CN103936718A - High purity delafloxacin preparation method - Google Patents
High purity delafloxacin preparation method Download PDFInfo
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- CN103936718A CN103936718A CN201310021838.4A CN201310021838A CN103936718A CN 103936718 A CN103936718 A CN 103936718A CN 201310021838 A CN201310021838 A CN 201310021838A CN 103936718 A CN103936718 A CN 103936718A
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- YGSINTKENBYYRG-ALCCZGGFSA-N CCOC(/C(/C(c(c(F)c1Cl)cc(F)c1F)=O)=C\Nc(c(F)c1)nc(N)c1F)=O Chemical compound CCOC(/C(/C(c(c(F)c1Cl)cc(F)c1F)=O)=C\Nc(c(F)c1)nc(N)c1F)=O YGSINTKENBYYRG-ALCCZGGFSA-N 0.000 description 1
- UAYOVOVLIAOJPV-UHFFFAOYSA-N CCOC(C(C(c(c1c2Cl)cc(F)c2F)=O)=CN1c(c(F)c1)nc(N)c1F)=O Chemical compound CCOC(C(C(c(c1c2Cl)cc(F)c2F)=O)=CN1c(c(F)c1)nc(N)c1F)=O UAYOVOVLIAOJPV-UHFFFAOYSA-N 0.000 description 1
- PDFOKSJBJLMSCL-UHFFFAOYSA-N CCOC(C(C(c(c1c2Cl)cc(F)c2N(C2)CC2O)=O)=CN1c(nc(c(F)c1)N)c1F)=O Chemical compound CCOC(C(C(c(c1c2Cl)cc(F)c2N(C2)CC2O)=O)=CN1c(nc(c(F)c1)N)c1F)=O PDFOKSJBJLMSCL-UHFFFAOYSA-N 0.000 description 1
- AVPAYFOQPGPSCC-UHFFFAOYSA-N COC1CNC1 Chemical compound COC1CNC1 AVPAYFOQPGPSCC-UHFFFAOYSA-N 0.000 description 1
- DYDCPNMLZGFQTM-UHFFFAOYSA-N Nc(c(F)c1)nc(N(C=C(C(O)=O)C(c2cc(F)c3N(C4)CC4O)=O)c2c3Cl)c1F Chemical compound Nc(c(F)c1)nc(N(C=C(C(O)=O)C(c2cc(F)c3N(C4)CC4O)=O)c2c3Cl)c1F DYDCPNMLZGFQTM-UHFFFAOYSA-N 0.000 description 1
- OPEAXMWREUZSIL-UHFFFAOYSA-N Nc(nc(c(F)c1)N(C=C2C(OCc3ccccc3)=O)c(c(Cl)c(c(F)c3)F)c3C2=O)c1F Chemical compound Nc(nc(c(F)c1)N(C=C2C(OCc3ccccc3)=O)c(c(Cl)c(c(F)c3)F)c3C2=O)c1F OPEAXMWREUZSIL-UHFFFAOYSA-N 0.000 description 1
- RDWUCCWORZJIJI-UHFFFAOYSA-N Nc(nc(c(F)c1)N(C=C2C(OCc3ccccc3)=O)c(c(Cl)c(c(F)c3)N(C4)CC4O)c3C2=O)c1F Chemical compound Nc(nc(c(F)c1)N(C=C2C(OCc3ccccc3)=O)c(c(Cl)c(c(F)c3)N(C4)CC4O)c3C2=O)c1F RDWUCCWORZJIJI-UHFFFAOYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
The invention belongs to the technical field of a high purity delafloxacin preparation method. The high purity delafloxacin preparation method is as follows: a compound shown as formula 14 is hydrolyzed into a salt, a purified solid salt is obtained by solid-liquid separation, and then the purified solid salt is acidified to obtain delafloxacin. The delafloxacin prepared by synthesis methods in the prior art is low in purity, and needs to be further refined; according to the high purity delafloxacin preparation method, a delafloxacin ester derivative is hydrolyzed into a salt, after separation, the salt is acidified for effective removal of impurities, so that the product delafloxacin can reach a high purity (more than 99.5%), and can meet the subsequent preparation requirements; by the high purity delafloxacin preparation method, the objective of refinement can be achieved in the reaction route, a further purification process is omitted, and the operation efficiency and the total yield are improved.
