CN101941969A - Preparation method of moxifloxacin hydrochloride - Google Patents
Preparation method of moxifloxacin hydrochloride Download PDFInfo
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- CN101941969A CN101941969A CN 201010298408 CN201010298408A CN101941969A CN 101941969 A CN101941969 A CN 101941969A CN 201010298408 CN201010298408 CN 201010298408 CN 201010298408 A CN201010298408 A CN 201010298408A CN 101941969 A CN101941969 A CN 101941969A
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- moxifloxacin
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- 229960005112 moxifloxacin hydrochloride Drugs 0.000 title claims abstract description 37
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims abstract description 34
- 229960003702 moxifloxacin Drugs 0.000 claims abstract description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 150000007530 organic bases Chemical class 0.000 claims abstract description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 12
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 12
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 claims description 2
- WQJZXSSAMGZVTM-UHFFFAOYSA-N 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(F)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 WQJZXSSAMGZVTM-UHFFFAOYSA-N 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 10
- 239000012043 crude product Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- KUGSJJNCCNSRMM-UHFFFAOYSA-N ethoxyboronic acid Chemical compound CCOB(O)O KUGSJJNCCNSRMM-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- VRYNZIGRLQJLKW-AREMUKBSSA-N CCCC[C@](C)(CN(C1)c(c(F)cc2c3N(C4CC4)C=C(C(OC)=O)C2=O)c3O)C1(C=C)C=C Chemical compound CCCC[C@](C)(CN(C1)c(c(F)cc2c3N(C4CC4)C=C(C(OC)=O)C2=O)c3O)C1(C=C)C=C VRYNZIGRLQJLKW-AREMUKBSSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- XUBOMFCQGDBHNK-UHFFFAOYSA-N gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCNC(C)C1 XUBOMFCQGDBHNK-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- JMVWCCOXRGFPJZ-UHFFFAOYSA-N propoxyboronic acid Chemical compound CCCOB(O)O JMVWCCOXRGFPJZ-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960004954 sparfloxacin Drugs 0.000 description 1
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 description 1
- 208000022218 streptococcal pneumonia Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of moxifloxacin hydrochloride, comprising the steps of: reacting the 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid and the S,S-2,8-diazabicyclo[4.3.0]nonane to prepare the moxifloxacin in the presence of organic base in organic solvent under the reaction temperature of 60 to 85 DEG C; separating the moxifloxacin, processing the moxifloxacin by concentrated hydrochloric acid in organic solvent under the reaction temperature of 60 to 85 DEG C to obtain the moxifloxacin hydrochloride.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of preparation method of Moxifloxacin hydrochloride.
Background technology
Moxifloxacin hydrochloride (moxifloxacin hydrochloride, 1-cyclopropyl-7-(S, S-2,8-diazabicyclo [4.3.0] nonane-8-yl)-6-fluoro-8-methoxyl group-4-oxo-1,4-dihydro-3-quinoline carboxylic acid hydrochloride) be the 4th generation the fluoroquinolone antibacterial agent thing.It has broad-spectrum antibacterial action, as human and animal's antibacterials, can treat the infection that various bacteria causes effectively, and structural formula is as follows:
Moxifloxacin is highly effective antiseptic-germicide, and describes first in patent EP0350733.EP0550903 discloses Moxifloxacin, and (S, S) structure demonstrate gram positive organism, comprise streptococcal pneumonia, streptococcus aureus, streptococcus pyogenes, have better anti-microbial activity than Sparfloxacin and Ciprofloxacin.
US5157117 discloses 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1, and 4-dihydro-3-quinoline carboxylic ester prepares the inner complex of corresponding ethyl-borate with boric acid and acetic anhydride in the presence of zinc chloride, it is prepared into GATIFLOXACIN.
CN101514201 discloses 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid ethyl ester prepares the inner complex of corresponding ethyl-borate with boric acid and acetic anhydride in the presence of zinc chloride, with S, S-2,8-diazabicyclo [4.3.0] the nonane 3h that in the presence of alkali and solvent, refluxes, the evaporated under reduced pressure solvent, resistates adds sherwood oil, filters the solid that obtains and is dissolved in 7% NaOH solution, 80 ℃ are stirred 3h down, reduce to the room temperature after-filtration, filtrate transfers to neutrality with 5% acetum, filtration drying, obtain Moxifloxacin, yield is 72.6%.
