CN101519361A - Preparation process of lavo-ofloxacin and ofloxacin - Google Patents
Preparation process of lavo-ofloxacin and ofloxacin Download PDFInfo
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- CN101519361A CN101519361A CN200910131332A CN200910131332A CN101519361A CN 101519361 A CN101519361 A CN 101519361A CN 200910131332 A CN200910131332 A CN 200910131332A CN 200910131332 A CN200910131332 A CN 200910131332A CN 101519361 A CN101519361 A CN 101519361A
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Abstract
The invention relates to a preparation process of lavo-ofloxacin and ofloxacin which are anti-infectious medicaments, belonging to the synthetic process with tetrafluorobenzoic aid as raw material. The preparation method is characterized in that (2, 3, 4, 5-phenyl tetrafluoride formyl) ethyl acetate and DMFA react for 1.0-1.5h in toluene at 50-55 DEG C with the existence of acylating catalyst; the reaction product is washed by water, and an aqueous layer is separated; at 30-35 DEG C, L-amino propanol is dripped in an oil layer to carry out replacement reaction for 1.5-2.0h; toluene is decompressed, recovered and dried proper quantity of DMF is added to the oil layer for diluting; the diluted oil layer is dripped into back-flow DMF with the existence of anhydrous potassium fluoride to carry out back-flow reaction for 6h; DMF is recovered, water is added for centrifugation, acid is added to the obtained solid to be hydrolyzed to prepare lavo-perfluorocarboxylic acid, the lavo-perfluorocarboxylic acid reacts with N-methyl piperazine in DMSO at 90-110 DEG C by taking triethylamine as an acid-binding agent, and the lavo-ofloxacin is obtained after the fine purification of the product of reaction. The process improves the reaction condition of (2, 3, 4, 5-phenyl tetrafluoride formyl) ethyl acetate and DMFA, lowers the reaction temperature, shortens the reaction time and improves the reaction yield of lavo-fluoro ester serving as a reaction intermediate by 20 percent.
Description
Technical field
The invention belongs to technical field, the preparation method of a kind of specifically Levofloxacin and Ofloxacine USP 23.
Background technology
Fluoroquinolones is obtaining great success with the antimicrobial characteristic of efficient, spectrum, low toxicity aspect the clinical anti-infective therapy, and the Ofloxacine USP 23 and the Levofloxacin of the exploitation of Japanese first drugmaker are exactly wherein outstanding representative medicine.
Levofloxacin, English name: Leovfloxacin, molecular formula: C
18H
20FN
3O
41/2H
2O, its structural formula is as follows:
Ofloxacine USP 23, English name: Floxacin, molecular formula: C
18H
20FN
3O
4, its structural formula is as follows:
Levofloxacin is synthetic, and the route of bibliographical information mainly contains following three kinds:
1, early stage route mostly is Split Method: comprise that high performance liquid phase splits EP206283 (1986) and enzyme Split Method (K, Sakano, Aina Biol.chem.:1987,51,1265), but Split Method is unwell to suitability for industrialized production;
2, be that starting raw material makes by trifluoronitrobenzene.EP273399(1988)，EP36841(1990)；
3, be that starting raw material makes Levofloxacin US4777253 (1988) through 7 steps by tetrafluorobenzoic aid.
Wherein to be starting raw material make Levofloxacin through 7 steps to route 3 is the most frequently used method of present industrial production by tetrafluorobenzoic aid.This method synthetic route is as follows:
In this route, when using D, the L-aminopropanol is replaced L-aminopropanol and intermediate (V) reaction, can synthesize Ofloxacine USP 23 with same route, and synthetic route is as follows:
In above-mentioned operational path, because the triethyl orthoformate unit consumption is big, unit price height, and reaction needed 110-120 ℃ of reaction in the presence of a large amount of aceticanhydrides, thereby cost is higher when this operational path production levofloxacin and Ofloxacine USP 23.In order to overcome this difficulty, with DMFA (N, the dinethylformamide dimethyl acetal) replaces triethyl orthoformate and (V) reaction, can avoid the consumption of a large amount of aceticanhydrides and the high unit consumption of triethyl orthoformate, (" the synthetic and relevant chemistry of quinolones anti-infectives ", Guo Huiyuan, Chinese microbiotic magazine obviously reduce production costs, 2000 Vol.25No.5), reaction is as follows:
In this route, when replacing D with the L-aminopropanol, L-aminopropanol and intermediate (XIII) reaction can be synthesized levofloxacin with same route.
