxifloxacin side chain by using secondary rectification |
| CN111454259A (en) * | 2019-01-18 | 2020-07-28 | 上海隆盛化工有限公司 | Preparation method of medical intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012131629A1 (en) * | 2011-03-31 | 2012-10-04 | Piramal Healthcare Limited | A process for preparation of intermediate of moxifloxacin |
| CN103788090A (en) * | 2014-01-26 | 2014-05-14 | 绍兴文理学院 | Racemization method of (1R, 6S)-8-benzyl-7, 9-dioxo-2, 8- diazabicyclo (4, 3, 0) nonane |
| WO2015007897A1 (en) * | 2013-07-19 | 2015-01-22 | Lek Pharmaceuticals D.D. | Method of racemisation of undesired enantiomers |
| CN105143219A (en) * | 2012-12-21 | 2015-12-09 | 曼康德研究中心 | Process for the preparation of (S,S)-6-benzloctahydro-1 h-pyrrolo[3,4-b]pyridine,an intermediate of azabicyclopyridine derivatives |
| CN105153155A (en) * | 2015-09-18 | 2015-12-16 | 华东师范大学 | Preparation method for 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo-[3,4-b] pyridine |
-
2016
- 2016-04-13 CN CN201610226627.8A patent/CN105777750A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012131629A1 (en) * | 2011-03-31 | 2012-10-04 | Piramal Healthcare Limited | A process for preparation of intermediate of moxifloxacin |
| CN105143219A (en) * | 2012-12-21 | 2015-12-09 | 曼康德研究中心 | Process for the preparation of (S,S)-6-benzloctahydro-1 h-pyrrolo[3,4-b]pyridine,an intermediate of azabicyclopyridine derivatives |
| WO2015007897A1 (en) * | 2013-07-19 | 2015-01-22 | Lek Pharmaceuticals D.D. | Method of racemisation of undesired enantiomers |
| CN103788090A (en) * | 2014-01-26 | 2014-05-14 | 绍兴文理学院 | Racemization method of (1R, 6S)-8-benzyl-7, 9-dioxo-2, 8- diazabicyclo (4, 3, 0) nonane |
| CN105153155A (en) * | 2015-09-18 | 2015-12-16 | 华东师范大学 | Preparation method for 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo-[3,4-b] pyridine |
Non-Patent Citations (5)
| Title |
|---|
| MARCO PALLAVICINI 等: "A highly efficient method for the α,β-dehydrogenation of α-amino esters and α-amino-β-diesters", 《TETRAHEDRON LETTERS》 * |
| 李波 等: "甲氨蝶呤的外消旋化", 《中国医药工业杂志》 * |
| 欧阳敬平 等: "动态动力学拆分中外消旋化方法的研究进展", 《沈阳药科大学学报》 * |
| 陈国才 等: "DBU——一种多功能的碱性试剂", 《化学试剂》 * |
| 高金华: "抗菌新药莫西沙星关键中间体的合成研究", 《浙江工业大学硕士学位论文》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108623583A (en) * | 2018-05-04 | 2018-10-09 | 新乡学院 | A kind of preparation method of the moxifloxacin side chain intermediate of iridium catalysis |
| CN108623583B (en) * | 2018-05-04 | 2021-01-15 | 新乡学院 | Preparation method of iridium-catalyzed moxifloxacin side chain intermediate |
| CN111454259A (en) * | 2019-01-18 | 2020-07-28 | 上海隆盛化工有限公司 | Preparation method of medical intermediate |
| CN110105273A (en) * | 2019-06-11 | 2019-08-09 | 江苏省药物研究所有限公司 | A kind of preparation method of Moxifloxacin important intermediate |
| CN110105273B (en) * | 2019-06-11 | 2023-06-13 | 江苏省药物研究所有限公司 | Preparation method of important intermediate of moxifloxacin |
| CN110903285A (en) * | 2019-12-13 | 2020-03-24 | 南京恒道医药科技有限公司 | Method for producing moxifloxacin side chain by using secondary rectification |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105777750A (en) | Synthesis method for moxifloxacin side chain | |
| CN104530044B (en) | A kind of synthetic method of the western croak of Leo | |
| CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
| CN102020636A (en) | Method for synthesizing and purifying Fasudil hydrochloride | |
| CN102040606A (en) | Synthetic method of vinpocetine | |
| CN103319414A (en) | Improved telmisartan preparation process | |
| CN112062767B (en) | Preparation method and intermediate of rumepilone | |
| CN101130640A (en) | Improved technique for synthesizing dispersion blue 60 | |
| CN103483324B (en) | The new preparation process of lapatinibditosylate | |
| US7145027B2 (en) | Method for producing chlorotris(triphenylphosphine) rhodium (i) | |
| CN102485723A (en) | Semi-synthesis of vinpocetine through one kettle way and preparation of water-soluble vinpocetine salt | |
| CN107298678B (en) | Preparation method of bulk drug suvorexant | |
| CN1321972C (en) | Process of preparing 4-nitro phthalic acid from the reaction mother liquor of nitrating phthalic anhydride to prepare 3-nitro phthalic acid | |
| CN113336761B (en) | Preparation method of JAK inhibitor key intermediate | |
| CN101781305A (en) | Method for artificially synthesizing galanthamine | |
| CN101565380A (en) | Preparation method of L(+)-p-fluorophenyl glycine | |
| CN103896889B (en) | Lapatinib intermediate and its preparation method and application | |
| CN111961114A (en) | Argatroban intermediate and preparation method and application thereof | |
| EP3931182A1 (en) | Process for preparing 6- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide | |
| CN105669539B (en) | A kind of preparation process of 2- amino -3- fluorine pyridines | |
| CN107652269A (en) | Methanesulfonic acid fluorine imatinib purification of intermediate method | |
| CN106883166A (en) | 4-（3- piperidyls）The preparation method of aniline and its tartrate | |
| CN108341768A (en) | A kind of method that reduction method prepares vitamin B6 | |
| CN104402798B (en) | A kind of 3-amino-1, the method for splitting of 2,3,4-tetrahydro carbazoles | |
| CN108341821B (en) | Synthesis method of epinastine hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160720 |