WO2008059223A2 discloses 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1, the inner complex of 4-dihydro-3-quinoline carboxylic acid ethyl ester and boric acid and the corresponding boric acid propyl ester of propionic anhydride prepared in reaction, in the presence of organic bases with S, S-2,100 ℃ of reactions of 8-diazabicyclo [4.3.0] nonane 3h, regulate PH to 1.0-2.0 with hydrochloric acid after cooling to 25-30 ℃, resistates adds entry behind the evaporate to dryness, regulates PH to 7.5-9.0 with ammoniacal liquor, extraction back solvent evaporated, the resistates dissolve with methanol, hydrochloric acid is regulated PH to 1.0-2.0, filters, drying under reduced pressure obtains Moxifloxacin hydrochloride, and yield is 55.6%.
EP1992626 discloses 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2,8-diazabicyclo [4.3.0] nonane, with DMF or DMSO is solvent, reacts 6-8h down at 65-70 ℃, and reaction system is cooled to 25-30 ℃, add entry and stir 2h, filtering product washes with water, and 75 ℃ of following drying under reduced pressure obtain the crude product Moxifloxacin.With L (+)-tartrate or fumaric acid is solvent with DMF, and Moxifloxacin is carried out chiral separation, removes (R, R) isomer impurities obtains corresponding Moxifloxacin salt, adds concentrated hydrochloric acid under the room temperature, filter, 50-55 ℃ of drying under reduced pressure obtains Moxifloxacin hydrochloride, and yield is 68.8%.
Exist in the aforesaid method yield on the low side, need the chirality folding problem of grading, had a strong impact on the cost of Moxifloxacin hydrochloride, restricted the industrial production of Moxifloxacin hydrochloride.
Summary of the invention
The objective of the invention is on the basis of existing technology, provide that a kind of technology is simple, cost is low, yield is high, be fit to the preparation method of industrial Moxifloxacin hydrochloride.
Purpose of the present invention can reach by following measure:
A kind of preparation method of Moxifloxacin hydrochloride may further comprise the steps:
(a) in organic solvent, temperature of reaction is 60-85 ℃, and organic bases exists down, with 1-cyclopropyl-6, and 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2,8-diazabicyclo [4.3.0] nonane prepared in reaction Moxifloxacin;
(b) Moxifloxacin is separated, in organic solvent, temperature of reaction is 60-85 ℃, handles Moxifloxacin with concentrated hydrochloric acid, is converted into Moxifloxacin hydrochloride.
The reaction scheme of present method is as follows:
Be selected from acetonitrile, tetrahydrofuran (THF), methyl alcohol, dehydrated alcohol or the Virahol one or more at the organic solvent described in the step (a); Be preferably selected from acetonitrile or the tetrahydrofuran (THF) one or more, more preferably acetonitrile.
1-cyclopropyl-6 in the step (a), 7-two fluoro-8-methoxyl group-4-oxos-1, the mass volume ratio of 4-dihydro-3-quinoline carboxylic acid and organic solvent is 1:3～1:20(g/ml), is preferably 1:4～1:10(g/ml), more preferably 1:5.Organic bases described in the step (a) is selected from triethylamine, 1,8-diazacyclo [5,4,0]-7-hendecene, N, in the N-diisopropylethylamine one or more are preferably selected from triethylamine, 1,8-diazacyclo [5,4,0]-in the 7-hendecene one or more, more preferably triethylamine.1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1, the mol ratio of 4-dihydro-3-quinoline carboxylic acid and organic bases is 1:0.1～1:2, is preferably 1:0.1～1:1, more preferably 1:0.2.
1-cyclopropyl-6 in the step (a), 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2, the mol ratio of 8-diazabicyclo [4.3.0] nonane is 1:1～1:1.2, is preferably 1:1～1:1.1, more preferably 1:1.1.
In one embodiment, step (a) adopts following steps: earlier with 1-cyclopropyl-6, and 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid is dissolved in the acetonitrile, stirs under the room temperature to add S, S-2 down, 8-diazabicyclo [4.3.0] nonane, triethylamine is warming up to backflow, reaction 5h, after being cooled to room temperature, 0 ℃ of crystallization 12h filters, the minor amounts of acetonitrile washing leaching cake obtains the crude product Moxifloxacin.
Organic solvent described in the step (b) is selected from one or more in anhydrous methanol, dehydrated alcohol, Virahol or the tetrahydrofuran (THF), is preferably selected from anhydrous methanol, dehydrated alcohol, the Virahol one or more, more preferably dehydrated alcohol.The mass volume ratio of Moxifloxacin and organic solvent is 1:10～1:30(g/ml) in the step (b), is preferably 1:15～1:25(g/ml), more preferably 1:20.
The mol ratio of Moxifloxacin and concentrated hydrochloric acid is 1:1～1:4 in the step (b), preferred 1:1～1:1.2, more preferably 1:1.Wherein concentrated hydrochloric acid can be selected the concentration of 31%-37% for use, preferably adopts the concentration of 35%-37%.