But, in intermediate (V) and the DMFA reaction process, long reaction time, impurity generates more, and the liquid content of product in the reaction solution (XIII) only is 76-80%.And pass through and discover that when temperature of reaction was reduced to 60 ℃, speed of response obviously reduced, after 10 hours, (V) still residual about 10%; And more than the elevated temperature to 80 ℃ the time, speed of response increases, and is very fast but side reaction also increases.
Summary of the invention
On the preparation method's of above related background art basis; the invention provides the preparation method of a kind of formula (VIII) compound or formula (XI) compound; described method comprises, in the presence of the acylation catalyst of catalytic amount, make formula V compound and DMFA react formula (XIII) compound.
Described acylation catalyst is aceticanhydride, DMAP (4-Dimethylamino pyridine), CaCl
2Perhaps benzoyl hydroperoxide.
In the above-described embodiment, preferably compare with the formula V compound, catalyst consumption is 0.01 equivalent.
In the above-described embodiment, preferred reaction is carried out under 50-55 ℃, preferably carries out 1.0-1.5 hour.
In the above-described embodiment, when preferred reaction finished, the time liquid content of XIII was 90%.
In another aspect of this invention, provide a kind of new Levofloxacin or the preparation method of Ofloxacine USP 23, comprising, in the presence of the acylation catalyst of catalytic amount, make formula V compound and DMFA react formula (XIII) compound.
Preferred acylation catalyst is aceticanhydride, DMAP (4-Dimethylamino pyridine), CaCl
2Perhaps benzoyl hydroperoxide etc.
In further embodiment, the invention provides a kind of method for preparing Levofloxacin or Ofloxacine USP 23, described method comprises, in the presence of the acylation catalyst of catalytic amount, makes formula V compound and DMFA reaction acquisition formula (XIII) compound:
By formula (XIII) compound and D, the reaction of L-aminopropanol makes formula (X) compound, formula (X) compound is in the presence of KF, cyclization and an accepted way of doing sth (XI) compound, (XI) get (XII) compound through acid-catalyzed hydrolysis, the condensation and obtain Ofloxacine USP 23 (II) in DMSO of this compound and N methyl piperazine:
Perhaps replace D with the L-aminopropanol, L-aminopropanol and intermediate (XIII) reaction makes formula (VII) compound, formula (VII) compound is in the presence of KF, cyclization and an accepted way of doing sth (VIII) compound, (VIII) get (IX) compound through acid-catalyzed hydrolysis, the synthetic levofloxacin (I) of this compound and N methyl piperazine condensation in DMSO
Preferred described acylation catalyst is aceticanhydride, DMAP, CaCl
2Perhaps benzoyl hydroperoxide.
In another embodiment, the present invention relates to the application of described acylation catalyst in preparation Levofloxacin or Ofloxacine USP 23.
Find after deliberation, use after the acylation catalyst of the present invention, can reduce temperature of reaction, shorten the reaction times, thereby reduce the generation of side reaction, improve the condensation reaction yield.Make the weight yield of formula (VIII) (or (XI)) can reach 110%[with formula (VIII) (or product weight (XI) is divided by the charging capacity of reactant (V)], improve 20% than present enterprise production level.
Embodiment:
Further specify the present invention below by embodiment.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, and the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.