Description
Technical field
The present invention relates to the preparation method's technical field for the preparation of New Fluoroquinolones-delafloxacin.
Background technology
Find that from late 1970s after norfloxicin, fluoroquinolone medicine is developed rapidly, existing large-tonnage product listing.Owing to having fluorine atom at 6 bit strips of parent nucleus quinolone ring, therefore claim fluoroquinolone.Delafloxacin is the fluorine quinolone compounds (numbering: WQ-3034) by a kind of brand new of Japanese Yong Yong pharmaceutical Co. Ltd development, chemistry 1-by name (6-amino-3, the fluoro-2-pyridyl of 5-bis-) the fluoro-7-of the chloro-6-of-8-(3-hydroxyl-1-azepine-1-tetramethylene base)-4-oxo-1,4-dihydro-3-quinoline carboxylic acid, U.S. Abbott company obtains its exploitation license (numbering: ABT-492), now carry out III clinical trial phase by Rib-X company subsequently.
Delafloxacin is wide spectrum fluoroquinolone antibiotic of new generation.This product is compared with other quinoline ketone antiseptic-germicides, more effective to gram-positive microorganism, particularly the methicillin-resistant staphylococcus aureus to other methods for quinolones antibacterial agents resistances (MRSA).FDA declares publicly first, delafloxacin is appointed as to the qualification medication with treatment acute bacterial skin and skin texture infection (ABSSSI) and the acquired pneumonia day after tomorrow (CABP).
Delafloxacin synthetic has multiple route, wherein the reaction scheme A(WO9711068 of Japanese Yong Yong drugmaker) as follows:
In above-mentioned route, the intramolecular condensation single step reaction temperature from compound 5 to compound 6 is high, produces more impurity and causes yield low, and the hydrolysis of compound 6 ester bonds needs high temperature reflux, and condition acutely causes impurity in products to increase, purity drop.
The reaction scheme B(WO2006015194 of U.S.'s Abbott Laboratories) as follows:
Route steps is corresponding simple, but makes taking compound 9 as raw material in reaction scheme, to need to introduce a step chloro, and needs to increase hydroxyl protection step, thereby in this route, NCS chloro may cause that multiple sites chloro introduces impurity, reduction yield and purity.
Yazaki etc. find (WO2001034595), by the alkali metal hydroxide such as delafloxacin and lithium hydroxide reflux in ethanol being obtained to an alkali metal salt of corresponding delafloxacin, regain delafloxacin to reach refining object with acidifying with acetic acid again, but this method increases by two step operating process, has reduced product yield.
Summary of the invention
Object of the present invention solves prior art problem exactly, and a kind of highly purified delafloxacin preparation method is provided.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
The preparation method of high purity delafloxacin, the method is by following formula: compound 14 hydrolysis salifyings, through solid-liquid separation, obtains after acidifying, obtaining after the solid salt 15 of purifying again:
MOH refers to alkali metal hydroxide; R is alkyl, aryl or aralkyl.Preferably, the alkyl that R is C1-C6, the more preferably alkyl of C1-C4.
The preparation method of above-mentioned high purity delafloxacin, compound shown in formula 14, in organic solvent, issues unboiled water solution in the effect of alkali metal hydroxide (MOH) aqueous solution and makes high-purity solid compound shown in formula 15:
Described alkali metal hydroxide MOH can be selected from lithium hydroxide, sodium hydroxide and potassium hydroxide etc., is preferably sodium hydroxide.Described organic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol and isopropylcarbinol etc., is preferably ethanol.Temperature of reaction is generally 0-100 DEG C, is preferably 20-60 DEG C, and the reaction times is generally 10 minutes by 48 hours, is preferably 1-5 hour.With respect to compound shown in formula 14, the usage quantity of alkali metal hydroxide is generally 1-5 times of molar weight of starting compound 14, preferably 1-3 times of molar weight, the more preferably molar weight of 2 times.
