CN105037388A - Preparing method for antofloxacin - Google Patents
Preparing method for antofloxacin Download PDFInfo
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- CN105037388A CN105037388A CN201510547978.4A CN201510547978A CN105037388A CN 105037388 A CN105037388 A CN 105037388A CN 201510547978 A CN201510547978 A CN 201510547978A CN 105037388 A CN105037388 A CN 105037388A
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- Prior art keywords
- antofloxacin
- cooled
- methyl
- antofloxacin hydrochlorid
- reactor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
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- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention discloses a preparing method for antofloxacin. (S)-9,10-difluoro-2,3-dihydro-3-methyl-8-amidogen-7-oxo-7H-pyrido[1,2,3-de]-[1,4]-benzoxazine-6-carboxylic acid and N-methyl piperazine are used as the raw materials, and meanwhile the N- methyl piperazine is used as a solvent. The reaction temperature is lowered, the reaction time is shortened, efficiency is improved, energy consumption is reduced, and the prepared antofloxacin is high in yield and purity.
Description
Technical field
The invention belongs to pharmaceutical field, specifically a kind of preparation method of Antofloxacin hydrochlorid.
Background technology
The preparation method of existing Antofloxacin hydrochlorid is by (S)-9, 10-bis-fluoro-2, 3-dihydro-3-methyl-8-amino-7-oxo-7H-pyrido [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acids (be called for short 8-amino levofloxacin carboxylic acid) and N methyl piperazine and pyridine are in mass ratio for 1:1.92:20 is placed in reactor, stirring makes it dissolve, then 110 ~ 120 DEG C are heated to, stir lower back flow reaction after 10 hours, be cooled to less than 70 DEG C, carry out vacuum decompression distillation, pyridine in removing reactant, cooling down again, by residu washed with ethanol several times, centrifugal drying obtains yellow Antofloxacin hydrochlorid crude product.
N methyl piperazine: colourless liquid, boiling point 138 DEG C, relative density 0.903, water-soluble, ether, ethanol, with water, methyl alcohol etc. arbitrarily than dissolving each other, in aqueous in weakly alkaline.Be harmful to skin contact.
Pyridine: colourless or micro-yellow liquid, foul smelling.Boiling point 115.3, relative density: 0.9827, water-soluble and most organic solvent such as alcohol, ether.There is intense stimulus, central nervous system can be anaesthetized, hormesis is had to eye and the upper respiratory tract, after high density sucks, the lighter has glad or sensation of asphyxia, then occur depression, myasthenia, vomiting, the severe one loss of consciousness, gatism, tonic spasm, blood pressure drops, long-term suction occurs that dizziness, headache, insomnia, instability of gait and tract function are disorderly.
The method not only needs to use a large amount of organic solvent pyridine, smell weight, and toxicity is large, volatile in air, totally unfavorable to staff's health, and pyridine is easily trapped in medicine, brings disadvantageous effect to the safety of medicine.
Summary of the invention
The technical problem to be solved in the present invention is for the deficiencies in the prior art, provides a kind of preparation method of Antofloxacin hydrochlorid, this method increases the usage quantity of reactant N methyl piperazine, alternative pyridine role in the reaction, eliminate the use of pyridine, environmental pollution is little, and quality product is high.
For solving the problems of the technologies described above, the invention provides a kind of preparation method of Antofloxacin hydrochlorid, comprising the following steps:
(1) by 1 weight part (S)-9,10-bis-fluoro-2,3-dihydro-3-methyl-8-amino-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acids and 10 weight part N methyl piperazines add in reactor, react complete to raw material reaction at 100 ~ 110 DEG C;
(2) be cooled to 65 ~ 80 DEG C, N methyl piperazine is reclaimed in underpressure distillation;
(3) add 5 parts by weight of ethanol, return stirring 1 ~ 3 hour, is cooled to 20 ~ 30 DEG C, centrifugal, solids washing with alcohol, dry Antofloxacin hydrochlorid crude product;
(4) Antofloxacin hydrochlorid crude product and 3 weight parts waters dropped in reactor, be warming up to 80 ~ 85 DEG C, stirs 0.5 hour, be cooled to room temperature, centrifugal, solids frozen water washs, dry must Antofloxacin hydrochlorid sterling.
Reaction formula of the present invention is:
Present method adds the consumption of reactant N methyl piperazine, replaces organic solvent pyridine, reduce temperature of reaction, shorten the reaction times with N methyl piperazine, improves efficiency and reduces energy consumption; Improve quality product, ensure that yield, avoid pyridine remaining in medicine.
Embodiment
Below by embodiment, invention is described further.Embodiment described herein only to explain invention, the protection domain be not intended to limit the present invention.