The preparation of embodiment 1 formula (VIII) compound
(1) preparation of formula (XIII) compound
150ml toluene, 50g (V), 27gDMFA, the 1.0g aceticanhydride drops into the 500ml three-necked bottle successively, stirs and is warming up to 52 ℃, the timing insulation.Behind the 50-55 ℃ of insulation 90min, add 200ml water and stir 3min, add appropriate hydrochloric acid, regulate PH=5-6.Branch vibration layer, oil reservoir are the toluene solution (liquid phase analysis is carried out in sampling, and the liquid content of compound (XIII) is 90%) of (XIII).Need not to separate, can be directly used in next step operation.
(2) preparation of formula (VII) compound
The toluene solution in last step (XIII) is warming up to 35 ℃, stirs and splashes into the 14gL-aminopropanol, and 30min drips off.After dripping Bi Baowen 60min, reclaim under reduced pressure toluene, maintenance temperature＜90 ℃, vacuum＜-.09MPa.Do not stop when toluene flows out to having, residue is (VII), is light red liquid.
(3) preparation of formula (VIII) compound
Add 200ml DMF in the 500ml three-necked bottle, 45g anhydrous K F stirs and is warming up to backflow.After adding 50ml DMF dissolving in the last step (VII), drop to slowly that 120-150min drips off among the DMF of backflow.Drip and finish, insulation 150min refluxes.
Insulation finishes, reclaim under reduced pressure DMF, and maintenance temperature＜110 ℃, vacuum＜-.09MPa.Do not stop when DMF flows out to having, add 300ml water in the residue, stir when being cooled to 40 ℃ and filter, filter cake 20ml methanol wash 2 times promptly get (VIII) 1 time with the 150ml water washing again.Wet product dry 55g, weight yield is 110% (with the product weight of formula (VIII) charging capacity divided by reactant (V)), white solid, fusing point are 250-256 ℃ (the data in literature fusing point is 250-260 ℃).
When in following table, having provided the use different catalysts, the yield contrast table of the compound (VIII) that the main peak liquid concentration of the compound of acquisition (XIII) and further reaction obtain:
| The catalyzer title | Catalyzer throwing amount | The main peak liquid concentration | The VIII yield |
| Aceticanhydride | 0.01 equivalent | 91％ | 110％ |
| DMAP (4-Dimethylamino pyridine) | 0.01 equivalent | 92％ | 112％ |
| CaCl2 | 0.01 equivalent | 89％ | 108％ |
| Benzoyl hydroperoxide | 0.01 equivalent | 90％ | 110％ |
2, the preparation of (IX)
Add 55g (VIII), 200ml glacial acetic acid in the 500ml three-necked bottle, 150ml water, the 9ml vitriol oil.Stirring is warming up to backflow.Treat (VIII) dissolving back backflow insulation 180-200min.
Insulation is finished, and the reclaim under reduced pressure glacial acetic acid keeps temperature＜80 ℃, vacuum＜-.09MPa.Stop when absence of liquid flows out, add 300ml water in the residue, stir when being cooled to 30 ℃ and filter, filter cake water thorough washing is to filtrate neutrality, and filtration cakes torrefaction promptly gets (IX).Dry product weight 49g, weight yield 89.1% (with the product weight of formula (IX) charging capacity) divided by reactant (VIII).Boiling point 317-320 ℃ (literature value 318-322 ℃)
3, the preparation of levofloxacin (I)
Add 49g (IX) in the 500ml three-necked bottle, 150ml DMSO, the 35mlN-methylpiperazine, the 23ml triethylamine stirs and is warming up to 90 ℃, insulation reaction 60-90min.Insulation is finished, and reclaim under reduced pressure DMSO keeps temperature＜90 ℃, vacuum＜-.098MPa, when absence of liquid flows out, add 150ml water, the 150ml chloroform adds less ammonia and regulates PH=7, stirs adding 1g gac after the rising temperature for dissolving.Filter standing demix in the time of 45 ℃.Tell chloroform layer, water layer 50ml chloroform extraction three times, the combined chloroform layer is concentrated into and does back adding 150ml alcohol recrystallization, the dry 54g levofloxacin (I) that gets of wet product.Weight yield 110.2% (with the product weight of formula (I) charging capacity) divided by reactant (IX).
