CN102093349B - Method for performing industrialized production on moxifloxacin hydrochloride - Google Patents

Method for performing industrialized production on moxifloxacin hydrochloride Download PDF

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CN102093349B
CN102093349B CN2011100089967A CN201110008996A CN102093349B CN 102093349 B CN102093349 B CN 102093349B CN 2011100089967 A CN2011100089967 A CN 2011100089967A CN 201110008996 A CN201110008996 A CN 201110008996A CN 102093349 B CN102093349 B CN 102093349B
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moxifloxacin hydrochloride
industrialized production
moxifloxacin
aqueous solution
drying
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CN102093349A (en
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叶海
晁阳
梁静
陈爱萍
刘雪
曹卫
陈雷
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Nanjing Uniclever Biological Pharmaceutical Ltd By Share Ltd
Nanjing Yoko Biological Pharmaceutical Group Co ltd
Nanjing Yoko Biomedical R & D Ltd
NANJING YOKO PHARMACEUTICAL CO Ltd
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NANJING YOKO BIOLOGICAL PHARMACEUTICAL CO Ltd
NANJING YOKO BIO-MEDICAL RESEARCH Co Ltd
XINGANG MEDICINE
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Abstract

The invention relates to a method for synthesizing moxifloxacin hydrochloride. The method is characterized in that: moxifloxacin hydrochloride is precipitated from solution according to solubility difference of the moxifloxacin hydrochloride in sodium chloride solution with different concentrations so as to fulfill the aim of separation. The method particularly comprises the following steps of: adding sodium chloride into moxifloxacin hydrochloride-containing aqueous solution; stirring to crystallize; filtering; drying; recrystallizing with water; filtering; and drying to obtain the moxifloxacin hydrochloride. The method is simple and convenient in operation; the product has high purity; a single impurity is less than 0.1 percent; the total impurities are less than 0.2 percent; and the method is suitable for industrialized production.

