CN104098561A - High optical purity moxifloxacin hydrochloride production method suitable for industrialized production - Google Patents

Abstract

The invention provides a high optical purity moxifloxacin hydrochloride production method suitable for industrialized production; moxifloxacin hydrochloride containing 0.2 ~ 5% of optical isomers is used as a raw material for preparation of moxifloxacin hydrochloride with the optical isomer content less than 0.01% (compound shown as formula I). The new high optical purity moxifloxacin hydrochloride production method avoids the resolution of a conventional chiral reagent, by use of own different basic strength, the high optical purity moxifloxacin hydrochloride can be obtained by the acid-base neutralization method, the high optical purity moxifloxacin hydrochloride product is low in production cost, high in yield, simple in process and suitable for industrialized production.

Description

A kind of method of preparing high-optical-purity Moxifloxacin hydrochloride of applicable suitability for industrialized production

Technical field

The present invention relates to a kind of for improving the preparation method of medicine industry Chinese traditional medicine active compound Moxifloxacin hydrochloride optical purity.

Technical background

Moxifloxacin hydrochloride (moxifloxacin hydrochloride), chemistry 1-cyclopropyl by name-7-[(S, S)-2,8-diazonium-bis-encircle [4.3.0] nonanal-8-group] the fluoro-8-of-6-methoxy-1,4-dihydro-4-oxygen-3-quinoline carboxylic acid hydrochloride, its structural formula is as formula I.This medicine is wide spectrum fluoroquinolone medicine of new generation, and gram-positive and negative pathogenic agent (comprising anerobe, intracellular pathogen and the bacterial strain to beta-lactam or Macrolide antimicrobial drug resistance) are all had to anti-microbial activity widely.Be used for the treatment of clinically the adult who suffers from the upper respiratory tract and lower respiratory infection.Moxifloxacin hydrochloride is developed by German Bayer company, and in September, 1999, examined December in the same year by U.S. FDA first in Germany's listing, and approval listing, successively in Britain, the U.S., Mexico's application.China is in 2002 by Bayer listing Moxifloxacin tablet, and Moxifloxacin sodium chloride injection goes on the market for 2004.

In Moxifloxacin hydrochloride molecular structure, having two chiral centres, is chipal compounds, belongs to chiral drug.

Large quantity research and clinical practice show, two kinds of enantiomorphs of chiral drug usually have different biologic activity and function, restriction chiral drug DL body is produced, and develops single enantiomer medicine, has become the set policy of various countries' medical control decision-making section and pharmaceutical industry.Therefore must the strict content of controlling isomer, how efficient highly selective make individual isomer, be pendulum huge challenge in face of us.

The synthetic of the Moxifloxacin hydrochloride of bibliographical information is mainly quinoline carboxylic acid's parent nucleus and chiral side chain condensation preparation under protection or unprotected condition:

The synthetic method of the disclosed Moxifloxacin hydrochloride of patent EP1832587 is as follows:

The synthetic method of patent WO2005012285, the disclosed Moxifloxacin hydrochloride of WO2008059223 is as follows:

Moxifloxacin hydrochloride chirality is introduced by chiral side chain ((S, S)-2,8-diazabicyclo [4,3,0] nonane), and in the preparation method of above-mentioned report, chiral side chain ee value is 100%, without isomer.(S, S)-2,8-diazabicyclo [4,3,0] nonane is synthetic as follows:

(S, S)-2, need through chiral separation in the preparation of 8-diazabicyclo [4,3,0] nonane, split weak effect, and product yield is low.(S, the S) selling on domestic market-2,8-diazabicyclo [4,3,0] nonane product content of isomer is 0.1 ~ 5%.Isomer follows reaction to be brought in the finished product Moxifloxacin hydrochloride.Such product cannot reach medicinal standard.

As obtained the more Moxifloxacin hydrochloride of high-optical-purity, can only carry out chiral separation to chiral side chain or Moxifloxacin.Chiral side chain is small molecules saturated alkane, a little less than resolution reagent bonding force, splits weak effect, and product yield is low, therefore with purity, improves, and product price sharply increases.

Patent EP1992626 use respectively L-TARTARIC ACID, fumaric acid, bis-pairs of toluyl tartrate of L-in N ' dinethylformamide (DMF) to splitting containing the Moxifloxacin hydrochloride of 3 ~ 5% isomer, split efficiency as following table:

Resolution reagent	Content of isomer before splitting	Content of isomer after splitting	Yield
				L-TARTARIC ACID	3~5%	0.04%	90.2%
Fumaric acid	3~5%	3~5%	89.2%
				Bis-pairs of toluyl tartrate of L-	3~5%	0.1%	81.9%

The method of preparing Moxifloxacin hydrochloride of above-mentioned bibliographical information need to split with chiral selectors, this method exist product cost high, need the problems such as chiral separation, DMF organic solvent aftertreatment trouble, restriction Moxifloxacin hydrochloride suitability for industrialized production.