Compound shown in formula 15 is in organic solvent, and under sour effect, acidifying makes delafloxacin:
Described acid can be selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, fumaric acid and formic acid etc., is preferably acetic acid.Described organic solvent is selected from acetonitrile, DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 1, and 3-dimethyl 2-imidazolidone, dimethyl sulfoxide (DMSO) etc. or its suitable mixture, be preferably DMF.Temperature of reaction is generally 0-100 DEG C, is preferably 0-50 DEG C.With respect to compound shown in formula 15, sour that usage quantity is generally the molar weight doubly of compound 1-20 shown in formula 15, preferably 5-10 molar weight doubly, the more preferably molar weight of 7 times.
The preparation method of above-mentioned general formula compound 14, the method is formula 16 compounds and 3-hydroxy azetidine hydrochloride, under alkali exists, nucleophilic substitution reaction to be occurred to make target compound 14:
Wherein, R is alkyl, aryl or aralkyl. preferably, and the alkyl that R is C1-C6, the more preferably alkyl of C1-C4.
The preparation method of above-mentioned general formula compound 14; available alkali comprises various mineral alkalis and organic bases, preferably organic bases. wherein mineral alkali is selected from the similar alkali such as salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, potassium hydride KH and sodium hydride; Organic bases is selected from triethylamine, various lutidine, diisopropylethylamine, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, 1,4-diazabicylo [2.2.2] octane, 1, the similar alkali such as 5-diazabicylo [4.3.0] 11 carbon-7-alkene. preferably 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene.
The preparation method of above-mentioned general formula compound 14, temperature of reaction is generally 0-100 DEG C, is preferably 20-60 DEG C; Reaction times is generally 10 minutes to 48 hours, is preferably 30 minutes-3 hours.
The preparation method of above-mentioned general formula compound 14, the consumption of 3-hydroxy azetidine hydrochloride is the molar weight of 1-5 times of starting compound 14, preferably 1-2 molar weight doubly, the most preferably molar weight of 1.2 times. the consumption of alkali is generally the molar weight of 1-5 times of starting compound 14, preferably 1-3 molar weight doubly, the most preferably molar weight of 2.5 times.
The present invention has following positively effect:
The delafloxacin purity that existing synthetic method makes is poor, need further refining, the present invention passes through with delafloxacin ester derivative hydrolysis salifying, after separating, impurity is removed in acidifying effectively, make product delafloxacin reach higher degree (> 99.5%), meet the demand of follow-up preparation, this method reaches refining object in reaction scheme, save further treating process, improved operation efficiency and total recovery.
Following embodiment is only to describe in detail the present invention, and unrestricted the present invention.
Embodiment
Embodiment 1: the preparation of compound shown in the formula 5 that wherein R is ethyl:
In there-necked flask, add compound 3(20g, 0.071mol), triethyl orthoformate (18.97mL, 0.11mol) and diacetyl oxide (20.21mL, 0.21mol) be heated with stirring to back flow reaction (~ 139 DEG C) 3h, be down to room temperature, reaction solution, with NMP-acetonitrile (50mL-50mL) dilution, adds 1mL distilled water, makes compound 4 and directly drops into next step reaction without separating.In there-necked flask, add 2,6-diamino-3,5-difluoro pyridine (11.38g, 0.078mol), NMP-acetonitrile (50mL-50mL), stirring and dissolving, under room temperature, is added dropwise to step reaction solution, drips complete stirring at room temperature reaction 1h.Reaction solution is added dropwise in 160mL distilled water, separates out glassy yellow solid, filters, and with acetonitrile-water (48mL-24mL), water (50mL) making beating washing, 60 DEG C of vacuum-dryings obtain 28.4g yellow powder, HPLC98.4% successively.Fusing point: 148-150 DEG C of 1HNMR (400MHz, CDCl3) δ 1.13 (t, 3H), 4.25 (q, 2H), 4.66 (brs, 2H), 7.33 (t, 1H), 7.58 (m, 1H), 8.96 (d, 1H), 11.33 (brs, 1H).