Description

A kind of method of suitability for industrialized production Moxifloxacin hydrochloride
Technical field
The present invention relates to a kind of method of industrialized production Moxifloxacin hydrochloride.Moxifloxacin hydrochloride is a fluoroquinolone antibiotics, can be used for treating responsive microbial infection.
Figure BSA00000419613200011
Formula I
Technical background
Moxifloxacin hydrochloride (Moxifloxacin hydrochloride) is the ultra wide spectrum quinolone antibiotic of Beyer Co., Ltd's development; Chemistry is by name: 1-cyclopropyl-6-fluoro-1; 4-dihydro-8-methoxyl group-7-[(4 α S; 7 α S)-octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl]-4-oxo-3-quinoline carboxylic acid hydrochloride.Its chemical structural formula is suc as formula shown in 1.
Moxifloxacin hydrochloride goes on the market in Germany in September, 1999 first, obtains the FDA approval December and goes on the market in the U.S..Keeping on the outstanding active basis of the anti-gram-negative bacteria of early stage fluoroquinolone; Anti-gram positive organism and atypia pathogenic agent have obviously been strengthened (like mycoplasma, chlamydozoan; Legionella and anerobes etc.) activity; Clinical being mainly used in treated acute sinus gland inflammation, the acute attack of chronic bronchitis, community acquired pneumonia, and uncomplicated skin infections and skin soft-tissue infection.
These article have broad-spectrum antibacterial activity, especially Gram-positive, mycoplasma, chlamydozoan, legionella isoreactivity are much better than CIPROFLOXACIN USP 24, and effective to anerobes.The human body long half time, 1 400mg of administration every day can reach encouraging result.Clinical being mainly used in treated acute sinus gland inflammation, the acute attack of chronic bronchitis, community acquired pneumonia, and uncomplicated skin infections and skin soft-tissue infection.The characteristics of these article are almost not have photosensitized reaction, are considered to " the treatment respiratory tract infection is near the ideal medicine ".
Moxifloxacin hydrochloride is synthetic to be shown in EP550903 the earliest, discloses structure and a kind of breadboard compound method of Moxifloxacin, has adopted parent nucleus 1-cyclopropyl-6; 7-two fluoro-8-methoxyl groups-1, and 4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester and side chain (s, s)-2; The method of 8-diazabicyclo [4.3.0] nonane condensation; Can prepare target compound through this method, but post-treating method is complicated extracting operation and a column chromatogram chromatography purifying of multistep, when suitability for industrialized production, is difficult to realize.
Patent CN02131962 discloses and a kind ofly in water and alcoholic solution, has reacted the method that makes Moxifloxacin hydrochloride with 8-BAY 128039 carboxylic acid derivative and potassium tert.-butoxide or sodium tert-butoxide.Its post-treating method is in reaction solution, to be added dropwise to Hydrogen chloride, and adds crystal seed, stirring and crystallizing.The gained crystal filters, and aqueous solution recrystallization can obtain the Moxifloxacin hydrochloride product.This method is simpler relatively, but product loss is bigger in reaction solution, has reduced yield, and needs to add the crystal seed crystallization.
Patent CN101817820 discloses the side chain compound (s with the Boc protection; S)-2; 8-diazabicyclo [4.3.0] nonane prepares the method for Moxifloxacin hydrochloride; Its method is that gained Moxifloxacin bullion is added stirring and crystallizing in the Hydrogen chloride, filters, and a large amount of frozen water washings obtain the Moxifloxacin hydrochloride bullion.There is the big shortcoming of product loss in same this method.
The prescription of Moxifloxacin hydrochloride sodium-chlor preparation is disclosed among the patent CN1368891; And the solubleness of 5 ℃ of following Moxifloxacin hydrochlorides in the sodium chloride solution of 0~0.9% concentration is provided in specification sheets; The solubleness of Moxifloxacin hydrochloride reduces with sodium chloride concentration from 0 to 0.9%.But this patent does not relate to the influence to Moxifloxacin hydrochloride solubleness of other temperature and 0.9% above concentration sodium chloride aqueous solution, finds to utilize saltouing of high density can in industry, prepare highly purified Moxifloxacin hydrochloride.
In research process; The discovery that we are surprised; The solubleness of Moxifloxacin hydrochloride in water is along with the reduction of temperature and the increase of sodium chloride concentration descend rapidly; In 1% above sodium chloride solution, can reach fully, from the aqueous solution, precipitate and isolate the purpose of highly purified Moxifloxacin hydrochloride with acceptable yield.This method is never seen and is applied in Moxifloxacin hydrochloride synthetic.
Utilize this characteristic, we have invented a kind of method of industrialized production Moxifloxacin hydrochloride, and the Moxifloxacin hydrochloride yield of producing through this method is high, and quality is good, can guarantee the single impurity of products obtained therefrom less than 0.1%, and total impurities is less than 0.2%.
Summary of the invention
The purpose of this invention is to provide a kind of simple to operate, mild condition, yield is higher and be easy to the working method of industrialized Moxifloxacin hydrochloride.Through a large amount of evidences, present method has extremely strong industriallization feasibility, can stablize the control quality product, obtains that highly purified Moxifloxacin hydrochloride list is assorted to be no more than 0.1%, always assortedly is no more than 0.2%.
Particularly, working method of the present invention is: following solid sodium chloride or sodium chloride aqueous solution, the insulated and stirred crystallization of adding of aqueous solution stirring that will contain Moxifloxacin hydrochloride through synthetic; Filter water recrystallization, 0~40 ℃ of crystallization; Filter, air blast or vacuum-drying promptly get product.