Before Moxifloxacin separates back and hydrochloric acid reaction in the step (b), be that 1.33～3.33kpa, temperature are dry under 30-50 ℃ the condition to Moxifloxacin at pressure earlier; Moxifloxacin hydrochloride preparation and separate after, be that 1.33～3.33kpa, temperature are drying treatment under 40-50 ℃ the condition at pressure.
The separation of indication can be various separation means commonly used such as crystallization, filtration in present method.
The Moxifloxacin hydrochloride that step (b) obtains can further carry out refinement treatment, with the higher product of preparation purity.
In one embodiment, step (b) adopts following steps: be dissolved in the dehydrated alcohol after will Moxifloxacin separating, reflux state adds concentrated hydrochloric acid down, be cooled to room temperature after, 0 ℃ of crystallization 12h filters, a small amount of absolute ethanol washing filter cake obtains Moxifloxacin hydrochloride.
According to a preferred embodiment of the invention, the method for preparing Moxifloxacin hydrochloride comprises the following steps:
(a) with the acetonitrile be solvent, temperature of reaction is 60-85 ℃, and triethylamine exists down, with 1-cyclopropyl-6, and 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2, the reaction of 8-diazabicyclo [4.3.0] nonane is converted into Moxifloxacin;
(b) with after the separation of the Moxifloxacin in the step (a), be 1.33～3.33kpa at pressure, temperature is a 30-50 ℃ of drying down;
(c) with ethanol be solvent, temperature of reaction is 60-85 ℃, and the Moxifloxacin with concentrated hydrochloric acid treatment step (b) obtains is converted into Moxifloxacin hydrochloride;
(d) with after the separation of the Moxifloxacin hydrochloride in the step (c), be 1.33～3.33kpa at pressure, temperature is a 40-50 ℃ of drying down.
The present invention is with 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid is a raw material, by with S, S-2,8-diazabicyclo [4.3.0] nonane replaces, be converted into the Moxifloxacin hydrochloride that hydrochloride, recrystallizing and refining have obtained high yield and purity with the concentrated hydrochloric acid reaction, its quality product height, and technology is simple, the reaction conditions gentleness is easy to control, reaction solvent easily reclaims and recycling, and the aftertreatment energy consumption is low, and reaction process is difficult for taking place racemization, need not to split, be difficult for producing dissolvent residual, cost is low, is fit to suitability for industrialized production.
Embodiment
Should be appreciated that those skilled in the art can carry out various various modifications and the improvement that do not depart from the spirit and scope of the invention to the present invention based on content disclosed herein.They should all drop in the application's the scope of patent protection of claim definition.In addition, should be appreciated that embodiment provided herein only is used to purpose of the present invention is described, and should not be construed as restriction of the present invention.
Embodiment 1: the preparation of Moxifloxacin
In three mouthfuls of round-bottomed flasks of 500 mL, add acetonitrile 300 mL, add 1-cyclopropyl-6 under the stirring at room successively, 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid 59.0 g(0.2 mol), S, S-2,8-diazabicyclo [4.3.0] nonane 27.8 g(0.22 mol), triethylamine 4.0 g(0.04 mol), be warming up to 80 ℃ gradually, stop heating behind the back flow reaction 5h, after continuation is stirred and is cooled to room temperature, 0 ℃ of following stirring and crystallizing 12h, filter, 10 mL * 3 acetonitrile washing leaching cakes are 1.33～3.33 kpa at pressure, temperature is under 50 ℃, drying obtains crude product Moxifloxacin 73.2 g, and yield is 91.2%, and it is 98.46% that HPLC detects purity.
Embodiment 2: the preparation of Moxifloxacin
In three mouthfuls of round-bottomed flasks of 2000 mL, add tetrahydrofuran (THF) 1180 mL, add 1-cyclopropyl-6 under the stirring at room successively, 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid 118.1 g(0.4mol), S, S-2,8-diazabicyclo [4.3.0] nonane 55.5 g(0.44 mol), N, N-diisopropylethylamine 25.8 g(0.2 mol), be warming up to 80 ℃ gradually, stop heating behind the back flow reaction 7h, after continuation was stirred and is cooled to room temperature, 0 ℃ of following stirring and crystallizing 12h filtered, 20 mL * 3 acetonitrile washing leaching cakes, at pressure is 1.33～3.33 KPa, and temperature is under 50 ℃, and drying obtains crude product Moxifloxacin 144.2 g, yield is 89.8%, and it is 98.79% that HPLC detects purity.