Summary of the invention

In order to improve the optical purity of Moxifloxacin hydrochloride product, reduce production costs, we are in Moxifloxacin hydrochloride preparation research process, develop a kind of method of raising Moxifloxacin hydrochloride optical purity of applicable suitability for industrialized production, technique of the present invention is simple, cost is low, yield is high, without chiral selectors, optical purity of products is high.

Whether Moxifloxacin alkalescence is relevant with the raw conjugation of quinoline environment-development to 8 nitrogen-atoms lone electron pairs of side chain, owing to being subject to sterically hindered impact, (S, S) configuration Moxifloxacin side chain 8-nitrogen-atoms lone electron pair can not with quinoline ring conjugation, and (R, R) configuration Moxifloxacin side chain 8-nitrogen-atoms lone electron pair can with quinoline ring conjugation.By conjugative effect, side chain 8-nitrogen-atoms cloud density is reduced, and alkalescence strengthen.

The technical solution adopted in the present invention is: will be containing the Moxifloxacin hydrochloride of 0.2 ~ 5% isomer in organic solvent, add alkali, by soda acid principle,displacement, by controlling the consumption of alkali, first by weakly alkaline (S, S) configuration Moxifloxacin hydrochloride is transformed into Moxifloxacin base form and is dissolved in organic solvent, and alkaline (R, R) configuration Moxifloxacin hydrochloride does not react, and is still insoluble to organic solvent, filters, filtering insolubles, filtrate adds concentrated hydrochloric acid, then is transformed into hydrochloride form and separates out, and is prepared into high optical purity Moxifloxacin hydrochloride.

The invention provides a kind of method of preparing high-optical-purity Moxifloxacin hydrochloride, its step is as follows:

Will be containing the Moxifloxacin hydrochloride of 0.2 ~ 5% isomer in organic solvent, add alkali, be converted into Moxifloxacin base form, it is dissolved in organic solvent, filter the solid salt that filtering is insoluble, filtrate adds concentrated hydrochloric acid, adjust pH to 1, stirring and crystallizing, is prepared into high optical purity Moxifloxacin hydrochloride.

Described organic solvent is any one or multiple mixed solvent in ethanol, methyl alcohol, acetone, Virahol, acetonitrile etc., preferred alcohol, more preferably dehydrated alcohol.

Described alkali is organic bases or mineral alkali, and particularly preferred is sodium hydroxide, triethylamine, ammoniacal liquor.

Described dissolving mineral alkali agents useful for same is anhydrous organic reagent.

Described is 1:0.9 ~ 1:1.2 for the molar fraction ratio with Moxifloxacin hydrochloride alkali, and particularly preferred ratio is 1:1.

Beneficial effect

Compared with prior art, improvements of the present invention are the methods that do not split by chiral reagent, by conventional soda acid neutralization method, prepare the Moxifloxacin hydrochloride of high-optical-purity.The present invention can greatly reduce the production cost of product: (1) (S, S)-2,8-diazabicyclo [4,3,0] nonane product price is relevant with content of isomer, content of isomer more low price is more expensive, and the Moxifloxacin hydrochloride that the present invention uses the high and low optical purity chiral side chain of content of isomer to prepare low optical purity is raw material, low price.(2) without chiral separation, avoid the chiral selectors that uses price high, use conventional organic solvent, be convenient to recycle and reuse.

Meanwhile, Moxifloxacin hydrochloride optical purity high (ee%>99.8%) prepared by this law, product yield is high, and technique is simple, and reaction conditions gentleness is easy to control, and aftertreatment energy consumption is low, is applicable to suitability for industrialized production.

Accompanying drawing explanation

Fig. 1 raceme Moxifloxacin hydrochloride HPLC figure

Fig. 2 processes front Moxifloxacin hydrochloride HPLC figure

The Moxifloxacin hydrochloride HPLC figure of Fig. 3 embodiment 1 preparation

The Moxifloxacin hydrochloride HPLC figure of Fig. 4 embodiment 2 preparations

The Moxifloxacin hydrochloride HPLC figure of Fig. 5 embodiment 3 preparations

The Moxifloxacin hydrochloride HPLC figure that Fig. 6 is prepared according to patent EP1992626

Specific implementation method

Should be appreciated that, those skilled in the art, based on this disclosed content, can carry out various various modifications and the improvement that do not depart from spirit and scope of the invention to the present invention.They should drop in the application's the scope of patent protection of patent requirements definition.In addition, should be appreciated that, embodiment provided herein is only for object of the present invention is described, and should not be construed as restriction of the present invention.

Embodiment 1: the preparation of Moxifloxacin hydrochloride

In 50L reactor, add dehydrated alcohol 20L, add Moxifloxacin hydrochloride 2kg, under the condition of stirring, splash into sodium hydrate methanol solution (1L, NaOH182.6g), stirring at room 0.5h, filters, filtrate is adjusted pH ≈ 1 with concentrated hydrochloric acid, and stirring at room 1h filters, and obtains Moxifloxacin hydrochloride 1.92kg.