Moxifloxacin hydrochloride working method of the present invention, the add-on of solid sodium chloride or sodium chloride aqueous solution is: the mass percent that adding post chlorization sodium accounts for overall solution volume is 1~36% (W/V), is preferably 5~10% (W/V);
Moxifloxacin hydrochloride working method of the present invention, recrystallization temperature is 0~40 ℃ behind the adding sodium-chlor, is preferably 5~20 ℃, most preferably is 15 ℃;
Moxifloxacin hydrochloride working method of the present invention, the crystallization time is 0.5~36h behind the adding sodium-chlor, is preferably 12~24h;
Moxifloxacin hydrochloride working method of the present invention, Heating temperature is 50~100 ℃ during recrystallization, is preferably 80~90 ℃;
Moxifloxacin hydrochloride working method of the present invention, the add-on of water is 7~20 times (W/W) during recrystallization, is preferably 8~10 times;
Moxifloxacin hydrochloride working method of the present invention, temperature was 60 ℃~110 ℃ when the Moxifloxacin hydrochloride highly finished product were dry, was preferably 80 ℃.
Embodiment
Embodiment only further specifies summary of the invention, is not limited to the embodiment content.
Embodiment 1
In the aqueous solution 1100L that contains the 43kg Moxifloxacin hydrochloride of having an appointment, add sodium-chlor 55kg, 15 ℃ are stirred the 24h crystallization, centrifugal, and 60 ℃ of vacuum-drying 12h get faint yellow Moxifloxacin hydrochloride bullion 29.3kg, yield: 68.1%.
Moxifloxacin hydrochloride bullion 29.3kg is dropped in the 650L water, be heated to backflow, all the dissolving back is centrifugal, and mother liquor leaves standstill crystallization 12h in 5 ℃, and centrifugal, 80 ℃ of forced air drying 5h promptly get Moxifloxacin hydrochloride finished product 21.2kg, yield: 71.7%.
Inspection after construction: content is greater than 99.5%, and the related substance list is assorted less than 0.1%, and total impurities is less than 0.2%.
Embodiment 2
Add sodium-chlor 25kg to the aqueous solution 250L that contains the 10kg Moxifloxacin hydrochloride of having an appointment, stirring at room 8h crystallization, centrifugal, 110 ℃ of forced air dryings get faint yellow Moxifloxacin hydrochloride bullion 7.15kg, yield: 71.5%.
To go up step gained bullion and drop in the 200L water, and be heated to backflow, all the dissolving back is centrifugal, and mother liquor leaves standstill crystallization 12h in 25 ℃, and centrifugal, 110 ℃ of forced air drying 5h promptly get Moxifloxacin hydrochloride finished product pale yellow powder 4.5kg, yield: 63.8%.
Inspection after construction: content is greater than 99.5%, and the related substance list is assorted less than 0.1%, and total impurities is less than 0.2%.
Embodiment 3
Add sodium-chlor 2.4kg to the aqueous solution 300L that contains the 20kg Moxifloxacin hydrochloride, 0 ℃ of stirring and crystallizing 12h, centrifugal, 60 ℃ of forced air dryings get faint yellow Moxifloxacin hydrochloride bullion 17.8kg, yield: 89%.
To go up step gained bullion and drop in the 320L water, and be heated to backflow, all the dissolving back is centrifugal, and mother liquor leaves standstill crystallization 8h in 0 ℃, and centrifugal, 90 ℃ of forced air drying 5h promptly get Moxifloxacin hydrochloride finished product pale yellow powder 12.6kg, yield: 71%.
Inspection after construction: content is greater than 99.5%, and the related substance list is assorted less than 0.1%, and total impurities is less than 0.2%.
Embodiment 4
Add sodium-chlor 12.5kg to the aqueous solution 250L that contains the 10kg Moxifloxacin hydrochloride, 40 ℃ of stirring and crystallizing 12h, centrifugal, 80 ℃ of forced air dryings get faint yellow Moxifloxacin hydrochloride bullion 3.81kg, yield: 38.1%.
To go up step gained bullion and drop in the 75L water, and be heated to backflow, all the dissolving back is centrifugal, and mother liquor leaves standstill crystallization 8h in 5 ℃, and centrifugal, 110 ℃ of forced air drying 5h promptly get Moxifloxacin hydrochloride finished product pale yellow powder 2.72kg, yield: 70.3%.
Inspection after construction: content is greater than 99.5%, and the related substance list is assorted less than 0.1%, and total impurities is less than 0.2%.
Embodiment 5
In the aqueous solution 30L that contains the 1kg Moxifloxacin hydrochloride, add sodium-chlor 10.8kg, 10 ℃ of stirring and crystallizing 6h, centrifugal, 60 ℃ of forced air dryings get faint yellow Moxifloxacin hydrochloride bullion 0.9kg, yield: 90%.
To go up step gained bullion and drop in the 20L water, and be heated to backflow, all the dissolving back is centrifugal, and mother liquor leaves standstill crystallization 8h in 5 ℃, and centrifugal, 80 ℃ of forced air drying 5h promptly get Moxifloxacin hydrochloride finished product pale yellow powder 0.63kg, yield: 69.7%.
Inspection after construction: content is greater than 99.5%, and the related substance list is assorted less than 0.1%, and total impurities is less than 0.2%.
Embodiment 6
In the aqueous solution 20L that contains the 2kg Moxifloxacin hydrochloride, add sodium chloride saturated solution (36%) 20L, 15 ℃ of stirring and crystallizing 36h, centrifugal, 60 ℃ of forced air dryings get faint yellow Moxifloxacin hydrochloride bullion 1.45kg, yield: 72.5%.
To go up step gained bullion and drop in the 15L water, and be heated to backflow, all the dissolving back is centrifugal, and mother liquor leaves standstill crystallization 8h in 5 ℃, and centrifugal, 80 ℃ of forced air drying 5h promptly get Moxifloxacin hydrochloride finished product pale yellow powder 1.01kg, yield: 69.7%.
Inspection after construction: content is greater than 99.5%, and the related substance list is assorted less than 0.1%, and total impurities is less than 0.2%.