Embodiment 1
The preparation method of Antofloxacin hydrochlorid, comprises the following steps:
(1) by 50g (S)-9,10-bis-fluoro-2,3-dihydro-3-methyl-8-amino-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid and 500gN-methylpiperazine add in 1L reactor, are warming up to 105 DEG C, stir 10h, complete to raw material reaction;
(2) raw material reaction completely after, be cooled to 65 DEG C, N methyl piperazine is reclaimed in underpressure distillation, to flowing out without cut;
(3) add 250g dehydrated alcohol, return stirring 1.5 hours, is cooled to 20 DEG C, centrifugal, solids washing with alcohol, dry Antofloxacin hydrochlorid crude product;
(4) the Antofloxacin hydrochlorid crude product of step (3) and 150g water are dropped in reactor, be warming up to 80 DEG C, stir 0.5 hour;
(5) be cooled to room temperature, centrifugal, solids frozen water washs, dry Antofloxacin hydrochlorid sterling 60g.
Embodiment 2
The preparation method of Antofloxacin hydrochlorid, comprises the following steps:
(1) by 50g (S)-9,10-bis-fluoro-2,3-dihydro-3-methyl-8-amino-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid and 550gN-methylpiperazine add in 1L reactor, are warming up to 102 DEG C, stir 10h, complete to raw material reaction;
(2) raw material reaction completely after, be cooled to 75 DEG C, N methyl piperazine is reclaimed in underpressure distillation, to flowing out without cut;
(3) add 300g dehydrated alcohol, return stirring 3 hours, is cooled to 30 DEG C, centrifugal, solids washing with alcohol, dry Antofloxacin hydrochlorid crude product;
(4) the Antofloxacin hydrochlorid crude product of step (3) and 150g water are dropped in reactor, be warming up to 85 DEG C, stir 0.5 hour;
(5) be cooled to room temperature, centrifugal, solids frozen water washs, dry Antofloxacin hydrochlorid sterling 61g.
Embodiment 3
The preparation method of Antofloxacin hydrochlorid, comprises the following steps:
(1) by 50g (S)-9,10-bis-fluoro-2,3-dihydro-3-methyl-8-amino-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid and 520gN-methylpiperazine add in 1L reactor, are warming up to 110 DEG C, stir 10h, complete to raw material reaction;
(2) raw material reaction completely after, be cooled to 80 DEG C, N methyl piperazine is reclaimed in underpressure distillation, to flowing out without cut;
(3) add 300g dehydrated alcohol, return stirring 1 hour, is cooled to 25 DEG C, centrifugal, solids washing with alcohol, dry Antofloxacin hydrochlorid crude product;
(4) the Antofloxacin hydrochlorid crude product of step (3) and 200g water are dropped in reactor, be warming up to 80 DEG C, stir 0.5 hour;
(5) be cooled to room temperature, centrifugal, solids frozen water washs, dry Antofloxacin hydrochlorid sterling 60g.
Claims (1)
1. a preparation method for Antofloxacin hydrochlorid, is characterized in that, comprises the following steps:
(1) by 1 weight part (S)-9,10-bis-fluoro-2,3-dihydro-3-methyl-8-amino-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acids and 10 ~ 11 weight part N methyl piperazines add in reactor, react complete to raw material reaction at 100 ~ 110 DEG C;
(2) be cooled to 65 ~ 80 DEG C, N methyl piperazine is reclaimed in underpressure distillation;
(3) add 5 ~ 6 parts by weight of ethanol, return stirring 1 ~ 3 hour, is cooled to 20 ~ 30 DEG C, centrifugal, solids washing with alcohol, dry Antofloxacin hydrochlorid crude product;
(4) Antofloxacin hydrochlorid crude product and 3 ~ 4 weight parts waters dropped in reactor, be warming up to 80 ~ 85 DEG C, stirs 0.5 hour, be cooled to room temperature, centrifugal, solids frozen water washs, dry must Antofloxacin hydrochlorid sterling.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510547978.4A CN105037388A (en) | 2015-08-28 | 2015-08-28 | Preparing method for antofloxacin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510547978.4A CN105037388A (en) | 2015-08-28 | 2015-08-28 | Preparing method for antofloxacin |
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| CN105037388A true CN105037388A (en) | 2015-11-11 |
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| CN201510547978.4A Pending CN105037388A (en) | 2015-08-28 | 2015-08-28 | Preparing method for antofloxacin |