4, the preparation of (X)
(XIII) toluene solution is warming up to 35 ℃, stirs and splashes into 14g D, L-aminopropanol, and 30min drips off.After dripping Bi Baowen 60min, reclaim under reduced pressure toluene, maintenance temperature＜90 ℃, vacuum＜-.09MPa.Do not stop when toluene flows out to having, residue is (X).
5, the preparation of (XI)
Add 200ml DMF in the 500ml three-necked bottle, 45g anhydrous K F stirs and is warming up to backflow.After adding 50ml DMF dissolving in the last step (X), drop to slowly that 120-150min drips off among the DMF of backflow.Drip and finish, insulation 150min refluxes.
Insulation finishes, reclaim under reduced pressure DMF, and maintenance temperature＜110 ℃, vacuum＜-.09MPa.Do not stop when DMF flows out to having, add 300ml water in the residue, stir when being cooled to 40 ℃ and filter, filter cake 20ml methanol wash 2 times promptly get (XI) 1 time with the 150ml water washing again.Wet product dry 54.8g, weight yield is 109.6% (with the product weight of formula (XI) charging capacity divided by reactant (V)).
6, the preparation of (XII)
Add 50g (XI), 200ml glacial acetic acid in the 500ml three-necked bottle, 50ml water, the 9ml vitriol oil.Stirring is warming up to backflow.Treat (XIII) dissolving back backflow insulation 180-200min.
Insulation is finished, and the reclaim under reduced pressure glacial acetic acid keeps temperature＜80 ℃, vacuum＜-.09MPa.Stop when absence of liquid flows out, add 300ml water in the residue, stir when being cooled to 30 ℃ and filter, filter cake water thorough washing is to filtrate neutrality, and filtration cakes torrefaction promptly gets (XII).Dry product weight 45g, weight yield 90% (with the product weight of formula (XII) charging capacity) divided by reactant (XI).Boiling point 318-321 ℃ (literature value 318-322 ℃)
7, the preparation of oxygen Ofloxacine USP 23 (II)
Add 45g (XII) in the 500ml three-necked bottle, 140ml DMSO, the 32mlN-methylpiperazine, the 21ml triethylamine stirs and is warming up to 90 ℃, insulation reaction 60-90min.
Insulation is finished, reclaim under reduced pressure DMSO keeps temperature＜90 ℃, vacuum＜-.098MPa, when absence of liquid flows out, add 150ml water, stir and splash into appropriate hydrochloric acid accent PH=3, material dissolution when being warming up to 60 ℃, add 1g activated carbon decolorizing after-filtration, filtrate is transferred PH=7 with alkali lye, separates out white solid, be cooled to 20 ℃ filter Ofloxacine USP 23.The dry 48g Ofloxacine USP 23 (II) that gets.Weight yield 106.7% (with the product weight of formula (II) charging capacity) divided by reactant (XII).
Claims (9)
1, the acylation catalyst that the preparation method of a kind of formula (XIII) compound, described method are included in catalytic amount exists down, makes formula V compound and N, dinethylformamide dimethyl acetal (DMFA) reaction,
2, according to the preparation method of claim 1, wherein said acylation catalyst is aceticanhydride, 4-Dimethylamino pyridine (DMAP), CaCl
2Perhaps benzoyl hydroperoxide.
3,, carry out under the described 50-55 of being reflected at ℃ according to the preparation method of claim 1 or 2.
4, a kind of method for preparing Ofloxacine USP 23, described method comprise, in the presence of the acylation catalyst of catalytic amount, make formula V compound and DMFA reaction acquisition formula (XIII) compound:
5, according to the preparation method of claim 4, wherein said acylation catalyst is aceticanhydride, 4-Dimethylamino pyridine (DMAP), CaCl
2Perhaps benzoyl hydroperoxide.