Embodiment 2: the preparation of compound shown in the formula 14 that wherein R is ethyl:
In there-necked flask, add compound 5(28g, 0.064mol), lithium chloride (5.45g, 0.13mol), add DMF (140mL) stirring and dissolving, under ice bath, be added dropwise to DBU(10.57mL, 0.071mol), drip Bi Shengzhi stirring at room temperature reaction 2h, make compound 16 and directly drop into next step reaction without separating.
Upwards walk in reaction solution and add 3-hydroxy azetidine hydrochloride (8.1g, 0.074mol), under ice bath, be added dropwise to DBU(22.98mL, 0.153mol), drip 50 DEG C of stirring reaction 1h of Bi Shengzhi.Under ice bath, in reaction solution, be added dropwise to aqueous citric acid solution (10%, 150mL), separate out yellow powder.Filter dry 28.1g yellow powder, the HPLC99.0% of obtaining.m/z（MH+）468.08，1H?NMR(400MHz，DMSO)δ1.28(t，3H)，3.32（s，1H），4.06(m，2H)，4.22（q，2H），4.44（m，1H），4.61（m，2H），5.66（d，1H），6.68（s，2H），7.72（d，1H），7.92（dd，1H）。
Embodiment 3: the preparation of compound shown in the formula 14-2 that wherein R is phenyl:
In there-necked flask, add compound 5-2(31g, 0.064mol), lithium chloride (5.45g, 0.13mol), add DMF (140mL) stirring and dissolving, under ice bath, be added dropwise to DBU(10.57mL, 0.071mol), drip Bi Shengzhi stirring at room temperature reaction 3h, make compound 16-2 and directly drop into next step reaction without separating.
Upwards walk in reaction solution and add 3-hydroxy azetidine hydrochloride (8.1g, 0.074mol), under ice bath, be added dropwise to DBU(22.98mL, 0.153mol), drip 50 DEG C of stirring reaction 1.5h of Bi Shengzhi.Under ice bath, in reaction solution, be added dropwise to aqueous citric acid solution (10%, 150mL), separate out deep yellow powder.Filter dry 29.2g deep yellow powder, the HPLC98.3% of obtaining.m/z（MH+）516.25，1H?NMR(400MHz，DMSO)δ3.25（s，1H），4.16(m，2H),4.47（m，1H），4.60（m，2H），5.69（d，1H），6.71（s，2H），6.81-7.22（m，5H），7.70（d，1H），7.96（dd，1H）。
Embodiment 4: the preparation of compound shown in the formula 14-3 that wherein R is benzyl:
In there-necked flask, add compound 5-3(31.8g, 0.064mol), lithium chloride (5.45g, 0.13mol), add DMF (140mL) stirring and dissolving, under ice bath, be added dropwise to DBU(10.57mL, 0.071mol), drip Bi Shengzhi stirring at room temperature reaction 2.5h, make compound 14-3 and directly drop into next step reaction without separating.
Upwards walk in reaction solution and add 3-hydroxy azetidine hydrochloride (8.1g, 0.074mol), under ice bath, be added dropwise to DBU(22.98mL, 0.153mol), drip 50 DEG C of stirring reaction 3h of Bi Shengzhi.Under ice bath, in reaction solution, be added dropwise to aqueous citric acid solution (10%, 150mL), separate out yellow powder.Filter dry 27.3g yellow powder, the HPLC98.2% of obtaining.m/z（MH+）530.13，1HNMR(400MHz，DMSO)δ3.33（s，1H），4.18（q，2H），4.41（m，1H），4.56（s，2H），463（m，2H），572（d，1H），668（s，2H），721-733（m，5H），783（d，1H），7.94（dd，1H）。
Embodiment 5: the preparation of compound shown in the formula 14 that wherein R is ethyl:
In there-necked flask, add compound 5(28g, 0.064mol), lithium chloride (5.45g, 0.13mol), add DMF (140mL) stirring and dissolving, under ice bath, be added dropwise to DBU(12.49mL, 0.084mol), drip Bi Shengzhi stirring at room temperature reaction 1h, make compound 16 and directly drop into next step reaction without separating.