Yield: 96.0%

Content of isomer: 0.01%

Embodiment 2: the preparation of Moxifloxacin hydrochloride

In 50L reactor, add dehydrated alcohol 20L, add Moxifloxacin hydrochloride 2kg, under the condition of stirring, splash into triethylamine 632mL, be heated to 60 ℃ of stirring reactions 30 minutes, be chilled to 20～25 ℃, filter, filtrate is adjusted pH ≈ 1 with concentrated hydrochloric acid, and stirring at room 1h filters, and obtains Moxifloxacin hydrochloride 1.78kg.

Yield is 89.0%.

Content of isomer: do not detect

Embodiment 3: the preparation of Moxifloxacin hydrochloride

In 50L reactor, add dehydrated alcohol 20L, add Moxifloxacin hydrochloride 2kg, under the condition of stirring, splash into strong aqua 280mL, stirring at room 0.5h, filters, and filtrate is adjusted pH ≈ 1 with concentrated hydrochloric acid, and stirring at room 1h filters, and obtains Moxifloxacin hydrochloride 1.69kg.

Yield: 84.5%

Content of isomer: 0.01%

Comparative example 1: patent EP1992626 method for splitting

In 750mlDMF solution, add 50g Moxifloxacin, 18.7gL-(+)-tartrate, stirring reaction is 3 hours at 75 ~ 80 ℃, is cooled to 25 ~ 30 ℃ and stirs 10 ~ 12 hours after reaction finishes.Suction filtration, solid washs with 100mlDMF, 75 ℃ of vacuum-dryings obtain tartrate Moxifloxacin 67.3g(98.08%).

50g tartrate Moxifloxacin is added in 250ml ethanol and the 250ml aqueous solution, stir, at 25 ~ 30 ℃, add 16.6ml concentrated hydrochloric acid, at this temperature, stirring reaction is 1 hour, suction filtration, filter cake 100ml washing with alcohol, 50 ~ 55 ℃ of vacuum-drying 3 hours, obtains Moxifloxacin hydrochloride 35.10g(88.3%).

Yield: 86.61%

Content of isomer: 0.05%

Analytical procedure

Get the product making in above-described embodiment 1 to 3 and comparative example 1 appropriate, add moving phase and dissolve and dilute the solution of making in every 1ml approximately containing 1.0mg, as need testing solution.According to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010), measure.With octadecylsilane chemically bonded silica, being weighting agent, is moving phase with copper sulfate L-Phe solution (get copper sulfate 1g and L-Phe 1.32g, add after water 1000ml dissolving, regulate pH to 3.5 with sodium hydroxide test solution)-methyl alcohol (71:29); Flow velocity is 1.0ml/min; Column temperature is 35 ℃, and detection wavelength is 293nm.Cancel that to revolve Moxifloxacin hydrochloride reference substance appropriate, add moving phase and dissolves and dilute in right amount and make the solution that approximately contains 0.2mg in every 1ml, get 10 μ l injection liquid chromatographies, record color atlas, dextrorotatory isomer, Moxifloxacin flow out successively, and resolution should meet the requirements.Precision measures need testing solution 10 μ l, and injection liquid chromatography, records color atlas, by normalization method, calculates.

Accordingly result sees the following form

?	Content of isomer (%) before processing	Content of isomer after processing	Yield (%)
				Embodiment 1	1.21	0.01	96.00
Embodiment 2	1.21	0	89.00
				Embodiment 3	1.21	0.01	84.50
Comparative example 1	1.21	0.05	86.61

Claims (7)

1. a method of preparing high-optical-purity Moxifloxacin hydrochloride, it is characterized in that: the Moxifloxacin hydrochloride of take containing 0.2 ~ 5% optical isomer is raw material, in organic solvent, add alkali, Moxifloxacin hydrochloride is transformed into Moxifloxacin base form, filter, filtering is not tolerant, adds concentrated hydrochloric acid in organic phase, filter, obtain high optically pure Moxifloxacin hydrochloride.

2. the method for claim 1, wherein organic solvent is any one or multiple mixed solvent in ethanol, methyl alcohol, acetone, Virahol, acetonitrile etc.

3. method as claimed in claim 2, wherein organic solvent is ethanol.

4. method as claimed in claim 3, wherein organic solvent is dehydrated alcohol.

5. the method for claim 1, wherein described in it, alkali is a kind of in sodium hydroxide, triethylamine, ammoniacal liquor.

6. method as claimed in claim 1, the molar fraction of Moxifloxacin hydrochloride and alkali is than being 1:(1-1.2).

7. the method for claim 1, wherein starting raw material Moxifloxacin is hydrochloride form.