6, according to the method for claim 5, described method further comprises: make formula (XIII) compound and D, the reaction of L-aminopropanol makes formula (X) compound, make formula (X) compound in the presence of KF, cyclization and an accepted way of doing sth (XI) compound, (XI) get (XII) compound through acid-catalyzed hydrolysis, the condensation and obtain Ofloxacine USP 23 (II) in DMSO of this compound and N methyl piperazine:
7, a kind of method for preparing Levofloxacin, described method comprise, in the presence of the acylation catalyst of catalytic amount, make formula V compound and DMFA reaction acquisition formula (XIII) compound:
8, according to the preparation method of claim 7, wherein said acylation catalyst is aceticanhydride, 4-Dimethylamino pyridine (DMAP), CaCl
2Perhaps benzoyl hydroperoxide.
9, method according to Claim 8, described method further comprises: make L-aminopropanol and intermediate (XIII) reaction, make formula (VII) compound, formula (VII) compound is in the presence of KF, cyclization and an accepted way of doing sth (VIII) compound, (VIII) get (IX) compound through acid-catalyzed hydrolysis, the synthetic levofloxacin (I) of this compound and N methyl piperazine condensation in DMSO
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113388A (en) * | 2013-02-01 | 2013-05-22 | 浙江国邦药业有限公司 | Preparation method of levofloxacin |
| CN103360410A (en) * | 2012-04-06 | 2013-10-23 | 河南天方药业股份有限公司 | Preparation method of ofloxacin |
| CN107141306A (en) * | 2017-06-19 | 2017-09-08 | 太仓大唐化纤厂 | A kind of method for preparing lavo-ofloxacin hydrochloride |
| CN108404990A (en) * | 2018-05-08 | 2018-08-17 | 邳州易萨新型材料有限公司 | A kind of catalyst and its application for synthesizing Levofloxacin pharmaceutical intermediate |
| WO2018233111A1 (en) * | 2017-06-19 | 2018-12-27 | 太仓卡斯特姆新材料有限公司 | Environmentally friendly method for preparing levofloxacin hydrochloride |
| CN113493466A (en) * | 2020-03-20 | 2021-10-12 | 上海安谱实验科技股份有限公司 | Stable isotope labeled ofloxacin and synthetic method thereof |
| CN115850297A (en) * | 2022-12-02 | 2023-03-28 | 常州兰陵制药有限公司 | Synthetic method of sarin antibiotic drug intermediate |
-
2009
- 2009-04-15 CN CN200910131332A patent/CN101519361A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103360410A (en) * | 2012-04-06 | 2013-10-23 | 河南天方药业股份有限公司 | Preparation method of ofloxacin |
| CN103113388A (en) * | 2013-02-01 | 2013-05-22 | 浙江国邦药业有限公司 | Preparation method of levofloxacin |
| CN103113388B (en) * | 2013-02-01 | 2016-02-10 | 浙江国邦药业有限公司 | A kind of preparation method of levofloxacin |
| CN107141306A (en) * | 2017-06-19 | 2017-09-08 | 太仓大唐化纤厂 | A kind of method for preparing lavo-ofloxacin hydrochloride |
| WO2018233111A1 (en) * | 2017-06-19 | 2018-12-27 | 太仓卡斯特姆新材料有限公司 | Environmentally friendly method for preparing levofloxacin hydrochloride |
| CN108404990A (en) * | 2018-05-08 | 2018-08-17 | 邳州易萨新型材料有限公司 | A kind of catalyst and its application for synthesizing Levofloxacin pharmaceutical intermediate |
| CN113493466A (en) * | 2020-03-20 | 2021-10-12 | 上海安谱实验科技股份有限公司 | Stable isotope labeled ofloxacin and synthetic method thereof |
| CN115850297A (en) * | 2022-12-02 | 2023-03-28 | 常州兰陵制药有限公司 | Synthetic method of sarin antibiotic drug intermediate |
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