Embodiment 3: the preparation of Moxifloxacin hydrochloride
In three mouthfuls of round-bottomed flasks of 3 L, add dehydrated alcohol 1.46 L, add crude product Moxifloxacin 73.2 g(0.182 mol under the stirring at room), be warming up to backflow gradually, add concentrated hydrochloric acid 18.5 g(0.182 mol), stop heating, after continuation was stirred and is cooled to room temperature, 0 ℃ of following stirring and crystallizing 12h filtered, 50 mL * 3 absolute ethanol washing filter cakes, at pressure is 1.33～3.33 kpa, and temperature is under 50 ℃, and drying obtains crude product Moxifloxacin hydrochloride 72.4 g, yield is 90.8%, and it is 99.87% that HPLC detects purity.
1H-NMR?(500MHz,?DMSO-d6)?δ(ppm):?0.88～0.90?(m,1H),?1.00～1.06?(m,1H),?1.08～1.13?(m,1H),?1.16～1.22?(m,1H),?1.69～1.84?(m,4H),?2.64～2.66?(m,1H),?2.90～2.94?(m,1H),?3.17-3.19?(m,1H),?3.59?(s,3H),?3.62?(s,1H),?3.73～3.77?(m,1H),?3.85～3.90?(m,2H),?4.05～4.09?(m,1H),?4.12～4.17?(m,1H),?7.68?(d,1H),?8.66?(s,1H),?8.87?(s,1H),?10.12?(s,1H),?15.12?(s,1H)。
13C-NMR?(125MHz,?DMSO-d6)?δ(ppm):?8.30,?9.48,?17.47,?20.46,?34.05,?40.52,?41.39,?51.78,?54.00,?54.37,?61.80,?106.38,?117.24,?134.44,?136.61,?140.38,?150.26,?151.44,?153.43,?165.73,?175.91。
MS?(ESI):?402?[M-HCl+H]
?+?。
Embodiment 4: the preparation of Moxifloxacin hydrochloride
In three mouthfuls of round-bottomed flasks of 5 L, add dehydrated alcohol 2.88L, add crude product Moxifloxacin 144.2 g(0.359 mol under the stirring at room), be warming up to backflow gradually, add concentrated hydrochloric acid 36.4 g(0.359 mol), stop heating, after continuation was stirred and is cooled to room temperature, 0 ℃ of following stirring and crystallizing 12h filtered, 100 mL * 3 absolute ethanol washing filter cakes, at pressure is 1.33～3.33 kpa, and temperature is under 50 ℃, and drying obtains crude product Moxifloxacin hydrochloride 143.8 g, yield is 91.5%, and it is 99.80% that HPLC detects purity.
Claims (10)
1. the preparation method of a Moxifloxacin hydrochloride may further comprise the steps:
(a) in organic solvent, temperature of reaction is 60-85 ℃, and organic bases exists down, with 1-cyclopropyl-6, and 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2,8-diazabicyclo [4.3.0] nonane prepared in reaction Moxifloxacin;
(b) Moxifloxacin is separated, in organic solvent, temperature of reaction is 60-85 ℃, handles Moxifloxacin with concentrated hydrochloric acid, is converted into Moxifloxacin hydrochloride.
2. the preparation method of Moxifloxacin hydrochloride according to claim 1 is characterized in that the organic solvent described in the step (a) is selected from one or more in acetonitrile, tetrahydrofuran (THF), methyl alcohol, dehydrated alcohol or the Virahol; Be preferably selected from acetonitrile or the tetrahydrofuran (THF) one or more.
3. the preparation method of Moxifloxacin hydrochloride according to claim 1, it is characterized in that 1-cyclopropyl-6 in the step (a), 7-two fluoro-8-methoxyl group-4-oxos-1, the mass volume ratio of 4-dihydro-3-quinoline carboxylic acid and organic solvent is 1:3～1:20(g/ml), is preferably 1:4～1:10(g/ml).
4. the preparation method of Moxifloxacin hydrochloride according to claim 1, it is characterized in that the organic bases described in the step (a) is selected from triethylamine, 1,8-diazacyclo [5,4,0]-and 7-hendecene, N, one or more in the N-diisopropylethylamine, be preferably selected from triethylamine, 1, in 8-diazacyclo [5,4,0]-7-hendecene one or more.
5. the preparation method of Moxifloxacin hydrochloride according to claim 1 is characterized in that 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1, and the mol ratio of 4-dihydro-3-quinoline carboxylic acid and organic bases is 1:0.1～1:2, is preferably 1:0.1～1:1.