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Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4382892A (en) * | 1980-09-02 | 1983-05-10 | Daiichi Seiyaku Co., Ltd. | Benzoxazine derivatives |
| US4777253A (en) * | 1986-04-25 | 1988-10-11 | Abbott Laboratories | Process for preparation of racemate and optically active ofloxacin and related derivatives |
| CN88101741A (en) * | 1987-04-02 | 1988-11-16 | 拜尔公司 | Quinolinone one and azanaphthalenes keto carboxylic acid derivatives that 5-replaces |
| US4859773A (en) * | 1985-06-22 | 1989-08-22 | Bayer Aktiengesellschaft | Preparation of 1,8-bridged 4-quinoline-3-carboxylic acids |
| US5053407A (en) * | 1985-06-20 | 1991-10-01 | Daiichi Pharmaceutical Co., Ltd. | Optically active pyridobenzoxazine derivatives and anti-microbial use |
| US5237060A (en) * | 1985-12-10 | 1993-08-17 | Bayer Aktiengesellschaft | Process of preparing enantiomerically pure 1,8-bridged 4-quinolone-3-carboxylic acids |
| US5521310A (en) * | 1992-10-07 | 1996-05-28 | Derivados Del Etilo, S.A. | Process to obtain benzoxazines to be used for the synthesis of ofloxazine, levofloxazine and derivatives |
| CN1181381A (en) * | 1997-11-18 | 1998-05-13 | 中国科学院上海药物研究所 | Synthetizing and application of laevo-rotation ofloxacin analogue |
| US20030144511A1 (en) * | 2001-10-03 | 2003-07-31 | Valerie Niddam-Hildesheim | Methods for the purification of levofloxacin |
| US20070244318A1 (en) * | 2004-11-08 | 2007-10-18 | Rao Davuluri R | Process for the Preparation of Levofloxacin Hemihydrate |
| CN101157619A (en) * | 1999-09-08 | 2008-04-09 | 第一三共株式会社 | Process for producing intermediate for benzoxazine derivative |
| CN101792452A (en) * | 2010-04-02 | 2010-08-04 | 安徽环球药业股份有限公司 | Preparation method of high-purity antofloxacin hydrochloride |
| CN101812074A (en) * | 2010-04-16 | 2010-08-25 | 安徽环球药业股份有限公司 | Method for preparing antofloxacin hydrochloride |
-
2015
- 2015-08-28 CN CN201510547978.4A patent/CN105037388A/en active Pending
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4382892A (en) * | 1980-09-02 | 1983-05-10 | Daiichi Seiyaku Co., Ltd. | Benzoxazine derivatives |
| US5053407A (en) * | 1985-06-20 | 1991-10-01 | Daiichi Pharmaceutical Co., Ltd. | Optically active pyridobenzoxazine derivatives and anti-microbial use |
| US4859773A (en) * | 1985-06-22 | 1989-08-22 | Bayer Aktiengesellschaft | Preparation of 1,8-bridged 4-quinoline-3-carboxylic acids |
| US5237060A (en) * | 1985-12-10 | 1993-08-17 | Bayer Aktiengesellschaft | Process of preparing enantiomerically pure 1,8-bridged 4-quinolone-3-carboxylic acids |
| US4777253A (en) * | 1986-04-25 | 1988-10-11 | Abbott Laboratories | Process for preparation of racemate and optically active ofloxacin and related derivatives |
| CN88101741A (en) * | 1987-04-02 | 1988-11-16 | 拜尔公司 | Quinolinone one and azanaphthalenes keto carboxylic acid derivatives that 5-replaces |
| US5521310A (en) * | 1992-10-07 | 1996-05-28 | Derivados Del Etilo, S.A. | Process to obtain benzoxazines to be used for the synthesis of ofloxazine, levofloxazine and derivatives |
| CN1181381A (en) * | 1997-11-18 | 1998-05-13 | 中国科学院上海药物研究所 | Synthetizing and application of laevo-rotation ofloxacin analogue |
| CN101157619A (en) * | 1999-09-08 | 2008-04-09 | 第一三共株式会社 | Process for producing intermediate for benzoxazine derivative |
| US20030144511A1 (en) * | 2001-10-03 | 2003-07-31 | Valerie Niddam-Hildesheim | Methods for the purification of levofloxacin |
| US20070244318A1 (en) * | 2004-11-08 | 2007-10-18 | Rao Davuluri R | Process for the Preparation of Levofloxacin Hemihydrate |
| CN101792452A (en) * | 2010-04-02 | 2010-08-04 | 安徽环球药业股份有限公司 | Preparation method of high-purity antofloxacin hydrochloride |
| CN101812074A (en) * | 2010-04-16 | 2010-08-25 | 安徽环球药业股份有限公司 | Method for preparing antofloxacin hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| OANA M. COCIORVA，等: "Synthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogen synthase kinase-3β", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 杨玉社，等: "左旋氧氟沙星类似物的合成及其构效关系", 《药学学报》 * |
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Application publication date: 20151111 |
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