Upwards walk in reaction solution and add 3-hydroxy azetidine hydrochloride (8.1g, 0.074mol), under ice bath, be added dropwise to DBU(27.57mL, 0.185mol), drip 50 DEG C of stirring reaction 1h of Bi Shengzhi.Under ice bath, in reaction solution, be added dropwise to aqueous citric acid solution (10%, 150mL), separate out yellow powder.Filter dry 28.1g yellow powder, the HPLC98.8% of obtaining.m/z（MH+）468.08，1H?NMR(400MHz，DMSO)δ1.28(t，3H)，3.32（s，1H），4.06(m，2H)，4.22（q，2H），4.44（m，1H），4.61（m，2H），5.66（d，1H），6.68（s，2H），7.72（d，1H），7.92（dd，1H）。
Embodiment 6: wherein R is ethyl, the preparation of compound shown in the formula 15-1 that M is Na
In there-necked flask, add compound 14(5g, 0.011mol), ethanol 50mL, stirring is faint yellow and is suspended, and adds 4% aqueous sodium hydroxide solution (containing NaOH0.85g) 20mL, be warming up to 50 DEG C of reaction 1h, be down to room temperature, filter, washing, vacuum-drying obtains white powder 4.2g, purity 99.2%(HPLC).
Embodiment 7: wherein R is phenyl, the preparation of compound shown in the formula 15-1 that M is Na
In there-necked flask, add compound 14(5g, 0.0097mol), ethanol 50mL, stirring is faint yellow and is suspended, and adds 4% aqueous sodium hydroxide solution (containing NaOH0.85g) 20mL, be warming up to 50 DEG C of reaction 1.5h, be down to room temperature, filter, washing, vacuum-drying obtains white powder 3.9g, purity 99.1%(HPLC).
Embodiment 8: wherein R is benzyl, the preparation of compound shown in the formula 15 that M is Na
In there-necked flask, add compound 14(5g, 0.0095mol), ethanol 50mL, stirring is faint yellow and is suspended, and adds 4% aqueous sodium hydroxide solution (containing NaOH0.85g) 20mL, be warming up to 50 DEG C of reaction 1.5h, be down to room temperature, filter, washing, vacuum-drying obtains white powder 3.8g, purity 99.0%(HPLC).
Embodiment 9: wherein R is ethyl, the preparation of compound shown in the formula 15 that M is Na
In there-necked flask, add compound 14(5g, 0.011mol), ethanol 50mL, stirring is faint yellow and is suspended, add 4% aqueous sodium hydroxide solution (containing NaOH0.85g) 20mL, stirring at room temperature 5h, filters, washing, vacuum-drying obtains white powder 3.5g, purity 99.1%(HPLC).
Embodiment 10: wherein R is ethyl, the preparation of compound shown in the formula 15-1 that M is Na
Solvent is changed to Virahol 50mL, and all the other feed intake and operate same embodiment 1, are warming up to 50 DEG C of reaction 2h, are down to room temperature, filter, and washing, vacuum-drying obtains white powder 3.8g, purity 99.5%(HPLC).
Embodiment 11: wherein R is ethyl, the preparation of compound shown in the formula 15-3 that M is Li
Change alkali into 4% lithium hydroxide aqueous solution (containing LiOH0.5g) 12.5mL, all the other feed intake and operate same embodiment 1, are warming up to 50 DEG C of reaction 1h, are down to room temperature, filter, and washing, vacuum-drying obtains white powder 3.8g, purity 99.1%(HPLC).
Embodiment 12: the preparation of the delafloxacin that the compound 15-1 that is Na by M is raw material
In there-necked flask, add compound 15-1(3.5g, 0.76mmol), DMF(35mL) suspension liquid that is creamy white, add Glacial acetic acid (3.0mL), stirring at room temperature is added dropwise to distilled water 70mL after solution is clarified completely, filter, washing, evaporate to dryness, obtain pale yellow powder 3.0g, purity 99.8%(HPLC), m/z(MH+) 441.03, 1H NMR (400MHz, DMSO) δ 4.20 (m, 2H), 4.45(m, 1H), 4.61 (m, 2H), 5.63(d, 1H), 6.69(s, 2H), 7.81(d, 1H), 7.95(dd, 1H), 8.69(d, 1H), 14.34(brs, 1H).