Claims (5)

1. the method for a suitability for industrialized production Moxifloxacin hydrochloride, concrete operation method is: in containing the aqueous solution of Moxifloxacin hydrochloride, add sodium-chlor, the stirring and crystallizing after-filtration, drying with the water recrystallization, is filtered, and is drying to obtain.
2. the method for suitability for industrialized production Moxifloxacin hydrochloride according to claim 1 is characterized in that, in containing the aqueous solution of Moxifloxacin hydrochloride, the amount of the sodium-chlor of adding is 0.8~36%W/V.
3. the method for suitability for industrialized production Moxifloxacin hydrochloride according to claim 1 is characterized in that, behind the adding sodium-chlor, the temperature that contains the aqueous solution crystallization of Moxifloxacin hydrochloride is 0~60 ℃.
4. the method for suitability for industrialized production Moxifloxacin hydrochloride according to claim 1 is characterized in that, drying means is 60 ℃~120 ℃ air blast or vacuum-drying.
5. the method for suitability for industrialized production Moxifloxacin hydrochloride according to claim 1 is characterized in that, the ratio of water is 1: 8~1 during recrystallization: 20W/V.
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CN102321083B (en) * 2011-07-14 2013-05-15 福建省福抗药业股份有限公司 Preparation method of new anhydrous moxifloxacin hydrochloride crystal F
CN102344447B (en) * 2011-07-20 2013-09-18 华润赛科药业有限责任公司 Moxifloxacin hydrochloride monohydrate crystal form and preparation method thereof
CN103183671A (en) * 2011-12-29 2013-07-03 天津康鸿医药科技发展有限公司 Novel moxifloxacin hydrochloride crystal, and preparation method and application thereof
CN103183672A (en) * 2011-12-29 2013-07-03 天津康鸿医药科技发展有限公司 Novel moxifloxacin hydrochloride crystal, and preparation method and application thereof
CN102603738B (en) * 2012-02-24 2013-12-11 天津市汉康医药生物技术有限公司 Stable moxifloxacin hydrochloride compound
CN102924449B (en) * 2012-10-30 2015-08-12 重庆福安药业集团庆余堂制药有限公司 Moxifloxacin hydrochloride H crystal form and preparation method thereof and pharmaceutical composition
CN103869033B (en) * 2012-12-14 2016-10-05 南京长澳医药科技有限公司 A kind of liquid chromatography for separating and determining moxifloxacin hydrochloride and the method for impurity thereof
CN103965189B (en) * 2013-12-30 2015-09-09 西安万隆制药股份有限公司 A kind of new moxifloxacin hydrochloride compound
CN104817557B (en) * 2014-04-04 2017-05-31 江苏天一时制药有限公司 Stable crystal form of moxifloxacin hydrochloride and preparation method thereof
CN104725377B (en) * 2014-04-04 2017-06-06 江苏天一时制药有限公司 Crystal form of moxifloxacin hydrochloride and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1368891A (en) * 1999-08-06 2002-09-11 拜尔公司 Moxilfloxacin formulation containing common salt
CN101817820A (en) * 2009-07-30 2010-09-01 重庆博腾精细化工有限公司 Method for synthesizing moxifloxacin hydrochloride

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1368891A (en) * 1999-08-06 2002-09-11 拜尔公司 Moxilfloxacin formulation containing common salt
CN101817820A (en) * 2009-07-30 2010-09-01 重庆博腾精细化工有限公司 Method for synthesizing moxifloxacin hydrochloride

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