6. the preparation method of Moxifloxacin hydrochloride according to claim 1 is characterized in that 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2, the mol ratio of 8-diazabicyclo [4.3.0] nonane is 1:1～1:1.2, is preferably 1:1～1:1.1.
7. the preparation method of Moxifloxacin hydrochloride according to claim 1, it is characterized in that the organic solvent described in the step (b) is selected from one or more in anhydrous methanol, dehydrated alcohol, Virahol or the tetrahydrofuran (THF), be preferably selected from anhydrous methanol, dehydrated alcohol, the Virahol one or more.
8. the preparation method of Moxifloxacin hydrochloride according to claim 1 is characterized in that in the step (b) that the mass volume ratio of Moxifloxacin and organic solvent is 1:10～1:30(g/ml), is preferably 1:15～1:25(g/ml).
9. the preparation method of Moxifloxacin hydrochloride according to claim 1 is characterized in that the mol ratio of middle Moxifloxacin of step (b) and concentrated hydrochloric acid is 1:1～1:4, preferred 1:1～1:1.2.
10. the preparation method of Moxifloxacin hydrochloride according to claim 1, it is characterized in that Moxifloxacin separates in the step (b) after, be that 1.33～3.33kpa, temperature are dry under 30-50 ℃ the condition to Moxifloxacin at pressure earlier; Moxifloxacin hydrochloride preparation and separate after, be that 1.33～3.33kpa, temperature are drying treatment under 40-50 ℃ the condition at pressure.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102321083A (en) * | 2011-07-14 | 2012-01-18 | 福建省福抗药业股份有限公司 | A kind of anhydrous hydrochloric acid Moxifloxacin new crystal F and preparation method thereof |
| CN102675313A (en) * | 2011-10-12 | 2012-09-19 | 郭峰 | Preparation method of moxifloxacin hydrochloride |
| CN102675306A (en) * | 2011-03-17 | 2012-09-19 | 苏州中科天马肽工程中心有限公司 | Preparing method of moxifloxacin or slat thereof |
| CN103543230A (en) * | 2012-07-09 | 2014-01-29 | 北大方正集团有限公司 | Method for separating and measuring moxifloxacin hydrochloride and enantiomer thereof |
| CN104725377A (en) * | 2014-04-04 | 2015-06-24 | 江苏天一时制药有限公司 | New crystal form of moxifloxacin hydrochloride and preparation method thereof |
| CN104817557A (en) * | 2014-04-04 | 2015-08-05 | 江苏天一时制药有限公司 | Moxifloxacin hydrochloride stable crystal form and preparation method thereof |
| CN111024831A (en) * | 2018-10-09 | 2020-04-17 | 江苏正大丰海制药有限公司 | Method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography |
| CN111320622A (en) * | 2018-12-15 | 2020-06-23 | 上虞京新药业有限公司 | Method for synthesizing moxifloxacin hydrochloride |
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| CN102675306A (en) * | 2011-03-17 | 2012-09-19 | 苏州中科天马肽工程中心有限公司 | Preparing method of moxifloxacin or slat thereof |
| CN102321083A (en) * | 2011-07-14 | 2012-01-18 | 福建省福抗药业股份有限公司 | A kind of anhydrous hydrochloric acid Moxifloxacin new crystal F and preparation method thereof |
| 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 |
| CN102675313A (en) * | 2011-10-12 | 2012-09-19 | 郭峰 | Preparation method of moxifloxacin hydrochloride |
| CN103543230A (en) * | 2012-07-09 | 2014-01-29 | 北大方正集团有限公司 | Method for separating and measuring moxifloxacin hydrochloride and enantiomer thereof |
| CN104725377A (en) * | 2014-04-04 | 2015-06-24 | 江苏天一时制药有限公司 | New crystal form of moxifloxacin hydrochloride and preparation method thereof |
| CN104817557A (en) * | 2014-04-04 | 2015-08-05 | 江苏天一时制药有限公司 | Moxifloxacin hydrochloride stable crystal form 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 |
| CN111024831A (en) * | 2018-10-09 | 2020-04-17 | 江苏正大丰海制药有限公司 | Method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography |
| CN111320622A (en) * | 2018-12-15 | 2020-06-23 | 上虞京新药业有限公司 | Method for synthesizing moxifloxacin hydrochloride |
| CN115322191A (en) * | 2022-07-25 | 2022-11-11 | 苏州汉德创宏生化科技有限公司 | Method for synthesizing moxifloxacin hydrochloride |
| CN115322191B (en) * | 2022-07-25 | 2023-12-26 | 苏州汉德创宏生化科技有限公司 | Synthetic method of moxifloxacin hydrochloride |
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