Embodiment 13: the preparation of the delafloxacin that the compound 15-1 that is Na by M is raw material
Change acid into formic acid (2mL), all the other operate with embodiment 6, obtain pale yellow powder 2.8g, purity 99.6%(HPLC), m/z(MH+) 441.03,1H NMR (400MHz, DMSO) δ 4.20 (m, 2H), 4.45(m, 1H), 4.61 (m, 2H), 5.63(d, 1H), 6.69(s, 2H), 7.81(d, 1H), 7.95(dd, 1H), 8.69(d, 1H), 14.34(brs, 1H).
Embodiment 14: the preparation of the delafloxacin that the compound 15-1 that is Na by M is raw material
Change acid into dilute hydrochloric acid 1mol/L(2mL), all the other operate with embodiment 6, obtain pale yellow powder 2.6g, purity 99.5%(HPLC), m/z(MH+) 441.03,1HNMR (400MHz, DMSO) δ 4.20 (m, 2H), 4.45(m, 1H), 4.61 (m, 2H), 5.63(d, 1H), 6.69(s, 2H), 7.81(d, 1H), 7.95(dd, 1H), 8.69(d, 1H), 14.34(brs, 1H).
Embodiment 15: the preparation of the delafloxacin that the compound 15-1 that is Na by M is raw material
Change solvent into NMP(35mL), all the other operate with embodiment 6, obtain pale yellow powder 2.9g, purity 99.7%(HPLC), m/z(MH+) 441.03,1HNMR (400MHz, DMSO) δ 4.20 (m, 2H), 4.45(m, 1H), 4.61 (m, 2H), 5.63(d, 1H), 6.69(s, 2H), 7.81(d, 1H), 7.95(dd, 1H), 8.69(d, 1H), 14.34(brs, 1H).
Embodiment 16: the preparation of the delafloxacin that the compound 15-3 that is Li by M is raw material
In there-necked flask, add compound 15-3(3.5g, 0.78mmol), DMF(35mL) suspension liquid that is creamy white, add Glacial acetic acid (3.1mL), stirring at room temperature is added dropwise to distilled water 70mL after solution is clarified completely, filter, washing, evaporate to dryness, obtain pale yellow powder 2.7g, purity 99.6%(HPLC), m/z(MH+) 441.03, 1H NMR (400MHz, DMSO) δ 4.20 (m, 2H), 4.45(m, 1H), 4.61 (m, 2H), 5.63(d, 1H), 6.69(s, 2H), 7.81(d, 1H), 7.95(dd, 1H), 8.69(d, 1H), 14.34(brs, 1H).
Claims (21)
1. the preparation method of high purity delafloxacin, the method is by following formula: compound 14 hydrolysis salifyings, through solid-liquid separation, obtains after acidifying, obtaining after the solid salt 15 of purifying again:
MOH refers to alkali metal hydroxide; R is alkyl, aryl or aralkyl.
2. the preparation method of high purity delafloxacin as claimed in claim 1, is characterized in that: the alkyl that R is C1-C6.
3. the preparation method of high purity delafloxacin as claimed in claim 2, is characterized in that: the alkyl that R is C1-C4.
4. the preparation method of high purity delafloxacin as claimed in claim 1, is characterized in that: alkali metal hydroxide MOH is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide.
5. the preparation method of high purity delafloxacin as claimed in claim 4, is characterized in that: alkali metal hydroxide MOH is sodium hydroxide.
6. the preparation method of high purity delafloxacin as claimed in claim 1, is characterized in that: the organic solvent that hydrolysis reaction uses is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol and isopropylcarbinol.
7. the preparation method of high purity delafloxacin as claimed in claim 6, is characterized in that: the organic solvent that hydrolysis reaction uses is ethanol.
8. the preparation method of high purity delafloxacin as claimed in claim 1, is characterized in that: the usage quantity of alkali metal hydroxide is 1-5 times of molar weight of starting compound 14.
9. the preparation method of high purity delafloxacin as claimed in claim 8, is characterized in that: the usage quantity of alkali metal hydroxide is 1-3 times of molar weight of starting compound 14.
10. the preparation method of high purity delafloxacin as claimed in claim 1, is characterized in that: described acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, fumaric acid and formic acid.
The preparation method of 11. high purity delafloxacin as claimed in claim 10, is characterized in that: described acid is acetic acid.
The preparation method of 12. high purity delafloxacin as claimed in claim 1, it is characterized in that: the organic solvent that acidification reaction uses is selected from acetonitrile, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, 1,3-dimethyl 2-imidazolidone, dimethyl sulfoxide (DMSO) or its optional suitable mixture.
The preparation method of 13. high purity delafloxacin as claimed in claim 12, is characterized in that: the organic solvent that acidification reaction uses is DMF.
The preparation method of 14. high purity delafloxacin as claimed in claim 1, is characterized in that: the usage quantity of acid is the molar weight doubly of compound 1-20 shown in formula 15.
The preparation method of 15. high purity delafloxacin as claimed in claim 1, is characterized in that: the usage quantity of acid is the molar weight doubly of compound 5-10 shown in formula 15.
16. as the arbitrarily preparation method of described high purity delafloxacin of claim 1-15, it is characterized in that: compound 14 is prepared by following method: formula 16 compounds and 3-hydroxy azetidine hydrochloride, under alkali existence, nucleophilic substitution reaction is occurred to and make target compound 14:
Wherein, R is alkyl, aryl or aralkyl.
The preparation method of 17. high purity delafloxacin as claimed in claim 16, is characterized in that: the alkali of use is organic bases.
The preparation method of 18. high purity delafloxacin as claimed in claim 17, it is characterized in that: the organic bases of use is selected from triethylamine, various lutidine, diisopropylethylamine, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, 1,4-diazabicylo [2.2.2] octane and 1,5-diazabicylo [4.3.0], 11 carbon-7-alkene.
The preparation method of 19. high purity delafloxacin as claimed in claim 18, is characterized in that: the organic bases of use is 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene.
The preparation method of 20. high purity delafloxacin as claimed in claim 16, is characterized in that: the consumption of 3-hydroxy azetidine hydrochloride is the molar weight of 1-5 times of starting compound 14.
The preparation method of 21. high purity delafloxacin as claimed in claim 16, is characterized in that: the consumption of alkali is generally the molar weight of 1-5 times of starting compound 14.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105968099A (en) * | 2016-05-12 | 2016-09-28 | 扬子江药业集团有限公司 | {0><}0{>Method for refining delafloxacin |
| CN113527262A (en) * | 2021-06-22 | 2021-10-22 | 安徽普利药业有限公司 | Refining method of delafloxacin and meglumine salt thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997011068A1 (en) * | 1995-09-22 | 1997-03-27 | Wakunaga Pharmaceutical Co., Ltd. | Novel pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient |
| WO2001034595A1 (en) * | 1999-11-11 | 2001-05-17 | Wakunaga Pharmaceutical Co., Ltd. | Alkali metal salts of quinolinecarboxylic acid derivatives and process for purifying quinoline-carboxylic acid derivatives by using the salts |
| WO2006015194A2 (en) * | 2004-07-30 | 2006-02-09 | Abbott Laboratories | Preparation of pyridonecarboxylic acid antibacterials |
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2013
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997011068A1 (en) * | 1995-09-22 | 1997-03-27 | Wakunaga Pharmaceutical Co., Ltd. | Novel pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient |
| WO2001034595A1 (en) * | 1999-11-11 | 2001-05-17 | Wakunaga Pharmaceutical Co., Ltd. | Alkali metal salts of quinolinecarboxylic acid derivatives and process for purifying quinoline-carboxylic acid derivatives by using the salts |
| WO2006015194A2 (en) * | 2004-07-30 | 2006-02-09 | Abbott Laboratories | Preparation of pyridonecarboxylic acid antibacterials |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105968099A (en) * | 2016-05-12 | 2016-09-28 | 扬子江药业集团有限公司 | {0><}0{>Method for refining delafloxacin |
| CN113527262A (en) * | 2021-06-22 | 2021-10-22 | 安徽普利药业有限公司 | Refining method of delafloxacin and meglumine salt thereof |
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| CN103936718B (en) | 2016-06-29 |
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